European journal of pharmacology最新文献

{"title":"Oridonin ameliorates hyperglycemia-induced bladder injury by promoting AMPK/PINK1/Parkin-mediated mitophagy","authors":"Kang-jing Li ,&nbsp;Zhenhua Qiu ,&nbsp;Tongduan Li ,&nbsp;Hongjun Zhao ,&nbsp;Xiaoping Liu ,&nbsp;Longchen Zhao ,&nbsp;Chubiao Zhuo ,&nbsp;Runqi Luo ,&nbsp;Yujie Yang ,&nbsp;Xiangmao Lai ,&nbsp;Jianwen Zeng","doi":"10.1016/j.ejphar.2026.178559","DOIUrl":"10.1016/j.ejphar.2026.178559","url":null,"abstract":"<div><div>Diabetic bladder dysfunction (DBD), characterized by impaired detrusor contractility, decreased bladder sensation, and increased bladder compliance, remains difficult to treat due to its complex and multifactorial pathogenesis, including chronic inflammation. Oridonin (ORI), known for its strong anti-inflammatory properties, may offer therapeutic benefits for DBD. This study investigated the effects and underlying mechanisms of ORI on hyperglycemia-induced bladder injury. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to evaluate potential mechanisms. The function and molecular events of ORI in DBD were explored using both rat and cell models. GO analysis revealed that ORI primarily regulates inflammatory processes, while KEGG analysis identified the AMPK pathway as a key mechanism. Additionally, molecular docking demonstrated strong interactions between ORI and AMPK. In vivo experiments showed that ORI significantly reduced hyperglycemia-induced inflammation and mitochondrial damage, promoted AMPK phosphorylation, and increased the expression of contraction- and mitophagy-related factors. These findings were further validated in human bladder smooth muscle cells (HBSMCs) exposed to high glucose. Notably, after inhibiting AMPK-mediated mitophagy using compound C or cyclosporine A <em>in vitro</em>, the anti-inflammatory effects of ORI were inhibited and the expression of contraction-related proteins were down-regulated. In conclusion, ORI alleviates inflammation and reverses changes in contraction-related proteins in HBSMCs in association with changes in AMPK/PINK1/Parkin-related mitophagy markers, suggesting its potential as a novel candidate for preventing or attenuating hyperglycemia-induced bladder injury and for further investigation in the management of DBD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178559"},"PeriodicalIF":4.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Nicotinamide Mononucleotide protects against endotoxemia-induced myocardial injury through Sirt5-dependent desuccinylation of succinate dehydrogenase","authors":"Hongmei Tao ,&nbsp;Qian Dong ,&nbsp;Yang Long ,&nbsp;Ling Liu ,&nbsp;Shu Qin ,&nbsp;Yu Wang","doi":"10.1016/j.ejphar.2026.178562","DOIUrl":"10.1016/j.ejphar.2026.178562","url":null,"abstract":"<div><div>During endotoxemia, dysfunction of succinate dehydrogenase (SDH) in myocardial tissue serves as a significant contributor to impaired cardiac function. Previous study has suggested that Sirtuin 5 (Sirt5)-mediated SDH desuccinylation exerts a cardioprotective effect. However, in the context of endotoxemia, the level of nicotinamide adenine dinucleotide (NAD⁺), an essential co-substrate for Sirt5 in myocardial tissue, is diminished, leading to the inability to maintain Sirt5 activity. This study aims to investigate whether supplementation with the NAD⁺ precursor β-nicotinamide mononucleotide (NMN) ameliorates endotoxemia-induced myocardial injury by activating Sirt5-mediated desuccinylation of SDH. Mice were intraperitoneally administered NMN (500 mg/kg) for 1, 7, 14, 21, and 28 consecutive days. Myocardial NAD⁺ levels gradually increased to a saturation level (peaking at 14 days), with no obvious adverse effects. In LPS-induced myocardial injury, NMN supplementation significantly improved survival rates, reduced serum cardiac troponin I (cTnI), enhanced cardiac function, restored ATP production, downregulated pro-inflammatory cytokines, and alleviated oxidative damage. We further discovered that NMN corrected the aberrant catalytic function of SDH, reduced succinate accumulation, and increased fumarate levels. Mechanistically, NMN supplementation specifically reduced SDH succinylation (but not acetylation) and promoted the binding of Sirt5 to SDH. After cardiomyocyte-specific knockdown of Sirt5, the protective effects of NMN on SDH desuccinylation and myocardial protection were significantly attenuated. In summary, NMN supplementation elevates myocardial NAD⁺ levels, promotes Sirt5-mediated SDH desuccinylation, corrects succinate metabolism disorder, and thereby mitigates endotoxemia-induced myocardial injury.