Vaccines (Basel). 2022 Aug 9;10(8):1284. doi: 10.3390/vaccines10081284.

ABSTRACT

Niclosamide, an FDA-approved oral anthelmintic drug, has broad biological activity including anticancer, antibacterial, and antiviral properties. Niclosamide has also been identified as a potent inhibitor of SARS-CoV-2 infection in vitro, generating interest in its use for the treatment or prevention of COVID-19. Unfortunately, there are several potential issues with using niclosamide for COVID-19, including low bioavailability, significant polypharmacology, high cellular toxicity, and unknown efficacy against emerging SARS-CoV-2 variants of concern. In this study, we used high-content imaging-based immunofluorescence assays in two different cell models to assess these limitations and evaluate the potential for using niclosamide as a COVID-19 antiviral. We show that despite promising preliminary reports, the antiviral efficacy of niclosamide overlaps with its cytotoxicity giving it a poor in vitro selectivity index for anti-SARS-CoV-2 inhibition. We also show that niclosamide has significantly variable potency against the different SARS-CoV-2 variants of concern and is most potent against variants with enhanced cell-to-cell spread including the B.1.1.7 (alpha) variant. Finally, we report the activity of 33 niclosamide analogs, several of which have reduced cytotoxicity and increased potency relative to niclosamide. A preliminary structure-activity relationship analysis reveals dependence on a protonophore for antiviral efficacy, which implicates nonspecific endolysosomal neutralization as a dominant mechanism of action. Further single-cell morphological profiling suggests niclosamide also inhibits viral entry and cell-to-cell spread by syncytia. Altogether, our results suggest that niclosamide is not an ideal candidate for the treatment of COVID-19, but that there is potential for developing improved analogs with higher clinical translational potential in the future.

PMID:36016172 | DOI:10.3390/vaccines10081284

Vaccines (Basel). 2022 Aug 3;10(8):1248. doi: 10.3390/vaccines10081248.

ABSTRACT

The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the situation is not under control because of the instability of RNA sequence patterns of SARS-CoV-2, which requires effective drugs. Several studies have suggested that the SARS-CoV-2 infection causing hub differentially expressed genes (Hub-DEGs). However, we observed that there was not any common hub gene (Hub-DEGs) in our analyses. Therefore, it may be difficult to take a common treatment plan against SARS-CoV-2 infections globally. The goal of this study was to examine if more representative Hub-DEGs from published studies by means of hub of Hub-DEGs (hHub-DEGs) and associated potential candidate drugs. In this study, we reviewed 41 articles on transcriptomic data analysis of SARS-CoV-2 and found 370 unique hub genes or studied genes in total. Then, we selected 14 more representative Hub-DEGs (AKT1, APP, CXCL8, EGFR, IL6, INS, JUN, MAPK1, STAT3, TNF, TP53, UBA52, UBC, VEGFA) as hHub-DEGs by their protein-protein interaction analysis. Their associated biological functional processes, transcriptional, and post-transcriptional regulatory factors. Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally.

PMID:36016137 | DOI:10.3390/vaccines10081248

Pharmaceutics. 2022 Aug 5;14(8):1634. doi: 10.3390/pharmaceutics14081634.

ABSTRACT

Toxoplasma gondii is a protozoan that infects up to a third of the world's population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when toxoplasmosis can cause miscarriage, or serious complications to the baby, or in an immunocompromised person, when the infection can possibly affect the patient's eyes or brain. To identify potential drug candidates that could counter toxoplasmosis, we selected 13 compounds which were pre-screened in silico based on the proteome of T. gondii to be evaluated in vitro against the parasite in a cell-based assay. Among the selected compounds, three demonstrated in vitro anti-T. gondii activity in the nanomolar range (almitrine, bortezomib, and fludarabine), and ten compounds demonstrated anti-T. gondii activity in the micromolar range (digitoxin, digoxin, doxorubicin, fusidic acid, levofloxacin, lomefloxacin, mycophenolic acid, ribavirin, trimethoprim, and valproic acid). Almitrine demonstrated a Selectivity Index (provided by the ratio between the Half Cytotoxic Concentration against human foreskin fibroblasts and the Half Effective Concentration against T. gondii tachyzoites) that was higher than 47, whilst being considered a lead compound against T. gondii. Almitrine showed interactions with the Na+/K+ ATPase transporter for Homo sapiens and Mus musculus, indicating a possible mechanism of action of this compound.

