British Journal of Pharmacology最新文献

{"title":"Synthesis and evaluation of a novel inhibitor for the α5-GABA_A receptor in the treatment of peripheral neuralgia: Evidence from MD simulation and in vivo studies.","authors":"Yanming Chen, Jiaxu Zhou, Yue Tian, Xiangyu Zhang, Yiqiao Liu, Weiping Lyu, Dehua Lu, Jie Cai, Xia Li, Cheng Shi, Guogang Xing, Zhenming Liu","doi":"10.1111/bph.70150","DOIUrl":"https://doi.org/10.1111/bph.70150","url":null,"abstract":"<p><strong>Background and purpose: </strong>Peripheral neuropathic pain (PNP) remains challenging to treat, because of the limited efficacy of current therapies and their central nervous system side effects. Targeting the α5-GABA_A receptor (GABRA5) has shown potential in addressing the limitations of existing therapies. This study aimed to develop and evaluate SR-419, a novel GABRA5 inhibitor, for its potential therapeutic application in PNP.</p><p><strong>Experimental approach: </strong>SR-419 was synthesised via an optimised route and characterised using nuclear magnetic resonance (NMR). Molecular docking and molecular dynamics (MD) simulations were performed to predict its binding mode. Analgesic efficacy was assessed in rat models of post-herpetic neuralgia (PHN) and spared nerve injury (SNI). Mechanistic studies included cellular thermal shift assays (CETSA) and pharmacological validation using QH-II-66, a GABRA5-selective agonist.</p><p><strong>Key results: </strong>The results of NMR analysis confirmed that we had successfully developed a novel chemistry route to synthesise the target compound. SR-419 bound stably to GABRA5 in silico and showed high selectivity in vitro. CETSA confirmed direct engagement of SR-419 with intracellular GABRA5. SR-419 produced dose-dependent analgesia in vivo, without crossing the blood-brain barrier or causing sedation or motor impairment. Its analgesic effect was abolished by QH-II-66, confirming GABRA5 involvement. Toxicology studies revealed excellent safety in acute and chronic settings.</p><p><strong>Conclusions and implications: </strong>SR-419 is a peripherally acting GABRA5 inhibitor with potent analgesic efficacy and a favourable safety profile. Its target-specific mechanism suggests that it is a promising candidate for treating PNP and avoiding central side effects.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-elemene ameliorates metabolic dysfunction-associated steatohepatitis by targeting PPARα in experimental diet-induced models.","authors":"Yongqiang Xiong, Wu Luo, Jiaxi Ye, Yaqian Cui, Xiangsheng Zheng, Leiming Jin, Shuaijie Lou, Qianhui Zhang, Ao Wang, Yi Fang, Tianyang Jin, Mengsha Lin, Hui Dong, Guang Liang, Xiang Hu, Weiwei Zhu","doi":"10.1111/bph.70161","DOIUrl":"https://doi.org/10.1111/bph.70161","url":null,"abstract":"<p><strong>Background and purpose: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is an escalating global health concern with few effective pharmacological treatment options available. β-elemene (ELE) is a natural product derived from Curcuma Rhizoma, which has anti-tumour and anti-inflammatory effects. However, its efficacy and molecular mechanism in MASH have not been elucidated.</p><p><strong>Experimental approach: </strong>Two diet-induced MASH models were used to evaluate the therapeutic potential of ELE in vivo. Additionally, RNA sequencing, network pharmacological analysis, and target validation were performed to elucidate the underlying mechanisms.</p><p><strong>Key results: </strong>ELE markedly ameliorated lipid dysfunction and the inflammatory response in MASH mice and fatty acids-stimulated hepatocytes. RNA-sequencing analysis indicated that ELE exerted its therapeutic effects through activating the PPARα signalling pathway. Particularly, we found that ELE directly binds to PPARα protein, preventing its degradation via K48-linked polyubiquitination. Notably, the protective effects of ELE on MASH were abolished in the absence of PPARα.</p><p><strong>Conclusion and implications: </strong>Our studies reveal that ELE is a novel stabiliser of PPARα, effectively inhibiting its ubiquitin-mediated degradation in MASH. By preserving the PPARα signalling pathway, ELE enhances lipid homeostasis and relieves the inflammation. Therefore, ELE holds significant potential as a therapeutic candidate for the treatment of MASH.