Pharmacology最新文献

{"title":"Nephroprotective Effects of Curcumin in Murine Models of Focal and Segmental Glomerulosclerosis.","authors":"Sufia Husain, Nervana Mustafa Kamal Bayoumy, Fatima Noor, Hanan Hagar","doi":"10.1159/000543293","DOIUrl":"10.1159/000543293","url":null,"abstract":"<p><strong>Introduction: </strong>This study aims to explore the reno-protective effect of curcumin in focal and segmental glomerulosclerosis (FSGS) in murine models, a common chronic glomerulopathy that leads to end-stage renal disease.</p><p><strong>Methods: </strong>Adult Wistar rats were used in this experiment. One group was treated with intravenous Adriamycin (ADR) injection to induce FSGS similar to that seen in humans and a second group was co-administered ADR and curcumin (ADR-CUR). Saline-treated rats served as controls. Renal injury was assessed by measuring the levels of serum creatinine, blood urea nitrogen (BUN), triglyceride, and urinary protein. The homogenates of renal cortex were used to estimate the renal content of the inflammatory marker tumor necrosis factor-a (TNF-a); oxidative stress marker malonaldehyde (MDA); and two antioxidants superoxide dismutase (SOD) and reduced glutathione (GSH). In addition, the rat kidneys were harvested by ends of week 8 and week 12 and examined for histological abnormalities.</p><p><strong>Results: </strong>The ADR-treated rats showed biochemical and histological evidence of FSGS, in the form of proteinuria, elevated serum creatinine, BUN, and triglycerides, elevated renal TNF-a and MDA, and segmental glomerulosclerosis. The ADR-CUR-treated rats showed significant correction of all these variables. Co-administration with curcumin resulted in improvement of the proteinuria, serum creatinine, BUN, and triglyceride. The renal tissue levels of antioxidants SOD and GSH increased and that of TNF-a and MDA decreased and the histology revealed reduction in the extent of segmental glomerulosclerosis. The FSGS-associated renal damage was notably antagonized by curcumin treatment.</p><p><strong>Conclusion: </strong>Our findings confirm the reno-protective effects of curcumin as a potential therapeutic agent in protection against the progression of FSGS and indicate that it is mitigated by inhibition of oxidant injury and inflammation and also by promotion of antioxidants. Curcumin ameliorated the ADR-induced FSGS in murine models. It may be a promising compound in the treatment of FSGS in human subjects. More human studies are needed to further elucidate its effects in FSGS.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"1-10"},"PeriodicalIF":2.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142953662","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":"Drug-Drug Interactions in Hospitalized Urological Patients: A Retrospective Cohort Study.","authors":"Ivan R Milovanovic, Ana V Pejcic","doi":"10.1159/000540427","DOIUrl":"10.1159/000540427","url":null,"abstract":"<p><strong>Introduction: </strong>Exposure to potential drug-drug interactions (pDDIs) can be a notable source of avoidable drug-related harm that requires adequate management to prevent medical errors. We aimed to evaluate pDDIs and associated factors in hospitalized urological patients on admission, during hospitalization, and on discharge.</p><p><strong>Methods: </strong>A retrospective cohort study was conducted at the Clinic of Urology of the University Clinical Centre Kragujevac, Serbia. To detect pDDIs, we used Lexicomp, which categorizes pDDIs as follows: X (avoid combination), D (consider therapy modification), C (monitor therapy), B (no action needed), and A (no known interaction). Multiple linear regression analysis was used to identify factors associated with the number of pDDIs.</p><p><strong>Results: </strong>More than half of the 220 included patients had at least one pDDI on admission and discharge (57.3% and 63.6%, respectively), whereas 95.0% had at least one pDDI during hospitalization. The total number and number of X, D, C, and B categories of pDDIs were the highest during hospitalization and the lowest on admission. Duration of hospitalization, arrhythmias, dementia, renal failure, cancer, surgery during hospitalization, number of prescribed drugs, and various pharmacological drug classes were risk factors for a higher number of pDDIs, while age, ischemic heart disease, hypertension, and development of infection during hospitalization were protective factors in at least one of the stages. The impact of renal colic depended on the stage and category of pDDI.</p><p><strong>Conclusion: </strong>More than half of the urological patients were exposed to at least one pDDIs at all stages. Medical professionals should regularly screen for pDDIs, particularly in patients with risk factors.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"15-25"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856287","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":"Population Pharmacokinetic of Vancomycin Administered by Continuous Infusion in Critically Ill Patients.","authors":"Haifa Ben Romdhane, Jean Baptiste Woillard, Najah Ben Fadhel, Zohra Chadli, Amel Chaabane, Naceur Boughattas, Nadia Ben Fredj, Karim Aouam","doi":"10.1159/000539866","DOIUrl":"10.1159/000539866","url":null,"abstract":"<p><strong>Introduction: </strong>Administration of vancomycin dose by continuous infusion (CI) according to population pharmacokinetic (Pop Pk) models is highly recommended in critically ill patients who exhibit pathophysiological changes.</p><p><strong>Objective: </strong>The objective of this study was to develop and validate a Pop Pk model of vancomycin administered by CI in critically ill patients with normal and impaired renal functions.</p><p><strong>Methods: </strong>The Pop Pk study was performed using a nonparametric approach (Pmetrics*). The influence of covariates (gender, age, weight, height, and creatinine clearance [Cr-Cl]) was tested on the model's Pk parameters. The performance of the final model was assessed using an external dataset.