Pharmacology最新文献

{"title":"Safety and Efficacy of Givinostat for Patients with Muscular Dystrophy: A Systematic Review.","authors":"Prasanjit Das, Bisweswar Ojha, Alapan Das, Bhairav Kumar Pathak, Kaushik Mukhopadhyay","doi":"10.1159/000547936","DOIUrl":"10.1159/000547936","url":null,"abstract":"<p><p><p>Introduction: Muscular dystrophy (MD) refers to a group of genetic disorders leading to progressive weakness and degeneration of skeletal muscle. Among them, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most common types. Histone deacetylase inhibitors (i.e., givinostat) is a recently approved therapy for DMD. In this systematic review, we aimed to evaluate givinostat in MD patients regarding safety and efficacy.</p><p><strong>Methods: </strong>A systematic review was performed according to the PRISMA guidelines by searching through Medline, Embase, Cochrane Library, and Web of Science. Only randomized control trials comparing givinostat vs. placebo or other therapies are included. The primary outcomes were motor function alteration and histopathologic muscle changes and the secondary outcomes were the adverse reactions.</p><p><strong>Results: </strong>A total of 188 records were identified, and after screening, two clinical trials met the inclusion criteria. In DMD patients, givinostat significantly slowed disease progression, improving four-stair climb times (p = 0.037) and reducing muscle fat infiltration. In BMD patients, fibrosis progression was not significantly different (p = 0.8282), but MRI showed reduced muscle fat replacement. Common adverse events included diarrhoea, thrombocytopenia, and hypertriglyceridemia, leading to dose reductions, though no new safety signals or treatment-related deaths were observed.</p><p><strong>Conclusion: </strong>Givinostat seems to be effective in slowing disease progression in DMD but has little benefit in BMD. Its safety profile requires rigorous monitoring. Efficacy difference might be explained by the pathophysiology of the disease and the progression rate. Larger and longer follow-up trials are warranted to confirm longer term benefits and to optimize dosing strategies. Givinostat offers potential as a disease-modifying therapy for DMD but requires further investigation to establish its role in BMD. </p>.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"347-359"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144856136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amphotericin-A21 Induces Antineoplastic Effects through the Modulation of Apoptosis in Human Tumoral Cells.","authors":"Lourdes Rodríguez-Fragoso, Rubi Escobar-Reséndiz, Arturo Galván-Hernández, Lucero Díaz-Peralta, Esdras Zamora-Morán, Ivan Ortega-Blake","doi":"10.1159/000547300","DOIUrl":"10.1159/000547300","url":null,"abstract":"<p><p><p>Introduction: While the high morbidity of cancer continues to affect the global population, there are currently no effective and safe therapeutic options. Amphotericin-A21 (AmB-A21) is a derivative of amphotericin B (AmB). Its efficacy is similar to that of its precursor, but it has greater safety. AmB-A21 can induce apoptosis in neoplastic cells, meaning it could potentially be employed as a safe chemotherapeutic agent.</p><p><strong>Methods: </strong>This study examined the antineoplastic effect of AmB-A21 on MCF-7, U-87MG, and A-549 cells by evaluating cytotoxicity, apoptosis, and protein expressions associated with cell death. MCF-7 cells were treated with AmB-A21 at 40 µ<sc>m</sc>, U-87MG cells with AmB-A21 at 423 µ<sc>m</sc>, and A-549 cells with AmB-A21 at 192 µ<sc>m</sc> for all experiments. Non-treated cells were used as negative control. Comparative studies using AmB and cisplatin were also carried out.</p><p><strong>Results: </strong>AmB-A21 reduced cell viability in a time-dependent manner. At 72 h, cell viability was reduced by 67% in MCF-7, 48% in U-87MG, and 47% in A-549 cells. AmB-A21 induced apoptosis by 50%, 58%, and 80% in MCF-7, U-87MG, and A-549 cells, respectively. A significant reduction in Bcl-2 expression and an important increase in Bax expression (55%/2.8-fold in MCF-7 cells, 40%/3.5 fold in U-87MG cells, and 45%/4.5-fold in A-549 cells) were also observed. AmB-A21 likewise increased caspase 9 activity 8.5-fold in MCF-7 cells, 4.1-fold in U-87MG cells, and 8-fold in A-549 cells.</p><p><strong>Conclusion: </strong>Although comparatively AmB-A21 concentration for U-87MG cells was higher, it has potential for cancer therapy due to its safer profile. </p>.