Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"DUSP1 Inhibits Mechanotransduction and MAPK Signalling to Alleviate Myocardial Cell Hypertrophy","authors":"Xiao Zhong,&nbsp;Lingran Kong,&nbsp;Youjun Zhang,&nbsp;Jian Li,&nbsp;Shaofeng Guan,&nbsp;Xinkai Qu","doi":"10.1111/1440-1681.70152","DOIUrl":"https://doi.org/10.1111/1440-1681.70152","url":null,"abstract":"<div>\u0000 \u0000 <p>Hypertrophic Cardiomyopathy (HCM) is one of the significant causes of heart failure. This study aimed to identify and validate potential therapeutic targets for HCM through bioinformatics analysis and in vitro and in vivo experiments. By analysing differentially expressed genes in HCM patients and combining multiple analytical approaches, key genes were screened. The functions of these genes were validated using AC16 cells under different mechanical force environments and Ang—II induction. HCM-like pathological cardiac remodelling mouse model was established to evaluate myocardial hypertrophy, fibrosis and cardiac remodelling. The results demonstrated that <i>DUSP1</i> expression was downregulated in the myocardium of HCM patients. Mechanical force transduction activated the MAPK pathway and overexpression of DUSP1 suppressed ERK/MAPK activation and attenuated mechanotransduction-associated cardiomyocyte hypertrophy and hypertrophic gene expression. In vivo experiments showed that cardiac-specific restoration of DUSP1 expression alleviated pathological cardiac remodelling and fibrosis. This study suggests that DUSP1 functions as an endogenous regulator of mechanically activated MAPK signalling, thereby limiting pathological myocardial hypertrophy. These findings identify a previously underappreciated role of DUSP1 in linking mechanical stress-induced signalling with MAPK activation and pathological cardiac remodelling, suggesting DUSP1 restoration as a potential therapeutic strategy for HCM-like cardiac remodelling.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 9","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783928","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":"Polyphyllin I Orchestrates Autophagy to Reprogram the Tumour Immune Microenvironment and Abrogate Cisplatin Resistance in Non-Small Cell Lung Cancer","authors":"Zongxu Liu,&nbsp;Yanping Li,&nbsp;Shumin Li,&nbsp;Zhen Wang,&nbsp;Huilan Zhao,&nbsp;Kunbin Ke,&nbsp;Chunping Wan,&nbsp;Xinan Shi","doi":"10.1111/1440-1681.70149","DOIUrl":"https://doi.org/10.1111/1440-1681.70149","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aims to elucidate the molecular mechanisms by which Polyphyllin I (PPI), a potent steroidal saponin, attenuates non-small cell lung cancer (NSCLC) progression via mechanistic reprogramming of an autophagy-dependent immunogenic response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Integrated in vitro (A549, H460) and in vivo (LLC xenograft) models were deployed to evaluate PPI's efficacy on autophagic flux and the tumour immune microenvironment. The regulatory role of autophagy in macrophage-mediated antigen presentation was scrutinised via ATG3-mediated genetic silencing or overexpression in tumour-macrophage co-culture systems. Concurrently, the capacity of PPI to sensitise NSCLC cells to cisplatin (DDP) and counteract chemoresistance was evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PPI activated the AMPK/p53/mTOR signalling axis, robustly inducing core autophagic markers (LC3-II and Beclin-1) in a dose-dependent manner. Mechanistically, PPI-induced autophagic flux served as a prerequisite for antitumoural M1 macrophage polarisation, characterised by significant upregulation of iNOS and MHC-II in co-cultured THP-1 cells. Genetic knockdown of ATG3 effectively abrogated these immunostimulatory profiles, whereas ATG3 overexpression potentiated PPI-driven antigen presentation. Furthermore, PPI administration markedly delayed the onset of DDP resistance sustained by functional autophagic flux. In vivo, PPI significantly suppressed tumour burden, accompanied by enhanced CD8+ T-cell infiltration and elevated cytotoxic effector levels (IFN-γ and Granzyme B).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings establish PPI as a dual autophagic-immune modulator that re-engineers the immunosuppressive microenvironment. By coupling intracellular autophagic stress with macrophage-mediated antigen presentation, PPI reinstates antitumour immunity and abrogates chemoresistance, offering a compelling therapeutic framework for managing recalcitrant NSCLC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 8","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754112","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":"CaV1.2 Is Implicated in IgE-Mediated Mast Cell Activation and Food Allergy","authors":"Tingting Deng,&nbsp;Wen Zhang,&nbsp;Jiahui Meng,&nbsp;Jie Gao,&nbsp;Chang