PMID:36015260 | DOI:10.3390/pharmaceutics14081634

Pharmaceutics. 2022 Jul 30;14(8):1590. doi: 10.3390/pharmaceutics14081590.

ABSTRACT

Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective anti-leishmanial through pointing to new drug targets in less time, having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future.

PMID:36015216 | DOI:10.3390/pharmaceutics14081590

Pharmaceutics. 2022 Jul 28;14(8):1573. doi: 10.3390/pharmaceutics14081573.

ABSTRACT

Expanding data suggest that glioblastoma is accountable for the growing prevalence of various forms of stroke formation, such as ischemic stroke and moyamoya disease. However, the underlying deterministic details are still unspecified. Bioinformatics approaches are designed to investigate the relationships between two pathogens as well as fill this study void. Glioblastoma is a form of cancer that typically occurs in the brain or spinal cord and is highly destructive. A stroke occurs when a brain region starts to lose blood circulation and prevents functioning. Moyamoya disorder is a recurrent and recurring arterial disorder of the brain. To begin, adequate gene expression datasets on glioblastoma, ischemic stroke, and moyamoya disease were gathered from various repositories. Then, the association between glioblastoma, ischemic stroke, and moyamoya was established using the existing pipelines. The framework was developed as a generalized workflow to allow for the aggregation of transcriptomic gene expression across specific tissue; Gene Ontology (GO) and biological pathway, as well as the validation of such data, are carried out using enrichment studies such as protein-protein interaction and gold benchmark databases. The results contribute to a more profound knowledge of the disease mechanisms and unveil the projected correlations among the diseases.

PMID:36015199 | DOI:10.3390/pharmaceutics14081573

Methods Mol Biol. 2022;2542:141-149. doi: 10.1007/978-1-0716-2549-1_10.

ABSTRACT

Candida albicans is one of the most common fungal pathogens in humans. Due to the development of resistance to antifungal drugs, today there is a need for finding new antifungal agents with new pharmacological targets for a more efficient management of C. albicans infections. Drug repositioning or drug repurposing has been exploited to develop new antifungal approaches. Natural products may be more easily developed because they have been a useful source of active antimicrobials. Additionally, new antifungals are needed to combat drug-resistant infections caused by fungi such as by Candida species. Once compounds are identified, determining the mode of action (MOA) of natural products is a key objective. Genetic screens utilizing the Saccharomyces cerevisiae heterozygous mutant library provides a direct link between a phenotypic screen (easy read-out) and the identity of the gene target. Screens using mutant libraries can identify chemical-genetic interactions and genes or pathways affected by compounds to decipher the mechanism of action. Herein, we describe a genetic screen of an anti-Candida natural product.

PMID:36008662 | DOI:10.1007/978-1-0716-2549-1_10

JMIR Form Res. 2022 Aug 9. doi: 10.2196/39582. Online ahead of print.

ABSTRACT

BACKGROUND: Since the beginning of the COVID-19 pandemic, over 480 million people have been infected, and more than 6 million people died from COVID-19 worldwide. In some patients with acute COVID-19, symptoms manifest over a longer period, also called "long-COVID". Unmet medi-cal need related to long-COVID is high, since there are no treatments approved. Patients exper-iment with various medications and supplements hoping to alleviate their suffering. They share their experiences on social media.

OBJECTIVE: We explore the feasibility of social media mining methods to extract important compounds from the perspective of patients. The goal is to provide an overview of different medication strategies and important agents mentioned in Reddit users' self-reports to support hypothesis generation for drug repurposing, by incorporating patients' experiences.

METHODS: We used Named Entity Recognition to extract substances representing medications or supple-ments used to treat long-COVID from almost 70,000 posts on the /r/covidlonghaulers subred-dit. We analyzed substances by frequency, co-occurrences and network analysis to identify im-portant substances and substance clusters.

RESULTS: The named entity recognition algorithm achieved an F1 score of 0.67. A total of 28,447 sub-stance entities and 5,789 word-co-occurrence pairs were extracted. "Histamine antagonists", "famotidine", "magnesium", "vitamins" and "steroids" were the most frequently mentioned sub-stances. Network analysis revealed three clusters of substances, indicating certain medication patterns.