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"321-332"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rat Model of Menopausal/Andropausal Hypertension with Different Sensitivities to Non-Genomic Antihypertensive Responses of Female and Male Sex Steroids.","authors":"Mercedes Perusquía, Nieves Herrera","doi":"10.1159/000542007","DOIUrl":"10.1159/000542007","url":null,"abstract":"<p><strong>Introduction: </strong>Hypertension is prevalent in older women and men, but the impact of sex differences is unclear.</p><p><strong>Methods: </strong>Blood pressure (BP) was evaluated weekly for 15 weeks using tail-cuff plethysmography in intact or gonadectomized female and male rats. Similarly, gonadectomized rats were subcutaneously treated daily for 15 weeks with estradiol in females or testosterone in males. Treatment with estrogen in males and androgen in females for BP was also examined. The non-genomic antihypertensive potency and efficacy of different sex steroids were determined; catheters were implanted in the carotid artery of hypertensive rats for BP recording with bolus injections in the jugular vein at cumulative doses (1 × 10-7-1 × 10-4<sc>M</sc> kg-1 min-1) of dehydroepiandrosterone (DHEA), estradiol, testosterone, or 5β-dihydrotestosterone (5β-DHT).</p><p><strong>Results: </strong>Data showed a time-dependent increase in BP after gonadectomy in female and male rats until hypertension values were reached. Males are more sensitive to the development of hypertension than females. The increases in BP in females and males were completely prevented by estradiol or testosterone, respectively. Testosterone completely prevented hypertension in females, whereas estradiol only partially in males. Antihypertensive potencies in conscious hypertensive rats were DHEA = 5β-DHT = testosterone >> estradiol, in females and DHEA = 5β-DHT >> testosterone >> estradiol in males. The efficacy was DHEA = 5β-DHT = testosterone >> estradiol in females and 5β-DHT = DHEA >> testosterone >> estradiol in males.</p><p><strong>Conclusion: </strong>Gonadectomized males developed hypertension faster than females, suggesting that androgen deficiency plays an important role in BP reduction. Antihypertensive responses of steroids are structure-dependent; estradiol demonstrated the lowest potency, whereas 5β-DHT was a potent antihypertensive without estrogenic and androgenic actions, suggesting it is as a therapeutic candidate for controlling hypertension in both sexes.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"98-109"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142472876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tranilast Treatment Prevents Chronic Radiation-Induced Colitis in Rats by Inhibiting Mast Cell Infiltration.","authors":"Kyung Jin Seo, Mohammad Rizwan Alam, Jamshid Abdul-Ghafar, Sang Woo Kim, Hyung Keun Kim, Hyun Ho Choi, Seung Ho Sin, Hae Kyung Lee, Hiun Suk Chae","doi":"10.1159/000541003","DOIUrl":"10.1159/000541003","url":null,"abstract":"<p><strong>Introduction: </strong>Mast cells are the principal cells involved in acute and chronic colitis due to radiation, known as radiation-induced colitis (RIC). In this study, we investigated whether pretreatment with tranilast, a mast cell inhibitor, could alleviate chronic RIC.</p><p><strong>Methods: </strong>A total of 23 Sprague-Dawley rats were randomly divided into three groups: control group (n = 5), radiation group (RG, n = 9), and tranilast-pretreated radiation group (TG, n = 9). The rats in the RG and the TG were irradiated in the pelvic area (1.5 cm from the anus) with a single dose of 20 Gy under general anesthesia. Tranilast (100 mg/kg) was administered intraperitoneally to the rats of the TG for 10 days, starting from the day of pelvic radiation. Ten weeks after radiation, the rats were euthanized. Rectal tissue samples were histologically evaluated for the total inflammation score (TIS) and mast cell count. The expression of MUC2, MUC5AC, and matrix metalloproteinase-9 (MMP-9) was also assessed immunohistochemically.</p><p><strong>Results: </strong>Both the TIS and specific components of TIS such as epithelial atypia, vascular sclerosis, and colitis cystica profunda (CCP) were significantly higher in the RG than in the TG (p = 0.02, 0.038, 0.025, and 0.01, respectively). Thein number of infiltrating mast cells was significantly higher in the RG than in the TG (median [range]: 20 [3-54] versus 6 [3-25], respectively; p = 0.034). Quantitatively, the number of MMP-9-positive cells was significantly higher in the RG (23.67 ± 19.00) than in the TG (10.25 ± 8.45) (mean ± standard deviation; p < 0.05). TIS and MMP-9 exhibited a strong association (correlation coefficient r = 0.56, p < 0.05). Immunohistochemically, the mucin-lake of CCP showed no staining for MUC5AC but was stained positive for MUC2.