Curcumin, a hydrophobic bioactive constituent from Curcuma longa, has several health promoting properties including anti-atherosclerotic properties. Further, curcumin has blood glucose- and lipid-lowering properties, prophylactic, and therapeutic effects in other cardiometabolic diseases. Atherosclerosis is an umbrella term for a series of degenerative and hyperplasic lesions such as thickening or sclerosis in large and medium -sized artery walls that decrease vascular-wall elasticity and lumen diameter. The atherosclerotic cerebro-cardiovascular disease has become a major concern to human health in recent years. Considering the notable cardiovascular actions of curcumin, the present review summarizes the current status and future perspective of research on curcumin and its ability to prevent or treat atherosclerosis

Psychedelics are drugs capable of eliciting profound alterations in the subjective experience of the users, sometimes with long-lasting consequences. Because of this, psychedelic research tends to focus on human subjects, given their capacity to construct detailed narratives about the contents of their consciousness experiences. In spite of its relevance, the interaction between serotonergic psychedelics and language production is comparatively understudied in the recent literature. This review is focused on two aspects of this interaction: how the acute effects of psychedelic drugs impact on speech organization regardless of its semantic content, and how to characterize the subjective effects of psychedelic drugs by analyzing the semantic content of written retrospective reports. We show that the computational characterization of language production is an emergent powerful tool to predict the therapeutic outcome of individual experiences, relate the effects elicited by psychedelics with those associated with other altered states of consciousness, draw comparisons between the psychedelic state and the symptomatology of certain psychiatric disorders, and investigate the neurochemical profile and mechanism of action of different psychedelic drugs. We conclude that researchers studying psychedelics can considerably expand the range of their potential scientific conclusions by analyzing brief interviews obtained before, during and after the acute effects. Finally, we list a series of questions and open problems that should be addressed to further consolidate this approach.

Pristimerin (PM) is a naturally occurring quinonemethide triterpenoid compound that isolated from the Celastraceae and Hippocrateaceae families. Its anticancer effects have attracted a great deal of attention, but the mechanisms of action remain obscure. In this study, we screened for the active compounds of Pristimerin using a drug-likeness approach. Potential protein targets of Pristimerin were predicted by PharmMapper and Coremine database. Candidate protein targets were then uploaded to GeneMANIA and GO pathway analysis. Finally, compound-target, target-pathway, and compound-target-pathway networks were constructed using Cytoscape 3.3. The results showed that Pristimerin had good drug ability and identified 13 putative protein targets. Network analysis revealed that these targets are associated with cancer, inflammation and other physiological processes. In summary, Pristimerin is predicted to target a variety of proteins and pathways to form a network that exerts systemic pharmacological effects.

Cannabis sativa is one of the oldest plants utilized by humans for both economic and medical purposes. Although the use of cannabis started millennia ago in the Eastern part of the hemisphere, its use has moved and flourished in the Western Nations in more recent centuries. C. sativa is the source of psychoactive cannabinoids that are consumed as recreational drugs worldwide. The C21 aromatic hydrocarbons are restricted in their natural occurrence to cannabis (with a few exceptions). Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component in cannabis with many pharmacological effects and various approved medical applications. However, a wide range of side effects are associated with the use of Δ9-THC, limiting its medical use. In 1966, another psychoactive cannabinoid, Delta-8-tetrahydrocannabinol (Δ8-THC) was isolated from marijuana grown in Maryland but in very low yield. Δ8-THC is gaining increased popularity due to its better stability and easier synthetic manufacturing procedures compared to Δ9-THC. Passing the U.S. Farm Bill in 2018 led to an increase in the sale of Δ8-THC in the United States. The marketed products contain Δ8-THC from synthetic sources. In this review, methods of extraction, purification, and structure elucidation of Δ8-THC will be presented. The issue of whether Δ8-THC is a natural compound or an artifact will be discussed, and the different strategies for its chemical synthesis will be presented. Δ8-THC of synthetic origin is expected to contain some impurities due to residual amounts of starting materials and reagents as well as side products of the reactions. The various methods of analysis and detection of impurities present in the marketed products will be discussed. The pharmacological effects of Δ8-THC, including its interaction with CB1 and CB2 cannabinoid receptors in comparison with Δ9-THC, will be reviewed.

The medical use of Cannabis has a very long history. Although many principles are present in cannabis, called cannabinoids, Δ9tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD) and can-nabinol (CBN) are the three main cannabinoids most present and described. CBD itself is not re-sponsible for psychotropic effects of cannabis since does not produce the typical behavioral effects associated to the consumption of this drug. Cannabidiol (CBD) has recently gained growing at-tention in modern society and seems to be more and more explored in dentistry. Several subjective findings suggest some therapeutic effects of CBD, which are strongly supported by research evi-dence. However, there is a plethora of data regarding CBD’s mechanism of action and therapeutic potential, which are in many cases contradictory. We will first provide an overview of scientific evidence on the molecular mechanism of CBD’s action. Furthermore, we will map the recent de-velopments regarding possible oral benefits of CBD. In summary, we will highlight CBD’s prom-ising biological features for dentistry application, despite exiting patents suggest current the compositions for oral care as the main interest for industry.

