Prerpints.org logo
Preprint
Review

This version is not peer-reviewed.

Plant-derived epi-nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents

A peer-reviewed article of this preprint also exists.

Submitted:

17 October 2023

Posted:

19 October 2023

You are already at the latest version

Abstract
Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to its inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The previous COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances when vaccination is not accessible or in individuals with compromised immune systems, drugs can give additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds including anti-viral. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Epigenetic modifications in the genome can affect gene expression without altering DNA sequence. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses have recruited cellular epi transcriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we are exploring the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing modulation processes and anti-viral effects on DNA and RNA viruses, and addressing future research objectives in this rapidly emerging field.
Keywords: 
Plant-derived substances
;  
Epigenetic modifications
;  
virus
;  
Broad-spectrum anti-viral
Subject: 
Biology and Life Sciences  -   Biochemistry and Molecular Biology

Introduction

Viruses represent a special category of organisms as they are unable to carry out essential life processes such as metabolism and reproduction, making them completely dependent on host cells for replication, rendering them obligate intracellular parasites [1]. The basic architecture of a virus includes a genome enclosed in a protective protein envelope called capsid [2]. The viral genome can consist of either DNA or RNA oligonucleotides, which can be either single-stranded or double-stranded. The type of genetic material a virus carries has significant implications for its replication strategy and overall life cycle. For example, DNA viruses (e.g., herpes simplex virus (HSV)) generally replicate in the nucleus of the host cell using the host's DNA and RNA synthesis machinery. In contrast, RNA viruses (such as influenza A virus (IAV)) usually replicate in the cytoplasm and therefore must encode or carry their own RNA polymerase to replicate their genome. In addition, some RNA viruses, called retroviruses (such as human immunodeficiency virus (HIV)), can reversely transcribe their RNA genome into DNA, which is then integrated into the host genome-a unique feature of this category of viruses [3].
The viral genome encodes structural and nonstructural proteins. The structural proteins are self-assembled after their synthesis to form the highly structured, typically geometrically symmetric capsid [4]. Capsid proteins can assemble into a variety of different structures depending on the virus, but most capsids fall into one of two categories: icosahedral or helical [5,6]. Additional complex layers are added in certain viruses that have an additional lipid bilayer, called the envelope, which is extracted from the host cell membrane during viral assembly and release [7]. Viral nonstructural proteins (NSPs) encoded by the viral genome are not part of the viral particle or virion but play a key role in the viral life cycle. These proteins contribute to a variety of functions, including viral replication and assembly [8,9], modulation of host immune responses [10], and manipulation of the cellular environment to favor viral reproduction [11,12].
Viruses can cause a wide range of diseases, from trivial to life-threatening. They are the causative agents of common illnesses such as the common cold (rhinoviruses) and influenza, but they can also cause serious diseases such as HIV/AIDS, Ebola hemorrhagic fever, and COVID-19 disease caused by SARS-CoV-2 [13,14]. The manifestation of these diseases depends largely on the host's immune response to viral infection and the extent of tissue damage caused by viral replication and cell death.
Some viruses are exclusively adapted to humans, whereas others, known as zoonotic viruses, can also infect animal hosts [15]. Viruses such as influenza, measles, and SARS-CoV-2 are transmitted through the respiratory tract by droplets that are emitted when an infected person coughs, sneezes, or talks and can then be inhaled by a susceptible person, resulting in infection [16,17]. Other viruses, such as norovirus and rotavirus, are transmitted orally by ingestion of contaminated food or water or by direct contact with the feces of an infected person [18]. Direct contact can result in viral transmission, either between people, as with HIV and hepatitis B (HBV) and C (HCV), which are transmitted through sexual contact, needle sharing, or at birth [19,20], or from animals to people, as exemplified by rabies virus, which is transmitted through the bite of an infected animal [21]. In addition, some viruses are transmitted by vectors, usually blood-sucking insects. For example, dengue, Zika, and yellow fever viruses are transmitted to humans through mosquito bites [22,23,24].
After invading the host, viruses navigate to their target tissues and begin invading cells through various mechanisms. A virus' preference for specific tissues is determined by a combination of factors, including the interaction between the virus' surface proteins and certain receptors on the host cell. For example, the SARS-CoV2 virus interacts with the ACE2 receptor through its spike protein [25], and influenza virus hemagglutinin binds to α-2,6-linked sialic acids on host cells [26,27]. Microenvironmental conditions, such as pH, can also influence this process. For example, pH-induced conformational changes in influenza virus hemagglutinin are critical for the ability of the virus to enter cells [28]. In addition, activation of inactive viral protein binding after cleavage by tissue-specific secreted proteases may also play an important role in facilitating viral invasion [29]. After attachment, some viruses, such as polio, influenza, and SARS-CoV-2, undergo endocytosis, activating various mechanisms that allow the release of the viral genome into the cytoplasm of the cell [25,30,31]. Conversely, some enveloped viruses, such as HIV, can fuse their envelope to the host cell membrane and release their genome into the cytoplasm [3]. Within the cell, the viral genome manipulates the host machinery to replicate and generate new viral particles that are released by budding or after host cell lysis, allowing infection of new host cells and transmission to new hosts.

Host signaling and virus life cycles

The viral life cycle involves multiple series of events in which it relies on host activities to effectively infect the host cell. During viral infection, a multitude of host components assume pivotal roles in either aiding or impeding the virus's capacity to successfully carry out its life cycle. Host factors as chemicals, proteins, or cellular machinery that are intrinsic to the host organism have the ability to interact with viral components, thereby influencing the process and outcomes of infection. These factors have the potential to either facilitate viral infection and dissemination or initiate a defensive response to restrict viral infection.
Within the different host factors, signaling molecules draw a lot of attention due to their role in regulating viral life cycles. Host signaling pathways were appreciated as therapeutic targets in cancer and viral infections, with tyrosine kinases (TKs) being profoundly explored, and many TK inhibitors (TKIs) were approved by the FDA for cancer treatment. [32,33] [34].
To combat viral infections an integrated strategy that combines immunizations and antiviral drugs is in need. Targeting host enzymes rather than viral targets is appealing due to their genetic stability. As observed with cancer [35], simultaneous inhibition of several host enzymes or pathways might improve viral resistance. Such a strategy may prompt the development of new technologies to combat current and future viral pandemics. For example, while dengue virus (DENV) is resistant to viral protein-targeting drugs, it is susceptible to kinase inhibitors such as Sunitinib and Erlotinib [36].
Usually, virus variants are developed due to a lack of proofreading during gene replication or through recombination of gene segments between co-infecting strains. Although coronavirus possesses some proofreading activity, which may reduce variant occurrence, a number of variants with greater infectivity and immune evading abilities have evolved within months from the primal emergence [37].
Protein kinases play a crucial role in viral infections. Protein phosphorylation is also important in the life cycle of different viruses [38]. Numerous viruses induce or inhibit protein phosphorylation at many different stages of signal transduction pathways from the plasma membrane to the nucleus [39] [40]. Phosphorylation might affect protein's stability, activity, crucial interactions with other cellular and viral proteins, which play a part in regulating virus infectivity. Viruses such as Epstein-Barr virus (EBV) [41], HCV [41], and SARS-COV2 [41] promote Mitogen-activated protein kinases (MAPK) phosphorylation. Protein phosphorylation changes have been observed during viral propagation for viral replication. MAPK and ERK-2, for example, phosphorylate the HIV protein p6 at a specific site (Thr 23). Additional viruses seem to activate the MAPK pathway, including DENV [42], coronavirus [43], Venezuelan equine encephalitis virus (VEEV) [44], and enterovirus 71 (EV71) [45], which rely on activated p38 for their replication. Activated p38α interacts with the N-terminal region of HCV's core protein and subsequently phosphorylates it, promoting HCV core protein oligomerization, which is an essential step for viral assembly [46].
Viral infection is associated with enhanced production of cytokines, called cytokine storm. During a cytokine storm, various inflammatory cytokines are produced at much higher levels than normal. This overproduction of cytokines results in a positive feedback loop on other immune cells, allowing more immune cells to reach the site of injury, which can lead to organ damage. Among the most notable clinical conditions associated with cytokine storms is acute respiratory distress syndrome (ARDS), which is responsible for a significant number of deaths from SARS-CoV-2. Viral-induced cytokine storm is mediated via intracellular cell signaling pathways such as p38 and eventually resulting in immunopathology [47].
MAPK p38 inhibitors exhibited broad-spectrum antiviral effect against a variety of viruses [46]. In HCV, p38 inhibitors disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), HSV-1 or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also activate p38 MAPK and p38 inhibitors effectively inhibited their replication [46]. Furthermore, many viruses utilize protein phosphorylation to regulate signaling in order to prevent apoptosis and enhance cellular survival and proliferation [48]. JNK signaling influences the replication of some viruses. JNK inhibition, for example, suppresses HSV, HIV, and rotavirus replication [49].
Host receptor tyrosine kinases can serve as entry receptors of some viruses. For example, the tyrosine kinase AXL facilitates the entrance of filoviruses such as the Ebola virus (EBOV) [50]. The epidermal growth factor receptor (EGFR) is a host factor that is frequently required by viruses [51]. Human cytomegalovirus (HCMV) and adeno-associated virus serotype 6 (AAV6) use EGFR as a co-receptor for entry [52,53].
Other receptor tyrosine kinases were implicated in regulating virus replications. The IAV lifecycle is regulated by nerve growth factor receptors (TrkA), human epidermal growth factor receptor 2 (HER2), and platelet-derived growth factor receptor (PDGFR). Tyrphostin AG879, which inhibits TrkA/HER2 signaling, and A9, which targets the PDGFR pathway, were efficient in inhibiting IAV [54]. AP2-associated protein kinase I (AAK1), a member of the numb-associated kinase (NAK) family, and a clathrin-mediated endocytosis regulator are among the other host kinases implicated in the SARS-COV2 lifecycle [55]. HCV, DENV, and EBOV infections require the kinases AAK1 and Cyclin G-associated kinase (GAK) [56]. Two FDA-approved drugs, Sunitinib, and Erlotinib, inhibit AAK1 and GAK activity in cultured cells, blocking HCV intracellular trafficking. The Sunitinib, and Erlotinib combination decreases mortality and morbidity in mice models of DENV and EBOV infection [36]. These findings illustrate the potential of a repurposed, host-targeted approach to combating emerging viruses. Interestingly, the kinase inhibitor Baricitinib, which is used to treat rheumatoid arthritis (RA) [57] and inhibits JAK/STAT, additionally blocks NAK and AAK1 kinases [58] exhibited anti-viral activity in COVID-19 patients [59]. Taken together, multiple host kinases regulate viral life cycles, therefore inhibitors of key kinases might have antiviral properties.
This review focuses on epigenetic modifications of host proteins caused by viral infection. Moreover, we examined the ability of plant-derived substances to exhibit epigenetic modifiers activity and consequently, the ability to block virus propagation. Plants are a rich source of pharmaceuticals that may be exploited to treat a wide range of human and animal illnesses. Newman et al., 2020 analyze all approved therapeutic drugs for all conditions from 1981 to 2019 and anti-tumor activity from 1946 to 2019. The authors emphasize in their review that a large number of developed drugs, including anti-infective agents, are derived from natural products [60].
As a result, in this review, we investigate the use of plant-derived bioactive compounds that influence epigenetic processes as potential broad-spectrum anti-viral agents.

Epigenetic modifications

Epigenetics has a key role in cell differentiation, genomic imprinting and X-chromosome inactivation. The epigenetic memory which dictates cell differentiation is acquired during early life and maintained across life in healthy subjects; to this aim a multitude of enzymes, which are regulated by several environmental stimuli (i.e., food intake, chemicals, stress, activators of immune system, virus, etc.), are employed. Loss of epigenetic memory can occur during life as it is associated with aging and may lead to susceptibility to diseases [61].
Epigenetics can be both inherited and reversible; it modulates gene expression without any change in DNA sequence. These modifications can be influenced by environmental factors such as diet, stress, and exposure to toxins, as well as by changes in gene expression during development. Epigenetic modifications include DNA methylation, histone remodeling, the utilization of alternative histone variants, modifications of histone tails and expression of noncoding RNAs, including miRNAs [62]. These activities are together known as epigenetic regulations [63] .

DNA methylation

The most studied epigenetic mechanism is the DNA methylation at cytosine residues (5mC); it consists in the addition of a methyl group to the carbon-5 of cytosine in the CpG dinucleotide, catalyzed by DNA methyltransferase enzymes (DNMTs) [64].
DNA methylation is carried out by the 5-cytosine DNMT enzyme using S-adenosylmethionine (SAM) as a methyl donor. In mammals, DNA methylation may occur at cytosines all over the genome [64]. However, in somatic cells, more than 98% of DNA methylation occurs in the vicinity of CpG dinucleotides.
DNA methylation has various impacts on gene expression. Generally, when the promoter is non-methylated, the gene expression is switched on (Figure 1A), while if methylation occurs at the promoter level, transcription factors cannot interact at the promoter region and the gene is silenced (Figure 1B). Outside of the promoter sequence, DNA methylation can have different effects on gene expression according to the location of methylated CpGs (Figure 1B). Typically, DNA methylation is removed during the zygote formation and subsequently restored in the embryo at the time of implantation [65]. DNA methylation is essential for proper development and cell differentiation [66,67].
DNA methylation is maintained during replication by DNMT1, while DNMT3a, DNMT3b and DNMT3c are responsible for de-novo methylation and responds to environmental factors. Stress, virus, bioactive compounds, chemicals, etc. can modulate the activity of DNMTs leading to a change in the methylome across life. On the other hand, ten-to-eleven translocation (TET) proteins demethylate 5mC to 5-hydroxymethylcytosine (5hmC) leading to physiological and pathological events [68]. These changes in DNA methylation can affect gene expression thus contributing to the development and progression of diseases and aging. These changes in DNA methylation at specific genes can be used to quantify the biological age of individuals; subjects can exhibit negative age acceleration leading to young and healthy biological age or positive age acceleration which is associated to various diseases [69]. Moreover, defects in DNA methylation are closely associated with cancer. To date, all examined tumor samples studied show a global reduction of DNA methylation [70].

Histone modifications.

Histone modifications are post-translational modifications (PTMs) to histone proteins that include methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation. PTMs on histones result in altered chromatin structure. Chromatin structure affects the accessibility of the DNA to transcription and replication machineries; histone dynamicity depends on a complex family of enzymes which add functional groups (i.e., acetyl, methyl, phosphate, etc.) to histone tails opening and closing chromatin, and regulating gene expression. PMT such as addition of acetyl groups to the positive charge of amino acids at the histone tails masks the electrostatic interaction between DNA and amino acids and relaxes wrapped DNA to guarantee the accessibility of the complex protein machinery required for gene transcription. Generally, the impact of the other functional groups (i.e., methyl, phosphate, etc) on chromatin structure depends on the position and the number of groups (i.e., methyl) bound to amino acid residues at histone tails (Figure 2).
Enzymes involved in histone modifications are histone acetyltransferases (HATs) which relaxes chromatin structure, while histone deacetylases (HDACs) remove acetyl groups, leading to chromatin condensation and transcriptional repression. More than 20 HATs have been discovered and they are classified into five families: GNAT1, MYST, TAFII250, P300/CBP, and nuclear receptor coactivators such ACTR [71].
An imbalance in histone acetylation is linked to carcinogenesis and development of other diseases. HDACs, similar to HATs, play a significant role in a variety of cellular processes involving histone H3 and H4. At least four classes of HDACs have been discovered so far. HDACs in Class I include 1, 2, 3, and 8. Class II HDACs include 4, 5, 6, 7, 9, and 10. Sirtuins (SIRTs) are class III enzymes that require NAD+ cofactors and include SIRTs 1-7. The Class IV enzyme, which only contains HDAC11, exhibits features of both Classes I and II. In cancer cells, HDAC inhibition has a significant effect on apoptosis, cell cycle arrest, and differentiation. HDAC inhibitors have being investigated as anti-cancer agents [72] .
Histone methyltransferases (HMTs) can add more than one methyl group to each residue, giving to transcriptional repression or activation; histone demethylases (HDMs) remove methyl groups with different impact on gene expression. Transcription silencing is also under the control of Polycomb group (PcG) proteins, which regulate the chromatin structure; polycomb repressive complex 1 (PCR1) is a histone ubiquitin ligase that modify histone H2A, while polycomb repressive complex 2 (PCR2) is a histone methyltransferase which transfers methyl groups to specific amino acid residues of histone H3 [73]
Histone tail acetylation at lysine residues implicated in increase gene expression in general. However, histone tail methylation activates or represses gene expression depending on which residue is methylated. Examples for such modifications were found on all four histones (H2A, H2B, H3 and H4). H3 and H4 acetylation are linked to active chromatin, while methylations have numerous functions. For example, the histone methylation can affect gene expression. Histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) are implicated in repression of gene activity [74]. In contrast, histone 3 lysine 24 trimethylation (H3K4me3) marks actively transcribed chromatin [75].

RNA modifications

RNA transcripts are subjected to a range of modifications at the single-nucleotide level, and over 100 such modifications have been identified, particularly on tRNAs and other non-coding RNAs (ncRNAs); several of these modifications have been shown to regulate ncRNA function [76]. The repertoire of epitranscriptomic modifications (primarily but not exclusively methylations) found on eukaryotic mRNAs is more limited than that found on ncRNAs, and functional data exist only for a fraction of these modified mRNAs.

miRNA

Non-coding microRNAs (miRNAs) are involved in the post-transcriptional control of gene expression [77]. Several classes of miRNAs have been identified in all cells. MiRNAs, involved in regulating gene expression, are small single-stranded RNAs of about 20 ribonucleotides length, possessing the reverse complement of another protein-coding gene's mRNA transcript. They are transcribed by RNA polymerase II, translocated to the cytosol, then further processed by Dicer and incorporated in the RNA-induced silencing complex (RISC). The complex miRNA-RISC binds the Argonaute protein family and together they interact with 3’-UTR regions of mRNAs; this step leads to translational repression by degradation of mRNA [78] (Figure 3). The miRNAs are involved in regulation of cellular homeostasis and play a role in several diseases due to their ability to silence gene expression.
miRNAs can act as epigenetic modulators by targeting key enzymes responsible for epigenetic machinery such as DNMTs, HDACs, and histone methyltransferases (EZH) [79,80,81]. Furthermore, epigenetic machinery such as DNA methylation, RNA modification, and histone modification regulate miRNA expression. The miRNA-epigenetic feedback loop is formed by a reciprocal relationship between miRNAs and epigenetic control. Some miRNAs were found to regulate DNMT3a and DNMT3b, as well as methylation-related proteins involved in de novo methylation [82]. For example, miR-148 targets DNMT3b [83]. Members of the miR-29 family were also shown to target DNMT3a and DNMT3b [84].

Viral infections and Epigenetic modifications

Research on the human epigenome is becoming increasingly important in cancer, immunology, and infectious diseases [85,86]. Viruses that infect animal cells were shown to cause epigenetic changes, and epigenetic processes influence the majority of virus-cell interactions [87] .
After entering the nucleus, viral DNA starts the replication process in close proximity to subnuclear structures known as pro-myelocytic leukemia nuclear bodies (PML-NBs). The PML-NBs serve as aggregation sites for many proteins associated with heterochromatic repression. These proteins facilitate the deposition of repressive heterochromatin on viral DNA, thereby repressing viral transcription. In absence of viral de-repression functions, viral episomal DNA contains repressive chromatin marks and has no active histone marks [88].
Certain DNA viruses, such as herpes simplex virus (HSV) and hepatitis B virus (HBV), use viral proteins that disperse or degrade components of PML-NBs to prevent viral gene silencing [89].
When the HSV enters the nucleus, viral DNA exists in a "naked" state, lacking histones. The viral DNA undergoes rapid epigenetic repression, primarily through the action of Daxx-ATRX and HIRA-loaded H3.3 associated with repressive H3K9me3 marks. Inhibition of HSV-1 is neutralized by a two-step process. First, the viral protein VP16 facilitates the recruitment of host proteins, resulting in the formation of a complex that subsequently recruits histone demethylases, including lysine-specific demethylase 1 (LSD1) and members of the Jumonji domain 2 (JMJD2) family. This recruitment process serves to remove repressive H3K9 marks from viral early promoters. The VP16 complex additionally recruits the methyltransferases Set1 and MLL1, facilitating the placement of activating H3K4me3 modifications on histone H3 associated with viral DNA. This enables the manifestation of the early viral protein ICP0, which coordinates the subsequent phase of de-repression. The ICP0 protein facilitates the stepwise elimination of the repressive histone modifications H3K9me3 and H3K27me3 throughout the viral DNA genome, enabling successful infection [89]. Recent research therefore supports the notion PML-NBs play a critical role in epigenetic suppression of viral DNA.
Retroviruses appear to circumvent epigenetic repression by integrating their DNA into euchromatic segments of the host cell genome. This is evident as the epigenetic repression observed with unintegrated retroviral DNA closely resembles that seen in mutant DNA viruses that lack the required defense mechanisms. When viruses invade host cells that are at least temporarily nonpermissive, they could use epigenetic suppression to enter a controlled, dormant state, thus forming viral reservoirs that have so far proven to be ineradicable.
The concept of epigenetic suppression has been proposed as a mechanism used by host cells as an intrinsic immunological defense against DNA viruses [90].
In an alternative hypothetical situation, it is possible that viruses use epigenetic repression as an approach to suppress their own gene expression. This could potentially promote the development of latent infections and prevent the production of immunogenic viral proteins [91].
On the other hand, it is well known that epitranscriptomic modifications tend to enhance the functionality of viral messenger RNAs (mRNAs). Consequently, both DNA and RNA viruses have evolved mechanisms to optimize the extent of these modifications on their transcribed genetic material. There are reports of four epitranscriptomic modifications that affect viral gene expression. These modifications include N6-methyladenosine (m6A), 5-methylcytidine (m5C), N4-acetylcytidine (ac4C), and 2′O-methylation of the ribose moiety of all four ribonucleosides (collectively referred to as Nm). Viral RNAs have significantly increased amounts of m6A, m5C, and Nm residues compared with cellular mRNAs expressed in infected cells [76] [78]. The amount of m5C in viral RNAs was found to be 14-30 times higher compared with cellular poly(A)+ RNA. The high prevalence of m6A, m5C, Nm, and possibly ac4C modifications on viral RNAs suggests that viral RNAs have adapted to enhance the incorporation of these epitranscriptomic modifications into their transcripts. This observation strongly implies that these modifications play a crucial role in facilitating various stages of the viral replication cycle [92].
HDACs that remove acetyl groups from histone proteins and alter gene expression resulted in interfering with viral replication. Thus, HDAC inhibitors was shown as promising antiviral drugs. While there are several synthetic HDAC inhibitors on the market, there are also natural bioactive compounds that have HDAC inhibitory action and consequently anti-viral activity.
Of note, SARS-CoV2 infection raised the levels of methylated histones H3K9me3 and H3K27me3 in A549 cells [93]. ORF8 encodes the SARS-CoV2 protein, which acts as a histone mimic of the ARKS motifs in histone H3 to impair host cell epigenetic control. ORF8, linked with chromatin, disturbs histone post-translational modification regulation, and increases chromatin compaction. Interestingly, SARS-CoV2 missing ORF8 is linked to a lower severity of COVID-19 [93] (Figure 4).

Virus infection promotes epigenetic modifications in the immune system and host genes

To survive and replicate in their host, viruses must use mechanisms to bypass the immune system. Some virus families engage the immune system through a variety of epigenetic mechanisms. The H3N2 IAV, for example, demonstrated the ability to block host's innate immune response by interfering with gene expression. Other cancer-causing animal viruses frequently impair cellular epigenetic mechanisms by reducing tumor suppressor genes and activating viral or host cell oncogenes .
Interferons (IFNs) serve as crucial anti-viral mediators as they stimulate interferon-stimulated genes (ISGs) and consequently trigger pathogen-driven immune responses [95,96]. During infection, viruses develop antagonistic mechanisms that neutralize certain ISG effectors [97]. IFN and innate immune responses are regulated by epigenetic modifications and chromatin remodeling complexes. H3K27me3 levels increase in MERS-CoV-infected cells while H3K4me levels decreased, indicating antagonistic mechanisms targeting the IFN innate immune response [98]. Histone mark occupancy differential at ISG promoters indicated that promoter regions had additional H3K4me monomethylation than repressive H3K27me3 marks, favoring accessible chromatin and promoting active transcription and ISG expression [99]. As DNA methylation and histone modifications govern ACE2 expression, DNMT1, HAT1, HDAC2, and KDM5B are possible viral targets for modulating the host immune response [100].
Virus-mediated epigenetic modifications have additionally been linked to cancer induction. The HBV is linked with HCC together with abnormal DNA methylation in the host genome. HBV-infected cells and tumors exhibit greater levels of DNMT1, DNMT3a, and DNMT3b . HBV X antigen (HBXAg) has been reported to induce DNMT1 and DNMT3a expression . HBXAg has demonstrated effective transcription repression from CpG-methylated E-cadherin and p16INK4A gene regulatory elements .
Human papillomavirus (HPV) strains HPV16 and 18 have been linked to the development of cervical carcinoma. A keratinocyte cell line with HPV16 episomes has been shown to have a lower level of E-cadherin [103]. This downregulation requires the oncoprotein HPV-E7, which was reversible following treatment with the DNMT inhibitor 5-aza-deoxycytidine [103]. Furthermore, E7 has been demonstrated to alter DNMT1 levels [103] and bind directly to DNMT1 and participate in the DNA methyltransferase activity [104]. E7 also stimulates the expression of the H3K27 methyltransferase EZH2 [105]. Interestingly, the gene p16INK4A, which is typically suppressed by EZH2 via H3K27me3 in cycling cells and is commonly hyper methylated in cancer, is frequently overexpressed in HPV-positive carcinoma [106] (Figure 4).
Simian vacuolating virus 40 (SV40) is a polyomavirus that infects both monkeys and humans. It is also suspected to induce epigenetic modifications in host cells. SV40, like HPV, is linked to RASSF1 promoter DNA methylation, with the presence of SV40 large T-antigen (Tag) sequences correlating with high levels of DNA methylation [107]. Furthermore, the expression of large T antigen upregulates DNMT1, promoting DNA methyltransferase activity and genomic methylation [108] (Figure 4).
Adenoviruses undergo a lytic rather than a dormant life cycle, and the viral oncoprotein small E1A was shown to reduce histone 3 lysine 18 acetylation (H3K18Ac) and block transcription of multiple genes [109].
Interestingly, the FDA authorized a variety of epigenetic modifiers as DNMT inhibitors (azacytidine, decitabine) and HDAC inhibitors (vorinostat, romidepsin, belinostat, panobinostat) [110]. Decitabine and 5-aza-2-deoxycytidine (5-azadC), are nucleoside-based DNMT inhibitor widely used for reducing inflammation and IFN response in macrophages [111]. Notably, decitabine has recently been incorporated in a clinical study for the treatment of COVID-19 Pneumonia-ARDS (CTI: NCT04482621).

Viral infection affects Host miRNA expression

In response to viral infection, the expression levels of host miRNAs vary. These up/downregulated miRNAs directly or indirectly target the viral genome to regulate viral replication and to modulate the innate immune system during viral infection [112].
Recent finding reveals the indispensable role of miRNAs in viral infection and disease progression. Hence, many researchers have been working on the idea of using such miRNAs as diagnostic/therapeutic tools. Altering the expression of miRNAs anti-viral therapy has so far been a difficult task because of their varied nature in different situations. A recent study provided evidences for eight different miRNA (miR-122, miR-155, miR-223, miR-150, miR-199, miR-149, miR-29, and miR-let7) that hold the potential to become biomarkers for HIV, HCV, or HIV/HCV co-infection [113]. Some of above-mentioned miRNAs such as members of the miR-29 family are targeting DNMT3a and DNMT3b [84] (Figure 4).
The most prevalent miRNA in the liver is miR-122 [114], which accounts for 60-70% of total miRNA in hepatocytes. Numerous studies have revealed that miR-122 is needed for HCV and HIV replication in infected cells [115,116,117].
MiR-223 expression is downregulated during IAV and HBV infection, as well as in inflammatory bowel disease, type 2 diabetes, leukemia, and lymphoma [118]. A growing body of data shows that miR-223 has a role in controlling inflammation and preventing collateral damage during infection. Granzyme B, IKK, and STAT3 [118] are all validated targets for miR-223 that have impacts on inflammation and infection. miRNA-223 can also target viruses directly, such as HIV [117]. Recently, miR-223 was shown to be increased in HIV-HCV co-infection, although its significance in co-infection remains unknown [117]. Furthermore, during SARS-CoV infection, miRNA-223-3p was identified as a host miRNA involved in the control of the lung inflammatory response mediated by the envelope (E) protein [119]. Inhibiting miRNA-223 in infected animals using antisense RNAs resulted in alterations in the expression of host components implicated in inflammation (cytokines, chemokines, and the nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome) as well as the resolution of pulmonary edema ion transporter cystic fibrosis transmembrane conductance regulator (CFTR). These findings demonstrate the role of miRNA-223 in the control of SARS-CoV-induced pathogenic processes and support the therapeutic potential of miRNA inhibition [119]. Interestingly, most viruses produce their own ncRNAs, which bind with proteins essential for their activity and stability. These ncRNAs control viral replication, persistence, host immune evasion, and cellular transformation [120]. Herpesvirus saimiri encodes HSUR 1, an uracil-rich ncRNA with sequence complementarity to miR-27. Binding to HSUR 1 triggers miR-27 cleavage, activating T cells during HSV infection [121,122,123] .

