Canadian journal of physiology and pharmacology最新文献

{"title":"Integrating network pharmacology and metabolomics to elucidate the mechanism of allopurinol in hyperuricemia treatment.","authors":"Yu Xu, Wenqian Ye, Pengyu Tian, Jiangtao Zhou, Zhijia Zhang, Fan Yang","doi":"10.1139/cjpp-2025-0391","DOIUrl":"10.1139/cjpp-2025-0391","url":null,"abstract":"<p><p>This study integrated network pharmacology and metabolomics to investigate the mechanism of allopurinol in treating hyperuricemia. Therapeutic targets were identified by screening drug and disease databases. A drug-target-disease network was constructed and validated by molecular docking using Cytoscape. A mouse model of hyperuricemia was established with yeast extract and potassium oxonate. Allopurinol efficacy was evaluated via body weight, renal histopathology, and serum biochemical indices. Enrichment analyses of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways were performed using DAVID platform. Serum metabolite profiles were analyzed by UPLC-Q-TOF/MS-based metabolomics, and metabolic pathways were explored using MetaboAnalyst 6.0. Network pharmacology and molecular docking identified 23 key targets and 43 signaling pathways related to allopurinol treatment. Animal experiments confirmed allopurinol significantly reduced serum levels of uric acid, creatinine, blood urea nitrogen, and xanthine oxidase activity. Metabolomic analysis revealed 5 differentially regulated metabolites and 13 key metabolic pathways associated with allopurinol intervention. The integrated results indicated that allopurinol treats hyperuricemia not only by modulating purine metabolism but also potentially through influencing oxidative stress and apoptosis-related pathways. This study provided preliminary experimental insights into the potential mechanistic basis of allopurinol in the treatment of hyperuricemia.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-11"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758815","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":"Autophagy-regulated myocardial fibrosis: from mechanistic exploration to therapeutic prospects.","authors":"Nuotong Wang, Wanqing Xu, Yan Hu, Zhenyu Wang, Xinyi Yang, Shiying Xu, Ziyu Ma, Joseph Adu-Amankwaah, Mingming Wang, Cui Li","doi":"10.1139/cjpp-2026-0032","DOIUrl":"10.1139/cjpp-2026-0032","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) represent a leading cause of global mortality. Myocardial fibrosis (MF), a common pathological hallmark in CVDs, signifies disease progression to severe stages. Its pathogenesis is highly complex, with autophagy playing a pivotal regulatory role. This narrative review synthesizes and critically evaluates the current literature to elucidate the interplay between MF and autophagy. The focus lies on systematically examining the molecular mechanisms and key signaling pathways involved in autophagy-mediated regulation of MF. We systematically examine key molecular pathways and components through which autophagy regulates MF, including mitophagy, the NLRP3 inflammasome, FOXO signaling, the ULK1 complex, the mTOR pathway, and TGF-β signaling. These pathways collectively influence fibroblast activation, collagen metabolism, and overall cardiac ECM remodeling. Autophagy serves as a crucial modulator of MF through multiple interconnected molecular pathways. Targeting specific nodes within the autophagic process holds significant therapeutic promise for mitigating MF and slowing CVD progression. This review consolidates current understanding and highlights novel insights, underscoring the need for further research to translate these mechanisms into effective clinical interventions.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-25"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788750","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":"Cardiotropic adeno-associated virus-based gene therapy via intracoronary delivery for nonischemic heart failure.","authors":"Joseph D Abraham, Eugene S Chung, Sitaramesh Emani, Ankit Bhatia, Gregory Egnaczyk, Santosh Sanganalmath, Luke Roberts, Timothy D Henry","doi":"10.1139/cjpp-2026-0115","DOIUrl":"10.1139/cjpp-2026-0115","url":null,"abstract":"<p><p>Heart failure (HF) remains a leading cause of morbidity and mortality with significant residual risk despite major advances in medical therapies. Development of cardiotropic vectors have allowed gene therapy to be revisited to target the molecular roots of HF to potentially improve structural cardiac remodeling and cardiac contractility on top of functional improvement offered by current standard of care therapies. In a first-in-human phase 1 trial, a cardiotropic vector gene AB-1002 targets a phosphorylation pathway responsible for calcium handling in cardiomyocytes. AB-1002 stimulates inhibitor 1 (I-1c), which functions to inhibit protein phosphatase 1 (PP1). PP1 overactivity contributes to maladaptive calcium dynamics. AB-1002 has favorable safety and efficacy profiles, potentially representing a promising new frontier in HF treatment.