Clinical and Experimental Pharmacology and Physiology最新文献

{"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}

{"title":"Blood–Brain Barrier-Permeable siRNA Nanodrugs With Dual-Gene Knockdown for Alzheimer's Disease Therapy","authors":"Feng Su,&nbsp;Shengnan Lu,&nbsp;Yaoyao Zhang,&nbsp;Yu Zhang,&nbsp;Ling Cheng,&nbsp;Jing Li,&nbsp;Junli Zhang,&nbsp;Ying Li,&nbsp;Yungen Xu,&nbsp;Guangwei He,&nbsp;Lifang Yin","doi":"10.1111/1440-1681.70108","DOIUrl":"10.1111/1440-1681.70108","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The presence of a blood–brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous neurodegenerative diseases, particularly Alzheimer's disease. Delivering small interfering RNA (siRNA) via nanoparticles represents a highly promising approach for treating Alzheimer's disease. Nevertheless, developing a safe and efficient siRNA delivery system remains challenging. To enhance brain targeting and therapeutic efficacy, we developed an siRNA nanocarrier system based on PAH-AM-PEG-ApoE (PAPA) nanoparticles (PAPA/siRNA NPs), which facilitates BBB penetration.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In this study, an siRNA nanocarrier delivery system modified with ApoE peptide (PAPA/siRNA NPs) developed by our research team was employed to simultaneously encapsulate BACE1-siRNA and GSK3β-siRNA. The PAPA/siRNA NPs were prepared through self-assembly and electrostatic binding. The particle size distribution profile and zeta potential of the PAPA/siRNA NPs were analysed with dynamic light scattering, while its morphology was examined with transmission electron microscopy. For in vitro assessments, flow cytometry, confocal laser scanning microscopy, PCR, and Western blotting were employed to evaluate the cellular uptake, gene silencing capacity, and endosomal escape. The biodistribution was investigated by in vivo imaging technology, and the therapeutic effect on AD was verified in AD model mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The prepared PAPA/siRNA NPs exhibited a regular spherical appearance with a uniform particle size distribution profile. In in vitro cell experiments, the PAPA/siRNA NPs demonstrated excellent cellular uptake ability and efficient endosomal escape. Meanwhile, the dual-loaded siRNA nanocarrier delivery system effectively inhibited the expression of GSK3β and BACE1 genes. In vivo experimental results showed that the siRNA could successfully cross the BBB and deliver to the brain. It not only significantly prolonged the half-life of siRNA but also greatly reduced the generation of pathological β-amyloid and phosphorylated microtubule-associated protein tau, showing excellent therapeutic effects in the treatment of AD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In this study, we successfully constructed a brain-targeted siRNA nanocarrier delivery system for double-gene knockdown. This system can efficiently overcome the obstacle of the BBB, markedly alleviating cognitive and memory deficits in AD mice. It paves the way for novel strategies in","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147302907","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":"Acepromazine Reduces Airway Contraction in a Murine Model of Asthma","authors":"Alembert Lino-Alvarado,&nbsp;Maria Aparecida de Oliveira,&nbsp;Carmen Silvia Moreno Serra,&nbsp;Isabella Victoria Santana Melhado,&nbsp;Rafael Campos,&nbsp;Yanira Riffo-Vasquez,&nbsp;Henrique Takachi Moriya","doi":"10.1111/1440-1681.70112","DOIUrl":"10.1111/1440-1681.70112","url":null,"abstract":"<p>Acepromazine (ACP) is one of the most used sedatives in veterinary medicine, and its cardiovascular effects are well documented. In contrast, its effects on the respiratory system remain less well understood, particularly in the context of assessment of respiratory mechanics in murine models of asthma, where its use has become more common in recent years. This study aims to investigate the effect of ACP on respiratory mechanics in BALB/c mice, specifically in an ovalbumin (OVA)-induced model of allergic asthma. Mice received ACP (2.5 mg/kg) in combination with standard ketamine (100 mg/kg) and xylazine (10 mg/kg) anaesthesia. Respiratory mechanics were assessed in vivo using forced oscillation technique (FOT) following methacholine (MCh) challenge. Additionally, tracheal rings and lung strips were evaluated in vitro for airway smooth muscle (ASM) responsiveness to MCh. ACP administration significantly reduced Newtonian resistance (Rn) in OVA-sensitised mice following MCh challenge, suggesting an inhibitory effect on ASM contractility. Furthermore, ACP mitigated increases in tissue damping (G) and hysteresivity (<i>η</i>), particularly in the inflamed lungs of OVA-treated mice. In vitro, ACP induced a rightward shift in MCh concentration–response curves in non-inflamed ASM and lung strips. These findings highlight the potential confounding effects of ACP in studies assessing airway hyperresponsiveness and offer insights into how sedative choice can shape the scientific validity of studies involving assessment of respiratory mechanics.