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Grifolic acid, a FFAR4 agonist, identified as a dual antagonist of voltage-gated sodium and Ca_V2.2 channels with potent antinociceptive effects.","authors":"Miao Zhao, Yuchen Jin, Jun Wu, Jimei Liu, Min Li, Jungui Dai, Haibo Yu","doi":"10.1111/bph.70165","DOIUrl":"https://doi.org/10.1111/bph.70165","url":null,"abstract":"<p><strong>Background and purpose: </strong>Chronic pain affects nearly 30% of the global population. Because of significant adverse effects of opioids, alternative therapies are urgently needed. In a drug discovery project, we identified grifolic acid (GA) as a potent Na_V1.7 antagonist. Here, we have evaluated its biophysical properties and efficacy in animal pain models.</p><p><strong>Experimental approach: </strong>A mechanistic investigation of GA was carried out on dorsal root ganglion (DRG) neurons, and various stable cell lines, using whole-cell patch clamp techniques. Site-directed mutagenesis and molecular docking analyses also were performed to identify the binding pocket of GA on Na_V1.7. The antinociceptive efficacy of GA was evaluated in inflammatory pain models.</p><p><strong>Key results: </strong>GA exhibited state-dependent blockade of Na_V1.7 channels and modulated channel gating kinetics. It suppressed native Na_V currents and action potential (AP) firing in DRG neurons. GA inhibited the increase in action potential firing frequency in DRG neurons induced by inflammatory mediators. Mutational and molecular docking studies revealed that GA and bupivacaine targeted anaesthetics binding sites, with their use-dependent properties almost abolished in the F1737A mutant. In formalin and CFA-induced inflammatory pain models in male mice, GA demonstrated analgesic effects comparable to, or exceeding, those of the indomethacin, lidocaine and carbamazepine. GA showed minimal effects on skeletal muscle function but exhibited an inhibitory effect on the Ca_V2.2 channel.</p><p><strong>Conclusions and implications: </strong>GA is a state-dependent sodium channel and Ca_V2.2 channel antagonist with potent analgesic effects. These findings support its potential as an antinociceptive agent in the treatment of chronic pain conditions.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPA1 ion channel activation context-dependently regulates gene expression in normal and psoriatic human skin.","authors":"Ágnes Kemény, Szabina Horváth, Júlia Szebényi, Péter Oláh, Viktória Németh, Péter Urbán, József Kun, Attila Gyenesei, Areej Jaber, Erika Pintér, Rolland Gyulai","doi":"10.1111/bph.70153","DOIUrl":"https://doi.org/10.1111/bph.70153","url":null,"abstract":"<p><strong>Background and purpose: </strong>Psoriasis is a chronic, relapsing, immune-mediated inflammatory skin disease. The transient receptor potential ankyrin 1 (TRPA1) ion channel plays a protective role in the formation of psoriasiform skin reactions. Here, we investigated the pharmacological activation and blockade of TRPA1 in human skin (patho)physiology.</p><p><strong>Experimental approach: </strong>Six-millimetre full-thickness biopsies were obtained from psoriatic lesional and non-lesional skin of four patients with psoriasis, and from normal skin of four healthy volunteers. Each biopsy was quartered: One segment was untreated, and the other three were cultured with vehicle (DMSO), TRPA1 agonist mustard oil (MO), or TRPA1 antagonist (HC030031), respectively. Global gene expression was measured by RNA sequencing, followed by differential expression and functional enrichment analyses, to identify TRPA1-modulated genes.</p><p><strong>Key results: </strong>Pre-evaluation of data with ordination assessment showed clear cluster formation according to treatments and condition of the skin. In healthy skin, TRPA1 activation down-regulated genes associated with interferon signalling, antimicrobial responses, and inflammation/oxidative stress. In lesional psoriatic skin, the genes of interleukin-4 (IL-4), IL-10 and IL-13 cytokine signalling-related proteins, circadian gene expression, and senescence-associated secretory phenotype (SASP) genes were down-regulated by MO treatment. Antagonist treatment did not cause significant gene expression changes, supporting the previous finding that basal TRPA1 activity is low in the skin. DMSO treatment in all three conditions increased expression of several inflammatory genes, which was normalised during data analysis.