In recent years, the emergence of cancer drug resistance is one of the crucial tumor hallmarks which is supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often results in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

Glioblastoma (GB), even though not frequent, is an extremely aggressive brain tumor, with a strong impact on patient outcomes, in terms of both length and quality of life. The protocol estab-lished by Stupp and coworkers in 2005, based on radiotherapy and temozolomide chemotherapy, after maximum safe surgical resection, remains the gold standard for GB treatment. However, it is evident nowadays that the extreme GB intratumoral and intertumoral heterogeneity, invasive-ness and recurrence are not compatible with a routinary and unfortunately uneffective treatment. In this review article, we summarize the principal challenging issues in finding new valuable therapies for GB and focus on the impact that extracellular vesicle (EV) research and exploitation can have in the field. EVs are natural particles delimited by a lipidic bilayer and full of functional cellular content, released and uptaken by cells as key means of cell communications. Moreover, being stable in body fluids, well-immunotolerated, able to cross physiological, inter-species, and inter-kingdom barriers, and to target specific cells, releasing inherent or externally loaded functionally active molecules, EVs can be potentially ideal allies in fighting GB and assuring to GB patients a better prognosis. Here we report the main results obtained until now, focusing on both EV sources and molecular cargo used in the different functional studies, mainly in vivo. Finally, we perform a SWOT analysis reporting both the main advantages and the pitfalls of developing EV-based GB therapeutic strategies to highlight the main directions to explore for realizing the promise of EV exploitation for GB treatment.

The field of biobanking human biospecimens has evolved significantly, transitioning from the basic, often poorly documented collection of clinical leftovers kept privately to well-organized and extensively documented collections overseen by both commercial and non-profit platforms. The increasing demand for high-quality and clinically annotated biospecimens is propelled by unprecedented levels of health research activities. Meeting this growing demand presents both new opportunities and challenges, particularly in developing strategies to establish international biospecimen sourcing (IBS) platforms. These platforms aim to facilitate collaboration among biobanks to address future biospecimen needs. In this manuscript, we delve into the advantages and challenges of establishing IBS platforms to provide high-quality and cost-effective biospecimens to drive drug discovery research, ultimately leading to improved health and quality of life for everyone.

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ soluble protofibrils was approved by US FDA for AD therapy thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms are widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7- Aβ) and the α4β2 nicotinic acetylcholine receptor.

Delivery of drugs through the nasal route provides an alternative, yet highly efficacious modality for administering both large and small pharmaceutic molecules. This method proves particularly advantageous for drugs that are unstable during oral administration, as they undergo significant degradation in the gastrointestinal tract or metabolization through the first-pass effect in the liver. Nasal administration stands as a viable alternative to parenteral therapy and is also suitable for long-term medical management. The nasal mucosa, characterized by high vascularity and permeability, facilitates rapid pharmaceutical absorption, ensuring a swift onset of therapeutic action. Despite its noninvasive nature, the nasal delivery technique finds broad applicability for both local treatment and systemic therapy, as the drug directly enters systemic circulation. This article explores the feasibility of a novel spray delivery mechanism for intranasal drug deposition. The study aims to determine whether users can correctly follow the state-of-the-art application instructions for a nasal spray with an optimal nozzle placement angle (namely, 12-15°) at the nostril while maintaining sufficient safety and efficacy, and without engaging in preventable usage errors that could harm the user. Additionally, the study evaluates the effectiveness of device labeling, instructions for use, and a short video in supporting the correct application of the nasal spray at the optimal angle (12-15°) and assesses whether users can differentiate the product from others with similar appearances. We have also performed physical spray tests to experimentally evaluate drug penetration to the nasopharynx (a key target site for viral infections) for two different nozzle placements – one for current package instructions coming with over-the-counter spray products and the other for the optimal spray usage procedure to enhance targeted drug delivery. Human Factors (HF) validation studies were also conducted, instructing users to follow the application instructions of the nasal spray bottle with the nozzle placed at the optimal angle to target the nasopharynx. The experimental tests consistently confirmed improved penetration with the 12-15° nozzle placement, with visual cues proving effective when used in tandem with written instructions for guiding the study participants to adhere to the recommended usage procedures.

4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The obtained compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC50 values of 3.47 μM for MAO-B and 43.3 μM for MAO-A. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for development anti-Parkinson’s disease agents.

Pharmaceutical aerosols play a key role in the treatment of lung disorders, but also systemic diseases, due to their ability to target specific areas of the respiratory system (RS). This article focuses on identifying and clarifying the influence of various factors involved in the generation of aerosol micro- and nanoparticles on their regional distribution and deposition in the RS. Attention is given to the importance of process parameters during aerosolization of liquids or powders and the role of aerosol flow dynamics in RS. The interaction of deposited particles with the fluid environment of the lung is also pointed out as an important step in the mass transfer of the drug to the RS surface. The analysis presented highlights the technical aspects of preparing the precursors to ensure that the properties of the aerosol are suitable for a given therapeutic target. Analyzing existing technical limitations, several potential strategies for enhancing the efficiency of targeted therapeutic delivery to or through the respiratory system are identified and presented, including the use of smart inhaling devices incorporating AI algorithms.

The expedited development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our comprehension of type 2 diabetes mellitus (T2DM). The virtual screening based on a three-dimensional (3D) protein structure has been expected as potential technique to accelerate a development of molecular target drugs. Among the targets implicated in insulin resistance, genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays notable variations in T2DM, and its gene product known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on 3D structure of IR tyrosine kinase domain (IRβ) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRβ. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein–protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14.

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following Death Receptors (DRs) activation by the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. Inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify, new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These compounds selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these 9 molecules using the human lung cancer cell line H1703 overexpressing c-FLIP. Our results showed that 6 of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC Immunoprecipitation assay. Overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis, however, combination of TRAIL with these selected molecules signifi-cantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical compounds efficiently prevent c-FLIP recruit-ment into the DISC complex, thus restoring caspase-8 dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory compounds that may serve as anticancer agents in tumors overexpressing c-FLIP.

Recently, nanotechnologies have become increasingly prominent in the field of bone tissue engineering (BTE), offering substantial potential to advance the field forward. These advancements manifest in two primary ways: the localized application of nanoengineered materials to enhance bone regeneration and their use as nano-vehicles for delivering bioactive compounds. Despite significant progress in the development of bone substitutes over the past few decades, it is worth noting that the quest to identify the optimal biomaterial for bone regeneration remains a subject of intense debate. Ever since its initial discovery, poly(lactic-co-glycolic acid) (PLGA) has found widespread use in BTE due to its favorable biocompatibility and customizable biodegradability. This review provides an overview of contemporary advancements in the development of bone regeneration materials using PLGA polymer. The review covers some of PLGA properties with a special focus on modifications of these properties towards bone regeneration. Furthermore, we delve into the techniques for synthesizing PLGA nanoparticles (NPs), the diverse forms in which these NPs can be fabricated, and the bioactive molecules that exhibit therapeutic potential for promoting bone regeneration. Additionally, we addressed some of the current concerns regarding the safety of PLGA NPs, and PLGA-based products available in the market. Finally, we briefly discussed some of the current challenges and proposed some strategies to functionally enhance the fabrication of PLGA NPs towards BTE. We envisage that the utilization of PLGA NP holds significant potential as a potent tool in advancing therapies for intractable bone diseases.

Transdermal drug delivery systems have become an intriguing research topic in healthcare technology and one of the most frequently developed pharmaceutical products in the global market. In recent years, researchers and pharmaceutical companies have made significant progress in developing new solutions in the field. This study sheds light on current trends, collaboration patterns, research hotspots, and emerging frontiers of transdermal drug delivery. Herein, a bib-liometric and patent analysis of data recovered from Scopus and The Lens databases, respectively, is reported over the last 20 years. From 2000 to 2022, the annual global publications increased from 131 in 2000 to 659 in 2022. Researchers in the United States, China, and India produced the highest number of publications. Likewise, most patent applications have been filed in the USA, China, and Europe. The recovered patents are 7,275, grouped into 2,997 patent families, of which 314 were granted. This study could support the work of decision-makers, scientific managers, or scientists to create new business opportunities or save money, time, and intellectual capital, thus, defining when a research or technology project should be a priority or not.

How crucial is big data in contemporary molecular design? In this publication we elucidate fundamental concepts and terminology in this field, critically addressing overlooked issues. We thoroughly examine the size, accessibility, quality, and structural aspects of big data alongside the primary methodologies employed for their analysis. Within chemical compounds, properties and descriptors represent two distinct data types, forming the basis for categorizing molecular big data. The primary objective of chemistry is property production, which means we are searching for novel drugs or materials rather than chemical compounds, and big data is the central issue of this philosophy. The increasing availability of data in computer-aided technology propels advancements in artificial intelligence (AI), machine learning (ML), and deep learning (DL). Accordingly, a broad chemical audience must comprehend these methods to understand data-centered chemistry. Thus, we aim to systemize big data issues through a simple illustrative framework with fundamental descriptor categories: coding, computer-generated descriptors, and property correlates. Although we employ computer-generated descriptors as big data for predictions, the measured data are irreplaceable for achieving high-quality and reliable outcomes and controlling molecular effects. The scarcity of property data remains a significant hurdle limiting comprehensive studies on the structure-property relationships within big data. Accordingly, guided by pragmatics not-so-big data is an option for drug design. We presented also a brief review of the recent big data literature.

Cardiovascular disease (CVD) accounts for nearly one-third of all global fatalities, establishing itself as a leading cause of death. To address this pressing issue, there is a growing demand for improved diagnostic methods and secure, non-invasive imaging techniques that can deliver precise insights into the progression of CVD. The success of personalized therapy for CVD depends on a couple of critical factors: accurate diagnosis and early detection. Therapeutic options for conditions like CVD, which develop over several decades, are highly specific to the individual's condition and the stage of the disease. In the field of biomedicine, nanotechnology has become increasingly prominent as a tool with diverse applications, including diagnostics, biosensing, and drug delivery. This review article offers an in-depth look at the most recent developments in the utilization of nanotechnology for detecting and managing prevalent cardiovascular diseases, providing valuable insights into this crucial area of healthcare research.

Over the few decades, cancer-associated mortalities and morbidities were continuously increased worldwide despite sophisticated technological advancements. Pharmaceutical interventions associated with drugs exhibit a high degree of side effects and toxicities in addition to very high costs. Subsequently, to reduce or to vanish the side effects and high costs, researchers are now exploring natural bioactive compounds such as quercetin in its nanoformulations along with biologics as cargo delivery vehicles. Quercetin along with mesenchymal stromal lineage-derived extracellular vesicles (EVs) possesses an anti-cancer potential that can be explored to treat hepatocellular carcinoma (HCC). Exerting enhanced effect, nano quercetin synergistically with EVs triggers the anti-cancer mechanisms by regulating and dysregulating several signalling mechanisms including NF-κB, p53, JAK/STAT, MAPK, Wnt/β-catenin and PI3K/AKT, in addition to PBX3/ERK1/2/CDK2, and miRNAs modulation. In addition, findings regarding the potential checkpoints of anti-cancer signalling pathways were investigated that offer opportunities to develop engineered EVs incorporated with nano quercetin for the development of novel therapeutics to treat HCC in future. In this present mechanistic review, we abridged the regulation of such signalling mechanisms synergetic approach of nano quercetin and EVs. The regulatory role of EVs in the manifestation of innumerable miRNAs has also been tailed with special context to HCC.

Background Candida auris is an emerging multidrug-resistant fungal pathogen that represents a serious threat to healthcare settings currently. Objective: Its objective was to determine the prevalence of C. auris in the hospital since its initial detection in late 2019. Methods: Using an adapted risk assessment tool, we reviewed the charts. and medical files of all suspected? and confirmed cases of C. auris cases reported at King Khalid University Hospital, Riyadh between November 2019 and December 2022. Anonymized data were retrieved in a pre-established datasheet and analyzed to determine the epidemiological characteristics of C. auris infection in our facility. We established our initial prevalence by age, gender, risk factors, and according to sampling source. Results: Of the 53 confirmed cases positive for C. auris during the study period, 33 (62%) were males. Their ages ranged between 15 and 98; most positive cases occurred in 50 and above. Only one of the confirmed cases was hospital-acquired. All patients had at least one risk factor, and Urine samples yielded the greatest number of positive cases while admission to healthcare facilities constituted the highest risk in our study. Conclusion: Establishing a local prevalence could serve as our baseline/benchmark to compare with regional and international benchmarks.

Breast cancer is a serious disease and the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are urgently needed. Repurposing FDA-approved drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on breast cancer cell lines including patient derived cell lines. Proguanil caused apoptosis through increased production of ROS and consequent decrease of mitochondrial membrane potential, mitochondrial respiration, and ATP production rates. ROS generation by proguanil was up to 3-fold higher when compared to the control. Proguanil treatment increased the expression of Bax, p-H2AX, cleaved-caspase 9, cleaved PARP, and down-regulated bcl-2 and survivin in breast cancer cell lines. The enlargement of 4T1 breast tumors in female Balb/c mice was suppressed by 55% through daily oral administration of 20mg/kg of proguanil. Western blot analyses of proguanil- treated tumors showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Proguanil proved to be an efficient in vitro and in-vivo inhibitor of breast cancer cells, hence should be considered further for clinical investigation against breast cancer.

