Pharmaceuticals最新文献

{"title":"Dietary Modulation of CYP3A4 and Its Impact on Statins and Antidiabetic Drugs: A Narrative Review.","authors":"Manuel Hernández-Lorca, Isabel M Timón, Pura Ballester, Paula Henarejos-Escudero, Ana María García-Muñoz, Desirée Victoria-Montesinos, Pablo Barcina-Pérez","doi":"10.3390/ph18091351","DOIUrl":"10.3390/ph18091351","url":null,"abstract":"<p><p>Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in the metabolism of nearly half of all clinically used drugs, including widely prescribed statins and antidiabetic agents. Dietary constituents can modulate CYP3A4 expression and activity through various mechanisms, thereby altering drug pharmacokinetics and potentially leading to therapeutic failure or toxicity. This narrative review compiles current evidence on dietary modulation of CYP3A4, with a particular focus on pharmacological and clinical implications for lipid-lowering and glucose-lowering drugs. Literature was identified through a comprehensive search in PubMed, Scopus, and Web of Science, including preclinical and clinical studies addressing food-drug interactions involving CYP3A4 substrates. Numerous dietary compounds, such as citrus furanocoumarins, polyphenols, herbal extracts, and vitamins, act as CYP3A4 inhibitors or inducers through competitive, mechanism-based, or nuclear receptor-mediated pathways. Specific examples include simvastatin, atorvastatin, repaglinide, and saxagliptin, whose systemic exposure can be significantly altered by dietary factors. Moreover, interindividual variability in CYP3A4 activity may be shaped by genetic polymorphisms, microbiota-derived metabolites, and epigenetic regulation, further influencing drug response. Understanding these interactions is crucial, especially in polymedicated patients or those receiving drugs with a narrow therapeutic index. Clinicians should remain aware of potential CYP3A4-related food-drug interactions and consider dietary habits and supplement use in therapeutic decision-making. Future research should aim to integrate pharmacogenomics, gut microbiome profiling, and personalized nutrition in order to improve the prediction and prevention of clinically significant interactions.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticonvulsant Potential of 1-Aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines: Insights from Strychnine and Nicotine Models in In Vivo and In Silico Studies.","authors":"Azizbek A Azamatov, Nilufar Z Mamadalieva, Asmaa A Mandour, Sherzod N Zhurakulov, Urkhiya K Aytmuratova, Valentina I Vinogradova, Fazliddin S Jalilov, Firuza M Tursunkhodzhaeva","doi":"10.3390/ph18091350","DOIUrl":"10.3390/ph18091350","url":null,"abstract":"<p><p><b>Background:</b> Epilepsy is a chronic, non-communicable brain disorder characterized by recurrent seizures. Some derivatives of 1,2,3,4-tetrahydroisoquinolines have demonstrated anticonvulsant effects. This study aims to investigate the effects of 33 derivatives of 1-aryl-1,2,3,4-tetrahydroisoquinoline on seizures induced by nicotine and strychnine. <b>Methods</b>: The anticonvulsant effects of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives were evaluated in white male mice. Convulsant agents were administered subcutaneously at doses of 10.0 mg/kg for nicotine and 1.5 mg/kg for strychnine, 60 min after the oral administration of the test compounds at doses ranging from 0.1 to 10 mg/kg. The onset time, duration of tremors and seizures, and survival rate of the animals were recorded. The docking studies were conducted for 32 tested compounds targeting the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (PDB ID: 1FTL). Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. <b>Results:</b> Compounds <b>20</b> and <b>25</b> exhibited the highest activity against strychnine-induced seizures. When evaluating the effects of 1-aryl-1,2,3,4-tetrahydroisoquinolines and reference drugs on the tremorogenic and convulsive actions of nicotine at doses of 0.1-5 mg/kg, compounds <b>3</b>, <b>6</b>, <b>8</b>, <b>14</b>, <b>16</b>, <b>25</b>, <b>27</b>, <b>29</b>, <b>30</b>, <b>31</b>, and <b>34</b> demonstrated comparable activity to the reference drugs. The docking results targeting AMPA (PDB ID: 1FTL) revealed comparable binding interactions for most of the compounds, with a (-)C-Docker interaction energy range of 33.82-45.41 Kcal/mol, compared to that of the ligand (41.60 Kcal/mol). The structural requirements of the studied scaffold were analyzed to identify the essential pharmacophoric features for anticonvulsant activity. Furthermore, a predictive ADMET study was conducted to evaluate the pharmacokinetic and toxicity profiles of the compounds. <b>Conclusions</b>: Certain derivatives of 1,2,3,4-tetrahydroisoquinolines may serve as potential anticonvulsant agents for epilepsy.