Canadian journal of physiology and pharmacology最新文献

We previously showed that male rats develop more severe cardiac hypertrophy than female rats following abdominal aortic constriction (AAC) and highlighted corresponding changes in cardiac cytochrome P450 (CYP) enzymes and their arachidonic acid (AA) metabolites. In this study, we report sex-specific changes in renal CYP enzymes and AA metabolites after AAC. Kidneys were isolated from adult male and female Sprague-Dawley rats 5 weeks after sham or AAC surgeries. Renal CYP, lipoxygenase, and epoxide hydrolase enzyme levels were measured by PCR and Western blot, and renal microsomal formation of hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs) was measured by liquid chromatography-tandem mass spectrometry. Protein levels of CYP2E1 and CYP4F were significantly elevated post-AAC only in female rats, paralleled by a significant increase in their respective metabolites, 19(R)-HETE and 20-HETE. On the other hand, CYP2C23 mRNA levels were significantly decreased only in male rats, with no significant decrease in EETs. Our findings indicate that renal CYP-mediated AA metabolism undergoes sex-specific reprogramming in response to cardiac pressure overload, which may contribute to the observed divergent cardiac remodeling. This research highlights the importance of the kidney-heart axis and supports the potential for sex-specific metabolic targets in the treatment of cardiovascular diseases.

Despite its proven efficacy in cancer treatment, doxorubicin's therapeutic potential is limited by cumulative, dose-dependent cardiotoxicity, primarily associated with oxidative stress. Given the well-documented antioxidant properties of Melissa officinalis L., this study aimed to assess the cardioprotective potential of its ethanolic extract (MOE) against doxorubicin-induced cardiotoxicity (DIC). Twenty-one female Wistar albino rats were randomly divided into three groups: CTRL (healthy, untreated), DOX (doxorubicin-treated), and DOX-MO (treated with both doxorubicin and MOE). Doxorubicin (15 mg/kg, i.p.) was administered on Day 7, while MOE (200 mg/kg, orally) was given daily for 10 days. Cardiac function was evaluated using echocardiography and Langendorff-perfused hearts, followed by analysis of oxidative stress markers and morphometric analysis. MOE improved cardiac function and partially preserved myocardial architecture following DIC, significantly reducing fibrosis compared to the DOX group. Nitrite levels were significantly elevated in MOE-treated rats, suggesting preserved endothelial function and enhanced nitric oxide-mediated vasodilation. These results suggest that MOE may mitigate DIC through antioxidative and vasodilatory mechanisms, as well as by preserving endothelial and myocardial integrity. Histological findings further indicate a possible reduction in inflammatory changes, supporting a modest anti-inflammatory effect. These findings suggest that MOE may have cardioprotective potential against DIC, warranting further investigation in preclinical and clinical settings.

Molecular hydrogen has gained attention for its potential antioxidant, anti-inflammatory, and ergogenic effects. However, its impact on blood oxygen saturation and autonomic cardiac regulation under resting conditions remains unclear. This randomized, double-blind, placebo-controlled crossover study investigated the effects of a 60 min molecular hydrogen inhalation on oxygen saturation and heart rate variability in healthy females. Twenty physically active participants (22.1 ± 1.6 years) completed two inhalation sessions with either molecular hydrogen or placebo (ambient air), separated by a 7-day washout period. Oxygen saturation and heart rate variability were continuously monitored during the 60 min of inhalation. The results using 60 min averages showed a statistically significant (p ≤ 0.007) decrease in oxygen saturation during molecular hydrogen inhalation (95.9 ± 1.0%) compared to placebo (96.7 ± 0.7%), but this decrease should not be considered clinically significant. No significant changes (all p ≥ 0.32) were observed in time-domain or frequency-domain heart rate variability indices. These findings suggest that, under resting conditions, molecular hydrogen inhalation does not induce functional changes in autonomic cardiac regulation, and the observed reduction in blood oxygen saturation does not compromise homeostatic stability.

Ischemia-reperfusion (IR) injury of vascular grafts used in coronary artery bypass surgery can compromise outcomes. This study examined whether GYY4137, a slow-release hydrogen sulfide donor, protects against IR-induced vascular damage in rat thoracic aorta. Twenty male Sprague-Dawley rats (21-22 months old) were randomly assigned to Control, IR, IR + GYY4137 (100 µM), and IR + GYY4137 (300 µM) groups. To induce IR injury, aortic rings were incubated in nitrogen-gassed saline at 4 °C for 24 h, then exposed to sodium hypochlorite (200 µM) at 37 °C for 30 min. Vascular function was evaluated in organ baths; malondialdehyde, glutathione, and caspase-3 were quantified. IR injury markedly impaired contraction and endothelium-dependent relaxation, which GYY4137 did not restore. In contrast, IR increased malondialdehyde (p = 0.02), which fell to near-control with both 100 µM (p = 0.008) and 300 µM GYY4137 (p = 0.012). IR lowered glutathione (p = 0.012) was restored by 300 µM GYY4137 (p = 0.004). Likewise, caspase-3 rose (p = 0.02) but returned to near-control with both 100 µM (p = 0.004) and 300 µM GYY4137 (p = 0.02). In conclusion, GYY4137 reduces oxidative stress and apoptosis markers without improving vascular dysfunction in an IR model of rat thoracic aorta. This disparity underscores the complex pathophysiology of vascular IR injury, where cellular-level protection does not readily translate to functional recovery.

