Canadian journal of physiology and pharmacology最新文献

In response to the COVID-19 pandemic, Canadian clinical researchers pivoted their research programs to investigate repurposing drugs, accelerating the development of experimental therapies, and developing novel disease-specific treatments. This systematic review analyzes the trial design, participant characteristics, and reported outcomes of all Health Canada authorized clinical trials of therapeutics to prevent or treat COVID-19 with published results as of March 2023. We conclude that there is a need for adaptive clinical trial designs, broader pan-Canadian clinical trial networks, more targeted participant recruitment to facilitate increased diversity and inclusion, and standardization in reporting participant characteristics, outcome measurement, and follow-up. Finally, guided by our findings, we make recommendations for improved clinical trial designs when faced with an emerging disease.

Doxorubicin is known for its significant cardiotoxicity, in part due to increased oxidative stress (OS). In addition, preclinical models have shown that doxorubicin induces skeletal muscle atrophy. While vitamin C has been recognized as a valuable pharmacological intervention to mitigate cardiac toxicity, its effect on doxorubicin-induced skeletal muscle atrophy remains to be determined. Therefore, the aim of this study was to investigate the effects of vitamin C on skeletal muscle of rats exposed to doxorubicin. Indeed, doxorubicin caused a reduction in body weight and gastrocnemius muscle weight, accompanied by an increase in hydrogen peroxide, protein oxidation, and lipid peroxidation in the gastrocnemius muscle. On the other hand, vitamin C was able to prevent the loss of skeletal muscle mass as well as the increase in markers of OS. In addition, negative correlations were found between gastrocnemius muscle mass and markers of cellular damage. In conclusion, vitamin C appears to be a protective agent against doxorubicin-induced skeletal muscle atrophy and OS. This suggests its potential application as a prophylactic measure for patients undergoing doxorubicin treatment.

The epicardial adipose tissue (EAT) serves in physiological conditions as a mechanical and thermal myocardial protective layer, as well as a readily available lipid-storage unit. In pathological conditions, EAT expansion becomes deleterious and is currently recognized as an independent risk factor for the progression of cardiovascular diseases. The EAT phenotypic shift from protective to pro-inflammatory/pro-oxidant is facilitated by the presence of metabolic diseases (obesity, metabolic syndrome, and diabetes), which further increase its expansion and dysregulation, favor the occurrence of complications (mainly atrial fibrillation), and promote progression towards heart failure. Glucagon-like peptide-1 (GLP-1) receptor agonists are novel antidiabetic medications belonging to the incretin class that have demonstrated efficacy beyond glycemic control, in terms of weight reduction and cardiorenal protection in patients with type 2 diabetes mellitus. The GLP-1 receptors and glucose-dependent insulinotropic polypeptide (GIP) receptors are expressed in the human EAT and are targeted by an increasing number of pharmacological agonists, with pleiotropic protective effects on EAT structure and function. Herein we review the literature characterizing the benefits of GLP-1 and GIP receptors activation by single and dual agonists with particular emphasis on their effects on EAT and highlight the role of incretin-based therapy for the management of cardiometabolic pathologies.

Fetal growth restriction is implicated in the programming of later-life neurodegeneration. We hypothesized that growth-restricted offspring would show accelerated changes to microglial white matter morphology, relative to controls. Control guinea pig sows were fed ad libitum, while maternal nutrient restriction sows received 70% of control diet switched to 90% from mid-gestation. Offspring were sacrificed at ∼26 days (neonate) or ∼110 days (adult) postpartum. Coronal brain sections from the frontal cortex were subject to IBA1 staining for microglial detection and analyzed by machine learning software. At birth, total body weight of growth-restricted offspring was reduced relative to control (p < 0.0001) with postnatal catch-up growth observed. Microglial density was reduced in the corpus callosum of control (p < 0.05) and growth-restricted (p = 0.13) adults, relative to neonates. Adults from both groups showed greater IBA1-positive area in the cingulum and periventricular white matter (p < 0.05) and increased microglial fractal dimension in the corpus callosum (p < 0.10) and periventricular white matter (p < 0.05), relative to neonates. At the time points studied, we report age-related changes in white matter microglial morphology. However, maternal nutrient restriction leading to fetal growth restriction in guinea pigs does not appear to exacerbate these white matter microglia morphological changes as a marker for later-life neurodegeneration.

Key points: Adverse events among drug users are frequent during hospital stay. Causality assessment of adverse events was poorly documented by healthcare professionals in a hospital setting.

Aerobic exercise (AE) is associated with a significant hypoglycemia risk in individuals with type 1 diabetes mellitus (T1DM). However, the mechanisms in the liver and skeletal muscle governing exercise-induced hypoglycemia in T1DM are poorly understood. This study examined the effects of a 60-min bout of AE on hepatic and muscle glucose metabolism in T1DM rats. Nineteen male Sprague-Dawley rats were divided into sedentary (SC; n = 5) and T1DM (DSC; n = 14) groups. T1DM rats were subcategorized into pre-exercise (DPRE; n = 6) and post-exercise (DPOST; n = 8). DPOST were sacrificed immediately after 60 min of AE. Results demonstrate that DPOST animals experienced reductions in BG following 30 and 60 min of AE compared to pre-exercise. Both DPRE and DPOST animals exhibited lower hepatic glycogen content, while muscle glycogen did not differ, suggesting impaired glycogenolysis in T1DM. Hepatic glucose-6-phosphatase content, and muscle and hepatic protein kinase B phosphorylation were significantly greater in DPOST animals, suggesting elevated gluconeogenesis and insulin stimulation during exercise. Glycogen phosphorylase activity did not differ between groups. These data suggest that drops in BG during AE in T1DM were due to lower glycogen levels in the liver and muscle and a lack of muscle glycogen utilization; leading to a reliance on gluconeogenesis and BG.