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178562"},"PeriodicalIF":4.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bombesin improves visceral hypersensitivity and colonic hyperpermeability via BB1 receptor–dependent multi-pathway mechanisms in a rat model of irritable bowel syndrome","authors":"Tsukasa Nozu ,&nbsp;Saori Miyagishi ,&nbsp;Masatomo Ishioh ,&nbsp;Kaoru Takakusaki ,&nbsp;Toshikatsu Okumura","doi":"10.1016/j.ejphar.2026.178566","DOIUrl":"10.1016/j.ejphar.2026.178566","url":null,"abstract":"<div><div>Visceral hypersensitivity and impaired gut barrier function, along with immune dysregulation, are hallmarks of irritable bowel syndrome (IBS). Key contributors to these gastrointestinal (GI) disturbances include corticotropin-releasing factor (CRF), Toll-like receptor 4 (TLR4) and proinflammatory cytokine signaling. Bombesin-related peptides and their receptors (BB₁ and BB₂) are widely expressed in the central nervous system and peripheral tissues, particularly within the GI tract, where they regulate gut function and exert anti-inflammatory effects. We hypothesized that bombesin could improve visceral hypersensitivity and restore gut barrier integrity to alleviate IBS symptoms. Using lipopolysaccharide (LPS)- and CRF-induced IBS rat models, visceral pain was assessed by electromyographic recording of abdominal muscle contractions during colonic balloon distention, and colonic permeability was measured by Evans blue dye absorption. Colonic occludin expression and interleukin (IL)-1β levels were quantified by immunoblotting and ELISA. Intraperitoneal bombesin dose-dependently attenuated LPS- and CRF-induced visceral hypersensitivity and colonic hyperpermeability. These effects were abolished by BB₁ receptor antagonism and reproduced by BB₁ receptor activation, whereas BB₂ receptor activation was ineffective. Mechanistic analyses revealed involvement of multiple gut–brain axis pathways, including AMP-activated protein kinase, GABA_A, nitric oxide, opioid, peripheral CRF receptor subtype 2, neurotensin receptor 1 signaling, and central orexin, dopamine D₂ and muscarinic receptors. Bombesin also prevented LPS-induced reductions in occludin expression and increases in colonic IL-1β. Collectively, these findings demonstrate that bombesin ameliorates IBS-related GI alterations <em>via</em> BB₁ receptor–dependent modulation of diverse gut–brain signaling networks, leading suppression of proinflammatory cytokine activity, highlighting its therapeutic potential for IBS.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178566"},"PeriodicalIF":4.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety of metformin in chronic kidney disease and type 2 diabetes mellitus: a systematic review and meta-analysis","authors":"Silvana Patiño-Cardona ,&nbsp;Carlos Pascual-Morena ,&nbsp;Irene Sequí-Domínguez ,&nbsp;Celia Álvarez-Bueno ,&nbsp;Héctor Martínez-Martínez ,&nbsp;Mar de Miguel-Brox ,&nbsp;Susana Priego-Jiménez ,&nbsp;Vicente Martínez-Vizcaíno","doi":"10.1016/j.ejphar.2026.178560","DOIUrl":"10.1016/j.ejphar.2026.178560","url":null,"abstract":"<div><h3>Background</h3><div>Metformin is the mainstay treatment for type 2 diabetes mellitus (T2DM), but its use in chronic kidney disease (CKD) remains controversial because of concerns about lactic acidosis. Previous meta-analyses have been limited by heterogeneous comparator groups and lack of CKD-stage stratification.