Welcome to CSPT official website The Canadian Society of Pharmacology and Therapeutics (CSPT) is a national, not-for-profit, charitable organization that aims to foster the application of educational and research excellence to drug discovery and therapeutic choice. CSPT is recognized for its involvement with the Royal College of Physicians and Surgeons of Canada fellowship training program in Clinical Pharmacology and Toxicology, as well as its support of graduate and postdoctoral trainees, as well as academic researchers across the country. CSPT is the official Canadian member of the International Union of Basic and Clinical Pharmacology (IUPHAR) and a proud chapter of the American Society for Pharmacology and Experimental Therapeutics (ASPET). Its official affiliated journal is The Canadian Journal of Physiology and Pharmacology (CJPP).
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The heterocyclic 2-aminothiazoles scaffolds are used in a wide range of therapeutic applications against various diseases for its antioxidant, anti-inflammatory, antimicrobial and anticancer actions. In this study, we synthesized novel aniline aromatic ring-substituted 2-aminothiazole derivatives. Molecular docking was performed using Glide module of the Schrödinger Suite to fit compounds JG-49, JG-62, and KBA-18 against the Nicotinamide phosphoribosyl transferase (Nampt) enzyme, an intracellular regulator of nicotinamide adenine dinucleotide (NAD) redox cofactor involved in energy metabolism and epigenetics and are implicated in aging and metabolic diseases. The three compounds viz. JG-49, JG-62, and KBA-18 showed an increase in Nampt enzymatic activity in vitro. All three substituted derivatives of 2-aminothiazole showed no cytotoxicity with the mouse C2C12 myoblasts cultures assessed with the MTT cell viability assay. Moreover, the wound closure of the mouse C2C12 myoblasts in vitro displayed no significant difference between the treatment groups of the 2-aminothiazole derivatives compared with the control naïve and DMSO treated myoblasts cultures, except for the 2-aminothiazole substituted derivatives JG-62 and KBA-18, which showed a significant increase in the wound closure compared with the control cells at different concentrations. Taken together, we demonstrated that 2-aminothiazole substituted derivatives provide enhanced Nampt activity, wound closure, and no cytotoxic effects in vitro. Further studies will allow to improve the substitution of 2-aminothiazole derivatives and test their potential therapeutic applications. The heterocyclic 2-aminothiazoles scaffolds are used in a wide range of therapeutic applications against various diseases for its antioxidant, anti-inflammatory, antimicrobial and anticancer actions. In this study, we synthesized novel aniline aromatic ring-substituted 2-aminothiazole derivatives. Molecular docking was performed using Glide module of the Schrödinger Suite to fit compounds JG-49, JG-62, and KBA-18 against the Nicotinamide phosphoribosyl transferase (Nampt) enzyme, an intracellular regulator of nicotinamide adenine dinucleotide (NAD) redox cofactor involved in energy metabolism and epigenetics and are implicated in aging and metabolic diseases. The three compounds viz. JG-49, JG-62, and KBA-18 showed an increase in Nampt enzymatic activity in vitro. All three substituted derivatives of 2-aminothiazole showed no cytotoxicity with the mouse C2C12 myoblasts cultures assessed with the MTT cell viability assay. Moreover, the wound closure of the mouse C2C12 myoblasts in vitro displayed no significant difference between the treatment groups of the 2-aminothiazole derivatives compared with the control naïve and DMSO treated myoblasts cultures, except for the 2-aminothiazole substituted derivatives JG-62 and KBA-18, which showed a significant increase in the wound closure compared with the control cells at different concentrations. Taken together, we demonstrated that 2-aminothiazole substituted derivatives provide enhanced Nampt activity, wound closure, and no cytotoxic effects in vitro. Further studies will allow to improve the substitution of 2-aminothiazole derivatives and test their potential therapeutic applications. 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. 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. 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. 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. 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. 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. 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. |
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