CONCLUSIONS: The feasibility study indicates that network analysis can be used to characterize the medication strategies discussed in social media. Comparison with existing literature shows that the ap-proach identifies substances that are promising candidates for drug repurposing such as antihis-tamines, steroids, or antidepressants. In the context of a pandemic, the proposed method could be used to support drug repurposing hypothesis development by prioritizing substances that are important to users.

PMID:36007131 | DOI:10.2196/39582

Mol Divers. 2022 Aug 25. doi: 10.1007/s11030-022-10516-3. Online ahead of print.

ABSTRACT

Drug repurposing opens new avenues in cancer therapy. Drug repurposing, or finding new uses for existing drugs, can substantially reduce drug discovery time and costs. Cheminformatics, genetics, and systems biology advances enable repositioning drugs. Clinical usage of PD-1/PD-L1 blocking has been approved because of its efficacy in improving prognosis in select groups. The PD-1/PD-L1 axis was considered to represent a mechanism for tumour evasion of host tumour antigen-specific T-cell immunity in early preclinical research. The expression of PD-L1 in cancer cells causes T lymphocytes to become exhausted by transmitting a co-inhibitory signal. A better understanding of how PD-L1 is regulated in cancer cells could lead to new therapeutic options. In this view, the study was aimed to repurpose the existing FDA-approved drugs as a potential PD-L1 inhibitor through e-Pharmacophore modelling, molecular docking and dynamic simulation. e-Pharmacophore screening retrieved 324 FDA-approved medications with the fitness score ≥ 1. The top 10-docked FDA candidates were compared with IN-35 (Clinical trial candidate) for its interaction pattern with critical amino acid residues. Mirabegron and Indacaterol exhibited a greater affinity for PD-L1 with docking scores of - 9.213 kcal mol-1 and - 8.023 kcal mol-1, respectively. Mirabegron retain interactions at all three major hotspots in the PD-L1 dimer interface similar to IN-35. MM-GBSA analyses indicated that Mirabegron uses less energy to create a more stable complex and retains all of the inhibitor's positive interactions found in clinical trial ligand IN-35. Molecular dynamics simulation analysis of the Mirabegron complex showed a similar pattern of deviation in correlation with IN-35, and it retains the interaction with the active key amino acids throughout the simulation time. Our present study has shown Mirabegron as a powerful inhibitor of PD-L1 expression in cancer cells using a drug-repurposing screen.

PMID:36006501 | DOI:10.1007/s11030-022-10516-3

Front Microbiol. 2022 Aug 8;13:953846. doi: 10.3389/fmicb.2022.953846. eCollection 2022.

ABSTRACT

Hepatic alveolar echinococcosis (HAE) is a zoonotic parasitic disease caused by the larvae of Echinococcus multilocularis. Because of its characteristics of diffuse infiltration and growth similar to tumors, the disability rate and mortality rate are high among patients. Although surgery (including hepatectomy, liver transplantation, and autologous liver transplantation) is the first choice for the treatment of hepatic alveolar echinococcosis in clinic, drug treatment still plays an important and irreplaceable role in patients with end-stage echinococcosis, including patients with multiple organ metastasis, patients with inferior vena cava invasion, or patients with surgical contraindications, etc. However, Albendazole is the only recommended clinical drug which could exhibit a parasitostatic rather than a parasitocidal effect. Novel drugs are needed but few investment was made in the field because the rarity of the cases. Drug repurposing might be a solution. In this review, FDA-approved drugs that have a potential curative effect on hepatic alveolar echinococcosis in animal models are summarized. Further, nano drug delivery systems boosting the therapeutic effect on hepatic alveolar echinococcosis are also reviewed. Taken together, these might contribute to the development of novel strategy for advanced hepatic alveolar echinococcosis.

PMID:36003932 | PMC:PMC9393627 | DOI:10.3389/fmicb.2022.953846

Front Pharmacol. 2022 Aug 8;13:917968. doi: 10.3389/fphar.2022.917968. eCollection 2022.