Plant-derived anti-viral activity

Although vaccines are used to combat certain viruses, antiviral therapy is still a common approach [124]. Interest in herbal products with antiviral activity has increased significantly, and in recent years more than 50% of approved antiviral drugs have been produced from herbal sources [125,126]. Indeed, they are particularly rich in compounds with a great structural diversity. Plant-derived products are mainly essential oils (EOs), extracts, and isolated compounds that have been extensively studied for their antiviral properties against different viral strains (Table 1, Table 2 and Table 3) [127,128].
EOs and extracts from different plant families such as Lamiaceae, Myrtaceae, Asteraceae, Brassicaceae, Rutaceae, Apiaceae, and Geraniaceae were found to be highly effective (Table 1). Among them, the essential oils of Illicium verum Hooker f. and Rosmarinus officinalis L. were extremely effective against HSV-1 with IC50 values of 1 and 0.18 µg/mL, respectively [129,130]. In addition, Cymbopogon citratus (DC.) Stapf, Cananga odorata (Lam.) Hook.f. & Thomson, and C. nardus (L.) Rendle showed great efficacy against HIV virus with IC50 values of 0.61, 0.60, and 1.2 µg/ml, respectively [131,132]. Finally, Eucalyptus globulus Labill. proved to be highly effective against Coxsackie virus B3 with an IC50 of 0.7 µg/mL.
As for the plant extracts listed in Table 2, most of them showed strong antiviral activity. For example, extracts of Schinus terebinthifolia Raddi and Quercus persica Jaub. & Spach inhibited HSV-1 virus with an IC50 of 0.21 and 0.26 µg/mL, respectively [131].
Comparing the data reported in Table 1, Table 2 and Table 3, herbal EOs and extracts are more effective than pure isolated compounds in some cases. EOs are usually complex mixtures of volatile secondary metabolites such as terpenes, alcohols, ethers, aldehydes, ketones, or esters. The extracts are also complex mixtures of organic compounds that are extracted depending on the polarity and solvent used. Consequently, the activity of EOs and extracts is not due to a single component but may be associated with the synergistic action of two or more components with antiviral activity.
Herbal products exert their antiviral activity with different modes of action. They may inhibit virus attachment, penetration, and entry into the host cell or by inhibiting other intercellular cell signaling pathways [133]. Other modes of action include disruption of the viral life cycle or inhibition of other essential enzymes for viral reproduction [134].
A wide range of compounds are found in plants and their extracts, some of which have been isolated and tested to identify the main contributors to antiviral activity (Table 3). Most of them belong to the classes of polyphenols, terpenes, or alkaloids. In some cases, the compounds have shown strong potential against several viruses.
Among terpenes, raoulic acid purified from Raoulia australis Hook. F. purified extract, showed antiviral activity against five virus strains, i.e., HRV2, HRV3, CB3, CB4, and EV71 (IC50 values of < 0.1, 0.19, 0.33, ,0.40, < 0.1 µg/mL, respectively) [135]. In addition, farnesol, β-eudesmol, and carvacrol showed great potency against HSV-1 with IC50 values of 0.25, 3.5, and 6 μg/mL, respectively [129]. The classes of polyphenols and flavonoids contain the most compounds with antiviral activity. For example, chebulagic acid, tannin derived from Terminalia chebula Retz, was effective against viruses that use glycosaminoglycans for entry such as HCMV, HCV, DENV-2, and RSV showing IC50 values of 25.50, 12.16, 13.11, and 0.38 µM, respectively [136]. Baicalein, belonging to the flavonoid class, potently suppressed HCMV and HSV1, and IC50s were determined to be 2.2 and 5 µM, respectively [137,138].
Finally, alkaloids, which are small nitrogen-containing molecules, have a molecular basis of specificity and the ability to act on multiple viruses with different mechanisms of action [125]. Among them, tetrandrine and cepharanthine showed strong potential against HcOV (IC50 values of 0.33 μM and 0.83 μM, respectively), while berberine was effective against HCMV, HSV1, and HSV2 (IC50 values of 2.65, 6.77, and 5.04 μM, respectively) [139,140,141].
aIC50, half maximal inhibitory concentration; bSI, selectivity index; cnr, not reported.
This review focuses on plant-derived substances exhibiting anti-viral activity by targeting host functions and, in particular, the epigenome machinery.
Andrographolide (AGL), has been used in traditional medicine for millennia to cure a range of diseases such as colds, flu, and malaria [185,186]. AGL contains many substances that have an antiviral effect [185,186]. AGL inhibited the HIV, HSV-1, HBV, HCV, Zika virus (ZIKV), Chikungunya virus (CHIKV), and IAV [341]. AGL and its analogues reduce ZIKV and DENV infection, which has been linked to a decrease in HSPA1A expression and an increase in PGK1 protein expression [184]. Foot-and-mouth disease (FMD) is caused by the FMD virus (FMDV) and has a detrimental impact on livestock all over the world. FMDV was suppressed by AGL in BHK-21 cells. AGL reduced FMDV 3Cpro activity as monitored in an intracellular protease assay. Furthermore, AGL greatly inhibited the 3Cpro's interferon (IFN) antagonistic effect by inhibiting the expression of interferon-stimulating gene (ISG) [342]. AGL prevents EBV reactivation in EBV-positive cancer cells by suppressing EBV lytic genes, most likely via histone modifications such as H3-K9 modification and H3-K27 methylation [187]. AGL has been shown to prevent the infection of DENV [184], ZIKV, and other arboviruses [343]. AGL and its derivative showed significant activity against IAV including the H5N1 avian influenza virus both in vitro and in vivo [344]. Moreover, IVA-induced inflammation was inhibited by AGL in a murine model through NF-κB and JAK-STAT signaling pathways [188].
AP has shown promising results in treating liver diseases, including viral hepatitis, liver injury, and liver fibrosis, fatty liver and liver cancer. However, clinical application of AP is rare due to its poor solubility and low bioavailability.
AP activity mediated the modulation of miRNA. Specifically, MiR-377, which controls heme oxygenase-1 (HO-1), was significantly decreased by AP-induced nuclear factor erythroid 2–related factor 2 (Nrf2) activity.
In addition, AP downregulate miR-433 that modulate the glutathione cysteine ligase. On the other hand, AP upregulate miR-17 and miR-224 that regulate expression of thioredoxin. Moreover, AP upregulate miR-181a that regulate the glutathione peroxidase [183].
Apigenin (4′,5,7-trihydroxyflavone) is a flavone found in a variety of plants, including medicinal plants [345]. Apigenin displayed a potent HDAC inhibitor activity in human prostate cancer PC-3 cells, specifically decreasing HDAC1 and HDAC3 activity [189]. It also increased the global acetylation of histones H3 and H4 and directed histone H3 hyperacetylation to the p21/WAF1 promoter [189]. Furthermore, molecular studies revealed that apigenin enhances acetylated H3, particularly in the p21WAF1/CIP1 promoter region, leading to upregulating p21WAF1/CIP1 transcription [346]. Moreover, apigenin inhibited expression of miR-155, one of the miRNA induced by virus infections, which result in increase of SHIP-1 expression and thus impacting anti-tumor immune responses in the bone marrow (BM) and tumor microenvironment (TME) [347].
Apigenin exhibited antiviral properties against IAV, human rhinoviruses (HRV), HSV, enterovirus, HBV, HCV, EV71, and SARS-COV2 [190,191,192,193]. Anti-viral activity is attributed, in part, by inhibiting HDAC activity and chromatin remodeling [189,195]. Apigenin, linalool and ursolic acid showed a strong anti-viral activity towards coxsackievirus B1 (CVB1) [194]. Apigenin reduced the expression of miRNAs like miR-103, whose overexpression is linked to glucose intolerance. By hindering miR-103's maturation and preventing ERK from phosphorylating the TRBP (trans-activating response RNA-binding protein) [196].
In addition, apigenin also reduces miR-122 levels in vitro [197]. Because miR-122 overexpression is essential for HCV and HIV replication [115,116,117], apigenin may have anti-HIV and HCV efficacy by downregulating miR-122.
Baicalein is a flavonoid derived from the roots of Scutellaria baicalensis, a traditional Chinese medicinal herb [348]. It has been investigated for its anti-viral properties against a variety of viruses, including HBV [198], HIV [199] , DENV [200], HSV-1 [201]. Baicalein was reported to inhibit DNMT and HDAC and thereby influence epigenetic modifications [202,203]. Baicalein inhibited HDAC-1/8, causing growth suppression and differentiation induction in AML cell lines. Baicalein might activate HDAC-1 degradation mediated by the ubiquitin-proteasome pathway, thereby increasing Histone H3 acetylation [202]. Additionally, baicalein regulate HDAC activity by upregulating the levels of miR-3,178 [204]. Later, experimental analysis revealed that HDAC10 is a target gene of miR-3,178 [203]. Furthermore, when exposed to high glucose concentrations, baicalin controlled the N6-adenosine-methyltransferase (METTL3)/ Hexokinase domain containing 1 (HKDC1)/JAK2/STAT1/caspase-3 Pathway in liver cancer cells [203]. Baicalein exerts potent antiviral activity against DENV. It exhibits activity against dengue virus adsorption and intracellular replication of DENV-2 [200].
Berberine (BBR) is a quaternary ammonium salt of the protoberberine group of benzylisoquinoline alkaloids found in plants such as Berberis vulgaris [349], which exhibited promising anticancer effects via epigenetic regulation and AMPK activation [205]. Berberine has exceptional anticancer effects via affecting the enzyme involved in histone acetylation and methylation in acute myeloid leukemia (AML) cell lines [292] and suppression of SIRT1 deacetylases in a p53-dependent manner [206]. Berberine inhibited miR-21 expression and promoted integrin β4 (ITGβ4) and Programmed Cell Death 4 (PDCD4) protein expression in colon cancer cell lines. Overexpression of miR-21 reduced the anti-cancer effects of berberine on cancer cells [207].
BBR was reported to influence multiple biological activities, including anticancer, anti-inflammatory, and anti-viral activities [350]. BBR targets multiple steps of the viral lifecycle rendering it an excellent candidate for use in innovative anti-viral drugs and therapies. BBR was discovered to inhibit viral replication by targeting specific interactions between the virus and its host. BBR binds to DNA, inhibiting DNA synthesis and reverse transcriptase activity. It was shown to inhibit the replication of HSV [208], HCMV [209], HPV [210], DENV [211], HIV [212], HCV [213] and SARS-COV2 [215]. BBR exhibited anti-viral effects on IAV both in vitro and in vivo [214]. BBR possess the ability to control the signaling pathways MEK-ERK, AMPK/mTOR, and NF-B, which are all necessary for viral replication. Furthermore, BBR has been reported to enhance the host immune response, leading to viral clearance.
Protein phosphorylation is crucial in the infection cycle of many viruses [38] , affecting cellular proteins stability, activity, interaction with other proteins, and infectivity. Viruses like EBV [41], HCV [41], SARS-COV2, DENV [42], and others [43,44] [45], rely on MAPK p38 for replication, suggesting that MAPK p38 inhibitors may exhibit broad-spectrum anti-viral activity.
Varghese et al. discovered that BBR significantly reduces MAPK activity. The p38 mitogen-activated protein kinases (p38), Extracellular Signal-regulated Kinases (ERK), and JNK signaling pathways are all significantly blocked by BBR, which specifically targets the ERK signaling pathway, resulting in a significant decrease in virions production. The reduction in viral protein expression following BBR treatment is most likely due to a decrease in virus-induced signaling. BBR treatment has no effect on virus entry or viral replicas enzymatic activity [351].
BBR was also demonstrated to inhibit p38 MAPK activity during HBV infection. HBV's virion contains a partly double-stranded relaxed circular DNA (rcDNA) genome, which is converted to covalently closed circular DNA (cccDNA) in the nucleus of an infected cell. The p38 MAPK is essential for the maintenance of HBV cccDNA in infected cells [216]. The cccDNA serves as a template for RNA synthesis, including mRNAs and pregenomic RNAs (pgRNAs). During the HBV life cycle, reverse transcriptase (RT) converts pgRNA to partly double-stranded rcDNA in the capsid. Inhibiting the activity of p38 MAPK is linked with a reduction in HBV surface antigen (HBsAg) synthesis, HBV e-antigen (HBeAg) secretion, and HBV replication. BBR's ability to inhibit MAPK might make it an attractive option for a novel anti-viral drug against HBV infection.
Betulinic acid (BA) is a naturally occurring pentacyclic triterpenoid found in the bark of various plant species, most notably the white birch (Betula pubescens) [352]. BA is capable of inducing apoptosis in tumor cells by directly activating the mitochondrial apoptosis pathway via a p53- and CD95-independent mechanism [353]. A computational approach demonstrated that BA has the capacity to alter HDAC6 and HDAC10 activity [217]. Furthermore, BA exhibited anti-cancer activity that is mediated through cannabinoid receptors (CBs). BA functions as both a CB1 antagonist and a CB2 agonist [354].
BA was used for the treatment of various viral diseases [159]. BA has demonstrated activity in inhibiting DENV-2 NS5 polymerase [218]. Furthermore, BA exhibited inhibitory effect on HBV replication [219]. Interestingly, C-3 esterification of BA led to the discovery of Bevirimat, an HIV-1 maturation inhibitor patented by Sanofi-Aventis.
Butyric acid is a fatty acid derived from multiple vegetable sources that have anticancer activity through several pathways, including its influence on epigenetic machineries. Butyrate, alone or in combination with other drugs, including nicotinamide (NA), was shown to have anticancer action in vivo [220]. Butyric acid exerts its anti-tumor effect by increasing HDAC expression and activity, which is accompanied by an upregulation of miR-203 promoter methylation [220].
Butyrate inhibited HBV replication and cell proliferation by inhibiting SIRT-1 expression in hepatoma cells. Specially, butyrate inhibited HBx protein expression, HBV-DNA and hepatitis B surface antigen (HBsAg) [221].
Cardamonin (CDN) is a natural chalcone isolated from the seeds of Alpinia katsumadai Hayata [355]. CDN has been shown to have a variety of pharmacological activities, including anticancer and anti-inflammatory properties [222]. It was recently revealed that CDN has anti-viral action against the human coronavirus HCoV-OC43. CDN exhibits significant efficacy in reducing the HCoV-OC43-induced cytopathic effects. CDN suppressed HCoV-OC43 infection by promoting the p38 MAPK signaling pathway and providing therapeutic potential against other human coronaviruses [222].
Cordycepin is a nucleotide analog derived from Cordyceps mushrooms [356]. In SNU719 cells, cordycepin treatment enhanced BAF Chromatin Remodeling Complex Subunit 7A (BCL7A) methylation while suppressing demethylation [223]. Cordycepin promoted methylation at EBV genomic sites near its Fp/Qp promoters. These findings indicate that cordycepin enhances DNMT3 activation, hence increasing methylation of both genomic and EBV DNA loci in SNU719 cells [223] causing reduced EBV replication [224]. Cordycepin was also shown to have anti-SARS-CoV-2 replication activity [224].
Cordycepin shows anti-viral activities that are attributable to its ability to inhibit several protein kinases [356]. Cordycepin, an adenosine derivative, differs from adenosine in that its ribose lacks an oxygen atom in the 3′ position [357]. Several research groups have reported that cordycepin has anti-viral activity against several viruses including IAV, plant viruses, HIV, murine leukemia virus, EBV [225,226,227,228,229] and COVID-19 [230].
Corosolic acid (CA) is a triterpene acid isolated from Lagerstroemia speciose [358]. This bioactive molecule is prevalent in foods such as guava, loquat, and olive, and has anti-inflammatory, anti-metabolic syndrome, and anti-neoplasic properties [233]. CA is implicated in the regulation of DNA methylation and histone H3 methylation. CA modulates CpG methylation sites, resulting in altered gene expression in treated cells [231]. Furthermore, CA inhibits the production and activity of epigenetic modulatory proteins, suggesting its capacity to prevent prostate carcinogenesis [359]. Furthermore, CA significantly increased the expression of acetylated histone H3 lysine 27 (H3K27ac) at the Nrf2 promoter, while decreasing histone H3 lysine 27 trimethylation (H3K27Me3) [232]. Moreover, anti-viral activity against a number of viruses were reported [233] .
Curcumin, the major bioactive in turmeric, is a polyphenol with anti-inflammatory and anti-cancer activities [360]. Curcumin has been demonstrated to be a powerful epigenetic regulator with multiple effects on HDAC expression and activity. Curcumin decreased the expression of HDAC1, HDAC3, and HDAC8 proteins, as well as histone acetyltransferase p300 while enhancing the acetylation of Ac-histone H4 protein [234]. Curcumin was shown to reduce HAT activity and has been proposed as a potential DNMT and HDAC inhibitor [235].
Curcumin reduced the amount of Hepatitis B surface antigen (HBsAg) and the number of cccDNA copies, resulting in the inhibition of HBV replication, which is accompanied by a decrease in the acetylation level of cccDNA-bound histone H3 and H4 [236]. MiRNAs array revealed that miR-350, miR-17-2-3p, let 7e-3p, miR-1224, miR-466b-1-3p, miR-18a-5p, and miR-322-5p were downregulated by curcumin while miR-122-5p, miR-3473, miR-182, and miR-344a-3p were upregulated [237]. Overall, the curcumin-modified miRNAs had an impact on a number of signaling pathways, such as Wnt, NK-B, MAPK, inflammatory response genes, and viral transmission [361].
Studies have shown that curcumin can inhibit the replication of various viruses, including HBV [236], HIV [238], and IAV [239]. It exerts its anti-viral effects by interfering with viral replication processes and by modulating the epigenetic regulation of genes involved in viral infection [236]. Curcuma longa L. (CLL) extract inhibits the transcription of HBV X (HBx) gene through a p53-mediated pathway, with no cytotoxicity to liver cells. These results highlight CLL extract as an efficient natural product with anti- HBV activity [362]. Curcumin interfered with the activator protein-1 (AP-1) binding activity in HeLa cells resulting in decreased transcription of HPV-18 genes [240]. The AP-1 transcription factor regulates the epithelial tissue-specific gene expression of almost all HPV types. These data indicated that curcumin, through apoptosis modulation and the downregulation of viral genes, can be a good candidate for the management of highly oncogenic HPV infections. Additionally, curcumin's anti-viral effect may be mediated by altering viral entrance, viral protease activity, and host intracellular signaling pathways [363]. Furthermore, Curcumin and its analogs were active in inhibiting ZIKV, CHIKV, VSV, Coxsackie B3 virus (CVB3), EV71, RSV, HSV-2, Kaposi’s sarcoma-associated herpesvirus (KSHV) and human adenovirus (HAdV) [241]. Curcumin was reported to affect virus replication directly or indirectly by modulating the host immune response leading to viral clearance [364].
Curcumin is known to have strong inhibitory effects on the expression of various pro-inflammatory cytokines accountable for the "cytokine storm" effect that occurs due to some viral infections. In-silico docking studies have recently supported the potential role of curcumin as a promising agent for reducing acute symptoms derived from SARS-CoV-2 infection [365].
Ellagic acid (EA) is a ubiquitous phenolic molecule isolated from a variety of fruits and vegetables which is well-known for its anti-cancer effect [366]. This bioactive substance has demonstrated effective induction of activity of HDAC. Human adipogenic stem cells treated with EA showed a substantial increase in HDACs gene expression. EA also suppresses adipocyte differentiation through coactivator-associated arginine methyltransferase 1 (CARM1) -mediated chromatin modification. This compound also inhibited adipocyte growth and differentiation by increasing histone arginine methylation [242], resulting in an increase in acetylated histone through epigenetic alterations mediated by coactivator-associated CARM1 inhibition. CARM1 inhibition was shown to limit H3R17 methylation, resulting in decreased H3K9 acetylation and HDAC9 dissociation [242]. Ellagic acid, and other plant-derived substances strongly bound with the multiple targets of the SARS-CoV-2 receptors, inhibiting viral entry, attachment, binding, replication, transcription, maturation, packaging and spread [243].
Epigallocatechin gallate (EGCG), is the most abundant catechin in tea leaves, comprising 50–80% of the total catechins [367]. EGCG was recognized as the primary contributor to the numerous health benefits associated with green tea [367] including symptom reduction of infectious diseases [368].
EGCG binds to various targets and exert its influence on the activity of diverse enzymes and signal transduction pathways. Studies with animal models and various cancer cell lines have shown that EGCG and other catechins modulate the activity of DNMTs [244]. Fang et al. suggested that EGCG inhibited DNMT activity resulted in reactivation of methylation-silenced genes [369]. In fact, EGCG can reduce DNA methylation through the direct inhibition of the activity of DNMT 1, DNMT 3a, and DNMT 3b, by directly binding to the active site within the enzyme [244]. In contrast, Lee et al. provided an alternative mechanism to explain the DNMT inhibition induced by EGCG. Their studies revealed that DNA methylation was primarily inhibited in vitro through competitive inhibition by promoting the formation of SAH (S-adenosylhomocysteine). Based on this mechanism, EGCG causes the reduction of intracellular concentration of SAM (S-adenosylmethionine), which is the universal methyl donor, while simultaneously increasing the concentration of SAH. Importantly, SAH acts as a feedback inhibitor for various methylation reactions that depend on SAM. Thus, the modulation of SAM and SAH levels by EGCG contributes to the inhibition of DNMT activity and other SAM-dependent enzymes such as Methyltransferases (MTases) [244,245,370].
EGCG also regulates histone modifications by inhibiting the activity of HDACs [245] and consequently inducing changes in gene expression patterns. The inhibition of HDAC activity by EGCG results in a decrease in HDAC enzyme activity and consequently leads to increased levels of acetylation on histone proteins both globally and at specific regions. In human colon cancer cell lines, EGCG inhibited HDAC1, HDAC2, and HDAC3 expression [246]. In addition, EGCG inhibited HAT activity [247]. EGCG has been demonstrated to prompt increased acetylation of lysine 14 and 9 (on histone H3) and lysine 12, 5, and 16 (H3-Lys and H4-Lys) levels [371]. Also, EGCG can increase the acetylation of H3K9/14ac and H3ac histones by up to 8-fold, as well as the concomitant hypermethylation of the active H3K4me3 (almost 2.5-fold) and the restrictive H3K9me3 chromatin proteins [372]. Furthermore, in cancer cell lines, EGCG inhibits DNMT’s activity and reactivates methylation-silenced genes such as p16INK4a and retinoic acid receptor beta (RAR) [373]. Moreover, a recent report showed a potential effect of EGCG in modulating NAD+ levels and thereby activity of SIRTs proteins [374].
EGCG has also been implicated as a potential modulator of miRNAs by regulating expression levels of epigenetic modifiers or viral proteins. EGCG can decrease the levels of let-7e-5p, miR-103a-3p, miR-151a-5p, miR-195-5p, miR-222-3p, miR-23a-3p, miR-23b-3p, miR-26a-5p, miR-27a-3p, miR-29b-3p, miR- 3195, miR-3651, miR-4281, miR-4459, miR-4516, miR-762, and miR-125b-5p [248]. Another study showed that EGCG enhances the expression of miR-3663-3p, miR-1181, miR-3613-3p, miR1281 and miR-1539, while decreasing miR-221-5p, miR-374b, miR-4306, miR-500a-5p and miR590-5p in human dermal papilla cells [249] and miR-140-3p and miR-221 in melanoma and hepatoma cell lines, respectively [250,251].
Anti-viral properties of EGCG have been demonstrated for a wide range of virus families, including Retroviridae, Orthomyxoviridae, and Flaviviridae. Furthermore, the molecule affects the replication cycle of DNA viruses such as HBV, HSV and AdV [375]. Particularly, EGCG has been shown to inhibit the replication of several viruses including IAV, HBV, HCV, HSV-1 and HSV-2, HPV, ZIKV, and SARS-COV2 [252,253,254,255,256,257,258]. EGCG showed an anti-proliferative effect in HPV-16 associated cervical cancer cell line CaSki via the arrest of the cell cycle in the G1 phase, leading to programmed cell death [376]. Remarkably, EGCG and other green tea catechins are effective against HPV mediated cervical lesions. Topical ointment preparation containing 15% green tea extract or sinecatechins (Veregen®) has been approved by US FDA to treat genital warts caused by HPV infection [256,377].
EGCG exert anti-viral activity also by modulating miRNA expression, such as upregulating miR-548m expression. miR-548m binding sites were identified in the CD81 mRNA 3′UTR, suggesting that miR-548m could suppress CD81 expression and thereby lower HCV infectivity. These findings imply that EGCG might function as an anti-HCV drug by increasing miR-548m expression while decreasing CD81 receptor expression required for HCV infection [255]. In addition, miR-194 was also reported for hindering HCV entry through targeting CD81 receptors [378]. The liver-specific miR-122 [114] is the most abundant miRNA in the liver, accounting for 60-70% of total miRNA in hepatocytes. Many investigations have found that miR-122 is required for HCV replication in infected cells [115,116,117]. EGCG (and also resveratrol) modulate the expression levels of miR-122 and thus might exert anti-HCV effect via this mechanism. IAV infection caused a significant decrease of micro-RNA let-7 expression in host cells that normally regulate the expression of type I interferon required for host cells anti-viral activity. Overexpression of let-7 increased interferon expression and effectively inhibit IAV infection. EGCG upregulates let-7 expression and thereby has the potential to exhibit anti-influenza activity [197] (Figure 6).
Galangin is a naturally occurring flavonoid found in honey, that is also an active ingredient in galangal, a spice used in traditional Chinese medicine [379]. This natural compound appears to be effective in inhibiting HDAC activity. In human neuroblastoma SH-SY5Y cells, treatment with galangin increased endogenous HDAC1-mediated deacetylation irrespective of DNA methylation status and subsequently lowered histone H3 acetylation in the BACE1 promoter regions [259]. Galangin upregulates miR-455-5p to modulate the regulatory subunit 12A of protein phosphatase 1 (PPP1R12A). This effect suppresses activation of the Mitogen-activated protein kinases (MAPK) and The phosphoinositide 3-kinases/ Protein kinase B (PI3K/AKT) pathways, controlling cancer cell survival and metastasis [260]. Galangin showed significant antiviral activity against HSV-1 and CoxB1 [261].
Garcinol is a polyisoprenylated benzophenone isolated from the peel of the Garcinia indica fruit [380]. Garcinol has anti-cancer, anti-inflammatory, and antioxidant properties (104). In tumor cells, it primarily inhibits the transcription factors NF-B and Janus Kinase (JAK)/STAT3 [380]. Garcinol has been shown to decrease HAT activity of p300 and pCAF in vitro and in vivo [262]. As a result, garcinol was discovered to be a potent inducer of apoptosis and to affect global gene expression in HeLa cells [262].
Garcinol is utilized in Ayurveda medicine for the treatment of infections and edema [381] [382]. The chemical structure of garcinol shows some similarities with curcumin (β-diketone, phenol). Garcinol has revealed significant anticancer activity by targeting NF-κB, 5-lipoxygenase (5-LOX), and STAT proteins [383,384]. In addition, garcinol is a well-documented HAT inhibitor and, thus, plays an important role in the epigenetic regulation of gene expression [385]. Garcinol downregulated miR-21, miR-494, miR-495, and miR-1977 in pancreas cancer cells [263] and upregulated the expression of the miR-453, miR-128, miR-1280 and miR-720 [386]. In breast cancer cells garcinol can induce the expression of the tumor suppressor miRNAs let-7a, let-7e, let-7f, miR-200b, and miR-200c both in vitro and in vivo [264]. A recent report provide evidence for the ability of garcinol to inhibit HIV-1 reverse transcriptase-associated ribonuclease H [265].
Genistein is a naturally occurring isoflavone isolated from the plant Genista tinctoria [266] and it is well-known for its potential chemotherapeutic action against a variety of cancer cells. Studies on HAT and HDAC activity revealed that genistein reduces HDAC while increasing HAT activity [266]. In prostate cancer cell lines, chromatin immunoprecipitation analysis with multiple antibodies revealed enrichment of acetylated histones H3, H4, and H3 di- and tri-methylated lysine 4 after incubation with genistein [387]. Furthermore, genistein inhibited the phosphorylation of serine 10 and the methylation of lysine 9 in the promoter regions of several genes, including Wingless-related integration site (Wnt5a), induced secretion of frizzled-related protein 5 (Sfrp5), and Frizzled Related Protein 2 (Sfrp2) [317]. Moreover, genistein treatment significantly inhibited miR-223 expression and up-regulated F-box and WD repeat domain-containing 7 (Fbw7) protein that act as a tumor suppressor gene. Moreover, down-regulation of miR-223 inhibited cell growth and induced apoptosis in PC cells [267]. In addition, other miR-223 targets such as Granzyme B, IκB kinases (IKKs), and Signal Transducer And Activator Of Transcription 3 (STAT3) are expected to be affected by genistein and thereby modulate immune response [118]. Interestingly, miR-223 expression is downregulated during IAV, HBV [118], HCV, HIV [117] and SARS-CoV infections [119]. Thus, it is reasonable to speculate that antiviral activity of genistein might be mediated by regulation of miR-223.
Ginkgolic acid (GIA) is a phenolic acid found in Ginkgo biloba L. with neuroprotective, antimicrobial, and antitumor properties [388]. Ginkgo biloba has been used in traditional Chinese medicine since at least the 11th century B.C. to treat various ailments such as dementia, asthma, bronchitis, kidney disease, and bladder disease. Ginkgolic acid as a potent multitarget inhibitor of key enzymes in the biosynthesis of proinflammatory substances [388].
Ginkgolic acid impairs SUMOylation by blocking the formation of an E1- SUMO thioester complex by binding directly to E1 [268]. SUMOylation is a process by which small ubiquitin-related modifier proteins (SUMO) covalently bind to specific lysine residues in target proteins, thereby regulating various aspects of protein function, including transcription, subcellular localization, DNA repair, and the cell cycle [389].
The Jumonji domain 2 (JMJD2) family member, JMJD2A, is the histone demethylase responsible for the accumulation of SUMO -2/3. JMJD2A is SUMOylated at lysine 471 by Kaposi’s sarcoma-associated herpesvirus (KSHV) K-bZIP, a viral SUMO -2/3-specific E3 ligase, in a SUMO -interacting motif (SIM)-dependent manner. SUMOylation is required for stabilization of chromatin association and gene transactivation by JMJD2A [390].
Recently, ginkgolic acid was reported to inhibit HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis [391]. In addition, ginkgolic acid exhibits broad-spectrum fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A, and Epstein Barr viruses [391]. Moreover, ginkgolic acid inhibited HIV protease activity in a concentration-dependent manner. In addition, treatment with ginkgolic acid inhibited HIV infection in PBMCs in a concentration-dependent manner [392].
Glycyrrhizic acid (GA) is a triterpene isolated from the roots and rhizomes of licorice (Glycyrrhiza glabra) [393]. GA is the principal bioactive ingredient of the licorice anti-viral [394], anti-inflammatory and hepatoprotective effects [395]. The Licorice plant is native to Europe and Asia, and has been used for centuries in traditional medicine. Ancient documentations from China, India and Greece stated traditional uses to alleviate the symptoms of viral respiratory tract infections and hepatitis [393]. Licorice is known for its ability to inhibit viral replication of various viruses including HBV, HCV, IAV H1N1 and HIV as reviewed by Zhong et al. [270]. Licorice's extract containing Glycyrrhiza inhibited replication of Newcastle disease virus (NDV) and were non-toxic in the embryonated eggs assay [271]. Glycyrrhizin exhibited antiviral activity by affecting cellular signaling pathways and increasing expression of nitrous oxide synthase (NOS) [396]. In vitro studies revealed anti-viral activity also against SARS related coronavirus, respiratory syncytial virus (RSV), arboviruses, vaccinia virus (VACV) and vesicular stomatitis virus (VSV) [275,276]. In animal studies treatment with glycyrrhizin reduced mortality and viral activity of HSV, encephalitis and IAV pneumonia [275].
In addition to anti-viral effect, glycyrrhizin also exhibited anti-inflammatory effects which were elicited by decreasing IL-6 release from macrophages, thus leading to reduced cytokine storm induction [277]. Moreover, in mouse macrophage RAW264.7 cells, high concentrations of licorice strongly inhibited LPS-induced nitric oxide production in concentration-dependent manner [397]. Presumably by controlling the expression of NF-B and PI3K signaling pathways, Glycyrrhizin anti-inflammatory impact may be obtained [278]. Glabridin licorice (Glycyrrhiza glabra) contains significant amounts of the isoflavan glabridin, which demonstrated anti-inflammatory, neuro- and cardioprotective activities in addition to distinct anti-cancer properties (growth inhibition, anti-angiogenic and anti-metastatic effects [398], [399], [400]. Glabridin suppressed cancer stem cell-like features in hepatocellular carcinoma cells, by upregulation of miR-148a that target SMAD2 (Mothers against decapentaplegic homolog 2) associated with inhibition of TGF (transforming growth factor)-β/SMAD2 signaling [401]. Similar results were obtained from breast cancer cells treated with glabridin [402]. Interestingly, miR-148, also targets DNMT3b [83]. In addition, glabridin inhibited angiogenesis of breast tumors by upregulation of miR-520a [403]. The expression of NF-κB was blocked by upregulated miR-520a in glabridin-treated breast cancer cells associated with inhibition of NF-κB/IL-6/STAT-3 signaling. The host signaling pathways regulated by glabridin are essential for virus infection and viral diseases.
Glycyrrhizic acid exhibited anti-viral activity [404,405] . It inhibits the HSV-1, HSV-2, VZV, HCMV, ZIKV, IAV, EBV, HIV, EBOV and SARS COV2 by varying mechanism of actions [269].
Grifolin is an adenosine derivative isolated from the fresh fruiting bodies of the fungus Albatrellus confluens [406]. Grifolin were shown to suppress tumor cell lines proliferation. Grifolin inhibited Bcl-2 expression while increasing Bax expression [406]. Grifolin reduced Elk1 transcription as well as its binding to the DNMT1 promoter region. The mRNA levels of pTEN and Timp2 are likewise increased by griforolin. Grifolin's anti-tumor effects may be exerted by ERK1/2-Elk1-DNMT1 signaling's epigenetic activation of metastasis-inhibitory genes [280].
Oleacein, a secoiridoid [407], is the most prominent phenolic compound in Olea europaea L. (olive). This substance exhibited anti-cancer activity against multiple myeloma cell lines (NCI-H929, RPMI-8226, U266, MM1s, and JJN3), and was found to be an effective epigenetic modulator oleacein reported to down-regulate several class I/II HDACs both at the mRNA and protein level; conversely, no effect on global DNA methylation was associated to this compound [281,282]. Oleacein inhibited the proliferation of numerous melanoma cell lines [408]. Oleacein was shown to exhibit antiviral effect on HIV-1 infection and replication by inhibiting cell-to-cell HIV-1 transmission and viral core antigen p24 production [283].
Organo Sulfur chemicals (OSC) are a group of compounds found in garlic (Allium sativum L.). More than thirty sulfur-containing compounds have been identified so far [409]. Garlic extracts were found to have broad-spectrum anti-viral activity [410]. Conversely, the mechanism by which these extracts or their purified constituents exert anti-viral activity may differ depending on the virus strains and viral lifecycle, which includes viral entry, fusion, replication, assembly, and virus-host-specific interactions [411]. Furthermore, one of the possible activities of garlic extracts and bioactive moieties that may combat viral infections resides in its immunomodulatory properties.
Garlic has been used as an ethnomedicinal herb to cure infectious diseases for ages [412]. It has been utilized to treat a variety of illnesses in African traditional medicine, including sexually transmitted diseases, Mycobacterium tuberculosis (TB), respiratory tract infections, and wounds [413,414]. Garlic was shown to have effects against viral infections in humans, animals, and plants. In addition to garlic extracts or powders, also purified bioactive components from garlic, exhibited anti-viral action. As an example, Alliin (S-allyl-L-cysteine sulfoxide) which is the most abundant sulfur compound found in fresh and dry garlic [415] is rapidly converted into allicin (diallyl thiosulfinate) by alliinase enzymes when fresh garlic is chopped, minced, crushed, or chewed [415,416]. Allicin is the primary component responsible for anti-viral activity [417,418], immunomodulatory characteristics [419], anti-inflammatory activities [420], antioxidant [421], and other pharmacological properties. Allicin is an extremely unstable and degrades into other OSCs including diallyl sulfide (DAS), diallyl disulfide (garlicin or DADS), diallyl trisulfide (allitridin or DATS), andajoene, and vinyl-dithiins [422,423]. In vivo, allicin may interact with cellular thiols such glutathione and L-cysteine to generate S-allyl-mercapto-glutathione (SAMG) and S-allyl-mercaptocysteine (SAMC) [424,425]. These compounds may be responsible for structural alterations of pathogen proteins [416]. Pre-clinical in vitro and in vivo studies revealed that allicin-derived OSCs such as ajoene, allitridin, garlicin, and DAS have anti-viral [426,427,428,429,430], immune enhancing [431,432,433] and other therapeutic activities [424,434,435].
Orobol 7-O-d-glucoside (O7G) isolated from banaba Lagerstroemia speciosa L. (Lythraceae) [436] was tested for anti-viral efficacy against eight different strains of HRV, a cause of common viral respiratory tract disease [436]. O7G displayed anti-viral activity against HRV A and B, as well as species resistant to pleconaril, a potent capsid inhibitor of HRVs [437].
Orsaponin (OSW-1) is a natural substance derived from the bulbs of the plant Ornithogalum saundersiae that has anti-proliferative and anti-cancer properties [438]. The enteroviruses (EV) employ the Oxysterol-Binding protein (OSBP) as a host lipid-transport protein [439]. Several studies have shown that OSW-1 binds to one of the two identified OSBP ligand binding sites and generates prophylactic anti-viral activity against all enteroviruses tested, including EV71, coxsackievirus A21 (CVA21), and HRV-B [440,441] .
Plitidepsin is a cyclic depsipeptide isolated from the Mediterranean marine tunicate Aplidium albicans [442]. Plitidepsin is synthesized and commercialized as Alpidin, a limited licensed drug for the treatment of multiple myeloma and its therapeutic target is the eukaryotic translation elongation factor 1A (eEF1A) [284]. This cellular component is essential for the enzymatic transport of aminoacyl tRNAs to the ribosome and has previously been identified as a key host factor in the replication of numerous viral infections, including RSV and gastroenteritis coronavirus [285]. In an in vitro and in vivo investigation, White and colleagues discovered that plitidepsin had anti-viral efficacy against SARS-CoV-2 via inhibiting eEF1A [286]. Plitidepsin was shown in vitro to be 27.5 times more potent than remdesivir in Vero E6 cells. In two animal models, plitidepsin treatment lowers SARS-CoV-2 replication and protected against the SARS CoV2 B.1.1.7 variant as well as lung inflammation [286] [287]. A phase I/II clinical trial for the use of Plitidepsin in the treatment of COVID-19 (NCT04382066) was conducted.
Pterostilbene (3,5-dimethoxy-4-hydroxystilbene) is a bioactive chemical found in grapes and several berries, mainly blueberries [443]. Pterostilbene altered gene expression in breast cancer cells which are mediated by epigenetic mechanisms such as HDAC modification [288]. It inhibited SIRT1 and regulates cell proliferation, apoptosis, stress response, metabolism, cellular senescence, and cancer [288] [289].
Interestingly, recent report demonstrated that resveratrol and pterostilbene inhibit SARS-CoV-2 replication in human primary bronchial epithelial cells [290]
Quercetin is a flavonoid found in many medicinal plants and food products [444]. This compound has a variety of biological properties, including anticancer activity, through several modes of action. Quercetin, alone or in combination with other drugs, promote epigenetic modifications. It enhanced histone H3 acetylation via FasL overexpression, activated HAT, and inhibited HDAC activities [291]. Furthermore, quercetin reduced histone methyltransferases (HMT) activities, particularly HMT-H3K9 activity [292]. In addition, quercetin reported to reduce the miRNA expression such as miR-146a [293], a regulator of HIV replication [294], and NF-κB signaling whom associated with anti-inflammation activity [445]. MiR-16, miR-217, and miR-145 were also modulated by quercetin [295,296,297].
Quercetin was shown to inhibit the replication of several viruses, including IAV H1N1, IVA H3N2, HBV, HCV, DENV, poliovirus, rhinovirus, CHIKV, MERS-CoV, HSV 1/2, EBV, RSV , Arbovirus, EBOV, HIV, Japanese encephalitis virus (JEV), hAdV, enterovirus (EV), ZIKV, NDV, Mayaro virus (MAYV) and SARS-COV2 [192,257,298,299,300]. It can modulate DNA methylation and histone acetylation [446]. Moreover, it has been reported to activate SIRT1 and exhibit anti-viral effects against several viruses [316]. Quercetin attenuate HCV production [301] and inhibit propagation of HSV-1 [298]. IAV infection cause a significant decrease of microRNA let-7 expression in host cells that normally regulate expression of type I interferon required for host cells anti-viral activity. Quercetin upregulate let-7 expression and thereby have the potential to exhibit anti-influenza activity [197].
Raoulic acid isolated from Raoulia australis [447] has shown a possible anti-viral action against coxsackievirus B3 (CVB3) and coxsackievirus B4 (CVB4), as well as HRV types A and B [447].
Resveratrol (3,5,4′-trihydroxystilbene) is a bioactive molecule isolated by Saiko et al. [448], from the roots of white hellebore (Veratrum grandiflorum Loes.). More than 50 plant species contain this bioactive substance, including grapes, apples, blueberries, plums, and peanuts. It has been intensively researched for its health benefits against a variety of diseases, including cancer [449]. Resveratrol treatment increased p21 expression in Caski cells by HDAC inhibition [302]. HDAC activity is decreased by resveratrol in a dose-dependent manner [303]. Pterostilbene is a phytoalexin dimethyl ether molecule that is a dimethoxylated derivative of resveratrol [450]. Interestingly, resveratrol is known to activate SIRT1 [304]. Despite the fact that research into the potential of SIRT1 activators anti-viral activities is continuously being conducted, it is important to keep in mind that this field is still in its infancy and that specific natural compounds that directly activate SIRT1 and have anti-viral effects are not yet well-established.
Over 100 scientific documents implicated miRNAs in resveratrol's health promoting activity. For example, in human colon cancer cells resveratrol significantly decreased the levels of miR-17, miR-21, miR-25, miR-92a-2, miR-103-1, and miR-103-2 [305]. While in lung tumors, resveratrol led to an upregulation of miR-200c [306].
Resveratrol intake in humans for six months increased miR-21, miR-181b, miR-663, and miR-30c, while reducing inflammatory cytokines like IL-6, CCL3, IL-1β, and TNF-α. This reduction was mediated by TLR and NF-B signaling pathways [307].
Resveratrol showed anti-viral properties [451]. It inhibit HSV infection in vitro and in vivo [308], but also inhibit beta-corona viruses such as MERS-COV and SARS-COV2 [309]. HSV-2 infection was regulated by resveratrol induced increased histone acetylation [452]. Varicella-zoster virus (VZV) replication in vitro was reduced by resveratrol in a dose- and time-dependent manner. Inhibited activation of IE62 gene by resveratrol was accompanied by reduced infection of both wild-type and DNA polymerase mutants with acyclovir-resistant VZV [310,311]. Furthermore, resveratrol exhibit activity against Venezuelan Equine Encephalitis Virus (VEEV) [312], EBV [313], Coxsackievirus (CV) [314] and the RSV. Resveratrol was shown to regulate TLR3 expression, inhibit the TIR domain containing adaptor molecule (TRIF) signaling pathway, and induce M2 receptor expression following RSV infection [453]. Mounting evidence reveals that HBV can alter the expression levels of all SIRT proteins, an NAD+-dependent deacetylate. In turn, all SIRTs regulate HBV replication via a cascade of molecular mechanisms. Furthermore, several studies suggest that targeting SIRTs using suitable drugs is a potential treatment strategy for HBV infection [315]. Additionally, resveratrol by activating SIRT1 inhibits RSV replication in human bronchial epithelial cells and stimulates TNF-α secretion, promoting cell death [316].
Silibinin is a flavonolignan derived from milk thistle [454] and has powerful anticancer effects, targeting multiple checkpoints, including epigenetic processes such as HDAC activity. Silibinin was shown to inhibit the expression of HDAC2 and HDAC3 proteins, as well as HDAC1, HDAC6, SET domain proteins (SETD1A, D4, D6), and lysine-specific demethylases (KDM 5B, 5C, 4A) in non-small lung cancer H1299 cells [317]. Silibinin also inhibited the expression of HDAC1-2 in human prostate cancer cell lines (DU145 and PC3) (56). Enhanced Lys27 trimethylation on H3 (H3K27me3) [455], inhibited activity of DNMTs and increased global DNA hypomethylation [318] [319,320] were also caused by silibinin in different test systems. Moreover, silibinin decreased the expression of miR-21 and miR-155 expression [321]. Recent studies have documented the antiviral activities of silibinin against several viruses, including the flaviviruses (HBV and DENV), togaviruses (CHIKV and MAYV), IVA, HIV, and HBV [322].
Silvestrol, a rocaglates family member isolated from Aglaia plants [456], has been shown to target the eukaryotic initiation factor-4A (eIF4A), an RNA helicase whose activity is required to unwind RNA secondary structures in the 5' untranslated region (5′-UTRs) and facilitate translation initiation [323]. Silvestrol exhibited activity against EBOV, ZIKV, CHIKV and coronaviruses [324,325,326]. Müller and colleagues found that silvestrol repressed MERS-CoV and HCoV-229E viral mRNA translation in human embryonic lung fibroblast (MRC-5) cells [327]. Furthermore, silvestrol suppresses the synthesis of MERS-CoV structural and nonstructural proteins (N, nsp8) as well as the production of viral replication/transcription complexes in peripheral blood mononuclear cells (PBMCs) [327]. Additional investigations have shown that a synthetic rocaglate CR-31-B (-) has antiviral effectiveness against HCoV-229E and SARS-CoV-2 replication in both in vitro and ex vivo experiments [328,329].
Sulforaphane (1-isothiocyanato-4(methylsulfinyl)butane) (SFN) is an isothiocyanate present mostly in cruciferous vegetables including broccoli, cabbage, brussel sprouts, and radishes [457]. In breast cancer cells, SFN significantly reduced HDAC activity [330]and increased the amounts of acetylated histones H3 and H4 expression [330]. Moreover, SFN enhanced the expression of the anti-oncogene proteins Dual Specificity Phosphatase 4 (DUSP4) and Cyclin-dependent kinases (CDKs), which associate with the downregulation of the HDAC5 and HDAC11 genes in the hepatocarcinoma HepG2 cell line [458]. A further benefit of SFN is that they increase let-7 expression, which may have anti-influenza (IAV) effects [197]. Moreover, SFN inhibit HCV [332] and DENV replication by enhancement of anti-viral interferon response through Nrf2-mediated HO-1 induction and inhibition of DENV protease [459]. Furthermore, SFN inhibited in vitro replication of six strains of SARS-CoV-2, including Delta and Omicron, as well as that of the seasonal coronavirus HCoV-OC43 [331]. In addition, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro [460]. SFN treatment diminished immune cell activation in the lungs [331] possibly mediated by overexpression of let-7 that regulate immune response in infected cells [197]. SFN anti-viral activity was exhibited both in vitro and in vivo by interfering with viral replications as well as modulating the inflammatory immune response and leading to decreasing viral load.
Tanshinone IIA is a natural bioactive compound found in Salvia miltiorrhiza Bunge rhizome [461]. Wang et al. investigated tanshinone IIA's role in epigenetic modifications, demonstrating its effect on HDAC modification [333]. This bioactive molecule decreased the enzymatic activity of HDACs. Tanshinone IIA significantly reduced the protein levels of HDAC1, HDAC3, and HDAC8 by lowering mRNA expression [333].
Tanshinone IIA was reported as an inhibitor of MAPK p38 [334]. MAPK p38 is explored by many viruses for their efficient replications [46]. Natural products that inhibit MAPK p38 activity might be a good candidate to exhibit broad-spectrum anti-viral activity [334] including DENV [42], coronavirus [43], VEEV [44], and EV71 [45], SFTSV, HSV-1 and SARS-CoV-2 [46,334].
Ursolic acid (3-beta-3-hydroxy-urs-12-ene-28-oic-acid) is a triterpenic acid found in ginseng (Panax Ginseng), rosemary (Rosmarinus officinalis), apple peel, pear, cranberry, and plum (Prunus domestica) [462]. It has been extensively studied for its chemo preventive and chemotherapeutic effects on a variety of malignancies. Ursolic acid significantly reduces the expression of various epigenetic regulatory factors, including HDAC1, HDAC2, HDAC3, and HDAC8 (Class I), as well as HDAC6 and HDAC7 (Class II) [335]. Zhao et al., 2012, reported an anti-cytomegalovirus effect of ursolic acid which was significantly stronger than ganciclovir [336].
Withaferin A (WFA) is a steroidal lactone derived from the plant Withania somnifera [337], known for its anticancer properties and ability to target several cancer hallmarks such as cell proliferation, migration, invasion, and angiogenesis, as well as the epigenetic process [337]. WFA displayed chemo preventive benefits against breast cancer cells by reversing epigenetic alterations via the downregulation of HDAC1 protein levels [337]. Furthermore, WFA, alone or in combination with SFN, significantly reduced HDAC1 expression at both the mRNA and protein levels [338]. WFA with SFN decreased HMT activity, but enhanced HAT activity, particularly in MDA-MB-231 cells [338].
WA as well as other plant-derived substances exhibited a high potential in modulating the main protease (Mpro) activity and cytokine storm in Covid-19 infection [339]. Moreover, WA has the potential to attenuate the neuraminidase (NA) of H1N1 IVA. Docking results predicted high binding affinity of the WA toward NA [340].