(1) Background: National health system databases represent one of the most obvious sources of information about epidemiology of adverse drug reactions including drug-induced allergy and anaphylaxis. (2) Methods: Retrospective analysis of data from national database of pharmacovigilance in the Russian Federation (analyzed period 02.04.2019 - 21.06.2023) was performed. The prevalence of anaphylactic reactions (ARs) was determined, the structure of drugs involved was estimated together with patients’ characteristics. (3) Results: ARs were reported in 8.3% of drug-induced allergic reactions (2304/27,727), mean age of patients was 48.2 ± 15.8 years, 53.2% were females. Main causative groups of drugs were antibiotics, ABs (44.62%), local anesthetics, (19.97%), and cyclooxygenase (COX)-inhibitors (10.07%). Fatal ARs was reported in 9.5% (218/2304), mean age 48.0 ± 16.7 years, 56.2% females. Pediatric population accounted for 5.8% (133/2304), mean age 11.8± 4.5 years, 51.9% females. Elderly population accounted for 2.8% (65/2304), mean age 73.0±5.3 years, 43.5% (27/65) females. ABs were the leading causative groups of ARs in the elderly (40%), children (42.86%), and among fatal cases (50%). (4) Conclusions: ARs accounted for 8.3% of all drug-induced allergic reactions, and ABs were the most common causative agents. Females predominated in all groups except elderly patients.

Infectious illnesses have always posed a threat to human health, with tuberculosis being a major concern. The use of various drugs in the fight against such TB has led to the emergence of drug-resistant tuberculosis, which has become increasingly difficult to manage. While there have been a few studies and proposed conceptual models on how to manage and prevent various drug-resistant TB mutations and lineages, a model aimed at limiting and controlling such mutations in rural areas burdened with tuberculosis is lacking. This study seeks to map a model that is to be used to bridge the gap by facilitating the exchange of knowledge among healthcare professionals in healthcare facilities, diagnostic laboratories, and research institutes, particularly for underprivileged communities in the Eastern Cape. The model information is based on three published manuscripts; therefore, this is a follow-up study. The model will also serve as a practical guide to monitor and evaluate epidemiological TB management plans.

2,4-dichlorophenoxyacetic acid (2,4-D) is a globally used herbicide and is frequently found in water samples. This fact has prompted studies on its effects in non-target organisms, revealing significant alterations on liver structure and function. In this review, we evaluated the literature on the hepatotoxicity of 2,4-D, focusing on morphological damages, biomarkers of toxicity and affected liver functions. Searches were conducted on PubMed, Web of Science and Scopus and 83 articles were selected after curation. Among the studies, 72% used in vivo models and 30% used in vitro models. Additionally, 48% used the active ingredient, and 35% used commercial formu-lations in exposure experiments. The most affected biomarkers were related to a decrease in an-tioxidant capacity, including alterations in the activities of catalase and superoxide dismutase, and in the levels of malondialdehyde. Changes in energy metabolism, lipids, liver function, and xenobiotic metabolism were also identified. Furthermore, we found studies about the effects of 2,4-D in mixtures with other pesticides, as well as hepatoprotection trials. The reviewed data in-dicate that the reduction in antioxidant capacity and oxidative stress play an important role in 2,4-D-induced hepatotoxicity. However, the mechanism of action of the herbicide is still not ful-ly understood and further research in this area is needed.

(1) Background: There is a need to assess the availability of essential antimicrobials as the availability of an antimicrobial is a critical element of its rational use. We aimed to assess the availability of antimicrobials listed in National List of Essential Medicines 2015, India (primary list) and a selected (secondary) list comprising of agents indicated for commonly encountered infectious illnesses in various healthcare settings and to identify the reasons for their non-availability. (2) Methods: A cross-sectional survey of 25 public, private, and other sector pharmacies was carried out in Rohtak, a district of North Indian state of Haryana, from April to June 2022. (3) Results: Most of the antimicrobials surveyed were optimally available in various sector pharmacies with the exception of benzathine benzyl penicillin, benzyl penicillin, cloxacillin, cefazolin, cefuroxime, cefadroxil, amphotericin B and antimalarials. Most frequent reasons for limited availability were low demand, no prescriptions and non-listing of drugs in state essential medicine list. (4) Conclusions: Enough evidence needs to be generated with respect to status of availability of essential antimicrobials from different regions of India as well as other lower-middle income countries to devise measures for ascertaining better availability of these agents especially antibiotics at regional, national and global scales.

The contamination of aquatic environments by pharmaceutical products consistently takes the attention of researchers due to the compounds' toxicity even at low concentrations. In response, we have developed an ecologically sustainable biosurfactant derived from a microorganism and incorporated into the bacterial cellulose. This bioproduct, along with the bacterial cellulose itself, was employed as a sorbent for pharmaceuticals (hormones and paracetamol) present in water. Bacterial cellulose membranes were generated through the cultivation of Gluconacetobacter xylinus ATCC 53582. The biosurfactant was produced by pre-inoculating Bacillus subtilis in a synthetic medium, followed by immersing the bacterial cellulose membranes in the biosurfactant solution, for incorporation. Tests were conducted using water experimentally contaminated with parace-tamol and 17α-ethinylestradiol (EE2), evaluating the biosurfactant's effect on bacterial cellulose sorption. Paracetamol levels were analyzed using spectrophotometry, and EE2 levels were as-sessed using high-performance liquid chromatography. In summary, bacterial cellulose exhibited superior adsorption for EE2 compared to paracetamol. The incorporation of biosurfactant onto bacterial cellulose reduced hormone adsorption but enhanced paracetamol sorption. Our findings indicated that adsorption is more effective with bacterial cellulose in its original and freeze-dried forms, without the incorporation of biosurfactant. Notably, we achieved more promising results in remediating the hormone EE2 compared to the paracetamol.

Malignant melanoma is one of the most aggressive and resistant tumor types which is often accompanied by poor prognosis when spread to nearby or distant tissues. Even though an increasing number of second-line therapies are available for cancer patients, the 5-year survival rate of melanoma patients with regional and distant metastases is still rather low. Therefore, there is an urgent need to develop new, highly efficient treatments. Melanocortin-1-receptor (MC1R) is a cell surface receptor for α-MSH. It is responsible for melanogenesis and is shown to be overexpressed on the surface of cancer cells in a subset of melanoma patients. Here, we designed and synthesized α-MSH analogs and conjugated them to daunomycin through oxime linkage. Using our peptide-drug conjugates (Dau-α-MSHs), we performed comparative in vitro and in vivo evaluations to reveal their suitability for tumor targeting. Firstly, the expression level of MC1R was determined in various melanoma cell lines via RT-qPCR. Then, we examined the antiproliferative effect of our Dau-α-MSHs, moreover we determined the cellular uptake profile and intracellular localization of Dau-α-MSHs. The most efficient Dau-α-MSHs were investigated in vivo using a murine xenograft melanoma model. We found that various cell lines show differential expression on the mRNA levels. We also showed that healthy primary cells have lower expression of MC1R compared to tumor cell lines. Moreover, the concentration-dependent cellular uptake profile of Dau-α-MSHs was detected and the compounds exhibited a great antiproliferative effect on melanoma cell lines. We also provided evidence that our novel Dau-α-MSHs can inhibit tumor expansion significantly and are suitable for targeted tumor therapy.

The practical application of a pH-responsive Nanoparticle Drug Delivery System (NDDS) in cancer treatment is often hampered by several issues such as the protection of therapeutic molecules from external stresses, inefficient targeted delivery, sustained drug release, and poor efficacy. This study presents an effective design strategy for the synthesis of a pH-sensitive controlled hydrophobic drug delivery method based on the formulation of chitosan (CS)-coated mesoporous silica nanoparticles (MSNs) through the sol-gel method, where hydrolysis takes place in the acidic medium followed by polycondensation of the hydrolyzed products. For this purpose, NH2 modified-MSNs were prepared by using tetraethyl orthosilicate (TEOS) as precursor and cetyltrimethylammonium bromide (CTAB) as a template, and 3-aminopropyltriethoxysilane (APTES) for amine modification, followed by hydrophobic drug loading and CS coating of various concentrations. Camptothecin (CPT) was used as a model drug. Fabricated monodispersed functionalized nanoparticles had sizes ranging from 200nm to 245nm with an encapsulation efficiency as high as 90%. The highest encapsulation efficiency was found for 1% CS coating, which released 50% drug in 120h at pH 6.4 and 20% at pH 7.4 respectively. These nanoformulations exhibited pH-responsive release patterns of CPT under two different pH values (pH=7.4 and pH=6.4). These results contribute to the optimization of NDDS, with potential implications for nanoformulations designed for controlled and sustained drug release particularly to tumors without affecting healthy cells owing to differences in the pH of the tumor microenvironment and the normal physiological environment of cells.

Onchocerciasis treatment and control relies mainly on the use of ivermectin which has high activity against the microfilarial stage of Onchocerca volvulus but limited activity against the long lived, tissue dwelling adult nematodes. As this neglected tropical disease has now been targeted for elimination there is an urgent need for new drugs to combat these parasites, ideally with macrofilaricidal activity. In this study we have examined the anti-Onchocerca activity of a range of existing FDA approved drugs with a view to repurposing, which can lead to rapid and relatively inexpensive development. From the Pharmakon-1600 library, 106 drugs were selected and tested against O. gutturosa adult male parasites using a concentration of 1.25 x 10-5 M in an in vitro 5-day standard assay to assess motility and viability (using MTT/formazan colorimetry). The findings revealed that 44 drugs produced marginal/moderate activity (50-99% motility and/or MTT reductions) including cefuroxime sodium, methenamine, primaquine phosphate, rivastigmine tartrate, while 23 drugs produced good activity (100% motility reductions and significant MTT reductions), including atovaquone, isradipine, losartan, rifaximin, cefaclor and pyrantel pamoate. Although this study represents only a first step, some of the identified hits indicate there are potential anti-Onchocerca drug candidates worthy of further investigation.

HIV incidence remains alarmingly high among female sex workers (FSWs) in low- and middle-income countries, with Uganda being no exception. The elevated risk of HIV transmission among this vulnerable population can be attributed to a complex interplay of factors, including engaging in sexual activities with multiple partners, inconsistent condom usage, substance use, and structural barriers, such as legal criminalization and pervasive stigmatization by healthcare providers. To combat this epidemic, various HIV prevention interventions have been devised, targeting these multi-faceted challenges. This study involved conducting focus groups among FSWs and healthcare providers in Uganda, with the overarching objective of informing the development of a tailored HIV prevention intervention aimed squarely at FSWs. Through these discussions, valuable insights were gained into FSWs’ perceptions of their HIV risk, their attitudes regarding HIV prevention strategies, and their recommendations regarding the content and delivery of future interventions.

Although conventional chemotherapeutic drugs are the first line of treatment for cancer, they have numerous side effects. One of the emerging challenges in cancer treatment is drug resistance. Nat-ural compounds have proven effective against various hallmarks of cancer for their multi-target inhibition properties, but especially for their ability to synergistically bypass low bioavailability. Methods: The present study investigated the in vivo antitumor effects of a combination of two natural dietary agents, epigallocatechin-3-gallate (EGCG) from Camelia Sinensis and curcumin, a component of turmeric (Curcuma longa). We aimed to compare, for the first time in vivo, the antiangiogenic and antitumor effects of sunitinib with the combination of curcumin and EGCG in a mouse model of renal cell carcinoma (ccRCC). It was shown that they are able to inhibit cell survival, proliferation of several type of cancer, including renal cell carcinoma (ccRCC), by mod-ulating different signaling pathways and that their combination respect to single compound syn-ergistically decreased angiogenesis. Results: Herein, we highlighted that these compounds inhib-ited the growth of xenografted renal cancer in nude mice by significant inhibition of tumor vol-ume, tumor weight and CD31 expression with no signs of hepatic toxicity. Moreover, mice treated with these natural compounds showed a significant reduction in angiogenesis and an improve-ment in survival rate with p<0.05. Finally, pretreatment of mice with a diet containing 0.6% curcumin before injection of tumor cells showed a significant inhibition of tumor engraftment in 60% of mice with respect to controls and other groups. Conclusions: Taken together, our data in-dicate, for the first time, that the combination of curcumin and EGCG acts in a synergistic manner to inhibit the growth and angiogenesis of ccRCC and with less toxicity than sunitinib and provide an important rationale for future clinical development for chemoprevention and treatment of re-nal cancer.

When it is in the template RNA, the naturally occurring m¹A epitranscriptomic RNA modification was recently reported to be able to stop the RNA polymerization reaction catalyzed by the RNA dependent RNA polymerase (RdRp) of SARS-CoV-2. In this report, we report that m¹A via its triphosphate form (m¹ATP) can be incorporated into RNA by the same RdRp. These two findings point a new direction for antiviral drug development based on m¹A for combatting COVID-19. More broadly, it is possible that the large pool of epigenetic RNA as well as DNA modifications could serve as a treasury for drug discovery aimed at combating various infectious and other diseases.

Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relation exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using "MESH terms." Bibliographic references from relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.

