Canadian journal of physiology and pharmacology最新文献

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.

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.

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.

Cigarette smoking is associated with numerous adverse pregnancy outcomes, due in part to polycyclic aromatic hydrocarbons and free radicals produced by combustion. Less is known about the impact of smokeless tobacco (ST) use during pregnancy. Alaska Native women report higher rates of cigarette and ST use during pregnancy than non-Native women. We investigated oxidative stress and hypoxia pathways in term placentae from Alaska Native women who did (commercial or iqmik; n = 10) or did not (n = 18) use ST during pregnancy. Despite substantial maternal exposure to nicotine, placentae of women who used ST had similar mRNA levels of antioxidant enzymes and markers of hypoxia compared to those who did not use tobacco. Although mRNA levels of angiogenesis markers vegf and vegfr2 were similar between groups, vegfr1 mRNA levels are increased in placentae of women using ST compared to women who did not use tobacco. Together these results suggest that, while ST use may not have as significant an effect on oxidative stress pathways in the placenta as cigarette smoking, an effect is present. It is not clear what this limited effect may have on the developing fetus.

The treatment of metabolic syndrome (MS), characterized by type 2 diabetes, obesity, dyslipidemias, and cardiovascular problems, requires integral treatment. In addition to its central activity, serotonin also has peripheral effects, implying regulation of blood glucose and insulin levels. Indorenate is a serotonin analog with antihypertensive properties and possible activity on the metabolism of carbohydrates. However, its effect on glucose levels has not been explored, which is relevant in searching for the indorenate's potential as an alternative to treatment of MS. This investigation aimed to study the effects of indorenate on glycemia through in vivo and in silico assays. In normal rats, indorenate was co-administrated with two serotoninergic antagonists: pelanserin (5-HT2a antagonist) and WAY-100635 (5-HT1a antagonist). Indorenate caused a hypoglycemic effect in normal rats. Pelanserin and WAY-100635 inhibited this effect. In diabetic rats, indorenate increased insulin levels. In addition, indorenate decreased glycemia in an euglycemic clamp test, while pelanserin inhibited this effect. In silico, indorenate exhibited a higher affinity and interactions than serotonin for 5-HT2a and 5HT1a receptors. The data suggest that the hypoglycemic effect of indorenate requires the participation of the 5-HT2a receptor and partially of the 5-HT1a receptor. Finding drugs with beneficial multimodal effects for blood pressure and glycemic control, such as indorenate, might be relevant for treating MS and its associated pathologies.

Clozapine remains the gold standard for treatment-resistant schizophrenia (TRS), offering unparalleled efficacy but accompanied by significant interindividual variability in response and risk of severe adverse effects. Pharmacogenomics (PGx), the study of how genetic variations influence drug response, has transformed treatment for other medications like warfarin but remains underutilized in clozapine prescribing. This review synthesizes current evidence on the potential of PGx to enhance clozapine treatment by improving the prediction of therapeutic response, metabolism, and adverse drug reactions. Key genetic markers, such as variants in serotonin receptor genes (e.g., HTR2A and HTR3A), metabolism-related enzymes (CYP1A2), and immune-related genes (HLA-DQB1 and HLA-B^*59:01), show promise in guiding personalized clozapine prescribing. However, economic, educational, and systemic challenges, particularly in Canada, hinder broader implementation. PGx testing in psychiatry is available but lacks standardization in cost, accessibility, and test panels. Additionally, PGx research remains Eurocentric, with limited data on Indigenous and diverse populations. In Canada, initiatives like Go-PGx reflect growing national interest, but mental health applications remain minimal. Bridging research with practice through inclusive research, clinician education, artificial intelligence and machine learning, and cost-effectiveness analyses may help unlock PGx's full potential for over 200 000 Canadians living with schizophrenia.