Summary

In this review, we narrowed our study to activity against 20 main viruses, and we reviewed 35 significant bioactive compounds (Table 3) that had anti-viral and epigenetic altering properties.
Not all bioactive substances that alter epigenetic modifications were reported to have anti-viral action. On the other hand, other bio actives exhibited anti-viral activity without evidence of epigenetic effects. This suggests that epigenetic pathways might contribute to the anti-viral effect of these bioactive compounds, but are not the exclusive mechanisms explaining their action. The missing information will need to be evaluated experimentally.
We have shown that a variety of bioactive compounds can modulate epigenetic modifications such as DNA methylation, histone modifications, and miRNA expression. Bioactive substances such as EGCG, apigenin, Curcumin, quercetin, berberine, resveratrol, genistein, silibinin, and sulforaphane were particularly interesting for their complex effect on different epigenetic pathways. Some bioactives, such as ellagic acid, tanshinone IIA, selenium, cordyceptin, grifolin, andrographolide, ursolic acid, corosolic acid, and betulinic acid, can affect just one epigenetic mark, while others, such as EGCG, showed activities on all epigenetic features.
Our conclusion is that bioactive chemicals perform a wide range of functions and can impact many targets in order to attain a certain biological activity.
It should be noted that not all bioactive chemicals that influence the activity of epigenetic mediators have been evaluated for anti-viral action. Others showed anti-viral efficacy but without definite mechanism of action. Some bioactives showed anti-viral action against a limited number of viruses, whilst others were efficient in inhibiting a wide range of viruses. Some bioactives have a broad-spectrum anti-viral action, inhibiting both RNA and DNA viruses. Among all the compounds, curcumin and glycyrrhizic acid are especially notable. Glycyrrhizic acid inhibited 80% and 65% of the DNA and RNA viruses (respectively) reviewed. Curcumin also inhibited 70% and 55% of the DNA and RNA viruses (respectively) examined. Others have been reported to inhibit just a few viruses, which
Table 3. Anti-viral activity of plant bioactive substances.
may be connected to the mechanism of action of such bioactive substances which target a specific protein or enzyme required by the particular virus. Alternatively, the bioactive-specific antiviral activity was neither examined nor evaluated against other viruses. It's not a lack of action, but rather a lack of experimental evidence.
Furthermore, we observed that many bioactive anti-viral compounds exhibited anti-viral activity against RNA viruses but had little or no effect against DNA viruses. This is especially evident in the case of sulforaphane, Silvestrol, Orsaponin, Plitidepsin and Raoulic acid which inhibited only RNA viruses and had no impact on any of the DNA viruses evaluated. Similarly, majority of viruses inhibited by apigenin and baicalein were RNA viruses.

Conclusions and Future directions

Natural product substances have shown epigenetic modifying activity and can affect the replication of various viruses. These plant-derived epigenetic modifiers alter gene expression by targeting the epigenome, reversible DNA/protein modification, and chromatin remodeling. Viruses rely on epigenome modification to ensure successful replication, latency, or escape from the immune response system. Reversal of the epigenome by plant-derived bioactive could result in blocking the viral life cycle, disrupting latency, and activating the immune response to fight viral infections.
The use of epigenetic modifiers as a means to combat viral infections has several advantages. As epigenetic modifications play an essential role in controlling viral gene expression, it is possible to block replication and expression of a variety of viruses by targeting these modifications. This approach is applicable against both DNA and RNA viruses, making it a viable tool to combat a broad-spectrum of viral diseases.
Because host epigenetic mechanisms are less susceptible to mutation, the likelihood of developing resistance is low, allowing for longer antiviral efficacy. Some viral infections, such as HSV and HIV, can lead to latent infections in host cells, making them difficult to eradicate. Epigenetic manipulations have the potential to reactivate dormant viruses so that they can be targeted and eliminated by the immune system or antiviral therapies. Focusing on epigenetic pathways may therefore offer potential approach to overcome viral latency and eliminate the virus completely. Epigenetic therapies might be used in future in conjunction with standard antiviral drugs or vaccines to increase their efficacy. By altering host factors, epigenetic therapies can create a hostile environment for viral replication and make viruses more susceptible to the direct antiviral effects of conventional drugs.
This synergy may improve therapeutic outcome and minimize the possibility of treatment failure. Treatment of viral infections via epigenetic signaling pathways presents some unique difficulties. The mechanisms of epigenetic regulation are complicated and not fully understood. This makes it difficult to develop safe and effective drugs that target epigenetic mechanisms. In addition, epigenetic mechanisms control gene expression in all cells, not just those infected with viruses. This means that plant-based agents with epigenetic targets must focus on the epigenetic processes involved in viral replication.
This review summarizes recent advances in natural products with a broad-spectrum antiviral activity that have the potential to treat various viral infections, including emerging and re-emerging infections. These compounds have different mechanisms of action, including inhibition of viral entry, replication and assembly, and modulation of the host immune response. Most natural products were shown to be safe and well tolerated in animal studies, but further clinical studies are needed to confirm their safety and efficacy in humans. These natural products represent a promising new class of antiviral agents because they target different steps in the viral life cycle, reducing the likelihood of developed resistance. Although there is no guarantee that natural products will be effective against all unknown viruses, it is likely that their ability to act on host functions will make them effective in combating future viral infections.
In the future, plant-derived epigenetic modifiers may be used as antiviral agents who may be less susceptible to resistance than conventional antiviral drugs that target viral targets. The bioavailability of natural products in humans is a complicated issue that is influenced by elements such as the properties of the compound, the route of administration, and individual physiology. The therapeutic potential of natural products is limited because they are often less bioavailable than synthetic drugs. However, there are many ways to improve the bioavailability of natural products, such as advanced delivery systems or focusing on specific tissues. These organic compounds are able to effectively prevent a variety of viral infections, including those caused by emerging and re-emerging viruses. They have multiple mechanisms of action, targeting multiple steps in the viral life cycle, and can alter the host immune responses. Further clinical studies are needed to confirm their safety and efficacy. Innovative in vitro and in vivo studies are among the avenues for exploring natural products with broad antiviral activity. Discovery of novel natural product derivatives with enhanced antiviral activity and improved bioavailability is a promising avenue of research. The development of innovative natural product delivery technologies, such as nanocarriers, could overcome the bioavailability issues faced by most plant-derived bioactive substances.

Author Contributions

RG and JM conceive the main idea of the review manuscript. RG, ES, CR, GDE, LB, GF, FZ, MF, FM, ES, and JM reviewed the relevant publication using international databases. JM wrote the paper, and LB did the English proofreading. All authors read and approved the manuscript.

