Frontiers in Pharmacology最新文献

{"title":"Case Report: Posterior reversible encephalopathy syndrome after lenvatinib treatment for hepatocellular carcinoma.","authors":"Minchun Chen, Jing Shen, Rongrong Jia, Mingze Chang, Jingyi Zhang, Jie Zheng, Runqing Xue, Lulu Guo, Kangkang Yan","doi":"10.3389/fphar.2025.1487009","DOIUrl":"10.3389/fphar.2025.1487009","url":null,"abstract":"<p><strong>Background: </strong>Posterior reversible encephalopathy syndrome (PRES) is characterized by headaches, vision loss, confusion, encephalopathy, seizures, and reversible focal edema on neuroimaging. Early recognition and treatment of PRES are essential to prevent severe complications. Lenvatinib is a multi-targeted kinase inhibitor that is used as a first-line treatment for patients with hepatocellular carcinoma (HCC). Lenvatinib-induced PRES is a less commonly recognized side effect.</p><p><strong>Case presentation: </strong>A 72-year-old female patient with HCC, who had no history of hypertension, received lenvatinib therapy. The patient exhibited symptoms such as confusion, altered mental status, headaches, and severe hypertension during treatment. Neuroimaging revealed characteristic findings of vasogenic edema in the white matter of the brain. The patient's neurological symptoms gradually improved after lenvatinib discontinuation, and follow-up imaging showed a reduction in the white matter abnormalities.</p><p><strong>Conclusion: </strong>The underlying mechanisms of PRES induced by lenvatinib remain unclear, but hypertension is considered a crucial factor in its pathogenesis. This case report adds to the understanding of the potential adverse effects associated with lenvatinib in patients with HCC, emphasizing the need for vigilance in monitoring and managing such complications to ensure the safety and wellbeing of patients undergoing this treatment.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1487009"},"PeriodicalIF":4.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crocin promotes ferroptosis in gastric cancer via the Nrf2/GGTLC2 pathway.","authors":"Nan Yan, Gaofu Li, Linglin Zhao, Qijing Guo, Jie Yang, Jianhong Liu, Wei Zhou, Yue Gao, Yushuang Luo","doi":"10.3389/fphar.2025.1527481","DOIUrl":"10.3389/fphar.2025.1527481","url":null,"abstract":"<p><p><b>Introduction:</b> Gastric cancer (GC) is characterized by high incidence and poor survival rates. Crocin, a natural carotenoid from saffron, exhibits antioxidant, anti-inflammatory, and anti-tumor properties. Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, plays a critical role in cancer progression and is a potential therapeutic target. This study investigates whether crocin inhibits GC cell proliferation by inducing ferroptosis and explores its underlying mechanisms. <b>Methods:</b> This study employed in vivo and in vitro models to assess crocin's effects on GC cell proliferation, apoptosis, migration, invasion, and ferroptosis. Pathway enrichment analysis was performed on differentially expressed genes post-crocin treatment. Lentiviral vectors were used to knockdown and overexpress GGTLC2, exploring its role in GC progression and crocin's therapeutic effects. The UCSC and JASPAR databases predicted Nrf2 binding sites in the GGTLC2 promoter. Molecular docking evaluated crocin's affinity for Nrf2 and GGTLC2. Immunofluorescence and nuclear-cytoplasmic fractionation assays analyzed Nrf2 expression and localization. ChIP-qPCR determined Nrf2's regulatory role on GGTLC2 and crocin's modulatory effects. <b>Results:</b> The results demonstrated that crocin significantly inhibited the proliferation, migration, and invasion of GC cells while promoting apoptosis. Differentially expressed genes following crocin treatment were predominantly enriched in pathways associated with oxidative stress and ferroptosis. Crocin downregulated the oncogene GGTLC2, thereby suppressing GC cell proliferation, invasion, and migration, while simultaneously promoting apoptosis and ferroptosis. Molecular docking analysis revealed a stable binding affinity between crocin and GGTLC2, suggesting that crocin may directly target GGTLC2 to modulate its expression. Additionally, crocin facilitated the translocation of Nrf2 from the nucleus to the cytoplasm. ChIP-qPCR results confirmed that Nrf2 directly binds to the GGTLC2 promoter region to regulate its expression, and crocin attenuated this binding interaction. <b>Discussion:</b> In conclusion, our findings suggest that crocin, as a promising natural compound for GC therapy, may inhibit ferroptosis in GC cells through the Nrf2/GGTLC2 signaling pathway, thereby suppressing tumor initiation and progression. This study provides novel insights into the molecular mechanisms underlying the anti-tumor effects of crocin and highlights its potential as a therapeutic agent for GC.