Fructose is a simple sugar or monosaccharide, which is abundant in nature and commonly used in food industry as a strong natural sweetener. The growing epidemic of high fructose consumption has been linked to increased prevalence of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. Increasing evidence indicates that high dietary fructose can exert direct effects on the heart as well as the vasculature. Several underlying mechanisms involving metabolic disturbances, oxidative stress, and inflammation have been demonstrated to induce cardiac dysfunction and vascular abnormalities. Accordingly, the intent of this review is to discuss the metabolic consequences of increased fructose consumption and to provide an overview of the mechanisms associated with fructose-enriched diet-induced cardiovascular abnormalities. A description of some novel interventions that attenuate both cardiac and vascular dysfunction subsequent to fructose over consumption is also provided. The high intakes of fructose present a public health hazard, and thus, there is a pressing need to increase public awareness on the harmful health effects, including cardiovascular health, of high intake of foods and beverages enriched with fructose. Furthermore, the supplementation of processed foods and beverages with fructose additives needs regulation.

Cannabis has attracted growing interest for its therapeutic potential, especially in pain management. This study explores the antinociceptive effects of two promising non-psychoactive cannabinoids, cannabivarin (CBV) and tetrahydrocannabivarin (THCV), using Caenorhabditis elegans, a nematode model that expresses homologs of mammalian cannabinoid and vanilloid receptors. Thermotaxis assays were employed to quantify the antinociceptive effects of CBV and THCV in C. elegans. Wild-type animals were exposed to increasing concentrations of each compound to establish dose-response relationships. To investigate potential molecular targets, additional experiments were performed using mutant strains deficient in vanilloid receptor homologs (OCR-2 and OSM-9) and cannabinoid receptor homologs (NPR-19 and NPR-32). Mass spectrometry-based proteomics combined with network biology analyses were used to identify the biological pathways associated with drug response. Results confirmed that both compounds elicit dose-dependent antinociceptive effects. Mutant analyses support the involvement of vanilloid and cannabinoid signaling pathways in mediating these responses. These findings highlight the potential of CBV and THCV as non-psychoactive analgesic agents and support further research into their mechanisms of action and translational relevance for mammalian pain management.

Incretin therapy, utilizing glucagon-like peptide-1 (GLP-1) receptor agonists and dual receptor agonists, is a cornerstone of obesity management due to effects on appetite suppression, weight loss, and metabolic improvement. Liraglutide, semaglutide, and tirzepatide promote weight reduction by modulating incretin hormone pathways, leading to decreased caloric intake. Recent studies with semaglutide and tirzepatide have demonstrated substantial weight loss outcomes beyond glucose-lowering benefits, shifting the paradigm of obesity treatment toward pharmacological interventions. While effective in weight loss, challenges remain regarding long-term efficacy, tolerability, and accessibility. Future directions include optimizing combination therapies and exploring novel incretin-based molecules with dual or triple receptor activity. This review focuses on the clinical application of incretin therapy in obesity, emphasizing practical considerations and highlighting therapeutic benefits for obesity to improve outcomes and public health.

Obesity is a global epidemic, posing significant challenges to individual health and healthcare systems. This article explores the pharmacology of incretin-based therapies beyond single receptor agonists and focuses on their emerging role in obesity management. The complex interplay between metabolic, environmental, and psychosocial factors contributes to obesity and its wide-ranging clinical sequelae. Emphasis is placed on the physiological functions of key hormones, such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), amylin, and glucagon, in regulating energy balance, appetite, and insulin secretion. The commentary discusses novel therapeutic approaches, including dual and triple receptor agonists. Future directions in personalized medicine are included to highlight innovative drug-delivery systems and potential new targets. Collectively, incretin-targeted therapies have the potential to be the next generation of obesity treatments, effective in achieving outcomes and tailored for individual patient needs.

Stigma surrounding substance use disorders (SUDs) is widespread and has even been identified among healthcare professionals and trainees, highlighting the need for educational interventions that foster compassionate care, understanding, and emphasize approaches that reflect the complexities of drug use. Community engaged learning (CEL) is an evidence-based pedagogy designed to connect classroom learning with real-world applications. Through community driven collaborative projects that integrate classroom learning with real-world experience, students develop the ability to connect scientific knowledge with social understanding. These experiences, combined with structured reflection and traditional assessments, prepare the next generation of pharmacologists that find careers in healthcare, academia, drug discovery or public health to approach their work with greater compassion, and a nuanced awareness of the complexities faced by individuals and communities affected by substance use. In this commentary, we aim to advance the dialogue on how CEL can contribute to a more empathetic, evidence-based approach to SUD care, research, and policy for the next generation.

Generation of reactive oxygen species (ROS) is a physiological product of cell activity that is mainly generated by the mitochondria as well as by transmembrane NADPH oxidases (NOX1-5) present at the plasma and nuclear envelope membranes. The level of basal intracellular ROS is regulated by endogenous antioxidants such as glutathione (GSH), and the endogenous and exogenous antioxidant taurine. These two antioxidants are present in all types of cells and more particularly in the heart and the vascular system. They regulate and control intrcellular normal ROS levels in order to prevent an increase that induces dysfunction of the cardiovascular system. There are also exogenous antioxidants that are present in many types of food such as vitamin C, vitamin E, and resveratrol. These exogenous antioxidants are necessary to complement the effect of endogenous antioxidants. However, according to the literature, it is difficult to generalize about the beneficial effect of exogenous antioxidants in preventing cardiovascular disease. This does not necessarily seem to be the case for endogenous antioxidants. In this review, we will discuss the advantages and disadvantages of using exogenous and endogenous antioxidants, and suggest the potential application of one of them.