Background: Poisoning is a growing public problem that has shown increased prevalence in many countries worldwide, contributing to increased costs and mortalities. A lack of or insufficient information regarding the circumstances, chemicals, drugs and people at risk due to imperfect reporting system is regarded as a barrier to successful poisoning prevention and intervention efforts. In Saudi Arabia, poisoning cases are monitored at the central level in the Ministry of Health, with meticulous follow-up of cases across country areas through public health departments. The current study's objective was to describe the poisoning notification and reporting system in Makkah.Subjects and methods: All reports of chemical and drug overdose poisoning delivered to the environmental health and occupational safety department in Makkah Almukarramah over two years (2018-2019) were reviewed, together with verification of all systems, rules and guidelines organizing the performance of the department.Results: The total number of cases reported in 2018 was 209 cases, while it reached 42 cases in 2019. The overwhelming majority of the cases were Saudi (91.6%), with a slight predominance of males (57.4%) over females (42.6%). Generally, almost two-thirds of the cases occurred in children below 13 years (61.4%), most of the poisoning cases resulted from drug overdose (63.3%), while 34.7% were chemical poisoning. The most common drug poisoning was attributed to analgesics followed by antiepileptics, antihypertensive drugs, antipsychotics and antimicrobials, while cleaning and detergent agents were the most commonly poisoned chemicals. The majority of these agents were taken by the oral route. Children's chemical poisoning was significantly higher than that in older age groups (p<0.05). All intentional poisoning occurred in adults; the great majority of them (88.9%) used drug overdosing rather than chemical substances.Conclusion and recommendations: The current study results are consistent with most of the previous studies carried out in different regions in Saudi Arabia. Reviewing the performance and adherence of the “Environmental Health and Occupational Safety Department” to the guidelines and instruction regulating monitoring, notification and reporting of poison cases are satisfactory and the poisoning surveillance system is effective. Further in-depth studies are needed to elaborate other socioeconomic and demographic factors associated with chemical and drug overdose poisoning. Public health plans, policies and legislations should be implemented to reduce these factors, including prohibition over-the-counter pharmaceutical sales, selling the possibly harmful substances in kid-proof bottles and additional stringent rules governing chemical sale and storage. Intensive supervision of children is needed. Suicidal poisoning patients should seek psychiatric help to limit the possibility of attempting suicide again in the future. Furthermore, efforts are needed to plan and implement health education programs and campaigns about the factors proven in the current study to be significantly related to chemical and drug overdose poisoning to raise public knowledge about exposure to chemicals and its consequences. Popular communication media, commercial malls, road ads, learning institutions and workplaces can be used to deliver health education campaigns and programs. Advice on how to store chemicals safely and how to keep kids safe should be focused on during such programs.

Chitosan nanoparticle delivery systems have potential for enhancing bone healing and addressing osteomyelitis. The objective was to deliver antimicrobial agents capable of preventing or treating osteomyelitis. Each formulation was optimized to achieve desired characteristics in terms of size (ranging from 100 to 400 nm), PDI (less than 0.5), zeta potential (typically negative), and in vitro release profiles for gentamicin. Entrapment percentages varied with gentamicin ranging from 10% to 65%. The chitosan nanoparticles exhibited substantial antimicrobial efficacy, particularly against both P. aeruginosa and MRSA, with zones of inhibition ranging from 13 to 24 mm and complete reduction in colony forming units observed between 3 to 24 hours. These chitosan nanoparticle formulations loaded with antimicrobials hold promise for addressing orthopedic complications.

Background: Poisoning is a challenging medical condition facing health care providers, as it usually results in serious outcomes in terms of morbidities or mortalities. Poisoning is a challenging medical condition facing health care providers, as it usually results in serious outcomes in terms of morbidities or mortalities. The lack of or inadequate information about the circumstances, substances and populations at risk are considered barriers to the actual prevention of poisoning and effective intervention strategies in Saudi Arabia. The aim of the current study was to describe the pattern and determinants of chemical and drug overdose poisoning in Makkah.Subjects and methods: All reports of chemical and drug overdose poisoning delivered to the Environmental Health and Occupational Safety Department in Makkah over two years (2018-2019) were reviewed.Results: The total number of cases reported in 2018 was 209 cases, while it reached 42 cases in 2019. The overwhelming majority of the cases were Saudi (91.6%), with a slight predominance of males (57.4%) over females (42.6%). Generally, almost two-thirds of the cases occurred in children below 13 years (61.4%), most of the poisoning cases resulted from drug overdose (63.3%), while 34.7% were chemical poisoning. The most common drug poisoning was attributed to analgesics followed by antiepileptics, antihypertensive drugs, antipsychotics and antimicrobials, while cleaning and detergent agents were the most commonly poisoned chemicals. The majority of these agents were taken by the oral route. Children's chemical poisoning was significantly higher than that in older age groups (p<0.05). All intentional poisoning occurred in adults; the great majority of them (88.9%) used drug overdosing rather than chemical substances.Conclusion and recommendations: The current study results are consistent with most of the previous studies carried out in different regions of Saudi Arabia. Further in-depth studies are needed to elaborate other social and demographic factors associated with chemical and drug overdose poisoning. Public health plans, policies and legislations should be implemented to reduce these factors. Intensive supervision of children is needed. Suicidal poisoning patients should seek psychiatric help to limit the possibility of attempting suicide again in the future. Furthermore, efforts are needed to plan and implement health education programs about the factors proven in the current study to be significantly related to chemical and drug overdose poisoning.

Toxoplasma gondii, a protozoan parasite with the ability to infect various warm-blooded vertebrates, including humans, is the causative agent of toxoplasmosis. This infection poses significant risks, leading to severe complications in immunocompromised individuals and potentially affecting the fetus through congenital transmission. A comprehensive understanding of the intricate molecular interactions between T. gondii and its host is pivotal for the development of effective therapeutic strategies. This review emphasizes the crucial role of proteomics in T. gondii research, with a specific focus on host-parasite interactions, post-translational modifications (PTMs), PTM crosstalk, and ongoing efforts in drug discovery. Additionally, we provide an overview of recent advancements in proteomics techniques, encompassing interactome sample preparation methods such as BioID, APEX, and Y2H, as well as various proteomics approaches, including single-cell analysis, DIA, targeted, top-down, and plasma proteomics. Furthermore, we discuss the integration of proteomics with other omics technologies, highlighting its potential in unraveling the intricate mechanisms of T. gondii pathogenesis and identifying novel therapeutic targets.

In the dynamic landscape of drug discovery, Computer-rAided Drug Design (CADD) emerges as a transformative force, bridging the realms of biology and technology. This paper overviews CADD's historical evolution, categorization into structure-based and ligand-based approaches, and its crucial role in rationalizing and expediting drug discovery. As CADD advances, incorporating diverse biological data and ensuring data privacy become paramount. Challenges persist, demanding the optimization of algorithms and robust ethical frameworks. Integrating Machine Learning and Artificial Intelligence amplifies CADD's predictive capabilities, yet ethical considerations and scalability challenges linger. Collaborative efforts and global initiatives, exemplified by platforms like Open Source Malaria, underscore the democratization of drug discovery. The convergence of CADD with personalized medicine offers tailored therapeutic solutions, though ethical dilemmas and accessibility concerns must be navigated. Emerging technologies like quantum computing, immersive technologies, and green chemistry promise to redefine the future of CADD. The trajectory of CADD, marked by rapid advancements, anticipates challenges in ensuring accuracy, addressing biases in AI, and incorporating sustainability metrics. The paper concludes by highlighting the need for proactive measures in navigating the ethical, technological, and educational frontiers of CADD to shape a healthier, brighter future in drug discovery.

Classical Hodgkin lymphoma (cHL) is a highly curable disease (70-80%), even though long-term toxicities, drug resistance, and predicting clinical responses to therapy are major challenges in cHL treatment. To solve these problems, we characterized two cHL cell lines with acquired resistance to doxorubicin, KM-H2dx and HDLM-2dx (HRSdx), generated from KM-H2 and HDLM-2 cells, respectively. HRSdx cells developed cross-resistance to vinblastine, bendamustin, cisplatin, dacarbazine, gem-citabine, brentuximab vedotin (BV), and γ-radiation. Both HDLM-2 and HDLM-2dx cells had an intrinsic resistance to BV but not to the drug MMAE. HDLM-2dx acquired cross-resistance to caelyx. HRSdx cells had in common: decreased CD71, CD80, CD54, cyt-ROS, HLA-DR, DDR1, CD44; increased Bcl-2, CD58, COX2, CD26, CCR5, invasive capability; increased CCL5, TARC, PGE2, TGF-β, and capability to hijack monocytes. In HRSdx cells, less sensitive to DNA damage and oxidative stress, the efflux drug transporters MDR1 and MRP1 were not up-regulated, and doxorubicin accumulated in cytoplasm rather than in nucleus. Both autophagy inhibitor chloroquine and extracellular vesicles (EVs) release inhibitor GW4869 enhanced doxorubicin activity and counteracted doxorubicin resistance. In conclusion, this study identifies common modulated antigens in HRSdx cells, the associated cross-resistance patterns, and new potential therapeutic options to enhance doxorubicin activity and overcome resistance.

Despite recent public health and hygiene advancements, enteric fever, commonly referred to as typhoid fever, remains a common disease in developing nations. The common mode of infection is contaminated water or food. Additionally, person-to-person transmission through poor hygiene and sewage contamination of water supplies has been blamed for most outbreaks. The exact burden of typhoid has yet to be discovered because of the lack of surveillance systems in many developing nations. This makes it difficult to estimate the number of cases. Recent studies have shown that the actual number of cases of typhoid has been estimated to be around 21.6 million annually. The mortality studies suggest that the incidence of typhoid is highest in children under five years old. Typhoid fever and paratyphoid fever have been demonstrated to be life-threatening illnesses. Salmonella serotype Typhi (S. Typhi) is the causative organism of typhoid fever whereas Salmonella serotype Paratyphi is the causative organism for paratyphoid fever. The S. Typhi bacterium is known to be resistant to various drugs. There is a dire need to develop new drugs to treat and overcome the current drug-resistant S. Typhi. The identification of new targets marks the beginning of the process of developing new anti-S. Typhi drugs. The S. Typhic genome sequencing and recent cutting-edge molecular biology tools have led to the discovery of numerous new inhibitors and targets. The goal of this review is to identify the most critical targets in the S. Typhi that are targeted by drugs. It also highlights the various promising vaccines on the market or are still in preclinical studies. A detailed understanding of the targets could help researchers develop safer and more efficient antibacterial agents against S. Typhi.Additionally, the advancement of molecular techniques and the knowledge of the Salmonella pathogenesis pathways have opened better avenues to develop effective antibiotics and vaccines against this pathogen. This review also sought to identify and summarize critical structures of this pathogen that play significant roles in the maturation, development, and pathogenesis of S. Typhi. The endpoint of this work is to provide valuable information on potential therapeutic targets of S. Typhi for drug and vaccine developers.

Multiple sclerosis is a chronic, autoimmune disease that mainly affects the central nervous system, including the brain, spinal cord, and optic nerve. This disease can cause clinical symptoms such as cognitive decline, muscle weakness, spasms, and fatigue in patients, and the onset tends to be younger. Current medication can only prevent or alleviate symptoms, so early diagnosis of this disease can increase patients' chances of treatment. Although the use of nuclear magnetic resonance detection can improve the efficiency of early auxiliary diagnosis, it still requires experienced doctors to spend too much time and energy on comprehensive judgment. To reduce the time cost and improve the efficiency of multiple sclerosis diagnosis, this article proposes a detection and recognition algorithm for multiple sclerosis based on wavelet entropy and self-adaptive particle swarm optimization. Firstly, a triple discrete wavelet transform is performed on the brain image of multiple sclerosis, and then 10 wavelet entropies are extracted from the decomposed wavelet subbands, which can reduce the feature dimensions of the image; Then, the algorithm of self-adaptive particle swarm optimization is used to optimize the feedforward neural network, in order to obtain the optimal connection weights and thresholds during the training process. The result of the model is with an average sensitivity of 92.29±1.89, specificity of 92.54±0.67, precision of 92.48±0.59, accuracy of 92.42±0.88, and F1 score of 84.85±1.74, Matthews correlation coefficient of 92.37±0.96, and Fowlkes223 Mallows Index of 92.38±0.96. The experimental results indicate that this algorithm has a very important data support role in detecting multiple sclerosis.

Cytochrome P450 oxidoreductase (POR) is an essential redox partner for steroid and drug-metabolizing cytochromes P450 located in the endoplasmic reticulum. Mutations in POR lead to metabolic disorders, including congenital adrenal hyperplasia, and affect the metabolism of steroids, drugs, and xenobiotics. In this study, we examined approximately 450 missense variants of the POR gene listed in the Genome Aggregation Database (gnomAD) using eleven different in silico prediction tools. We found that 64 novel variants were consistently predicted to be disease-causing by most tools. To validate our findings, we conducted population analysis and selected two variations in POR for further investigation. The human POR wild type, along with the R268W and L577P variants, were expressed in bacteria and subjected to enzyme kinetic assays using model substrate. We also examined the activities of several cytochrome P450 proteins in the presence of POR (WT or variants) by combining P450 and reductase proteins in liposomes. We observed a decrease in enzymatic activities (ranging from 35% to 85%) of key drug metabolizing enzymes, supported by POR variants R288W and L577P compared to WT-POR. These results validate our approach of curating a vast amount of data from genome projects and provide an updated and reliable reference for diagnosing POR deficiency.

Zika Virus (ZIKV) is a pathogenic member of the flavivirus family, with several unique charac-teristics. Unlike any other arbovirus, ZIKV can be transmitted sexually and maternally, and thus produce congenital syndromes (CZS) due to its neurotropism. This challenges the search for safe active molecules that can protect pregnant women and their fetuses. In this context, and in the ab-sence of any existing treatment, it seemed worthwhile to test whether the known cytoprotective properties of adiponectin and its pharmacological analog, AdipoRon, could influence the outcome of ZIKV infection. We showed that both AdipoRon and adiponectin could significantly reduce in vitro infection of A549 epithelial cells, a well-known cell model for flaviviruses infection studies. This effect was particularly observed when a pre-treatment was carried out. Conversely, ZIKV revealed an ability to down-regulate adiponectin receptor expression and thereby limit adi-ponectin signaling.