Funding

No external funding for this project.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Forterre, P. Defining life: the virus viewpoint. Orig Life Evol Biosph 2010, 40, 151–160. [Google Scholar] [CrossRef]
  2. Caspar, D.L.; Klug, A. Physical principles in the construction of regular viruses. Cold Spring Harb Symp Quant Biol 1962, 27, 1–24. [Google Scholar] [CrossRef]
  3. Wilen, C.B.; Tilton, J.C.; Doms, R.W. HIV: cell binding and entry. Cold Spring Harb Perspect Med 2012, 2. [Google Scholar] [CrossRef]
  4. Zlotnick, A. Theoretical aspects of virus capsid assembly. J Mol Recognit 2005, 18, 479–490. [Google Scholar] [CrossRef] [PubMed]
  5. Palmer, K.J.; Tichelaar, W.; Myers, N.; Burns, N.R.; Butcher, S.J.; Kingsman, A.J.; Fuller, S.D.; Saibil, H.R. Cryo-electron microscopy structure of yeast Ty retrotransposon virus-like particles. J Virol 1997, 71, 6863–6868. [Google Scholar] [CrossRef]
  6. Wilson, D.P. Protruding Features of Viral Capsids Are Clustered on Icosahedral Great Circles. PLoS One 2016, 11, e0152319. [Google Scholar] [CrossRef]
  7. Scheiffele, P.; Rietveld, A.; Wilk, T.; Simons, K. Influenza viruses select ordered lipid domains during budding from the plasma membrane. J Biol Chem 1999, 274, 2038–2044. [Google Scholar] [CrossRef] [PubMed]
  8. Louis, J.M.; Weber, I.T.; Tozser, J.; Clore, G.M.; Gronenborn, A.M. HIV-1 protease: maturation, enzyme specificity, and drug resistance. Adv Pharmacol 2000, 49, 111–146. [Google Scholar] [CrossRef] [PubMed]
  9. Subissi, L.; Posthuma, C.C.; Collet, A.; Zevenhoven-Dobbe, J.C.; Gorbalenya, A.E.; Decroly, E.; Snijder, E.J.; Canard, B.; Imbert, I. One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities. Proc Natl Acad Sci U S A 2014, 111, E3900–3909. [Google Scholar] [CrossRef]
  10. Garcia-Sastre, A.; Egorov, A.; Matassov, D.; Brandt, S.; Levy, D.E.; Durbin, J.E.; Palese, P.; Muster, T. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 1998, 252, 324–330. [Google Scholar] [CrossRef]
  11. Neuman, B.W.; Angelini, M.M.; Buchmeier, M.J. Does form meet function in the coronavirus replicative organelle? Trends Microbiol 2014, 22, 642–647. [Google Scholar] [CrossRef]
  12. Schubert, K.; Karousis, E.D.; Jomaa, A.; Scaiola, A.; Echeverria, B.; Gurzeler, L.A.; Leibundgut, M.; Thiel, V.; Muhlemann, O.; Ban, N. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nat Struct Mol Biol 2020, 27, 959–966. [Google Scholar] [CrossRef] [PubMed]
  13. Drosten, C.; Gunther, S.; Preiser, W.; van der Werf, S.; Brodt, H.R.; Becker, S.; Rabenau, H.; Panning, M.; Kolesnikova, L.; Fouchier, R.A.; et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003, 348, 1967–1976. [Google Scholar] [CrossRef] [PubMed]
  14. Feldmann, H.; Geisbert, T.W. Ebola haemorrhagic fever. Lancet 2011, 377, 849–862. [Google Scholar] [CrossRef]
  15. Taylor, L.H.; Latham, S.M.; Woolhouse, M.E. Risk factors for human disease emergence. Philos Trans R Soc Lond B Biol Sci 2001, 356, 983–989. [Google Scholar] [CrossRef]
  16. Tellier, R.; Li, Y.; Cowling, B.J.; Tang, J.W. Recognition of aerosol transmission of infectious agents: a commentary. BMC Infect Dis 2019, 19, 101. [Google Scholar] [CrossRef]
  17. Morawska, L.; Cao, J. Airborne transmission of SARS-CoV-2: The world should face the reality. Environ Int 2020, 139, 105730. [Google Scholar] [CrossRef]
  18. Tate, J.E.; Burton, A.H.; Boschi-Pinto, C.; Parashar, U.D. ; World Health Organization-Coordinated Global Rotavirus Surveillance, N. Global, Regional, and National Estimates of Rotavirus Mortality in Children <5 Years of Age, 2000-2013. Clin Infect Dis, 2. [CrossRef]
  19. Cohen, M.S.; Chen, Y.Q.; McCauley, M.; Gamble, T.; Hosseinipour, M.C.; Kumarasamy, N.; Hakim, J.G.; Kumwenda, J.; Grinsztejn, B.; Pilotto, J.H.; et al. Antiretroviral Therapy for the Prevention of HIV-1 Transmission. N Engl J Med 2016, 375, 830–839. [Google Scholar] [CrossRef] [PubMed]
  20. Schillie, S.; Vellozzi, C.; Reingold, A.; Harris, A.; Haber, P.; Ward, J.W.; Nelson, N.P. Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2018, 67, 1–31. [Google Scholar] [CrossRef]
  21. Jackson, A.C. Current and future approaches to the therapy of human rabies. Antiviral Res 2013, 99, 61–67. [Google Scholar] [CrossRef] [PubMed]
  22. Guzman, M.G.; Harris, E. Dengue. Lancet 2015, 385, 453–465. [Google Scholar] [CrossRef] [PubMed]
  23. Bhatt, S.; Gething, P.W.; Brady, O.J.; Messina, J.P.; Farlow, A.W.; Moyes, C.L.; Drake, J.M.; Brownstein, J.S.; Hoen, A.G.; Sankoh, O.; et al. The global distribution and burden of dengue. Nature 2013, 496, 504–507. [Google Scholar] [CrossRef] [PubMed]
  24. Saiz, J.C.; Vazquez-Calvo, A.; Blazquez, A.B.; Merino-Ramos, T.; Escribano-Romero, E.; Martin-Acebes, M.A. Zika Virus: the Latest Newcomer. Front Microbiol 2016, 7, 496. [Google Scholar] [CrossRef] [PubMed]
  25. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Kruger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280. [Google Scholar] [CrossRef] [PubMed]
  26. Gambaryan, A.S.; Tuzikov, A.B.; Piskarev, V.E.; Yamnikova, S.S.; Lvov, D.K.; Robertson, J.S.; Bovin, N.V.; Matrosovich, M.N. Specification of receptor-binding phenotypes of influenza virus isolates from different hosts using synthetic sialylglycopolymers: non-egg-adapted human H1 and H3 influenza A and influenza B viruses share a common high binding affinity for 6'-sialyl(N-acetyllactosamine). Virology 1997, 232, 345–350. [Google Scholar] [CrossRef]
  27. Matrosovich, M.; Tuzikov, A.; Bovin, N.; Gambaryan, A.; Klimov, A.; Castrucci, M.R.; Donatelli, I.; Kawaoka, Y. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J Virol 2000, 74, 8502–8512. [Google Scholar] [CrossRef] [PubMed]
  28. White, J.; Kartenbeck, J.; Helenius, A. Membrane fusion activity of influenza virus. EMBO J 1982, 1, 217–222. [Google Scholar] [CrossRef] [PubMed]
  29. Klenk, H.D.; Garten, W. Host cell proteases controlling virus pathogenicity. Trends Microbiol 1994, 2, 39–43. [Google Scholar] [CrossRef]
  30. Hogle, J.M. Poliovirus cell entry: common structural themes in viral cell entry pathways. Annu Rev Microbiol 2002, 56, 677–702. [Google Scholar] [CrossRef]
  31. Lakadamyali, M.; Rust, M.J.; Zhuang, X. Endocytosis of influenza viruses. Microbes and Infection 2004, 6, 929–936. [Google Scholar] [CrossRef]
  32. Hirose, T.; Fujita, K.; Kusumoto, S.; Oki, Y.; Murata, Y.; Sugiyama, T.; Ishida, H.; Shirai, T.; Nakashima, M.; Yamaoka, T.; et al. Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer. Lung Cancer 2016, 93, 69–76. [Google Scholar] [CrossRef] [PubMed]
  33. Hojjat-Farsangi, M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci 2014, 15, 13768–13801. [Google Scholar] [CrossRef] [PubMed]
  34. Wu, Q.; Qian, W.; Sun, X.; Jiang, S. Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. J Hematol Oncol 2022, 15, 143. [Google Scholar] [CrossRef] [PubMed]
  35. Knight, Z.A. Small molecule inhibitors of the PI3-kinase family. Curr Top Microbiol Immunol 2010, 347, 263–278. [Google Scholar] [CrossRef] [PubMed]
  36. Bekerman, E.; Neveu, G.; Shulla, A.; Brannan, J.; Pu, S.Y.; Wang, S.; Xiao, F.; Barouch-Bentov, R.; Bakken, R.R.; Mateo, R.; et al. Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects. J Clin Invest 2017, 127, 1338–1352. [Google Scholar] [CrossRef] [PubMed]
  37. Eaaswarkhanth, M.; Al Madhoun, A.; Al-Mulla, F. Could the D614G substitution in the SARS-CoV-2 spike (S) protein be associated with higher COVID-19 mortality? Int J Infect Dis 2020, 96, 459–460. [Google Scholar] [CrossRef] [PubMed]
  38. Keck, F.; Ataey, P.; Amaya, M.; Bailey, C.; Narayanan, A. Phosphorylation of Single Stranded RNA Virus Proteins and Potential for Novel Therapeutic Strategies. Viruses 2015, 7, 5257–5273. [Google Scholar] [CrossRef]
  39. Kumar, R.; Barua, S.; Tripathi, B.N.; Kumar, N. Role of ROCK signaling in virus replication. Virus Res 2023, 329, 199105. [Google Scholar] [CrossRef] [PubMed]
  40. Chander, Y.; Kumar, R.; Khandelwal, N.; Singh, N.; Shringi, B.N.; Barua, S.; Kumar, N. Role of p38 mitogen-activated protein kinase signalling in virus replication and potential for developing broad spectrum antiviral drugs. Rev Med Virol 2021, 31, 1–16. [Google Scholar] [CrossRef]
  41. Adamson, A.L.; Darr, D.; Holley-Guthrie, E.; Johnson, R.A.; Mauser, A.; Swenson, J.; Kenney, S. Epstein-Barr virus immediate-early proteins BZLF1 and BRLF1 activate the ATF2 transcription factor by increasing the levels of phosphorylated p38 and c-Jun N-terminal kinases. J Virol 2000, 74, 1224–1233. [Google Scholar] [CrossRef]
  42. Sreekanth, G.P.; Yenchitsomanus, P.T.; Limjindaporn, T. Role of mitogen-activated protein kinase signaling in the pathogenesis of dengue virus infection. Cell Signal 2018, 48, 64–68. [Google Scholar] [CrossRef] [PubMed]
  43. Fung, T.S.; Liu, D.X. Activation of the c-Jun NH(2)-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun. Cell Death Dis 2017, 8, 3215. [Google Scholar] [CrossRef] [PubMed]
  44. Voss, K.; Amaya, M.; Mueller, C.; Roberts, B.; Kehn-Hall, K.; Bailey, C.; Petricoin, E., 3rd; Narayanan, A. Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells. Virology 2014, 468-470, 490–503. [Google Scholar] [CrossRef] [PubMed]
  45. Shi, W.; Hou, X.; Peng, H.; Zhang, L.; Li, Y.; Gu, Z.; Jiang, Q.; Shi, M.; Ji, Y.; Jiang, J. MEK/ERK signaling pathway is required for enterovirus 71 replication in immature dendritic cells. Virol J 2014, 11, 227. [Google Scholar] [CrossRef] [PubMed]
  46. Cheng, Y.; Sun, F.; Wang, L.; Gao, M.; Xie, Y.; Sun, Y.; Liu, H.; Yuan, Y.; Yi, W.; Huang, Z.; et al. Virus-induced p38 MAPK activation facilitates viral infection. Theranostics 2020, 10, 12223–12240. [Google Scholar] [CrossRef] [PubMed]
  47. Kumar, N.; Sharma, S.; Kumar, R.; Tripathi, B.N.; Barua, S.; Ly, H.; Rouse, B.T. Host-Directed Antiviral Therapy. Clin Microbiol Rev 2020, 33. [Google Scholar] [CrossRef] [PubMed]
  48. Keating, J.A.; Striker, R. Phosphorylation events during viral infections provide potential therapeutic targets. Rev Med Virol 2012, 22, 166–181. [Google Scholar] [CrossRef] [PubMed]
  49. Chen, J.; Ye, C.; Wan, C.; Li, G.; Peng, L.; Peng, Y.; Fang, R. The Roles of c-Jun N-Terminal Kinase (JNK) in Infectious Diseases. Int J Mol Sci 2021, 22. [Google Scholar] [CrossRef]
  50. Shimojima, M.; Ikeda, Y.; Kawaoka, Y. The mechanism of Axl-mediated Ebola virus infection. J Infect Dis 2007, 196 Suppl 2, S259–263. [Google Scholar] [CrossRef]
  51. Zheng, K.; Kitazato, K.; Wang, Y. Viruses exploit the function of epidermal growth factor receptor. Rev Med Virol 2014, 24, 274–286. [Google Scholar] [CrossRef]
  52. Wang, X.; Huong, S.M.; Chiu, M.L.; Raab-Traub, N.; Huang, E.S. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 2003, 424, 456–461. [Google Scholar] [CrossRef] [PubMed]
  53. Weller, M.L.; Amornphimoltham, P.; Schmidt, M.; Wilson, P.A.; Gutkind, J.S.; Chiorini, J.A. Epidermal growth factor receptor is a co-receptor for adeno-associated virus serotype 6. Nat Med 2010, 16, 662–664. [Google Scholar] [CrossRef] [PubMed]
  54. Kumar, N.; Liang, Y.; Parslow, T.G.; Liang, Y. Receptor tyrosine kinase inhibitors block multiple steps of influenza a virus replication. J Virol 2011, 85, 2818–2827. [Google Scholar] [CrossRef] [PubMed]
  55. Karim, M.; Saul, S.; Ghita, L.; Sahoo, M.K.; Ye, C.; Bhalla, N.; Lo, C.-W.; Jin, J.; Park, J.-G.; Martinez-Gualda, B.; et al. Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies. Antiviral Research 2022, 204, 105367. [Google Scholar] [CrossRef] [PubMed]
  56. Neveu, G.; Ziv-Av, A.; Barouch-Bentov, R.; Berkerman, E.; Mulholland, J.; Einav, S. AP-2-Associated Protein Kinase 1 and Cyclin G-Associated Kinase Regulate Hepatitis C Virus Entry and Are Potential Drug Targets. Journal of Virology 2015, 89, 4387–4404. [Google Scholar] [CrossRef] [PubMed]
  57. Urits, I.; Israel, J.; Hakobyan, H.; Yusin, G.; Lassiter, G.; Fackler, N.; Berger, A.A.; Kassem, H.; Kaye, A.; Viswanath, O. Baricitinib for the treatment of rheumatoid arthritis. Reumatologia 2020, 58, 407–415. [Google Scholar] [CrossRef] [PubMed]
  58. Richardson, P.; Griffin, I.; Tucker, C.; Smith, D.; Oechsle, O.; Phelan, A.; Stebbing, J. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020, 395, e30–e31. [Google Scholar] [CrossRef] [PubMed]
  59. Richardson, P.J.; Stebbing, J. Baricitinib as the treatment of choice for hospitalised individuals with COVID-19. EClinicalMedicine 2022, 49, 101493. [Google Scholar] [CrossRef] [PubMed]
  60. Newman, D.J.; Cragg, G.M. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J Nat Prod 2020, 83, 770–803. [Google Scholar] [CrossRef]
  61. Lu, A.T.; Fei, Z.; Haghani, A.; Robeck, T.R.; Zoller, J.A.; Li, C.Z.; Lowe, R.; Yan, Q.; Zhang, J.; Vu, H.; et al. Universal DNA methylation age across mammalian tissues. Nature Aging, 1038; -6. [Google Scholar] [CrossRef]
  62. Bird, A. Perceptions of epigenetics. Nature 2007, 447, 396–398. [Google Scholar] [CrossRef]
  63. Musselman, C.A.; Lalonde, M.E.; Côté, J.; Kutateladze, T.G. Perceiving the epigenetic landscape through histone readers. Nat Struct Mol Biol 2012, 19, 1218–1227. [Google Scholar] [CrossRef] [PubMed]
  64. Lister, R.; Pelizzola, M.; Dowen, R.H.; Hawkins, R.D.; Hon, G.; Tonti-Filippini, J.; Nery, J.R.; Lee, L.; Ye, Z.; Ngo, Q.M.; et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009, 462, 315–322. [Google Scholar] [CrossRef] [PubMed]
  65. Zhu, J.K. Active DNA demethylation mediated by DNA glycosylases. Annu Rev Genet 2009, 43, 143–166. [Google Scholar] [CrossRef] [PubMed]
  66. Gopalakrishnan, S.; Van Emburgh, B.O.; Robertson, K.D. DNA methylation in development and human disease. Mutat Res 2008, 647, 30–38. [Google Scholar] [CrossRef] [PubMed]
  67. Jin, B.; Tao, Q.; Peng, J.; Soo, H.M.; Wu, W.; Ying, J.; Fields, C.R.; Delmas, A.L.; Liu, X.; Qiu, J.; et al. DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 2008, 17, 690–709. [Google Scholar] [CrossRef] [PubMed]
  68. Zhang, X.; Zhang, Y.; Wang, C.; Wang, X. TET (Ten-eleven translocation) family proteins: structure, biological functions and applications. Signal Transduction and Targeted Therapy 2023, 8, 297. [Google Scholar] [CrossRef] [PubMed]
  69. Horvath, S.; Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics 2018, 19, 371–384. [Google Scholar] [CrossRef]
  70. Feinberg, A.P.; Ohlsson, R.; Henikoff, S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006, 7, 21–33. [Google Scholar] [CrossRef]
  71. Kuo, M.H.; Allis, C.D. Roles of histone acetyltransferases and deacetylases in gene regulation. Bioessays 1998, 20, 615–626. [Google Scholar] [CrossRef]
  72. Dokmanovic, M.; Clarke, C.; Marks, P.A. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 2007, 5, 981–989. [Google Scholar] [CrossRef]
  73. Blackledge, N.P.; Klose, R.J. The molecular principles of gene regulation by Polycomb repressive complexes. Nat Rev Mol Cell Biol 2021, 22, 815–833. [Google Scholar] [CrossRef] [PubMed]
  74. Healey, M.A.; Hu, R.; Beck, A.H.; Collins, L.C.; Schnitt, S.J.; Tamimi, R.M.; Hazra, A. Association of H3K9me3 and H3K27me3 repressive histone marks with breast cancer subtypes in the Nurses' Health Study. Breast Cancer Res Treat 2014, 147, 639–651. [Google Scholar] [CrossRef] [PubMed]
  75. Handy, D.E.; Castro, R.; Loscalzo, J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation 2011, 123, 2145–2156. [Google Scholar] [CrossRef] [PubMed]
  76. Li, S.; Mason, C.E. The pivotal regulatory landscape of RNA modifications. Annu Rev Genomics Hum Genet 2014, 15, 127–150. [Google Scholar] [CrossRef] [PubMed]
  77. Hombach, S.; Kretz, M. Non-coding RNAs: Classification, Biology and Functioning. Adv Exp Med Biol 2016, 937, 3–17. [Google Scholar] [CrossRef] [PubMed]
  78. Lujambio, A.; Lowe, S.W. The microcosmos of cancer. Nature 2012, 482, 347–355. [Google Scholar] [CrossRef] [PubMed]
  79. Kwa, F.A.A.; Jackson, D.E. Manipulating the epigenome for the treatment of disorders with thrombotic complications. Drug Discovery Today 2018, 23, 719–726. [Google Scholar] [CrossRef] [PubMed]
  80. Silva, J.; Tavares, V.; Afonso, A.; Garcia, J.; Cerqueira, F.; Medeiros, R. Plasmatic MicroRNAs and Treatment Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer: A Hospital-Based Cohort Study and In Silico Analysis. International Journal of Molecular Sciences 2023, 24. [Google Scholar] [CrossRef] [PubMed]
  81. Li, Y.; He, Q.; Wen, X.; Hong, X.; Yang, X.; Tang, X.; Zhang, P.; Lei, Y.; Sun, Y.; Zhang, J.; et al. EZH2-DNMT1-mediated epigenetic silencing of miR-142-3p promotes metastasis through targeting ZEB2 in nasopharyngeal carcinoma. Cell Death & Differentiation 2019, 26, 1089–1106. [Google Scholar] [CrossRef]
  82. Chhabra, R. miRNA and methylation: a multifaceted liaison. Chembiochem 2015, 16, 195–203. [Google Scholar] [CrossRef]
  83. Duursma, A.M.; Kedde, M.; Schrier, M.; le Sage, C.; Agami, R. miR-148 targets human DNMT3b protein coding region. Rna 2008, 14, 872–877. [Google Scholar] [CrossRef] [PubMed]
  84. Liao, X.; Zhou, Z.; Zhang, X. Effects of miR-195-5p on cell proliferation and apoptosis in gestational diabetes mellitus via targeting EZH2. Mol Med Rep 2020, 22, 803–809. [Google Scholar] [CrossRef] [PubMed]
  85. Portela, A.; Esteller, M. Epigenetic modifications and human disease. Nat Biotechnol 2010, 28, 1057–1068. [Google Scholar] [CrossRef] [PubMed]
  86. Obata, Y.; Furusawa, Y.; Hase, K. Epigenetic modifications of the immune system in health and disease. Immunol Cell Biol 2015, 93, 226–232. [Google Scholar] [CrossRef] [PubMed]
  87. Smale, S.T.; Tarakhovsky, A.; Natoli, G. Chromatin contributions to the regulation of innate immunity. Annu Rev Immunol 2014, 32, 489–511. [Google Scholar] [CrossRef] [PubMed]
  88. Tsai, K.; Cullen, B.R. Epigenetic and epitranscriptomic regulation of viral replication. Nat Rev Microbiol 2020, 18, 559–570. [Google Scholar] [CrossRef]
  89. Tsai, K.; Cullen, B.R. Epigenetic and epitranscriptomic regulation of viral replication. Nature Reviews Microbiology 2020, 18, 559–570. [Google Scholar] [CrossRef] [PubMed]
  90. Knipe, D.M. Nuclear sensing of viral DNA, epigenetic regulation of herpes simplex virus infection, and innate immunity. Virology 2015, 479-480, 153–159. [Google Scholar] [CrossRef] [PubMed]
  91. Knipe, D.M.; Raja, P.; Lee, J. Viral gene products actively promote latent infection by epigenetic silencing mechanisms. Curr Opin Virol 2017, 23, 68–74. [Google Scholar] [CrossRef]
  92. Tsai, K.; Jaguva Vasudevan, A.A.; Martinez Campos, C.; Emery, A.; Swanstrom, R.; Cullen, B.R. Acetylation of Cytidine Residues Boosts HIV-1 Gene Expression by Increasing Viral RNA Stability. Cell Host Microbe 2020, 28, 306–312. [Google Scholar] [CrossRef]
  93. Kee, J.; Thudium, S.; Renner, D.M.; Glastad, K.; Palozola, K.; Zhang, Z.; Li, Y.; Lan, Y.; Cesare, J.; Poleshko, A.; et al. SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature 2022, 610, 381–388. [Google Scholar] [CrossRef] [PubMed]
  94. Jung, J.K.; Arora, P.; Pagano, J.S.; Jang, K.L. Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway. Cancer Res 2007, 67, 5771–5778. [Google Scholar] [CrossRef] [PubMed]
  95. Liang, Y.; Vogel, J.L.; Narayanan, A.; Peng, H.; Kristie, T.M. Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nat Med 2009, 15, 1312–1317. [Google Scholar] [CrossRef] [PubMed]
  96. Schneider, W.M.; Chevillotte, M.D.; Rice, C.M. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014, 32, 513–545. [Google Scholar] [CrossRef] [PubMed]
  97. García-Sastre, A.; Biron, C.A. Type 1 interferons and the virus-host relationship: a lesson in détente. Science 2006, 312, 879–882. [Google Scholar] [CrossRef] [PubMed]
  98. Menachery, V.D.; Eisfeld, A.J.; Schafer, A.; Josset, L.; Sims, A.C.; Proll, S.; Fan, S.; Li, C.; Neumann, G.; Tilton, S.C.; et al. Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. mBio 2014, 5, e01174–01114. [Google Scholar] [CrossRef] [PubMed]
  99. Chen, Y.; Liu, Q.; Guo, D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol 2020, 92, 418–423. [Google Scholar] [CrossRef] [PubMed]
  100. Cole, J.; Morris, P.; Dickman, M.J.; Dockrell, D.H. The therapeutic potential of epigenetic manipulation during infectious diseases. Pharmacol Ther 2016, 167, 85–99. [Google Scholar] [CrossRef] [PubMed]
  101. Vivekanandan, P.; Daniel, H.D.; Kannangai, R.; Martinez-Murillo, F.; Torbenson, M. Hepatitis B virus replication induces methylation of both host and viral DNA. J Virol 2010, 84, 4321–4329. [Google Scholar] [CrossRef]
  102. Zheng, D.L.; Zhang, L.; Cheng, N.; Xu, X.; Deng, Q.; Teng, X.M.; Wang, K.S.; Zhang, X.; Huang, J.; Han, Z.G. Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. J Hepatol 2009, 50, 377–387. [Google Scholar] [CrossRef]
  103. Laurson, J.; Khan, S.; Chung, R.; Cross, K.; Raj, K. Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. Carcinogenesis 2010, 31, 918–926. [Google Scholar] [CrossRef] [PubMed]
  104. Burgers, W.A.; Blanchon, L.; Pradhan, S.; de Launoit, Y.; Kouzarides, T.; Fuks, F. Viral oncoproteins target the DNA methyltransferases. Oncogene 2007, 26, 1650–1655. [Google Scholar] [CrossRef] [PubMed]
  105. Holland, D.; Hoppe-Seyler, K.; Schuller, B.; Lohrey, C.; Maroldt, J.; Dürst, M.; Hoppe-Seyler, F. Activation of the enhancer of zeste homologue 2 gene by the human papillomavirus E7 oncoprotein. Cancer Res 2008, 68, 9964–9972. [Google Scholar] [CrossRef] [PubMed]
  106. Gil, J.; Peters, G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 2006, 7, 667–677. [Google Scholar] [CrossRef] [PubMed]
  107. Toyooka, S.; Pass, H.I.; Shivapurkar, N.; Fukuyama, Y.; Maruyama, R.; Toyooka, K.O.; Gilcrease, M.; Farinas, A.; Minna, J.D.; Gazdar, A.F. Aberrant methylation and simian virus 40 tag sequences in malignant mesothelioma. Cancer Res 2001, 61, 5727–5730. [Google Scholar] [PubMed]
  108. Slack, A.; Cervoni, N.; Pinard, M.; Szyf, M. DNA methyltransferase is a downstream effector of cellular transformation triggered by simian virus 40 large T antigen. J Biol Chem 1999, 274, 10105–10112. [Google Scholar] [CrossRef]
  109. Ferrari, R.; Pellegrini, M.; Horwitz, G.A.; Xie, W.; Berk, A.J.; Kurdistani, S.K. Epigenetic reprogramming by adenovirus e1a. Science 2008, 321, 1086–1088. [Google Scholar] [CrossRef]
  110. Li, J.; Hao, D.; Wang, L.; Wang, H.; Wang, Y.; Zhao, Z.; Li, P.; Deng, C.; Di, L.J. Epigenetic targeting drugs potentiate chemotherapeutic effects in solid tumor therapy. Sci Rep 2017, 7, 4035. [Google Scholar] [CrossRef] [PubMed]
  111. El Baba, R.; Herbein, G. Management of epigenomic networks entailed in coronavirus infections and COVID-19. Clin Epigenetics 2020, 12, 118. [Google Scholar] [CrossRef]
  112. Zheng, B.; Zhou, J.; Wang, H. Host microRNAs and exosomes that modulate influenza virus infection. Virus Res 2020, 279, 197885. [Google Scholar] [CrossRef]
  113. Moghoofei, M.; Najafipour, S.; Mostafaei, S.; Tavakoli, A.; Bokharaei-Salim, F.; Ghorbani, S.; Javanmard, D.; Ghaffari, H.; Monavari, S.H. MicroRNAs Profiling in HIV, HCV, and HIV/HCV Co-Infected Patients. Curr HIV Res 2021, 19, 27–34. [Google Scholar] [CrossRef]
  114. Kunden, R.D.; Khan, J.Q.; Ghezelbash, S.; Wilson, J.A. The Role of the Liver-Specific microRNA, miRNA-122 in the HCV Replication Cycle. Int J Mol Sci 2020, 21. [Google Scholar] [CrossRef] [PubMed]
  115. Jopling, C.L.; Yi, M.; Lancaster, A.M.; Lemon, S.M.; Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 2005, 309, 1577–1581. [Google Scholar] [CrossRef]
  116. Panigrahi, M.; Thibault, P.A.; Wilson, J.A. MicroRNA 122 Affects both the Initiation and the Maintenance of Hepatitis C Virus Infections. J Virol 2022, 96, e0190321. [Google Scholar] [CrossRef]
  117. Yousefpouran, S.; Mostafaei, S.; Manesh, P.V.; Iranifar, E.; Bokharaei-Salim, F.; Nahand, J.S.; Mirzaei, H.; Taran, M.; Babaei, F.; Sayad, B.; et al. The assessment of selected MiRNAs profile in HIV, HBV, HCV, HIV/HCV, HIV/HBV Co-infection and elite controllers for determination of biomarker. Microb Pathog 2020, 147, 104355. [Google Scholar] [CrossRef]
  118. Haneklaus, M.; Gerlic, M.; O'Neill, L.A.; Masters, S.L. miR-223: infection, inflammation and cancer. J Intern Med 2013, 274, 215–226. [Google Scholar] [CrossRef] [PubMed]
  119. Morales, L.; Oliveros, J.C.; Enjuanes, L.; Sola, I. Contribution of Host miRNA-223-3p to SARS-CoV-Induced Lung Inflammatory Pathology. mBio 2022, 13, e0313521. [Google Scholar] [CrossRef] [PubMed]
  120. Tycowski, K.T.; Guo, Y.E.; Lee, N.; Moss, W.N.; Vallery, T.K.; Xie, M.; Steitz, J.A. Viral noncoding RNAs: more surprises. Genes Dev 2015, 29, 567–584. [Google Scholar] [CrossRef]
  121. Cazalla, D.; Yario, T.; Steitz, J.A. Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 2010, 328, 1563–1566. [Google Scholar] [CrossRef]
  122. Guo, Y.E.; Riley, K.J.; Iwasaki, A.; Steitz, J.A. Alternative capture of noncoding RNAs or protein-coding genes by herpesviruses to alter host T cell function. Mol Cell 2014, 54, 67–79. [Google Scholar] [CrossRef]
  123. Abedini, M.; Zhang, C. Performance assessment of concrete and steel material models in ls-dyna for enhanced numerical simulation, a state of the art review. Archives of Computational Methods in Engineering 2021, 28, 2921–2942. [Google Scholar] [CrossRef]
  124. Kitazato, K.; Wang, Y.; Kobayashi, N. Viral infectious disease and natural products with antiviral activity. Drug Discov Ther 2007, 1, 14–22. [Google Scholar] [PubMed]
  125. Abookleesh, F.L.; Al-Anzi, B.S.; Ullah, A. Potential Antiviral Action of Alkaloids. Molecules 2022, 27, 903. [Google Scholar] [CrossRef] [PubMed]
  126. Denaro, M.; Smeriglio, A.; Barreca, D.; De Francesco, C.; Occhiuto, C.; Milano, G.; Trombetta, D. Antiviral activity of plants and their isolated bioactive compounds: An update. Phytother Res 2020, 34, 742–768. [Google Scholar] [CrossRef] [PubMed]
  127. Behl, T.; Rocchetti, G.; Chadha, S.; Zengin, G.; Bungau, S.; Kumar, A.; Mehta, V.; Uddin, M.S.; Khullar, G.; Setia, D.; et al. Phytochemicals from Plant Foods as Potential Source of Antiviral Agents: An Overview. Pharmaceuticals (Basel) 2021, 14. [Google Scholar] [CrossRef] [PubMed]
  128. Jassim, S.A.; Naji, M.A. Novel antiviral agents: a medicinal plant perspective. J Appl Microbiol 2003, 95, 412–427. [Google Scholar] [CrossRef] [PubMed]
  129. Astani, A.; Reichling, J.; Schnitzler, P. Screening for antiviral activities of isolated compounds from essential oils. Evid Based Complement Alternat Med 2011, 2011, 253643. [Google Scholar] [CrossRef] [PubMed]
  130. Gavanji, S.; Sayedipour, S.S.; Larki, B.; Bakhtari, A. Antiviral activity of some plant oils against herpes simplex virus type 1 in Vero cell culture. Journal of Acute Medicine 2015, 5, 62–68. [Google Scholar] [CrossRef]
  131. Feriotto, G.; Marchetti, N.; Costa, V.; Beninati, S.; Tagliati, F.; Mischiati, C. Chemical Composition of Essential Oils from Thymus vulgaris, Cymbopogon citratus, and Rosmarinus officinalis, and Their Effects on the HIV-1 Tat Protein Function. Chem Biodivers 2018, 15. [Google Scholar] [CrossRef]
  132. Mori, K.; Obossou, E.K.; Suwa, S.; Miura, S.; Oh, S.-H.; Jinbo, N.; Ishibashi, Y.; Shikamoto, Y.; Hosono, T.; Toda, T. Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Inhibitory Effect of Cymbopogon Nardus Essential Oil.
  133. Ma, L.; Yao, L. Antiviral Effects of Plant-Derived Essential Oils and Their Components: An Updated Review. Molecules 2020, 25. [Google Scholar] [CrossRef]
  134. Naithani, R.; Huma, L.C.; Holland, L.E.; Shukla, D.; McCormick, D.L.; Mehta, R.G.; Moriarty, R.M. Antiviral activity of phytochemicals: a comprehensive review. Mini Rev Med Chem 2008, 8, 1106–1133. [Google Scholar] [CrossRef] [PubMed]
  135. Choi, H.J.; Lim, C.H.; Song, J.H.; Baek, S.H.; Kwon, D.H. Antiviral activity of raoulic acid from Raoulia australis against Picornaviruses. Phytomedicine 2009, 16, 35–39. [Google Scholar] [CrossRef] [PubMed]
  136. Lin, L.T.; Chen, T.Y.; Lin, S.C.; Chung, C.Y.; Lin, T.C.; Wang, G.H.; Anderson, R.; Lin, C.C.; Richardson, C.D. Broad-spectrum antiviral activity of chebulagic acid and punicalagin against viruses that use glycosaminoglycans for entry. BMC Microbiol 2013, 13, 187. [Google Scholar] [CrossRef] [PubMed]
  137. Cotin, S.; Calliste, C.A.; Mazeron, M.C.; Hantz, S.; Duroux, J.L.; Rawlinson, W.D.; Ploy, M.C.; Alain, S. Eight flavonoids and their potential as inhibitors of human cytomegalovirus replication. Antiviral Res 2012, 96, 181–186. [Google Scholar] [CrossRef] [PubMed]
  138. Lyu, S.Y.; Rhim, J.Y.; Park, W.B. Antiherpetic activities of flavonoids against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro. Arch Pharm Res 2005, 28, 1293–1301. [Google Scholar] [CrossRef] [PubMed]
  139. Kim, D.E.; Min, J.S.; Jang, M.S.; Lee, J.Y.; Shin, Y.S.; Song, J.H.; Kim, H.R.; Kim, S.; Jin, Y.H.; Kwon, S. Natural Bis-Benzylisoquinoline Alkaloids-Tetrandrine, Fangchinoline, and Cepharanthine, Inhibit Human Coronavirus OC43 Infection of MRC-5 Human Lung Cells. Biomolecules 2019, 9. [Google Scholar] [CrossRef] [PubMed]
  140. Luganini, A.; Mercorelli, B.; Messa, L.; Palù, G.; Gribaudo, G.; Loregian, A. The isoquinoline alkaloid berberine inhibits human cytomegalovirus replication by interfering with the viral Immediate Early-2 (IE2) protein transactivating activity. Antiviral Res 2019, 164, 52–60. [Google Scholar] [CrossRef] [PubMed]
  141. Song, S.; Qiu, M.; Chu, Y.; Chen, D.; Wang, X.; Su, A.; Wu, Z. Downregulation of cellular c-Jun N-terminal protein kinase and NF-κB activation by berberine may result in inhibition of herpes simplex virus replication. Antimicrob Agents Chemother 2014, 58, 5068–5078. [Google Scholar] [CrossRef] [PubMed]
  142. Gómez, L.A.; Stashenko, E.; Ocazionez, R.E. Comparative study on in vitro activities of citral, limonene and essential oils from Lippia citriodora and L. alba on yellow fever virus. Nat Prod Commun 2013, 8, 249–252. [Google Scholar] [CrossRef]
  143. Haddad, J.G.; Picard, M.; Bénard, S.; Desvignes, C.; Desprès, P.; Diotel, N.; El Kalamouni, C. Ayapana triplinervis Essential Oil and Its Main Component Thymohydroquinone Dimethyl Ether Inhibit Zika Virus at Doses Devoid of Toxicity in Zebrafish. Molecules 2019, 24, 3447. [Google Scholar] [CrossRef]
  144. Vimalanathan, S.; Hudson, J.B. Anti-influenza virus activity of essential oils and vapors. American Journal of Essential Oils and Natural Products 2014, 2, 47–53. [Google Scholar]
  145. Mokni, R.E.; Youssef, F.S.; Jmii, H.; Khmiri, A.; Bouazzi, S.; Jlassi, I.; Jaidane, H.; Dhaouadi, H.; Ashour, M.L.; Hammami, S. The Essential Oil of Tunisian Dysphania ambrosioides and its Antimicrobial and Antiviral Properties. Journal of Essential Oil Bearing Plants 2019, 22, 282–294. [Google Scholar] [CrossRef]
  146. Elaissi, A.; Rouis, Z.; Salem, N.A.; Mabrouk, S.; ben Salem, Y.; Salah, K.B.; Aouni, M.; Farhat, F.; Chemli, R.; Harzallah-Skhiri, F.; et al. Chemical composition of 8 eucalyptus species' essential oils and the evaluation of their antibacterial, antifungal and antiviral activities. BMC Complement Altern Med 2012, 12, 81. [Google Scholar] [CrossRef] [PubMed]
  147. Nabaweya, A. Ibrahim, S.S.E.-H., Magdy M. D. Mohammed, Mohamed A. Farid, Nayera A. M. AbdelWahed, Mohamed A. Ali, Eman A. W. El-Abd. Chemical Composition, Antiviral against avian Influenza (H5N1) Virus and Antimicrobial activities of the Essential Oils of the Leaves and Fruits of Fortunella margarita, Lour. Swingle, Growing in Egypt, 5: 1: 2015; Vol. Volume, 2015; 5. [Google Scholar]
  148. Sharifi-Rad, J.; Salehi, B.; Schnitzler, P.; Ayatollahi, S.A.; Kobarfard, F.; Fathi, M.; Eisazadeh, M.; Sharifi-Rad, M. Susceptibility of herpes simplex virus type 1 to monoterpenes thymol, carvacrol, p-cymene and essential oils of Sinapis arvensis L., Lallemantia royleana Benth. and Pulicaria vulgaris Gaertn. Cell Mol Biol (Noisy-le-grand) 2017, 63, 42–47. [Google Scholar] [CrossRef] [PubMed]
  149. Pilau, M.R.; Alves, S.H.; Weiblen, R.; Arenhart, S.; Cueto, A.P.; Lovato, L.T. Antiviral activity of the Lippia graveolens (Mexican oregano) essential oil and its main compound carvacrol against human and animal viruses. Braz J Microbiol 2011, 42, 1616–1624. [Google Scholar] [CrossRef] [PubMed]
  150. Garozzo, A.; Timpanaro, R.; Stivala, A.; Bisignano, G.; Castro, A. Activity of Melaleuca alternifolia (tea tree) oil on Influenza virus A/PR/8: study on the mechanism of action. Antiviral Res 2011, 89, 83–88. [Google Scholar] [CrossRef] [PubMed]
  151. Civitelli, L.; Panella, S.; Marcocci, M.E.; De Petris, A.; Garzoli, S.; Pepi, F.; Vavala, E.; Ragno, R.; Nencioni, L.; Palamara, A.T.; et al. In vitro inhibition of herpes simplex virus type 1 replication by Mentha suaveolens essential oil and its main component piperitenone oxide. Phytomedicine 2014, 21, 857–865. [Google Scholar] [CrossRef] [PubMed]
  152. da Silva, J.K.R.; Figueiredo, P.L.B.; Byler, K.G.; Setzer, W.N. Essential Oils as Antiviral Agents, Potential of Essential Oils to Treat SARS-CoV-2 Infection: An In-Silico Investigation. International Journal of Molecular Sciences 2020, 21, 3426. [Google Scholar] [CrossRef] [PubMed]
  153. Cagno, V.; Sgorbini, B.; Sanna, C.; Cagliero, C.; Ballero, M.; Civra, A.; Donalisio, M.; Bicchi, C.; Lembo, D.; Rubiolo, P. In vitro anti-herpes simplex virus-2 activity of Salvia desoleana Atzei & V. Picci essential oil. PLoS One 2017, 12, e0172322. [Google Scholar] [CrossRef]
  154. Toujani, M.M.; Rittà, M.; Civra, A.; Genovese, S.; Epifano, F.; Ghram, A.; Lembo, D.; Donalisio, M. Inhibition of HSV-2 infection by pure compounds from Thymus capitatus extract in vitro. Phytother Res 2018, 32, 1555–1563. [Google Scholar] [CrossRef]
  155. Shin, W.J.; Lee, K.H.; Park, M.H.; Seong, B.L. Broad-spectrum antiviral effect of Agrimonia pilosa extract on influenza viruses. Microbiol Immunol 2010, 54, 11–19. [Google Scholar] [CrossRef] [PubMed]
  156. Rezazadeh, F.; Moshaverinia, M.; Motamedifar, M.; Alyaseri, M. Assessment of Anti HSV-1 Activity of Aloe Vera Gel Extract: an In Vitro Study. J Dent (Shiraz) 2016, 17, 49–54. [Google Scholar] [PubMed]
  157. Makau, J.N.; Watanabe, K.; Mohammed, M.M.D.; Nishida, N. Antiviral Activity of Peanut (Arachis hypogaea L.) Skin Extract Against Human Influenza Viruses. J Med Food 2018, 21, 777–784. [Google Scholar] [CrossRef] [PubMed]
  158. Namazi, R.; Zabihollahi, R.; Behbahani, M.; Rezaei, A. Inhibitory Activity of Avicennia marina, a Medicinal Plant in Persian Folk Medicine, against HIV and HSV. Iran J Pharm Res 2013, 12, 435–443. [Google Scholar] [PubMed]
  159. Prinsloo, G.; Marokane, C.K.; Street, R.A. Anti-HIV activity of southern African plants: Current developments, phytochemistry and future research. Journal of ethnopharmacology 2018, 210, 133–155. [Google Scholar] [CrossRef] [PubMed]
  160. Mushi, N.F.; Mbwambo, Z.H.; Innocent, E.; Tewtrakul, S. Antibacterial, anti-HIV-1 protease and cytotoxic activities of aqueous ethanolic extracts from Combretum adenogonium Steud. Ex A. Rich (Combretaceae). BMC Complementary and Alternative Medicine 2012, 12, 163. [Google Scholar] [CrossRef] [PubMed]
  161. Churqui, M.P.; Lind, L.; Thörn, K.; Svensson, A.; Savolainen, O.; Aranda, K.T.; Eriksson, K. Extracts of Equisetum giganteum L and Copaifera reticulate Ducke show strong antiviral activity against the sexually transmitted pathogen herpes simplex virus type 2. Journal of ethnopharmacology 2018, 210, 192–197. [Google Scholar] [CrossRef] [PubMed]
  162. Lavoie, S.; Côté, I.; Pichette, A.; Gauthier, C.; Ouellet, M.; Nagau-Lavoie, F.; Mshvildadze, V.; Legault, J. Chemical composition and anti-herpes simplex virus type 1 (HSV-1) activity of extracts from Cornus canadensis. BMC Complement Altern Med 2017, 17, 123. [Google Scholar] [CrossRef]
  163. Hossan, M.S.; Fatima, A.; Rahmatullah, M.; Khoo, T.J.; Nissapatorn, V.; Galochkina, A.V.; Slita, A.V.; Shtro, A.A.; Nikolaeva, Y.; Zarubaev, V.V.; et al. Antiviral activity of Embelia ribes Burm. f. against influenza virus in vitro. Arch Virol 2018, 163, 2121–2131. [Google Scholar] [CrossRef]
  164. Cho, W.K.; Weeratunga, P.; Lee, B.H.; Park, J.S.; Kim, C.J.; Ma, J.Y.; Lee, J.S. Epimedium koreanum Nakai displays broad spectrum of antiviral activity in vitro and in vivo by inducing cellular antiviral state. Viruses 2015, 7, 352–377. [Google Scholar] [CrossRef]
  165. Derksen, A.; Kühn, J.; Hafezi, W.; Sendker, J.; Ehrhardt, C.; Ludwig, S.; Hensel, A. Antiviral activity of hydroalcoholic extract from Eupatorium perfoliatum L. against the attachment of influenza A virus. Journal of ethnopharmacology 2016, 188, 144–152. [Google Scholar] [CrossRef] [PubMed]
  166. Gyuris, A.; Szlávik, L.; Minárovits, J.; Vasas, A.; Molnár, J.; Hohmann, J. Antiviral activities of extracts of Euphorbia hirta L. against HIV-1, HIV-2 and SIVmac251. In Vivo 2009, 23, 429–432. [Google Scholar] [PubMed]
  167. Ghosh, M.; Civra, A.; Rittà, M.; Cagno, V.; Mavuduru, S.G.; Awasthi, P.; Lembo, D.; Donalisio, M. Ficus religiosa L. bark extracts inhibit infection by herpes simplex virus type 2 in vitro. Arch Virol 2016, 161, 3509–3514. [Google Scholar] [CrossRef] [PubMed]
  168. Bonvicini, F.; Lianza, M.; Mandrone, M.; Poli, F.; Gentilomi, G.A.; Antognoni, F. Hemidesmus indicus (L.) R. Br. extract inhibits the early step of herpes simplex type 1 and type 2 replication. New Microbiol 2018, 41, 187–194. [Google Scholar] [PubMed]
  169. Shoji, M.; Woo, S.Y.; Masuda, A.; Win, N.N.; Ngwe, H.; Takahashi, E.; Kido, H.; Morita, H.; Ito, T.; Kuzuhara, T. Anti-influenza virus activity of extracts from the stems of Jatropha multifida Linn. collected in Myanmar. BMC Complement Altern Med 2017, 17, 96. [Google Scholar] [CrossRef] [PubMed]
  170. Ho, J.Y.; Chang, H.W.; Lin, C.F.; Liu, C.J.; Hsieh, C.F.; Horng, J.T. Characterization of the anti-influenza activity of the Chinese herbal plant Paeonia lactiflora. Viruses 2014, 6, 1861–1875. [Google Scholar] [CrossRef]
  171. Ojha, D.; Das, R.; Sobia, P.; Dwivedi, V.; Ghosh, S.; Samanta, A.; Chattopadhyay, D. Pedilanthus tithymaloides Inhibits HSV Infection by Modulating NF-κB Signaling. PLoS One 2015, 10, e0139338. [Google Scholar] [CrossRef] [PubMed]
  172. Oh, C.; Price, J.; Brindley, M.A.; Widrlechner, M.P.; Qu, L.; McCoy, J.A.; Murphy, P.; Hauck, C.; Maury, W. Inhibition of HIV-1 infection by aqueous extracts of Prunella vulgaris L. Virol J 2011, 8, 188. [Google Scholar] [CrossRef] [PubMed]
  173. Bisignano, C.; Mandalari, G.; Smeriglio, A.; Trombetta, D.; Pizzo, M.M.; Pennisi, R.; Sciortino, M.T. Almond Skin Extracts Abrogate HSV-1 Replication by Blocking Virus Binding to the Cell. Viruses 2017, 9. [Google Scholar] [CrossRef]
  174. Karimi, A.; Rafieian-Kopaei, M.; Moradi, M.T.; Alidadi, S. Anti-Herpes Simplex Virus Type-1 Activity and Phenolic Content of Crude Ethanol Extract and Four Corresponding Fractions of Quercus brantii L Acorn. J Evid Based Complementary Altern Med 2017, 22, 455–461. [Google Scholar] [CrossRef]
  175. Reichling, J.; Neuner, A.; Sharaf, M.; Harkenthal, M.; Schnitzler, P. Antiviral activity of Rhus aromatica (fragrant sumac) extract against two types of herpes simplex viruses in cell culture. Pharmazie 2009, 64, 538–541. [Google Scholar] [PubMed]
  176. Nocchi, S.R.; Companhoni, M.V.; de Mello, J.C.; Dias Filho, B.P.; Nakamura, C.V.; Carollo, C.A.; Silva, D.B.; Ueda-Nakamura, T. Antiviral Activity of Crude Hydroethanolic Extract from Schinus terebinthifolia against Herpes simplex Virus Type 1. Planta Med 2017, 83, 509–518. [Google Scholar] [CrossRef]
  177. Di Sotto, A.; Di Giacomo, S.; Amatore, D.; Locatelli, M.; Vitalone, A.; Toniolo, C.; Rotino, G.L.; Lo Scalzo, R.; Palamara, A.T.; Marcocci, M.E.; et al. A Polyphenol Rich Extract from Solanum melongena L. DR2 Peel Exhibits Antioxidant Properties and Anti-Herpes Simplex Virus Type 1 Activity In Vitro. Molecules 2018, 23. [Google Scholar] [CrossRef] [PubMed]
  178. Boff, L.; Silva, I.T.; Argenta, D.F.; Farias, L.M.; Alvarenga, L.F.; Pádua, R.M.; Braga, F.C.; Leite, J.P.; Kratz, J.M.; Simões, C.M. Strychnos pseudoquina A. St. Hil.: a Brazilian medicinal plant with promising in vitro antiherpes activity. J Appl Microbiol 2016, 121, 1519–1529. [Google Scholar] [CrossRef] [PubMed]
  179. Benassi-Zanqueta, É.; Marques, C.F.; Valone, L.M.; Pellegrini, B.L.; Bauermeister, A.; Ferreira, I.C.P.; Lopes, N.P.; Nakamura, C.V.; Dias Filho, B.P.; Natali, M.R.M.; et al. Evaluation of anti-HSV-1 activity and toxicity of hydroethanolic extract of Tanacetum parthenium (L.) Sch.Bip. (Asteraceae). Phytomedicine 2019, 55, 249–254. [Google Scholar] [CrossRef]
  180. Hsieh, C.F.; Chen, Y.L.; Lin, C.F.; Ho, J.Y.; Huang, C.H.; Chiu, C.H.; Hsieh, P.W.; Horng, J.T. An extract from Taxodium distichum targets hemagglutinin- and neuraminidase-related activities of influenza virus in vitro. Sci Rep 2016, 6, 36015. [Google Scholar] [CrossRef]
  181. Donalisio, M.; Cagno, V.; Civra, A.; Gibellini, D.; Musumeci, G.; Rittà, M.; Ghosh, M.; Lembo, D. The traditional use of Vachellia nilotica for sexually transmitted diseases is substantiated by the antiviral activity of its bark extract against sexually transmitted viruses. Journal of ethnopharmacology 2018, 213, 403–408. [Google Scholar] [CrossRef]
  182. Hafidh, R.R.; Abdulamir, A.S.; Abu Bakar, F.; Sekawi, Z.; Jahansheri, F.; Jalilian, F.A. Novel antiviral activity of mung bean sprouts against respiratory syncytial virus and herpes simplex virus -1: an in vitro study on virally infected Vero and MRC-5 cell lines. BMC Complement Altern Med 2015, 15, 179. [Google Scholar] [CrossRef]
  183. Khole, S.; Mittal, S.; Jagadish, N.; Ghosh, D.; Gadgil, V.; Sinkar, V.; Ghaskadbi, S. Andrographolide enhances redox status of liver cells by regulating microRNA expression. Free Radical Biology and Medicine 2019, 130, 397–407. [Google Scholar] [CrossRef]
  184. Li, F.; Khanom, W.; Sun, X.; Paemanee, A.; Roytrakul, S.; Wang, D.; Smith, D.R.; Zhou, G.C. Andrographolide and Its 14-Aryloxy Analogues Inhibit Zika and Dengue Virus Infection. Molecules 2020, 25. [Google Scholar] [CrossRef]
  185. Latif, R.; Wang, C.Y. Andrographolide as a potent and promising antiviral agent. Chin J Nat Med 2020, 18, 760–769. [Google Scholar] [CrossRef] [PubMed]
  186. Gupta, S.; Mishra, K.P.; Ganju, L. Broad-spectrum antiviral properties of andrographolide. Arch Virol 2017, 162, 611–623. [Google Scholar] [CrossRef] [PubMed]
  187. Malat, P.; Ekalaksananan, T.; Heawchaiyaphum, C.; Suebsasana, S.; Roytrakul, S.; Yingchutrakul, Y.; Pientong, C. Andrographolide Inhibits Epstein-Barr Virus Lytic Reactivation in EBV-Positive Cancer Cell Lines through the Modulation of Epigenetic-Related Proteins. Molecules 2022, 27. [Google Scholar] [CrossRef] [PubMed]
  188. Ding, Y.; Chen, L.; Wu, W.; Yang, J.; Yang, Z.; Liu, S. Andrographolide inhibits influenza A virus-induced inflammation in a murine model through NF-κB and JAK-STAT signaling pathway. Microbes Infect 2017, 19, 605–615. [Google Scholar] [CrossRef] [PubMed]
  189. Pandey, M.; Kaur, P.; Shukla, S.; Abbas, A.; Fu, P.; Gupta, S. Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: in vitro and in vivo study. Mol Carcinog 2012, 51, 952–962. [Google Scholar] [CrossRef] [PubMed]
  190. Zakaryan, H.; Arabyan, E.; Oo, A.; Zandi, K. Flavonoids: promising natural compounds against viral infections. Arch Virol 2017, 162, 2539–2551. [Google Scholar] [CrossRef] [PubMed]
  191. Khan, T.; Khan, M.A.; Mashwani, Z.U.; Ullah, N.; Nadhman, A. Therapeutic potential of medicinal plants against COVID-19: The role of antiviral medicinal metabolites. Biocatal Agric Biotechnol 2021, 31, 101890. [Google Scholar] [CrossRef]