</div></div><div><h3>Aim</h3><div>To assess the association between metformin use and the risk of all-cause mortality, major cardiovascular events (MACE), end-stage renal disease (ESRD) and lactic acidosis in population with CKD and T2DM.</div></div><div><h3>Methods</h3><div>A systematic search was conducted using Medline, Scopus, Web of Science and the Cochrane Library from inception to September 2025. Observational studies evaluating these associations in populations with CKD and T2DM were included. The associations were expressed as Hazard Ratios (HR) with 95 % confidence intervals (95 % CI). Meta-analyses were performed with subgroup analyses according to CKD stage.</div></div><div><h3>Results</h3><div>Twelve studies were included. Metformin use was associated with a reduction in both all-cause mortality (HR = 0.76, 95 % CI: 0.64, 0.90) and ESRD (HR = 0.61, 95 % CI: 0.49, 0.76). However, there was a trend towards an increased lactic acidosis risk in stage 4 (HR = 1.93, 95 % CI: 0.95, 3.87). Metformin use was not associated with MACE.</div></div><div><h3>Conclusions</h3><div>In this updated meta-analysis, based on observational evidence with very low certainty, metformin was inversely associated with all-cause mortality and ESRD. However, the results were inconsistent, and a potential increase in lactic acidosis risk in stage 4 was observed. Future studies examining the effect of dosage on these associations are required.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178560"},"PeriodicalIF":4.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STING inhibition by H-151 is associated with amelioration of psoriasis severity via modulation of pathogenic T helper cell subsets","authors":"Yerim Cho,&nbsp;Yebin Oh,&nbsp;Jiyeong Park,&nbsp;Jiho Kwon,&nbsp;Tae Sung Kim","doi":"10.1016/j.ejphar.2026.178564","DOIUrl":"10.1016/j.ejphar.2026.178564","url":null,"abstract":"<div><div>Psoriasis is a chronic immune-mediated skin disorder characterized by dysregulated activation of T helper (Th) cells. While Th1 and Th17 subsets are well-established contributors to disease pathology, the role of Th9 cells remains poorly understood. To investigate the relationship between disease severity and Th cell dynamics, we established a time-course imiquimod (IMQ)-induced psoriasis mouse model. Prolonged IMQ application resulted in progressive worsening of psoriatic inflammation, accompanied by increased populations of Th1, Th17, and Th9 cells, along with elevated levels of their associated cytokines. These findings indicate a strong correlation between the accumulation of pathogenic Th subsets and the severity of psoriatic inflammation. Stimulator of interferon genes (STING) signaling has been implicated in psoriasis pathogenesis, and the STING inhibitor H-151 has shown therapeutic potential by reducing inflammation in previous studies. However, its effect on the regulation of pathogenic Th subsets has not been elucidated. In this study, topical administration of H-151 significantly ameliorated disease phenotypes and reduced the populations of IFN-γ⁺, IL-17A⁺, and IL-9⁺ CD4⁺ T cells in lymph nodes, as well as their cytokine levels in CD4⁺ T cell supernatants and lesional tissues. Our findings provide the first evidence that H-151 exerts its therapeutic effects in psoriasis through coordinated suppression of multiple pathogenic Th subsets, including Th9 cells, thereby offering novel insight into the immunomodulatory mechanism of STING inhibition in psoriatic inflammation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178564"},"PeriodicalIF":4.