</p><p><strong>Results: </strong>A one-compartment model (volume of distribution [Vd], elimination from compartment [Ke]) was found to show a good prediction performance. The influence of covariates has shown that age and Cr-Cl affected significantly Vd and Ke, respectively. The distribution of simulated vancomycin clearance (CLv) according to different renal function levels showed a negative correlation between CLv and the severity of the renal impairment. The internal validation of the final model showed that the plot of individual-predicted concentration versus observed concentration resulted in r2 = 0.86 in the final model. The external validation of the final model showed an acceptable predictive performance.</p><p><strong>Conclusion: </strong>We developed a Pop Pk model for vancomycin administered by CI in critically ill patients. A significant impact of Cr-Cl and different stages of renal failure on CLv has been demonstrated. The establishment of an individualized proposal dose based on this model may be helpful to achieve the target range which is critical in optimizing the efficacy and safety of this antibiotic.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"65-76"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000564","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":"Non-Coding RNA Networks in Pulmonary Arterial Hypertension.","authors":"Bing Chen, Yu Xia, Yanjiao Jiang, Zengxian Sun, Yanyan Zhang, Yun Liu","doi":"10.1159/000541060","DOIUrl":"10.1159/000541060","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary artery hypertension (PAH) is a severe cardiovascular disease marked by a persistent increase in pulmonary artery resistance and pressure, leading to right ventricular strain, hypertrophy, and eventually right heart failure and death. Despite numerous available targeted therapies, the clinical needs for treating PAH remain unmet. Current treatments primarily aim to dilate pulmonary vessels rather than reverse pulmonary vascular remodeling, failing to offer a fundamental solution for PAH. Therefore, developing new therapies for this condition is urgently required.</p><p><strong>Summary: </strong>Recent research has highlighted the crucial role of non-coding RNAs (ncRNAs) in the occurrence and development of PAH. NcRNAs, such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and PIWI-interacting RNAs (piRNAs), are a class of transcripts that do not translate proteins but affect various diseases at different levels, including chromatin modification, transcription regulation, post-translational processes.</p><p><strong>Key message: </strong>The current study delves into recent advancements in understanding how lncRNAs, circRNAs, miRNAs, and piRNAs contribute to the pathogenesis of PAH. This review addresses the existing research challenges and explores the potential of ncRNAs as both biomarkers and therapeutic targets, suggesting that ncRNAs may serve as valuable indicators and treatment options for the disease.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"110-121"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352535","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":"Additive Inhibition of HERG Channels Expressed in Xenopus Oocytes by Antipsychotic Drugs and Citrus Juice Flavonoid Naringenin.","authors":"Keun-Hang Susan Yang, Dmytro Isaev, Murat Oz","doi":"10.1159/000541005","DOIUrl":"10.1159/000541005","url":null,"abstract":"<p><strong>Introduction: </strong>Citrus juice has been shown to cause QT prolongation in electrocardiograms of healthy volunteers, and naringenin, a major flavonoid found in citrus juice, has been identified as the potent inhibitor of human ether-a-go-go-related gene (HERG) channels as the cause of QT prolongation. Inhibition of HERG channels and prolongation of QT interval by antipsychotic drugs such as haloperidol, chlorpromazine, and clozapine have also been shown. However, naringenin's effect on HERG channel function in conjunction with antipsychotic medications has not been investigated.</p><p><strong>Methods: </strong>In the present study, we evaluated the effect of combining naringenin with antipsychotics on the function of HERG channels expressed in Xenopus oocytes.</p><p><strong>Results: </strong>When 30 µ<sc>m</sc> naringenin was added to antipsychotic drugs (1 µ<sc>m</sc> haloperidol, 10 µ<sc>m</sc> chlorpromazine, or 10 µ<sc>m</sc> clozapine), significantly greater HERG inhibition was demonstrated, compared to the inhibition caused by antipsychotic drugs alone. Co-application studies also showed that the magnitudes of inhibitions caused by naringenin + antipsychotics were similar to that predicted by the allotopic interaction model, suggesting that naringenin and antipsychotics bind to the HERG channel at different sites.</p><p><strong>Conclusion: </strong>The results suggest that there is an additive interaction between antipsychotics and naringenin. Due to the potential for repolarization heterogeneity and a decrease in repolarization reserve, this additive HERG inhibition may increase the risk of arrhythmias.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"122-126"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352534","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":"10.1159/000542299","DOIUrl":"10.1159/000542299","url":null,"abstract":"","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"62"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605999","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":"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":"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":"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":2.9,"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}