</p><p><strong>Conclusion and implications: </strong>Exploration of the interactions between TRPA1 and identified signalling pathways may open new opportunities to target psoriasis, alleviate disease symptoms and optimise therapies.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal control in biomedicine: photoswitchable peptides and foldamers","authors":"Eszter Erdei,&nbsp;Juan Toledo Marcos,&nbsp;Nikolett Varró,&nbsp;Kata Horváti,&nbsp;Bernadett Bacsa,&nbsp;István M. Mándity","doi":"10.1111/bph.70163","DOIUrl":"10.1111/bph.70163","url":null,"abstract":"<p>Photopharmacology integrates light-based technology with pharmacology to achieve precise control over biological processes, offering non-invasive activation and spatiotemporal regulation of biomolecular activity. Within this field, photoswitchable peptides and foldamers provide a powerful approach in precision medicine, enabling reversible conformational changes that toggle between active and inactive states. This light-driven modulation enhances targeted drug delivery, molecular sensing, and the development of photoresponsive biomaterials and optical devices. These dynamic systems hold immense potential for creating ‘smart’ therapeutics and biomaterials that adapt to environmental cues, revolutionizing biomedical applications. However, challenges persist in optimizing their stability, specificity and responsiveness in complex biological environments. Advances in light-responsive technologies and nanotechnology continue to push the boundaries of their applications, driving innovation in precision medicine and materials science. As research progresses, these systems are poised to transform drug delivery, diagnostics and next-generation biomaterials.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 19","pages":"4458-4465"},"PeriodicalIF":7.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793541","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":"Emerging therapeutic frontiers in cardiometabolic and inflammatory diseases","authors":"Jun Ren,&nbsp;Xiuping Chen,&nbsp;Xin Wang","doi":"10.1111/bph.70159","DOIUrl":"10.1111/bph.70159","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> LINKED ARTICLES</h3>\u0000 \u0000 <p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 20","pages":"4737-4740"},"PeriodicalIF":7.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70159","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788357","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":"Correction to “Hippocampal α7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice”","authors":"","doi":"10.1111/bph.70173","DOIUrl":"10.1111/bph.70173","url":null,"abstract":"&lt;p&gt;\u0000 &lt;span&gt;Mineur, Y.S.&lt;/span&gt;, &lt;span&gt;Mose, T.N.&lt;/span&gt;, &lt;span&gt;Blakeman, S.&lt;/span&gt;, &amp; &lt;span&gt;Picciotto, M.R.&lt;/span&gt; (&lt;span&gt;2018&lt;/span&gt;). &lt;span&gt;Hippocampal α7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice&lt;/span&gt;. &lt;i&gt;British Journal of Pharmacology&lt;/i&gt;, &lt;span&gt;175&lt;/span&gt;(&lt;span&gt;11&lt;/span&gt;): &lt;span&gt;1903&lt;/span&gt;–14. PMC5979617&lt;/p&gt;&lt;p&gt;Following an initial corrigendum, we realized that parts of the manuscript text and conclusions had not been updated accordingly, which could cause confusion for the reader. Changes to the text are &lt;span&gt;underlined&lt;/span&gt;:&lt;/p&gt;&lt;p&gt;- The Results should read: &lt;b&gt;MLA has an antidepressant-like effect in the forced swim test, but does not affect response to &lt;span&gt;tail suspension&lt;/span&gt; and social defeat stress.&lt;/b&gt;&lt;/p&gt;&lt;p&gt;In the tail suspension test, an ANOVA showed that there was an overall effect of treatment in female (F2, 27 = 15.8) and male mice (F2, 27 = 4.8). In female mice, post hoc analyses revealed that GTS-21 had no effect compared with saline, but that MLA significantly decreased the time spent immobile, &lt;span&gt;despite significant variability due to several animals moving continuously&lt;/span&gt; (Table 2). In male mice, there was no significant effect on immobility following GTS-21 treatment, whereas MLA treatment resulted in a &lt;span&gt;non-significant (p = .06)&lt;/span&gt; decrease in time spent immobile (Figure 1A).