This post-hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visit and hospitalization in women and men. During the study period (January 2007 – December 2018), 61,855 reports of ADE leading to ED visit were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13-176), antidepressants (ROR 1.12, CI 1.03-1.23) and antidiabetics (ROR 1.13, CI 1.02-1.24). Among men only vitamin K antagonists (ROR 1.28, CI 1.09-1.50), opioids (ROR 1.30, CI 1.06-1.60) and digitalis glycosides (ROR 1.32, CI 1.09-1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidi-ties were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing and adverse event following immunization (ROR 0.36, CI 0.27-0.48 and 0.83, 0.42-0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes.

The vastness of chemical-space constrains traditional drug-discovery methods to the organic laws that are guiding the chemistry involved in filtering through candidates. Leveraging computing with machine-learning to intelligently generate compounds that meet a wide range of objectives can bring significant gains in time and effort needed to filter through a broad range of candidates. This paper details how the use of Generative-Adversarial-Networks, novel machine learning techniques to format the training dataset and the use of quantum computing offer new ways to expedite drug-discovery.

Bioactive plant compounds, also known as phytochemicals, are essential for plant resistance, growth, and development. These chemicals often possess therapeutic properties that have been used in traditional medicine for centuries as herbal remedies for a variety of diseases. As a member of the Lamiaceae family, Rydingia (Syn: Otostegia) is found in Asia and northeastern Africa. R. michauxii, is a unique shrub that grows in the Southern region of Iran, Fars province. Rydingia species have been used as traditional herbal medicine in Iran for many years. It seems that R. michauxii offers great potential for in-depth research on its diverse biological properties, especially its antioxidant and lipid-lowering effects. Nevertheless, no clinical investigation has been carried out on the phytochemical characteristics of this plant to date. Therefore, this study aims to contribute to the scientific knowledge on the pharmacological properties of R. michauxii and its phytochemical compounds and encourage researchers to evaluate its biological properties in animal models. In this study, all available scientific literature was compiled and all phytochemical and pharmacological properties of the R. michauxii plant were investigated, including antibacterial, antifungal, antiviral, antioxidant, antimalarial, cytotoxic, and lipid-lowering effects, which may prove useful in developing novel formulations with greater therapeutic benefits in clinical applications.

Diabetes mellitus (DM) comprises a range of metabolic disorders characterized by high blood glucose levels caused by defects in insulin release, insulin action, or both. DM is a widespread condition that affects a substantial portion of the global population, causing high morbidity and mortality rates. The prevalence of this major public health crisis is predicted to increase in the forthcoming years. Although, several drugs are available to manage DM, these are associated with adverse side effects, which limits their use. In underdeveloped countries, where such drugs are often costly and not widely available, many people continue to rely on alternative traditional medicine, including medicinal plants. The latter serve as a source of primary healthcare and plant-based foods in many low and middle-income countries. Interestingly, many of the phytochemicals they contain have been demonstrated to possess antidiabetic activity such as lowering blood glucose levels, stimulating insulin secretion and alleviating diabetic complications. Therefore, such plants may provide protective effects that could be used in the management of DM. The purpose of this article was to review the medicinal plant-based foods traditionally used for the management of DM, including their therapeutic effects, pharmacologically-active phytoconstituents and antidiabetic mode of action at the molecular level. It also presents future avenues for research in this field.

The multitarget therapeutic strategy, as opposed to the more traditional ‘one disease-one tar-get-one drug’, may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer’s disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy- 2,3-dihydro-1H-inden-1-one (1a), which in the E diastereomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound the thermal stable E diastereoisomer, along with the E/Z mixture as produced by UV-B light irradia-tion in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-diastereoisomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, re-spectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z diastereoselectivity of 1h toward the two target enzymes.

Artocarpus camansi Blanco or breadnut (Family: Moraceae) is primarily found in tropical regions of the world. Different parts of the plant provide potential use in medicine, nutraceutical development, and livelihood. The present review attempts to document literature on the traditional use, nutritional value, phytochemistry, and pharmacological investigation carried out with breadnuts. The included literatures of the plant were collected from various sources and databases like Google scholar, PubMed, ScienceDirect, Crossref, and Scopus. Breadnuts are rich in secondary metabolites. Studies have reported the isolation of several triterpenoid compounds and the broad spectrum of its pharmacological activities such as antidiabetic, antimalarial, antioxidant, anti-tumor, antibacterial, and immunomodulatory properties. The approximate composition of the seed and the fruit also highlights the nutritional importance of this plant. A. camansi Blanco is an underutilized tree that holds significant potential if further research and sustainable conservation is applied. Efforts to mainstream its use as functional food and increase awareness among the locals should also be given attention.

Pain is a natural bioassay for detecting and quantifying biological activities of venoms. The painfulness of stings delivered by ants, wasps, and bees can be easily measured in the field or lab using the stinging insect pain scale that rates the pain intensity from 1 to 4, with 1 being minor pain, and 4 being extreme, debilitating, excruciating pain. The painfulness of stings of 96 species of stinging insects and the lethalities of the venoms of 90 species was determined and utilized for pinpointing future promising directions for investigating venoms having pharmaceutically active principles that could benefit humanity. The findings suggest several under- or unexplored insect venoms worthy of future investigations, including: those that have exceedingly painful venoms, yet with extremely low lethality – tarantula hawk wasps (Pepsis) and velvet ants (Mutillidae); those that have extremely lethal venoms, yet induce very little pain – the ants, Daceton and Tetraponera; and those that have venomous stings and are both painful and lethal – the ants Pogonomyrmex, Paraponera, Myrmecia, Neoponera, and the social wasps Synoeca, Agelaia, and Brachygastra. Taken together, and separately, sting pain and venom lethality point to promising directions for mining of pharmaceutically active components derived from insect venoms.