The new coronavirus SARS-CoV-2 is the cause of the COVID-19 pandemic, which has created an incomparable global health problem. PLpro is a key protein involved in viral polyprotein processing and immune system evasion, making it a prime target for the development of antiviral drugs to combat COVID-19. The review begins by elucidating the functional and structural properties of SARS-CoV-2 PLpro, underscoring its significance in viral pathogenicity and replication. Employing homology modeling, a tertiary structure model of PLpro is constructed, laying the groundwork for subsequent investigations. To expedite the search for potential therapeutic candidates, the study harnesses computational methodologies. Molecular docking techniques are employed to explore binding sites for antiviral drugs within the catalytic region of PLpro. This computational approach not only aids in drug development but also provides crucial preliminary data before experimental research commences. The stability of drug-PLpro complexes is assessed through comprehensive all-atom molecular dynamics (MD) simulations, affording dynamic insights into drug-PLpro interactions. By evaluating binding energy estimates from MD simulations, stable drug-PLpro complexes with potential antiviral properties are identified. However, it is emphasized that experimental validation is imperative to confirm these computational findings, necessitating in vitro and in vivo tests to assess safety and efficacy. This pivotal stage bridges the computational realm with real-world clinical applications. The review emphasizes the imperative need for enhancements in the existing PLpro-targeting drugs currently on the market. Their actions are insufficient for clinical use and necessitate thorough characterization and improvement. The Supervised Molecular Dynamics (SuMD) simulation technique reveals critical information about drug unbinding pathways, shedding light on opportunities for refinement. In addition to optimizing existing drugs, the investigation of sub-structurally similar molecules emerges as a promising avenue for drug development. In conclusion, the review underscores the pivotal role of targeting SARS-CoV-2 PLpro in the ongoing battle against COVID-19. By integrating molecular dynamics simulations, structural modeling, and computational insights, a robust foundation is established for identifying promising antiviral drug candidates. The continual need for improvement in existing drugs and the exploration of novel compounds remain paramount in the global effort to combat COVID-19. The evolution and management of COVID-19 hinge on the symbiotic relationship between computational insights and experimental validation, illustrating the interdisciplinary synergy crucial to this endeavor.

Human serum albumin (HSA) is multifunctional protein, known to be a natural carrier for a number of endogenous and exogenous compounds, including drugs. Formulating anticancer drugs with HSA is a clinically validated approach to improve the pharmacological properties and provide targeted delivery (passive and active) of cytotoxic payload to the tumor (such as in Abraxane). A number of receptors facilitating HSA uptake from systemic circulation have been characterized. What is interesting, such uptake may differ depending on the nature and quantity of ligands bound to HSA. Based on this, one might like to modify the HSA in a way that its distribution is more favorable for certain therapeutic purposes, thus ensuring more efficient delivery of the therapeutic cargo to disease site. E.g. Levofloxacin (LV), broad spectrum antibiotic drug, could benefit from extended systemic exposure, and stronger interaction with plasma proteins could be useful for this purpose. We have engrafted monomeric or polymeric CDs on the surface of HSA molecules to strengthen the LV adsorption (CD-LV dissociation constant is three orders of magnitude lower than that for HSA-LF). We have found that (HSA-HPolS)conj+LV exhibited the highest activity against E. coli, whereas (HSA-HPCD)conj+LV was the most effective against B. subtilis; and both HSA conjugates were more potent than LV alone or LV with HSA. Further fine-tuning of HSA could yield an improvement in biodistribution, and thus a more favorable risk/benefit ratio.

Treatment of bladder cancer remains a critical unmet need and requires advanced approaches, particularly the development of local drug delivery systems. The physiology of the urinary bladder causes the main difficulties in the local treatment of bladder cancer: regular voiding prevents the maintenance of optimal concentration of the instilled drugs, while poor permeability of the urothelium limits the penetration of the drugs into the bladder wall. Therefore, much research effort is spent to overcome these hurdles, thereby improving the efficacy of available therapies. The explosive development of nanotechnology, polymer science and related fields has contributed to the emergence of a number of nanostructured vehicles (nano- and micro scale) applicable for intravesical drug delivery. Moreover, the engineering approach has facilitated the design of several macro-sized depot systems (centimeter scale) capable of remaining in the bladder for weeks and months. In this article, the main rationales and strategies for improved intravesical delivery are reviewed. Here, we focused on analysis of colloidal nano- and micro-sized drug carriers, and indwelling macro-scale devices which were evaluated for applicability in local therapy of bladder cancer in vivo.

This article discusses the fabrication of pullulan/polyvinyl alcohol (PVA) and PVA blends as carrier polymers for drug delivery. This study utilized coaxial electrospinning to encapsulate doxorubicin (DOX), a common anticancer drug, within nanofibers, which helped mitigate the adverse effects of DOX on normal cells. The study also demonstrated that the coaxial electrospinning technique using PVA/pullulan cores was effective in inhibiting the attachment and proliferation of HeLa cells, a type of cervical cancer cell. The use of pullulan/PVA and PVA blends as carrier polymers in conjunction with coaxial electrospinning could provide a safe and effective drug delivery system for the treatment of cervical and other solid malignancies. The study concluded that nanofibers showed promising results in inhibiting the growth of HeLa cells, indicating their potential as safe and effective drug delivery systems for treating cervical cancer and other solid malignant tumors.

Casein Kinase ІІ (CK2) is one of the most versatile kinases. Its involvement in almost all cellular pathways makes it the Master Regulator of biochemical processes in a cell. This kinase is essential in regulating inflammation, cell differentiation, and cell cycle regulation. Often simultaneously. Its emerging role in senescence also indicates its function's centrality in cellular metabolism. The strategy to target this kinase to treat musculoskeletal disorders seems effective. These disorders often include a component of inflammation, dysregulated cell differentiation, and aging. This review focuses on CK2 target discovery and the diversity of its substrate interactions. We then transition toward the implication of CK2 in musculoskeletal disorders. Through a summary of current strategies for CK2 targeting with a new approach, we discuss the potential aspects that could be addressed in future drug research.

Central Nervous System (CNS) cancers pose a formidable challenge in the medical world, characterized by aggressive behaviors and limited therapeutic options. The emergence of nanomedicine has offered new hope in CNS cancer treatment. The COVID-19 pandemic has further accelerated the need for innovative therapeutic strategies, emphasizing the significance of nanomedicine in this era. This mini review explores the current status of nanomedicine in CNS cancer therapy, with a particular focus on the post-COVID-19 landscape. We discuss the unique challenges presented by CNS cancers, the potential of nanomedicine in overcoming these challenges, and the recent developments in the field. Additionally, we highlight the lessons learned from the pandemic and how they can be applied to improve CNS cancer therapeutics. We also shed light on the evolving regulatory landscape and the prospects of personalized nanomedicine in CNS cancer treatment. The integration of nanomedicine in CNS cancer therapy is becoming increasingly promising, and its role in the post-COVID-19 era is poised to shape the future of neuro-oncology.

Xpert MTB/RIF is rapid molecular diagnostic tool capable of simultaneously detecting Mycobacterium tuberculosis and rifampicin resistance. This study aimed to access the diagnostic precision of Xpert MTB/RIF assay to detect pulmonary and extra-pulmonary tuberculosis and to evaluate the performance for the detection of rifampicin resistance. Of 37695 samples, 7156(18.98%) were tuberculosis positive, 509(7.11%) were rifampicin-resistant. The sensitivity, specificity, PPV, NPV, Diseases prevalence and accuracy of Xpert MTB/RIF assay for PTB were 99.87% (95%CI:99.75-99.94), 99.92%(95%CI:99.88-99.95), 99.71%(95%CI:99.54-99.82),99.97%(95%CI:99.93-99.98),21.38% (95%CI:20.92-21.86),and 99.91%(95%CI:99.87-99.94), respectively. For EPTB, the sensitivity, specificity, PPV, NPV, Diseases prevalence and accuracy of Xpert MTB/RIF assay accounted for 99.45% (95%CI:98.73-99.82),99.84%(95%CI:99.73-99.92),98.70%(95%CI:97.73-99.25),99.93% (95%CI:99.84-99.97),10.64%(95%CI:9.99-11.31),and 99.80%(95%CI:99.68-99.88), respectively. Despite its high sensitivity for detecting tuberculosis and rifampicin resistance, Xpert MTB/RIF had contradictory results for 20.5% of cases among patients with negative smear results and 54.9% of cases among patients with a high risk of Multidrug-resistant tuberculosis. Of 47 fluoroquinolone-resistant, 16.56% (26/157) of Multidrug-resistant tuberculosis isolates and 4.02% (20/498) isoniazid-resistant are fluoroquinolone-resistant, a characteristic distribution leading to about 17.2% of fluoroquinolone resistance events and relevant marker gyr-A mutations in MDR tuberculosis isolates. Further, our study indicated that increased fluoroquinolone resistance among Rifampicin-resistant and isoniazid-resistant tuberculosis endangers the success of newly endorsed MDR-TB regimens.

Drug delivery through Liposomes has shown tremendous potential in terms of the therapeutic application of nanoparticles. There are several drug-loaded liposomal formulations approved for clinical use that help mitigate harmful effects of life-threatening diseases. Developments in the field of liposomal formulations and drug delivery have made it possible for clinicians and researchers to find therapeutic solutions for complicated medical conditions. A key aspect in the development of drug-loaded liposomes is a careful review of optimization techniques to improve the overall formulation stability and efficacy. Optimization studies help in improving/modulating the various properties of drug-loaded liposomes and are vital for the development of this class of delivery systems. A comprehensive overview of the various process variables and factors involved in the optimization of drug-loaded liposomes is presented in this review. The influence of different independent variables on drug release and loading properties with the application of a statistical experimental design is also explained in this article.

Drug-target affinity (DTA) prediction is crucial for understanding molecular interactions and aiding drug discovery and development. While various computational methods have been proposed for DTA prediction, their predictive accuracy remains limited, failing to delve into the structural nuances of interactions. With increasingly accurate and accessible structure prediction of targets, we developed a novel deep learning model, named S2DTA, to accurately predict DTA by fusing sequence and structural knowledge of drugs, targets, and pockets using heterogeneous models based on graph and semantic networks. Experimental findings underscored that complex feature representations imparted negligible enhancements to the model’s performance. However, the integration of heterogeneous models demonstrably bolstered predictive accuracy. In comparison to three state-of-the-art methodologies, the supremacy of S2DTA became strikingly apparent. It showcased a noteworthy 25.2% reduction in Mean Absolute Error (MAE) and an impressive 20.1% decrease in Root Mean Square Error (RMSE). Furthermore, S2DTA exhibited substantial advancements in other pivotal metrics, including Pearson Correlation Coefficient (PCC), Spearman, Concordance Index (CI), and R2. These metrics experienced remarkable increments of at least 19.6%, 17.5%, 8.1%, and a remarkable 49.4%, respectively. Finally, we conducted interpretability analysis on the effectiveness of S2DTA by bidirectional self-attention mechanism, fully proving that S2DTA is a valuable and accurate tool for predicting DTA. For further exploration, the source data and code repository can be accessed at https://github.com/dldxzx/S2DTA.

The integration of bioinformatics in drug discovery has revolutionized the field of pharmaceutical research. The use of computational tools and techniques has enabled researchers to analyze vast amounts of data, identify potential drug targets, and design new drugs with greater precision and efficiency. The integration of bioinformatics has also facilitated the development of personalized medicine, where drugs can be tailored to individual patients based on their genetic makeup. However, there are still challenges that need to be addressed, such as the need for more accurate predictive models and the ethical considerations surrounding the use of patient data. Overall, the integration of bioinformatics in drug discovery holds great promise for improving human health and advancing our understanding of disease mechanisms. In this mini-review, we discuss how Bioinformatics plays a crucial role in each step of drug discovery by providing tools and techniques to analyze large amounts of data generated from various sources, as well as the challenges and the opportunities offered by bioinformatics.

The dynamic interaction between carbon nanodots (CNDs) and cannabidiol (CBD) has captured significant attention as an innovative avenue for redefining drug delivery and amplifying therapeutic effectiveness. This in-depth review delves into the intricate synergy between these two elements, unveiling their profound potential in medicine. Commencing with an examination of the unique characteristics of CNDs and the techniques governing their synthesis, we discuss their versatility as drug carriers, highlighting their invaluable role in advancing CBD delivery. Cannabidiol, a non-psychoactive compound sourced from cannabis, has emerged as a focal point for its diverse therapeutic attributes. Nevertheless, the limitations posed by its restricted bioavailability and susceptibility to degradation pose substantial hindrances to realizing its full potential. Here, we elucidate how the amalgamation of CBD with CNDs transcends these challenges. We delve into the mechanisms that underlie this synergy, such as the augmentation of solubility and the safeguarding of CBD against premature breakdown, providing an intricate analysis. We will also journey you through a comprehensive exploration of diverse CBD loading techniques onto CNDs, dissecting the realms of physical encapsulation, covalent bonding, and adsorption processes. In summation, the combination of CNDs and CBD presents an extraordinary opportunity to elevate therapeutic outcomes. This synergetic paradigm masterfully tackles pivotal challenges in drug delivery, thereby paving the path for pioneering medical solutions.

Intermolecular interactions are the fabrics underlying almost all processes in living organisms, where two cornerstone concepts, intermolecular binding affinity (K d ) and binding energy (ΔG), have long been established to physically describe the strengths of biomolecular interactions, e.g., drug-target K d and ΔG to describe the strength of drug-target interaction. The past two-three years saw a big step forward in the use of artificial intelligence (AI) in structural biology (e.g., AlphaFold for protein structure prediction) and drug discovery & design. In light of the roles of K d and ΔG in drug discovery & design, the speed of this AI progress raises a question of what’s next for its practical application in the pharmaceutical industry, in addition to a system-wide account of biomolecular structures and motions. Last August, the concept of a general intermolecular binding affinity calculator (GIBAC) was for the first time coined and proposed in an MDPI-published preprint. Here, this article puts forward an updated conceptual and practical framework of GIBAC, including its inception, definition, construction, practical applications, technical challenges and limitations, and future directions. Moreover, this article argues that the time is now ripe for the construction of such an accurate, precise and efficient GIBAC to be on the agenda of the entire drug discovery & design community, to ensure its applicability & reliability, and to enhance its value in drug R&D in future.