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-5"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788787","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":"Cardiovascular effects of incretin receptor agonists: beyond glycemic control.","authors":"Marko P Ravic, Ivan M Srejovic, Isidora M Milosavljevic, Jovana N Novakovic, Vladimir Lj Jakovljevic, Ksenija V Vucicevic, Djurdjina M Petrovic, Maja D Muric","doi":"10.1139/cjpp-2026-0184","DOIUrl":"10.1139/cjpp-2026-0184","url":null,"abstract":"<p><p>Incretin-based therapies have evolved from selective glucagon-like peptide-1 receptor agonists (GLP-1RA) to dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists and unimolecular triple GLP-1/GIP/glucagon receptor agonists. This review examines the cardiovascular effects of these three pharmacological tiers, with emphasis on mechanisms that operate beyond glycaemic control. Mediation analyses of major cardiovascular outcome trials indicate that glycaemic improvement accounts for less than 15%-20% of the reduction in major adverse cardiovascular events achieved by these agents. The remainder reflects converging effects on weight reduction, lipid remodelling, blood pressure, systemic inflammation, and direct myocardial protection. At the cellular level, incretin signalling preserves mitochondrial bioenergetics, activates antioxidant defences, and inhibits multiple cardiomyocyte death pathways. At the tissue level, recent investigations in isolated human atrial preparations demonstrate direct positive inotropic effects of both GLP-1RA and the triple agonist retatrutide. Cardiac magnetic resonance evidence from the SUMMIT programme documents reverse left ventricular remodelling with tirzepatide in obesity-related heart failure with preserved ejection fraction. Phase 2 data for triple agonists have produced unprecedented surrogate cardiovascular improvements, while Phase 3 outcome data from the TRIUMPH programme remain awaited. The cardiovascular pharmacology of metabolic disease has been fundamentally reshaped, and ongoing trials will determine whether multi-receptor agonism establishes a new therapeutic standard.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-13"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148928933","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":"Endothelin receptor antagonism in sickle cell disease: Is the time now?","authors":"Bryant J Kane, Vimal K Derebail, Malgorzata Kasztan","doi":"10.1139/cjpp-2026-0168","DOIUrl":"10.1139/cjpp-2026-0168","url":null,"abstract":"<p><p>Sickle cell disease (SCD) is a severe heritable hemoglobinopathy characterized by chronic hemolysis, episodic vaso-occlusion, and progressive multi-organ damage. Although hydroxyurea remains the most established disease-modifying therapy and that newer approaches such as L-glutamine, voxelotor, crizanlizumab, and gene therapy have expanded the therapeutic landscape, important limitations remain. These include incomplete efficacy, recent clinical or regulatory setbacks, as well as high cost and access barriers. Thus, safe, accessible, and mechanistically targeted treatments remain urgently needed, particularly for patients with progressive end-organ injury. Mounting evidence implicates the peptide endothelin-1 (ET-1) as a mediator of SCD pathology, and blockade of one of its primary receptors, endothelin receptor A (ET_A), may ameliorate several adverse effects. In humanized SCD mice, selective ET_A antagonism provides robust nephroprotection, while Phase I clinical data suggest a favorable safety profile in addition to signals of improved albuminuria and vascular function. In parallel, selective ET_A antagonists have rapidly advanced owing to multiple FDA approvals for proteinuric kidney diseases outside the context of SCD, in addition to approvals as antihypertensives. Here, we highlight emerging evidence supporting endothelin pathway blockade as a potential targeted therapy for complications such as sickle cell nephropathy, vasculopathy, and pain, while discussing key considerations for future trials.