Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"Paeoniflorin-6′-O-Benzenesulfonate Mediates Dendritic Cell Differentiation to Alleviate Diabetic Kidney Disease","authors":"Wei Liang,&nbsp;Dongchun Zhu,&nbsp;Lei Xiao,&nbsp;Xiaoqian Wu,&nbsp;Hongwei Zhang,&nbsp;Li Cao,&nbsp;Mengxue Hu,&nbsp;Chun Wang,&nbsp;Feng Xiao,&nbsp;Wei Wei,&nbsp;Tingting Liu","doi":"10.1111/1440-1681.70124","DOIUrl":"10.1111/1440-1681.70124","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Recent studies demonstrated that the mature dendritic cells (DCs) exhibit renal pathogenicity and promote diabetic kidney disease (DKD). This study investigates the therapeutic potential and mechanisms of paeoniflorin-6<b>′</b>-O-benzene sulfonate (CP-25) to DCs in DKD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>DKD mouse model was established by high-fat (HFD) feeding combined with intraperitoneal streptozotocin (STZ) injection. Renal histopathological changes were assessed via haematoxylin and eosin (H&amp;E), masson, and periodic acid-schiff (PAS) staining. Renal function, oxidative stress, and lipid were also quantified. Immune cell differentiation and function were analysed by flow cytometry (FCM). The expression of renal injury markers and fibrosis-associated mRNA and proteins were evaluated by quantitative real-time PCR (qPCR) and western blotting. The target G protein-coupled receptor kinase 2 (GRK2), PI3K-AKT–mTOR, and JAK2-STAT3-SOCS3 pathways were examined to analyse the mechanism of CP-25 to DKD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CP-25 alleviated renal histopathological damage, inflammatory infiltration, and fibrosis in DKD. CP-25 also reversed renal function, lipid, and oxidative stress indicators of DKD. Additionally, CP-25 inhibited pro-inflammatory cytokines (IL-12) and promoted anti-inflammatory cytokines (IL-4 and IL-10) secretion in the serum of DKD. CP-25 inhibited the differentiation of CD103⁺DCs and the maturity of DCs in the bone marrow and kidney. Subsequently, CD8⁺T cells in the spleen and kidney, NKT in the spleen, and T_regs in the spleen and kidney of DKD mice were inhibited by CP-25 treatment. Other immune cells in other immune organs were less affected by CP-25. The communication of DC and T cell was down-regulated by CP-25. The specific mechanism involved CP-25 targeting GRK2 to inhibit the JAK2-STAT3-SOCS3 pathway, thereby suppressing DC maturation and T cell communication in the renal inflammatory response to treat DKD. However, the inhibition of CP-25 to PI3K was indistinctive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>CP-25 exhibits therapeutic efficacy against kidney injury in DKD. Its primary mechanism involves modulating the differentiation and function of DCs, which affects the activation of T cells. In terms of mechanism, CP-25 targets the GRK2-mediated JAK2-STAT3-SOCS3 signalling pathway to inhibit inflammation for alleviating DKD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670934","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":"Inhibition of Bilirubin Generation Exacerbates Oxidative Stress and Liver Injury in Early-to-Intermediate Obstructive Cholestasis","authors":"Pamela L. Martín,&nbsp;Geraldine L. Hillotte,&nbsp;María V. Razori,&nbsp;Estefanía M. A. Massa,&nbsp;Alejandra I. Martínez,&nbsp;María del Luján Corbo,&nbsp;Enrique J. Sánchez Pozzi,&nbsp;Fernando A. Crocenzi,&nbsp;Marcelo G. Roma,&nbsp;Cecilia L. Basiglio","doi":"10.1111/1440-1681.70123","DOIUrl":"10.1111/1440-1681.70123","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We have previously shown that hemeoxygenase-1 (HO1) induction and resulting elevation of bilirubin (BR) protects the liver from oxidative stress (OS)-induced acute cholestasis in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To characterise the protective role of BR at the early-to-intermediate stages of obstructive cholestasis by investigating the consequences of inhibiting BR generation in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Zinc protoporphyrin IX (ZnPP), a HO1 inhibitor, was administered 24 h before BDL to male Wistar rats. After confirming establishment of obstructive cholestasis and successful impairment in BR generation, we studied the impact of these interventions on redox status and histopathological features in liver tissue.