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1527481"},"PeriodicalIF":4.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Takeda G protein-coupled receptor 5 (TGR5): an attractive therapeutic target for aging-related cardiovascular diseases.","authors":"Yufeng He, Siqi Liu, Yali Zhang, Yumei Zuo, Keming Huang, Li Deng, Bin Liao, Yi Zhong, Jian Feng","doi":"10.3389/fphar.2025.1493662","DOIUrl":"10.3389/fphar.2025.1493662","url":null,"abstract":"<p><p>Aging is an independent risk factor for many chronic diseases, including cancer and cardiovascular, pulmonary, and neurodegenerative diseases. In recent years, the mechanisms of aging-related cardiovascular diseases (CVDs) have been studied intensively. Takeda G protein-coupled receptor 5 (TGR5) is a membrane receptor for bile acids that has been found to play an important role in various disease processes, such as inflammation, oxidative stress, and metabolic disorders, all of which contribute to aging-related CVDs. In this review, we summarise the role of TGR5 in aging-related CVDs and propose TGR5 as an attractive therapeutic target based on its mechanism of involvement, which may contribute to future drug target design.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1493662"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum: Astragalus-Scorpion drug pair inhibits the development of prostate cancer by regulating GDPD4-2/PI3K/AKT/mTOR pathway and autophagy.","authors":"Xujun You, Yongrong Wu, Qixin Li, Wen Sheng, Qing Zhou, Wei Fu","doi":"10.3389/fphar.2025.1417603","DOIUrl":"https://doi.org/10.3389/fphar.2025.1417603","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fphar.2022.895696.].</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1417603"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MEPED as salvage therapy for relapsed/refractory Hodgkin's lymphoma incorporating edited non-oncogene addiction: mTOR as a bottleneck.","authors":"Dennis Christoph Harrer, Florian Lüke, Tobias Pukrop, Lina Ghibelli, Albrecht Reichle, Daniel Heudobler","doi":"10.3389/fphar.2025.1553331","DOIUrl":"10.3389/fphar.2025.1553331","url":null,"abstract":"<p><p>Rescue therapies of relapsed/refractory (r/r) Hodgkin's lymphoma (HL) in the third to sixth-line provide major, yet unresolved problems. The MEPED regimen includes nuclear receptor agonists such as pioglitazone and dexamethasone, which counterbalance HL homeostasis, HL stress response inhibitors, everolimus and COX-2 inhibitor, and a stress response inducer, low-dose metronomic treosulfan. CR (six of seven patients) and long-term cCR in patients receiving no consolidating allogeneic stem cell transplantation highlight MEPED as a potent salvage therapy in advanced refractory HL. MEPED edits everolimus activities in such a way that mTORC1 becomes a non-oncogene addiction bottleneck, hence determining long-term therapy outcome. The implications of the therapeutic paradigm shift toward editing of HL tissue, and particularly mTOR addiction, could prove to be profound for clinical practice, both in terms of outcome and treatment tolerability. The long-term results of MEPED treatment indicate the urgent evaluation of the schedule in a multicenter trial for r/r HL.