</p><p><strong>Conclusion: </strong>Tranilast pretreatment of chronic RIC showed an anti-inflammatory effect associated with the reduction of mast cell infiltration and MMP-9 expression.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"77-86"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Tolerability, Pharmacokinetics, and Effects of Gene Polymorphisms on Furaprevir (TG-2349), a Novel Hepatitis C Inhibitor: A Randomized Phase I Study.","authors":"Su-Mei Xu, Ying-Jun Zhang, Li-Wen Chang, Cheng-Yuan Tsai, Dai Li, Ping-Sheng Xu, Ping-Sheng Xu","doi":"10.1159/000543416","DOIUrl":"10.1159/000543416","url":null,"abstract":"<p><strong>Introduction: </strong>The purpose of our study was to evaluate the safety, tolerability, and pharmacokinetics of furaprevir, a new highly selective hepatitis C virus NS3/4A protease inhibitor.</p><p><strong>Methods: </strong>The study was divided into 2 parts: part A (single ascending dose study [SAD]) and part B (multiple ascending dose study [MAD]). A total of 62 healthy subjects were enrolled in the studies. DNA samples were extracted from all subjects, and genotypes of CYP3A5*3, CYP3A4*1 G, and POR*28 were analyzed by ligase detection reaction.</p><p><strong>Results: </strong>We used nonlinear mixed-effects model (NONMEM) to construct furaprevir population pharmacokinetics model. (1) In SAD, C_max and area under the curve (AUC) were greater than dose increased ratio in the dose rang of 100-400 mg; (2) In MAD, C_max and AUC increased in an approximately dose-proportional manner in the dose range of 200-600 mg; (3) A one-compartment model with transit absorption described the plasma concentrations of furaprevir. The apparent clearance was estimated at 33.4 L/h. The distribution volume of compartment (V2) was 219.0 L. No serious adverse event occurred in the studies. But other screening gene mutations had no statistically significant effects on the pharmacokinetics of furaprevir.</p><p><strong>Conclusion: </strong>Food significantly impacts the bioavailability of furaprevir. Furaprevir does not accumulate in vivo after multiple rising doses and has demonstrated safety and tolerability in healthy subjects, supporting its further investigation in patients with hepatitis C.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"193-206"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation of Sodium Butyrate's Potential to Reduce Alcohol Consumption: A Dose-Escalation Study in C57BL/6J Mice in Antibiotic-Enhanced Binge-Like Drinking Model.","authors":"Gregory C Havton, Alex T C Tai, Surabhi Vasisht, Daryl L Davies, Liana Asatryan","doi":"10.1159/000540882","DOIUrl":"10.1159/000540882","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;In our earlier efforts to establish gut-brain axis during alcohol use disorder (AUD), we have demonstrated that supplementation of C57BL/6J male mice with 8 mg/mL sodium butyrate, a major short-chain fatty acid, in drinking water reduced ethanol intake and neuroinflammatory response in antibiotic (ABX)-enhanced voluntary binge-like alcohol consumption model, drinking in the dark (DID).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To further evaluate the preclinical potential of SB, we have set a dose-escalation study in C57BL/6J male mice to test effects of ad libitum 20 mg/mL SB and 50 mg/mL SB and their combinations with ABX in the DID procedure for 4 weeks. Effects of these SB concentrations on ethanol consumption and bodily parameters were determined for the duration of the treatments. At the end of study, blood, liver, and intestinal tissues were collected to study any potential adverse effects ad to measure blood ethanol concentrations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Increasing SB concentrations in the drinking water caused a loss in the protective effect against ethanol consumption and produced adverse effects on body and liver weights, reduced overall liquid intake. The hypothesis that these effects were due to aversion to SB smell/taste at these high concentrations were further tested in a follow up proof-of-concept study with intragastric gavage administration of SB. The higher gavage dose (320 mg/kg) caused reduction in ethanol consumption without any adverse effects.