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Echinops</i> as a Source of Bioactive Compounds-A Systematic Review.","authors":"Simona Ivanova, Alexandra Ivanova, Mina Todorova, Vera Gledacheva, Stoyanka Nikolova","doi":"10.3390/ph18091353","DOIUrl":"10.3390/ph18091353","url":null,"abstract":"<p><p><b>Background</b>: <i>Echinops</i> is a genus of spiny, herbaceous perennials in the <i>Asteraceae</i> family, known for its distinct morphology and broad pharmacological potential. Both traditional and modern medicinal systems have identified species in this genus as sources of bioactive compounds with anti-inflammatory, antimalarial, antidiabetic, anticancer, and neuroprotective effects. <b>Aims</b>: This study aimed to conduct a systematic literature review and update previous overviews of the recently reported phytochemicals and pharmacological properties of <i>Echinops</i>, systematically summarizing biological activities and their therapeutic applications. <b>Methods</b>: Major electronic medical databases-PubMed, Scopus, Science Direct, Web of Science, and Google Scholar-were systematically searched for publications from 1990 to 2025. <b>Results</b>: A total of 134 studies met our inclusion criteria. Thiophenes and terpenes emerged as characteristic metabolites of the genus, and along with flavonoids and alkaloids, contributed to a wide range of bioactivities. Experimental evidence supports the potential of these compounds as multifunctional agents, although clinical validation remains limited. <b>Conclusions</b>: <i>Echinops</i> is a promising source of structurally diverse metabolites with therapeutic relevance. Further pharmacological and toxicological studies are needed to establish their efficacy and ensure safe medical application.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nasal Administration of <i>Durvillaea antarctica</i> Fucoidan Inhibits Lung Cancer Growth in Mice Through Immune Activation.","authors":"Hee Sung Kim, Peter C W Lee, Jun-O Jin","doi":"10.3390/ph18091354","DOIUrl":"10.3390/ph18091354","url":null,"abstract":"<p><p><b>Background:</b> Various studies have demonstrated fucoidan's immunomodulatory effects. A previous study reported the anticancer effects of <i>Durvillaea antarctica</i> fucoidan (DAF) via immune activation in mice. <b>Methods:</b> In this study, we confirmed the DAF's pulmonary immune activation ability by nasal administration of the dendritic cells (DCs) and T cells. Furthermore, we examined its ability to enhance the efficacy of lung cancer treatment by combining it with anti-PD-L1 antibodies to activate the lung immune response. <b>Results:</b> Nasal DAF administration increased C-C chemokine receptor type 7 expression in DCs and promoted DC migration to the mediastinal lymph nodes (mLN). Specifically, DAF increased conventional DC type 1 (cDC1) and cDC2 numbers in mLN and potently activated cDC1. Furthermore, the nasal administration of DAF increased the production of inflammatory cytokines in the lungs and peripheral blood. Repeated intranasal administration of DAF induced T-cell activation, resulting in the enhanced production of interferon-gamma and tumor necrosis factor-alpha in CD4 T and CD8 T cells. CD8 T cells also showed increased secretion of cytotoxic mediators after DAF treatment, and the proportion of Tregs expressing FoxP3 decreased in the mLN. DAF inhibited lung cancer growth in Lewis lung carcinoma 2 cells, which was enhanced by combining it with an anti-programmed death-ligand 1 antibody. Finally, the anticancer effects of DAF were not observed in mice with depleted CD4-positive and CD8-positive cells. <b>Conclusions:</b> Nasal administration of DAF may inhibit lung cancer growth by inducing lung immune activation and is expected to be helpful as an immune activator for nasal administration.