The COVID-19 pandemic has unveiled the critical role that supercomputers play in addressing global health crises. This perspective article explores the transformative impact of supercomputing in pandemic response, highlighting how these powerful machines have transitioned from crisis management tools to essential components of preparedness strategies. In this article, we examine the key contributions of supercomputers in combating the pandemic, including their ability to accelerate scientific research, facilitate data analysis, model complex scenarios, and optimize resource allocation. Furthermore, we delve into the role of supercomputing in strengthening public health infrastructure and preparedness. We analyze the lessons learned from the pandemic and emphasize the need for proactive investment in supercomputing capabilities, data infrastructure, and computational expertise as a crucial element of pandemic preparedness efforts. By harnessing the potential of supercomputers, countries can establish robust computational frameworks that enable real-time monitoring, early detection, and effective response to future outbreaks. Moreover, we address the challenges faced by supercomputing initiatives, including the need for enhanced international collaboration, equitable access to computing resources, and the ethical considerations associated with data privacy and security. We discuss potential strategies to overcome these challenges and foster a global network of interconnected supercomputing centers dedicated to pandemic preparedness and response. Finally, we highlight ongoing research and development efforts aimed at advancing supercomputing technologies, such as exascale computing and quantum computing, and their potential to revolutionize pandemic response. We emphasize the importance of sustained investment in research and development to ensure that supercomputing remains at the forefront of future pandemic preparedness strategies.

(1) Background: The incidence of vancomycin-induced neutropenia in hospitalized patients is estimated to be around 2 to 8 percent [1,2]. Data surrounding vancomycin-induced neutropenia is limited as it is based on a small number of observational case reports. Additionally, it is difficult to provide generalized conclusions since patient characteristics and indications for treatment vary between reports. (2) Case Reports: We present two cases of vancomycin-induced neutropenia that occurred at our facility; a 50-year-old male who developed neutropenia after treatment with vancomycin for a gluteal abscess and a 51-year-old female who developed neutropenia after treatment with vancomycin for lumbar osteomyelitis. In both cases, neutropenia resolved within 2 days of discontinuation of vancomycin. (3) Conclusion: The risk of developing neutropenia increases with age, prolonged drug exposure, decreased renal clearance, and in those of female sex. Treatment involves discontinuation of vancomycin with or without administration of granulocyte colony-stimulating factor (G-CSF). Additional studies are needed to better understand the true incidence of this adverse drug reaction and to identify risk factors that may predispose patients to vancomycin-induced neutropenia.

Encapsulated nanofibers have emerged as a promising approach for the treatment of acne, owing to their ability to provide controlled release, targeted delivery, increased efficacy, and improved stability. Electrospinning is a well-established method for producing encapsulated nanofibers and has been shown to be effective for encapsulating various active ingredients. However, there are still several challenges that need to be addressed in the development of encapsulated nanofibers for acne treatment. One major challenge is the need for comprehensive in vitro and in vivo studies to evaluate the safety and efficacy of these treatments. The cost and scalability of production also need to be considered to make these treatments accessible and affordable for patients. In addition, the long-term stability of encapsulated active ingredients is another challenge in the development of encapsulated nanofibers for acne treatment. Regulatory frameworks need to be developed to ensure the safety and efficacy of these treatments. Future research may focus on developing multifunctional nanofibers that combine active ingredients with other properties, such as antimicrobial, anti-inflammatory, and wound-healing properties, to provide a comprehensive approach to acne treatment. Moreover, the development of nanofiber-based skincare products may have a significant impact on the cosmetic industry. Overall, while there are still challenges to overcome, the potential benefits of encapsulated nanofibers for acne treatment make them an exciting and promising area of research for the future. In particular, the integration of smart drug delivery systems and responsive materials may enable the development of more personalized and effective treatments for acne. The development of new materials and encapsulation techniques, as well as the exploration of combination therapies that target multiple aspects of acne pathogenesis, are also future perspectives for encapsulated nanofibers in acne treatment.

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nevertheless, the responder rates of recently approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and receptor inhibitors remain around 50 percent. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge on PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.

Complex-structured polymeric microparticles hold significant promise as advance in next-generation medicine mostly due to demand from developing targeted drug delivery. However, the conventional methods for producing these microparticles of defined size, shape and sophisticated composition often face challenges in scalability, reliance on specialized components such as micro-patterned templates, or have limited control over particle size distribution and cargo release kinetics. In this study, we introduce a novel and reliably scalable approach for manufacturing microparticles of defined structures and sizes with variable parameters. The concept behind this method involves the deposition of a specific number of polymer layers on a substrate with low surface energy. Each layer can serve as either the carrier for cargo or a programmable shell-former with predefined permeability. Subsequently, this layered structure is precisely cut into desired-sized blanks using a laser. The manufacturing process is completed by applying of heat to the substrate what results on sealing the edges of the blanks. The combination of the high surface tension of the molten polymer and the low surface energy of the substrate enables the formation of discrete particles, each possessing semi-spherical or other designed geometries determined by their internal composition. Such anisotropic microparticles are envisaged versatile applications.

The type III receptor tyrosine kinase FLT3 is a pivotal kinase for hematopoietic progenitor cell regulation, with significant implications in acute myeloid leukemia (AML) through mutations like internal tandem duplication (ITD). This study delves into the structural intricacies of FLT3, the roles of activation loop mutants, and their interaction with tyrosine kinase inhibitors. Coupled with this, the research leverages molecular contrastive learning and protein language modeling to examine interactions between small molecule inhibitors and FLT3 activation loop mutants. Utilizing the ConPLex platform, over 5.7 million unique FLT3 activation loop mutants-small molecule pairs were analyzed. The binding free energies of three inhibitors were assessed, and cellular apoptotic responses were evaluated under drug treatments. Notably, the introduction of the Xepto50 scoring system provides a nuanced metric for drug efficacy. The findings underscore the modulation of molecular interactions and cellular responses by Y842 mutations in FLT3-KD, highlighting the need for tailored therapeutic approaches in FLT3-ITD-related malignancies.

Worldwide, hypoxia-related conditions, including cancer, COVID-19, and neuro-degenerative diseases, often lead to multi-organ failure and significant mortality. Oxygen, crucial for cellular function, becomes scarce as levels drop below 10 mmHg (<2% O2), triggering mitochondrial dysregulation and activating hypoxia-induced factors (HiFs). Herein, Oxygen nanoBubbles (OnB), an emerging versatile oxygen de-livery platform, implies to offer a novel approach to address hypoxia-related pathologies. This review explores OnB oxygen delivery strategies and systems, including diffusion, ultrasound, photodynamic, and pH-responsive nanobubbles. It delves into the nanoscale mechanisms of OnB, elucidating their role in mitochondrial metabolism (TFAM, PGC1alpha), hypoxic responses (HiF-1alpha), and their interplay in chronic pathologies including cancer and neurodegenerative disorders, amongst others. By understanding these dynamics and underlying mechanisms, this article aims to contribute to our accruing knowledge of OnB and the developing potential in ameliorating hypoxia- and metabolic stress-related conditions and fostering innovative therapies.

The release of drugs from core/shell nanoparticles (NPs) is a crucial factor in ensuring high re-producibility, stability, and quality control. It serves as the scientific basis for the development of nanocarriers. Several factors, such as composition, composition ratio, ingredient interactions, and preparation methods, influence the drug release from these carrier systems. The objective of our study was to investigate and discuss the relationship between modifications of core/shell NPs as multifunctional drug delivery systems and the properties and kinetics of drug release using an in vitro drug release model. In this paper, we prepared four core/shell NPs consisting of a super-paramagnetic iron oxide NPs (Fe3-δO4) core encapsulated by a biocompatible thermo-responsive copolymer, poly(2-(2-methoxy) ethyl methacrylate-oligo (ethylene glycol) methacrylate) or P(MEO2MAx-OEGMA100-x) (where x and 100-x represent the molar fractions of MEO2MA and OEGMA, respectively), and loaded with doxorubicin (DOX). Colloidal behavior measurements in water and PBS as a function of temperature showed an optimization of the lower critical solu-tion temperature (LCST) depending on the molar fractions of MEO2MA and OEGMA used to form each NPs. In vitro studies of doxorubicin release as a function of temperature demonstrated a high control of release based on the LCST. A temperature of approximately 45°C for 60 h was sufficient to release 100 % of the DOX loaded in the NPs for each sample. In conclusion, external stimuli can be used to modulate the drug release behavior. Core/shell NPs hold great promise as a technique for multifunctional drug delivery systems.

Biofilm-associated proteins (BAPs) are important in the development and resilience of biofilms, which are intricate populations of microbes protected by extracellular matrix. All members of the BAP family are known to possess common characteristics such as high molecular weight and a signal sequence for extracellular secretion. It has been shown that BAPs are directly linked to the pathogenicity of many bacteria. This mini review highlights several potential strategies to target BAPs for drug development.

Combining antiviral drugs with different mechanisms of action can help prevent the development of resistance by attacking the infectious agent through multiple pathways. Additionally, by using faster and more economical screening methods, effective synergistic drug candidates can be rapidly identified, facilitating faster paths to clinical testing. In this work, a rapid method was standardized to identify possible synergisms from drug combinations. We analyzed the possible reduction of antiviral effective concentration of drugs already approved by the FDA, such as ivermectin  (IVM), ribavirin (RIBA) and acyclovir (ACV) against Zika virus (ZIKV), Chikungunya virus (CHIKV) and herpes virus type 2 (HHV-2). Essential oils (EOs) were also included in the study since they have been reported for more than a couple of decades to have broad-spectrum antiviral activity. We also continued studying the antiviral properties of one of our patented molecule with broad-spectrum antiviral activity, the ferruginol analogue 18-(phthalimid-2-yl)ferruginol (phthFGL). In general, the combination of IVM, phthFGL and Oregano EO showed the greatest synergism potential against CHIKV, ZIKV and HHV-2, obtaining a reduction in the EC99 value of up to ~8, and ~27, and ~12-fold for CHIKV, in example, respectively. The ternary combination RIBA, phthFGL, Oregano EO was slightly more efficient than the binary combination RIBA/phthFGL but much less efficient than IVM, phthFGL, Oregano EO which indicates that IVM could contribute more to the differentiations of cell targets (for example by inhibition of host heterodimeric importin IMP α/β1 complex) than ribavirin. PhthFGL showed a good pharmacokinetic profile.

This article reviews the introduction of Alzheimer's Disease (AD), neural networks, training and learning of neural networks, applications of neural networks in early diagnosis of AD, applications of neural networks in AD drug discovery, other brain diseases, and challenges faced by AD. First, the paper introduces the background and characteristics of AD. AD is a degenerative neurological disorder characterized by impaired memory, decreased cognitive function, and loss of neurons. These characteristics place a huge burden on the lives and families of patients. Next, the basic principle and structure of neural network are discussed. A neural network is a computational model made up of multiple neurons that can perform tasks by learning and adapting to input data. In particular, the key concepts of neural network hierarchy, activation function and weight adjustment are discussed. Then, the training and learning methods of neural networks are discussed. Common techniques such as backpropagation algorithm and gradient descent optimizer are introduced in detail, as well as the importance of data preprocessing and model evaluation. Next, the paper focuses on the application of neural network in early diagnosis of AD. By extracting features from brain image data, neural networks can automatically identify differences between AD patients and healthy subjects, enabling early diagnosis and intervention. In addition, the application of neural networks in AD drug discovery is also discussed. By analyzing and predicting a database of known drugs, neural networks can help discover potential treatments for AD and speed up the drug discovery process. The paper further explores the application of neural networks in other brain diseases and highlights the challenges faced by AD, such as the lack of reliable biomarkers, complex pathological mechanisms, etc. In summary, this paper presents a systematic overview of AD, neural networks, training and learning of neural networks, applications of neural networks in early diagnosis of AD and drug discovery, and other brain diseases and challenges associated with AD.

The resistance of Candida spp to fluconazole is a serious problem; Therefore, it must be investigated to expand the understanding of the phenomenon with a view to its clinical applicability. The aim was to evaluate the expression of ERG3, ERG11, CDR1, and SNQ2 genes involving computational analysis. Relative expression was quantified by RT-qPCR. Metrics were obtained by molecular docking and through Fisher's discriminant functions, a predictive classification against susceptibility to fluconazole was performed. The expression of ERG3, CDR1, and SNQ2 genes was higher in resistant strains than in dose-dependent sensitive strains. The gene with the highest expression in strains exposed to fluconazole was CDR1 and, in both resistant and dose-dependent sensitive strains exposed to fluconazole, the ERG11 gene had lower expression. The molecular docking model generated lower median fluconazole-ERG11 contacts than the median fluconazole-ERG3, -CDR1, and -SNQ2 contacts. The predicted classification through the multivariate model for fluconazole sensitivity obtained an accuracy of 73.5%. Resistant strains had a significant expression of CDR1, SNQ2 and ERG3 genes, compared to a comparatively low expression of ERG11. Molecular analysis identified a low affinity between fluconazole and its drug target, which may explain a lower intrinsic susceptibility of the fungus.