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Overall, these findings added more support for the therapeutic potential of SB in management of AUD, given a proper form of administration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;In our earlier efforts to establish gut-brain axis during alcohol use disorder (AUD), we have demonstrated that supplementation of C57BL/6J male mice with 8 mg/mL sodium butyrate, a major short-chain fatty acid, in drinking water reduced ethanol intake and neuroinflammatory response in antibiotic (ABX)-enhanced voluntary binge-like alcohol consumption model, drinking in the dark (DID).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To further evaluate the preclinical potential of SB, we have set a dose-escalation study in C57BL/6J male mice to test effects of ad libitum 20 mg/mL SB and 50 mg/mL SB and their combinations with ABX in the DID procedure for 4 weeks. Effects of these SB concentrations on ethanol consumption and bodily parameters were determined for the duration of the treatments. At the end of study, blood, liver, and intestinal tissues were collected to study any potential adverse effects ad to measure blood ethanol concentrations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Increasing SB concentrations in the drinking water caused a loss in the protective effect against ethanol consumption and produced adverse effects on body and liver weights, reduced overall liquid intake. The hypothesis that these effects were due to aversion to SB smell/taste at these","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"36-48"},"PeriodicalIF":2.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide Ameliorates Hepatocyte Steatosis in a Cell Co-Culture System by Downregulating the IRE1α-XBP1-C/EBPα Signaling Pathway in Macrophages.","authors":"Qin Hu, Li Zhang, YiTing Tao, ShuangLin Xie, AiYun Wang, Caiying Luo, RenHua Yang, Zhiqiang Shen, Bo He, Yu Fang, Peng Chen","doi":"10.1159/000540654","DOIUrl":"10.1159/000540654","url":null,"abstract":"<p><strong>Introduction: </strong>Non-alcoholic fatty liver disease (NAFLD) is currently the most common type of chronic liver disease. Semaglutide is a glucose-lowering drug administered for the treatment of type 2 diabetes mellitus (T2DM) and is clinically effective in the treatment of NAFLD. X-box binding protein 1 (XBP1) is related to the pathogenesis of both NAFLD and T2DM. The aim of the present study was to demonstrate whether the underlying mechanism of semaglutide treatment for NAFLD is via downregulation of the inositol-requiring transmembrane kinase/endonuclease-1α (IRE1α)-XBP1-CCAAT/enhancer binding protein α (C/EBPα) signaling pathway in macrophages.</p><p><strong>Methods: </strong>In the present study, NAFLD cell modeling was induced by oleic acid (0.4 m<sc>m</sc>) and palmitic acid (0.2 m<sc>m</sc>). Hepatocytes (AML12) and macrophages (RAW264.7) were co-cultured in 6-well Transwell plates. Semaglutide (60 or 140 n<sc>m</sc>) was administrated for 24 h, while pioglitazone (2 μ<sc>m</sc>) and toyocamycin (200 n<sc>m</sc>) were used as a positive control drug and a XBP1 inhibitor, respectively. Autophagy and apoptosis of AML12 cells were detected by transmission electron microscopy and Western blotting (WB). Hepatocyte steatosis was evaluated by adopting total intracellular triglyceride determination, analysis of the relative expression of proteins and genes associated with lipid metabolism and hepatocyte Oil red O staining. Detection of inflammation factors was conducted by ELISA and WB. To explore the underlying mechanism of NAFLD treatment with semaglutide, the relative expression of related proteins and genes were tested.</p><p><strong>Results: </strong>Our study demonstrated that semaglutide treatment improved autophagy and inhibited apoptosis of hepatocytes, while notably ameliorating steatosis of hepatocytes. In addition, inflammation was attenuated in the NAFLD cell co-culture model after semaglutide administration. Semaglutide also significantly reduced the protein and gene expression levels of the IRE1α-XBP1-C/EBPα signaling pathway in macrophages.</p><p><strong>Conclusion: </strong>Semaglutide partially ameliorated NAFLD by downregulating the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. These findings may provide a potential theoretical basis for semaglutide therapy for NAFLD.