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Basis of Non-Syndromic Childhood Glaucoma Associated with Anterior Segment Dysgenesis: A Narrative Review.","authors":"Nicola Cronbach, Cécile Méjécase, Mariya Moosajee","doi":"10.3390/ph18091352","DOIUrl":"10.3390/ph18091352","url":null,"abstract":"<p><p>Twenty causative genes have been reported that cause non-syndromic childhood glaucoma associated with anterior segment dysgenesis. <i>FOXC1</i>, <i>PAX6</i> and <i>PITX2</i> are the most well-known, but cases linked to <i>SLC4A11</i>, <i>PITX3</i> and <i>SOX11</i> have also been reported. As genetic testing becomes increasingly widespread and rates of molecular diagnosis rise, the extent of phenotypic overlap between the different genetic causes of non-syndromic glaucoma associated with anterior segment dysgenesis is becoming more evident. Taking aniridia as an example, whilst <i>PAX6</i> mutations remain the predominant cause, variants in <i>CYP1B1</i>, <i>FOXC1</i>, <i>PXDN</i> and <i>SOX11</i> have also been reported in patients with childhood glaucoma and aniridia. Developments in molecular-based therapies for retinal and corneal disease are advancing rapidly, and pre-clinical studies of gene-based treatments for glaucoma and aniridia are showing promising results. Use of adeno-associated viral vectors for gene delivery is most common, with improvements in intraocular pressure and retinal ganglion cell survival in Tg-<i>MYOC^Y437H</i> mouse models of glaucoma, and successful correction of a germline <i>PAX6^G194X</i> nonsense variant in mice using CRISPR-Cas9 gene editing. This review will explore the actions and interactions of the genetic causes of non-syndromic glaucoma associated with anterior segment dysgenesis and discuss the current developments in molecular therapies for these patients.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Tribulus terrestris</i>-Mediated ZnO/Ag-Halloysite Nanohybrids for Targeted Cisplatin and Carboplatin Delivery in Cervical Cancer Treatment.","authors":"Ammar AlAbdullatif, Sarah Almofty, Gazali Tanimu, Hatim Dafalla, Fatimah Alahmari, B Rabindran Jermy","doi":"10.3390/ph18091349","DOIUrl":"10.3390/ph18091349","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Cervical cancer remains a major health challenge, especially in low-resource regions with limited diagnostic and advanced treatment options. Nanotechnology-based strategies offer promising alternatives to conventional chemotherapy by reducing systemic toxicity and enabling site-specific delivery. <b>Methods:</b> In this study, halloysite (Hall) was functionalized with green-synthesized 2 wt% zinc oxide (GZn) and silver (GAg) nanoparticles (NPs) using <i>Tribulus terrestris</i> extract (25 mM) to enhance cisplatin (Cp) and carboplatin (Cbpt) delivery for targeted cervical cancer therapy. <b>Results:</b> Structural and morphological analyses confirmed the successful integration of GZn and GAg NPs into the Hall without compromising its tubular integrity. Cp or Cbpt adsorption studies with varying times (0.15-12 h), as well as drug/Hall ratios (10-50) and pH levels (5; 6.6; 7.4; 9.0; and 10.5), revealed greater Cp adsorption than Cbpt, attributed to its higher reactivity and affinity toward the Hall surface. pH-responsive release studies biphasic drug release for non-PEGYlated formulations, with Cp (14% with 2 h) and Cbpt (10% with 0.5 h), whereas PEGYlated systems exhibited sustained release under acidic tumor-like conditions, achieving 14% in 72 h for Cp and 4.5% in 72 h for Cbpt. Release kinetics followed either Fickian or non-Fickian diffusion depending on pH and drug type, with the Korsmeyer-Peppas model offering a strong fit (R² > 0.85). In vitro assays revealed that Cbpt/GZn-Hall/PEG, Cp/GZn-Hall/PEG, and Cbpt/GAg-Hall/PEG induced dose-dependent cytotoxicity against HeLa while sparing HFF-1 fibroblasts. <b>Conclusions:</b> These findings indicate that green-synthesized nanohybrids are promising carriers for targeted Cp and Cbpt delivery, warranting further in vivo evaluation for cervical cancer therapy.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Glutathione Concentrations Are Associated with Leukocyte and Neutrophils' Counts in Clozapine-Treated Patients.","authors":"Erick José Martínez-Rodríguez, Verónica Barón-Flores, Jesús Ramirez-Bermudez, Carlos Aviña-Cervantes, Dinora González-Esquivel, Araceli Diaz-Ruiz, Camilo Ríos","doi":"10.3390/ph18091345","DOIUrl":"10.3390/ph18091345","url":null,"abstract":"<p><p>Clozapine's potential hematological toxicity, particularly its effect on white blood cell counts, is well documented and routinely monitored in clinical practice. In this study, a significant association was identified between reduced glutathione levels and neutrophil counts in patients undergoing clozapine treatment. Among the variables analyzed, glutathione concentration showed the strongest correlation with neutrophil levels, suggesting a potential role for antioxidant status in mediating clozapine's hematological effects. <b>Objective</b>: The study aimed to evaluate the relationship between plasma concentrations of clozapine, its active metabolite N-desmethylclozapine, reduced