&lt;/p&gt;&lt;p&gt;- In the Discussion, the text should read: Systemic administration of the α7 nAChR antagonist MLA resulted in &lt;span&gt;anxiolytic- and&lt;/span&gt; &lt;span&gt;limited&lt;/span&gt; antidepressant-like effects, as has been observed previously in male mice (Andreasen et al., 2009). MLA administration decreased immobility in the tail suspension test &lt;span&gt;only in female mice&lt;/span&gt;, but &lt;span&gt;high&lt;/span&gt; variability was observed in the behavioural outcomes &lt;span&gt;in both sexes&lt;/span&gt;, making the results difficult to interpret.&lt;/p&gt;&lt;p&gt;We apologize if the previous version of the Corrigendum was confusing to the readers.&lt;/p&gt;&lt;p&gt;Furthermore, while updating the text and in partnership with Wiley, an independent statistical expert, and the BJP editors, we thoroughly reviewed all experimental data, including raw data files, values, group labels, and statistical analyses, comparing them with the information presented in the published article. During this process, we identified a few issues that were missed/introduced during the review corrections. These do not affect the conclusions of the study, but nonetheless warrant clarification:&lt;/p&gt;&lt;p&gt;- During the revision process a scatterplot of all datapoints was added to Figure 2, but the datapoints were somewhat shifted compared to the bar graph values. The statistics and conclusions are unaffected, and the realigned version is included below.&lt;/p&gt;&lt;p&gt;- In the Methods section (Statistics) and Legend 4 we used a (Fischer's) &lt;span&gt;Protected&lt;/span&gt; Least Square Differences, not a “Partial” Least Square Differences, an incorrect description of","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 19","pages":"4729-4731"},"PeriodicalIF":7.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788277","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":"Bioactive ligands targeting ectopic olfactory receptors: Implications for therapeutic strategies","authors":"Hui Zhao,&nbsp;Jingyi Qiao,&nbsp;Lihua Cao,&nbsp;Zhenzhen Wang,&nbsp;Shuaike Yu,&nbsp;Miaoxin Jin,&nbsp;Jinying Zhang,&nbsp;Zhiguo Mao,&nbsp;Shun Tang,&nbsp;Mingsan Miao","doi":"10.1111/bph.70130","DOIUrl":"10.1111/bph.70130","url":null,"abstract":"<p>Ectopic olfactory receptors (EORs) are a class of olfactory receptors found outside the olfactory system. This review delves into the anatomical structure, tissue distribution, signalling pathways, and physiological functions modulated by EORs, and systematically categorises the bioactive ligands that specifically bind to these receptors, aiming to provide a solid scientific foundation for clinical therapeutic interventions. In this review we have analysed, meticulously and extensively, the published reports of the architectural composition of EORs, their distribution across various human systems, transmission mechanisms, biochemical processes in which they participate, and their bioactive ligands, with the goal of elucidating their significant role in human physiological processes. The EORs belong to the family of G protein-coupled receptors and are widely distributed across multiple tissues and organs, including the CNS and the digestive system. Upon binding to specific ligands, these receptors are involved in regulating a variety of physiological functions. A wide range of bioactive ligands have been shown to interact with EORs, including chemically synthesised compounds, food-derived constituents, endogenous substances, metabolic byproducts, as well as traditional Chinese medicines and their active components. The EORs are emerging as realistic drug targets and, consequently, the molecular design and development of drugs targeting EORs will open up novel therapeutic strategies for intractable diseases and malignant tumours.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5119-5148"},"PeriodicalIF":7.