Antimicrobial peptides (AMPs) have emerged as a promising solution to tackle bacterial infections and combat antibiotic resistance. However, their clinical application has been hindered by their vulnerability to protease degradation and toxicity towards mammalian cells. To overcome these challenges, our study aims to develop a method to enhance the stability and safety of AMPs, applicable to effective drug-device combination products. KR12 antimicrobial peptide was chosen and in order to further enhance its delivery and efficacy, HIV TAT protein-derived cell-penetrating peptide (CPP) was fused to form CPP-KR12. A new product, CPP-KR12@Si, was developed by forming silica nanoparticles with self-entrapped CPP-KR12 peptide using the biomimetic silica precipitability due to its cationic nature. Peptide delivery from CPP-KR12@Si to bacteria and cells was delivered at a slightly delayed rate with improved stability against trypsin treatment and a reduction in cytotoxicity over CPP-KR12. Finally, the antimicrobial potential of CPP-KR12@Si/bone graft substitute (BGS) combination product was demonstrated, which is coated with CPP-KR12 in the form of nanoparticles on the surface of BGS. Self-entrapped AMP in silica nanoparticles is a safe and effective AMP delivery method that will be useful for developing a drug/device combination product for tissue regeneration.

Cancer is among the leading causes of death worldwide. Therefore, timely diagnosis and appropriate treatment are very important. There are many disadvantages that come with traditional cancer treatments, such as chemotherapy and radiotherapy. In these treatments, the specific drug concentration affects not only the tumor site but also healthy tissues or organs. One of the foremost promising uses of nanotechnology is in the field of medical technology and specific site targeting can be achieved due to manipulation of materials at a nanometric scale. Nanotechnology offers specific benefits in terms of cancer therapy by enhancing it and reducing its adverse effects by guiding drugs to selectively target cancer cells. In addition, the use of minute amounts of medicine can lead to cost savings. Furthermore, nanoparticles can also be used as imaging agents to improve cancer diagnostics, therapeutics, and treatment management. Thus, this review has focused on the different types of nanoparticles used in cancer therapy, their action mechanisms, and their benefits and applications in diagnosis, imaging, and treatment. This review sums up the parameters that need to be considered when designing systems for cancer therapy while considering the desired characteristics of the nanoparticles from the biological point of view.

(1) Background: Type-2 Diabetes (T2DM) is a long-term medical disorder characterized by Insulin deficiency and high blood glucose levels. Among other medication to cure T2DM, the review of the literature found that various Pyrimidine derivative act as an agonist for G-protein-coupled receptor 119 (GPR119) was proposed to control blood glucose levels by enhancing the function of pancreatic beta-cells and its mechanism of action with fewer adverse effects.; (2) Methods: In the present research work, in-silico investigations were carried out to investigate the potential of Pyrimidine analogue as an agonists to the protein target GPR119 receptor. We performed exhaustive molecular modelling and protein modelling methodologies such as homology mod-elling, molecular docking along with various drug designing tools such as 3D-QSAR and pharmacophore mapping to ascertain the design of better GPR119 agonists.; (3) Results: On the basis of in-depth computa-tional studies, we designed new pyrimidine moiety and analyzed them for GPR-119 receptor agonist and fur-ther explored the ADME properties. Designed compounds found to exhibit better predicted activities as com-pared to reference compound; (4) Conclusions: The current research on pyrimidine derivatives, using molec-ular docking, 3D-QSAR and Pharmacophore mapping demonstrated that the obtained computational model has significant properties and the designed molecules and Dataset from this model, produced antidiabetic compound against the target GPR119 i.e., compound 1S, 1Z and 1D with the docking score of −11.696, -9.314 and -8.721 respectively. The pharmacokinetics and drug-likeness studies revealed that these compounds may be the future candidate for the treatment of diabetes acting via GPR119 agonist mechanism.

Background: Chronic Hepatitis B Virus (HBV) infection is a global health concern, associated with severe liver diseases, necessitating ongoing research on novel drug candidates. This study aims to identify potential drug candidates targeting HBV core protein (HBcAg) and disrupting capsid assembly, a critical step in the virus's life cycle. Methods: HBcAg in complex with HBV inhibitors were obtained from the Protein Data Bank (PDB). CavityPlus server was used for analysis of druggable cavity. Structure-based pharmacophores were extracted from identified cavities, and potential allosteric ligand binding sites were assessed using CavPharmer, CorrSite, and CovCys. LigandScout was employed for ligand-based pharmacophore screening against an FDA-approved library. The ZINC database was screened with features extracted from CavPharmer. Molecular docking studies were conducted using Autodock Vina. Lead compounds were selected based on docking scores, binding modes, and interactions within the druggable cavity. Results: Strong druggable pockets were found for Ciclopirox, while Compound 24, NVR10-001E2, and others showed medium to weak pockets. Ligand-based pharmacophores varied in size and complexity. Screening revealed potential hits matching these pharmacophores, including Ciclopirox olamine, Voriconazole, Enasidenib, and Statins. A large compound database search yielded additional hits like ZINC86859997 and ZINC63280172. Docking analyses confirmed these hits' potential, highlighting their interactions with critical HBc protein residues, offering promising leads for hepatitis B drug development. Conclusions: Voriconazole, Enasidenib, and Lovastatin have shown promises. These hits displayed favorable interactions with crucial HBc protein residues, indicating their potential as lead compounds The mechanism of action of statins with anti-HBV activities also highlighted. This comprehensive approach offers valuable insights into targeting HBc protein for antiviral drug discovery.

The number of people affected by eye conditions is growing every year, due to the popularity of electronic devices and an aging population. In the world of medicine, accomplishing eye medication administration has always been a difficult task. Despite the fact that there are many eye drops on the market, most of them have important limitations due to quick clearance mechanisms and ocular barriers. One solution with tremendous potential is the contact lens used as medication delivery vehicle to bypass this constraint. Therapeutic contact lenses for ocular medication delivery have attracted a lot of attention because they have the potential to improve ocular bioavailability, patient compliance, and reduce side effects. However, it is essential not to compromise essential features such as water content, optical transparency, and modulus in order to target successful in vitro and in vivo sustained drug delivery profile from impregnated contact lenses. Aside from difficulties like drug stability and burst release, the changing of lens physical and chemical properties caused by therapeutic or non-therapeutic components can limit the commercialization potential of pharmaceutical-loaded lenses. Research has progressed towards bioinspired techniques and smart materials to improve the efficacy of drug-eluting contact lenses. The bioinspired method uses bioinspired polymeric materials to improve biocompatibility, a specialized molecule recognition technique called molecular imprinting, or a stimuli-responsive system to improve biocompatibility and support drug delivery efficacy of drug-eluting contact lenses. This review encompasses strategies of material design, lens manufacturing and drug impregnation under the current auspices in ophthalmic therapies and projects an outlook onto future opportunities in the field of eye conditions management by means of active principles-eluting contact lens.

Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora Kinase A (AURKA), Kinesin Family Member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911), given phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1-3%) and increased percent accumulation of cells in G2/M phase with the combination treatment (45-52%) upon cell-cycle analysis indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs vehicle control (p≤0.01), SB-743921 (p≤0.01) and VIC-1911 (p≤0.05). Kaplan-Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p≤0.0001).

Tuberculosis (TB) continues to pose a global health challenge, exacerbated by the rise of drug-resistant strains. The development of new TB therapies is an arduous and time-consuming process. To expedite the discovery of effective treatments, computational structure-based drug re-purposing has emerged as a promising strategy. From this perspective, conditionally essential targets present a valuable opportunity, and the mycobactin biosynthesis pathway stands out as a prime example highlighting the intricate response of Mycobacterium tuberculosis (Mtb) to changes in iron availability. This study focuses on the re-purposing and revival of FDA-approved drugs (library) as potential inhibitors of MbtA, a crucial enzyme in mycobactin biosynthesis in Mtb conserved among all species of mycobacteria. Literature suggests this pathway to be associated with drug efflux pumps, which potentially contribute to drug resistance. This makes it a potential target for antitubercular drug discovery. Herein we utilized cheminformatics and structure-based drug repurposing approaches, viz., molecular docking, dynamics, and PCA analysis, to decode the intermolecular interactions and binding affinity of the FDA-reported molecules against MbtA. The virtual screening revealed ten molecules with significant binding affinities and interactions with MbtA. These drugs, originally designed for different therapeutic indications (4: antiviral, 3: anticancer, 1: CYP450 inhibitor, 1: ACE inhibitor, and 1: leukotriene antagonist), are repurposed as potential MbtA inhibitors. Furthermore, our study explores the binding modes and interactions between these drugs and MbtA, shedding light on the structural basis of their inhibitory potential. Principal component analysis highlighted significant motions in MbtA-bound ligands, emphasizing the stability of the top Protein-Ligand Complexes (PLCs). This computational approach provides a swift and cost-effective method for identifying new MbtA inhibitors, which can subsequently undergo validation through experimental assays. This streamlined process is facilitated by the fact that these compounds are already FDA-approved and have established safety and efficacy profiles. This study has the potential to lay the groundwork for addressing the urgent global health challenge at hand, specifically in the context of combating Antimicrobial Resistance (AMR) and Tuberculosis (TB).

Discovery and development of effective strategies to treat emerging and often drug resistant strains of viral and microbial pathogens presents one of the greatest challenges of the 21st century. Despite nearly a century of progress in developments in antimicrobial and antiviral therapies, infectious diseases still account for a substantial proportion of deaths worldwide, including over 100 million globally in the recent pandemic to date. In recent decades, the plague of antimicrobial resistance also represents an additional and alarming signal for both human and animal healthcare and signals a renewed sense of urgency in addressing this issue. This has made the search for novel classes of antibiotics, antivirals and therapeutics found to be capable of bypassing the microbial and viral resistance mechanisms necessary to in order to replenish our current arsenal of antimicrobial and antiviral drugs and update our therapeutic regimens. In addition, the tremendous impact exerted by viral infections and related pathologies on our lives during the recent decade has forced scientists to acknowledge the opportunities and challenges associated with tackling infectious diseases by developing effective antiviral agents endowed with novel mechanisms of action. The discovery of new antimicrobial/antiviral agents, as well as the repurposing of existing drugs and therapeutic options will be crucial to fight the ever-increasing resistance of “superbugs”, pathogenic fungi, viruses, and parasites. Proponents of modern biophoton therapy proposed in this paper can trace its origins to the Russian scientist Alexander Gurwitsch, who a century ago observed ultra-weak emissions of light emerging from an onion root and soon found additional living tissues to be emanating similar energetic phenomena, thus energizing research which continues to the present day and projected toward the development of useful applications of the new-found biological photonic phenomena. The purpose of the present paper is to introduce the past experiences, potential applications and highly successful outcomes of biophotonic therapy as an option to treat infectious diseases including HIV, Hepatitis C, MRSA, and others, with emphasis on efficacy of using biophotonic therapies to treat and ameliorate the drug resistant variants of the above infectious agents, including potential applications for the current COVID-19 pandemic and in preparation for the emergence of the next epidemic or pandemic.

Background – Mali was one of the first countries in sub-Saharan Africa to initiate a National Schistosomiasis Control Programme (NSCP) in 1982. The WHO's 2021-30 roadmap sets out criteria for eliminating and controlling schistosomiasis as a public health problem. Our study aimed to assess the impact of annual Mass Drug Distribution (MDD) with praziquantel (PZQ) among school-age children in the sentinel sites (SS) of the NSCP. Methods –The study took place at twelve SS in Kayes and Koulikoro regions. Two-round observational cross-sectional studies were carried out in December 2014-2015 and in April 2018 after four to five years of annually MDD. Overall, 2442 schoolchildren aged 7 to 14 were successfully examined. The urine filtration and Kato-Katz method were used for determining Schistosoma haematobium and S. mansoni eggs, respectively. Results –Of the twelve SS treated from 2014-2015, one has achieved the criterion of elimination of S. haematobium as a public health problem (prevalence of heavy intensity infection PHI < 1%) (ie, ≥50 S. haematobium eggs per 10 mL of urine or ≥400 S. mansoni eggs per g of stool), four met the morbidity control criterion (PHI< 5%) while two sites remained confined below the morbidity control criterion (PHI>5%). Five SS had no heavy intensity infection. The prevalence of S. mansoni was less than 1%. Conclusion –The impact evaluation of MDD with praziquantel in the SS of NSCP highlights that MDD has significantly reduced the PHI of schistosomiasis. However, the high prevalence of schistosomiasis or its increase in some sites requires in-depth studies.

Wound infection is a common complication of chronic wounds. It can impair healing, which may not occur without external help. Antimicrobial dressings (AMDs) are a type of external help to infected chronic wounds. In this study, highly porous membranes made of only chitosan and containing the antiseptic polyhexanide (poly(hexamethylene biguanide); PHMB) were prepared by cryogelation, aiming to be used in AMDs. These membranes exhibited high water swelling capacity, fast water absorption and high water vapor transmission. The best drug loading method involved simultaneous loading by soaking in a PHMB solution and sterilization by autoclaving, resulting in sterilized, drug-loaded membranes. The drug release kinetics was comparable to that of a commercial PHMB-releasing AMD assayed under the same conditions. These membranes exhibited high antibacterial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, which are bacterial species commonly found in infected wounds, and blood clotting activity. The obtained results suggest that these membranes may be suitable for use in the development of AMDs.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining nolecules, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain, however achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches to novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offers the ability to repurpose FDA approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation, to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations, and ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms which have strong potential to determine novel and effective treatment regimens.