glutathione, and treatment duration, in relation to total leukocyte and neutrophil counts in patients attending an outpatient psychiatric clinic. <b>Methods</b>: Plasma levels of clozapine, N-desmethylclozapine, and reduced glutathione were quantified using validated analytical techniques. Complete blood counts were obtained, and a multiple regression analysis was conducted to identify factors most strongly associated with variations in neutrophil count. <b>Results</b>: Reduced glutathione levels were significantly associated with neutrophil counts (<i>p</i> = 0.009), representing the most robust association among the variables examined. Clozapine concentration and duration of treatment were also found to be relevant contributors to changes in hematological parameters. <b>Conclusions</b>: These findings suggest that individual antioxidant capacity, particularly involving glutathione metabolism, may influence susceptibility to clozapine-related neutropenia. This insight could inform future strategies for monitoring and managing clozapine-treated patients, potentially aiding in the identification of those at increased risk for hematological side effects.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect and Mechanism of Qihua Tongtiao Formula (QHTTF) on Improving Glucose and Lipid Metabolism Disorders in ZDF Rats by Integrating Network Pharmacology, Metabolomics, and Biological Validation.","authors":"Yuhua Jiang, Hong Yu, Yajing Pan, Binghan Zhang, Yeteng Jing, Jingjing Lei, Ning Li, Jinsheng Yang","doi":"10.3390/ph18091347","DOIUrl":"10.3390/ph18091347","url":null,"abstract":"<p><p><b>Background:</b> The dysregulation of both glucose and lipid metabolism is the main clinical features of type 2 diabetes. Qihua Tongtiao Formula (QHTTF) is our team's current clinical empirical formula, and the related patent has been granted. It is composed of <i>Astragalus membranaceus</i>, <i>Atractylodes macrocephala koidz</i>, <i>Aurantii Fructus Immaturus</i>, <i>Radix Bupleuri</i>, <i>Ligusticum chuanxiong hort</i>, <i>Angelicae sinensis radix</i>, <i>Raphanus sativus</i>, and <i>Polyporus umbellatus</i>. It can alleviate tissue pathological damage in type 2 diabetic rats by improving glycolipid metabolism disorders. Nevertheless, the specific mechanisms of QHTTF in the treatment of type 2 diabetes remain unclear. Purpose: This research aims to explore the fundamental effect and underlying mechanism of the QHTTF formula in ZDF rats via network pharmacology, biological validation, and metabolomics technology. <b>Methods:</b> The chemical compounds of QHTTF were initially identified via UHPLC-MS/MS analysis. Meanwhile, drug targets, genes, related diseases, and differential metabolites of QHTTF in the treatment of T2DM were obtained through network pharmacology, molecular docking, and metabolomics. Then, we conducted animal experiments to further explore the therapeutic molecular mechanism of QHTTF in ZDF rats. <b>Results:</b> A total of 39 main chemical components were recognized through LC-MS/MS technology, and 22 remained after the second screening. Network pharmacology and molecular docking results revealed that 59 intersection targets were involved in the treatment of glycolipid metabolic disorders, and the PPARα, PPARγ, and TNF proteins were identified as crucial targets through PPI network analysis. Additionally, serum metabolomics analysis of ZDF rats showed that QHTTF could regulate linoleic acid metabolism, fructose and mannose metabolism, galactose metabolism, fatty acid biosynthesis, and other related signaling pathways. The results of biological experiments proved that QHTTF effectively lowered blood glucose and lipid levels, alleviated hepatic and pancreatic pathological damage, increased the expression of IRS-1 and GLUT4 in the pancreas, and improved insulin resistance, while inhibiting the inflammatory response and oxidative stress, as well as enhancing the expression of liver PPARα, PPARγ, and AMPK proteins in ZDF rats. <b>Conclusions:</b> In summary, QHTTF exerted a significant effect in improving glycolipid metabolism disorders of ZDF rats, which might show therapeutic effects by relieving insulin resistance, mitigating inflammation and oxidative damage, regulating related glucose, fatty acid, and amino acid metabolism, and increasing the expression of PPARα, PPARγ, and AMPK proteins by combining network analysis, metabolomics, and biological research.