  192. Sharma, R.; Bhattu, M.; Tripathi, A.; Verma, M.; Acevedo, R.; Kumar, P.; Rajput, V.D.; Singh, J. Potential medicinal plants to combat viral infections: A way forward to environmental biotechnology. Environmental Research 2023, 227, 115725. [Google Scholar] [CrossRef] [PubMed]
  193. Xu, X.; Miao, J.; Shao, Q.; Gao, Y.; Hong, L. Apigenin suppresses influenza A virus-induced RIG-I activation and viral replication. J Med Virol, 1002. [Google Scholar] [CrossRef]
  194. Chiang, L.C.; Ng, L.T.; Cheng, P.W.; Chiang, W.; Lin, C.C. Antiviral activities of extracts and selected pure constituents of Ocimum basilicum. Clin Exp Pharmacol Physiol 2005, 32, 811–816. [Google Scholar] [CrossRef]
  195. Ożarowski, M.; Karpiński, T.M. The Effects of Propolis on Viral Respiratory Diseases. Molecules 2023, 28. [Google Scholar] [CrossRef]
  196. Ohno, M.; Shibata, C.; Kishikawa, T.; Yoshikawa, T.; Takata, A.; Kojima, K.; Akanuma, M.; Kang, Y.J.; Yoshida, H.; Otsuka, M.; et al. The flavonoid apigenin improves glucose tolerance through inhibition of microRNA maturation in miRNA103 transgenic mice. Sci Rep 2013, 3, 2553. [Google Scholar] [CrossRef] [PubMed]
  197. Meerson, A.; Khatib, S.; Mahajna, J. Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics. Int J Mol Sci 2021, 22. [Google Scholar] [CrossRef] [PubMed]
  198. Huang, H.; Zhou, W.; Zhu, H.; Zhou, P.; Shi, X. Baicalin benefits the anti-HBV therapy via inhibiting HBV viral RNAs. Toxicol Appl Pharmacol 2017, 323, 36–43. [Google Scholar] [CrossRef] [PubMed]
  199. Li, B.Q.; Fu, T.; Yan, Y.D.; Baylor, N.W.; Ruscetti, F.W.; Kung, H.F. Inhibition of HIV infection by baicalin--a flavonoid compound purified from Chinese herbal medicine. Cell Mol Biol Res 1993, 39, 119–124. [Google Scholar] [PubMed]
  200. Zandi, K.; Teoh, B.-T.; Sam, S.-S.; Wong, P.-F.; Mustafa, M.R.; AbuBakar, S. Novel antiviral activity of baicalein against dengue virus. BMC Complementary and Alternative Medicine 2012, 12, 214. [Google Scholar] [CrossRef] [PubMed]
  201. Luo, Z.; Kuang, X.-P.; Zhou, Q.-Q.; Yan, C.-Y.; Li, W.; Gong, H.-B.; Kurihara, H.; Li, W.-X.; Li, Y.-F.; He, R.-R. Inhibitory effects of baicalein against herpes simplex virus type 1. Acta Pharmaceutica Sinica B 2020, 10, 2323–2338. [Google Scholar] [CrossRef] [PubMed]
  202. Yu, X.; Li, H.; Hu, P.; Qing, Y.; Wang, X.; Zhu, M.; Wang, H.; Wang, Z.; Xu, J.; Guo, Q.; et al. Natural HDAC-1/8 inhibitor baicalein exerts therapeutic effect in CBF-AML. Clin Transl Med 2020, 10, e154. [Google Scholar] [CrossRef] [PubMed]
  203. Jiang, H.; Yao, Q.; An, Y.; Fan, L.; Wang, J.; Li, H. Baicalin suppresses the progression of Type 2 diabetes-induced liver tumor through regulating METTL3/m(6)A/HKDC1 axis and downstream p-JAK2/STAT1/clevaged Capase3 pathway. Phytomedicine 2022, 94, 153823. [Google Scholar] [CrossRef] [PubMed]
  204. Qi, J.; Li, J.; Bie, B.; Shi, M.; Zhu, M.; Tian, J.; Zhu, K.; Sun, J.; Mu, Y.; Li, Z.; et al. miR-3,178 contributes to the therapeutic action of baicalein against hepatocellular carcinoma cells via modulating HDAC10. Phytother Res 2023, 37, 295–309. [Google Scholar] [CrossRef]
  205. Jin, Y.; Liu, S.; Ma, Q.; Xiao, D.; Chen, L. Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes. Eur J Pharmacol 2017, 794, 106–114. [Google Scholar] [CrossRef]
  206. Lou, G.; Liu, Y.; Wu, S.; Xue, J.; Yang, F.; Fu, H.; Zheng, M.; Chen, Z. The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis. Cell Physiol Biochem 2015, 35, 2192–2202. [Google Scholar] [CrossRef] [PubMed]
  207. Lü, Y.; Han, B.; Yu, H.; Cui, Z.; Li, Z.; Wang, J. Berberine regulates the microRNA-21-ITGΒ4-PDCD4 axis and inhibits colon cancer viability. Oncol Lett 2018, 15, 5971–5976. [Google Scholar] [CrossRef]
  208. Cui, Y.; Zhang, L.; Hu, D.; Yang, Y. Berberine Inhibits Herpes Simplex Virus 1 Replication in HEK293T Cells. Comput Math Methods Med 2022, 2022, 7137401. [Google Scholar] [CrossRef]
  209. Hayashi, K.; Minoda, K.; Nagaoka, Y.; Hayashi, T.; Uesato, S. Antiviral activity of berberine and related compounds against human cytomegalovirus. Bioorg Med Chem Lett 2007, 17, 1562–1564. [Google Scholar] [CrossRef] [PubMed]
  210. Mahata, S.; Bharti, A.C.; Shukla, S.; Tyagi, A.; Husain, S.A.; Das, B.C. Berberine modulates AP-1 activity to suppress HPV transcription and downstream signaling to induce growth arrest and apoptosis in cervical cancer cells. Mol Cancer 2011, 10, 39. [Google Scholar] [CrossRef]
  211. Ratanakomol, T.; Roytrakul, S.; Wikan, N.; Smith, D.R. Berberine Inhibits Dengue Virus through Dual Mechanisms. Molecules 2021, 26. [Google Scholar] [CrossRef]
  212. Zha, W.; Liang, G.; Xiao, J.; Studer, E.J.; Hylemon, P.B.; Pandak, W.M., Jr.; Wang, G.; Li, X.; Zhou, H. Berberine inhibits HIV protease inhibitor-induced inflammatory response by modulating ER stress signaling pathways in murine macrophages. PLoS One 2010, 5, e9069. [Google Scholar] [CrossRef]
  213. Hung, T.C.; Jassey, A.; Liu, C.H.; Lin, C.J.; Lin, C.C.; Wong, S.H.; Wang, J.Y.; Yen, M.H.; Lin, L.T. Berberine inhibits hepatitis C virus entry by targeting the viral E2 glycoprotein. Phytomedicine 2019, 53, 62–69. [Google Scholar] [CrossRef] [PubMed]
  214. Wu, Y.; Li, J.Q.; Kim, Y.J.; Wu, J.; Wang, Q.; Hao, Y. In vivo and in vitro antiviral effects of berberine on influenza virus. Chin J Integr Med 2011, 17, 444–452. [Google Scholar] [CrossRef]
  215. Pizzorno, A.; Padey, B.; Dubois, J.; Julien, T.; Traversier, A.; Dulière, V.; Brun, P.; Lina, B.; Rosa-Calatrava, M.; Terrier, O. In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Res 2020, 181, 104878. [Google Scholar] [CrossRef]
  216. Kim, S.Y.; Kim, H.; Kim, S.W.; Lee, N.R.; Yi, C.M.; Heo, J.; Kim, B.J.; Kim, N.J.; Inn, K.S. An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor. Antimicrob Agents Chemother 2017, 61. [Google Scholar] [CrossRef] [PubMed]
  217. Adewole, K.E.; Ishola, A.A. A Computational Approach to Investigate the HDAC6 and HDAC10 Binding Propensity of Psidium guajava-derived Compounds as Potential Anticancer Agents. Curr Drug Discov Technol 2021, 18, 423–436. [Google Scholar] [CrossRef]
  218. Peyrat, L.A.; Eparvier, V.; Eydoux, C.; Guillemot, J.C.; Litaudon, M.; Stien, D. Betulinic Acid, The First Lupane-Type Triterpenoid Isolated from Both a Phomopsis sp. and Its Host Plant Diospyros carbonaria Benoist. Chem Biodivers 2017, 14. [Google Scholar] [CrossRef] [PubMed]
  219. Yao, D.; Li, H.; Gou, Y.; Zhang, H.; Vlessidis, A.G.; Zhou, H.; Evmiridis, N.P.; Liu, Z. Betulinic acid-mediated inhibitory effect on hepatitis B virus by suppression of manganese superoxide dismutase expression. Febs j 2009, 276, 2599–2614. [Google Scholar] [CrossRef] [PubMed]
  220. Tiwari, P.; Gupta, K.P. Modulation of miR-203 and its regulators as a function of time during the development of 7, 12 dimethylbenz [a] anthracene induced mouse skin tumors in presence or absence of the antitumor agents. Toxicol Appl Pharmacol 2014, 278, 148–158. [Google Scholar] [CrossRef] [PubMed]
  221. Pant, K.; Mishra, A.K.; Pradhan, S.M.; Nayak, B.; Das, P.; Shalimar, D.; Saraya, A.; Venugopal, S.K. Butyrate inhibits HBV replication and HBV-induced hepatoma cell proliferation via modulating SIRT-1/Ac-p53 regulatory axis. Mol Carcinog 2019, 58, 524–532. [Google Scholar] [CrossRef] [PubMed]
  222. Jin, Y.H.; Min, J.S.; Kwon, S. Cardamonin as a p38 MAPK Signaling Pathway Activator Inhibits Human Coronavirus OC43 Infection in Human Lung Cells. Nutrients 2023, 15. [Google Scholar] [CrossRef] [PubMed]
  223. Ryu, E.; Son, M.; Lee, M.; Lee, K.; Cho, J.Y.; Cho, S.; Lee, S.K.; Lee, Y.M.; Cho, H.; Sung, G.H.; et al. Cordycepin is a novel chemical suppressor of Epstein-Barr virus replication. Oncoscience 2014, 1, 866–881. [Google Scholar] [CrossRef] [PubMed]
  224. Rabie, A.M. Potent Inhibitory Activities of the Adenosine Analogue Cordycepin on SARS-CoV-2 Replication. ACS Omega 2022, 7, 2960–2969. [Google Scholar] [CrossRef]
  225. Rose, K.M.; Bell, L.E.; Jacob, S.T. Specific inhibition of chromatin-associated poly(A) synthesis in vitro by cordycepin 5'-triphosphate. Nature 1977, 267, 178–180. [Google Scholar] [CrossRef]
  226. Mahy, B.W.; Cox, N.J.; Armstrong, S.J.; Barry, R.D. Multiplication of influenza virus in the presence of cordycepin, an inhibitor of cellular RNA synthesis. Nat New Biol 1973, 243, 172–174. [Google Scholar] [CrossRef] [PubMed]
  227. Müller, W.E.; Weiler, B.E.; Charubala, R.; Pfleiderer, W.; Leserman, L.; Sobol, R.W.; Suhadolnik, R.J.; Schröder, H.C. Cordycepin analogues of 2',5'-oligoadenylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase. Biochemistry 1991, 30, 2027–2033. [Google Scholar] [CrossRef] [PubMed]
  228. Lonai, P.; Declève, A.; Kaplan, H.S. Spontaneous induction of endogenous murine leukemia virus-related antigen expression during short-term in vitro incubation of mouse lymphocytes. Proc Natl Acad Sci U S A 1974, 71, 2008–2012. [Google Scholar] [CrossRef] [PubMed]
  229. Doetsch, P.W.; Suhadolnik, R.J.; Sawada, Y.; Mosca, J.D.; Flick, M.B.; Reichenbach, N.L.; Dang, A.Q.; Wu, J.M.; Charubala, R.; Pfleiderer, W.; et al. Core (2'-5')oligoadenylate and the cordycepin analog: inhibitors of Epstein--Barr virus-induced transformation of human lymphocytes in the absence of interferon. Proc Natl Acad Sci U S A 1981, 78, 6699–6703. [Google Scholar] [CrossRef] [PubMed]
  230. Wang, Z.; Wang, N.; Yang, L.; Song, X.Q. Bioactive natural products in COVID-19 therapy. Front Pharmacol 2022, 13, 926507. [Google Scholar] [CrossRef] [PubMed]
  231. Hudlikar, R.R.; Sargsyan, D.; Wu, R.; Su, S.; Zheng, M.; Kong, A.N. Triterpenoid corosolic acid modulates global CpG methylation and transcriptome of tumor promotor TPA induced mouse epidermal JB6 P+ cells. Chem Biol Interact 2020, 321, 109025. [Google Scholar] [CrossRef] [PubMed]
  232. Yang, J.; Wu, R.; Li, W.; Gao, L.; Yang, Y.; Li, P.; Kong, A.N. The triterpenoid corosolic acid blocks transformation and epigenetically reactivates Nrf2 in TRAMP-C1 prostate cells. Mol Carcinog 2018, 57, 512–521. [Google Scholar] [CrossRef] [PubMed]
  233. Zhao, J.; Zhou, H.; An, Y.; Shen, K.; Yu, L. Biological effects of corosolic acid as an anti-inflammatory, anti-metabolic syndrome and anti-neoplasic natural compound. Oncol Lett 2021, 21, 84. [Google Scholar] [CrossRef] [PubMed]
  234. Liu, H.L.; Chen, Y.; Cui, G.H.; Zhou, J.F. Curcumin, a potent anti-tumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation. Acta Pharmacol Sin 2005, 26, 603–609. [Google Scholar] [CrossRef]
  235. Shu, L.; Khor, T.O.; Lee, J.H.; Boyanapalli, S.S.; Huang, Y.; Wu, T.Y.; Saw, C.L.; Cheung, K.L.; Kong, A.N. Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. Aaps j 2011, 13, 606–614. [Google Scholar] [CrossRef]
  236. Wei, Z.Q.; Zhang, Y.H.; Ke, C.Z.; Chen, H.X.; Ren, P.; He, Y.L.; Hu, P.; Ma, D.Q.; Luo, J.; Meng, Z.J. Curcumin inhibits hepatitis B virus infection by down-regulating cccDNA-bound histone acetylation. World J Gastroenterol 2017, 23, 6252–6260. [Google Scholar] [CrossRef] [PubMed]
  237. Sohn, E.J.; Bak, K.M.; Nam, Y.K.; Park, H.T. Upregulation of microRNA 344a-3p is involved in curcumin induced apoptosis in RT4 schwannoma cells. Cancer Cell Int 2018, 18, 199. [Google Scholar] [CrossRef] [PubMed]
  238. Butnariu, M.; Quispe, C.; Koirala, N.; Khadka, S.; Salgado-Castillo, C.M.; Akram, M.; Anum, R.; Yeskaliyeva, B.; Cruz-Martins, N.; Martorell, M.; et al. Bioactive Effects of Curcumin in Human Immunodeficiency Virus Infection Along with the Most Effective Isolation Techniques and Type of Nanoformulations. Int J Nanomedicine 2022, 17, 3619–3632. [Google Scholar] [CrossRef] [PubMed]
  239. Chen, D.-Y.; Shien, J.-H.; Tiley, L.; Chiou, S.-S.; Wang, S.-Y.; Chang, T.-J.; Lee, Y.-J.; Chan, K.-W.; Hsu, W.-L. Curcumin inhibits influenza virus infection and haemagglutination activity. Food Chemistry 2010, 119, 1346–1351. [Google Scholar] [CrossRef]
  240. Prusty, B.K.; Das, B.C. Constitutive activation of transcription factor AP-1 in cervical cancer and suppression of human papillomavirus (HPV) transcription and AP-1 activity in HeLa cells by curcumin. Int J Cancer 2005, 113, 951–960. [Google Scholar] [CrossRef] [PubMed]
  241. Jennings, M.R.; Parks, R.J. Curcumin as an Antiviral Agent. Viruses 2020, 12, 1242. [Google Scholar] [CrossRef] [PubMed]
  242. Kang, I.; Okla, M.; Chung, S. Ellagic acid inhibits adipocyte differentiation through coactivator-associated arginine methyltransferase 1-mediated chromatin modification. The Journal of Nutritional Biochemistry 2014, 25, 946–953. [Google Scholar] [CrossRef] [PubMed]
  243. Dinata, R.; Nisa, N.; Arati, C.; Rasmita, B.; Uditraj, C.; Siddhartha, R.; Bhanushree, B.; Saeed-Ahmed, L.; Manikandan, B.; Bidanchi, R.M.; et al. Repurposing immune boosting and anti-viral efficacy of Parkia bioactive entities as multi-target directed therapeutic approach for SARS-CoV-2: exploration of lead drugs by drug likeness, molecular docking and molecular dynamics simulation methods. J Biomol Struct Dyn, 1080; -39. [Google Scholar] [CrossRef]
  244. Li, F.; Qasim, S.; Li, D.; Dou, Q.P. Updated review on green tea polyphenol epigallocatechin-3-gallate as a cancer epigenetic regulator. Semin Cancer Biol 2022, 83, 335–352. [Google Scholar] [CrossRef] [PubMed]
  245. Henning, S.M.; Wang, P.; Carpenter, C.L.; Heber, D. Epigenetic effects of green tea polyphenols in cancer. Epigenomics 2013, 5, 729–741. [Google Scholar] [CrossRef]
  246. Moseley, V.R.; Morris, J.; Knackstedt, R.W.; Wargovich, M.J. Green tea polyphenol epigallocatechin 3-gallate, contributes to the degradation of DNMT3A and HDAC3 in HCT 116 human colon cancer cells. Anticancer Res 2013, 33, 5325–5333. [Google Scholar]
  247. Meeran, S.M.; Patel, S.N.; Chan, T.H.; Tollefsbol, T.O. A novel prodrug of epigallocatechin-3-gallate: differential epigenetic hTERT repression in human breast cancer cells. Cancer Prev Res (Phila) 2011, 4, 1243–1254. [Google Scholar] [CrossRef] [PubMed]
  248. Rasheed, Z.; Rasheed, N.; Al-Shaya, O. Epigallocatechin-3-O-gallate modulates global microRNA expression in interleukin-1β-stimulated human osteoarthritis chondrocytes: potential role of EGCG on negative co-regulation of microRNA-140-3p and ADAMTS5. Eur J Nutr 2018, 57, 917–928. [Google Scholar] [CrossRef] [PubMed]
  249. Shin, S.; Kim, K.; Lee, M.J.; Lee, J.; Choi, S.; Kim, K.S.; Ko, J.M.; Han, H.; Kim, S.Y.; Youn, H.J.; et al. Epigallocatechin Gallate-Mediated Alteration of the MicroRNA Expression Profile in 5α-Dihydrotestosterone-Treated Human Dermal Papilla Cells. Ann Dermatol 2016, 28, 327–334. [Google Scholar] [CrossRef] [PubMed]
  250. Chen, X.; Chang, L.; Qu, Y.; Liang, J.; Jin, W.; Xia, X. Tea polyphenols inhibit the proliferation, migration, and invasion of melanoma cells through the down-regulation of TLR4. Int J Immunopathol Pharmacol 2018, 32, 394632017739531. [Google Scholar] [CrossRef] [PubMed]
  251. Arffa, M.L.; Zapf, M.A.; Kothari, A.N.; Chang, V.; Gupta, G.N.; Ding, X.; Al-Gayyar, M.M.; Syn, W.; Elsherbiny, N.M.; Kuo, P.C.; et al. Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis. PLoS One 2016, 11, e0167435. [Google Scholar] [CrossRef] [PubMed]
  252. Tsvetkov, V.; Varizhuk, A.; Kozlovskaya, L.; Shtro, A.; Lebedeva, O.; Komissarov, A.; Vedekhina, T.; Manuvera, V.; Zubkova, O.; Eremeev, A.; et al. EGCG as an anti-SARS-CoV-2 agent: Preventive versus therapeutic potential against original and mutant virus. Biochimie 2021, 191, 27–32. [Google Scholar] [CrossRef] [PubMed]
  253. da Silva-Júnior, E.F.; Silva, L.R. Multi-target Approaches of Epigallocatechin-3-O-gallate (EGCG) and its Derivatives against Influenza Viruses. Curr Top Med Chem 2022, 22, 1485–1500. [Google Scholar] [CrossRef] [PubMed]
  254. Miyoshi, N.; Tanabe, H.; Suzuki, T.; Saeki, K.; Hara, Y. Applications of a Standardized Green Tea Catechin Preparation for Viral Warts and Human Papilloma Virus-Related and Unrelated Cancers. Molecules 2020, 25. [Google Scholar] [CrossRef]
  255. Mekky, R.Y.; El-Ekiaby, N.; El Sobky, S.A.; Elemam, N.M.; Youness, R.A.; El-Sayed, M.; Hamza, M.T.; Esmat, G.; Abdelaziz, A.I. Epigallocatechin gallate (EGCG) and miR-548m reduce HCV entry through repression of CD81 receptor in HCV cell models. Arch Virol 2019, 164, 1587–1595. [Google Scholar] [CrossRef]
  256. Date, A.A.; Destache, C.J. Natural polyphenols: potential in the prevention of sexually transmitted viral infections. Drug Discovery Today 2016, 21, 333–341. [Google Scholar] [CrossRef]
  257. Shorobi, F.M.; Nisa, F.Y.; Saha, S.; Chowdhury, M.A.H.; Srisuphanunt, M.; Hossain, K.H.; Rahman, M.A. Quercetin: A Functional Food-Flavonoid Incredibly Attenuates Emerging and Re-Emerging Viral Infections through Immunomodulatory Actions. Molecules 2023, 28. [Google Scholar] [CrossRef]
  258. Carneiro, B.M.; Batista, M.N.; Braga, A.C.S.; Nogueira, M.L.; Rahal, P. The green tea molecule EGCG inhibits Zika virus entry. Virology 2016, 496, 215–218. [Google Scholar] [CrossRef] [PubMed]
  259. Zeng, H.; Huang, P.; Wang, X.; Wu, J.; Wu, M.; Huang, J. Galangin-induced down-regulation of BACE1 by epigenetic mechanisms in SH-SY5Y cells. Neuroscience 2015, 294, 172–181. [Google Scholar] [CrossRef]
  260. Deng, X.; Zuo, M.; Pei, Z.; Xie, Y.; Yang, Z.; Zhang, Z.; Jiang, M.; Kuang, D. MicroRNA-455-5p Contributes to Cholangiocarcinoma Growth and Mediates Galangin's Anti-Tumor Effects. J Cancer 2021, 12, 4710–4721. [Google Scholar] [CrossRef] [PubMed]
  261. Meyer, J.J.; Afolayan, A.J.; Taylor, M.B.; Erasmus, D. Antiviral activity of galangin isolated from the aerial parts of Helichrysum aureonitens. Journal of ethnopharmacology 1997, 56, 165–169. [Google Scholar] [CrossRef] [PubMed]
  262. Kopytko, P.; Piotrowska, K.; Janisiak, J.; Tarnowski, M. Garcinol-A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug. Int J Mol Sci 2021, 22. [Google Scholar] [CrossRef] [PubMed]
  263. Parasramka, M.A.; Ali, S.; Banerjee, S.; Deryavoush, T.; Sarkar, F.H.; Gupta, S. Garcinol sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association with microRNA signatures. Mol Nutr Food Res 2013, 57, 235–248. [Google Scholar] [CrossRef]
  264. Ahmad, A.; Sarkar, S.H.; Bitar, B.; Ali, S.; Aboukameel, A.; Sethi, S.; Li, Y.; Bao, B.; Kong, D.; Banerjee, S.; et al. Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Mol Cancer Ther 2012, 11, 2193–2201. [Google Scholar] [CrossRef]
  265. Corona, A.; Seibt, S.; Schaller, D.; Schobert, R.; Volkamer, A.; Biersack, B.; Tramontano, E. Garcinol from Garcinia indica inhibits HIV-1 reverse transcriptase-associated ribonuclease H. Arch Pharm (Weinheim) 2021, 354, e2100123. [Google Scholar] [CrossRef]
  266. Sharifi-Rad, J.; Quispe, C.; Imran, M.; Rauf, A.; Nadeem, M.; Gondal, T.A.; Ahmad, B.; Atif, M.; Mubarak, M.S.; Sytar, O.; et al. Genistein: An Integrative Overview of Its Mode of Action, Pharmacological Properties, and Health Benefits. Oxid Med Cell Longev 2021, 2021, 3268136. [Google Scholar] [CrossRef]
  267. Ma, J.; Cheng, L.; Liu, H.; Zhang, J.; Shi, Y.; Zeng, F.; Miele, L.; Sarkar, F.H.; Xia, J.; Wang, Z. Genistein down-regulates miR-223 expression in pancreatic cancer cells. Curr Drug Targets 2013, 14, 1150–1156. [Google Scholar] [CrossRef] [PubMed]
  268. Fukuda, I.; Ito, A.; Hirai, G.; Nishimura, S.; Kawasaki, H.; Saitoh, H.; Kimura, K.; Sodeoka, M.; Yoshida, M. Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem Biol 2009, 16, 133–140. [Google Scholar] [CrossRef]
  269. Ibrahim, M.A.; Ramadan, H.H.; Mohammed, R.N. Evidence that Ginkgo Biloba could use in the influenza and coronavirus COVID-19 infections. J Basic Clin Physiol Pharmacol 2021, 32, 131–143. [Google Scholar] [CrossRef] [PubMed]
  270. Zhong, L.L.D.; Lam, W.C.; Yang, W.; Chan, K.W.; Sze, S.C.W.; Miao, J.; Yung, K.K.L.; Bian, Z.; Wong, V.T. Potential Targets for Treatment of Coronavirus Disease 2019 (COVID-19): A Review of Qing-Fei-Pai-Du-Tang and Its Major Herbs. Am J Chin Med 2020, 48, 1051–1071. [Google Scholar] [CrossRef] [PubMed]
  271. Omer, M.O.; Almalki, W.H.; Shahid, I.; Khuram, S.; Altaf, I.; Imran, S. Comparative study to evaluate the anti-viral efficacy of Glycyrrhiza glabra extract and ribavirin against the Newcastle disease virus. Pharmacognosy Res 2014, 6, 6–11. [Google Scholar] [CrossRef] [PubMed]
  272. Huan, C.; Xu, Y.; Zhang, W.; Guo, T.; Pan, H.; Gao, S. Research Progress on the Antiviral Activity of Glycyrrhizin and its Derivatives in Liquorice. Front Pharmacol 2021, 12, 680674. [Google Scholar] [CrossRef] [PubMed]
  273. Wolkerstorfer, A.; Kurz, H.; Bachhofner, N.; Szolar, O.H. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral Res 2009, 83, 171–178. [Google Scholar] [CrossRef] [PubMed]
  274. Zuo, J.; Meng, T.; Wang, Y.; Tang, W. A Review of the Antiviral Activities of Glycyrrhizic Acid, Glycyrrhetinic Acid and Glycyrrhetinic Acid Monoglucuronide. Pharmaceuticals 2023, 16, 641. [Google Scholar] [CrossRef] [PubMed]
  275. Fiore, C.; Eisenhut, M.; Krausse, R.; Ragazzi, E.; Pellati, D.; Armanini, D.; Bielenberg, J. Antiviral effects of Glycyrrhiza species. Phytother Res 2008, 22, 141–148. [Google Scholar] [CrossRef]
  276. Chen, F.; Chan, K.H.; Jiang, Y.; Kao, R.Y.; Lu, H.T.; Fan, K.W.; Cheng, V.C.; Tsui, W.H.; Hung, I.F.; Lee, T.S.; et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004, 31, 69–75. [Google Scholar] [CrossRef]
  277. Yang, R.; Liu, H.; Bai, C.; Wang, Y.; Zhang, X.; Guo, R.; Wu, S.; Wang, J.; Leung, E.; Chang, H.; et al. Chemical composition and pharmacological mechanism of Qingfei Paidu Decoction and Ma Xing Shi Gan Decoction against Coronavirus Disease 2019 (COVID-19): In silico and experimental study. Pharmacol Res 2020, 157, 104820. [Google Scholar] [CrossRef] [PubMed]
  278. Liu, W.; Huang, S.; Li, Y.; Li, Y.; Li, D.; Wu, P.; Wang, Q.; Zheng, X.; Zhang, K. Glycyrrhizic acid from licorice down-regulates inflammatory responses via blocking MAPK and PI3K/Akt-dependent NF-κB signalling pathways in TPA-induced skin inflammation. Medchemcomm 2018, 9, 1502–1510. [Google Scholar] [CrossRef] [PubMed]
  279. El Omari, N.; Bakrim, S.; Bakha, M.; Lorenzo, J.M.; Rebezov, M.; Shariati, M.A.; Aboulaghras, S.; Balahbib, A.; Khayrullin, M.; Bouyahya, A. Natural Bioactive Compounds Targeting Epigenetic Pathways in Cancer: A Review on Alkaloids, Terpenoids, Quinones, and Isothiocyanates. Nutrients 2021, 13. [Google Scholar] [CrossRef] [PubMed]
  280. Luo, X.; Yang, L.; Xiao, L.; Xia, X.; Dong, X.; Zhong, J.; Liu, Y.; Li, N.; Chen, L.; Li, H.; et al. Grifolin directly targets ERK1/2 to epigenetically suppress cancer cell metastasis. Oncotarget 2015, 6, 42704–42716. [Google Scholar] [CrossRef] [PubMed]
  281. Fabiani, R.; Vella, N.; Rosignoli, P. Epigenetic Modifications Induced by Olive Oil and Its Phenolic Compounds: A Systematic Review. Molecules 2021, 26, 273. [Google Scholar] [CrossRef] [PubMed]
  282. Juli, G.; Oliverio, M.; Bellizzi, D.; Gallo Cantafio, M.E.; Grillone, K.; Passarino, G.; Colica, C.; Nardi, M.; Rossi, M.; Procopio, A.; et al. Anti-tumor Activity and Epigenetic Impact of the Polyphenol Oleacein in Multiple Myeloma. Cancers (Basel) 2019, 11. [Google Scholar] [CrossRef] [PubMed]
  283. Lee-Huang, S.; Huang, P.L.; Zhang, D.; Lee, J.W.; Bao, J.; Sun, Y.; Chang, Y.T.; Zhang, J.; Huang, P.L. Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part I. fusion [corrected] inhibition. Biochemical and biophysical research communications 2007, 354, 872–878. [Google Scholar] [CrossRef] [PubMed]
  284. Gomes, N.G.M.; Valentão, P.; Andrade, P.B.; Pereira, R.B. Plitidepsin to treat multiple myeloma. Drugs Today (Barc) 2020, 56, 337–347. [Google Scholar] [CrossRef] [PubMed]
  285. Wei, T.; Li, D.; Marcial, D.; Khan, M.; Lin, M.H.; Snape, N.; Ghildyal, R.; Harrich, D.; Spann, K. The eukaryotic elongation factor 1A is critical for genome replication of the paramyxovirus respiratory syncytial virus. PLoS One 2014, 9, e114447. [Google Scholar] [CrossRef]
  286. White, K.M.; Rosales, R.; Yildiz, S.; Kehrer, T.; Miorin, L.; Moreno, E.; Jangra, S.; Uccellini, M.B.; Rathnasinghe, R.; Coughlan, L.; et al. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science 2021, 371, 926–931. [Google Scholar] [CrossRef]
  287. Reuschl, A.-K.; Thorne, L.G.; Zuliani-Alvarez, L.; Bouhaddou, M.; Obernier, K.; Hiatt, J.; Soucheray, M.; Turner, J.; Fabius, J.M.; Nguyen, G.T. Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B. 1.1. 7 variant. BioRxiv 2021. [Google Scholar]
  288. Kala, R.; Shah, H.N.; Martin, S.L.; Tollefsbol, T.O. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting SIRT1 and DNMT enzyme expression, including SIRT1-dependent γ-H2AX and telomerase regulation in triple-negative breast cancer. BMC cancer 2015, 15, 1–18. [Google Scholar] [CrossRef] [PubMed]
  289. Liu, T.; Liu, P.Y.; Marshall, G.M. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer research 2009, 69, 1702–1705. [Google Scholar] [CrossRef] [PubMed]
  290. Ter Ellen, B.M.; Dinesh Kumar, N.; Bouma, E.M.; Troost, B.; van de Pol, D.P.I.; van der Ende-Metselaar, H.H.; Apperloo, L.; van Gosliga, D.; van den Berge, M.; Nawijn, M.C.; et al. Resveratrol and Pterostilbene Inhibit SARS-CoV-2 Replication in Air-Liquid Interface Cultured Human Primary Bronchial Epithelial Cells. Viruses 2021, 13. [Google Scholar] [CrossRef]
  291. Lee, W.J.; Chen, Y.R.; Tseng, T.H. Quercetin induces FasL-related apoptosis, in part, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncology reports 2011, 25, 583–591. [Google Scholar] [CrossRef] [PubMed]
  292. Kedhari Sundaram, M.; Hussain, A.; Haque, S.; Raina, R.; Afroze, N. Quercetin modifies 5'CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells. J Cell Biochem 2019, 120, 18357–18369. [Google Scholar] [CrossRef] [PubMed]
  293. Ahmed, F.; Ijaz, B.; Ahmad, Z.; Farooq, N.; Sarwar, M.B.; Husnain, T. Modification of miRNA Expression through plant extracts and compounds against breast cancer: Mechanism and translational significance. Phytomedicine 2020, 68, 153168. [Google Scholar] [CrossRef]
  294. Huang, Q.; Chen, L.; Luo, M.; Lv, H.; Luo, D.; Li, T.; Huang, S.; Xie, L.; Teng, Y.; Liu, Z.; et al. HIV-1-Induced miR-146a Attenuates Monocyte Migration by Targeting CCL5 in Human Primary Macrophages. AIDS Res Hum Retroviruses 2018, 34, 580–589. [Google Scholar] [CrossRef]
  295. Sonoki, H.; Sato, T.; Endo, S.; Matsunaga, T.; Yamaguchi, M.; Yamazaki, Y.; Sugatani, J.; Ikari, A. Quercetin Decreases Claudin-2 Expression Mediated by Up-Regulation of microRNA miR-16 in Lung Adenocarcinoma A549 Cells. Nutrients 2015, 7, 4578–4592. [Google Scholar] [CrossRef]
  296. Zhang, X.; Guo, Q.; Chen, J.; Chen, Z. Quercetin Enhances Cisplatin Sensitivity of Human Osteosarcoma Cells by Modulating microRNA-217-KRAS Axis. Mol Cells 2015, 38, 638–642. [Google Scholar] [CrossRef]
  297. Zhou, J.; Gong, J.; Ding, C.; Chen, G. Quercetin induces the apoptosis of human ovarian carcinoma cells by upregulating the expression of microRNA-145. Mol Med Rep 2015, 12, 3127–3131. [Google Scholar] [CrossRef] [PubMed]
  298. Di Petrillo, A.; Orrù, G.; Fais, A.; Fantini, M.C. Quercetin and its derivates as antiviral potentials: A comprehensive review. Phytother Res 2022, 36, 266–278. [Google Scholar] [CrossRef] [PubMed]
  299. Zarenezhad, E.; Abdulabbas, H.T.; Kareem, A.S.; Kouhpayeh, S.A.; Barbaresi, S.; Najafipour, S.; Mazarzaei, A.; Sotoudeh, M.; Ghasemian, A. Protective role of flavonoids quercetin and silymarin in the viral-associated inflammatory bowel disease: an updated review. Arch Microbiol 2023, 205, 252. [Google Scholar] [CrossRef] [PubMed]
  300. Brito, J.C.M.; Lima, W.G.; Cordeiro, L.P.B.; da Cruz Nizer, W.S. Effectiveness of supplementation with quercetin-type flavonols for treatment of viral lower respiratory tract infections: Systematic review and meta-analysis of preclinical studies. Phytother Res 2021, 35, 4930–4942. [Google Scholar] [CrossRef] [PubMed]
  301. Gonzalez, O.; Fontanes, V.; Raychaudhuri, S.; Loo, R.; Loo, J.; Arumugaswami, V.; Sun, R.; Dasgupta, A.; French, S.W. The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production. Hepatology 2009, 50, 1756–1764. [Google Scholar] [CrossRef] [PubMed]
  302. Parashar, G.; Capalash, N. Promoter methylation-independent reactivation of PAX1 by curcumin and resveratrol is mediated by UHRF1. Clinical and experimental medicine 2016, 16, 471–478. [Google Scholar] [CrossRef] [PubMed]
  303. Izquierdo-Torres, E.; Hernández-Oliveras, A.; Meneses-Morales, I.; Rodríguez, G.; Fuentes-García, G.; Zarain-Herzberg, Á. Resveratrol up-regulates ATP2A3 gene expression in breast cancer cell lines through epigenetic mechanisms. The International Journal of Biochemistry & Cell Biology 2019, 113, 37–47. [Google Scholar]
  304. Borra, M.T.; Smith, B.C.; Denu, J.M. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 2005, 280, 17187–17195. [Google Scholar] [CrossRef] [PubMed]
  305. Tili, E.; Michaille, J.J. Resveratrol, MicroRNAs, Inflammation, and Cancer. J Nucleic Acids 2011, 2011, 102431. [Google Scholar] [CrossRef]
  306. Bai, T.; Dong, D.S.; Pei, L. Synergistic antitumor activity of resveratrol and miR-200c in human lung cancer. Oncology reports 2014, 31, 2293–2297. [Google Scholar] [CrossRef]
  307. Smoliga, J.M.; Blanchard, O.L. Recent data do not provide evidence that resveratrol causes 'mainly negative' or 'adverse' effects on exercise training in humans. J Physiol 2013, 591, 5251–5252. [Google Scholar] [CrossRef] [PubMed]
  308. Docherty, J.J.; Smith, J.S.; Fu, M.M.; Stoner, T.; Booth, T. Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. Antiviral Res 2004, 61, 19–26. [Google Scholar] [CrossRef]
  309. Ayipo, Y.O.; Yahaya, S.N.; Alananzeh, W.A.; Babamale, H.F.; Mordi, M.N. Pathomechanisms, therapeutic targets and potent inhibitors of some beta-coronaviruses from bench-to-bedside. Infect Genet Evol 2021, 93, 104944. [Google Scholar] [CrossRef] [PubMed]
  310. Docherty, J.J.; Sweet, T.J.; Bailey, E.; Faith, S.A.; Booth, T. Resveratrol inhibition of varicella-zoster virus replication in vitro. Antiviral Res 2006, 72, 171–177. [Google Scholar] [CrossRef]
  311. Sasivimolphan, P.; Lipipun, V.; Likhitwitayawuid, K.; Takemoto, M.; Pramyothin, P.; Hattori, M.; Shiraki, K. Inhibitory activity of oxyresveratrol on wild-type and drug-resistant varicella-zoster virus replication in vitro. Antiviral Res 2009, 84, 95–97. [Google Scholar] [CrossRef]
  312. Lehman, C.W.; Kehn-Hall, K.; Aggarwal, M.; Bracci, N.R.; Pan, H.C.; Panny, L.; Lamb, R.A.; Lin, S.C. Resveratrol Inhibits Venezuelan Equine Encephalitis Virus Infection by Interfering with the AKT/GSK Pathway. Plants (Basel) 2021, 10. [Google Scholar] [CrossRef] [PubMed]
  313. Eladwy, R.A.; Vu, H.T.; Shah, R.; Li, C.G.; Chang, D.; Bhuyan, D.J. The Fight against the Carcinogenic Epstein-Barr Virus: Gut Microbiota, Natural Medicines, and Beyond. Int J Mol Sci 2023, 24. [Google Scholar] [CrossRef] [PubMed]
  314. Yu, K.; Zhou, L.; Wang, Y.; Yu, C.; Wang, Z.; Liu, H.; Wei, H.; Han, L.; Cheng, J.; Wang, F.; et al. Mechanisms and Therapeutic Strategies of Viral Myocarditis Targeting Autophagy. Front Pharmacol 2022, 13, 843103. [Google Scholar] [CrossRef] [PubMed]
  315. Kong, F.; Li, Q.; Zhang, F.; Li, X.; You, H.; Pan, X.; Zheng, K.; Tang, R. Sirtuins as Potential Therapeutic Targets for Hepatitis B Virus Infection. Front Med (Lausanne) 2021, 8, 751516. [Google Scholar] [CrossRef]
  316. Alway, S.E.; McCrory, J.L.; Kearcher, K.; Vickers, A.; Frear, B.; Gilleland, D.L.; Bonner, D.E.; Thomas, J.M.; Donley, D.A.; Lively, M.W.; et al. Resveratrol Enhances Exercise-Induced Cellular and Functional Adaptations of Skeletal Muscle in Older Men and Women. J Gerontol A Biol Sci Med Sci 2017, 72, 1595–1606. [Google Scholar] [CrossRef]
  317. Zhang, Y.; Li, Q.; Chen, H. DNA methylation and histone modifications of Wnt genes by genistein during colon cancer development. Carcinogenesis 2013, 34, 1756–1763. [Google Scholar] [CrossRef] [PubMed]
  318. Barros, T.M.B.; Lima, A.P.B.; Almeida, T.C.; da Silva, G.N. Inhibition of urinary bladder cancer cell proliferation by silibinin. Environ Mol Mutagen 2020, 61, 445–455. [Google Scholar] [CrossRef] [PubMed]
  319. Kauntz, H.; Bousserouel, S.; Gossé, F.; Raul, F. Epigenetic effects of the natural flavonolignan silibinin on colon adenocarcinoma cells and their derived metastatic cells. Oncol Lett 2013, 5, 1273–1277. [Google Scholar] [CrossRef] [PubMed]
  320. Bouyahya, A.; Mechchate, H.; Oumeslakht, L.; Zeouk, I.; Aboulaghras, S.; Balahbib, A.; Zengin, G.; Kamal, M.A.; Gallo, M.; Montesano, D.; et al. The Role of Epigenetic Modifications in Human Cancers and the Use of Natural Compounds as Epidrugs: Mechanistic Pathways and Pharmacodynamic Actions. Biomolecules 2022, 12, 367. [Google Scholar] [CrossRef] [PubMed]
  321. Zadeh, M.M.; Motamed, N.; Ranji, N.; Majidi, M.; Falahi, F. Silibinin-Induced Apoptosis and Downregulation of MicroRNA-21 and MicroRNA-155 in MCF-7 Human Breast Cancer Cells. jbc 2016, 19, 45–52. [Google Scholar] [CrossRef] [PubMed]
  322. Liu, C.H.; Jassey, A.; Hsu, H.Y.; Lin, L.T. Antiviral Activities of Silymarin and Derivatives. Molecules 2019, 24. [Google Scholar] [CrossRef] [PubMed]
  323. Chu, J.; Galicia-Vázquez, G.; Cencic, R.; Mills, J.R.; Katigbak, A.; Porco, J.A., Jr.; Pelletier, J. CRISPR-Mediated Drug-Target Validation Reveals Selective Pharmacological Inhibition of the RNA Helicase, eIF4A. Cell Rep 2016, 15, 2340–2347. [Google Scholar] [CrossRef] [PubMed]
  324. Biedenkopf, N.; Lange-Grünweller, K.; Schulte, F.W.; Weißer, A.; Müller, C.; Becker, D.; Becker, S.; Hartmann, R.K.; Grünweller, A. The natural compound silvestrol is a potent inhibitor of Ebola virus replication. Antiviral Res 2017, 137, 76–81. [Google Scholar] [CrossRef] [PubMed]
  325. Elgner, F.; Sabino, C.; Basic, M.; Ploen, D.; Grünweller, A.; Hildt, E. Inhibition of Zika Virus Replication by Silvestrol. Viruses 2018, 10. [Google Scholar] [CrossRef]
  326. Henss, L.; Scholz, T.; Grünweller, A.; Schnierle, B.S. Silvestrol Inhibits Chikungunya Virus Replication. Viruses 2018, 10. [Google Scholar] [CrossRef]
  327. Müller, C.; Schulte, F.W.; Lange-Grünweller, K.; Obermann, W.; Madhugiri, R.; Pleschka, S.; Ziebuhr, J.; Hartmann, R.K.; Grünweller, A. Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against corona- and picornaviruses. Antiviral Res 2018, 150, 123–129. [Google Scholar] [CrossRef] [PubMed]
  328. Müller, C.; Obermann, W.; Schulte, F.W.; Lange-Grünweller, K.; Oestereich, L.; Elgner, F.; Glitscher, M.; Hildt, E.; Singh, K.; Wendel, H.G.; et al. Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (-) and the eIF4A-inhibitor Silvestrol. Antiviral Res 2020, 175, 104706. [Google Scholar] [CrossRef] [PubMed]
  329. Müller, C.; Obermann, W.; Karl, N.; Wendel, H.G.; Taroncher-Oldenburg, G.; Pleschka, S.; Hartmann, R.K.; Grünweller, A.; Ziebuhr, J. The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo. Antiviral Res 2021, 186, 105012. [Google Scholar] [CrossRef] [PubMed]
  330. Jiang, L.-L.; Zhou, S.-J.; Zhang, X.-M.; Chen, H.-Q.; Liu, W. Sulforaphane suppresses in vitro and in vivo lung tumorigenesis through downregulation of HDAC activity. Biomedicine & Pharmacotherapy 2016, 78, 74–80. [Google Scholar]
  331. Ordonez, A.A.; Bullen, C.K.; Villabona-Rueda, A.F.; Thompson, E.A.; Turner, M.L.; Merino, V.F.; Yan, Y.; Kim, J.; Davis, S.L.; Komm, O.; et al. Sulforaphane exhibits antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses in vitro and in mice. Commun Biol 2022, 5, 242. [Google Scholar] [CrossRef] [PubMed]
  332. Yu, J.-S.; Chen, W.-C.; Tseng, C.-K.; Lin, C.-K.; Hsu, Y.-C.; Chen, Y.-H.; Lee, J.-C. Sulforaphane suppresses hepatitis C virus replication by up-regulating heme oxygenase-1 expression through PI3K/Nrf2 pathway. PloS one 2016, 11, e0152236. [Google Scholar] [CrossRef] [PubMed]
  333. Wang, L.; Zhang, C.; Guo, Y.; Su, Z.-Y.; Yang, Y.; Shu, L.; Kong, A.-N.T. Blocking of JB6 cell transformation by tanshinone IIA: epigenetic reactivation of Nrf2 antioxidative stress pathway. The AAPS journal 2014, 16, 1214–1225. [Google Scholar] [CrossRef] [PubMed]
  334. Valipour, M. Therapeutic prospects of naturally occurring p38 MAPK inhibitors tanshinone IIA and pinocembrin for the treatment of SARS-CoV-2-induced CNS complications. Phytother Res, 1002. [Google Scholar] [CrossRef]
  335. Zhang, C.; Wang, C.; Li, W.; Wu, R.; Guo, Y.; Cheng, D.; Yang, Y.; Androulakis, I.P.; Kong, A.N. Pharmacokinetics and Pharmacodynamics of the Triterpenoid Ursolic Acid in Regulating the Antioxidant, Anti-inflammatory, and Epigenetic Gene Responses in Rat Leukocytes. Mol Pharm 2017, 14, 3709–3717. [Google Scholar] [CrossRef] [PubMed]
  336. Zhao, J.; Chen, J.; Liu, T.; Fang, J.; Wan, J.; Zhao, J.; Li, W.; Liu, J.; Zhao, X.; Chen, S. Anti-viral effects of urosolic acid on guinea pig cytomegalovirus in vitro. J Huazhong Univ Sci Technolog Med Sci 2012, 32, 883–887. [Google Scholar] [CrossRef]
  337. Bungau, S.; Vesa, C.M.; Abid, A.; Behl, T.; Tit, D.M.; Purza, A.L.; Pasca, B.; Todan, L.M.; Endres, L. Withaferin A-A Promising Phytochemical Compound with Multiple Results in Dermatological Diseases. Molecules 2021, 26. [Google Scholar] [CrossRef]
  338. Royston, K.J.; Udayakumar, N.; Lewis, K.; Tollefsbol, T.O. A novel combination of withaferin A and sulforaphane inhibits epigenetic machinery, cellular viability and induces apoptosis of breast cancer cells. International journal of molecular sciences 2017, 18, 1092. [Google Scholar] [CrossRef]
  339. Choe, J.; Har Yong, P.; Xiang Ng, Z. The Efficacy of Traditional Medicinal Plants in Modulating the Main Protease of SARS-CoV-2 and Cytokine Storm. Chem Biodivers 2022, 19, e202200655. [Google Scholar] [CrossRef] [PubMed]
  340. Cai, Z.; Zhang, G.; Tang, B.; Liu, Y.; Fu, X.; Zhang, X. Promising Anti-influenza Properties of Active Constituent of Withania somnifera Ayurvedic Herb in Targeting Neuraminidase of H1N1 Influenza: Computational Study. Cell Biochem Biophys 2015, 72, 727–739. [Google Scholar] [CrossRef] [PubMed]
  341. Mishra, A.; Shaik, H.A.; Sinha, R.K.; Shah, B.R. Andrographolide: A Herbal-Chemosynthetic Approach for Enhancing Immunity, Combating Viral Infections, and Its Implication on Human Health. Molecules 2021, 26. [Google Scholar] [CrossRef]
  342. Theerawatanasirikul, S.; Lueangaramkul, V.; Thangthamniyom, N.; Chankeeree, P.; Semkum, P.; Lekcharoensuk, P. Andrographolide and Deoxyandrographolide Inhibit Protease and IFN-Antagonist Activities of Foot-and-Mouth Disease Virus 3C(pro). Animals (Basel) 2022, 12. [Google Scholar] [CrossRef] [PubMed]
  343. Li, F.; Lee, E.M.; Sun, X.; Wang, D.; Tang, H.; Zhou, G.C. Design, synthesis and discovery of andrographolide derivatives against Zika virus infection. Eur J Med Chem 2020, 187, 111925. [Google Scholar] [CrossRef] [PubMed]
  344. Chen, J.X.; Xue, H.J.; Ye, W.C.; Fang, B.H.; Liu, Y.H.; Yuan, S.H.; Yu, P.; Wang, Y.Q. Activity of andrographolide and its derivatives against influenza virus in vivo and in vitro. Biol Pharm Bull 2009, 32, 1385–1391. [Google Scholar] [CrossRef] [PubMed]
  345. Shukla, S.; Gupta, S. Apigenin: a promising molecule for cancer prevention. Pharm Res 2010, 27, 962–978. [Google Scholar] [CrossRef] [PubMed]
  346. Tseng, T.H.; Chien, M.H.; Lin, W.L.; Wen, Y.C.; Chow, J.M.; Chen, C.K.; Kuo, T.C.; Lee, W.J. Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21(WAF1/CIP1) expression. Environ Toxicol 2017, 32, 434–444. [Google Scholar] [CrossRef]
  347. Husain, K.; Villalobos-Ayala, K.; Laverde, V.; Vazquez, O.A.; Miller, B.; Kazim, S.; Blanck, G.; Hibbs, M.L.; Krystal, G.; Elhussin, I.; et al. Apigenin Targets MicroRNA-155, Enhances SHIP-1 Expression, and Augments Anti-Tumor Responses in Pancreatic Cancer. Cancers (Basel) 2022, 14. [Google Scholar] [CrossRef]
  348. Tao, Y.; Zhan, S.; Wang, Y.; Zhou, G.; Liang, H.; Chen, X.; Shen, H. Baicalin, the major component of traditional Chinese medicine Scutellaria baicalensis induces colon cancer cell apoptosis through inhibition of oncomiRNAs. Sci Rep 2018, 8, 14477. [Google Scholar] [CrossRef] [PubMed]
  349. Cicero, A.F.; Baggioni, A. Berberine and Its Role in Chronic Disease. Adv Exp Med Biol 2016, 928, 27–45. [Google Scholar] [CrossRef] [PubMed]
  350. Warowicka, A.; Nawrot, R.; Goździcka-Józefiak, A. Antiviral activity of berberine. Arch Virol 2020, 165, 1935–1945. [Google Scholar] [CrossRef] [PubMed]
  351. Varghese, F.S.; Thaa, B.; Amrun, S.N.; Simarmata, D.; Rausalu, K.; Nyman, T.A.; Merits, A.; McInerney, G.M.; Ng, L.F.P.; Ahola, T. The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling. J Virol 2016, 90, 9743–9757. [Google Scholar] [CrossRef] [PubMed]
  352. Zuco, V.; Supino, R.; Righetti, S.C.; Cleris, L.; Marchesi, E.; Gambacorti-Passerini, C.; Formelli, F. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Letters 2002, 175, 17–25. [Google Scholar] [CrossRef] [PubMed]
  353. Fulda, S. Betulinic Acid for cancer treatment and prevention. Int J Mol Sci 2008, 9, 1096–1107. [Google Scholar] [CrossRef] [PubMed]
  354. Liu, X.; Jutooru, I.; Lei, P.; Kim, K.; Lee, S.O.; Brents, L.K.; Prather, P.L.; Safe, S. Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer. Mol Cancer Ther 2012, 11, 1421–1431. [Google Scholar] [CrossRef] [PubMed]
  355. Voon, F.L.; Sulaiman, M.R.; Akhtar, M.N.; Idris, M.F.; Akira, A.; Perimal, E.K.; Israf, D.A.; Ming-Tatt, L. Cardamonin (2',4'-dihydroxy-6'-methoxychalcone) isolated from Boesenbergia rotunda (L.) Mansf. inhibits CFA-induced rheumatoid arthritis in rats. Eur J Pharmacol 2017, 794, 127–134. [Google Scholar] [CrossRef] [PubMed]
  356. Das, S.K.; Masuda, M.; Sakurai, A.; Sakakibara, M. Medicinal uses of the mushroom Cordyceps militaris: current state and prospects. Fitoterapia 2010, 81, 961–968. [Google Scholar] [CrossRef]
  357. Ling, J.Y.; Sun, Y.J.; Zhang, H.; Lv, P.; Zhang, C.K. Measurement of cordycepin and adenosine in stroma of Cordyceps sp. by capillary zone electrophoresis (CZE). J Biosci Bioeng 2002, 94, 371–374. [Google Scholar] [CrossRef]
  358. Hou, W.; Li, Y.; Zhang, Q.; Wei, X.; Peng, A.; Chen, L.; Wei, Y. Triterpene acids isolated from Lagerstroemia speciosa leaves as alpha-glucosidase inhibitors. Phytother Res 2009, 23, 614–618. [Google Scholar] [CrossRef] [PubMed]
  359. Ratovitski, E.A. Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression. Curr Genomics 2017, 18, 175–205. [Google Scholar] [CrossRef] [PubMed]
  360. Hewlings, S.J.; Kalman, D.S. Curcumin: A Review of Its Effects on Human Health. Foods 2017, 6. [Google Scholar] [CrossRef] [PubMed]
  361. Hassan, F.U.; Rehman, M.S.; Khan, M.S.; Ali, M.A.; Javed, A.; Nawaz, A.; Yang, C. Curcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects. Front Genet 2019, 10, 514. [Google Scholar] [CrossRef] [PubMed]
  362. Kim, H.J.; Yoo, H.S.; Kim, J.C.; Park, C.S.; Choi, M.S.; Kim, M.; Choi, H.; Min, J.S.; Kim, Y.S.; Yoon, S.W.; et al. Antiviral effect of Curcuma longa Linn extract against hepatitis B virus replication. Journal of ethnopharmacology 2009, 124, 189–196. [Google Scholar] [CrossRef] [PubMed]
  363. Zahedipour, F.; Hosseini, S.A.; Sathyapalan, T.; Majeed, M.; Jamialahmadi, T.; Al-Rasadi, K.; Banach, M.; Sahebkar, A. Potential effects of curcumin in the treatment of COVID-19 infection. Phytother Res 2020, 34, 2911–2920. [Google Scholar] [CrossRef] [PubMed]
  364. Sordillo, P.P.; Helson, L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. In Vivo 2015, 29, 1–4. [Google Scholar] [PubMed]
  365. Wen, C.C.; Kuo, Y.H.; Jan, J.T.; Liang, P.H.; Wang, S.Y.; Liu, H.G.; Lee, C.K.; Chang, S.T.; Kuo, C.J.; Lee, S.S.; et al. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 2007, 50, 4087–4095. [Google Scholar] [CrossRef] [PubMed]