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>OS biomarkers were significantly elevated in ZnPP-pretreated BDL animals versus BDL-only controls, showing that under cholestatic conditions, oxidative damage is increased when BR production is impaired. Levels of antioxidant defences were lower in animals lacking BR generation, indicating that hepatic oxidative damage is more severe and antioxidant defences are weaker when BR production is inhibited. Histopathological analysis revealed significantly more severe obstructive injury in HO1-inhibited animals than in those subjected to BDL alone, indicating that BR generation impairment worsens the outcome of obstructive injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The inhibition of HO1 and consequent decrease in the endogenous levels of BR negatively impacts the outcome of obstructive cholestasis due to the loss of BR's antioxidant and cytoprotective effects. BR accumulation during cholestasis serves as a critical defence against oxidative damage induced by retained bile salts.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632422","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":"Attenuation of Vascular Dementia Associated Neuroinflammation by Inhibition of the JNK Pathway in HFD/STZ-Induced Diabetic Rat Model","authors":"Sundas Firdoos,&nbsp;Rongji Dai,&nbsp;Fawad Ali Shah,&nbsp;Zahid Younas","doi":"10.1111/1440-1681.70120","DOIUrl":"10.1111/1440-1681.70120","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetes-associated cognitive impairment represents a major global health burden and is driven by metabolic dysregulation, neuroinflammation, oxidative stress and vascular dysfunction. High-fat diet (HFD)-induced metabolic stress is known to exacerbate insulin resistance, cerebrovascular injury while activation of stress-responsive pathways, including c-Jun N-terminal kinase (JNK), thereby contributing to neuroinflammatory and cognitive alterations relevant to vascular cognitive impairment. The present study evaluated the therapeutic potential of JNK inhibition in ameliorating diabetes-associated cognitive and neuroinflammatory changes using a HFD and streptozotocin (STZ) rat model. Male Sprague Dawley rats were allocated to control (HFD-fed), disease (HFD + STZ), control+treatment (HFD + SP600125) and treatment (HFD + STZ + SP600125) groups. The treatment groups were administered JNK inhibitor (SP600125) for 2 weeks, and cognitive performance was assessed using the Y-Maze and Morris water maze tests. Disease rats exhibited significant impairments in learning and memory, accompanied by neuronal damage and elevated neuroinflammatory markers in the hippocampus and cortex. Treatment with the JNK inhibitor SP600125 significantly improved cognitive performance, attenuated neuronal injury and reduced inflammatory signalling. Notably, SP600125 decreased brain levels of NLRP3 and inducible nitric oxide synthase, as measured by enzyme-linked immunosorbent assay and modulated immunohistochemical markers by increasing TREM-2 while reducing P53 and TNF-α levels. Collectively, these results demonstrated JNK activation contributes to diabetes-associated cognitive and neuroinflammatory alterations and that pharmacological JNK inhibition may mitigate pathological features relevant to vascular cognitive impairment without implying exclusive causality. This study supports JNK signalling as a mechanistically relevant target for addressing cognitive complications associated with diabetes.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616014","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":"BRAP Homologue Deficiency Exacerbates Airway Inflammation in Mouse Models of Experimental Asthma-Like Disease","authors":"Hui Wang,&nbsp;Rujiao Liu,&nbsp;Wenrui Zhang,&nbsp;Jie Wang,&nbsp;Jiaoyun Zheng,&nbsp;Horst Christian Weber,&nbsp;Xiangping Qu","doi":"10.1111/1440-1681.70119","DOIUrl":"10.1111/1440-1681.70119","url":null,"abstract":"<div>\u0000 \u0000 <p>Bronchial epithelial cells (BECs) play a critical role in asthma pathogenesis through structural and functional alterations that contribute to disease severity. Bombesin receptor-activated protein (BRAP), encoded by the human <i>C6orf89</i> gene, shares 83% identity with its mouse homologue encoded by <i>BC004004</i>. Both proteins have been identified in bronchial epithelial cells, and our previous studies found that BRAP overexpression alters the biological behaviour of cultured human bronchial epithelial cells, suggesting a potential role in regulating immune homeostasis in the respiratory tract. In this study, we used BC004004 knockout (<i>BC004004</i>^−/−) mice, which lack expression of the BRAP homologue, to establish ovalbumin (OVA)-induced or house dust mite (HDM)-induced asthma models. Following OVA or HDM challenge, <i>BC004004</i>^−/− mice exhibited exacerbated airway inflammation compared with wild-type controls, characterised by increased mucus production in the airway lumen, enhanced shedding of bronchial epithelial cells, and more pronounced infiltration of inflammatory cells surrounding the bronchi and bronchioles. Meanwhile, the levels of Th2 cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) were significantly elevated in <i>BC004004</i>^−/− mice after allergen