Panax notoginseng, as traditional Chinese medicine, has a long history of high clinical value, such as anti-inflammatory, anti-oxidation, inhibition of platelet aggregation, regulation of blood glucose and blood pressure, inhibition of neuronal apoptosis and neuronal protection, and its main ingredients are Panax notoginseng saponins (PNS). Currently, Panax notoginseng may improve mental function, have anti-insomnia and anti-depression effects, alleviate anxiety, and decrease neural network excitation. However, the underlying effects and the mechanisms of Panax notoginseng and its containing chemical constituents (PNS) on these depression-related or anxiety-related diseases has not been completely established. This review summarized the antidepressant or anxiolytic effects and mechanisms of PNS, and analyzed network targets of antidepressant or anxiolytic actions with network pharmacology tools to provide directions and references for further pharmacological studies and new ideas for clinical treatment of nervous system diseases and drug studies and development.

For centuries, Foeniculi fructus (F. fructus) has been used as a traditional herbal medicine in China and Europe and is widely used as a natural therapy for digestive disorders, including indigestion, flatulence, and bloating. The mechanism by which F. fructus alleviates functional dyspepsia was analyzed through network pharmacology, and its therapeutic effect on an animal model of functional dyspepsia was investigated. The compounds, targets, and related diseases of F. fructus were studied utilizing the traditional Chinese medicine systems pharmacology (TCMSP) database. Information on the target genes was classified using the UniProt database. A network was built using Cytoscape 3.9.1, and functional dyspepsia-related genes were checked using the Cytoscape string application. The efficacy of F. fructus on functional dyspepsia, including gastroparesis and gastrointestinal motility, was confirmed by treatment with its extract in a mouse model of loperamide-induced functional dyspepsia. Seven compounds targeted twelve functional dyspepsia-associated genes. In a functional dyspepsia mouse model, F. fructus significantly suppressed the symptoms when compared to that in the control group. Our animal studies showed that the mechanism of action of F. fructus is closely related to gastrointestinal motility. Based on animal experimental results, the results showed that F. fructus provides a potential means to treat functional dyspepsia, suggesting that its medical mechanism for functional dyspepsia can be described by the relationship between seven key compounds of F. fructus, including oleic acid and β-sitosterol, and 12 functional dyspepsia-related genes.

Local anaesthetic agents suppress action potentials in excitable tissues by blocking voltage-gated sodium channels. In doing so they inhibit the depolarisation of nociceptive nerve fibres and so prevent the transmission of pain impulses. UK legislation allows HCPC-registered Podiatrists with POM-A annotation access to six local anaesthetic drugs and two of these with the addition of adrenaline. The use of local anaesthetia has transformed the treatment of nail pathology by Podiatrists. In the UK, the drug of choice in podiatric practice is 3% mepivacaine hydrochloride: it is a good choice of drug for digital anaesthesia. This paper will review the chemistry, pharmacology and dose calculation of mepivacaine, and challenge some of the orthodoxy over the rigid calculation of maximum safe dosages.

Ipomoea batatas L. (IBL) has gained significant popularity as a complementary therapy or herbal medicine in the treatment of anti-diabetes. The objective of this review is to examine the mechanism of action of flavonoid compounds found in IBL that can activate GLP-1 as an anti-diabetic agent. The review article refers to PRISMA guidelines. The literature search was conducted using electronic databases such as Crossref, Pubmed, Scopus, and Science Direct. The search query was based on specific keywords, including Ipomoea batatas OR sweet potato AND anti-diabetic OR hypoglycemic. A total of 1055 articles were found, but only 32 articles were selected for further review based on inclusion and exclusion criteria. IBL contains various compounds, including phenolic acid, flavonols, flavanols, flavones, and anthocyanins, which exhibit activity against anti-diabetes. Flavonols, flavonols, and flavones belong to a group of flavonoids that possess the ability to form complexes with AlCl3 and Ca2+. Retention of Ca2+ within intracellular L cells, resulting in the release of GLP-1. Flavonols, flavones, and flavone groups have been found to strongly interact with DPP-IV, which inhibits the degradation of GLP-1. This mechanism effectively prolongs the half-life of GLP-1 in the systemic system, thereby contributing to the anti-diabetic activity of IBL

Rivea hypocrateriformis (Desr.) Choisy is a robust woody climbing shrub of the genus Rivea which is found in India, Nepal, Sri Lanka, Pakistan, Bangladesh, Myanmar and Thailand. R. hypocrateriformis is a promising medicinal herb with enormous helpful and wellbeing advancing impacts. R. hypocrateriformis has been utilized as a customary medication for a long time to treat rheumatic pain, fever, urogenital problem, snake bite, cough, piles, malaria, and skin disease. Apart from the traditional uses its leaves and young shoots are cooked and eaten as a vegetable and for preparation of bread with millet flour. This review comprehensively summarizes the up-to-date information on the botanical characterization, distribution, traditional uses, phytochemistry, pharmacology and toxicity study of R. hypocrateriformis. Phytochemical investigation has been revealed that alkaloids, glycosides, coumarins, flavonoids, xanthones, stilbenes, and other organic compounds are contained in R. hypocrateriformis. Crude extracts and isolated compounds have exhibited numerous pharmacological activities such as anovulatory effect, antifertility activity, antiarthritic, antimicrobial, anticancer, antioxidant, hepatoprotective, antilithiatic, antimitotic. R. hypocrateriformis is a promising restorative spice with monstrous remedial and wellbeing advancing impacts. Along these lines, further investigations on the bioactive mixtures and systems of R. hypocrateriformis are justified. Extra clinical and toxicological examinations are expected to assess its wellbeing.