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-11"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929054","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":"Role of aerobic exercise training on myocardial infarction-induced cardiac dysfunction, dysautonomia, and oxidative stress in female ob/ob mice.","authors":"Filipe F Stoyell-Conti, Danielle S Dias, Michelle Sartori, Leandro E Souza, Rodolfo P Vieira, Jacqueline F Machi, Vera M C Salemi, Maria C Irigoyen, Kátia De Angelis","doi":"10.1139/cjpp-2025-0154","DOIUrl":"10.1139/cjpp-2025-0154","url":null,"abstract":"<p><p>We investigated the effects of aerobic exercise training (ET) on cardiac function, autonomic modulation, and inflammatory and oxidative stress markers in an experimental model of diabetes and obesity following myocardial infarction (MI). Female ob/ob mice were randomized into sham sedentary (S), MI sedentary (MIS), and MI + ET (MIT) groups. MI was induced by coronary artery occlusion. Cardiac function was evaluated in the beginning and at the end of the protocol. Aerobic exercise training was performed on treadmill for 4 weeks. RR interval was recorded in awake animals at the end of the protocol. Cardiac autonomic modulation was evaluated by linear and nonlinear analysis of heart rate variability. Oxidative stress and inflammatory markers were assessed. As expected, in the beginning of the protocol, the MI and MIT had a reduced ejection fraction (MIS: -44%; MIT: -33% vs. S), stroke volume (SV) (MIS: -46%; MIT: -52% vs. S), and cardiac output (CO) (MIS: -55%; MIT: -55% vs. S). At the end of the protocol, the MIS group presented lower vagal modulation, higher cardiac lipoperoxidation and protein oxidation, and lower catalase activity in the heart. On the other hand, the animals submitted to ET showed higher exercise capacity, parasympathetic modulation (RMSSD index and SD1), cardiac IL-10 and catalase activity, and lower lipoperoxidation and protein oxidation in the heart, as well as higher SV (MIT: 90% vs. Initial) and CO (MIT: 90% vs. Initial). Altogether, the results showed that myocardial infarction led to a reduction in vagal modulation and cardiac function, which was accompanied by an increased oxidative stress, while aerobic exercise training prevented/attenuated these impairments in female ob/ob mice.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-12"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148981980","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":"Note of appreciation.","authors":"","doi":"10.1139/cjpp-2025-0356","DOIUrl":"https://doi.org/10.1139/cjpp-2025-0356","url":null,"abstract":"","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":"104 ","pages":"1"},"PeriodicalIF":1.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910345","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":"Redox homeostasis and therapeutic modulation: the central role of oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2) activation in systemic diseases and reproductive dysfunction.","authors":"Abhishek Kumar, Sivaraman Ramanarayanan","doi":"10.1139/cjpp-2025-0153","DOIUrl":"10.1139/cjpp-2025-0153","url":null,"abstract":"<p><p>Oxidative stress plays a critical role in the pathogenesis of various diseases. Oxygen-containing reactive molecules commonly called as reactive oxygen species (ROS), generated during the utilization of oxygen molecule by aerobic metabolism, often form the primary cause of oxidative stress. It leads to oxidative damage to lipids, proteins, and DNA, thus contributing to mitochondrial dysfunction, inflammation, and cell death. In systemic conditions such as neurodegenerative, cardiovascular, metabolic, and oncological disorders, ROS function both as signaling molecules and mediators of pathological processes. Central to the cellular defense against oxidative stress is the transcription factor called nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of antioxidant and cytoprotective genes. Activation of the Nrf2 pathway enhances redox homeostasis, detoxification, and cell survival, thereby offering significant therapeutic potential across diverse disease states. Particularly in the field of reproductive biology, ROS-induced damage to sperm DNA, membranes, and mitochondria impairs sperm function and viability, especially under pathological conditions