The mitochondrial antioxidant SS-31 increases SIRT1 levels and ameliorates inflammation, oxidative stress and leukocyte-endothelium interactions in type 2 diabetes

Abstract

There is growing focus on mitochondrial impairment and cardiovascular diseases (CVD) in type 2 diabetes (T2D), and the development of novel therapeutic strategies in this context. It is unknown whether mitochondrial-targeting antioxidants such as SS-31 protect sufficiently against oxidative damage in diabetes. We aimed to evaluate if SS-31 modulates SIRT1 levels and ameliorates leukocyte-endothelium interactions, oxidative stress and inflammation in T2D patients. Anthropometric and metabolic parameters were studied in 51 T2D patients and 57 controls. Production of mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, glutathione content, leukocyte-endothelium interactions, NFκB-p65, TNFα and SIRT1 levels was measured in leukocytes treated or not with SS-31. We observed increased mitochondrial ROS production that was restored by SS-31 treatment. SS-31 also increased mitochondrial membrane potential, glutathione content, SIRT1 levels and leukocyte rolling velocity and reduced rolling flux and adhesion in T2D patients. NFκB-p65 and TNFα, which were enhanced in diabetic patients, were also reduced by SS-31 treatment. Our results reveal that SS-31 exerts beneficial effects on the leukocytes of T2D patients by reducing oxidative stress, leukocyte-endothelium interactions, NFκB and TNFα and by increasing SIRT1 levels. These actions support its use as a potential agent against CVD risk.

Empagliflozin Ameliorates Leukocyte – Endothelium Cell Interactions and Inflammation in Type 2 Diabetic Patients

“…We have evaluated the effects of empaglifozin on leukocyte-endothelial cell interactions by using an ex vivo parallel-ow chamber assay which mimics physiological blood ow [16]. As a result, we have observed that empagli ozin increases PMNs rolling velocity in consonance with a decrease in PMN rolling ux and adhesion at 24-weeks of treatment.…”

“…After 12 h of overnight fasting, blood samples were taken from 8:00 to 10:00 a.m. and centrifuged (1.500 g, 10 min, 4 °C) to separate serum or plasma prior to determining biochemical and molecular parameters. Biochemical determinations were carried out by our Hospital´s Clinical Analysis Service and evaluated as usual [16]: glucose, triglycerides and total cholesterol levels in serum were measured by means of an enzymatic method; insulin levels were calculated by immunochemiluminescence and insulin resistance by homeostasis model assessment…”

The Impact of Oxidative Stress on Adipose Tissue Energy Balance

“…Interventions that enhance adipocyte mitochondrial function may also improve whole-body insulin sensitivity. Mitigation of mitochondrial ROS production and oxidative stress may be a possible therapeutic target in type 2 diabetes and IEMs because some mitochondrial-targeted antioxidants and other small molecule drugs improve metabolic profiles in mouse models (Feillet-Coudray et al, 2014;Fouret et al, 2015;Rivera-Barahona et al, 2017) and human studies (Escribano-Lopez et al, 2018).…”

Ação Quimiopreventiva dos Fitoquímicos por meio da Regulação do Fator de Transcrição Nrf2: Revisão Integrativa da Literatura

“…Quando esses radicais estão em grandes concentrações, tornam-se tóxicos e interrompem o sistema de defesa antioxidante do organismo, podendo reagir com diferentes biomoléculas, lipídios, DNA e proteínas, causando danos oxidativos nelas 6 . Esse estresse oxidativo pode desencadear várias doenças, como diabetes, inflamação crônica, distúrbios neurodegenerativos e muitos tipos de câncer [7][8][9] . Uma das maneiras de auxiliar na regulação desse equilíbrio é via fator nuclear eritroide 2 relacionado ao fator 2 (Nrf2) 10 .…”