Background: The commonly known assumption that combinations of several herbs in one formulation can have better efficacy due to additive or synergistic effects has not been systematically studied despite some evidence supporting the synergy concept. Study aim: The study aimed to reveal the molecular interactions in situ of host cells in response to the intervention of BHP and justify the benefits of implementing BHP in clinical practice. Results: This overview provides the results of recent clinical and network pharmacology studies of botanical herbal preparations (BHP) of Rhodiola with other plants, including Ashwagandha, Green Tea, Eleutherococcus, Schisandra, Eleutherococcus, Leuzea, Caffeine, Cordyceps, Gingko, Black Cohosh, saffron, and L-carnosine. Conclusions: The most important finding from network pharmacology studies of BHP was the evidence supporting the synergistic interaction of BHP ingredients, revealing unexpected new pharmacological activities unique and specific to the new BHP. Some studies show the superior efficacy of BHP compared with mono-drugs. At the same time, some a priori-designed combinations can fail, presumably due to antagonistic interactions and crosstalk between molecular targets within molecular networks involved in the cellular and overall response of organisms on the intervention. Network pharmacology studies help predict the results of studies to discover new indications and unpredicted adverse events.

Potentilla nepalensis belongs to the Rosaceae family, and has numerous therapeutic applications as potent plant-based medicine. Forty phytoconstituents (PCs) from the root and stem through n-hexane (NR and NS) and methanolic (MR and MS) extracts were identified in our earlier studies. However, the PCs affecting human genes and their roles in the body are not disclosed till now. In this study, we employed network pharmacology, molecular docking, molecular dynamics simulations (MDS), and MMGBSA methodologies. SMILES format of PCs from the PubChem used as input to DIGEP-Pred, 764 identified as the inducing genes. Their enrichment studies have shown inducing genes gene ontology descriptions, involved pathways, associated diseases, and drugs. PPI networks constructed in String DB and network topological analysing parameters done in Cytoscape v3.10 revealed three biomarkers, TP53 from MS, NR, and NS induced genes; HSPCB and Nf-kB1 from MR induced genes. From 40 PCs, two PCs 1b (MR) and 2a (MS), showed better binding scores (kcal/mol) with p53 protein of -8.6, and -8.0; three PCs 3a, (NR) 4a and 4c (NS) with HSP protein of -9.6, -8.7, and -8.2. MDS and MMGBSA revealed these complexes are stable without higher deviations with better free energy values. Biomarkers identified in this study, have a prominent role in numerous cancers. Thus, further investigations such as in-vivo and in-vitro should be done to find the molecular functions and interlaying mechanism of the identified biomarkers on numerous cancer cell lines in considering the PCs of P.nepalensis.

This research investigated the antihypertensive effects of tamarind products and compared their potentials based on their animal model’s data verified by molecular docking, multitarget interactions in network pharmacology, and dynamic simulation assays. The GC-MS characterized tamarind products were administered to the cholesterol-induced hypertensive Wistar albino rat models. Two-week-intervened animals were dissected to collect serum and organs which were respectively subjected to the analyses of hypertension-linked markers and tissue architectures. Lead biometabolites of tamarinds interacted with eight target receptors in molecular docking and dynamic simulation studies and they were tested for multitarget interactions using network pharmacological analyses. Results showed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), C-reactive protein (CRP), Troponin I, and lipid profiles were maximally reinstated by the phenolic-enriched ripened sour over the sweet tamarind flesh extracts, but seed extracts had a smaller influence. Among the tamarind’s biometabolites, Gamma-sitosterol (ϒ-sitosterol) was found to be the best ligand in managing hypertension via the possible ligand-receptor interactions with the guanylate cyclase which displayed the best drug-likeliness through the highest binding energy -9.3 Kcal. Multitargeted interactions-based degree algorithm and phylogenetic tree of pathways showed 14 targeted genes, of which NR3C1, REN, PPARG, and CYP11B1 hub genes, were consistently modulated by the ϒ-sitosterol to reduce hypertension and related risk factors. The dynamic simulation study showed that the P-RMSD values of ϒ-sitosterol-guanylate cyclase were stable between 75.00 to 100.00 ns at the binding pocket. The findings demonstrate that ripened sour tamarind extract may be supplemented to be a more prospective antihypertensive target or nutraceuticals affirming through advanced preclinical and clinical studies.

A clinical case of atypical endophthalmitis in an 82-year-old patient who underwent complicated cataract phacoemulsification. Clinical manifestations showed signs of a bacterial process, however, the treatment was not effective. Antifungal therapy had yielded positive results, despite the low probability of a fungal etiology of the process.

