Canadian journal of physiology and pharmacology最新文献

This study aimed to examine the effect of thiopental monotherapy as well as its combination with different agents used in anesthesia induction, on cardiac function and redox state of rats with type 1 diabetes mellitus (T1DM). A total of 40 Wistar albino male rats were used in this study and randomly divided into five groups: thiopental (TIO), fentanyl + thiopental (FEN + TIO), remifentanil + thiopental (REM + TIO), midazolam + thiopental (MID + TIO), and dexmedetomidine + thiopental (DEX + TIO). Animals were anesthetized by intraperitoneal injection of thiopental 85 mg/kg, fentanyl 0.005 mg/kg, remifentanil 0.04 mg/kg, midazolam 2.5 mg/kg, and dexmedetomidine 0.05 mg/kg of body weight. Four weeks after T1DM induction, all animals were subjected to a short narcosis of tested anesthetic, sacrificed by cervical dislocation and the hearts were retrogradely perfused according to Langendorff technique. Our research demonstrated that most combined anesthetics negatively influenced cardiodynamic parameters and redox state in diabetic rats. However, significantly improved cardiac contractility associated with enhanced antioxidative capacity was achieved in the combination of TIO with REM, which distinguishes this anesthetic combination as the therapy with the most pronounced positive effect on cardiac function in state of T1DM.

Integrating artificial intelligence (AI) into healthcare prompts the need to measure its proficiency relative to human experts. This study evaluates the proficiency of ChatGPT, an OpenAI language model, in offering guidance concerning bariatric surgery compared to bariatric surgeons. Five clinical scenarios representative of diverse bariatric surgery situations were given to American Society for Metabolic and Bariatric Surgery (ASMBS)-accredited bariatric surgeons and ChatGPT. Both groups proposed medical or surgical management for the patients depicted in each scenario. The outcomes from both the surgeons and ChatGPT were examined and matched with the clinical benchmarks set by the ASMBS. There was a high degree of agreement between ChatGPT and physicians on the three simpler clinical scenarios. There was a positive correlation between physicians' and ChatGPT answers for not recommending surgery. ChatGPT's advice aligned with ASMBS guidelines 60% of the time, in contrast to bariatric surgeons, who consistently aligned with the guidelines 100% of the time. ChatGPT showcases potential in offering guidance on bariatric surgery, but it does not have the comprehensive and personalized perspective that doctors exhibit consistently. Enhancing AI's training on intricate patient situations will bolster its role in the medical field.

The FDA Adverse Event Reporting System (FAERS) is a large-scale repository of reports concerning adverse drug events (ADEs). The same published clinical study or report may be reviewed by multiple companies or healthcare professionals and reported separately to the FDA, leading to a significant presence of duplicate reports in FAERS. These duplicate records can result in the identification of false associations between a given drug and an ADE. In this study, we first assessed the consistency of drug and ADE information in FAERS reports from Alzheimer's disease patients. Our findings showed greater congruence in drug-related information compared to ADE-related information, likely due to the greater heterogeneity and variety of terms or phrases used to describe ADEs. We then demonstrated that text comparison methods are effective in identifying duplicate records based on literature citations, testing 10 different comparison functions for their overall efficacy. Token-based methods (such as COSINE, QGRAM, and JACCARD), edit-based approaches (including OSA, LV, and DL), and sequence-based techniques like LCS have proven highly effective in accurately detecting identical publications within free text, demonstrating both high sensitivity and specificity. These results offer valuable insights for identifying duplicate FAERS reports and improving the reliability of detected associations between drugs and ADEs.

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 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 Sca1⁺ 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.

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-minute 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-minute of AE. Results demonstrate that DPOST animals experienced reductions in BG following 30 and 60 minutes 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 glycogen-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.

During cardiopulmonary resuscitation, pulmonary vasoconstriction due to hypoxia and hypercarbia restricts blood flow from the right to the left heart, resulting in reduced cardiac output that further inhibits adequate oxygenation and the ability to distribute oxygenated blood and medications. An inhaled pulmonary vasodilator could attenuate vasoconstriction and, therefore, increase cardiac output. We used rat isolated lungs to test if inhaled Argon leads to pulmonary vasodilation in phenylephrine-treated lungs. Lungs of 13 adult male Sprague-Dawley rats were isolated, ventilated, and perfused. Pulmonary artery and left atrium were cannulated and lungs perfused at constant flow with 4% albumin physiological saline solution. Controls (n = 6) were ventilated with 65% N₂, 5% CO₂, 30% O₂, and Argon lungs (n = 7) with 65% Argon, 5% CO₂, and 30% O₂. Pulmonary mean arterial pressure (pMAP) and airway pressure (AWP) were recorded continuously, and pulmonary vascular resistance (PVR) was calculated. Following baseline readings, phenylephrine, a pulmonary vasoconstrictor, was perfused at increasing concentrations from 10^-7 to 10^-3 mol/L every 5 min. Statistics: Student's t test, α = 0.05. Argon led to significantly lower pMAPs and PVRs, independent of AWP. Thus, it significantly dilated pre-constricted pulmonary vessels in an ex vivo lung model. When given during resuscitation, this might aid to increase cardiac output.