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABAergic dynamics in thalamocortical circuits: Insights into absence seizures and hyperinhibition","authors":"Mohammad J. Eslamizade ,&nbsp;Ali Dabbagh ,&nbsp;Fariba Karimzadeh ,&nbsp;Mahyar Janahmadi ,&nbsp;Fatemeh Saffarzadeh","doi":"10.1016/j.ejphar.2026.178550","DOIUrl":"10.1016/j.ejphar.2026.178550","url":null,"abstract":"<div><div>Over the last decade, experimental and clinical evidence has shaped the excitation/inhibition imbalance doctrine, which serves as our contemporary understanding of the mechanisms underlying various epilepsies. In addition, emerging findings have highlighted the peculiar role of γ-aminobutyric acid (GABA), the brain's main inhibitory neurotransmitter, as an underappreciated factor in hyperexcitation disorders such as epilepsy. Intriguingly, the unique neuroanatomy and synaptic physiology of thalamocortical (TC) circuits have made this axis a distinctive field of study. In this review, we focus on the current literature that explores the detailed structure of the GABAergic system in TC circuits under both normal conditions and absence seizures. Augmented excitability of TC neurons as well as cortical somatosensory neurons due to differential activity of various GABAergic neurons and synapses contributes to hyperoscillatory circuits in absence seizures. Furthermore, subtle yet significant differential expression of GABA receptor subunits in the thalamus and somatosensory cortex plays crucial roles in the pathophysiology of absence seizures. Convincing evidence also underscores the pivotal importance of the lower expression of GABA transporters, particularly in astrocytes, which increases synaptic concentration of GABA and promotes persistent tonic inhibition in the thalamus. This, in turn, creates a priming membrane potential that facilitates activation of transient (T)-type calcium channels, thereby increasing the excitability of TC neurons. In summary, this review accentuates hyperinhibition as a leading pathophysiology of absence seizures. Thus, there is a pressing need to develop targeted pharmacologic interventions or precision medicine approaches to treat absence seizures and potentially other TC related disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178550"},"PeriodicalIF":4.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulated cell death in COPD: Modulators, crosstalk mechanisms, and therapeutic opportunities","authors":"Weibin Ruan ,&nbsp;Mingsi Huang ,&nbsp;Xiaohua Li ,&nbsp;Zhimin Peng ,&nbsp;Yaqin Wei ,&nbsp;Ziqing Mai ,&nbsp;Mianluan Pan ,&nbsp;Jiehua Deng ,&nbsp;Xinyan Chen ,&nbsp;Hui Zhang ,&nbsp;Xia Meng ,&nbsp;Jianquan Zhang","doi":"10.1016/j.ejphar.2026.178557","DOIUrl":"10.1016/j.ejphar.2026.178557","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disorder, with emerging evidence highlighting the central role of regulated cell death (RCD) in its pathogenesis. However, the regulatory mechanisms, crosstalk between different RCD pathways, and their role in intercellular communication remain poorly understood. This review examines major forms of RCD (apoptosis, necroptosis, ferroptosis, pyroptosis, NETosis, and PANoptosis) in COPD, exploring their regulation, crosstalk, role in intercellular signaling, and potential as therapeutic targets.</div><div>Mechanistically, RCD is regulated through membrane receptors, epigenetic modifications, and post-translational processes. Endoplasmic reticulum (ER) stress, reactive oxygen species, and autophagy serve as common nodes across multiple RCD types. Excessive ER stress triggers apoptosis, while impaired autophagy promotes oxidative stress, cellular senescence, and inflammation. Conversely, excessive autophagy—including mitophagy, ferritinophagy, lysosomal autophagy, ER-phagy, and chaperone-mediated autophagy—can induce apoptosis, necroptosis, and ferroptosis.</div><div>Regarding inter-pathway crosstalk and RCD-mediated intercellular communication: reduced macrophage apoptosis exacerbates epithelial inflammation and apoptosis; macrophage inflammation or ferroptosis can further promote epithelial ferroptosis or inflammatory responses. Ferroptosis in airway epithelial cells aggravates their own pyroptosis, and pyroptotic epithelial cells secrete exosomes that induce macrophage pyroptosis. NETotic neutrophils release extracellular DNA, driving inflammation in airway epithelia. Therapeutically, current exploratory strategies target these death pathways through diverse approaches, including existing pharmaceuticals, hormones, phytochemicals, recombinant proteins and nucleic acids, stem cell and regenerative therapies, and modulation of the airway microbiome. Deciphering the RCD network in COPD not only enhances our understanding of disease heterogeneity but also paves the way for developing precision therapeutics.