Numerous in vitro studies on isolated cells have been conducted to uncover the molecular mechanisms of action of Panax ginseng Meyer root extracts and purified ginsenosides. However, the concentrations of ginsenosides and the extracts used in these studies were much higher than detected in pharmacokinetic studies in humans and animals orally administered with ginseng preparations at therapeutic doses. Our study aimed to assess: (a) the effects of ginsenoside Rg5, the major "rare" ginsenoside of Red Ginseng, on gene expression in the murine neuronal cell line HT22 in a wide range of concentrations, from 10-4 to 10-18 M, and (b) the effects of differentially expressed genes on cellular and physiological functions in organismal disorders and diseases. Gene expression profiling was performed by transcriptome-wide mRNA microarray analyses in HT22 cells after treatment with ginsenoside Rg5. Ginsenoside Rg5 exhibits soft-acting effects on gene expression of neuronal cells in a wide range of physiological concentrations and strong reversal impact at high (toxic) concentration: significant up- or downregulation of expression of about 300 genes at concentrations from 10-6 M to 10-18 M, and dramatically increased both the number of differentially expressed target genes (up to 1670) and the extent of their expression (fold changes compared to unexposed cells) at a toxic concentration of 10-4 M. Network pharmacology analyses of genes expression profiles using Ingenuity pathway analysis (IPA) software showed that at low physiological concentrations, ginsenoside Rg5 has the potential to activate the biosynthesis of cholesterol and to exhibit predictable effects in senescence, neuroinflammation, apoptosis, and immune response, suggesting soft-acting, beneficial effects on organismal death, movement disorders, and cancer.

Ion channels contribute fundamental properties to all cell membranes. The ion channels are highly diverse in conductivity, structure, location and function. However, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Considering primarily pain-related ion channels, this review covers more novel and less known features of ion channel function, also with the aim to transfer knowledge between fields, which get inevitably more separate due to their size.

It’s been reported that Mori Folium (MF) and Eucommiae Cortex (EC) exhibit pharmacological effects on the treatment of immunosuppression. However, the mechanism of MF and EC against immunosuppression remains unclear. This study aims to explore the mechanism of action of MF and EC for the treatment of immunosuppression through network pharmacology, molecular docking, molecular dynamics simulations and animal experiments. As a result, 11 critical components, 9 hub targets, and related-signaling pathways of treatment of immunosuppression were obtained based on network pharmacology. The molecular docking suggested that 11 critical components exhibited great binding affinity to 9 hub targets of immunosuppression. The molecular dynamics simulations results showed that (-)-Tabernemontanine-AR, beta-sitosterol-AR and Dehydrodieugenol-HSP90AA1 complexes are stably bound. Additionally, in the animal experiments, the treated group results compared to the control group suggest that MF and EC have a significant effect on the treatment of immunosuppression. Therefore, the MF and EC treatment for immunosuppression may take effects in a multi-component, multi-target, and multi-pathway manner. The results would provide novel insights into the treatment of immunosuppression in humans.

Panax ginseng C.A.Mey. is an adaptogenic plant traditionally used to enhance mental and physical capacities in cases of weakness, exhaustion, tiredness, loss of concentration, and during recovery. According to ancient records, Red Ginseng root preparations enhance longevity with long-term intake. Recent pharmacokinetic studies of ginsenosides in humans and our in vitro study in neuronal cells suggest that ginsenosides are effective when their level in blood is shallow - at concentrations from 10-6 to 10-18 M. In the present study, we compared the effects of Red Ginseng root preparation HRG80TM(HRG) at concentrations from 0.01 to 10,000 ng/ml with effects of White Ginseng (WG) and purified ginsenosides Rb1, Rg3, Rg5 and Rk1 on gene expression of isolated hippocampal neurons. The aim of this study was to predict the effects of differently expressed genes on cellular and physiological functions in organismal disorders and diseases. Gene expression profiling was performed by transcriptome-wide mRNA microarray analyses in murine HT22 cells after treatment with ginseng preparations. Ingenuity pathway downstream/upstream analysis (IPA) was performed with datasets of significantly up-or downregulated genes, and expected effects on cellular function and disease were identified by IPA software. Ginsenosides Rb1, Rg3, Rg5, and Rk1 have substantially various effects on gene expression profiles (signatures) and are different from signatures of HRG and WG. Furthermore, the signature of HRG is changed significantly with dilution from 10000 to 0.01 ng/ml. Network pharmacological analyses of gene expression profiles showed that HRG exhibits predictable positive effects in neuroinflammation, senescence, apoptosis, and immune response, suggesting beneficial soft-acting effects in cancer, gastrointestinal, and endocrine systems diseases and disorders in a wide range of low concentrations in blood.

Preclinical animal studies provide valuable opportunities to better understand human diseases and contribute to major advances in medicine. This review provides a comprehensive overview of ocular parameters in humans and selected animals, with a focus on the ocular surface, detailing species differences in ocular surface anatomy, physiology, tear film dynamics and tear film composition. We describe major pitfalls that tremendously limit the translational potential of traditional laboratory animals (ie., rabbits, mice and rats) in ophthalmic research, and highlight the benefits of integrating companion dogs with clinical analogues to human diseases into preclinical pharmacology studies. This One Health approach can help accelerate and improve the framework in which ophthalmic research is translated to the human clinic. Studies can be conducted in canine subjects with naturally occurring or non-invasively induced ocular surface disorders (eg., dry eye disease, conjunctivitis), reviewed herein, and tear fluid can be easily retrieved from canine eyes for various bioanalytical purposes. In this review, we discuss common tear collection methods, including capillary tubes and Schirmer tear strips, and provide guidelines for tear sampling and extraction to improve the reliability of analyte quantification (drugs, proteins, others).