Gao,&nbsp;Shiyu Li,&nbsp;Jiaxing Wang,&nbsp;Zijian Zeng,&nbsp;Yongjing Zhang,&nbsp;Nan Wang","doi":"10.1111/1440-1681.70148","DOIUrl":"10.1111/1440-1681.70148","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Food allergy (FA) is a disorder marked by a significant incidence of detrimental immunological responses to certain dietary constituents, while preventive measures and regulatory treatments are scarce. Mast cells (MCs) are integral to the pathogenesis of FA mediated by Immunoglobulin E (IgE). The activation of MCs is modulated by their intracellular Ca²⁺ concentrations, with Ca_V1.2 serving as a voltage-gated calcium channel that regulates calcium influx in MCs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The aim of this study was to examine the influence of Ca_V1.2 on MCs' activation and its role in the onset and progression of FA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The inhibitory effect of nimodipine (Nim) on MCs activation in vitro was evaluated by detecting LAD2 degranulation and cytokine release; the anti-food allergy effect of Nim was examined by the establishment of an IgE-mediated FA model; the effect of Ca_V1.2 on the occurrence of FA was investigated using conditional knockout of Ca_V1.2 in MCs (CKO) mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Nim inhibited MCs activation in vitro and alleviated ovalbumin (OVA)-induced FA in vivo. The expression of Ca_V1.2 in MCs exhibited detrimental effects, whereas its deficiency ameliorated local and systemic allergy and significantly alleviated FA in mice. When Ca_V1.2 was replenished in CKO mice by BMMC injection, such supplementation exacerbated FA symptoms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Depression of Ca_V1.2 in MCs attenuates the activation of MCs and alleviates the symptoms of FA. These results suggest that Ca_V1.2 could be a new target for FA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 8","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148725279","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":"Brazilin From Biancaea sappan as a Multi-Target Candidate in Thalassaemia: Mechanistic Insights Into Iron Chelation, Antioxidant Activity, and Potential JAK2 Modulation","authors":"Racy Youngest,&nbsp;Yusof Kamisah,&nbsp;Ratu Safitri,&nbsp;Ani Melani Maskoen","doi":"10.1111/1440-1681.70145","DOIUrl":"10.1111/1440-1681.70145","url":null,"abstract":"<div>\u0000 \u0000 <p>Thalassaemia is a hereditary haemoglobinopathy characterised by impaired globin synthesis, resulting in ineffective erythropoiesis and systemic iron overload. While current management relies on blood transfusions and chelation, these often fail to address the underlying molecular signalling dysregulation that contributes to the disease's progression, such as the imbalance in erythropoietin production and the activation of inflammatory pathways. Brazilin, the primary homoisoflavonoid from <i>Biancaea sappan</i> L., presents a multifaceted therapeutic profile. This review synthesises evidence of brazilin's activity as a potent iron chelator and reactive oxygen species (ROS) scavenger and anti-inflammatory agent, while evaluating its potential as a novel JAK2 inhibitor. Molecular docking suggests brazilin may bind to the JAK2 ATP-binding pocket, though functional validation is still required. By modulating the erythroferrone (ERFE)–hepcidin (HAMP) axis, brazilin potentially restores iron homeostasis and mitigates splenomegaly. We further evaluate its pharmacokinetics and safety profile, highlighting low toxicity and high oral bioavailability. This positions brazilin as a promising lead candidate for thalassaemia adjunct treatment, warranting further in vivo validation.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 8","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705667","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":"Targeting of Pentraxin 3 Alleviated Cardiac Hypertrophy in Mice Induced by Angiotensin II","authors":"Qiming Tan,&nbsp;Xiaoxuan Gong,&nbsp;Tian Wu,&nbsp;Chen Li,&nbsp;Kun Liu,&nbsp;Daorong Hou","doi":"10.1111/1440-1681.70139","DOIUrl":"10.1111/1440-1681.70139","url":null,"abstract":"<p>Pentraxin 3 (PTX3) responds rapidly to inflammatory signals. This study investigated the functional involvement of PTX3 in angiotensin II (Ang II)-mediated cardiac hypertrophy pathogenesis, with particular focus on its potential regulation through inflammatory pathways and oxidative stress mechanisms. In vivo, chronic Ang II infusion over 4 weeks was used to induce hypertrophic cardiomyopathy in mice. In parallel, an in vitro model of cardiomyocyte hypertrophy was established by treating neonatal rat cardiomyocytes (NRCMs) with Ang II for 24 h. Ang II treatment significantly increased PTX3 expression, an effect observed in both mouse heart tissue and NRCMs. The