Canadian journal of physiology and pharmacology最新文献

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.

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), exert a wide range of beneficial effects beyond glycemic control, largely mediated by their anti-inflammatory properties. Chronic low-grade inflammation is a common pathological mechanism underlying metabolic, cardiovascular, hepatic, and neurodegenerative diseases. GLP-1RAs reduce systemic and tissue-specific inflammation through both direct and indirect mechanisms, including inhibition of nuclear factor kappa B signaling, reduction of proinflammatory cytokines, and modulation of immune cell activity, such as that of macrophages and microglia. In type 2 diabetes and obesity, GLP-1RAs improve insulin sensitivity and endothelial function by attenuating inflammation. In metabolic dysfunction-associated steatotic liver disease, GLP-1RAs reduce hepatic steatosis and fibrosis by modulating inflammation in hepatocytes and Kupffer cells. In cardiovascular disease, they mitigate atherosclerosis progression and improve vascular health. GLP-1RAs also exert direct nephroprotective effects by reducing renal inflammation, oxidative stress, and glomerular hyperfiltration in both diabetic and nondiabetic models. GLP-RAs have been also associated with the preservation of cognitive and motor function. Preclinical studies suggest that these neuroprotective effects may involve the attenuation of neuroinflammation and reduced aggregation of pathological proteins. Overall, these pleiotropic actions position incretin-based therapies as promising tools for the management of complex chronic diseases with an inflammatory component.

In this study, we evaluate the exposure and pharmacokinetic/pharmacodynamic target attainment of meropenem in critically ill patients. We conducted a prospective observational study in two Canadian intensive care units (ICUs) from January 2021 to December 2023. We included adult patients admitted in the ICU who received meropenem. On study days 1, 4, and 7 of antimicrobial therapy, three blood samples were collected: 1 h after end of infusion, at the middle, and at the end of the dosing interval. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector. The pharmacokinetic profile of meropenem was evaluated, as well as the attainment of serum concentrations above minimum inhibitory concentrations of 2, 4, and 8 mg/L at midpoint and at trough. We enrolled 28 patients and analyzed 167 meropenem concentrations. We observed large interindividual variability, but intraindividual variability was low. At midpoint, 52% of concentrations were below the target concentration of 8 mg/L, while this proportion increased to 73% for trough concentrations. Patients who failed to reach therapeutic concentrations all had normal to increased renal function. The majority of ICU patients who received meropenem were underexposed for a target concentration of 8 mg/L, with notable interindividual variability but low intraindividual variability. More aggressive dosing administration protocols are warranted to facilitate target attainment of meropenem.

Despite the known association between hypertension and nonalcoholic fatty liver disease (NAFLD), the cut-off values of blood pressure for identifying risk of NAFLD have not yet been determined. The aim of this study was to determine the diagnostic performance and optimal cut-off values of blood pressure for detecting NAFLD defined by fatty liver index (FLI). This cross-sectional study included 1227 participants aged 35-55 years. NAFLD was determined by FLI with a cut-off value of ≥60. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic ability of blood pressure parameters for screening FLI-defined NAFLD and to determine their cut-off values. The results of this study showed that systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly correlated with FLI values. The prevalence of NAFLD defined by FLI was 23.5% in men and 18.2% in women. The ROC curve analysis showed a good ability of blood pressure for the prediction of FLI-defined NAFLD. The optimal cut-off values of SBP and DBP were 136 and 88 mmHg in men and 137 and 85 mmHg in women, respectively. Thus, high-normal blood pressure is associated with the risk of NAFLD defined by FLI in both men and women.