exposure. In addition, serum levels of thymic stromal lymphopoietin (TSLP), a key epithelial-derived mediator of type 2 immune responses, were increased in <i>BC004004</i>^−/− mice following OVA or HDM challenge. In cultured immortalised human bronchial epithelial cells, TSLP release was upregulated by BRAP knockdown and suppressed by BRAP overexpression. Further analysis revealed that BRAP homologue deficiency resulted in reduced E-cadherin expression in asthmatic lung tissues. Together with the enhanced epithelial shedding observed in the lungs of allergen-challenged <i>BC004004</i>^−/− mice, these findings suggest that loss of BRAP homologue compromises epithelial barrier integrity. The enhanced disruption of epithelial barrier integrity in <i>BC004004</i>^−/− mice may promote increased TSLP release from airway epithelial cells, thereby contributing to the exacerbation of allergic inflammation and asthma pathogenesis. Collectively, these results indicate a role for BRAP in maintaining epithelial barrier function during allergic asthma.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590322","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":"Interaction of mtROS-Immune-Inflammatory Vicious Cycle Activation in Sepsis-Induced Cardiomyopathy","authors":"Yu Wang,&nbsp;Qiong Yuan","doi":"10.1111/1440-1681.70122","DOIUrl":"10.1111/1440-1681.70122","url":null,"abstract":"<div>\u0000 \u0000 <p>Mitochondrial reactive oxygen species (mtROS) serve as a central mediator in the pathogenesis of mitochondrial energy metabolism disorders and play a pivotal role in sepsis-induced cardiomyopathy (SICM). The production and regulation of mtROS involve multiple molecular mechanisms, including VDAC1-mediated mitochondrial impairment and the STK3/KEAP1/Nrf2 signalling pathway. Once generated, mtROS contribute to cellular damage through dual effects on the nitric oxide-lipid metabolic axis and complex interactions with ferroptosis. The pathological impact of mtROS is further amplified by mitochondria-endoplasmic reticulum interactions involving the DUSP1/PHB2 pathway. Critically, mtROS drive immune-related organ damage in sepsis by modulating the immune microenvironment, characterised by dynamic changes in cytokine storms, local cardiac immune cell infiltration, and aberrant activation of inflammatory signalling pathways. The SIRT3-SOD2 axis plays a key regulatory role in this process, as cardiac-specific overexpression of SOD2 improves heart function by controlling mtROS levels. Together, this review interconnected mechanisms establish mtROS as a central hub linking mitochondrial dysfunction, immune dysregulation, and myocardial injury in SICM, suggesting that targeting mtROS and its regulatory pathways represents a promising therapeutic strategy.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572438","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":"Hepatoprotection by Garlic Essential Oil Nanoemulsion Through Nrf2-Mediated Antioxidant Response and Inhibition of TLR4/NF-κB/NLRP3 Axis in High-Fat Diet-Fed Rats","authors":"Mohammed Saleh Alfawaz,&nbsp;Huda A. Al Doghaither,&nbsp;Ayat B. Al-Ghafari,&nbsp;Ahd A. Mansour,&nbsp;Ahmad Najem Alshammari,&nbsp;Ekramy M. Elmorsy,&nbsp;Marwa Mahmoud Fawzy Atta,&nbsp;Aya Megahed","doi":"10.1111/1440-1681.70115","DOIUrl":"10.1111/1440-1681.70115","url":null,"abstract":"<div>\u0000 \u0000 <p>The present study evaluated the hepatoprotective effects of garlic essential oil nanoemulsion (GEONE) against high-fat diet (HFD)-induced liver injury and metabolic disturbances, compared to crude garlic essential oil (GEO). Sixty rats were randomly divided into six groups: control, GEO-treated (40 mg/kg), GEONE-treated (40 mg/kg), HFD-fed and HFD combined with either GEO or GEONE (40 mg/kg) for 4 weeks following 16 weeks of HFD feeding. GEONE demonstrated superior hepatoprotective activity compared with crude GEO, effectively ameliorating metabolic abnormalities, including dyslipidemia and liver dysfunction, in HFD-fed rats. This effect was associated with attenuation of lipid peroxidation, enhanced activities of antioxidant enzymes, including superoxide dismutase, catalase and glutathione peroxidase and elevated reduced glutathione levels. GEONE also upregulated the expression of key antioxidant genes, <i>Nrf2</i>, <i>HO-1</i> and <i>NQO1</i>, highlighting activation of cytoprotective pathways. Furthermore, GEONE mitigated HFD-induced inflammation by downregulating the expression of <i>TLR3</i>, <i>TLR4</i>, <i>NF-κB</i>, <i>TNF-α</i>, <i>IL-6</i> and <i>NLRP3</i>. In addition, co-treatment with GEONE suppressed pro-apoptotic gene expression (<i>Bax</i> and <i>caspase-3</i>) while enhancing anti-apoptotic <i>Bcl-2</i> levels, indicating protection against hepatocyte apoptosis. Histopathological and ultrastructural analyses confirmed the previous biochemical findings. Overall, GEONE provides effective protection against HFD-induced liver injury by activating the Nrf2/HO-1 antioxidant defence system and suppressing the TLR4/NF-κB/NLRP3 inflammatory cascade.