ABSTRACT

A target-based drug discovery strategy has led to a bias away from low molecular weight (MWT) drug discovery. Analysis of the ACS chemistry registration system shows that most low MWT drugs were first made in the time era before target-based drug discovery. Therapeutic activity among most low MWT drugs was identified in the era of phenotypic drug discovery when drugs were selected based on their phenotypic effects and before in vitro screening, mechanism of action considerations and experiences with fragment screening became known. The common perception that drugs cannot be found among low MWT compounds is incorrect based on both drug discovery history and our own experience with MLR-1023. The greater proportion of low MWT compounds that are commercially available compared to higher MWT compounds is a factor that should facilitate biology study. We posit that low MWT compounds are more suited to identification of new therapeutic activity using phenotypic screens provided that the phenotypic screening method has enough screening capacity. On-target and off-target therapeutic activities are discussed from both a chemistry and biology perspective because of a concern that either phenotypic or low MWT drug discovery might bias towards promiscuous compounds that combine on-target and off-target effects. Among ideal drug repositioning candidates (late-stage pre-clinical or clinically-experience compounds), pleiotropic activity (multiple therapeutic actions) is far more likely due to on-target effects arising where a single target mediates multiple therapeutic benefits, a desirable outcome for drug development purposes compared to the off-target alternative. Our exemplar of a low MWT compound, MLR-1023, discovered by phenotypic screening and subsequently found to have a single mechanism of action would have been overlooked based on current era medicinal chemistry precedent. The diverse therapeutic activities described for this compound by us, and others arise from the same pleiotropic lyn kinase activation molecular target. MLR-1023 serves as a proof-of-principle that potent, on target, low MWT drugs can be discovered by phenotypic screening.

PMID:36003497 | PMC:PMC9393533 | DOI:10.3389/fphar.2022.917968

Curr Microbiol. 2022 Aug 24;79(10):300. doi: 10.1007/s00284-022-02990-7.

ABSTRACT

The persistence and resurgence of cancer, characterized by abnormal cell growth and differentiation, continues to be a serious public health concern critically affecting public health, social life, and the global economy. Hundreds of putative drug molecules of synthetic and natural origin were approved for anticancer therapy in the last few decades. Although conventional anticancer treatment strategies have promising aspects, several factors such as their limitations, drug resistance, and side effects associated with them demand more effort in repositioning or developing novel therapeutic regimens. The rich heritage of microbial bioactive components remains instrumental in providing novel avenues for cancer therapeutics. Actinobacteria, Firmicutes, and fungi have a plethora of bioactive compounds, which received attention for their efficacy in cancer treatment targeting different pathways responsible for abnormal cell growth and differentiation. Yet the full potential remains underexplored to date, and novel compounds from such microbes are reported regularly. In addition, the advent of computational tools has further augmented the mining of microbial secondary metabolites and identifying their molecular targets in cancer cells. Furthermore, the drug-repurposing strategy has facilitated the use of approved drugs of microbial origin in regulating cancer cell growth and progression. The wide diversity of microbial compounds, different mining approaches, and multiple modes of action warrant further investigations on the current status of microbial metabolites in cancer therapeutics. Hence, in this review, we have critically discussed the untapped potential of microbial products in mitigating cancer progression. The review also summarizes the impact of drug repurposing in cancer therapy and discusses the novel avenues for future therapeutic drug development against cancer.

PMID:36002695 | DOI:10.1007/s00284-022-02990-7

Chem Biol Drug Des. 2022 Aug 24. doi: 10.1111/cbdd.14136. Online ahead of print.

ABSTRACT

Application of materials capable of energy harvesting to increase the efficiency and environmental adaptability is sometimes reflected in ability of discovery of some traces in an environment-either experimentally of computationally-to enlarge practical application window. The emergence of computational methods, particularly computer-aided drug discovery (CADD), provides ample opportunities for the rapid discovery and development of unprecedented drugs. The expensive and time-consuming process of traditional drug discovery is no longer feasible, for nowadays the identification of potential drug candidates is much easier for therapeutic targets through elaborate in silico approaches allowing the prediction of the toxicity of drugs, such as drug repositioning (DR) and chemical genomics (chemogenomics). Coronaviruses (CoVs) are cross-species viruses that are able to spread expeditiously from the into new host species, which in turn cause epidemic diseases. In this sense, this review furnishes an outline of computational strategies and their applications in drug discovery. An especial focus is placed on chemogenomics and DR as unique and emerging system-based disciplines on CoVs drug and target discovery to model protein networks against a library of compounds. Furthermore, to demonstrate the special advantages of CADD methods in rapidly finding a drug for this deadly virus, numerous examples of the recent achievements grounded on molecular docking, chemogenomics, and DR are reported, analyzed, and interpreted in detail. It is believed that the outcome of this review assists developers of energy harvesting materials and systems for detection of future unexpected kinds of CoVs or other variants.