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial Activity of 1,3,4-Thiadiazole Derivatives.","authors":"Sebastian Górecki, Agnieszka Kudelko, Monika Olesiejuk","doi":"10.3390/ph18091348","DOIUrl":"10.3390/ph18091348","url":null,"abstract":"<p><p>The 1,3,4-thiadiazole core has attracted significant attention due to its unique electronic structure, physicochemical properties, and wide-ranging pharmacological potential. This heterocyclic scaffold exhibits a broad spectrum of biological activities, often attributed to its capacity to modulate enzyme function, interact with receptors, and disrupt key biochemical pathways in both pathogens and host cells. Additionally, 1,3,4-thiadiazoles typically display favorable pharmacokinetic properties, including high metabolic stability and appropriate lipophilicity, which enhance their drug-likeness and bioavailability. This review presents an overview of antibacterial and antifungal compounds bearing the 1,3,4-thiadiazole scaffold that have been reported over the past five years. This publication details the chemical structures of novel 1,3,4-thiadiazole derivatives and reports the results of antibacterial and antifungal activity assays conducted against a range of microbial strains. Furthermore, it provides conclusions regarding the structural features that influence the observed biological activity of the synthesized compounds. Antimicrobial activity assessments conducted against ten Gram-negative and nine Gram-positive bacterial strains revealed that 79 newly synthesized 1,3,4-thiadiazole derivatives exhibited either superior inhibitory efficacy relative to standard reference antibiotics or achieved a high level of bacterial growth suppression, defined as 90-100% inhibition. In antifungal assays, the compounds were evaluated against 25 fungal species representing 15 genera. Among the tested derivatives, 75 compounds demonstrated antifungal potency exceeding that of reference antifungal agents or produced growth inhibition within the 90-100% range. The information provided herein may serve as a valuable resource for medicinal and agricultural chemists engaged in the development of novel drug candidates and plant protection agents.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Methylstat as a Potential Therapeutic Agent for Human Glioma Cells by Targeting Cell Cycle Arrest.","authors":"Haoge Yao, Tingyi Meng, Yingying Yang, Huaping Tao, Wenwen Lu, Mingqi Liu, Xiaofeng Zhao, Mengsheng Qiu, Aifen Yang","doi":"10.3390/ph18091344","DOIUrl":"10.3390/ph18091344","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a poor prognosis and limited therapeutic options. This study aimed to repurpose methylstat, a selective histone demethylase inhibitor, as a novel anti-glioma agent. We characterized its anti-proliferative efficacy, elucidated mechanisms of cell cycle regulation, and evaluated its blood-brain barrier (BBB) permeability potential. <b>Methods</b>: Compounds with transcriptional profiles enriched for cell cycle arrest and tumor-suppressive pathways were identified via Connectivity Map (CMAP) analysis. Methylstat was selected based on its high connectivity score and favorable physicochemical properties. In vitro assays were performed to evaluate its effects on cell viability, proliferation, cell cycle progression, and expression of related molecular markers in U251 and HOG glioma cell lines. Molecular docking and 200 ns molecular dynamics (MD) simulations were performed to evaluate the binding mode and stability of the Methylstat-JMJD2A complex. An in vitro BBB model was established to assess the ability of Methylstat to cross the BBB. <b>Results</b>: Methylstat significantly inhibited glioma cell proliferation in a dose-dependent manner without inducing apoptosis. It caused G1-phase arrest in U251 cells and G2-phase arrest in HOG cells. Mechanistically, methylstat downregulated cyclins and cyclin-dependent kinases via the p53/p21 pathway. Additionally, methylstat reduced the expression of JMJD2A and its downstream targets, including PDK1, AKT, and mTOR. Molecular docking studies and 200 ns MD simulations confirmed the stable binding of methylstat to the catalytic pocket of JMJD2A, effectively inhibiting its enzymatic activity. HPLC analysis confirmed that methylstat could penetrate the in vitro BBB model to varying extents. <b>Conclusions</b>: Methylstat is a promising small-molecule agent that effectively suppresses glioma cell growth by modulating key cell cycle regulators. Its ability to cross the BBB highlights its potential as a novel therapeutic strategy for GBM and other brain tumors.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 9","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12472336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}