Curcumin is one of the bioactive metabolites of turmeric (Curcuma longa), known for its pleiotropic pharmacological actions, including antioxidant and anti-inflammation, anticholinesterase, immunomodulation, and neuroprotection. Substantial evidence suggests the therapeutic benefits of curcumin against neurodegenerative disorders, including Alzheimer’s disease (AD), acting on a diverse array of brain targets that make the molecular mechanisms complicated. System biology level-investigation could potentially present a comprehensive molecular mechanism to delineate the neuropharmacological action of curcumin. In this study, we used integrated system pharmacology and molecular simulation analysis to gain insights into the underlying mechanism of curcumin action against AD. Network pharmacology study identified curcumin-targeted potential cellular pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling, neurotrophin signaling, toll-like receptor (TLR) signaling, and autophagy, and proteins such as tropomyosin receptor kinase B (TrkB), liver X-receptor-beta (LXR-β), estrogen receptor-β (ER-β), mammalian target of rapamycin (mTOR), TLR-2, N-methyl-D-acetate receptor subunit 2B (GluN2B), β-secretase and glycogen synthase kinase-3β (GSK-3β), which are intimately associated with neuronal growth and survival, immune response, and inflammation. Moreover, the molecular modeling further verified that curcumin showed a significant binding affinity to mTOR, TrkB, LXR-β, TLR-2, ER-β, GluN2B, β-secretase, and GSK-3β, which are the crucial regulators of molecular and cellular processes associated with AD. Together, the present system pharmacology and in silico findings demonstrate that curcumin might play a significant role in modulating AD-pathobiology, supporting its therapeutic application for the prevention and treatment of AD.

Alzheimer’s Disease (AD) is a neurodegenerative condition that currently has no known cure. The principles of the expanding field of network medicine (NM) have recently been applied to AD research. The main principle of NM proposes that diseases are much more complicated than one mutation in one gene, and incorporate different genes, connections between genes, and pathways that may include multiple diseases to create full scale disease networks. AD research findings as a result of the application of NM principles have suggested that functional network connectivity, myelination, myeloid cells, and genes and pathways may play an integral role in AD progression, and may be integral to the search for a cure. Different aspects of the AD pathology could be potential targets for drug therapy to slow down or stop the disease from advancing, but more research is needed to reach definitive conclusions. Additionally, the holistic approaches of network pharmacology in traditional Chinese medicine (TCM) research may be viable options for the AD treatment, and may lead to an effective cure for AD in the future.

Geijera Schott is a plant genus of the Rutaceae Juss. (rue and citrus) family, comprising six species which are all native to Oceania. Of the plants belonging to this genus, the most significant species that has a customary use is Geijera parviflora, which was used by Indigenous Australians, primarily as a pain reliever. Herein, a comprehensive review of the literature published on the genus Geijera from 1930-2023 was conducted. This is the first review for this plant genus and it highlights the chemical constituents reported to date, together with the range of pharmacological properties described from the various species and different parts of the plant. These properties include anti-inflammatory, anti-microbial, anti-parasitic, insect repellent, analgesic, neuroactive, and anti-cancer activities. Finally, a reflection on some of the important areas for future focused studies of this plant genus is provided.

Scientific, technical and bioinformatics advances have made it possible to establish analytics-based molecular biosimilarity for the approval of biosimilars. If the molecular structure and other product- and process-related attributes are comparable within the limits of testing then a biosimilar candidate would have safe safety and efficacy as its reference products. The current model of animal and human testing becomes redundant since all of these studies have much lower sensitivity and reproducibility in confirming biosimilarity. The recent AI-based protein structure prediction model has confirmed that the 3D structure can be predicted from the amino acid sequence, reducing the need for structural analysis; however, the new test methods based on MS are millions of times more sensitive and accurate. While the regulatory agencies have begun waiving animal testing and, in some cases, clinical efficacy testing, removing clinical pharmacology profiling brings a dramatic paradigm shift, reducing development costs without compromising safety and efficacy. Also shared is a list of 160+ products ready to enter as biosimilars. Major actions from regulatory agencies and developers are required to make this paradigm shift.

Tyrosine Kinase Inhibitors work by blocking the tyrosine kinases responsible of the dysregulation of intracellular signalling pathways in tumour cells. This study looked at the impact of age and sex on the levels of imatinib, dasatinib, nilotinib, and ponatinib in plasma and cerebrospinal fluid samples of patients with chronic myeloid leukaemia. Imatinib and dasatinib were used to treat the majority of the enrolled patient and most of them were paediatrics. The 82.4% of patients were men; however, sex-related differences in drugs pharmacokinetics were not found. Age and imatinib plasma concentration were found to be inversely correlated: as patients ages increased, drug levels decreased. The dasatinib concentrations in plasma were found to be substantially lower than those found in cerebrospinal fluid, particularly in paediatrics. Analysing the obtained data, we can state that Therapeutic Drug Monitoring is a useful method for adjusting a patient treatment schedule depending on drug concentrations in biological fluids. The use of Therapeutic Drug Monitoring in conjunction with Tyrosine Kinase Inhibitors for the treatment of chronic myeloid leukaemia is supported by a number of sources of evidence. As a result, as the research develops, Tyrosine Kinase Inhibitors Therapeutic Drug Monitoring classification needs to be refined in terms of factors like sexes and ages.

