Slowly activating voltage-gated potassium current potentiation by ML277 is a novel cardioprotective intervention.

Cardiovascular disease is thought to account for nearly a third of deaths worldwide, with ischemic heart disease, including acute coronary syndromes such as myocardial infarction, accounting for 1.7 million deaths per year. There is a clear need for interventions to impart cardioprotection against ischemia. Here, we show that the slowly activating voltage-gated potassium current (IKs) potentiator ML277 imparts cardioprotection against ischemia in cellular and whole-heart models by modulating the action potential duration. In three different metabolic inhibition and reperfusion models, an increased contractile recovery and cell survival was observed with ML277, indicative of protection. Finally, ML277 reduced infarct size in an ex vivo Langendorff coronary ligation model, including if only applied on reperfusion. In conclusion, potentiation of the IKs with ML277 imparted a cardioprotection that was equivalent to the protection reported previously by ischemic preconditioning. These data suggest that IKs potentiation may be therapeutically useful in acute coronary syndromes.

Selective protein kinase C inhibition switches time-dependent glucose cardiotoxicity to cardioprotection.

Hyperglycaemia at the time of myocardial infarction has an adverse effect on prognosis irrespective of a prior diagnosis of diabetes, suggesting glucose is the damaging factor. In ex vivo models of ischaemia, we demonstrated that deleterious effects of acutely elevated glucose are PKCα/ß-dependent, and providing PKCα/ß are inhibited, elevated glucose confers cardioprotection. Short pre-treatments with high glucose were used to investigate time-dependent glucose cardiotoxicity, with PKCα/ß inhibition investigated as a potential mechanism to reverse the toxicity. Freshly isolated non-diabetic rat cardiomyocytes were exposed to elevated glucose to investigate the time-dependence toxic effects. High glucose challenge for >7.5 min was cardiotoxic, proarrhythmic and lead to contractile failure, whilst cardiomyocytes exposed to metabolic inhibition following 5-min high glucose, displayed a time-dependent protection lasting ∼15 min. This protection was further enhanced with PKCα/ß inhibition. Cardioprotection was measured as a delay in contractile failure and KATP channel activation, improved contractile and Ca2+ transient recovery and increased cell survival. Finally, the effects of pre-ischaemic treatment with high glucose in a whole-heart coronary ligation protocol, where protection was evident with PKCα/ß inhibition. Selective PKCα/ß inhibition enhances protection suggesting glycaemic control with PKC inhibition as a potential cardioprotective therapeutics in myocardial infarction and elective cardiac surgery.

Efficacy of probiotic supplementation in patients with diabetic nephropathy: A systematic review and meta-analysis.

BACKGROUND: Diabetic nephropathy (DN) is one of the diabetes mellitus complications, which develops in approximately one-third of diabetic patients. Probiotics are microorganisms such as Lactobacillus and Bifidobacterium which have some benefits with gastrointestinal disorders and diabetic patients. AIM: We aim to assess the efficacy of probiotic supplementation in patients with diabetic nephropathy (DN). METHODS: We searched PubMed, Scopus, Web of Science, and Cochrane on 20 august 2019 and updated the search on 26 April 2020 using relevant keywords. Studies were screened for eligibility. We extracted the data from the relevant articles and then these data were pooled as mean difference (MD) with a 95% confidence interval (CI), using Review Manager software (ver. 3.5). RESULTS: Pooled data from four trials compared probiotics with a placebo showed a significant reduction in insulin (MD = -1.99, 95% CI [-3.99, 0.01]) and Homeostatic Model Assessment for Insulin Resistance (MD = -3.87, 95% CI [-7.51, -0.22]), High-sensitivity C-reactive protein (MD = -1.55, 95% CI [-2.19, -0.92]), malondialdehyde (MD = -0.77, 95% CI [-0.96, -0.58]), sodium (MD = -0.93, 95% CI [-1.87, -0.01]), but the total antioxidant capacity was significantly increased (MD = 62.29, 95% CI [18.34, 106.24]), while no significant effect on other lipid profiles, oxidative stress biomarkers or kidney function parameters like creatinine and glomerular filtration rate. Two trials showed that probiotic soy is better than conventional soy in terms of kidney function and lipid profiles. CONCLUSION: Probiotics supplementation decreases serum insulin and insulin resistance, but it has no beneficial effect regarding kidney function, body-weight, and lipid profiles, with a moderate positive effect regarding some oxidative stress biomarkers. Also, probiotic soy protein may improve kidney function and lipid profiles. Further studies are needed to confirm our findings and to assess the long-term effect.