and during sperm cryopreservation. Similarly, in female reproductive disorders, oxidative stress disrupts hormonal balance, follicular development, and implantation. Activation of Nrf2 through natural or synthetic compounds has shown promise in preserving sperm integrity, improving post-thaw outcomes, enhancing oocyte quality, and overall reproductive outcomes by augmenting antioxidant defense. The Nrf2 activators, such as flavonoid-based modulators, offer a protective mechanism by reducing oxidative injury and restoring reproductive homeostasis. Emerging evidence from both human and animal studies highlights the utility of flavonoids and Nrf2 activators in enhancing reproductive health, providing a foundation for novel antioxidant-based therapeutic interventions.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-29"},"PeriodicalIF":1.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145343692","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":"Clinical diagnostic criteria for cardiogenic shock should be based on pathophysiology.","authors":"Petr Ostadal","doi":"10.1139/cjpp-2025-0224","DOIUrl":"10.1139/cjpp-2025-0224","url":null,"abstract":"<p><p>Cardiogenic shock is a clinical syndrome characterized by cardiac pump failure, resulting in low cardiac output and subsequent tissue hypoperfusion. Current guidelines recommend diagnosing cardiogenic shock based on the presence of hypotension and signs of hypoperfusion. However, recent randomized clinical trials have demonstrated that these criteria are imperfect and may not reliably distinguish cardiogenic shock from other forms of shock, such as hypovolemic, distributive, or mixed types. Therefore, new clinical diagnostic criteria are urgently needed. A revised definition, grounded in the underlying pathophysiology, should diagnose cardiogenic shock based on low cardiac output, objective evidence of tissue hypoperfusion from reliable biomarkers, and the exclusion of hypovolemia. Enhancing the accuracy of cardiogenic shock diagnosis could significantly improve patient selection for therapies specifically targeted at this condition.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-5"},"PeriodicalIF":1.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367562","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":"Interplay between cardiomyocytes and nonmyocytes plays a vital role in cardiac metabolism and function: early-phase metabolic syndrome and short QT.","authors":"Belma Turan, Yasemin Atici, Deniz Billur","doi":"10.1139/cjpp-2025-0184","DOIUrl":"10.1139/cjpp-2025-0184","url":null,"abstract":"<p><p>The heart is a complex organ composed of diverse cell types, primarily cardiomyocytes and nonmyocytes, which engage in intricate intercellular communication. This dynamic multicellular network is essential for maintaining cardiac function and metabolic homeostasis under physiological conditions. However, in the context of early- and late-phase metabolic syndrome (MetS), particularly induced by a high-carbohydrate diet, this cellular crosstalk becomes differentially disrupted. Among them, the early phase of MetS, characterized by hyperglycemia, insulin resistance, and dyslipidemia, promotes structural and functional remodeling of the heart, including metabolic reprogramming and increased susceptibility to arrhythmia, characterized by a short QT interval (SQT) in electrocardiograms. Concurrently, SQT, a cardiac channelopathy affecting ventricular repolarization, can exacerbate these electrophysiological disturbances. Emerging evidence suggests that interactions between cardiomyocytes and nonmyocytes mainly regulate mitochondrial dynamics, substrate metabolism, and inflammatory signaling pathways, which are crucial processes involved in both the progression of MetS and arrhythmogenic remodeling. This review examines the role of cardiomyocyte-nonmyocyte interactions in maintaining cardiac metabolic balance. It highlights how their disruption contributes to arrhythmias, such as SQT, in the early phase of MetS. Understanding this cellular interplay offers potential therapeutic avenues to restore metabolic flexibility and preserve cardiac electrophysiological integrity in metabolic and channelopathic disease states.</p>","PeriodicalId":9520,"journal":{"name":"Canadian journal of physiology and pharmacology","volume":" ","pages":"1-17"},"PeriodicalIF":1.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762311","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}