Breast cancer affects one in eight Canadian women over their lifetime. Triple-negative breast cancer (TNBC) represents 10%-20% of all advanced stage breast cancers, often developing multidrug resistance (MDR), commonly resulting in treatment failure. Jadomycin B (JB), a natural product of Streptomyces venezuelae, maintains cytotoxicity against MDR TNBCs, and its activity is enhanced when combined with selective cyclooxygenase-2 inhibitor, celecoxib (CXB) in vitro. Our objectives were to evaluate the toxicity and anticancer effects of JB combined with CXB using zebrafish larval xenografts as a model system. Fluorescent human TNBC MDA-MB-231 cells (231-enhanced green fluorescent protein (EGFP)) were generated and characterized for zebrafish larval xenografts. A maximum tolerated dose (MTD) in zebrafish larvae were determined for JB (20 µM) and CXB (5 µM). Zebrafish embryos were xenotransplanted with 50-100 231-EGFP cells and treated with the MTDs of JB and CXB alone or in combination. The combination of JB and CXB resulted in a 75% reduction in 231-EGFP fluorescence intensity, significantly higher than reductions caused by either drug alone (39% for JB, 15% for CXB) (p < 0.05). This study demonstrates that combining JB with CXB enhances anticancer activity in a zebrafish larval xenograft model of human TNBC, validating effects previously determined in vitro.

Cardiovascular autonomic dysfunction (CVAD) is a prevalent yet underrecognized nonmotor manifestation of Parkinson's disease (PD) that adversely affects morbidity, prognosis, and quality of life. Framed by the heart-brain axis, this review examines bidirectional interactions between neurodegeneration and cardiovascular control, synthesizing clinical and preclinical evidence from 2015 to 2025. We searched PubMed for English-language studies addressing autonomic involvement in PD and cardiovascular outcomes; of 1035 records identified, more than 240 met inclusion criteria following removal of duplicates, commentaries, and off-topic articles. Consistent clinical observations include orthostatic hypotension, diminished heart rate variability, impaired baroreflex sensitivity, and blood pressure lability, though heterogeneity in acquisition protocols and analytics limits comparability. Experimental models reveal mechanistic leads but often lack integration of central and peripheral endpoints, sex-inclusive cohorts, aging variables, and longitudinal designs. We highlight methodological constraints, particularly the interpretive limits of HRV, anesthesia effects in preclinical work, and inconsistent preprocessing, and outline priorities for standardized, multimodal approaches that couple neural markers with cardiovascular readouts. Advancing an integrative, translational framework may enable earlier diagnosis, robust autonomic biomarkers, risk stratification across "body-first" and "brain-first" trajectories, and targeted interventions, including neuromodulation and metabolic strategies, aimed at mitigating CVAD and potentially modifying PD progression.

Acitretin, a widely used second-generation retinoid, has diverse systemic effects, yet its influence on osteogenic processes remains unclear. This study investigated the effects of acitretin on in vitro osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (BMD-MSCs). BMD-MSCs were isolated from femur and tibia of six male Wistar rats (200-250 g, 4-6 weeks). At Passage 3, cells exhibited spindle-shaped morphology, expressed mesenchymal markers (CD90, CD44, CD29, CD54, and CD106), and lacked hematopoietic marker CD45. Multipotency was confirmed by adipogenic, chondrogenic, and osteogenic differentiation assays. Cells were then exposed to acitretin (10, 100, and 1000 µg/L) or vehicle (dimethyl sulfoxide, DMSO), and osteogenic differentiation was assessed at day 14 by Alizarin Red-S staining and semiquantitative RT-PCR analysis of collagen I alpha 2, osteonectin, and osteopontin expression. High-dose acitretin (1000 µg/L) significantly inhibited osteogenic differentiation, independent of DMSO, while lower concentrations showed no marked effect. These findings demonstrate that acitretin suppresses osteogenic differentiation of BMD-MSCs under in vitro conditions, suggesting potential implications for bone metabolism in patients receiving retinoid therapy. Further studies should focus on elucidating the mechanism of this effect, determining the frequency of skeletal system-related side effects in patients using retinoids, and determining the conditions of use of acitretin in high-risk patients.