cardiac hypertrophy and fibrosis in mice treated with Ang II were alleviated by PTX3 knockout. Genetic ablation of PTX3 attenuated Ang II-induced upregulation of cardiac hypertrophy markers in mice hearts, including atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain. Additionally, PTX3 knockout suppressed the elevation of pro-inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-1beta, following Ang II stimulation. Genetic deficiency of PTX3 significantly ameliorated cardiac oxidative stress potentiated by Ang II infusion. These outcomes showed that targeting of PTX3 could ameliorate hypertrophic cardiomyopathy via attenuation of inflammatory response and oxidative stress. PTX3 may be a target for therapy of hypertrophic cardiomyopathy in the future.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 8","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683587","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":"Bosutinib Inhibits USP9X to Suppress the Proliferation, Migration, Angiogenesis and Glycolysis of Hepatocellular Carcinoma Cells by Deubiquitinating PLK1","authors":"Cuiping Lu,&nbsp;Tiantian Cao,&nbsp;Zirong Li,&nbsp;Fobao Lai","doi":"10.1111/1440-1681.70147","DOIUrl":"10.1111/1440-1681.70147","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness is deemed inadequate, and the range of therapeutic targets is limited. This study aimed to explore the efficacy of Bosutinib (BOS) in HCC and the underlying molecular mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatic analysis, machine learning, and online databases were used for screening targets and molecular docking studies. The mRNA level of mammalian polo-like kinase 1 (<i>PLK1</i>) was identified via real-time quantitative PCR. The protein expression of PLK1, PTK2, and USP9X was detected using western blot. Cell viability, apoptosis, and migration were evaluated by MTT, flow cytometry, and transwell assay. The angiogenesis capacity was determined using tube formation assay. The glucose consumption, lactate production, and ATP/ADP ratios were analysed using commercial kits. CO-IP assay was used to confirm the interaction between <i>PLK1</i> and <i>USP9X</i>. A mouse model was used for exploring BOS in vivo. Immunochemistry was used to examine <i>PLK1</i> and <i>USP9X</i> expression in tumours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This study illustrated that BOS inhibited proliferation, migration, angiogenesis, and glycolysis of HCC cells. Bioinformatic analysis and machine learning identified <i>PLK1</i> as a core gene related to the glycolysis of HCC. <i>PLK1</i> was upregulated in HCC and correlated with an unfavourable prognosis. Further evaluation showed that the anti-tumour effects of BOS were impaired by <i>PLK1</i> overexpression. In addition, BOS treatment inhibited PLK1 protein level, while its mRNA level was not affected. Moreover, Bosutinib inhibited USP9X to reduce the deubiquitination of PLK1. CO-IP assay indicated that reduced USP9X could enhance the ubiquitination of PLK1 and reduce protein stability. Finally, BOS showed anti-tumour effects in a mouse model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study revealed that BOS inhibited cell proliferation, migration, angiogenesis, and glycolysis via suppressing <i>USP9X</i>, thus reducing deubiquitination of <i>PLK1</i> in HCC, demonstrating the potential of BOS for the treatment of HCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 7","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444820","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":"Electroacupuncture Alleviates Focal Cerebral Ischemia–Reperfusion Injury and Is Associated With Modulation of Autophagy-Ferroptosis Involving the STAT3/HIF-1α Signalling Pathway","authors":"Sisi Li,&nbsp;Liping Gao,&nbsp;Linjie Mu,&nbsp;Junhong Lu,&nbsp;Hongyi Chen,&nbsp;Wenzhan Tu,&nbsp;Qiaoyun Wu,&nbsp;Zhongxiao Lin","doi":"10.1111/1440-1681.70146","DOIUrl":"10.1111/1440-1681.70146","url":null,"abstract":"<div>\u0000 \u0000 <p>Focal cerebral ischemia–reperfusion injury remains a major clinical challenge in stroke management. Electroacupuncture (EA) may confer neuroprotection by modulating key cellular processes; however, its precise role in regulating autophagy-ferroptosis crosstalk remains largely unclear. The present study aimed to investigate the neuroprotective potential of EA in cerebral ischemia–reperfusion injury, with a focus on exploring potential pathways involving autophagy and ferroptosis regulation. Focal cerebral ischemia–reperfusion injury was modelled using middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and oxygen–glucose deprivation/reperfusion (OGD/R) in vitro. The therapeutic effect of EA on MCAO/R mice was assessed using several methods, including behavioural tests, cerebral blood flow measurement, and cerebral