  366. Sharifi-Rad, J.; Quispe, C.; Castillo, C.M.S.; Caroca, R.; Lazo-Vélez, M.A.; Antonyak, H.; Polishchuk, A.; Lysiuk, R.; Oliinyk, P.; De Masi, L.; et al. Ellagic Acid: A Review on Its Natural Sources, Chemical Stability, and Therapeutic Potential. Oxid Med Cell Longev 2022, 2022, 3848084. [Google Scholar] [CrossRef]
  367. Prasanth, M.I.; Sivamaruthi, B.S.; Chaiyasut, C.; Tencomnao, T. A Review of the Role of Green Tea (Camellia sinensis) in Antiphotoaging, Stress Resistance, Neuroprotection, and Autophagy. Nutrients 2019, 11. [Google Scholar] [CrossRef]
  368. Ngwe Tun, M.M.; Luvai, E.; Nwe, K.M.; Toume, K.; Mizukami, S.; Hirayama, K.; Komatsu, K.; Morita, K. Anti-SARS-CoV-2 activity of various PET-bottled Japanese green teas and tea compounds in vitro. Arch Virol 2022, 167, 1547–1557. [Google Scholar] [CrossRef]
  369. Bag, A.; Bag, N. Tea Polyphenols and Prevention of Epigenetic Aberrations in Cancer. J Nat Sci Biol Med 2018, 9, 2–5. [Google Scholar] [CrossRef] [PubMed]
  370. Sun, Q.; Huang, M.; Wei, Y. Diversity of the reaction mechanisms of SAM-dependent enzymes. Acta Pharmaceutica Sinica B 2021, 11, 632–650. [Google Scholar] [CrossRef] [PubMed]
  371. Nandakumar, V.; Vaid, M.; Katiyar, S.K. (-)-Epigallocatechin-3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis 2011, 32, 537–544. [Google Scholar] [CrossRef] [PubMed]
  372. Ciesielski, O.; Biesiekierska, M.; Balcerczyk, A. Epigallocatechin-3-gallate (EGCG) Alters Histone Acetylation and Methylation and Impacts Chromatin Architecture Profile in Human Endothelial Cells. Molecules 2020, 25. [Google Scholar] [CrossRef] [PubMed]
  373. Fang, M.Z.; Wang, Y.; Ai, N.; Hou, Z.; Sun, Y.; Lu, H.; Welsh, W.; Yang, C.S. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 2003, 63, 7563–7570. [Google Scholar] [PubMed]
  374. Guo, C.; Huang, Q.; Wang, Y.; Yao, Y.; Li, J.; Chen, J.; Wu, M.; Zhang, Z.; E, M.; Qi, H.; et al. Therapeutic application of natural products: NAD(+) metabolism as potential target. Phytomedicine 2023, 114, 154768. [Google Scholar] [CrossRef] [PubMed]
  375. Steinmann, J.; Buer, J.; Pietschmann, T.; Steinmann, E. Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea. Br J Pharmacol 2013, 168, 1059–1073. [Google Scholar] [CrossRef] [PubMed]
  376. Ahn, W.S.; Huh, S.W.; Bae, S.M.; Lee, I.P.; Lee, J.M.; Namkoong, S.E.; Kim, C.K.; Sin, J.I. A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression. DNA and cell biology 2003, 22, 217–224. [Google Scholar] [CrossRef]
  377. Stockfleth, E.; Meyer, T. Sinecatechins (Polyphenon E) ointment for treatment of external genital warts and possible future indications. Expert Opinion on Biological Therapy 2014, 14, 1033–1043. [Google Scholar] [CrossRef]
  378. Mekky, R.Y.; El-Ekiaby, N.M.; Hamza, M.T.; Elemam, N.M.; El-Sayed, M.; Esmat, G.; Abdelaziz, A.I. Mir-194 is a hepatocyte gate keeper hindering HCV entry through targeting CD81 receptor. J Infect 2015, 70, 78–87. [Google Scholar] [CrossRef]
  379. Kong, Y.; Feng, Z.; Chen, A.; Qi, Q.; Han, M.; Wang, S.; Zhang, Y.; Zhang, X.; Yang, N.; Wang, J.; et al. The Natural Flavonoid Galangin Elicits Apoptosis, Pyroptosis, and Autophagy in Glioblastoma. Front Oncol 2019, 9, 942. [Google Scholar] [CrossRef] [PubMed]
  380. Aggarwal, V.; Tuli, H.S.; Kaur, J.; Aggarwal, D.; Parashar, G.; Chaturvedi Parashar, N.; Kulkarni, S.; Kaur, G.; Sak, K.; Kumar, M.; et al. Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells. Biomedicines 2020, 8. [Google Scholar] [CrossRef] [PubMed]
  381. Padhye, S.; Ahmad, A.; Oswal, N.; Sarkar, F.H. Emerging role of Garcinol, the antioxidant chalcone from Garcinia indica Choisy and its synthetic analogs. J Hematol Oncol 2009, 2, 38. [Google Scholar] [CrossRef] [PubMed]
  382. Saadat, N.; Gupta, S.V. Potential role of garcinol as an anticancer agent. J Oncol 2012, 2012, 647206. [Google Scholar] [CrossRef]
  383. Aggarwal, V.; Tuli, H.S.; Kaur, J.; Aggarwal, D.; Parashar, G.; Chaturvedi Parashar, N.; Kulkarni, S.; Kaur, G.; Sak, K.; Kumar, M.; et al. Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells. Biomedicines 2020, 8, 103. [Google Scholar] [CrossRef]
  384. Kim, J.-Y.; Jo, J.; Leem, J.; Park, K.-K. Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice. Antioxidants 2020, 9, 1271. [Google Scholar] [CrossRef]
  385. Balasubramanyam, K.; Altaf, M.; Varier, R.A.; Swaminathan, V.; Ravindran, A.; Sadhale, P.P.; Kundu, T.K. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem 2004, 279, 33716–33726. [Google Scholar] [CrossRef]
  386. Biersack, B. Current state of phenolic and terpenoidal dietary factors and natural products as non-coding RNA/microRNA modulators for improved cancer therapy and prevention. Noncoding RNA Res 2016, 1, 12–34. [Google Scholar] [CrossRef]
  387. Fang, M.Z.; Chen, D.; Sun, Y.; Jin, Z.; Christman, J.K.; Yang, C.S. Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res 2005, 11, 7033–7041. [Google Scholar] [CrossRef]
  388. Gerstmeier, J.; Seegers, J.; Witt, F.; Waltenberger, B.; Temml, V.; Rollinger, J.M.; Stuppner, H.; Koeberle, A.; Schuster, D.; Werz, O. Ginkgolic Acid is a Multi-Target Inhibitor of Key Enzymes in Pro-Inflammatory Lipid Mediator Biosynthesis. Front Pharmacol 2019, 10, 797. [Google Scholar] [CrossRef] [PubMed]
  389. Flotho, A.; Melchior, F. Sumoylation: a regulatory protein modification in health and disease. Annu Rev Biochem 2013, 82, 357–385. [Google Scholar] [CrossRef] [PubMed]
  390. Yang, W.S.; Campbell, M.; Chang, P.C. SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication. PLoS Pathog 2017, 13, e1006216. [Google Scholar] [CrossRef] [PubMed]
  391. Bhutta, M.S.; Shechter, O.; Gallo, E.S.; Martin, S.D.; Jones, E.; Doncel, G.F.; Borenstein, R. Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice. Viruses 2021, 13. [Google Scholar] [CrossRef] [PubMed]
  392. Lü, J.M.; Yan, S.; Jamaluddin, S.; Weakley, S.M.; Liang, Z.; Siwak, E.B.; Yao, Q.; Chen, C. Ginkgolic acid inhibits HIV protease activity and HIV infection in vitro. Med Sci Monit 2012, 18, Br293–298. [Google Scholar] [CrossRef] [PubMed]
  393. Pastorino, G.; Cornara, L.; Soares, S.; Rodrigues, F.; Oliveira, M. Liquorice (Glycyrrhiza glabra): A phytochemical and pharmacological review. Phytother Res 2018, 32, 2323–2339. [Google Scholar] [CrossRef] [PubMed]
  394. Sun, Z.G.; Zhao, T.T.; Lu, N.; Yang, Y.A.; Zhu, H.L. Research Progress of Glycyrrhizic Acid on Antiviral Activity. Mini Rev Med Chem 2019, 19, 826–832. [Google Scholar] [CrossRef]
  395. Cao, L.; Ding, W.; Jia, R.; Du, J.; Wang, T.; Zhang, C.; Gu, Z.; Yin, G. Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl4-induced damage in precision-cut liver slices from Jian carp (Cyprinus carpio var. jian) through inhibition of the nf-kƁ pathway. Fish & Shellfish Immunology 2017, 64, 234–242. [Google Scholar] [CrossRef] [PubMed]
  396. Cinatl, J.; Morgenstern, B.; Bauer, G.; Chandra, P.; Rabenau, H.; Doerr, H.W. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003, 361, 2045–2046. [Google Scholar] [CrossRef]
  397. Yue, G.G.; Chan, B.C.; Kwok, H.F.; To, M.H.; Hon, K.L.; Fung, K.P.; Lau, C.B.; Leung, P.C. Screening for anti-inflammatory and bronchorelaxant activities of 12 commonly used Chinese herbal medicines. Phytother Res 2012, 26, 915–925. [Google Scholar] [CrossRef]
  398. Kwon, H.S.; Oh, S.M.; Kim, J.K. Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis. Clin Exp Immunol 2008, 151, 165–173. [Google Scholar] [CrossRef] [PubMed]
  399. Yu, X.Q.; Xue, C.C.; Zhou, Z.W.; Li, C.G.; Du, Y.M.; Liang, J.; Zhou, S.F. In vitro and in vivo neuroprotective effect and mechanisms of glabridin, a major active isoflavan from Glycyrrhiza glabra (licorice). Life Sci 2008, 82, 68–78. [Google Scholar] [CrossRef] [PubMed]
  400. Hsu, Y.L.; Wu, L.Y.; Hou, M.F.; Tsai, E.M.; Lee, J.N.; Liang, H.L.; Jong, Y.J.; Hung, C.H.; Kuo, P.L. Glabridin, an isoflavan from licorice root, inhibits migration, invasion and angiogenesis of MDA-MB-231 human breast adenocarcinoma cells by inhibiting focal adhesion kinase/Rho signaling pathway. Mol Nutr Food Res 2011, 55, 318–327. [Google Scholar] [CrossRef] [PubMed]
  401. Jiang, F.; Mu, J.; Wang, X.; Ye, X.; Si, L.; Ning, S.; Li, Z.; Li, Y. The repressive effect of miR-148a on TGF beta-SMADs signal pathway is involved in the glabridin-induced inhibition of the cancer stem cells-like properties in hepatocellular carcinoma cells. PLoS One 2014, 9, e96698. [Google Scholar] [CrossRef] [PubMed]
  402. Jiang, F.; Li, Y.; Mu, J.; Hu, C.; Zhou, M.; Wang, X.; Si, L.; Ning, S.; Li, Z. Glabridin inhibits cancer stem cell-like properties of human breast cancer cells: An epigenetic regulation of miR-148a/SMAd2 signaling. Mol Carcinog 2016, 55, 929–940. [Google Scholar] [CrossRef] [PubMed]
  403. Mu, J.; Ning, S.; Wang, X.; Si, L.; Jiang, F.; Li, Y.; Li, Z. The repressive effect of miR-520a on NF-κB/IL-6/STAT-3 signal involved in the glabridin-induced anti-angiogenesis in human breast cancer cells. RSC Advances 2015, 5, 34257–34264. [Google Scholar] [CrossRef]
  404. Zhou, C.; Li, X.; Du, W.; Feng, Y.; Kong, X.; Li, Y.; Xiao, L.; Zhang, P. Antitumor effects of ginkgolic acid in human cancer cell occur via cell cycle arrest and decrease the Bcl-2/Bax ratio to induce apoptosis. Chemotherapy 2010, 56, 393–402. [Google Scholar] [CrossRef]
  405. Lü, J.-M.; Yan, S.; Jamaluddin, S.; Weakley, S.M.; Liang, Z.; Siwak, E.B.; Yao, Q.; Chen, C. Ginkgolic acid inhibits HIV protease activity and HIV infection in vitro. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research 2012, 18, BR293. [Google Scholar] [CrossRef]
  406. Ye, M.; Liu, J.K.; Lu, Z.X.; Zhao, Y.; Liu, S.F.; Li, L.L.; Tan, M.; Weng, X.X.; Li, W.; Cao, Y. Grifolin, a potential antitumor natural product from the mushroom Albatrellus confluens, inhibits tumor cell growth by inducing apoptosis in vitro. FEBS Lett 2005, 579, 3437–3443. [Google Scholar] [CrossRef]
  407. Nediani, C.; Ruzzolini, J.; Romani, A.; Calorini, L. Oleuropein, a Bioactive Compound from Olea europaea L., as a Potential Preventive and Therapeutic Agent in Non-Communicable Diseases. Antioxidants (Basel) 2019, 8. [Google Scholar] [CrossRef]
  408. Juli, G.; Oliverio, M.; Bellizzi, D.; Gallo Cantafio, M.E.; Grillone, K.; Passarino, G.; Colica, C.; Nardi, M.; Rossi, M.; Procopio, A. Anti-tumor activity and epigenetic impact of the polyphenol oleacein in multiple myeloma. Cancers 2019, 11, 990. [Google Scholar] [CrossRef] [PubMed]
  409. Yamaguchi, Y.; Kumagai, H. Characteristics, biosynthesis, decomposition, metabolism and functions of the garlic odour precursor, S-allyl-L-cysteine sulfoxide. Exp Ther Med 2020, 19, 1528–1535. [Google Scholar] [CrossRef] [PubMed]
  410. Tolo, F.M.; Rukunga, G.M.; Muli, F.W.; Njagi, E.N.; Njue, W.; Kumon, K.; Mungai, G.M.; Muthaura, C.N.; Muli, J.M.; Keter, L.K.; et al. Anti-viral activity of the extracts of a Kenyan medicinal plant Carissa edulis against herpes simplex virus. Journal of ethnopharmacology 2006, 104, 92–99. [Google Scholar] [CrossRef] [PubMed]
  411. Lin, L.T.; Hsu, W.C.; Lin, C.C. Antiviral natural products and herbal medicines. J Tradit Complement Med 2014, 4, 24–35. [Google Scholar] [CrossRef] [PubMed]
  412. Tsai, Y.; Cole, L.L.; Davis, L.E.; Lockwood, S.J.; Simmons, V.; Wild, G.C. Antiviral properties of garlic: in vitro effects on influenza B, herpes simplex and coxsackie viruses. Planta Med 1985, 51, 460–461. [Google Scholar] [CrossRef] [PubMed]
  413. Abiy, E.; Berhe, A. Anti-bacterial effect of garlic (Allium sativum) against clinical isolates of Staphylococcus aureus and Escherichia coli from patients attending Hawassa Referral Hospital, Ethiopia. Journal of Infectious Diseases and Treatment 2016, 2, 1–5. [Google Scholar] [CrossRef]
  414. Gebreyohannes, G.; Gebreyohannes, M. Medicinal values of garlic: A review. International Journal of Medicine and Medical Sciences 2013, 5, 401–408. [Google Scholar]
  415. Lawson, L.D.; Bauer, R. Phytomedicines of Europe: chemistry and biological activity; ACS Publications: 1998.
  416. Borlinghaus, J.; Albrecht, F.; Gruhlke, M.C.; Nwachukwu, I.D.; Slusarenko, A.J. Allicin: chemistry and biological properties. Molecules 2014, 19, 12591–12618. [Google Scholar] [CrossRef] [PubMed]
  417. Wang, L.; Jiao, H.; Zhao, J.; Wang, X.; Sun, S.; Lin, H. Allicin Alleviates Reticuloendotheliosis Virus-Induced Immunosuppression via ERK/Mitogen-Activated Protein Kinase Pathway in Specific Pathogen-Free Chickens. Front Immunol 2017, 8, 1856. [Google Scholar] [CrossRef]
  418. Weber, N.D.; Andersen, D.O.; North, J.A.; Murray, B.K.; Lawson, L.D.; Hughes, B.G. In vitro virucidal effects of Allium sativum (garlic) extract and compounds. Planta Med 1992, 58, 417–423. [Google Scholar] [CrossRef]
  419. Arreola, R.; Quintero-Fabián, S.; López-Roa, R.I.; Flores-Gutiérrez, E.O.; Reyes-Grajeda, J.P.; Carrera-Quintanar, L.; Ortuño-Sahagún, D. Immunomodulation and anti-inflammatory effects of garlic compounds. J Immunol Res 2015, 2015, 401630. [Google Scholar] [CrossRef] [PubMed]
  420. Metwally, D.M.; Al-Olayan, E.M.; Alanazi, M.; Alzahrany, S.B.; Semlali, A. Antischistosomal and anti-inflammatory activity of garlic and allicin compared with that of praziquantel in vivo. BMC Complement Altern Med 2018, 18, 135. [Google Scholar] [CrossRef] [PubMed]
  421. Prasad, K.; Laxdal, V.A.; Yu, M.; Raney, B.L. Antioxidant activity of allicin, an active principle in garlic. Mol Cell Biochem 1995, 148, 183–189. [Google Scholar] [CrossRef] [PubMed]
  422. Amagase, H. Clarifying the real bioactive constituents of garlic. J Nutr 2006, 136, 716s–725s. [Google Scholar] [CrossRef] [PubMed]
  423. Harris, J.C.; Cottrell, S.L.; Plummer, S.; Lloyd, D. Antimicrobial properties of Allium sativum (garlic). Applied microbiology and biotechnology 2001, 57, 282–286. [Google Scholar] [CrossRef] [PubMed]
  424. El-Saber Batiha, G.; Magdy Beshbishy, A.; L, G.W.; Elewa, Y.H.A.; A, A.A.-S.; Abd El-Hack, M.E.; Taha, A.E.; Y, M.A.-E.; Prasad Devkota, H. Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review. Nutrients 2020, 12. [Google Scholar] [CrossRef] [PubMed]
  425. Trio, P.Z.; You, S.; He, X.; He, J.; Sakao, K.; Hou, D.X. Chemopreventive functions and molecular mechanisms of garlic organosulfur compounds. Food Funct 2014, 5, 833–844. [Google Scholar] [CrossRef] [PubMed]
  426. Fang, F.; Li, H.; Cui, W.; Dong, Y. Treatment of hepatitis caused by cytomegalovirus with allitridin injection--an experimental study. J Tongji Med Univ 1999, 19, 271–274. [Google Scholar] [CrossRef] [PubMed]
  427. Keyaerts, E.; Vijgen, L.; Pannecouque, C.; Van Damme, E.; Peumans, W.; Egberink, H.; Balzarini, J.; Van Ranst, M. Plant lectins are potent inhibitors of coronaviruses by interfering with two targets in the viral replication cycle. Antiviral Res 2007, 75, 179–187. [Google Scholar] [CrossRef]
  428. Liu, Z.F.; Fang, F.; Dong, Y.S.; Li, G.; Zhen, H. Experimental study on the prevention and treatment of murine cytomegalovirus hepatitis by using allitridin. Antiviral Res 2004, 61, 125–128. [Google Scholar] [CrossRef]
  429. Terrasson, J.; Xu, B.; Li, M.; Allart, S.; Davignon, J.L.; Zhang, L.H.; Wang, K.; Davrinche, C. Activities of Z-ajoene against tumour and viral spreading in vitro. Fundam Clin Pharmacol 2007, 21, 281–289. [Google Scholar] [CrossRef]
  430. Walder, R.; Kalvatchev, Z.; Garzaro, D.; Barrios, M.; Apitz-Castro, R. In vitro suppression of HIV-1 replication by ajoene [(e)-(z)-4,5,9-trithiadodeca-1,6,11-triene-9 oxide]. Biomed Pharmacother 1997, 51, 397–403. [Google Scholar] [CrossRef] [PubMed]
  431. Hall, A.; Troupin, A.; Londono-Renteria, B.; Colpitts, T.M. Garlic Organosulfur Compounds Reduce Inflammation and Oxidative Stress during Dengue Virus Infection. Viruses 2017, 9. [Google Scholar] [CrossRef]
  432. Li, Y.N.; Huang, F.; Liu, X.L.; Shu, S.N.; Huang, Y.J.; Cheng, H.J.; Fang, F. Allium sativum-derived allitridin inhibits Treg amplification in cytomegalovirus infection. J Med Virol 2013, 85, 493–500. [Google Scholar] [CrossRef]
  433. Yi, X.; Feng, F.; Xiang, Z.; Ge, L. The effects of allitridin on the expression of transcription factors T-bet and GATA-3 in mice infected by murine cytomegalovirus. J Med Food 2005, 8, 332–336. [Google Scholar] [CrossRef] [PubMed]
  434. Kaschula, C.H.; Hunter, R.; Parker, M.I. Garlic-derived anticancer agents: structure and biological activity of ajoene. Biofactors 2010, 36, 78–85. [Google Scholar] [CrossRef]
  435. Yi, L.; Su, Q. Molecular mechanisms for the anti-cancer effects of diallyl disulfide. Food Chem Toxicol 2013, 57, 362–370. [Google Scholar] [CrossRef] [PubMed]
  436. Choi, H.J.; Bae, E.Y.; Song, J.H.; Baek, S.H.; Kwon, D.H. Inhibitory effects of orobol 7-O-D-glucoside from banaba (Lagerstroemia speciosa L.) on human rhinoviruses replication. Lett Appl Microbiol 2010, 51, 1–5. [Google Scholar] [CrossRef]
  437. Pevear, D.C.; Tull, T.M.; Seipel, M.E.; Groarke, J.M. Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 1999, 43, 2109–2115. [Google Scholar] [CrossRef]
  438. Burgett, A.W.; Poulsen, T.B.; Wangkanont, K.; Anderson, D.R.; Kikuchi, C.; Shimada, K.; Okubo, S.; Fortner, K.C.; Mimaki, Y.; Kuroda, M.; et al. Natural products reveal cancer cell dependence on oxysterol-binding proteins. Nat Chem Biol 2011, 7, 639–647. [Google Scholar] [CrossRef]
  439. Albulescu, L.; Bigay, J.; Biswas, B.; Weber-Boyvat, M.; Dorobantu, C.M.; Delang, L.; van der Schaar, H.M.; Jung, Y.S.; Neyts, J.; Olkkonen, V.M.; et al. Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307. Antiviral Res 2017, 140, 37–44. [Google Scholar] [CrossRef] [PubMed]
  440. Roberts, B.L.; Severance, Z.C.; Bensen, R.C.; Le-McClain, A.T.; Malinky, C.A.; Mettenbrink, E.M.; Nuñez, J.I.; Reddig, W.J.; Blewett, E.L.; Burgett, A.W.G. Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds. Antiviral Res 2019, 170, 104548. [Google Scholar] [CrossRef] [PubMed]
  441. Albulescu, L.; Strating, J.R.; Thibaut, H.J.; van der Linden, L.; Shair, M.D.; Neyts, J.; van Kuppeveld, F.J. Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP. Antiviral Res 2015, 117, 110–114. [Google Scholar] [CrossRef] [PubMed]
  442. Alonso-Álvarez, S.; Pardal, E.; Sánchez-Nieto, D.; Navarro, M.; Caballero, M.D.; Mateos, M.V.; Martín, A. Plitidepsin: design, development, and potential place in therapy. Drug Des Devel Ther 2017, 11, 253–264. [Google Scholar] [CrossRef] [PubMed]
  443. Duke, S.O. Benefits of Resveratrol and Pterostilbene to Crops and Their Potential Nutraceutical Value to Mammals. Agriculture 2022, 12, 368. [Google Scholar] [CrossRef]
  444. Anand David, A.V.; Arulmoli, R.; Parasuraman, S. Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacogn Rev 2016, 10, 84–89. [Google Scholar] [CrossRef] [PubMed]
  445. Noratto, G.D.; Kim, Y.; Talcott, S.T.; Mertens-Talcott, S.U. Flavonol-rich fractions of yaupon holly leaves (Ilex vomitoria, Aquifoliaceae) induce microRNA-146a and have anti-inflammatory and chemopreventive effects in intestinal myofibroblast CCD-18Co cells. Fitoterapia 2011, 82, 557–569. [Google Scholar] [CrossRef] [PubMed]
  446. Pop, S.; Enciu, A.M.; Tarcomnicu, I.; Gille, E.; Tanase, C. Phytochemicals in cancer prevention: modulating epigenetic alterations of DNA methylation. Phytochemistry Reviews 2019, 18, 1005–1024. [Google Scholar] [CrossRef]
  447. Choi, H.J.; Lim, C.H.; Song, J.H.; Baek, S.H.; Kwon, D.H. Antiviral activity of raoulic acid from Raoulia australis against Picornaviruses. Phytomedicine 2009, 16, 35–39. [Google Scholar] [CrossRef]
  448. Saiko, P.; Pemberger, M.; Horvath, Z.; Savinc, I.; Grusch, M.; Handler, N.; Erker, T.; Jaeger, W.; Fritzer-Szekeres, M.; Szekeres, T. Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29 human colon cancer cells: inhibition of ribonucleotide reductase activity. Oncology reports 2008, 19, 1621–1626. [Google Scholar]
  449. Koushki, M.; Amiri-Dashatan, N.; Ahmadi, N.; Abbaszadeh, H.A.; Rezaei-Tavirani, M. Resveratrol: A miraculous natural compound for diseases treatment. Food science & nutrition 2018, 6, 2473–2490. [Google Scholar]
  450. Kala, R.; Tollefsbol, T.; Li, Y. Potential of resveratrol in inhibiting cancer and slowing aging. J Nutr Food Sci S 2012, 5. [Google Scholar] [CrossRef]
  451. Chen, X.; Song, X.; Zhao, X.; Zhang, Y.; Wang, Y.; Jia, R.; Zou, Y.; Li, L.; Yin, Z. Insights into the Anti-inflammatory and Antiviral Mechanisms of Resveratrol. Mediators Inflamm 2022, 2022, 7138756. [Google Scholar] [CrossRef] [PubMed]
  452. Ding, L.; Jiang, P.; Xu, X.; Lu, W.; Yang, C.; Zhou, P.; Liu, S. Resveratrol promotes HSV-2 replication by increasing histone acetylation and activating NF-κB. Biochem Pharmacol 2020, 171, 113691. [Google Scholar] [CrossRef] [PubMed]
  453. Xie, X.H.; Zang, N.; Li, S.M.; Wang, L.J.; Deng, Y.; He, Y.; Yang, X.Q.; Liu, E.M. Resveratrol Inhibits respiratory syncytial virus-induced IL-6 production, decreases viral replication, and downregulates TRIF expression in airway epithelial cells. Inflammation 2012, 35, 1392–1401. [Google Scholar] [CrossRef] [PubMed]
  454. Bijak, M. Silybin, a Major Bioactive Component of Milk Thistle (Silybum marianum L. Gaernt.)-Chemistry, Bioavailability, and Metabolism. Molecules 2017, 22. [Google Scholar] [CrossRef] [PubMed]
  455. Anestopoulos, I.; Sfakianos, A.P.; Franco, R.; Chlichlia, K.; Panayiotidis, M.I.; Kroll, D.J.; Pappa, A. A novel role of silibinin as a putative epigenetic modulator in human prostate carcinoma. Molecules 2016, 22, 62. [Google Scholar] [CrossRef] [PubMed]
  456. Edwards, R.B.; Lucas, D.M.; Lozanski, G.; Johnson, A.J.; Su, B.-N.; Lin, T.S.; Byrd, J.C.; Kinghorn, A.D.; Grever, M.R. Silvestrol, a Rocaglate Derivative from the Indonesian Plant Aglaia foveolata, Has Significant Bcl-2- and p53-Independent Anti-Tumor Activity against Chronic Lymphocytic Leukemia Cells. Blood 2006, 108, 2600. [Google Scholar] [CrossRef]
  457. M de Figueiredo, S.; S Binda, N.; A Nogueira-Machado, J.; A Vieira-Filho, S.; B Caligiorne, R. The antioxidant properties of organosulfur compounds (sulforaphane). Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2015, 9, 24–39. [Google Scholar]
  458. Dos Santos, P.W.d.S.; Machado, A.R.T.; De Grandis, R.A.; Ribeiro, D.L.; Tuttis, K.; Morselli, M.; Aissa, A.F.; Pellegrini, M.; Antunes, L.M.G. Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food and Chemical Toxicology 2020, 136, 111047. [Google Scholar] [CrossRef]
  459. Chen, W.-C.; Huang, C.-H.; Liu, W.; Lee, J.-C. Sulforaphane suppresses dengue virus replication by inhibition of dengue protease and enhancement of antiviral interferon response through Nrf2-mediated heme oxygenase-1 induction. Antiviral Research 2022, 207, 105400. [Google Scholar] [CrossRef] [PubMed]
  460. Ordonez, A.A.; Bullen, C.K.; Villabona-Rueda, A.F.; Thompson, E.A.; Turner, M.L.; Davis, S.L.; Komm, O.; Powell, J.D.; D'Alessio, F.R.; Yolken, R.H.; et al. Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses. bioRxiv, 1101. [Google Scholar] [CrossRef]
  461. Zeng, A.; Wang, D.; Wu, N.; Yang, R.; Nan, G.; Bian, X.; Yang, G. Extraction of Tanshinone IIA and Cryptotanshinone from the Rhizome of Salvia miltiorrhiza Bunge: Kinetics and Modeling. Separation Science and Technology 2014, 49, 2330–2337. [Google Scholar] [CrossRef]
  462. Machado, D.G.; Neis, V.B.; Balen, G.O.; Colla, A.; Cunha, M.P.; Dalmarco, J.B.; Pizzolatti, M.G.; Prediger, R.D.; Rodrigues, A.L. Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: evidence for the involvement of the dopaminergic system. Pharmacol Biochem Behav 2012, 103, 204–211. [Google Scholar] [CrossRef] [PubMed]
Preprints 88054 g001
Figure 1. DNA methylation and its modulation of gene expression. Transcriptions factors recognize gene promoter and bring RNA polymerase to transcript the gene (A); DNA methylation at CpG island switch on/off gene according to the locus where methylation occurs (B).
Figure 1. DNA methylation and its modulation of gene expression. Transcriptions factors recognize gene promoter and bring RNA polymerase to transcript the gene (A); DNA methylation at CpG island switch on/off gene according to the locus where methylation occurs (B).
Preprints 88054 g001
Preprints 88054 g002
Figure 2. Nucleosome structure and histone modifications. The amino acids chain includes functional groups at specific amino acid residues (histone tails) which modify the interaction between DNA and histones (left); acetylation of histone N-terminal tails facilitates the transcription initiation (right).
Figure 2. Nucleosome structure and histone modifications. The amino acids chain includes functional groups at specific amino acid residues (histone tails) which modify the interaction between DNA and histones (left); acetylation of histone N-terminal tails facilitates the transcription initiation (right).
Preprints 88054 g002
Preprints 88054 g003
Figure 3. MicroRNA synthesis, translational repression, and degradation of mRNA. MiRNA are transcribed by RNA polymerase (Pol II), processed by DROSHA and DGCR8 to give pre-miRNA; pre-miRNA is transported to the cytosol where DICER enzyme together with other proteins process the miRNA into a single strand RNA which is incorporated into RISC complex and binds ARGONAUTE. The interaction of miRNA with mRNA is followed by mRNA decay and translational repression.
Figure 3. MicroRNA synthesis, translational repression, and degradation of mRNA. MiRNA are transcribed by RNA polymerase (Pol II), processed by DROSHA and DGCR8 to give pre-miRNA; pre-miRNA is transported to the cytosol where DICER enzyme together with other proteins process the miRNA into a single strand RNA which is incorporated into RISC complex and binds ARGONAUTE. The interaction of miRNA with mRNA is followed by mRNA decay and translational repression.
Preprints 88054 g003
Preprints 88054 g004
Figure 4. Viral infection and epigenetic machinery. Viral infection affects global DNA methylation and the expression and activity of DNMTs. In addition, viral infection affects global histone modifications and modulates the expression and activity of HAT and HDAC. Viral infection also modulates the expression of miRNA, which is required to evade immune response and to promote viral replication.
Figure 4. Viral infection and epigenetic machinery. Viral infection affects global DNA methylation and the expression and activity of DNMTs. In addition, viral infection affects global histone modifications and modulates the expression and activity of HAT and HDAC. Viral infection also modulates the expression of miRNA, which is required to evade immune response and to promote viral replication.
Preprints 88054 g004
Preprints 88054 g005
Figure 5. Anti-viral activity of curcumin. The figure shows the broad spectrum of antiviral activity of curcumin, which attacks most of the viruses studied.
Figure 5. Anti-viral activity of curcumin. The figure shows the broad spectrum of antiviral activity of curcumin, which attacks most of the viruses studied.
Preprints 88054 g005
Preprints 88054 g006
Figure 6. Anti-viral activity of EGCG against Influenza (IAV), human papilloma (HPV) and Hepatitis C (HCV) viruses. HCV replication dependent on host CD81 and host miR-122. EGCG upregulated miR-548m expression which in turn regulate CD81 expression and downregulate miR-122 (also mediated by other bioactive substances such as resveratrol) to exert anti-HCV activity. IAV infection caused a significant decrease of microRNA let-7 expression which is required for regulating expression of type I interferon. EGCG and other bioactive substances, such as quercetin, upregulate let-7 to increase interferon expression and effectively inhibit IAV infection.
Figure 6. Anti-viral activity of EGCG against Influenza (IAV), human papilloma (HPV) and Hepatitis C (HCV) viruses. HCV replication dependent on host CD81 and host miR-122. EGCG upregulated miR-548m expression which in turn regulate CD81 expression and downregulate miR-122 (also mediated by other bioactive substances such as resveratrol) to exert anti-HCV activity. IAV infection caused a significant decrease of microRNA let-7 expression which is required for regulating expression of type I interferon. EGCG and other bioactive substances, such as quercetin, upregulate let-7 to increase interferon expression and effectively inhibit IAV infection.
Preprints 88054 g006
Preprints 88054 g007
Figure 7. Natural bioactive substances with epigenetic modifying activity. Shows plant-derived bioactive compounds that modulate DNA methylation (left), histone medication (middle), and miRNA expression (right).
Figure 7. Natural bioactive substances with epigenetic modifying activity. Shows plant-derived bioactive compounds that modulate DNA methylation (left), histone medication (middle), and miRNA expression (right).
Preprints 88054 g007
Table 1. Plant-derived essential oils (EOs) with antiviral activity.
Table 1. Plant-derived essential oils (EOs) with antiviral activity.
Plant Plant part Main bioactive constituents Virus IC50 a SIb Mode of action References
Aloysia citriodora Palau (Verbenaceae) nr geranial (18.9%), neral (15.6%), limonene (10.7%), 1,8-cineole (5.0%), spathulenol (4.7%), geraniol (2.7%) Yellow fever virus 19.4 μg/mL 2.6 nrc [142]
Artemisia kermanensis Podlech (Compositae) aerial parts α-thujone (13.8%), camphore (10.2%), β-thujone (6.2%), p-Mentha-1,5-dien-8-ol (4.4%) HSV-1 0.004% 66.4 nr [130]
Ayapana triplinervis (Vahl) R.M.King & H.Rob. (Compositae) aerial parts thymohydroquinone dimethyl ether (87.1%), α-phellandrene (2.0%), β-selinene (1.9%) Zika virus 38 μg/mL 12.5 inhibitor of internalization process [143]
Cananga odorata (Lam.) Hook.f. & Thomson (Annonaceae) nr benzyl salicylate (49.3%), benzyl benzoate (18.7%), linalool (16.6%), α-gurjunene (7.1%) HIV-1 0.60 µg/mL nr nr [131]
Cinnamomum zeylanicum Blume (Lauraceae) leaves eugenol (nr) H1N1 < 3.1 µL/mL > 4 intercellular [144]
Citrus × bergamia Risso & Poit. (Rutaceae) fruit peel (–)-linalyl acetate (nr), (–)-linalool (nr), (+)-limonene (nr), γ-terpinene (nr), β-pinene (nr), α-pinene (nr), α-terpinene (nr) H1N1 < 3.1 µL/mL > 5 intercellular [144]
Cymbopogon citratus (DC.) Stapf (Poaceae) nr cis-citral (59.2%), β-pinene (22.5%), cis-verbenol (6.1%), nerol (5.0%) HIV-1 0.61 µg/mL 1.1 nr [131]
Cymbopogon flexuosus (Nees ex Steud.) W.Watson (Poaceae) grass geranial (nr), neral (nr) H1N1 < 3.1 µL/mL > 4 nr [144]
Cymbopogon nardus (L.) Rendle (Poaceae) nr nr HIV-1 1.2 mg/mL nr nr [132]
Dysphania ambrosioides (L.) Mosyakin & Clemants (Amaranthaceae) aerial parts cis-ascaridole (60.3%), m-cymene (22.2%), α-terpinene (1.8 %), thymol (1.1%) Coxsackie virus B4 21.7 μg/mL 74.3 nr [145]
Eucalyptus caesia Benth. (Myrtaceae) aerial parts 1,8-cineole (40.2%), p-cymene (14.1%), γ-terpinene (12.4%), α-pinene (7.7%), terpinen-4-ol (5.6%) HSV-1 0.007% 38.8 nr [130]
Eucalyptus globulus Labill. (Myrtaceae) leaves 1,8-cineole (nr), α-pinene (nr) H1N1 < 50µL/mL > 0.5 intercellular [131]
1,8-cineole (68.0%), globulol (5.4%), trans-pinocarveol (4.6%), α-pinene (3.7%) Coxsackie virus B3 0.7 mg/mL 22.8 intercellular [146]
Fortunella margarita Lour. Swingle (Rutaceae) fruits terpineol (55.5%), τ-carveol (5.5%), limonene (1.7%), muurolene (5.5%), cadinene (2.0%) H5N1 6.8 µg/mL nr nr [147]
Illicium verum Hooker f. (Schisandraceae) fruits (E)-anethole (80.0%) HSV-1 1 µg/mL 160 intercellular [129]
Lallemantia royleana (Benth.) Benth. (Lamiaceae) aerial parts (E)-pinocarvyl acetate (26.0%), pinocarvone (20.0%), verbenone (7.1%), (E)-β-ocimene (4.1%), (E)-carveol (5.3%), 3-thujen-2-one (5.1%), pulegone (4.4%), (Z)-carveol (3.5%), linalool (3.4%) HSV-1 0.011% 6.4 intercellular [148]
Lavandula officinalis Chaix (Lamiaceae) flowers linalyl acetate (nr), linalool (nr) H1N1 < 3.1 µL/mL > 8 intercellular [131]
Lippia alba (Mill.) N.E.Br. ex Britton & P.Wilson (Verbenaceae) nr carvone (39.7%), limonene (30.6%), bicyclosesquiphellandrene (8.9%), piperitenone (4.5%), piperitone (2.8%), β-bourbonene (1.7%) Yellow fever virus 4.3 μg/mL 30.6 intercellular and intracellular [142]
Lippia graveolens Kunth (Verbenaceae) nr carvacrol (56.8%), o-cymene (32.2%), γ-terpinene (3.7%) HSV-1 99.6 µg/mL 7.4 intercellular [149]
ACVR-HHV-1 55.9 µg/mL 13.1 intercellular
Bovine viral diarrhoea virus 78 μg/mL 7.2 intracellular
Respiratory syncytial virus 68 μg/mL 10.8 intercellular
Bovine herpes virus 2 58.4 μg/mL 9.7 intercellular and intracellular
Melaleuca alternifolia (Maiden & Betche) Cheel (Myrtaceae) leaves nr HSV-1 13.2 µg/mL 43 intracellular [150]
Mentha suaveolens Ehrh. (Lamiaceae) leaves piperitenone oxide (86.8%), α-cubebene (2.1%), pulegone (1.4%), limonene (1.4%), caryophyllene (1.3%) HSV-1 5.1 µg/mL 67 intracellular [151]
Osmunda regalis L. (Osmundaceae) aerial parts hexahydrofarnesyl acetone (11.8%), 2,4-di-t-butylphenol (6.8%), phytol (6.5%), neophytadiene (4.6%), 1-octadecene (4.4%), 1- eicosene (4.4%), 1-hexadecene (4.1%) Coxsackie virus B4 2.2 μg/mL 789.8 nr [152]
Pelargonium graveolens L'Hér. (Geraniaceae) flowering aerial parts citronellol (nr), geraniol (nr) H1N1 < 3.1 µL/mL > 21 intercellular [131]
Pulicaria vulgaris Gaertn. (Compositae) aerial parts thymol (50.2%), p-menth-6-en-2-one (carvotanacetone, 20.2%), thymol isobutyrate (16.9%), menthan-2-one (4.3%) HSV-1 0.001% 1 intercellular [148]
Rosmarinus officinalis L. (Lamiaceae) aerial parts α-pinene (23.9%), verbenon (15.4%), camphor (11.0%), p-cymene (7.5%), 3-octanone (5.6%) HSV-1 0.006% 46.1 nr [130]
eucaliptol (50.6%), camphor (13.3%), α-pinene (10.1%), β-pinene (7.7%), camphene (4.6%) HIV-1 0.18 µg/mL 3.6 nr [131]
Salvia desoleana Atzei & V.Picci (Lamiaceae) aerial parts linalyl acetate (30.2%), germacrene D (18.7%), α-terpinyl acetate (16.8%), 1,8-cineole (10.2%), linalool (5.1%) Acyclovir-resistant HSV-2 28.6 µg/mL 55.2 intercellular and intracellular [153]
Satureja hortensis L. (Lamiaceae) aerial parts carvacrol (32.4%), γ-terpinene (32.0%), thymol (10.0%), p-cymene (6.6%), α-pinene (4.3%) HSV-1 0.008% 32.2 nr [130]
Sinapis arvensis L. (Brassicaceae) flowers cubenol (14.3%), 2-phyenyl isothiocyanate (7.5), dimethyl trisulfide (5.2%), thymol (4.6%), δ-cadinene (3.4%) HSV-1 0.035% 1.5 intercellular [148]
Thymbra capitata (L.) Cav. (Lamiaceae) aerial parts cinnamaldehyde (nr), carvacrol (nr) HSV-1 17.6 µg/mL 6.0 intercellular [154]
HSV-2 18.6 µg/mL 6.9 intercellular
Thymus vulgaris L. (Lamiaceae) aerial parts 1,8-cineole (nr), terpenyl acetate (nr), borneol (nr) H1N1 < 3.1 µL/mL > 4 intercellular [144]
thymol (37.8%), iso-thymol (23.2%), γ-terpinene (13.2%), β-caryophyllene (4.2%), linalool (3.3%) HIV-1 1.30 1.6 nr [131]
Zataria multiflora Boiss. (Lamiaceae) aerial parts thymol (33.1%), carvacrol (25.9%), p-cymene (11.3%), α-pinene (3.9%) HSV-1 0.003% 55.4 nr [130]
aIC50, half maximal inhibitory concentration; bSI, selectivity index; cnr, not rep.
Table 2. Plant-derived extracts with antiviral activity.
Table 2. Plant-derived extracts with antiviral activity.
Plant Plant part Extract Main bioactive constituents Virus IC50 a SIb Mode of action References
Agrimonia pilosa Ledeb. (Rosaceae) whole plant ethanol extract nr H1N1,
HV A-B		 0.5-1 μg/mL nr block uncoating process [155]
Aloe vera (L.) Burm.f. (Xanthorrhoeaceae) leaf Gel nr HSV-1 5% nr replication inhibitor [156]
Arachis hypogaea L. (Leguminosae) peanut skin ethanol extract nr H1N1 1.3 μg/mL 5.2 early stages of infection inhib. [157]
Avicennia marina (Forssk.) Vierh. (Acanthaceae) leaf methanol extract nr HSV-1 9 μg/mL 9.1 viral replication inhib. [158]
HIV 15 μg/mL 5.2 interference with replication cycle
Centella asiatica (L.) Urb. (Apiaceae) leaf water extract nr HIV 36 μg/mL nr immunomodulatory effect [159]
alcoholic extract HIV 8 μg/mL
Combretum adenogonium Steud. ex A.Rich. (Combretaceae) root water/ethanol extract nr HIV-1 24.7 μg/mL nr protease inhibitor [160]
Copaifera reticulate Ducke (Leguminosae) stem, barkand leaf water/ethanol extract phenolics, alcohols, organic acids HSV-2 50 μg/mL nr block virus attachment [161]
Cornus canadensis L. (Cornaceae) leaf water/ethanol extract tellimagrandin I and other hydrolysable tannins HSV-1 9 μg/mL nr virus absorption inhibitor [162]
Embelia ribes Burm.f. (Primulaceae) fruit ethylacetate extract embelin H1N1 0.2 μg/mL 32 block virus entry [163]
Epimedium koreanum Nakai (Berberidaceae) bark water extract nr HSV 0.20 μg/mL 23.5 immunomodulatory effect [164]
Equisetum giganteum L. (Equisetaceae) root and stem water/ethanol extract phenolics, alcohols, organic acids HSV-2 18 μg/mL nr block virus attachment [161]
Eupatorium perfoliatum L. (Compositae) aerial part hydroalcoholic extract nr H1N1 7 μg/mL 52 viral attachment inhibitor [165]
Euphorbia hirta L. (Euphorbiaceae) aerial part methanol extract nr HIV-1 38 μg/mL nr RT inhib. [166]
HIV-2 22 μg/mL
Ficus religiosa L. (Moraceae) bark methanol extract nr HSV-2 5.2 μg/mL 31.1 nr [167]
Hemidesmus indicus L. Br. ex Schult. (Apocynaceae) root water/methanol extract 2-hydroxy-4-methoxybenzaldehyde (0.41 mg/g), 3-hydroxy-4- methoxybenzaldehyde (0.16 mg/g) HSV-1 66.8 μg/mL nr anti-ER α-glucosidase inhib. [168]
2-hydroxy-4-methoxybenzaldehyde (0.41 mg/g), 3-hydroxy-4- methoxybenzaldehyde (0.16 mg/g) HSV-2 70.6 μg/mL
Jatropha multifida L. (Euphorbiaceae) stem water extract nr H1N1 25 μg/mL nr block virus entry [169]
Paeonia lactiflora Pall. (Paeoniaceae) root ethanol extract nr H1N1 0.016 mg/mL 13.5 block several stages of infection [170]
Pedilanthus tithymaloides (L.) Poit. (Euphorbiaceae) leaf methanol extract 2-(3,4-dihydroxy-phenyl)-5,7-dihydroxy-chromen-4-one or luteolin HSV-2 48.5 μg/mL 9.0 NF-B signalling pathway modulation [171]
Prunella vulgaris L. (Lamiaceae) flowers water extract nr HIV 0.8 μg/mL nr early post-virus binding interference [172]
Prunus dulcis (Mill.) DA Webb (Rosaceae) almond skin methanol/HCl extract nr HSV-1 0.04 mg/mL nr block virus entry [173]
Quercus brantii Lindl. (Fagaceae) fruit chloroform extract nr HSV-1 2.9 μg/mL nr block virus entry [174]
Quercus persica Jaub. & Spach (Fagaceae) fruit water/ethanol extract nr HSV-1 0.26 μg/ml nr attachment inhib. [164]
Rhus aromatica Aiton (Anacardiaceae) root/stem bark water extract gallic acid HSV-1 0.0005 % nr nr [175]
Rhus aromatica Aiton (Anacardiaceae) root/stem bark water extract gallic acid HSV-2 0.0043% nr nr [175]
Schinus terebinthifolia Raddi (Anacardiaceae) bark water/ethanol extract condensed tannins (catechin, 5.4 mg/L) HSV-1 0.21 μg/mL < 49.0 virucidal effect [176]
Solanum melongena L. (Solenaceae) peel ethanol/HCl extract delphinidin-3-rutinoside (90.3-115.0 μg/mg), chlorogenic acid (24.5-60.7 μg/mg) HSV-1 83.4 μg/mL nr reduction of viral protein expression [177]
Strychnos pseudoquina A. St.-Hil. (Loganiaceae) stem bark ethyl acetate extract nr HSV-1 5.29 μg/mL nr interference with various step of virus cycle [178]
Strychnos pseudoquina A. St.-Hil. (Loganiaceae) stem bark ethyl acetate extract nr HSV-2 6.55 μg/mL nr interference with various step of virus cycle [178]
Tanacetum parthenium (L.) Sch.Bip. (Compositae) aerial parts water/ethanol extract chlorogenic acid, flavonoids (aglycones and glycosylated flavonoids), parthenolide HSV-1 3.1 μg/mL nr viral replication inhib. [179]
Taxodium distichum (L.) Rich. (Cupressaceae) cone, leaf, stem water extract nr H1N1 0.05 mg/mL 5.6 block virus entry [180]
Vachellia nilotica (L.) P.J.H. Hurter & Mabb. (Leguminosae) bark methanol extract nr HSV-2 4.71 μg/mL 30.6 block virus attachment [181]
Vachellia nilotica (L.) P.J.H. Hurter & Mabb. (Leguminosae) bark methanol extract nr HPV-16 1.80 μg/mL 32.6 block virus attachment [181]
Vachellia nilotica (L.) P.J.H. Hurter & Mabb. (Leguminosae) bark methanol extract nr HSV-2 acyclovir resistant 6.71 µg/mL 21.5 block virus attachment [181]
Vigna radiata (L.) R.Wilczek (Leguminosae) sprout methanol/HCl extract nr HSV-1 7.62 μg/mL nr virucidal effect [182]
Table 3. Anti-viral activity of plant bioactive substances.
Table 3. Anti-viral activity of plant bioactive substances.
Name Structure Anti-viral activity and mode of action
Andrographolide Preprints 88054 i001 Modulates miR-377 to regulate HO-1.
Downregulates miR-433 to regulate glutathione cysteine ligase.
Upregulates miR-17, miR-224 and miR-181a [183].
Inhibits virus replications such HIV, HSV-1, HBV, HCV,ZIKV, DENV, CHIKV, FMDV, and IAV [184] [185,186].
Prevents EBV reactivation by suppressing EBV lytic genes via histone modifications [187].
Also prevents IVA-induced inflammation through modulation of NF-κB and JAK-STAT signaling pathways [188].
Apigenin A potent inhibitor of HDAC1, 3 [189].
Exhibits antiviral properties against IAV, HRV, HSV, enterovirus, HBV, HCV, EV71, CVB1 and SARS-COV2 [190,191,192,193] [194]. Anti-viral activity is attributed by inhibiting HDAC activity and chromatin remodeling [189,195].
Downregulates miR-103 [196], miR-155 [113]and miR-122 [197] to affect HCV and HIV replication [115,116,117].
Baicalein Preprints 88054 i002 Inhibits HBV [198], HIV [199] , DENV [200], HSV-1 [201].
Inhibits DNMT and HDAC and affect influence epigenetic modifications [202,203].
Upregulates miR-3,178 [204] which target HDAC10 [203].
Exhibits potent antiviral activity against DENV [200]
Berberine Regulates AMPK activity [205] and suppresses of SIRT1 deacetylases [206].
inhibits miR-21 expression [207].
inhibits replication of HSV [208], HCMV [209], HPV [210], DENV [211], HIV [212], HCV [213], IAV [214] and SARS-COV2 [215].
Also inhibits p38 MAPK activity [38] which might attributed for anti-viral activity [41], [41], [42], [43,44] [45], [216].
Betulinic acid Preprints 88054 i003 A computational approach predicted the capacity to alter HDAC6 and HDAC10 activity [217].
Inhibits DENV-2 NS5 polymerase activity [218] and HBV replication [219].
C-3 esterification of lead resulted in the discovery of Bevirimat, an HIV-1 maturation inhibitor.
Butyric acid
Induces HDAC expression and activity by upregulation of miR-203 promoter methylation [220].
Inhibits HBV replication by reducing HBx protein expression, HBV-DNA and hepatitis B surface antigen (HBsAg) [221].
Cardamonin Preprints 88054 i004 Exhibits antiviral action against the human coronavirus HCoV-OC43 which was mediated by induction of p38 MAPK signaling pathway [222].
Cordycepin Promotes methylation of EBV genomic sites near Fp/Qp promoters.
Increases DNMT3 [223] and reducing EBV replication [224].
As adenosine derivative exhibits antiviral activity against several viruses including IAV, plant viruses, HIV, murine leukemia virus, EBV [225,226,227,228,229] and COVID-19 [230].
Corosolic acid Alters CpG methylation sites, resulting in altered gene expression [231].
Increases the expression of acetylated histone H3 lysine 27 (H3K27ac), while decreasing histone H3 lysine 27 trimethylation (H3K27Me3) [232].
Exhibits anti-viral activity against a number of viruses were reported [233] .
Curcumin Preprints 88054 i005 Decreases the expression of HDAC1, HDAC3, HDAC8 and histone acetyltransferase p300 while enhancing the expression of Ac-histone H4 protein [234].
Reduces HAT activity and inhibits DNMT [235].
Inhibition of HBV replication was attributed to a decrease in the acetylation level of cccDNA-bound histone H3 and H4 [236].
Downregulates miR-350, miR-17-2-3p, let 7e-3p, miR-1224, miR-466b-1-3p, miR-18a-5p, and miR-322-5p
Upregulates miR-122-5p, miR-3473, miR-182, and miR-344a-3p [237].
inhibits the replication of various viruses, including HBV [236], HIV [238], IAV [239], HPV-18 [240], ZIKV, CHIKV, VSV, CVB3, EV71, RSV, HSV-2, KSHV and HAdV [241].
Ellagic acid Increases HDACs gene expression and histone arginine methylation [242],
Decreases H3K9 acetylation and HDAC9 dissociation [242].

