Canadian journal of physiology and pharmacology最新文献

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.

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.

Ischemic stroke is characterized by brain tissue iron accumulation. Alpha-synuclein (α-Syn) is a neuronal protein, its overexpression in ischemic stroke triggers apoptosis. Lymphocyte activation gene-3 (LAG-3), a receptor for α-Syn, enhances its neurotoxic effects. It is split from the cell membrane forming soluble LAG-3 (sLAG-3) in the bloodstream. The expression of LAG-3 in the brain, its relation to iron and α-Syn, as well as the association between serum sLAG-3 levels, iron, α-Syn, and stroke severity remains poorly understood. A case-control study was generated involving 24 patients with acute ischemic stroke and 24 healthy controls. In addition, an experimental study was designed involving 24 Wistar-albino rats. We randomly assigned rats to three groups: sham-operated, brain ischemia, and deferoxamine treated ischemic rats. Ischemia decreased serum levels of iron, while increased serum levels of α-Syn and sLAG-3. Significant diagnostic performance of serum α-Syn and sLAG-3 was determined using the ROC curve (AUC = 0.962, 83.33% sensitivity, and 95.83 % specificity for α-Syn; AUC = 0.755 with 62.50% sensitivity and 87.50% specificity for LAG-3). In rats, ischemia elevated brain tissue iron, α-Syn, and LAG-3 which were reduced following deferoxamine treatment. In conclusion, brain ischemia is associated with iron accumulation that promotes α-Syn expression and aggregation potentially through increasing LAG-3 expression which improved after deferoxamine injection. In addition this study illuminates the future beneficial targeting of LAG-3 in brain ischemia.

Chronic sleep restriction (SR) disrupts blood glucose regulation, leading to glucose intolerance and insulin resistance. Regular exercises, however, are known to enhance glycemic control. This study aimed to evaluate the regulatory effects of three distinct exercise protocols on blood glucose alterations caused by chronic rapid eye movement SR. Thirty-four Sprague-Dawley rats were allocated into five groups: control (CTRL), SR, SR plus aerobic exercise (SR + Ex_A), SR plus resistance exercise (SR + Ex_R), and SR plus combined exercises (SR + Ex_C). Except for the control group, all rats underwent 18 h of SR daily for 8 weeks using a modified multi-platform model. Exercise protocols included 30 min of swimming and/or vertical ladder climbing (15 repetitions/day) performed 3 days per week for 8 weeks. Following the intervention, glucose and insulin tolerance tests were conducted. Chronic SR increased blood glucose levels, while aerobic and/or resistance exercises effectively reduced or prevented this elevation. Glucose tolerance was significantly improved in all exercise groups compared to the sedentary group (intraperitoneal glucose tolerance test blood glucose 120 min: SR + Ex_A = 95 ± 7.7, SR + Ex_R = 100 ± 7.3, SR + Ex_C = 90 ± 12.6, SR = 119 ± 14.5 mg/dL; P < 0.05). Regular exercise may mitigate adverse metabolic effects of SR.

Angiogenesis, the formation of new blood vessels, is crucial in ischemic heart disease to improve blood supply to the heart. Meanwhile, in cancer, inhibiting angiogenesis can limit tumor growth by reducing oxygen and nutrients. Calcium ions, key in cellular functions like proliferation and migration, play an important role in this process. Transient Receptor Potential Cation Channel, Vanilloid Subfamily Member 4 (TRPV4), a calcium-permeable channel, is highly expressed in endothelial cells lining blood vessels. This study explored the connection between TRPV4 and angiogenesis using an aortic ring assay. Aortic rings from 3-day-old C57Bl/6 pups were exposed to TRPV4 agonist (GSK1016790) and antagonist (HC067047) and standard growth media (control) after which maximal length and number of new sprouts were measured. The study found that the antagonist significantly reduced the number and length of new micro vessels, while the agonist increased sprout length. These findings highlight TRPV4's role in vascular remodeling, suggesting it could be a therapeutic target for treating diseases related to impaired blood flow and abnormal angiogenesis.