Jadomycin B, a natural product isolated from Streptomyces venezuelae, exerts an anti-cancer effect on human triple negative breast cancer cells in vitro and has anti-tumoral effects in vivo in animal models of breast cancer. One proposed mechanism for this anti-cancer effect is through interaction with topoisomerase 2 (TOP2). Based on the previously described interactions between jadomycin B and TOP2 we hypothesized that jadomycin B will act additively with TOP2 poisons and produce a similar functional outcome in eliciting cell cycle arrest. Combined treatments of jadomycin B and the TOP2 poisons doxorubicin or mitoxantrone produced moderately synergistic to additive cytotoxicity (combination index values ranging from 0.72-0.94) in MDA-MB-231 cells. In comparison, combined mitoxantrone and doxorubicin produced additive cytotoxicity (combination index values 0.96-1.11). Jadomycin B combined with the proteosome inhibitor MG132 had additive cytotoxicity (combination index values 0.76-1.18). In contrast, mitoxantrone or doxorubicin cytotoxicity was antagonized by MG132 (combination index values 1.21-2.31). Jadomycin B treatment arrested cells in S-phase (P = 0.0024) as opposed to mitoxantrone which caused G₂/M-phase arrest (P < 0.0001). In conclusion, jadomycin B interacts differently than known TOP2 poisons in combination, supporting a novel pharmacological mechanism(s) of action for jadomycin B cytotoxicity.

Research on airway smooth muscle has traditionally focused on its putative detrimental role in asthma, emphasizing on how its shortening narrows the airway lumen, without much consideration about its potential role in subserving the function of the entire respiratory system. New experimental evidence on mice suggests that not only the smooth muscle is required to sustain life postnatally, but its stiffening effect on the lung tissue also protects against excessive airway narrowing and, most importantly, against small airway narrowing heterogeneity and closure. These results suggest that the smooth muscle plays an vital role in the lung periphery, essentially safeguarding alveolar ventilation by preventing small airway closure. These results also shed light on perplexing clinical observations, such as the long-standing doubts about the safety of bronchodilators. Since there seems to be an optimal level of smooth muscle contraction, at least in small airways, the therapeutic goal of maximizing the relaxation of the smooth muscle in asthma needs to be revisited. A bronchodilator with an excessive potency for inhibiting smooth muscle contraction, and that is still potent at concentrations reaching the lung periphery, may foster airway closure and air trapping, resulting in no net gain or even a decline in lung function.

Perivascular adipose tissue (PVAT) plays an important role in many physiological and pathological processes, such as regulation of vascular tone. The aim of this study is to evaluate the effects of pioglitazone on functional, structural, and biochemical properties of PVAT in an experimental model of type-2 diabetes (T2DM). T2DM was induced by high-fat-diet/low-dose-streptozotocin in rats, and pioglitazone (20 mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters, PVAT-mass, vascular-reactivity in thoracic-aorta, as well as PVAT adipocytokine and PPARG-expression levels, and histopathology were evaluated. Pioglitazone administration improved blood glucose and lipid profiles in T2DM. Pioglitazone did not change the anticontractile effect of PVAT on aortic contractile reactivity and besides, had no influence on endothelium-dependent and -independent relaxation responses. Pioglitazone administration increased PVAT-mass and tumor necrotizing factor-α levels, while adiponectin, leptin, and interleukin-6 levels were unchanged. Also, a prominent increase was observed in PPARG-expression in T2DM-Pio group. Moreover, pioglitazone decreased liver steatosis, aortic wall thickening, and myocardial damage, whereas increased adipocyte size and adiposity in PVAT. Overall, pioglitazone treatment changed the mass and in part the inflammatory profile of PVAT but did not modify vasoreactivity in T2DM. This study provides novel findings in relationship with the adipogenic effect of pioglitazone and PVAT function.