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticosteroid insensitivity in asthma associated with obstructive sleep apnoea: Role of oxidative stress and histone acetylation.","authors":"Chun-Yu Lo, Chun-Hua Wang, Chun-Yu Lin, Ting-Yu Lin, Po-Jui Chang, Yu-Lun Lo, Tsai-Yu Wang, Tzu-Ting Huang, Jung-Ru He, Chih-Chen Heh, Huei-Ru Luo, Li-Pang Chuang, Shih-Wei Lin, Ning-Hung Chen, Shu-Min Lin, Horng-Chyuan Lin, Kian Fan Chung","doi":"10.1111/bph.70157","DOIUrl":"https://doi.org/10.1111/bph.70157","url":null,"abstract":"<p><strong>Background and purpose: </strong>Obstructive sleep apnoea (OSA) worsens asthma control. Oxygen desaturation increases oxidative stress, contributing to corticosteroid insensitivity, a hallmark of severe asthma. This study investigated the impact of hypoxaemia and reactive oxygen species on corticosteroid responsiveness in asthma with OSA.</p><p><strong>Experimental approach: </strong>Asthmatic patients with apnoea-hypopnoea index (AHI) ≥ 5 h^-1 were classified as OSA. Interleukin (IL)-8 and IL-6 production by peripheral blood mononuclear cells (PBMCs), serum cytokines, oxidative stress markers and nuclear histone deacetylase 2 (HDAC2) were quantified by enzyme-linked immunosorbent assay. HDAC2 and hypoxia-inducible factor-1α (HIF-1α) expression were evaluated by Western blotting and flow cytometry.</p><p><strong>Key results: </strong>Compared with non-OSA asthmatics, OSA patients used higher inhaled corticosteroid doses and had increased serum thiobarbituric acid-reactive substances and 8-hydroxy-2-deoxyguanosine, but lower superoxide dismutase and total antioxidant capacity. HDAC2 was lower in OSA PBMCs and in non-OSA PBMCs exposed to 5% O₂ than in normoxia. HDAC2 was correlated inversely with AHI, corticosteroid dose, serum IL-8, oxidative stress, baseline production of IL-8/IL-6 and dexamethasone-induced IL-8 suppression. Dexamethasone inhibited TNF-α-induced IL-8 and lipopolysaccharide (LPS)-induced IL-6 in non-OSA PBMCs, but not in OSA PBMCs. HDAC2 inhibitor CAY10683 impaired corticosteroid action, while N-acetylcysteine and inhibitors of HIF-1α (CAY10585) or phosphoinositide 3-kinase (LY294002) restored HDAC2 and corticosteroid sensitivity.</p><p><strong>Conclusions and implications: </strong>OSA is associated with oxidative stress, reduced HDAC2, and corticosteroid insensitivity in asthma. Antioxidants may help restore corticosteroid efficacy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-chain fatty acids regulate T cell heterogeneity to alleviate recurrent spontaneous abortion.","authors":"Yao Yao, Xiaoyu Cai, Dan He, Yongquan Zheng, Mingqi Liu, Meng Zhang, Zhi Li, Weidong Fei, Caihong Zheng","doi":"10.1111/bph.70155","DOIUrl":"https://doi.org/10.1111/bph.70155","url":null,"abstract":"<p><strong>Background and purpose: </strong>The aetiology of recurrent spontaneous abortion (RSA) is multifactorial, with immune factors playing a critical role. Gut microbiota and its metabolites have been found to participate in host immune regulation. This study explores the role of gut microbiota-derived short-chain fatty acids (SCFAs) in immune tolerance in RSA.</p><p><strong>Experimental approach: </strong>Single-cell sequencing was used to analyse the cell profile of RSA patients. 16S rDNA sequencing was used to analyse the gut microbiota structure. Faecal microbiota transplantation (FMT) was used to explore the role of the gut microbiota in immune-related RSA in mice. SCFAs supplementation was used to explore the role of SCFAs in immune-related RSA mice. Conventional molecular biology methods were used to explore molecular mechanisms.</p><p><strong>Key results: </strong>The peripheral immune cell profile of RSA patients was altered. The gut microbiota structure of RSA patients was also altered, with a decrease in their SCFA levels. FMT significantly improved pregnancy outcomes in immune-related RSA in mice. SCFAs affected the differentiation of peripheral CD4⁺ T cells and the expression of marker genes. SCFA supplementation altered the gut microbiota structure in immune-related RSA mice and improved colonic barrier function. SCFAs regulate CD4⁺ T cell differentiation by targeting GPR43. Finally, the colon-targeted SCFA delivery nanoparticle system that we designed optimised the therapeutic effects of SCFAs.</p><p><strong>Conclusion and implications: </strong>Gut microbiota-derived SCFAs regulate T cell heterogeneity to alleviate RSA. The findings of this study increase the understanding of maternal-fetal immune tolerance mechanisms and provide new insights for future therapeutic strategies for RSA.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}