PMID:36002440 | DOI:10.1111/cbdd.14136

Emerg Microbes Infect. 2022 Aug 24:1-30. doi: 10.1080/22221751.2022.2117101. Online ahead of print.

ABSTRACT

Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.

PMID:36000328 | DOI:10.1080/22221751.2022.2117101

Assay Drug Dev Technol. 2022 Aug 23. doi: 10.1089/adt.2022.065. Online ahead of print.

NO ABSTRACT

PMID:35998239 | DOI:10.1089/adt.2022.065

Discov Oncol. 2022 Aug 23;13(1):80. doi: 10.1007/s12672-022-00547-5.

ABSTRACT

Cancer is a major health problem as it is the first or second leading cause of death worldwide. The global cancer burden is expected to rise 47% relative to 2020 cancer incidence. Recently, the fields of neuroscience, neuroimmunology and oncology have elaborated the neuroimmune crosstalk role in tumor initiation, invasion, progression, and metastases. The nervous system exerts a broad impact on the tumor microenvironment by interacting with a complex network of cells such as stromal, endothelial, malignant cells and immune cells. This communication modulates cancer proliferation, invasion, metastasis, induce resistance to apoptosis and promote immune evasion. This paper has two aims, the first aim is to explain neuroimmune crosstalk in cancer, tumor innervation origin and peripheral nervous system, exosomes, and miRNA roles. The second aim is to elaborate neuroimmune crosstalk impact on cancer therapy and research highlighting various potential novel strategies such as use of immune checkpoint inhibitors and anti-neurogenic drugs as single agents, drug repurposing, miRNA-based and si-RNA-based therapies, tumor denervation, cellular therapies, and oncolytic virus therapy.

PMID:35997976 | DOI:10.1007/s12672-022-00547-5

Adv Appl Bioinform Chem. 2022 Aug 15;15:59-77. doi: 10.2147/AABC.S366111. eCollection 2022.

ABSTRACT

BACKGROUND: Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the well-established strategies is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study, an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease (3CLpro).

MATERIAL AND METHODS: Molecular docking calculations were performed to investigate the binding affinity of the ligands within the active site of 3CLpro. The best binding candidates were further considered for molecular dynamics simulations for 100 ns to gain a time-resolved understanding of the behavior of the guest-host complexes. Furthermore, the profile of druggability of the best binding ligands was assessed based on ADMET predictions. Finally, their chemical reactivity was elucidated using different reactivity descriptors, namely the molecular electrostatic potential (MEP), Fukui functions and frontier molecular orbitals.

RESULTS AND DISCUSSION: From the calculations performed, four candidates (compounds 14, 15, 16 and 18) show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. These compounds are maintained inside the active site of 3CLpro thanks to a variety of noncovalent interactions, especially hydrogen bonds, involving important amino acids such as GLU166, HIS163, GLY143, ASN142, HIS172, CYS145. Molecular dynamics simulations suggest that the four ligands are well trapped within the active site of the protein over a time gap of 100 ns, ligand 18 being the most retained.

CONCLUSION: In line with the findings reported herein, we recommend that further in-vitro and in-vivo investigations are carried out to shed light on the possible mechanism of pharmacological action of the proposed ligands.

PMID:35996620 | PMC:PMC9391940 | DOI:10.2147/AABC.S366111

Biosci Rep. 2022 Aug 31;42(8):BSR-2021-2791_EDN. doi: 10.1042/BSR-2021-2791_EDN.

NO ABSTRACT

PMID:35994294 | DOI:10.1042/BSR-2021-2791_EDN

Microb Pathog. 2022 Aug 19:105691. doi: 10.1016/j.micpath.2022.105691. Online ahead of print.