Idiosyncratic drug induced liver injury (DILI) is an unpredictable reaction of exposed individual on a certain drug, and the drug-induced autoimmune hepatitis (DIAIH) presents a DILI phenotype that mimics idiopathic autoimmune hepatitis (AIH) when considering the clinical, biochemical, serological and histological parameters. We present a case of a 48-year-old male that was hospitalized due to severe hepatocellular liver injury two months after the self-treatment with the muscle-building dietary supplement based on arginine-alpha-ketoglutarate, L-citrulline, L tyrosine, creatine malate and beet extract. His immunology panel was positive with increased IgG levels, and the radiologic methods showed no signs of chronic liver disease. He underwent corticosteroid treatment with adequate response. After the therapy withdrawal, a clinical relapse occurred. Seven months after the initial presentation liver MR suggested the initial cirrhotic changes of the right liver lobe. Liver biopsy revealed abundant lymphoplasmacytic infiltrate with piecemeal necrosis and grade 2 fibrosis. He responded well on the corticosteroid treatment again, and was further treated with low dose prednisone without additional relapses. Several years later, further management confirmed presence of liver cirrhosis with no histological or biochemical signs of the disease activity. DIAIH is a DILI phenotype difficult to distinguish from idiopathic AIH despite a wide armamentarium of diagnostic methods. Regular patient monitoring and clinical open-mindedness with the adjustment of therapeutic approaches according to the disease course are more important than strict labelling of the disease.

Background: Although triptorelin acetate (TA) is generally considered a safe medication, severe adverse drug reactions (ADRs) to triptorelin have occurred. In this study, we present the largest retrospective analysis of ADRs related to TA during the treatment of pediatric central precocious puberty. Methods: We describe a total of 38 suspected cases of TA-induced ADRs reported to the pharma-covigilance center of Shenzhen Children’s Hospital from September 2015 to December 2022. Causality assessment was carried out using the validated Kramer’s algorithm. The severity of ADRs was evaluated using the Modified Hartwig and Siegel Scale. Results: The most common ADRs attributed to TA were damage to the cutaneous tissues (29.3%) and reactions affecting the systemic and digestive systems (20.7%). The majority (61.1%) of ADRs occurred within 2 hours of administration. Among the 12 patients with severe ADRs, the three most frequent symptoms were anaphylactic reactions, hip synovitis, and arthralgia. Additional-ly, six patients experienced ADRs due to a change in the manufacturing process. Conclusion: The majority of ADRs observed in pediatric cases were type I anaphylactic reactions, which are rare but life-threatening. It is advisable to perform skin prick tests and intradermal tests when switching pharmaceutical manufacturers.

Hydrogels prepared from natural polymer have attracted extensive attentions in biomedical fields such as drug delivery, wound healing, and regenerative medicine due to their good biocompatibility, degradability and flexibility. This review outlines the commonly used natural polymer in hydrogel preparation, including cellulose, chitosan, collagen/gelatin, alginate, hyaluronic acid and starch. The polymeric structure and process/synthesis of natural polymers are illustrated, and natural polymer-based hydrogels including the hydrogel formation and properties are elaborated. Subsequently, the biomedical application of hydrogels based on natural polymer in drug delivery, tissue regeneration, wound healing and other biomedical field is summarized. Finally, the future perspectives of natural polymers and hydrogels based on them are discussed. For natural polymer, novel technologies such as enzymatic and biological methods are developed to improve the structural properties and the development of new natural based polymers or natural polymer derivatives with high performance is still very important and challenging. For natural polymer-based hydrogels, novel hydrogel materials, like double-network hydrogel, multifunctional composite hydrogels and hydrogel microrobots are designed to meet the advanced requirements in biomedical application, and new strategies such as dual-crosslinking, microfluidic chip, micropatterning and 3D/4D bioprinting, have been explored to fabricate advanced hydrogel materials with designed properties for biomedical application. Overall, natural polymeric hydrogels have attracted increasing interests in biomedical application, and the development of novel natural polymer-based materials and new strategies/methods for hydrogel fabrication is badly desirable and still challenging.

Background: no reports have examined the profile of drug-induced dysphagia in detail. The goal of this study was to investigate if there are any differences in the profiles of drug-induced dysphagia. Methods: This study used the Japanese Adverse Drug Event Report (JADER) database. Further, reported odds ratios (RORs) were used to analyze data on adverse drug events from 2004 to 2021. The top ten drugs with the most drug-induced dysphagia occurrences were used as target drugs. The association between RORs and drug-induced dysphagia caused by the target drugs was evaluated, and the age distribution and time of onset of drug-induced dysphagia for each drug were compared. RORs were the primary endpoint. Moreover, age and time of onset of drug-induced dysphagia were secondary outcomes. Results: In total, 756,965 reports were analyzed. All the target drugs were associated with drug-induced dysphagia. Among them, cevimeline was a novel finding, as no dysphagia was observed during the clinical trial. For most drugs, the onset of drug-induced dysphagia was occurring within approximately 25 days of administration. However, even after long-term use, paroxetine and milnacipran were associated with drug-induced dysphagia. Conclusion: The onset profile of drug-induced dysphagia may differ from one drug to the next.

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, and can impact quality of life significantly. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, 3-period, drug-drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), and a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron reduced by approximately 17%, when administered along with tamsulosin. No clinically significant changes in safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug-drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination therapy could be a promising treatment option for patients with OAB.

(1) Background: Hemispherotomy is the generally accepted treatment for hemispheric drug resistant epilepsy (DRE). Lateral or vertical approaches are performed according to the surgeon's preference. Multiples technical variations have been proposed since Delalande first described his vertical technique. We propose a sub-insular variation of the vertical parasagittal hemispherotomy (VPH) and describe our case series of patients operated on with this procedure. (2) Methods: a continuous series of patients operated on by the senior author (CR) with the modified sub-insular VPH was retrospectively analyzed. We report the demographic pre-operative characteristics, epilepsy and functional outcome as well as the surgical complications.(3) Results: Twenty-five patients were operated on between August 2008 and August 2023, twenty-three of them have at least a 3-month follow-up. On this last group 86,3% of patients were seizure-free. Only two patients developed post-operative hydrocephalus (8.7%), all patients with autonomous preoperative walk and 86,3% of the total series were able to walk without assistance (86.3%) and perform adapted social activities at last follow-up.(4) Conclusion: The modified vertical parasagittal sub-insular hemispherotomy is a successful surgical technique for hemispheric DRE with seizure freedom rates similar to the biggest series reported in the literature. Compared to other series, patients operated with our modified technique had a lower rate of postoperative hydrocephalus and excellent long-term motor and cognitive outcome.

Recent studies suggest that PEBP1/RKIP and YY1, despite having distinct molecular functions, may interact and mutually influence one another's activity. They exhibit reciprocal control over each other's expression through regulatory loops, prompting the hypothesis that their interplay could be pivotal in cancer advancement and resistance to drugs. To delve into this interplay's functional characteristics, we conducted a comprehensive analysis using bioinformatics tools across a range of cancers. Our results confirm the association between elevated YY1 mRNA levels and varying survival outcomes in diverse tumors. Furthermore, we observed differing degrees of inhibitory or stimulatory effects of these two genes in various cancer pathways, along with correlations between their mRNA expression and immune infiltration. Additionally, YY1/PEBP1 expression (or methylation) displayed connections with genomic alterations across cancer types. Notably, we uncovered links between YY1/PEBP1 and different indicators of immunosuppression, such as immune checkpoint blockade response, and T-cell dysfunction/exclusion levels, across different patient groups. Overall, our findings underscore the significant role of the interplay between YY1 and PEBP1 in cancer progression, influencing genomic changes, tumor immunity or the tumor microenvironment. Additionally, these two gene products appear to impact the sensitivity of anticancer drugs, opening new avenues for cancer therapy.

Adenylosuccinic acid (ASA) is a small molecule dicarboxylate that could be a strong clinical development candidate for inherited myopathies involving dysregulated purine nucleotide metabo-lism. Currently, there are no published pharmacokinetic/dynamic or toxicology data available, albeit 10-year clinical trial data in Duchenne muscular dystrophy patients suggests a chronically safe drug. In this study, we tested the toxicity of ASA to cultured myoblasts in vitro and acute systemic toxicity in mice. ASA is a non-toxic small molecule with an LD50> 5000mg/kg. Some background necrotic foci in the liver, kidney and gastrointestinal tract were shown that are likely incidental but warrant follow-up sub-/chronic oral exposure studies.

We recently developed a novel hyperspectral excitation-resolved near-infrared fluorescence imaging system (HER-NIRF) based on a continuous-wave wavelength-swept laser. In this study, this technique is applied for measuring the distribution of the therapeutic agent dimethyl sulfoxide (DMSO) by utilizing solvatochromic shift in the spectral profile of albumin-bound Indocyanine green (ICG). Using wide-field imaging in turbid media, complex dynamics of albumin-bound ICG is measured in mixtures of dimethyl sulfoxide (DMSO) and water. Phantom experiments are conducted to evaluate the performance of the HER-NIRF system. The results show that the distribution of DMSO can be visualized in the wide-field reflection geometry. One of the main purposes of the DMSO is to act as a carrier for other drugs, enhancing their effects by facilitating skin penetration. Understanding solubility and permeability of drugs in vivo is very important in drug discovery and development. Hence, this HER-NIRF technique has a great potential to advance the utilization of the therapeutic agent DMSO by mapping its distribution via solvatochromic shift of ICG. By customizing the operational wavelength range, this system can be applied to any other fluorophores in the near infrared region and utilized for a wide variety of drug delivery studies.

Parasitic diseases are among the most serious public health problems in developing countries, causing high mortality and economic burdens. The Trypanosomatidae family includes Leishmania spp. and Trypanosoma cruzi, which cause leishmaniasis and Chagas disease, respectively. Both these parasites are among the major agents of neglected tropical diseases (NTDs). Leishmaniasis is currently the second most widespread vector-borne parasitic disease after malaria. The World Health Organization (WHO) records approximately 0.7-1 million newly diagnosed leishmaniasis cases each year, resulting in approximately 20,000-30,000 deaths. Also, 25 million people worldwide are at risk of Chagas disease and an estimated 6 million people are infected with Trypanosoma cruzi. Despite the similarity of the parasites, the evolution of the disease and the clinical indexes are explicitly different in African, Asian, and American forms of infection. Clinical therapies are associated with drug resistance and side effects. As a result, the discovery of novel therapeutic agents has emerged as a top priority and a promising alternative. Peptide-based drugs are an attractive class of therapeutic agents. They are recognized for being highly selective and effective, as well as safe and well tolerated. Moreover, they are now being explored in the development of novel therapeutics for a variety of health disorders, including oncology, endocrinology, metabolic, cardiovascular, and bone diseases. In addition, they are being explored in tropical diseases such as leishmaniasis and Chagas disease. We will discuss current knowledge regarding the parasite life cycle, signs and symptoms, diagnosis, and treatment options for leishmaniasis and Chagas disease.

Skin cancer is a disease that reflects most malignant neoplasms worldwide, whose rate of involvement has increased significantly in recent decades. Treatments that offer efficient results with attenuation of adverse reactions and greater patient compliance have been the subject of many systematic investigations. This review aims to qualitatively present published works that showed new strategies to increase the penetration power of natural substances through the skin in the topical treatment against skin cancer. In this sense, nanoengineering mechanisms, the iontophoresis technique, and photodynamic therapy using natural products (NP) contribute to new knowledge about substance carrier strategies in topical treatments against skin cancer.

BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.

Over the past decade, significant developments have occurred in treatment strategies for ovarian cancer, yet targeted therapy with few side effects is still a major issue. The cytochrome P450 (CYP) enzyme family plays a vital role in the tumorigenesis process and metabolism of drugs, with a negative impact on therapy outcomes. Gaining more insight into CYP expression is crucial for understanding the pathophysiology of ovarian cancer since many isoforms are essential for the metabolism of xenobiotics and steroid hormones, which drive the disease's development. The purpose of this review is to provide a clear understanding of differential CYP expression in ovarian cancer and its implications for the prognosis of ovarian cancer patients, together with their polymorphisms' effect on chemotherapy metabolism. Finally, we provide our thoughts on opportunities to exploit metabolic CYP expression for novel therapeutic development to treat ovarian cancer.

Background: This study aimed to estimate the prevalence of sexualized drug use (SDU) in gay, bisexual, and other men who have sex with men living with HIV (HIV+GBMSM) in Madrid during 2019/2020 and compare it with data from 2016/2017. Methods: We analysed the frequency of SDU in a sample of HIV+GBMSM attending HIV clinics, who participated in an anonymous online survey regarding sexual behaviour and recreational drug use. The association between SDU, sexual risk behaviours, and STIs was evaluated. The methodology employed in the present study(U-SEX-2) in 2019/2020 was consistent with that of a previous study(U-SEX-1) in 2016/2017. Results: The study included 424 HIV+GBMSM, with a mean age of 40(10.43) years. Overall, 94% (396) reported being sexually active. Additionally, 33% (140) had been diagnosed with an STI within the previous year. Moreover, 54% (229) had used drugs in the last year, 25% (107) engaged in SDU, and 15% (17) reported engagement in slamsex. After adjusting for confounding factors, SDU was associated with STIs, fisting, unprotected anal intercourse, and having &gt; 24 sexual partners in the last year. According to the DUDIT test scores, 76% (81) probably had problematic drug use (≥6 points), and 5% (8) probable drug dependence (≥25 points). When comparing the U-SEX-1(2016/2017) data with the U-SEX-2(2019/2020) data, no significant differences were found in the proportion of participants practicing SDU or slamsex. Conclusion: The prevalence of SDU among HIV+GBMSM has remained high in recent years and without significant changes. We observed a clear association between SDU, high-risk sexual behaviors, STIs, and the risk of drug related problems.