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178557"},"PeriodicalIF":4.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacodynamic profile of Hexadimethrine Bromide–induced eosinophilia – Roles of pro-eosinophilic mediators","authors":"Bruno M. Vieira ,&nbsp;Richard E. Kast ,&nbsp;Vanessa M.S. Bezerra ,&nbsp;Beatriz A. Fernandes ,&nbsp;Milla B. Paiva ,&nbsp;Hugo C. Castro-Faria-Neto ,&nbsp;Edson F. de Assis ,&nbsp;Marcelo Pelajo-Machado ,&nbsp;Vivaldo Moura-Neto","doi":"10.1016/j.ejphar.2026.178554","DOIUrl":"10.1016/j.ejphar.2026.178554","url":null,"abstract":"<div><div>Hexadimethrine Bromide (HxB) has been reported to trigger marked eosinophilia even under conditions that typically cause eosinopenia. We investigated how HxB modulates eosinopoiesis and eosinophil accumulation in mice. Swiss Webster, C57BL/6, and BALB/c mice received HxB (1 or 10 mg/kg, intraperitoneally). Eosinophils were quantified in bone marrow, blood, and spleen by cytology and flow cytometry; serum cytokines/chemokines were profiled; serum transfer and montelukast pre-treatment tested mechanisms. HxB increased circulating and tissue eosinophils in a dose-dependent manner, peaking at 10 mg/kg, without neutrophilia. Bone marrow eosinopoietic potential rose, with higher frequencies of eosinophil-committed progenitors and mature eosinophils; effects generalized across strains. Serum from HxB-treated donors transferred eosinophilia to naïve recipients. A Th2-skewed burst of mediators (IL-3, IL-4, IL-5, IL-9, IL-13, eotaxin, RANTES, MIP-1α/β, and TNF-α) peaked at 24 h and returned to baseline by day 3. Montelukast did not blunt responses, indicating CysLT-independence. A second HxB dose on day 3 sustained eosinophilia through day 6. HxB elicits a rapid, cytokine-mediated, CysLT-independent pro-eosinophilic state that can be maintained with dosing every three days. This robust model yields abundant, mature eosinophils, supports mechanistic studies, and may inform future translational investigations of pharmacologically induced eosinophilia.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1014 ","pages":"Article 178554"},"PeriodicalIF":4.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The anoikis signature in rheumatoid arthritis: Insights into methotrexate resistance and the complementary therapeutic role of triptolide","authors":"Yuping Zhang ,&nbsp;Bo Cai ,&nbsp;Ju Shao ,&nbsp;Nuoshi Chen ,&nbsp;Yinghua Zhu ,&nbsp;Weijia Bao ,&nbsp;Zelin He ,&nbsp;Qiaoyi Le ,&nbsp;Qingwen Wang ,&nbsp;Hongyan Du ,&nbsp;Ligang Jie","doi":"10.1016/j.ejphar.2026.178547","DOIUrl":"10.1016/j.ejphar.2026.178547","url":null,"abstract":"<div><h3>Background</h3><div>Anoikis is programmed cell death triggered by loss of cell–extracellular matrix adhesion and is essential for synovial homeostasis. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) can acquire anoikis resistance, promoting synovial hyperplasia and inflammation. We tested whether inadequate responses to methotrexate (MTX) relate to persistent anoikis resistance and sought compounds that may restore anoikis sensitivity.</div></div><div><h3>Methods</h3><div>RA synovial transcriptomic datasets were analyzed to quantify anoikis-related gene (ARG) signatures before and after MTX therapy. Anoikis-related differentially expressed genes were used for network analysis and compound screening using the Connectivity Map (CMap). Triptolide was prioritized, assessed by molecular docking, and validated in detachment-induced anoikis assays in RA-FLS and in a collagen-induced arthritis (CIA) rat model.