Inhibits SARS-CoV-2 viral entry, and replication [243].
Epigallocatechin gallate (EGCG) Preprints 88054 i006 Inhibits the activity of DNMT 1, DNMT 3a, DNMT 3b [244] and HDACs [245] and downregulates the expression of HDAC1, HDAC2, and HDAC3 expression [246]. Inhibits HAT activity [247].
Decreases the levels of let-7e-5p, miR-103a-3p, miR-151a-5p, miR-195-5p, miR-222-3p, miR-23a-3p, miR-23b-3p, miR-26a-5p, miR-27a-3p, miR-29b-3p, miR-3195, miR-3651, miR-4281, miR-4459, miR-4516, miR-762, and miR-125b-5p [248].
Induces the expression of miR-3663-3p, miR-1181, miR-3613-3p, miR1281, miR-1539, miR-221-5p, miR-374b, miR-4306, miR-500a-5p, miR590-5p miR-140-3p and miR-221 [249] [250,251].
Inhibits the replication of IAV, HBV, HCV, HSV-1 and HSV-2, HPV, ZIKV and SARS-COV2 [252,253,254,255,256,257,258].
Upregulates miR-548m and inhibit miR-122 expression which modulate HCV infectivity [255].
Upregulates let-7 to increased interferon expression and inhibit IAV infection [197].
Galangin Inhibits HDAC activity [259] and upregulates miR-455-5p [260].
Exhibits antiviral activity against HSV-1 and CoxB1 [261].
Garcinol Preprints 88054 i007 Decreases HAT activity of p300 and pCAF [262].
Downregulates miR-21, miR-494, miR-495, and miR-1977 [263].
Upregulates miR-453, miR-128, miR-1280 and miR-720, let-7a, let-7e, let-7f, miR-200b, and miR-200c [264].
Inhibits HIV-1 reverse transcriptase-associated ribonuclease H [265].
Genistein Reduces HDAC while increasing HAT activity [266].
Inhibits miR-223 and miR-223 expression [267] whom involved in regulation of immune response and viral infections [117,118] [119].
Ginkgolic acid Preprints 88054 i008 Impairs protein SUMOylation [268].
Inhibits HSV-1, HSV-2, VZV, HCMV, ZIKV, IAV, EBV, HIV, EBOV and Coronavirus COVID-19 [269].
Glycyrrhizic acid Inhibits replications of various viruses including HBV, HCV, IAV H1N1, HIV [270], NDV [271], SARS-COV2 [272,273,274], RSV, VACV, HSV [275] and VSV [275,276].