Striatal medium spiny neurons (MSN) form two subpopulations (MSN-D₁ and MSN-D₂) according to the expression of dopamine D₁ or D₂ receptors and their target regions. The activation of postsynaptic histamine H₁ and H₂ receptors increases MSN-D₁ and MSN-D₂ excitability. Since MSN also express H₃ receptors (H₃Rs), in this work we explored the effect of their activation on MSN firing. Electrophysiological recordings (whole-cell patch-clamp, current-clamp mode) were conducted on forebrain slices from infantile rats (12-16 postnatal days). In both MSN-D₁ and MSN-D₂ perfusion with the H₃R agonist immepip (1 µmol/L) increased neuronal firing evoked by current injection, an effect reproduced by R-α-methylhistamine (1 µmol/L) and prevented by the antagonist clobenpropit (10 µmol/L). Blockade of N- or P/Q-type voltage-activated calcium channels by ω-conotoxin-GVIA (1 µmol/L) or ω-agatoxin-TK (400 nmol/L) increased MSN firing but did not preclude the immepip effect. The potassium channel blockers 4-aminopyridine (1 mmol/L) and tetraethylammonium (300 µmol/L) increased neuronal firing and prevented the immepip action. Likewise, the K_V7 channel blocker XE-991 (10 µmol/L) and the muscarinic receptor agonist carbachol (10 µmol/L) increased MSN firing frequency and occluded the immepip effect. These data indicate that the activation of postsynaptic H₃Rs facilitates MSN-D₁ and MSN-D₂ firing by inhibiting K_V7 potassium channels.

The growing epidemic of opioid misuse presents numerous challenges for healthcare practitioners and patients alike as friction exists between ease of use and efficacy, and potential for overuse and addiction. With over 82 000 deaths related to opioid overdose in North America in 2020, it is imperative to gain a better understanding of the underlying mechanisms behind the addiction process, as well as the current methods being used in the arsenal against this disease. The current best pharmacological approaches for mediating opioid use disorder are methadone, buprenorphine, naltrexone, and naloxone, which act on opioid receptors to produce diverse effects based upon the patients' needs. The variety of effects that these drugs produce, which include removing opioid withdrawal, reversing overdose effects, and blocking opioid properties, makes this arsenal of therapeutics a global necessity in addressing the opioid use epidemic. Accordingly, this narrative review provides a summary of the available data regarding the physiological processes by which opioid addiction takes place and discusses the current and future potential of interventional methods used to mitigate opioid use disorder. The mechanisms of action and subsequent functional outcomes must be understood to reduce the number of opioid-related deaths worldwide.

Diabetic cardiomyopathy (DCM) is a growing clinical entity and major health burden characterized by comorbid diabetes mellitus and heart failure. DCM has been commonly associated with impaired function of the left ventricle (LV); however, DCM likely also occurs in the right ventricle (RV) which has distinct physiology and pathophysiology from the LV. RV dysfunction is the strongest determinant of mortality in several clinical contexts yet remains poorly studied in diabetes. We investigated RV-specific pathophysiology using two models of diabetes-a well-characterized type 2 diabetes (T2DM) model of high-fat diet and low-dose streptozotocin (STZ) in the mouse and a large animal model of type I diabetes in domestic pigs rendered diabetic with STZ. RV global and systolic function deteriorated with diabetes, alongside hypertrophic and fibrotic remodeling. We report evidence of impaired RV insulin sensitivity, dysregulated RV metabolic gene expression, and impaired mitochondrial dynamics. Importantly, while some of these outcomes were similar to those widely reported in the LV, others were not, such as unchanged antioxidant gene expression and regulators of fatty acid uptake. Importantly, these RV-specific changes occurred in both male and female T2DM mice, together emphasizing the importance of distinguishing the RV from the LV when studying DCM and begging the consideration of RV-specific therapies.

A growing body of evidence suggest that the stem cell antigen-1 expressing (Sca-1⁺) cells in the heart may be the cardiac endothelial stem/progenitor cells. Their endothelial cell (EC) functions, and their role in right ventricle (RV) physiology and pathophysiology of right heart failure (RHF) remains poorly defined. This study investigated EC characteristics of rat cardiac Sca-1⁺ cells, assessed spatial distribution and studied changes in Sca-1⁺ cells during RV remodelling in monocrotaline (MCT) model of pulmonary hypertension and RV remodeling. First, flow-cytometry analysis of adult male and female Sprague Dawley (SD) and Fischer CDF rat heart cells was performed, and we observed that the majority of Sca-1⁺ cells also expressed CD31, an EC marker. Furthermore, Sca-1⁺ cells showed acetylated low-density lipoprotein (ac-LDL) uptake and lectin binding similar to CD31⁺ cells from the same heart. The Sca-1⁺ cells also demonstrated network formation when plated on Matrigel. In the MCT treated rats, we observed increase in RV hypertrophy that correlated with the reduction in the abundance of Sca-1⁺CD31⁺ cells in the RV. Together, the cardiac Sca-1⁺ cells in the heart are endothelial stem/progenitor-like cells. These cells have higher abundance in the RV and may play a role in RV adaptation.