ABSTRACT

The current study was designed to characterize methicillin-resistant Staphylococcus aureus (MRSA) isolated from bovine milk, along with its response to antibiotics, and ultimately reverse its mechanism of resistance by modulation with non-antibiotics. The synergistic combination of antibiotics with NSAIDs were tested in-vivo by giving MRSA challenge to rabbits. The current study reported an overall 23.79% prevalence of MRSA. The BLAST alignment of current study sequences revealed 99% similarity with mecA gene of MRSA from NCBI database. The current study isolates were more similar to each other and also with reference sequences as compared to other mecA gene sequences from Turkey, India, and Russia. Antibiogram of MRSA isolates showed a highly resistant response to cefoxitin, amoxicillin, and gentamicin. Amoxicillin, gentamicin, tylosin, vancomycin, and ciprofloxacin elicited a significant response (p < 0.05) in combination with non-antibiotics against tested MRSA isolates. The highest zone of inhibition (ZOI) increase was noted for vancomycin in combination with flunixin meglumine (145.45%) and meloxicam (139.36%); gentamicin with flunixin meglumine (85.71%) and ciprofloxacin with ivermectin (71.13%). Synergistic behavior was observed in the combination of gentamicin with ketoprofen; sulfamethoxazole and oxytetracycline with meloxicam. Hematological analysis showed significant differences (p < 0.05) among lymphocyte count and bilirubin. On histopathological examination of skin tissue, hyperplasia of epithelium, sloughed off epidermis, hyperkeratosis, infiltration of inflammatory cells, and hemorrhages were observed. The highest cure rate was observed in case of gentamicin in combination with ketoprofen as compared to other treatment groups. The current study concluded antibiotics in combination with non-antibiotics as potential therapeutic agents for resistance modulation against MRSA. This study will help to devise treatment and control strategies against bovine mastitis. Although the prospect of using NSAIDs to manage infections caused by MRSA appears to be a promising direction, further studies should be conducted to test these medications using suitable in-vivo models in controlled clinical trials to justify their repurposing as a treatment for MRSA infections.

PMID:35995254 | DOI:10.1016/j.micpath.2022.105691

Neuropeptides. 2022 Aug 17;96:102283. doi: 10.1016/j.npep.2022.102283. Online ahead of print.

ABSTRACT

Epidemiological studies indicate a higher occurrence of breast cancer (BRCA) in patients with Parkinson's disease. However, the exact molecular mechanism is still not precise. Herein, we tested the hypothesis that this inverse comorbidity result from shared genetic and molecular processes. We conducted an integrated omics analysis to identify the common gene signatures associated with PD and BRCA. Secondly, several dysregulated biological processes in both indications were analyzed by functional enrichment methods, and significant overlapping processes were identified. To establish common regulatory mechanisms, information about transcription factors and miRNAs associated with both the disorders was extracted. Finally, disease-specific gene expression signatures were compared through LINCS L1000 analysis to identify potential repurposing drugs for PD. The potential repurposed drug candidates were then correlated with PD-specific gene signatures by Cmap analysis. In conclusion, this study highlights the shared genes, biological pathways and regulatory signatures associated with PD and BRCA with an improved understanding of crosstalk involved. Additionally, the role of therapeutics was investigated in context with their comorbid associations. These findings could help to explain the complex molecular patterns of associations between PD and BRCA.

PMID:35994781 | DOI:10.1016/j.npep.2022.102283

J Environ Pathol Toxicol Oncol. 2022;41(3):45-64. doi: 10.1615/JEnvironPatholToxicolOncol.2022039271.

ABSTRACT

On December 2019, the world faced a new pandemic caused by a novel type of coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is named as "coronavirus disease 2019 (COVID-19)." This RNA virus infected millions of people around the world causing millions of deaths. It takes approximately 8-10 years to develop a new drug and it seems hard to have a specific pharmaceutical agent against COVID-19. So far, there is only one drug that has applied for registration. The drugs used in clinics against COVID-19 were approved for malaria, human immunodeficiency syndrome (HIV), influenza A and B, and other viral diseases. All these drugs for COVID-19 treatment are being applied according to "drug repurposing (drug repositioning)" strategy. However, they could cause some severe adverse effects on susceptible populations. In some cases, patients can survive after disease. However, the adverse effects of these drugs may lead to morbidity and mortality later. In this review, drugs used against COVID-19 in clinics, their mechanisms of action and possible adverse effects on susceptible populations will be discussed.

PMID:35993955 | DOI:10.1615/JEnvironPatholToxicolOncol.2022039271