This study aimed to evaluate the effects of insulin therapy on oxidative stress markers, matrix metalloproteinases (MMPs) 2 and 9 activities, and cardiac remodeling in alloxan-induced diabetic rats. Forty-two male Wistar rats were randomly allocated into three groups (n ≤ 14 animals), for 30 days: control (CON; saline, IP); diabetes mellitus (DM; alloxan 60 mg/kg, IP); and insulin-treated diabetic (DINS; NPH insulin 4 U, twice daily, IP). After the treatment, the animals were anesthetized and euthanized, and plasma and heart were collected for biochemical, histological, and enzymatic analysis. Compared to DM, the DINS exhibited improved body and heart masses, as well as reduced food intake. Insulin significantly decreased glycemia, triglycerides, and total cholesterol. The antioxidant defenses were enhanced (increased catalase activity and concentrations of reduced glutathione), while the oxidative damage was reduced (decreased protein carbonyls and thiobarbituric acid reactive substance concentrations). Histological analysis revealed a reduction in the inflammatory nuclei and collagen deposition. MMP-2 and MMP-9 activities were lower in the DINS compared to the DM. The insulin treatment attenuated oxidative stress, modulated MMP activity, and collagen accumulation in the heart of diabetic rats. These findings support the potential role of insulin in mitigating diabetes-induced cardiac remodeling through redox balance.

High-sensitivity cardiac troponin I (hs-TnI) is a promising biomarker for cardiovascular disease (CVD) risk stratification. This study assessed clinical outcomes and cost-effectiveness of an hs-TnI-guided CVD screening strategy in a general asymptomatic adult population. In a modeled observational program, 4000 adults aged 40-70 years without known CVD underwent hs-TnI testing. Participants were stratified into low (<4 ng/L), moderate (4-10 ng/L), and high (>10 ng/L) risk categories, and underwent further cardiac evaluation, and intervention, if indicated. A discrete-event microsimulation estimated CVD events, mortality, quality-adjusted life years (QALYs), and costs over 10 years. Among 4000 participants (mean age 57.1 ± 8.6 years; 52% women), 3548 (88.7%) were low-risk, 390 (9.8%) moderate-risk, and 62 (1.5%) high-risk. Noninvasive cardiac workup was performed in 452 (11.3%), and coronary angiography in 112 (2.8%). Significant coronary artery disease (CAD) was diagnosed in 49 (1.2%), with revascularization in 45. Compared to standard care, hs-TnI screening reduced CVD events by 37% and cardiovascular deaths by 34%, gaining 16.3 QALYs per 1000 participants. Incremental cost per person was €528, with an incremental cost-effectiveness ratio of €32 100/QALY, remaining cost effective in 93% of simulations. hs-TnI-guided cardiovascular risk assessment effectively stratifies asymptomatic adults, identifies subclinical CAD, and facilitates preventive intervention, appearing cost effective in reducing CVD burden.

Aquaporin-3 (AQP3) is expressed in the basolateral membrane of the renal principal cell, contributing to vasopressin-mediated water reabsorption and urine concentration. We reported that post-translational acetylation of lysine 282 of AQP3 promotes water permeability. In this study, we hypothesized that AQP3 acetylation may improve polyuria in a mouse model of lithium-induced nephrogenic diabetes insipidus (Li-NDI). Wild type, AQP3 acetylation (K282Q), and deacetylation (K282R) mimetic mice were fed a lithium-containing diet or a control diet for 14 days. Body masses and spot urines were collected overtime, while urine flow and osmolality, plasma osmolality, and kidneys were collected on day 14 of the diets. All Li-NDI mice had greater urine output and water intake compared to control fed mice, and unexpectedly, this was exacerbated in female Li-NDI AQP3-acetylation and AQP3-deacetylation mice. After 14 days of lithium diet, acetylated AQP3 was almost undetectable in the kidneys of WT mice, and AQP3 localization in acetylated and deacetylated mice was minimal. In the setting of LI-NDI, the significant loss of AQP3 was not prevented in acetylated-AQP3 mice and in female mice mutation of K282 resulted in a worsened Li-NDI phenotype, suggesting that this lysine is critical for promoting sex-specific AQP3-water permeability.

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.