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1553331"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells.","authors":"Stefania Braidotti, Rosalba Monica Ferraro, Raffaella Franca, Elena Genova, Francesco Giambuzzi, Andrea Mancini, Valentina Marinozzi, Letizia Pugnetti, Giulia Zudeh, Alessandra Tesser, Alberto Tommasini, Giuliana Decorti, Silvia Clara Giliani, Gabriele Stocco","doi":"10.3389/fphar.2025.1549183","DOIUrl":"10.3389/fphar.2025.1549183","url":null,"abstract":"<p><p>Aicardi-Goutières syndrome (AGS) is a rare genetic disorder classified among type I interferonopathies. Current pharmacological management of AGS is symptomatic and supportive, with recent clinical applications of JAK inhibitors (JAKi) and antiretroviral therapies (RTIs). To investigate the effects of these therapies, patient-specific induced pluripotent stem cells (iPSCs) were generated by reprogramming fibroblasts from three AGS patients with distinct genetic mutations (AGS1, AGS2, AGS7) and differentiated into neural stem cells (NSCs). iPSCs and NSCs derived from commercial BJ fibroblasts of a healthy donor served as control. The cytotoxic effects of glucocorticoids, thiopurines, JAK inhibitors (ruxolitinib, baricitinib, tofacitinib, pacritinib), and RTIs (abacavir, lamivudine, zidovudine) were evaluated using the MTT assay. Results showed that glucocorticoids did not compromise NSC viability. Among thiopurines, thioguanine, but not mercaptopurine, exhibited cytotoxicity in NSCs. All tested JAK inhibitors, except pacritinib, were non-toxic to iPSCs and NSCs. Interestingly, high concentrations of certain JAK inhibitors (ruxolitinib, baricitinib, tofacitinib) led to an unexpected increase in cell viability in AGS patient-derived cells compared to control, suggesting potential alterations in cell proliferation or stress responses. RTIs demonstrated no cytotoxicity, except for zidovudine, which showed selective toxicity in AGS2-derived iPSCs compared to controls. These findings suggest that glucocorticoids, JAK inhibitors (excluding pacritinib), and RTIs are likely safe for NSCs of AGS patients, while caution is warranted with thioguanine and pacritinib. Further studies are needed to explore the mechanisms underlying increased cell viability at high JAK inhibitor concentrations and the selective sensitivity to zidovudine.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1549183"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Chinese herbal medicine on colorectal adenoma recurrence following polypectomy: a systematic review and meta-analysis.","authors":"Yi Cheng, Yuan Ming Di, Brian May, Anthony Lin Zhang, Charlie Changli Xue, Beiping Zhang","doi":"10.3389/fphar.2025.1460900","DOIUrl":"10.3389/fphar.2025.1460900","url":null,"abstract":"<p><strong>Objective: </strong>Preventing colorectal adenoma (CRA) recurrence after polypectomy is essential. However, the current evidence of Chinese herbal medicine (CHM) for CRA recurrence is still limited. This study aims to synthesize the effects of CHM as a prevention method for CRA recurrence.</p><p><strong>Methods: </strong>Nine databases were searched up to May 2024. Randomised controlled trials identifying the preventive effects of CHM among people with CRA post-polypectomy were included. spreadsheets were used to collect and extract data. RevMan and STATA were used for data analysis. We performed subgroup and sensitivity analyses to explore potentially influencing variables.</p><p><strong>Results: </strong>Twenty trials (2,325 participants) were included. The commonly used botanical drugs belonged to the categories of strengthening the spleen and anti-tumour metabolites. Compared to routine care (RC) alone, oral CHM plus RC significantly reduced the CRA recurrence rate at 12 months (RR 0.51, 95% CI [0.39, 0.67], I² = 42%), 6 months (RR 0.44, 95% CI [0.36, 0.55], I² = 0%), and 3 months (RR 0.46, 95% CI [0.22, 0.96], I² = 0%) post-polypectomy. Compared to CHM placebo plus RC, <i>San zi</i> granule combined with RC significantly reduced CRA recurrence at 12 months post-polypectomy (RR 0.39, 95% CI [0.16, 0.93], I² = 0%) and during the 2-year follow-up (RR 0.73, 95% CI [0.58, 0.90]). There were no significant differences between groups for treatment duration and syndromes. Additional analysis showed that oral CHM containing the botanical drugs of <i>Si jun zi</i> decoction plus RC reduced CRA recurrence at 12 months post-polypectomy with a low heterogeneity, compared to RC alone (RR 0.26, 95% CI [0.13, 0.54], I² = 0%). Adverse events were similar in the above two comparisons.</p><p><strong>Conclusion: </strong>Oral CHM combined with RC may reduce CRA recurrence and be well-tolerated. <i>San zi</i> granule and <i>Si jun zi</i> decoction may be representative prescriptions Experimental studies of the frequent botanical drugs have found anti-cancer effects that may account for the clinical findings. Future rigorous clinical trials are needed due to low-to-moderate certainty of evidence.