BACKGROUND: Few studies have examined the use of immunoassay urine drug testing of cancer patients in palliative care clinics. OBJECTIVES: We examined the frequency of immunoassay urine drug test (UDT) abnormalities and the factors associated with aberrancy at a safety-net hospital palliative medicine clinic. METHODS: A retrospective review of the electronic medical records of consecutive eligible patients seen at the outpatient palliative medicine clinic in a resource-limited safety net hospital system was conducted between September 1, 2015 and December 31, 2020. We collected longitudinal data on patient demographics, UDT findings, and potential predictors of aberrant results. RESULTS: Of the 913 patients in the study, 500 (55%) underwent UDT testing, with 455 (50%) having the testing within the first three visits. Among those tested within the first three visits, 125 (27%) had aberrant UDT results; 44 (35%) of these 125 patients were positive for cocaine. In a multivariable regression model analysis of predictors for aberrant UDT within the first 3 visits, non-Hispanic White race (odds ratio [OR]=2.13; 95% confidence interval [CI]: 1.03-4.38; p=0.04), history of illicit drug use (OR=3.57; CI: 1.78-7.13; p< 0.001), and history of marijuana use (OR=7.05; CI: 3.85-12.91; p< 0.001) were independent predictors of an aberrant UDT finding. CONCLUSION: Despite limitations of immunoassay UDT, it was able to detect aberrant drug taking behaviors in a significant number of patients seen at a safety net hospital palliative care clinic, including cocaine use. These findings support universal UDT monitoring and utility of immunoassay-based UDT in resource limited settings.

Culinary herbs and spices are widely used in daily diets. Pakistan flora is enriched with phytochemicals due to a diverse range of land. Phytochemicals, including volatile and non-volatile compounds, have captured much interest due to their numerous health advantages and significance in daily diet. The present study aimed to conduct in-depth metabolomic profiling of Pakistani-grown fenugreek leaves (Trigonella foenum-graecum), fennel seeds (Foeniculum vulgare), mint leaves (Mentha royleana), coriander seeds (Coriandrum sativum) and basil leaves (Ocimum basilicum) by using liquid chromatography–mass spectrometry (LC-MS/MS) and gas chromatography–mass spectrometry (GC-MS). The first study was conducted to optimize extraction using different solvents (methanol, ethanol, chloroform, acetone, and water). Total phenolic content (TPC), total flavonoid content (TFC), and total condensed tannins (TCT) were quantified along with the antioxidant and anti-diabetic activities. The highest TPC (125.42 ± 10.89 mg GAE/g) and the highest antioxidant and anti-diabetic potential were quantified in mint. Seventy-one phytochemical metabolites were identified using LC-MS/MS, while forty-nine volatile constituents were identified using the GC-MS. A positive correlation was identified between phenolic contents and their biological activities. Furthermore, molecular docking helped to find drug molecules with more excellent anti-diabetic activity based on their binding affinities. This study suggests that selected medicinal herbs from Pakistan have significant nutraceutical and phytopharmaceutical potential. This study could further help in drug discovery.

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1-14 years enrolled March 2019 to December 2020 from five facilities in Kisumu County, Kenya were included. Children were randomized 1:1 to control (standard-of-care) or intervention (point-of-care viral load (POC VL) testing every three months with targeted genotypic drug resistance testing (DRT) for VF (&gt; 1000 copies/ml)). A multidisciplinary committee reviewed CHIV with DRT results and offered treatment recommendations. We describe DR mutations and present logistic regression models to identify factors associated with clinically significant DR. We enrolled 704 children in the study; median age was 9 years (interquartile range (IQR) 7,12), 344 (49%) were female and median time on ART was 5 years (IQR 3, 8). During the study period, 106 (15%) children had DRT results (84 intervention and 22 control). DRT detected mutations associate with DR in all participants tested, with 93 (88%) having major mutations, including 51 (54%) with dual class resistance. A history of VF in prior 2 years (adjusted odds ratio (aOR) 11.1; 95% confidence interval (CI) 6.3, 20.0) and less than 2 years on ART at enrollment (aOR 2.2; 95% CI 1.1, 4.4) were associated with increased odds of major DR. DR is highly prevalent among CHIV on ART with VF in Kenya. Factors associated with drug resistance may be used to determine which children should be prioritized for DRT.

Infection with Ebola virus (EBOV) is responsible for haemorrhagic fever in humans with a high mortality rate. Combined efforts of prevention and therapeutic intervention are required to tackle highly variable RNA viruses, whose infections often lead to outbreaks. Here, we have screened the 2P2I3D chemical library using a nanoluc-based protein complementation assay (NPCA) and isolated two compounds disrupting the interaction of the EBOV protein fragment VP35IID with the N terminus of the dsRNA-binding proteins PKR and PACT, involved in IFN response and/or intrinsic immunity, respectively. The two compounds inhibited EBOV infection in cell culture as well as infection by measles virus (MV) independently of IFN induction. Consequently, we propose the compounds are antiviral by restoring intrinsic immunity driven by PACT. Given that PACT is highly conserved across mammals, we support further testing of the compounds in other species, as well as against further negative sense RNA viruses.

Since the first published genome sequence of Trypanosoma cruzi in 2005, there has been tremendous technological advance in genomics, reverse genetics, and assay development for this elusive pathogen. However, there is still an unmet need for new and better drugs to treat Chagas disease. Here we introduce a T. cruzi assay strain that is useful for drug research as well as basic studies in host-pathogen interaction. Trypanosoma cruzi STIB980 is a strain of discrete typing unit TcI that grows well in culture as axenic epimastigotes or intracellular amastigotes. We have evaluated the optimal parameters for genetic transfection and constructed derivatives of T. cruzi STIB980 that express reporter genes for fluorescence- or bioluminescence-based drug efficacy testing, as well as a Cas9-expressing line for CRISPR/Cas9-mediated gene editing. The genome of T. cruzi STIB980 was sequenced by combining short-read Illumina with long-read Oxford Nanopore technologies. The latter served for the primary assembly, the former to correct mistakes and fill the gaps. This resulted in a high-quality nuclear haplotype assembly of 28 Mb in 400 contigs, containing 10,043 open-reading frames with a median length of 1077 bp. We believe that T. cruzi STIB980 is a useful addition to the antichagasic toolbox, and propose that it can serve as a DTU TcI reference strain for drug efficacy testing.

Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease worldwide and significantly increases the risk of premature death due to cardiovascular diseases. Elevated urinary albumin levels are an important clinical feature of DKD. Effective control of albuminuria not only delays glomerular filtration rate (GFR) decline but also markedly reduces cardiovascular disease risk and all-cause mortality. New drugs for treating DKD proteinuria, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), mineralocorticoid receptor antagonists (MRAs), and endothelin receptor antagonists (REAs), have shown significant efficacy. Auxiliary treatment with proprietary Chinese medicine has also yielded promising results; however, it also faces a broader scope for development. The mechanisms by which these drugs treat albuminuria in patients with DKD should be described more thoroughly. The positive effects of combination therapy with two or more drugs in reducing albuminuria and protecting the kidneys warrant further investigation. Therefore, this review explores the pathophysiological mechanism of albuminuria in patients with DKD, the value of clinical diagnosis and prognosis, new progress and mechanisms of treatment, and multidrug therapy in patients who have type 2 diabetic kidney disease (T2DKD), providing a new perspective on the clinical diagnosis and treatment of DKD.

While biologic originators’ patents are expiring, biosimilars are emerging to take their place, offering significant cost savings to healthcare systems. Many challenges still need to be addressed in the clinical practice of inflammatory bowel disease (IBD). A global survey was organized to highlight physicians’ current knowledge and beliefs and to gain insight about their practical management and remaining concerns and obstacles associated with starting a biosimilar, switching from an originator to a biosimilar, or switching from one biosimilar to another (multiple switches and reverse switching). Fifteen physicians with expertise in the field of IBD from 13 countries attended a virtual international consensus meeting to develop practical guidance regarding biosimilar adoption worldwide, considering the survey results. Consensus was reached on 10 statements regarding biosimilar effectiveness, safety, indications and rationale, multiple switches, therapeutic drug monitoring of biosimilars, non-medical switching and future perspectives.

Antibiotics have played a crucial role in the reduction of TB incidence globally as evidenced by the fact that before the mid-20th century, the mortality rate within five years of the onset of the disease was 50%. The use of antibiotics has eliminated TB as a devastating disease, but the challenge of resistance to anti-TB drugs, which had already been described at the time of the introduction of streptomycin, has become a major global issue in disease management. Mismanagement of multidrug-resistant tuberculosis (MDR-TB) cases, resulting from intermittent drug use, prescription errors and non-compliance of patients, has been identified as a critical risk factor for the development of extensively drug-resistant tuberculosis (XDR-TB). Antimicrobial resistance (AMR) in TB is a multi-factorial, complex problem of microbes evolving to escape antibiotics, the gradual decline of antibiotic development, and different economic and social conditions. In this review, we summarise recent advances in our understanding of how Mycobacterium tuberculosis evolves drug resistance. We also highlight the importance of developing shorter regimens that rapidly reach bacteria in diverse host environments, eradicating all mycobacterial populations and preventing the evolution of drug resistance. Lastly, we also emphasise that the current burden of this ancient disease is driven by a combination of complex interactions between mycobacterial and host factors, and that only a holistic approach that effectively addresses all the critical issues associated with drug resistance will limit the further spread of drug-resistant strains throught the community.

Still, the most common in vitro model for absorption, distribution, metabolism and excretion (ADME) purposes is the Caco-2 cell line. However, clear differences in gene- and protein expression towards the small intestine and an at best fair prediction accuracy of intestinal drug absorption restrict the usefulness as model for intestinal epithelial cells. To overcome these limitations, we evaluated a panel of low-passaged patient-derived colorectal cancer cell lines of the HROC collection concerning similarities to small intestinal epithelial cells and their potential to predict intestinal drug absorption. After initial screen of a larger panel, ten cell lines with confluent outgrowth and long-lasting barrier forming potential were further characterized in close detail. Tight junctional complexes and microvilli structures were detected in all lines, differentiated epithelial cells were abundant in 7/10. All lines expressed multiple transporter molecules, with expression levels in three lines being close to those of small intestinal epithelial cells. Compared to the Caco-2 model, three HROC lines demonstrated both higher similarity to jejunal epithelial tissue cells and higher regulatory potential of relevant drug transporters. In sum, these lines would be better suited human small intestinal epithelium models for basic and translational research; especially for ADME studies.

Primary central nervous system and brain tumors are one of the global burdens that are continuously increasing in cases and requiring more treatment options. Surgery has been the leading treatment option for tumors, however, the localization of the tumor and its infiltrating nature make this option challenging. DNA microarray expression profiles of different CNS tumors provide insight into potential biomarkers for identifying different tumor types and subtypes. Here, we utilized the differentially expressed genes common in four expression profiles, GSE66354, GSE68848, GSE74195, and GSE43290 to reconstruct the gene co-expression network. In this study, we were able to identify preserved cluster genes, hub genes, co-regulating transcription factors, miRNA families, and candidate repurposed drugs. Fourteen identified hub genes, which were, CACNA1A, DNM1, GABRA1, GRIA2, MAPT, SLC17A7, SNAP25, SNAP91, STXBP1, SYT1, COL1A1, COL6A2, FBN2, and FN1 appeared to play a role in tumor progression and may serve as drug targets. We also reported the DEGs in each tumor type, which were ATRT, EPN, PA, MED, PNET, MEN, ACM, ODG, and GBM. Five identified miRNA families, which were, let-7 family, mir-124 family, mir-1 family, mir-103 family, and mir-27 family described in the literature to have tumor-suppressing characteristics. Drug-gene and drug-transcription factor network revealed 32 candidate repurposed drugs and 13 were validated through connectivity map analysis. Here, two main repurposed drugs fit the regulatory requirement for gene interaction, these were, quercetin and vorinostat. Future validation in experimental studies may utilize the future use of the candidate repurposed drugs. Our study provides insights into drug repurposing prospects and understanding tumor expressions.

Curcumin, a nontoxic and cheap natural medicine, has high therapeutic efficacy for many diseases including diabetes and cancers. Unfortunately, its exceedingly low water-solubility and rapid degradation in the body severely limit its bioavailability. In this work, we prepare a series of biocompatible poly(vinyl anisole)@nonlinear poly(ethylene glycol) (PVAS@PEG) core-shell nanogels with different PEG gel shell thickness to provide high water solubility, good stability, and controllable sustained release of curcumin. The PVAS nanogel core is designed to attract and store curcumin molecules for high drug loading capacity and the hydrophilic nonlinear PEG gel shell is designed to offer water dispersibility and thermo-responsive drug release. The obtained nanogels are monodispersed in spherical shape with clear core-shell morphology. The size and shell thickness of the nanogels can be easily controlled by changing the core-shell precursor feeding ratios. The optimized PVAS@PEG nanogels display a high curcumin loading capacity of 38.0 wt%. The nanogels can stabilize the curcumin from degradation at pH =7.4 and release the curcumin in response to heat in the physiologically important temperature range. The nanogels can enter cells effectively and exhibit negligible cytotoxicity to both the B16F10 and HL-7702 cells at a concentration up to 2.3 mg/mL. Such designed PVAS@PEG nanogels have a great potential to be used for delicate drug delivery.

Stellatolides are natural compounds that have shown promising biological activities, including antitumor, antimicrobial, and anti-inflammatory properties, making them potential candidates for drug development. Chemical Reactivity Theory (CRT) is a branch of chemistry that explains and predicts the behavior of chemical reactions based on the electronic structure of molecules. Conceptual Density Functional Theory (CDFT) and Computational Peptidology (CP) are computational approaches used to study the behavior of atoms, molecules, and peptides. In this study, we present the results of our investigation of the chemical reactivity and ADMET properties of Stellatolides A-H using a novel computational approach called Conceptual DFT-based Computational Peptidology (CDFT-CP). Our study uses CDFT and CP to predict the reactivity and stability of molecules and to understand the behavior of peptides at the molecular level. We also predict the ADMET properties of the Stellatolides A-H to provide insight into their effectiveness, potential side effects, and optimal dosage and route of administration. This study sheds light on the potential of Stellatolides A-H as promising candidates for drug development and highlights the potential of CDFT-CP for the study of other natural compounds and peptides.