In an era of unparalleled technical advancement, the pharmaceutical industry is struggling to transform data into increased research and development efficiency, and as a corollary, new drugs for patients. Here, we briefly review some of the commonly discussed issues around this counterintuitive innovation crisis. Looking at both industry and science related factors, we posit that traditional preclinical research is front-loading the development pipeline with data and drug candidates that are unlikely to succeed in patients. Applying a first principles analysis, we highlight the critical culprits and provide suggestions as to how these issues can be rectified through pursuit of a Human Data-driven Discovery (HD3) paradigm. Consistent with other examples of disruptive innovation, we propose that new levels of success are not dependent on new inventions, but rather the strategic integration of existing data and technology assets. In support of these suggestions, we highlight the power of HD3, through recently published proof-of-concept applications in the areas of drug safety analysis and prediction, drug repositioning, rational design of combination therapies and the global response to the Covid19 pandemic. We conclude that innovators must play a key role in expediting the path to a largely human focused, systems-based approach to drug discovery and research.

Breast cancer (BC) is the most common type of cancer in both men and women alike, but it is more prevalent in women. Natural compounds that can modulate the oncogenic process can be considered a significant anti-cancer agent for treating BC. These natural compounds are more effective than synthetic drugs, which have profound side effects on the normal cell and resistance to cancer cells. Genistein is a type of dietary phytoestrogen included in the flavonoid group with a similar structure of estrogen that might provide a strong alternative and complementary medicine to existing chemotherapeutics drugs. Several research studies demonstrated that it can target the estrogen receptor (ER), Human epidermal growth factor receptor-2 (HER2), and Breast cancer gene-1 (BRCA-1) in multiple BC cell lines, as well as sensitize cancer cell lines to this compound when used at an optimal inhibitory concentration. Genistein effectively showed anti-cancer activities through apoptosis induction, arresting cell cycle, inhibiting angiogenesis with metastasis, reducing inflammation, mammosphere formation, tumor growth, up-regulating tumor suppressor gene, and downregulating oncogene in suppressing cancer progression in vitro and animal model study. In addition, research studies have also suggested that these phytochemicals synergistically reverse the resistance mechanism of chemotherapeutic drugs, increasing the efficacy of some chemoinformatics drugs. Our review article aims to unbox and validate the molecular pharmacology in breast tissue, cell-specific anti-cancer mechanism with synergistic activity, and possible pharmacokinetic parameters of Genistein as a potential alternative therapeutic option for the treatment of BC.

Drug repurposing is a valuable tool for combating the slowing rates of novel therapeutic discovery. The Computational Analysis of Novel Drug Opportunities (CANDO) platform performs shotgun repurposing of 2030 indications/diseases using 3733 drugs/compounds to predict interactions with 46,784 proteins and relating them via proteomic interaction signatures. An accuracy is calculated by comparing interaction similarities of drugs approved for the same indications. We performed a unique subset analysis by breaking down the full protein library into smaller subsets and then recombining the best performing subsets into larger supersets. Up to 14% improvement in accuracy is seen upon benchmarking the supersets, representing a 100–1000 fold reduction in the number of proteins considered relative to the full library. Further analysis revealed that libraries comprised of proteins with more equitably diverse ligand interactions are important for describing compound behavior. Using one of these libraries to generate putative drug candidates against malaria results in more drugs that could be validated in the biomedical literature than the list suggested by the full protein library. Our work elucidates the role of particular protein subsets and corresponding ligand interactions that play a role in drug repurposing, with implications for drug design and machine learning approaches to improve the CANDO platform.

Leptadenia reticulata (Ritz.) Wight (Asclepiadaceae), a traditional medicinal plant species, is widely used in traditional medicine to treat various ailments such as tuberculosis, hematopoiesis, emaciation, cough, dyspnea, fever, burning sensation, night blindness, cancer, and dysentery. In Ayurveda, it is known for its revitalizing, rejuvenating, and lactogenic properties. This plant is one of the major ingredients in many commercial herbal formulations, including Speman, Envirocare, Calshakti, Antisept, and Chyawanprash. The therapeutic potential of this herb is because of the presence of diverse bioactive compounds such as α-amyrin, β-amyrin, ferulic acid, luteolin, diosmetin, rutin, β-sitosterol, stigmasterol, hentriacontanol, a triterpene alcohol simiarenol, apigenin, reticulin, deniculatin, and leptaculatin. However, most biological studies on L. reticulata are restricted to crude extracts, and many biologically active compounds are yet to be identified in order to claim the traditional uses of L. reticulata into evidence-based uses. At present, L. reticulata is a threatened endangered plant because of overexploitation, unscientific harvesting, and habitat loss. The increased demand from pharmaceutical, nutraceutical, and veterinary industries has prompted its large-scale propagation. However, its commercial cultivation is hampered because of the non-availability of genuine planting material and the lack of knowledge on its agronomical practices. In this regard, micropropagation technique will be useful to obtain true-to-type L. reticulata planting materials from an elite germplasm to meet the current demand. Adopting other biotechnological approaches such as synthetic seed technology, cryopreservation, cell culture, and genetic transformation can warrant conservation as well as increased metabolite production from L. reticulata. The present review summarizes scientific information on the botanical, agronomical, phytochemical, pharmacological, and biotechnological aspects of L. reticulata. This comprehensive information will certainly allow better utilization of this industrially important herb towards the discovery of lead drug molecules.