infarction volume analysis. Molecular analyses used immunofluorescence staining, western blot analysis, and transmission electron microscopy to examine signal transducer and activator of transcription 3 (STAT3)/hypoxia-inducible factor-1α (HIF-1α) pathway activity and its relationship with autophagy/ferroptosis markers. In MCAO/R mice, EA intervention improved neurological functional recovery, decreased cerebral infarction, and enhanced blood flow. EA also downregulated activation of the STAT3/HIF-1α signalling pathway. Furthermore, EA was associated with reduced markers of excessive autophagy and reduced ferroptosis markers in neurons. IL-6-mediated enhancement of STAT3 phosphorylation significantly weakened EA's protective effects against cerebral ischemia–reperfusion injury. In vitro, STAT3 knockdown prevented OGD/R-induced activation of STAT3/HIF-1α signalling and was accompanied by reduced autophagy and ferroptosis markers. Our results suggest that EA exerts neuroprotective effects against cerebral ischemic injury, which may be associated with modulation of autophagy and ferroptosis markers via the STAT3/HIF-1α signalling pathway.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 7","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396150","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":"Relationship Between Long-Term Exposure to Airborne Particulate Matter and the Intrinsic Capacity of Middle-Aged and Older Adults in China: A Retrospective Cohort Study Based on CHARLS","authors":"Jiatong Li,&nbsp;Yuxin Wu,&nbsp;Yaru Zhou,&nbsp;Jitong Zhou,&nbsp;Yigeng Huang,&nbsp;Xinyi Sun,&nbsp;Tongtong Ye,&nbsp;Mingxing Xu,&nbsp;Huanqin Wang,&nbsp;Shu Wang","doi":"10.1111/1440-1681.70144","DOIUrl":"10.1111/1440-1681.70144","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intrinsic capacity (IC), proposed by the World Health Organization, reflects the composite of an individual's physical and mental capacities and is considered a key indicator of healthy aging. Although air pollution has been associated with multiple adverse health outcomes, evidence on its relationship with IC—a multidimensional indicator of overall functional ability—remains limited.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aimed to examine the longitudinal associations between long-term exposure to particulate matter of different sizes (PM₁, PM_2.5 and PM₁₀) and declines in intrinsic capacity among middle-aged and older adults in mainland China.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data were obtained from the nationally representative longitudinal cohort of the China Health and Retirement Longitudinal Study (CHARLS), including adults aged ≥ 45 years. Annual average concentrations of PM₁, PM_2.5 and PM₁₀ were estimated using satellite-based models based on participants' residential locations. A composite IC score was constructed according to the WHO intrinsic capacity framework. Multivariable logistic regression models were used to evaluate associations between particulate matter exposure and IC decline. Restricted cubic spline models were applied to assess nonlinear dose–response relationships. Mixed-exposure effects were further evaluated using weighted quantile sum regression, Bayesian kernel machine regression and quantile g-computation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Long-term exposure to PM₁, PM_2.5 and PM₁₀ was significantly associated with a higher risk of IC decline and lower composite IC scores. Nonlinear dose–response relationships were observed between particulate matter exposure and IC decline. In mixed-exposure analyses, PM₁₀ and PM_2.5 showed the strongest contributions to the joint effects, with PM₁₀ having the highest weight and posterior inclusion probability. Each one-quantile increase in the overall pollutant mixture was significantly associated with a decline in composite IC scores.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 7","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359694","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":"Dapagliflozin Improves Mitochondrial Function to Reduce the Risk of Atrial Fibrillation in a High-Glucose Environment by Activating the AMPK/PGC-1α/SIRT3 Signalling Pathway","authors":"Xingxing Li,&nbsp;Guibing He,&nbsp;Fen Zhang,&nbsp;Jie Wu,&nbsp;Shu Chen,&nbsp;Yang Dong","doi":"10.1111/1440-1681.70143","DOIUrl":"10.1111/1440-1681.70143","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;Type 2 Diabetes Mellitus (T2DM) and AF (Atrial Fibrillation) frequently coexist, amplifying cardiovascular risks via shared mitochondrial dysfunction involving metabolic dysregulation, oxidative stress, and inflammation. While the SGLT2 inhibitor dapagliflozin (DAPA) demonstrates cardiorenal protection through mitochondrial improvement, its direct mechanistic actions in T2DM-AF patients remain unknown. Our study aimed to elucidate DAPA's mitochondrial regulatory mechanisms in T2DM-AF to break the vicious cycle of mitochondrial dysfunction remodelling, addressing an unmet clinical need in this high-risk population.