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"26-35"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Statement.","authors":"","doi":"10.1159/000545109","DOIUrl":"10.1159/000545109","url":null,"abstract":"","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"192"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<italic>Ginkgo biloba</italic> Extract Improved Paraquat-Induced Pulmonary Fibrosis via Inhibiting p38 MAPK Pathway.","authors":"Yan Luo, Minxuan Peng, Genlin Liu, Ting Sun, Xiaoyan He, Yan Luo","doi":"10.1159/000545929","DOIUrl":"10.1159/000545929","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to reveal the potential mechanism of Ginkgo biloba extract (GBE) in alleviating pulmonary fibrosis.</p><p><strong>Methods: </strong>We examined cell viability, PTEN-induced putative kinase 1 (PINK1), Parkin, and microtubule-associated protein 1 light chain 3 (LC3) II/I ratio in paraquat (PQ)-stimulated rat alveolar epithelial type II cells (RLE-6TN) receiving GBE treatment. LC3 enrichment in mitochondria was detecting the immunofluorescence co-staining of LC3 and TOMM20. Then, epithelial-mesenchymal transition (EMT) was evaluated by α smooth muscle actin (α-SMA) and E-cadherin using immunofluorescence. Also, p-p38 and p38 were measured to evaluate p38 mitogen-activated protein kinase (MAPK) pathway using Western blot. SB203580 was used to inhibiting p38 in RLE-6TN cells. The changes in histopathological alteration, α-SMA, E-cadherin, PINK1, Parkin, LC3 II/I ratio, and collagen deposition were also investigated in rats with PQ stimulation and GBE treatment.</p><p><strong>Results: </strong>PQ caused the decrease in cell viability and E-cadherin, and the increase in LC3 enrichment, α-SMA, PINK1, Parkin, and LC3 II/I ratio (p < 0.05). p-p38 was increased after PQ stimulation (p < 0.05). In PQ-stimulated RLE-6TN cells, GBE elevated cell viability and E-cadherin and reduced LC3 enrichment, α-SMA, PINK1, Parkin, LC3 II/I ratio, and p-p38 (p < 0.05). Both of GBE and SB203580 significantly reversed PQ-induced changes abovementioned in cells. Rats with PQ stimulation developed the increase in hydroxyproline activity, α-SMA, p-p38, PINK1, Parkin LC3 II/I ratio, and the decrease in E-cadherin (p < 0.05). GBE significantly reversed PQ-induced changes abovementioned in rats. GBE mitigated inflammatory infiltrates, alveolar wall thickening, and collagen deposition in rats undergoing PQ stimulation.</p><p><strong>Conclusion: </strong>GBE significantly inhibited EMT and mitophagy in alveolar epithelial type II cells exposed to PQ via suppressing p38 MAPK pathway.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"290-300"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Characterization of GB1908, a Selective Galectin-1 Carbohydrate Binding Domain Inhibitor for the Treatment of Cancer.","authors":"Kimberly D Herman, Ian Holyer, Duncan C Humphries, James A Roper, Kristoffer Peterson, Fredrik R Zetterberg, Anders Pedersen, Alison C MacKinnon, Robert J Slack, Robert Slack","doi":"10.1159/000543234","DOIUrl":"10.1159/000543234","url":null,"abstract":"<p><strong>Introduction: </strong>Galectin-1 (Gal-1) is a lectin that has been shown to be involved in a number of pro-tumorigenic mechanisms and has also been shown to be immune-suppressive. Therefore, pharmacological blockade of Gal-1 has the potential to be therapeutically beneficial in cancers that overexpress this lectin where it is hypothesized to be driving cancer progression.</p><p><strong>Methods: </strong>GB1908 is a novel, selective and high affinity inhibitor of the Gal-1 carbohydrate recognition domain and in this study, we have pharmacologically characterized this small molecule in a range of in vitro and in vivo systems in the context of cancer therapy. In addition, we used a data-driven approach to identify the cancer types which may benefit from Gal-1 inhibitor therapy.</p><p><strong>Results: </strong>The selectivity of GB1908 for Gal-1 compared with galectin-3 (Gal-3) was confirmed in biophysical and cellular assays. GB1908 attenuated Gal-1-induced T cell (Jurkat) apoptosis and reduced the production of immunosuppressive cytokines in a stromal non-small cell lung cancer tumor microenvironment model. Breast carcinoma and metastatic skin cutaneous melanoma were identified as cancers in which high Gal-1 expression correlated with poorer survival outcomes in patients. Treatment with GB1908 slowed tumor growth in syngeneic mouse models of these cancers.</p><p><strong>Conclusion: </strong>The inhibition of both tumor growth and immune-suppressive cytokines, in cancers in which high Gal-1 is associated with poorer survival outcomes, suggests a potential therapeutic benefit for Gal-1 inhibitors such as GB1908.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"207-220"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}