Euphorbia ingens is traditionally used to treat and manage cancer in Ambeere community of Embu County in Kenya. Whilst research has demonstrated the bioactivities of E. ingens including antimicrobial, antitubercular and antifungal activities, scientific validation of its anticancer properties is limited. This study evaluated the antiproliferative potentials of E. ingens on human prostate cancer cell line (DU-145). The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was used to assess the antiproliferative activity, chemical constituents were analysed by qualitative colour method and Gas Chromatography-Mass Spectrometry analysis. At the same time, the investigation of putative molecular targets and mechanisms of action of E. ingens was done through network pharmacological analysis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was carried out to validate the network predictions of putative targets. Our result showed E. ingens ethyl acetate inhibited DU-145 growth (IC50 of 9.71 ± 0.4 µg/ml) with a high selectivity index of 8.26. There was the presence of phenols, terpenoids, flavonoids, tannins, sterols, and saponins; additional 18 compounds were identified by the GC-MS approach. ESR1, IL6, MMP9, CDK2, MAP2K1, AR, PRKCD, CDK1, CDC25B, and JAK2 were indicated as key targets of E. ingens against prostate cancer with the PI3K-AKT, MAPK, and p53 signalling pathways identified as the most probable mechanisms of action. There was significant downregulation of AR and BCL2, and upregulation of p53 and caspase-3 in E. ingens-treated DU-145 cells compared to 0.2 % DMSO negative control. Our results suggest that E. ingens has phytochemical compounds efficacious at inhibiting the proliferation of DU-145 cells; therefore, the plant can be considered a potential source of compounds that may be used to manage and treat prostate cancer; however, further in vivo evaluations are needed.

Songorine (SON) is a diterpenoid alkaloid from Aconitum plants. Preparations of Aconitum roots have been employed in traditional oriental herbal medicine, however, their mechanisms of action are still unclear. Since GABA-receptors are possible brain targets of SON, we investigated which subtypes of GABA-receptors contribute to the effects of SON, and how SON affects anxiety-like trait behavior and psychomotor cognitive performance of rats. First, we investigated the effects of microiontophoretically applied SON alone and combined with GABA-receptor agents picrotoxin and saclofen on neuronal firing activity in various brain areas. Next, putative anxiolytic effects of SON (1.0-3.0 mg/kg) were tested against the GABA-receptor positive allosteric modulator refer-ence compound diazepam (1.0-5.0 mg/kg) in the elevated zero maze (EOM). Furthermore, basic cognitive effects were assessed in a rodent version of the psychomotor vigilance task (PVT). Local application of SON predominantly inhibited the firing activity of neurons. This inhibitory effect of SON was successfully blocked by GABA(A)-receptor antagonist picrotoxin but not by GABA(B)-receptor antagonist saclofen. Similar to GABA(A)-receptor positive allosteric modulator diazepam, SON increased the time spent by animals in the open quadrants of the EOM without any signs of adverse psychomotor and cognitive effects observed in the PVT. We showed that, under in vivo conditions SON acts as a potent GABA(A)-receptor agonist and effectively decreases anxiety without observable side effects. The present findings facilitate the deeper understanding of the mechanism of action and the widespread pharmacological use of diterpene alkaloids in various CNS indications.

Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80-125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80-125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40-50%, a dose reduction of 15% is warranted in neonates, infants and children, 25% in adolescents and adults. Conclusions: PBPK driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, proportionally greater in adults. Consequently, age group specific dose reductions for propofol are required in LCO conditions.

Skin melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Thus, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis identified two potent drugs (Cialis and Finasteride) that can efficiently inhibit AKT1 and MDM2 protein signatures respectively, and with better therapeutic properties. We proposed that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.

Eating disorders (EDs) are serious, life-threatening psychiatric conditions associated with physical and psychosocial impairments, as well as high morbidity and mortality. Given the chronic refractory nature of EDs and the paucity of evidence-based treatments, there is a pressing need to identify novel approaches for this population. The noncompetitive N-methyl-D-aspartate receptor (NMDAr) antagonist, ketamine, has recently been approved for treatment-resistant depression, exerting rapid and robust antidepressant effects. It is now being investigated for several new indications, including obsessive-compulsive, post-traumatic, and substance use disorder; and shows transdiagnostic potential for EDs, particularly among clinical non-responders. As such, the aim of this review is to examine contemporary findings on the treatment of EDs with ketamine, whether used as a primary, adjunctive, or combination psychopharmacotherapy. Avenues for future research are also discussed. Overall, results are encouraging and point to therapeutic value, yet are limited to case series and reports on anorexia nervosa. Further empirical work is thus needed to explore ketamine efficacy across ED subgroups; establish safety profiles and optimize dosing; and develop theory-driven, targeted treatment strategies at the individual patient level.

The network pharmacology (NP) approach is a valuable novel methodology for understanding the complex pharmacological mechanisms of medicinal herbs. In addition, various in silico analysis techniques combined with the NP can improve the understanding of various issues in natural product research. This study assessed the therapeutic effects of Arum ternata (AT), Poria cocos (PC), and Zingiber officinale (ZO) on hyperlipidemia after network pharmacologic analysis. A protein–protein interaction (PPI) network of forty-one key targets was analyzed to discover core functional clusters of the herbal compounds. The KEGG pathway and gene ontology (GO) term enrichment analysis identified significant categories of hypolipidemic mechanisms. The STITCH database indicated a high connection with several statin drugs deduced by the similarity in targets. AT, PC, and ZO regulated the genes related to the energy metabolism and lipogenesis in HepG2 cells loaded with free fatty acids (FFAs). Furthermore, a combinational effect of the mixture of three herbs was found. The herbal combination exerted superior efficacy compared to a single herb, particularly in regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1 (CPT-1). In conclusion, the network pharmacologic approach was used to assess potential targets of the herbal combination for treatment. Experimental data from FFAs-induced HepG2 cells suggested that the combination of AT, PC, and ZO might attenuate hyperlipidemia and its associated hepatic steatosis.