</p><p><strong>Systematic review registration: </strong>PROSPERO (CRD42023324197), https://www.crd.york.ac.uk/PROSPERO/view/CRD42023324197.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1460900"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation and platelet hyperresponsiveness in coronary artery disease and the influence of Talin-1/αIIbβ3-mediated bidirectional signaling pathway.","authors":"Shengnan Shi, Jiaming Gao, Yehao Zhang, Min Zhan, Zhanfei Tan, Peili Wang, Jianhua Fu, Jianxun Liu","doi":"10.3389/fphar.2025.1535182","DOIUrl":"10.3389/fphar.2025.1535182","url":null,"abstract":"<p><strong>Background: </strong>While platelet hyperreactivity constitutes an independent risk factor for major adverse cardiovascular events (MACEs) in coronary artery disease, its molecular underpinnings remain poorly characterized. Recent advances in transcriptomic profiling have revealed potential associations with specific RNA signatures. Through systematic bioinformatics analysis of differential gene expression patterns and pathway activation in CHD patients, this study aims to elucidate key molecular regulators of platelet hyperactivity, establishing a theoretical framework for developing precision therapeutic strategies to mitigate post-CHD complications.</p><p><strong>Methods: </strong>This randomized controlled study included 16 CHD patients and 16 healthy controls. Inflammation markers, platelet aggregation function, and CD62p levels were assessed using flow cytometry. Mitochondrial morphology and organelles were observed using scanning electron microscopy and transmission electron microscopy. Genes related to symptom alteration between CHD patients and healthy controls were identified using the criteria of p < 0.05. The molecular correlations of these genes were analyzed using a comprehensive perspective that included Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Western blot and correlation analyses were also conducted to validate the expression and diagnostic value of the DEGs.</p><p><strong>Results: </strong>CHD patients exhibited alterations in platelet organelles ultrastructure, heightened platelet activation and aggregation, and disturbance of the inflammatory equilibrium. RNA sequencing demonstrated distinct changes in the gene expression profiles of circulating platelets from CHD patients. The increase in platelet activation and aggregation could be partially associated with the upregulation of the Talin-1 and αIIbβ3 proteins expression.</p><p><strong>Conclusion: </strong>Abnormal transcription and platelet activation occur after CHD onset, and upregulation of the Talin-1/αIIbβ3-mediated bidirectional signaling pathway are the primary pathological features.</p><p><strong>Clinical trial registration: </strong>https://www.chictr.org.cn/, identifier ChiCTR2100041998.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1535182"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The efficacy of polymyxin B in treating stroke-associated pneumonia with carbapenem-resistant Gram-negative bacteria infections: a multicenter real-world study using propensity score matching.","authors":"Hai-Hui Zhuang, Qi-Hua Chen, Wei Wang, Qiang Qu, Wei-Xin Xu, Qin Hu, Xiao-Li Wu, Ying Chen, Qing Wan, Tian-Tian Xu, Wen-Ming Long, Yue Luo, Hai-Nan Zhang, Jian Qu","doi":"10.3389/fphar.2025.1413563","DOIUrl":"10.3389/fphar.2025.1413563","url":null,"abstract":"<p><strong>Objectives: </strong>Infection with Carbapenem-resistant Gram-negative bacteria (CR-GNB) poses further challenges in treating stroke-associated pneumonia (SAP) patients. This multicenter retrospective study aimed to evaluate the efficacy of polymyxin B (PMB) in CR-GNB-infected SAP patients and to identify factors that may influence its effectiveness.</p><p><strong>Methods: </strong>From 1 September 2019, and 30 December 2022, a total of 196 CR-GNB-infected SAP patients from five hospitals in China were included in the study based on specific criteria. Demographics and clinical data were obtained from the electronic medical records. Propensity score matching (PSM) was used to minimize the effect of potential confounding variables. Univariate analysis and multivariate logistic analysis were performed to identify risk factors affecting microbial efficacy.