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430968","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":"Effectiveness and Safety of Omalizumab in the Adjuvant Treatment of Patients With Refractory Acute Urticaria: A Real-World Case–Control Study","authors":"Mengyan Zhu,&nbsp;Bo Xie,&nbsp;Xiaoyan Pei,&nbsp;Yijin Zhang,&nbsp;Yujian Ye","doi":"10.1111/1440-1681.70117","DOIUrl":"10.1111/1440-1681.70117","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Severe acute urticaria with systemic involvement often remains uncontrolled despite systemic corticosteroid therapy, while prolonged high-dose regimens carry significant safety risks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>This study aimed to evaluate the effectiveness and safety of omalizumab as an adjunctive therapy in patients with refractory acute urticaria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a single-centre, retrospective real-world case–control study of 65 patients with refractory acute urticaria selected from 3006 hospitalised patients with acute urticaria (September 2021–August 2023). Patients aged 12–75 years received either intensified corticosteroids (control group, <i>n</i> = 39) or 300 mg of single-dose omalizumab as an adjunct treatment to corticosteroids (omalizumab group, <i>n</i> = 26) after ≥ 3 days of prednisone [1 mg (kg day)⁻¹] failure. The primary outcome was postintervention corticosteroid duration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After treatment regimen adjustment, the duration of corticosteroid use was 13.00 (11.25, 15.00) days in the omalizumab group and 16.00 (13.00–17.00) days in the corticosteroid group, with a statistically significant difference (<i>p</i> = 0.035). Further exclusion of covariates with <i>p</i> &lt; 0.05 revealed statistically significant differences in the primary outcome; the omalizumab group had 2.41 (95% CI: −4.44 to −0.37) fewer treatment days (<i>p</i> = 0.024, &lt; 0.05) compared with controls. Secondary outcomes revealed a 2.41 (95% CI: −4.44 to −0.37)-day reduction in total prednisone exposure (<i>p</i> = 0.024), 8.70 (95% CI: −16.70 to −0.71) mg (kg day)⁻¹ lower peak prednisone dosage (<i>p</i> = 0.037), and cumulative prednisone dosage was reduced by 215.62 (95% CI: −388.51 to −42.73) mg following treatment adjustment (<i>p</i> = 0.018) in the omalizumab group versus controls. No significant intergroup differences in adverse events, hospitalisation duration, direct medication costs or progression to chronic urticaria were observed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that omalizumab may be a safe and effective corticosteroid-sparing adjunct treatment for patients with refractory acute urticaria.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442953","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":"Mechanisms of IL-17A Neutralisation in Alleviating Renal Fibrosis and Inflammation in Spontaneously Hypertensive Rats","authors":"Anshuai Ba,&nbsp;Zhenzhen Chen,&nbsp;Meng Wu,&nbsp;Weiyi Li,&nbsp;Yu Wang","doi":"10.1111/1440-1681.70116","DOIUrl":"10.1111/1440-1681.70116","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study investigated the therapeutic effects and mechanisms of IL-17A neutralisation on renal interstitial fibrosis and inflammation in spontaneously hypertensive rats (SHRs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SHRs were treated with an IL-17A-neutralising antibody (NAb) for 20 weeks. Blood pressure and renal function were monitored. Renal tissues were analysed for histopathology, macrophage polarisation, epithelial-mesenchymal transition (EMT), inflammatory cytokines, and relevant signalling pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>IL-17A NAb treatment significantly attenuated hypertension progression and improved renal function. It also ameliorated renal fibrosis and histopathological damage. Mechanistically, IL-17A neutralisation suppressed M2 macrophage polarisation and downregulated the TGF-β/Smad pathway, an effect associated with attenuated extracellular matrix (ECM) remodelling. This was accompanied by reduced levels of pro-inflammatory cytokines and inhibition of key inflammatory signalling pathways, including JAK/STAT, PI3K/AKT, and NF-κB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings demonstrate that IL-17A neutralisation alleviates renal fibrosis and inflammation in SHRs. The protective effects are associated with the inhibition of M2 macrophage polarisation, suppression of the TGF-β/Smad pathway and the associated EMT process, and attenuation of systemic and renal inflammation, concomitant with the coordinated downregulation of the JAK/STAT, PI3K/AKT, and NF-κB signalling pathways.