&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;The high-glucose atrial fibrillation (HG-AF) model was established using 30 mM glucose combined with 10 Hz electrical stimulation, followed by validation through glucose uptake assay, electrophysiology, and fibrosis-related protein and calcium transient analysis. Mitochondrial function was evaluated using ROS/JC-1 probes, ATP quantification, and mitochondrial-related protein expression. To investigate the role of DAPA, we assessed its activation of the AMPK/PGC-1α/SIRT3 signalling pathway via western blot and further confirmed the mechanism using the AMPKα inhibitor Compound C. In addition, a mouse model of HG-AF was established to further validate the in vitro results.&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;Cell experiments showed that after treatment with 30 mM glucose and 10 Hz electrical stimulation, HL-1 cells exhibited increased 2-NBDG uptake, decreased Fluo-4 AM intensity, upregulation of glucose transporters and fibrosis-related proteins, and disrupted electrophysiological protein expression, confirming the successful establishment of the HG-AF model. DAPA treatment attenuated fibrosis, restored electrophysiological protein expression, decreased Drp1, and increased OPA1 and SOD2 levels. It also enhanced Fluo-4 AM intensity, reduced ROS, improved JC-1 aggregates, and boosted ATP production. In vivo experiments further confirmed that in HG-AF mice, the duration of AF and the RR interval were significantly prolonged, and there was upregulation of CaMKII/ox-CaMKII, downregulation of ion channel proteins, and elevated levels of fibronectin in cardiac tissue. DAPA treatment activated the AMPK/PGC-1α/SIRT3 pathway, reduced the acetylation levels of OPA1 and SOD2, increased ATP levels, and decreased MDA levels. Pretreatment with Compound C abolished the DAPA-induced activation of the aforementioned pathway and the improvement in mitochondrial function.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In the HG-AF setting, DAPA at","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 7","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350905","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":"Hypertension-Mediated Organ Damage: Pathophysiological Mechanisms, Clinical Consequences, and Implications for Early Risk Stratification","authors":"Ali Hussein Choker","doi":"10.1111/1440-1681.70142","DOIUrl":"https://doi.org/10.1111/1440-1681.70142","url":null,"abstract":"<div>\u0000 \u0000 <p>Hypertension-mediated organ damage (HMOD) represents a critical and dynamic stage on the cardiovascular continuum, serving as the primary mechanistic link between sustained arterial pressure elevation and major adverse cardiovascular and renal events. HMOD is often subclinical at first occurrence and is a systemic, cumulative process, representing structural and functional injury of the heart, brain, kidneys, and vasculature. This narrative review synthesises current evidence on the pathogenesis and clinical sequelae of HMOD, specifically focusing on the interplay between chronic haemodynamic load, endothelial dysfunction, oxidative stress, neurohormonal activation, inflammation, and microvascular remodelling. Key manifestations such as left ventricular hypertrophy, hypertensive nephrosclerosis, cerebral small vessel disease, and arterial stiffness can be regarded as dynamic and partly modifiable phenomena of subclinical injury rather than inevitable sequelae of long-standing hypertension. This review aims to summarise contemporary detection and risk stratification approaches, drawing on the 2023 European Society of Hypertension (ESH) and 2024 European Society of Cardiology (ESC) guidelines, combining imaging and biomarker-based assessment. Evidence supporting organ protection as an important therapeutic objective is also reviewed, with particular attention to regression of left ventricular mass and reduction in albuminuria as treatment endpoints associated with improved prognosis beyond blood pressure reduction alone. Finally, unresolved issues such as causal versus associative properties of candidate biomarkers, comparative validity of vascular indices, and heterogeneity in organ-specific response to therapy are critically analysed. The overarching goal of this review is to support a clinically applicable framework for early HMOD detection and organ-protective treatment strategies in routine hypertension care.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 7","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148274842","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}