</p><p><strong>Results: </strong>Among the 196 SAP patients infected with CR-GNB, 24.5% received PMB combined inhalation and 75.5% received non-combined inhalation treatment. The clinical success rate was 68.9%, with 25.5% achieving microbial efficacy within 7 days and 37.8% achieving microbial cure. The 30-day all-cause mortality rate was 14.8%. The incidence of acute kidney injury was 34.7%. After adjustment by propensity score matching, the PMB combined inhalation group exhibited significantly higher microbial efficacy compared to the non-combined inhalation group (46.7% vs. 26.7%, p = 0.049). Multivariate logistic analysis identified multi-site infections and Carbapenem-resistant <i>Pseudomonas aeruginosa</i> infection as independent risk factors for microbial efficacy.</p><p><strong>Conclusion: </strong>Combined inhalation of PMB demonstrated superior effectiveness in microbial clearance compared to non-combined inhalation in treating CR-GNB-infected SAP patients. We recommend aerosol combined inhalation of PMB and suggest developing personalized PMB-based regimens for individual patients to enhance treatment outcomes.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1413563"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interaction between a leflunomide-response methylation site (cg17330251) and variant (rs705379) on response to leflunomide in patients with rheumatoid arthritis.","authors":"Feng Zhao, Yulan Chen, Haina Liu, Lei Jin, Xin Feng, Bingbing Dai, Meng Chen, Qiao Wang, Yuxin Yao, Ruobing Liao, Junyi Zhao, Bingjia Qu, Ying Song, Lingyu Fu","doi":"10.3389/fphar.2025.1499723","DOIUrl":"10.3389/fphar.2025.1499723","url":null,"abstract":"<p><strong>Objectives: </strong>This research aims to reveal the mechanisms of the effect of the Paraoxonase 1 (<i>PON1</i>) gene on response to leflunomide (LEF) in rheumatoid arthritis (RA) patients, in terms of single nucleotide polymorphism (SNP), DNA methylation levels.</p><p><strong>Methods: </strong>A total of 240 RA patients enrolled were categorized into the good response group and the non-response group according to the difference in DAS28 scores between baseline and 6 months after LEF administration. The identified LEF-response cytosine-phosphate-guanines (CpGs) island (cg17330251) and its internal SNPs (rs705379, etc.) located at the <i>PON1</i> promoter were detected by Sanger sequencing and methyl target sequencing.</p><p><strong>Results: </strong>A total of 12 CpG sites at cg17330251 could be identified in our RA patients. There were significant difference between the responders and non-responders in nine CpG sites: cg17330251_2, cg17330251_3, cg17330251_4, cg17330251_6, cg17330251_7, cg17330251_8, cg17330251_9, cg17330251_10, cg17330251_12, [OR (95CI%) = 0.492 (0.250, 0.969), 0.478 (0.243, 0.940), 0.492 (0.250, 0.969), 0.461 (0.234, 0.907), 0.492 (0.250, 0.969), 0.437 (0.225, 0.849), 0.478 (0.243, 0.941), 0.421 (0.212, 0.836), 0.424 (0.213, 0.843), <i>P</i> < 0.05, respectively]. At all these nine CpG sites, the proportions of low methylation levels in the responders were higher than those in the non-responders (<i>P</i> < 0.05). In a dominant model, there was a significant difference in rs705379 wildtype CC and mutant genotypes (CT + TT) between the responders and non-responders (<i>P</i> < 0.05). The average methylation level of 12 CpG sites was lowest in rs705379-CC (median 0.229, IQR 0.195-0.287), then rs705379-CT (median 0.363, IQR 0.332-0.395), and rs705379-TT (median:0.531, IQR:0.496-0.557). The average methylation levels of 12 CpG sites were significantly negative correlated with ΔDAS28 (<i>r</i> = -0.13, <i>P</i> < 0.05). The Logistic regression indicated that combined effect of rs705379, DNA methylation of the <i>PON1</i> gene [OR (95CI%) = 1.277 [1.003, 1.626)], systemic inflammation index (SIRI) [OR (95CI%) = 1.079 (1.018, 1.143)] served as protective factors on response to LEF in RA patients.</p><p><strong>Conclusion: </strong>The RA patients with SNP-rs705379-CC, the low methylation level of <i>PON1</i>-cg17330251 and more SIRI would be susceptible of response to LEF and more suitable to choose LEF treatment.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1499723"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}