</div></div><div><h3>Results</h3><div>ARG signatures remained dysregulated after MTX treatment, consistent with persistent anoikis resistance. Protein–protein interaction analysis identified CDKN1A, PARP1, MAPK1, and CASP8 as hub genes. CMap ranked triptolide as the top candidate, and docking supported stable interactions with these targets. In vitro, triptolide increased detachment-induced apoptosis in RA-FLS versus MTX alone and regulated ARG expression, with corresponding protein changes confirmed by western blotting. In vivo, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) showed increased synovial apoptosis in triptolide-treated CIA rats.</div></div><div><h3>Conclusion</h3><div>MTX does not fully reverse anoikis resistance in RA synovium, whereas triptolide enhances anoikis-associated responses and modulates key hubs, supporting anoikis dysregulation as a therapeutic target and triptolide as a potential adjunct strategy for MTX-insufficient RA.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178547"},"PeriodicalIF":4.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hirsutine attenuates renal injury in diabetic kidney disease by regulating Th17 cell differentiation via the TGFβ/SMAD Pathway","authors":"Zhenzhen Pei,&nbsp;Yang Zhang,&nbsp;Zhige Wen,&nbsp;Yupeng Chen,&nbsp;Shan Zhang,&nbsp;Qing Ni,&nbsp;Boran Ni","doi":"10.1016/j.ejphar.2026.178549","DOIUrl":"10.1016/j.ejphar.2026.178549","url":null,"abstract":"<div><h3>Background</h3><div>Hirsutine (HS), a bioactive indole alkaloid isolated from <em>Uncaria rhynchophylla</em>, a traditional Chinese herb, has long been used in the treatment of hypertension and inflammatory disorders. However, its nephroprotective potential in diabetic kidney disease (DKD),—a primary cause of end-stage renal failure, remains insufficiently studied, particularly regarding its immunomodulatory mechanisms.</div></div><div><h3>Materials and methods</h3><div>High-throughput RNA sequencing was performed on renal tissues to identify differentially expressed genes (DEGs). Network pharmacology was employed to uncover potential HS targets and associated pathways relevant to DKD, while molecular docking predicted protein interactions. <em>In vivo</em> validation was conducted using db/db mice treated with HS, with evaluations of renal function, histopathology, Th17 cell differentiation, and the TGFβ/SMAD signaling pathway.</div></div><div><h3>Results</h3><div>Transcriptome analysis identified 837 DEGs. Enrichment analysis of these DEGs and network pharmacology revealed that TGFβ signaling-mediated Th17 cell differentiation could be a critical mechanism underlying the therapeutic effects of HS in DKD. <em>In vivo</em> experiments demonstrated that HS treatment inhibited Th17 cell differentiation and downregulated the expression of TGFβ1, p-SMAD2, and p-SMAD3. Histological analysis via HE staining showed only mild edema in renal tubular epithelial cells following HS treatment. Furthermore, HS treatment improved metabolic abnormalities, such as hyperglycemia and dyslipidemia, as well as renal function markers, including 24-h urinary protein excretion, (Urine albumin-to-creatinine ratio)UACR, blood urea nitrogen (BUN) and serum creatinine (Scr) levels. Co-administration of SRI with HS reversed these effects, with metabolic and renal function parameters returning to levels comparable to untreated db/db mice. This suggests that HS mediates its renoprotective effects by inhibiting the TGFβ signaling pathway, a key target in diabetic nephropathy.</div></div><div><h3>Conclusion</h3><div>In conclusion, HS alleviates the progression of DKD by suppressing Th17 cell differentiation through modulation of the TGFβ/SMAD pathway. This study provides the first evidence of HS as a novel immunomodulatory agent for DKD, highlighting its potential as a promising botanical-based therapeutic strategy for DKD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178549"},"PeriodicalIF":4.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}