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12979023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430997","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":"METTL14 Aggravates Sepsis-Induced Acute Kidney Injury by Promoting Ferroptosis Through m6A Modification of BMAL1","authors":"Yishu Wang,&nbsp;Yang Li,&nbsp;Na Wu,&nbsp;Xinyue Xu,&nbsp;Xiaoxuan Fan,&nbsp;Haifeng Wang","doi":"10.1111/1440-1681.70107","DOIUrl":"10.1111/1440-1681.70107","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute kidney injury (AKI) is a common and severe complication of sepsis and represents an independent risk factor for mortality in septic patients. Despite its clinical significance, the mechanisms of sepsis-induced AKI (Sepsis-AKI) remain incompletely understood. This study investigates the role of methyltransferase like 14 (METTL14)-mediated m6A modification in regulating brain and muscle ARNT-like protein-1 (BMAL1) stability and its effect on tubular epithelial cell injury and ferroptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Human renal proximal tubular epithelial (HK-2) cells were treated with lipopolysaccharide (LPS) to establish an in vitro model of Sepsis-AKI. Cell proliferation and viability were assessed using EdU and CCK-8 assays; apoptosis was evaluated by TUNEL staining, and inflammatory cytokines Interleukin-6 (IL-6) and IL-1β were measured by ELISA. Ferroptosis indices were detected using corresponding kits. RT-qPCR and Western blotting were used to detect mRNA and protein expression. MeRIP and RIP assays were used to evaluate BMAL1 m6A modification and RNA-protein interaction. The stability of BMAL1 mRNA was determined using an Actinomycin D chase assay. A Sepsis-AKI model was established to examine the effect of METTL14 silencing on renal injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>BMAL1 overexpression significantly alleviated LPS-induced apoptosis, inflammatory responses, and ferroptosis in HK-2 cells. Furthermore, METTL14 silencing reduced BMAL1 m6A modification, stabilized BMAL1 mRNA, and consequently improved HK-2 cell injury. In addition, YTHN6-methyladenosine RNA binding protein 1 (YTHDF1) was identified as the critical m6A reader mediating BMAL1 mRNA degradation. Consistently, in vivo experiments demonstrated that METTL14 knockdown mitigated Sepsis-AKI and ferroptosis in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>METTL14 enhanced BMAL1 m6A modification and promoted YTHDF1-mediated BMAL1 degradation, thereby facilitating ferroptosis and aggravating Sepsis-AKI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147376241","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":"Ajugoside Promotes the Repair of Osteoporotic Bone by Inducing Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells","authors":"Ruifeng Yang,&nbsp;Chong Wang,&nbsp;Panpan Xie,&nbsp;Jifei Ye,&nbsp;Shuming Huang","doi":"10.1111/1440-1681.70114","DOIUrl":"10.1111/1440-1681.70114","url":null,"abstract":"<div>\u0000 \u0000 <p>Bone marrow mesenchymal stem cells (BMSCs) are multipotent cells that play a critical role in bone formation and are vulnerable to oxidative stress-induced dysfunction in osteoporosis (OP). This study investigates the pro-osteogenic potential of ajugoside, a naturally occurring iridoid monoterpene from <i>Ajuga reptans</i>, through a two-phase experimental design involving both in vitro and in vivo models. In the in vitro phase, an oxidative stress model was established in BMSCs using H₂O₂, followed by ajugoside treatment or lentiviral overexpression of solute carrier family 5 member 1 (Slc5a1). Cell viability, osteogenic differentiation, oxidative stress, and mitophagy were assessed. In the in vivo phase, an ovariectomy-induced OP mouse model was utilized to examine the therapeutic effects of ajugoside, resveratrol (a positive control), or adeno-associated virus-mediated Slc5a1 overexpression. Ajugoside inhibited Slc5a1 expression and activated AMPK signalling, leading to enhanced mitophagy and reduced oxidative stress. Ajugoside demonstrated a significant capacity to alleviate H₂O₂-induced injury in BMSCs, exhibiting a comparable mitigating effect on oxidative stress and mitophagy impairment in OP mice. However, the reactivation of Slc5a1 led to the reversal of these effects. Collectively, these findings demonstrate that ajugoside promotes osteogenic differentiation by suppressing Slc5a1 and activating AMPK-mediated mitophagy, offering a promising therapeutic strategy for OP.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353962","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}