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275838","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":"Sympathetic Nerve Activation Drives Cardiac Fibrosis and Arrhythmia in Lean Metabolic Dysfunction-Associated Steatohepatitis Mice Concurrently Exposed to Ethanol and a High-Fat/High-Cholesterol Diet","authors":"Jinyao Liu,&nbsp;Seiko Yamano","doi":"10.1111/1440-1681.70111","DOIUrl":"10.1111/1440-1681.70111","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lean metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognised in non-obese individuals and is associated with cardiovascular complications, including arrhythmias. Although sympathetic activation and inflammation have been implicated in disease progression, their mechanistic roles in cardiac fibrosis and arrhythmogenesis in lean MASH remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate the contribution of sympathetic nerve activation to myocardial fibrosis and arrhythmia in a lean MASH mouse model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>Male C57BL/6J mice were fed a high-fat/high-cholesterol diet (STHD-01) with or without ethanol for 12 weeks. Hepatic and cardiac changes were evaluated by histology, immunohistochemistry, reverse transcription–polymerase chain reaction, and plasma biochemistry. Arrhythmias were recorded by electrocardiogram telemetry. Despite reduced body weight, mice receiving STHD-01 plus ethanol developed marked hepatic and cardiac inflammation and fibrosis. Sympathetic activation, indicated by tyrosine hydroxylase co-localization with cluster of differentiation 68-positive macrophages and with α-smooth muscle actin–positive fibroblast-like stromal cells, was associated with increased expression of tumour necrosis factor-α and transforming growth factor-β1, respectively. These mice exhibited a significantly higher incidence of lethal arrhythmias. Expression of inflammatory and fibrotic genes showed moderate to strong correlations between the liver and heart.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Sympathetic nerve–associated activation of macrophages and fibroblast-like stromal cells is linked to myocardial fibrosis and increased arrhythmia susceptibility in lean MASH. Even modest ethanol intake appears to accelerate disease progression and heighten arrhythmia risk when combined with a high-fat/high-cholesterol diet. These findings suggest that targeting sympathetic activation and inflammation may represent a potential therapeutic strategy for cardiovascular prevention in lean MASH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269839","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":"Gemfibrozil Prevents Myocardial Ischemia–Reperfusion Injury in Mice Through AMPK Activation","authors":"Yilong Jiang,&nbsp;Weijing Wang,&nbsp;Qi Li,&nbsp;Tianchen Xia,&nbsp;Boyu Xia,&nbsp;Chao Huang,&nbsp;Xu Lu,&nbsp;Le Yin,&nbsp;Qingsheng You,&nbsp;Rongrong Yang","doi":"10.1111/1440-1681.70106","DOIUrl":"10.1111/1440-1681.70106","url":null,"abstract":"<div>\u0000 \u0000 <p>Myocardial ischemia–reperfusion injury (MIRI) causes severe clinical complications in patients. Although gemfibrozil (GEM) has been extensively studied in metabolic diseases, its effects on MIRI remain unknown. In this study, we investigated the pharmacological effects and molecular mechanisms of GEM in alleviating MIRI through adenosine 5′-monophosphate-activated protein kinase (AMPK) modulation. The results showed that pre-administration of GEM (100 mg/kg) provided significant protection against MIRI in mice, as indicated by reduced infarct size, lower cardiac injury markers such as hydrogen peroxide (H₂O₂), lactate dehydrogenase (LDH), and creatine kinase (CK), and improved cardiac function. This cardioprotective effect of GEM was associated with enhanced myocardial antioxidant capacity, as shown by decreased dihydroethidium (DHE) fluorescence density and reduced nitric oxide (NO) and malondialdehyde (MDA) levels in ischemic cardiac tissue. GEM pretreatment also prevented the I/R-induced increase in TUNEL-positive cells and expression of caspase-3, caspase-9, and Bax, as well as the I/R-induced decrease in Bcl-2 expression in ischemic cardiac tissue, indicating an anti-apoptotic effect of GEM in MIRI. In addition, GEM pretreatment prevented the I/R-induced increase in mRNA expression levels of tumour necrosis factor-<i>α</i> (<i>Tnf-α</i>), interleukin-<i>β</i> (<i>Il-1β</i>), and <i>Il-6</i> in ischemic cardiac tissue. Further analysis showed that GEM administration prevented the I/R-induced decrease in phospho-AMPK levels in ischemic cardiac tissue, and pharmacological inhibition of AMPK with dorsomorphin (DSMF) abolished all cardioprotective effects of GEM. Taken together, these results suggest that GEM mitigates MIRI-induced cardiac injury by inhibiting apoptosis and oxidative stress via modulation of AMPK, supporting its potential for reducing MIRI-related cardiac damage.