Exhibits anti-inflammatory effects decreasing IL-6 release [277] by regulating NF-κB, PI3K signaling pathways [278].
Inhibits viral replication of various viruses including HBV, HCV, IAV H1N1 and HIV [270].
Grifolin Preprints 88054 i009 Reduces Elk1 transcription as well as its binding to the DNMT1 promoter region [279].
Modulates of ERK1/2-Elk1-DNMT1 signaling [280].
Oleacein down-regulates several class I/II HDACs [281,282].
Exhibits antiviral effect against HIV-1 [283].
Plitidepsin Preprints 88054 i010 Targets the eukaryotic translation elongation factor 1A (eEF1A) [284].
Exhibits anti-viral activity against RSV and gastroenteritis coronavirus [285] and SARS-CoV-2 [286] [287].
Pterostilbene Modulates HDAC activity and inhibited SIRT1 [288] [289].
Inhibits SARS-CoV-2 Replication [290]
Quercetin Preprints 88054 i011 Enhances histone H3 acetylation, activates HAT, and inhibits HDAC activities [291].
Inhibits HMT [292].
Inhibits miR-146a expression [293], a regulator of HIV replication [294], and miR-16, miR-217, and miR-145 [295,296,297].
Inhibits replication of IAV H1N1, IVA H3N2, HBV, HCV, DENV, poliovirus, rhinovirus, CHIKV, MERS-CoV, HSV 1/2, EBV, RSV , Arbovirus, EBOV, HIV, Japanese encephalitis virus , hAdV, enterovirus, ZIKV, NDV, Mayaro virus (MAYV) and SARS-COV2 [192,257,298,299,300].
Activates SIRT1 which resulted in inhibition of HCV [301]
Upregulates let-7 which restore anti-viral immune response and thus exhibits anti-influenza activity [197].
Resveratrol Inhibits HDAC [302,303] and activates SIRT1 [304].
Decreases the levels of miR-17, miR-21, miR-25, miR-92a-2, miR-103-1, miR-103-2 [305] and upregulates miR-200c [306].
In humans study increases miR-21, miR-181b, miR-663, and miR-30c, while reduces inflammatory cytokines like IL-6, CCL3, IL-1β, and TNF-α [307].
Inhibits HSV infection [308], beta-corona viruses such as MERS-COV and SARS-COV2 [309], Varicella-zoster virus (VZV) wild-type and DNA polymerase mutants with acyclovir-resistant VZV [310,311], VEEV [312], EBV [313], CV [314] and RSV.
SIRT proteins regulate HBV replication and thus SIRTs modulators such as resveratrol are suitable as anti-HBV and anti-RSV infections [315] [316].
Silibinin Preprints 88054 i012 Inhibits the expression of HDAC1, HDAC2, HDAC3, HDAC6, SET domain proteins (SETD1A, D4, D6), and lysine-specific demethylases (KDM 5B, 5C, 4A) [317].
Inhibits DNMTs [318] [319,320].
Downregulates expression of miR-21 and miR-155 [321].
Exhibits anti-viral activity againsdt HBV, DENV, CHIKV, MAYV, IVA, HIV, and HBV [322].
Silvestrol Targets the eukaryotic initiation factor-4A (eIF4A) [323].
Exhibits activity against EBOV, ZIKV, CHIKV and coronaviruses, MERS-CoV, HCoV-229E and SARS-CoV-2 [324,325,326] [327,328,329].
Sulforaphane Preprints 88054 i013 Reduces HDAC activity [330] while increases acetylated histones H3 and H4 expression [330].
Upregulates let-7 expression and exhibits anti-IVA activity [197] and diminishes viral-induced immune cell activation in the lungs [331].
inhibits replications of HCV and DENV [332]
Tanshinone IIA Decreases the expression and activity of HDACs [333].
By inhibiting MAPK p38 compromised the replications of number of viruses including DENV [42], coronavirus [43], VEEV [44], and EV71 [45], SFTSV, HSV-1 and SARS-CoV-2 [46,334].
Ursolic acid Preprints 88054 i014 Reduces the expression of HDAC1, HDAC2, HDAC3, HDAC8 (Class I), HDAC6 and HDAC7 (Class II) [335].
Exhibits anti-cytomegalovirus activity [336].
Withaferin A Downregulates HDAC1 [337] [338].
Decreases HMT activity, but enhanced HAT activity [338].
Inhibits Mpro main protease of SARS-COV2 [339]. Attenuates H1N1 IVA [340].
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
bsky
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

Privacy Settings

© 2025 MDPI (Basel, Switzerland) unless otherwise stated