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212406","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":"The TNF-α–FABP4–Dhhc7 Axis Mediates Olanzapine-Induced Insulin Resistance in Rats and Humans","authors":"Jing Wang,&nbsp;Peiru Chen,&nbsp;Chuyue Tu,&nbsp;Qian Wu,&nbsp;Yahui Deng,&nbsp;Lixiu Yu,&nbsp;Xiaojin Xu,&nbsp;Xiangming Fang,&nbsp;Weiyong Li","doi":"10.1111/1440-1681.70104","DOIUrl":"10.1111/1440-1681.70104","url":null,"abstract":"<div>\u0000 \u0000 <p>A rapid increase in the incidence of insulin resistance (IR) induced by long-term olanzapine treatment has been observed; however, there are no more efficient ways to prevent IR. Our study aimed to demonstrate the mechanism underlying olanzapine-induced insulin resistance. In this study, we first analysed the data of 120 schizophrenia patients who had been taking olanzapine for at least 3 months. Eventually, it was found that an increase in circulating tumour necrosis factor-α (TNF-α, <i>p</i> &lt; 0.05). Subsequently, we verified this finding in a rat model. We detected the expression levels of the target genes fatty acid binding protein 4 (FABP4) and the palmitoyltransferase <i>Dhhc7</i> in both rats and three T3-L1 adipocytes by using Western blotting and polymerase chain reaction (<i>p</i> &lt; 0.05). Exposure to olanzapine increased the expression of FABP4 while decreasing the expression of <i>Dhhc7</i>. Additionally, we demonstrated that it may affect metabolism by inhibiting glucose transporter 4 (GLUT4) membrane transport. Finally, we improved olanzapine-induced insulin resistance by injecting FABP4 adenovirus and elucidating its underlying mechanism. In summary, our study demonstrated that long-term exposure to olanzapine increases circulating plasma levels of TNF-α, thus leading to increased expression of FABP4 protein in white adipose tissue and subsequently inhibiting <i>Dhhc7</i>expression, which correspondingly leads to reduced membrane translocation of GLUT4 and consequent insulin resistance. In conclusion, this study elucidated the signalling pathway through which olanzapine inhibits GLUT4 membrane transport via the TNF-α/FABP4/<i>Dhhc7</i> axis, thus ultimately leading to insulin resistance.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200237","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":"Acupuncture Alleviates Cerebral Ischemia–Reperfusion Injury by Inhibiting Ferroptosis Through the IRP2/IRE Pathway","authors":"Jia Yuan,&nbsp;Litong Chen,&nbsp;Qianjun Li,&nbsp;Rongqi Wei,&nbsp;Xiaoyue Liu,&nbsp;Chutao Chen,&nbsp;Haomei Tian","doi":"10.1111/1440-1681.70109","DOIUrl":"10.1111/1440-1681.70109","url":null,"abstract":"<p>Acupuncture (AC) has been demonstrated to improve outcomes in ischemic stroke. However, its precise mechanism of action remains incompletely understood. This study investigated the effects of AC in a rat model of cerebral ischemia–reperfusion injury (CIRI). A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established to create CIRI rats. Rats were randomly assigned to the Sham, MCAO/R, AC + MCAO/R, IRP2⁽⁺⁾ + MCAO/R, IRP2⁽⁻⁾ + MCAO/R and IRP2⁽⁻⁾ + AC + MCAO/R groups. Neurological function was assessed using the Garcia scores. TTC staining was used to observe cerebral infarction volume ratios. Transmission electron microscopy (TEM) examined mitochondrial structure in neurons within the ischemic penumbra. Colorimetric assays measured Fe²⁺ content in neurons, along with ferroptosis-related biomarkers Reactive oxygen species (ROS), Glutathione peroxidase 4 (GPX4), Malondialdehyde (MDA) and Glutathione (GSH). Immunofluorescence staining detected Transferrin receptor 1 (TFR1), Ferritin (FER), Ferroportin (FPN) and Iron regulatory protein 2 (IRP2) expressions in the ischemic penumbra. RT-qPCR measured IRP2 mRNA expression, whilst RNA immunoprecipitation (RIP) analysis assessed the impact of each group on IRP2 binding to IRE. Our results showed AC improved neurological deficits, reduced infarct volume, decreased Fe²⁺ overload, enhanced antioxidant markers GPX4 and GSH, and lowered lipid peroxidation levels of ROS and MDA. It also attenuated mitochondrial structural damage related to ferroptosis. Immunofluorescence staining and RT-qPCR analyses revealed that AC downregulated TFR1 and FER expression whilst upregulating FPN and IRP2 expression. Furthermore, RNA immunoprecipitation assays revealed enhanced binding affinity between IRP2 and IRE after AC. These findings indicate that AC inhibits neuronal ferroptosis after CIRI and protects brain tissue, possibly by promoting IRP2-IRE binding, modulating neuronal iron metabolism, and reducing lipid peroxidation.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 2","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12900629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178134","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}