Pleiotropic Effects of Sodium - Glucose Co-Transporter 2 Inhibitors

Diabetes mellitus, insulin rezistansı, insulin sekresyonundaki bozukluk veya sekresyonunun olmayışından ya da bunların bir arada bulunmasından kaynaklanan hiperglisemi ile karakterize kronik metabolik bir hastalıktır. Diyabetik bireyler için iyi bir glisemik kontrol çok önemlidir. Ne yazık ki, diyabetik bireylerin pek çoğunda, kabul edilebilir bir glisemik kontrole ulaşılamamaktadır. Bu nedenle de diyabet ile ilgili komplikasyonlardan kaynaklanan morbidite ve mortalite yüksektir. Sodyum glukoz ko-transporter-2 (SGLT2) inhibitörleri, benzersiz etki mekanizmasına sahip, yeni bir antidiyabetik ilaç sınıfıdır. Bu çalışma, SGLT2 inhibitörlerinin pleiotropik etkilerine ilişkin genel bilgi sağlamaktadır. Bu amaçla, ilgili makaleler PubMed ve Uluslararası Farmasötik Özetler aracılığıyla taranmıştır. Taramada kullanılan anahtar kelimeler: "canagliflozin, dapagliflozin, empagliflozin, pleiotropic effects, sodium-glucose co transporter 2 inhibitors" olarak seçilmiştir.Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia because of insulin resistance, diminished or absent insulin secretion or both. Good glycemic control is one of the most important issues for diabetic individual. Unfortunately, most of the diabetics fail to achieve acceptable glycemic control. Therefore, diabetes-associated morbidity and mortality is high resulting from complications. The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a unique mechanism of action. This article provides an overview of pleiotropic effects of SGLT2 inhibitors. For this purpose, relevant articles were identified through searches of PubMed and International Pharmaceutical Abstracts by using the key words diabetes, canagliflozin, dapagliflozin, empagliflozin, pleiotropic effects, sodium-glucose co transporter 2 inhibitors

Resveratrol Inhibits Palmitic Acid Induced Endoplasmic Reticulum Stres: Anti-Apoptotic Effect

Giriş: Endoplazmik retikulum (ER) stresin obezite patofizyolojisinde yeri bilinmesine karşın, obezite ile indüklenen kardiyovasküler hastalıklarda (ER) stresin rolü tam olarak bilinmemektedir. Çalışmamız, doğal bir polifenolik bileşik olan resveratrolün H9c2 hücre dizisinde serbest yağ asidi olan palmitik asid (PA) ile indüklenen ER-stres üzerine olan etkilerini incelemek amacıyla gerçekleştirilmiştir. Gereç ve Yöntem: H9c2 hücre dizisi çeşitli konsantrasyon ve zaman aralıklarında PA ile inkübe edilerek, ER-stres oluşumu sağlanmıştır. Resveratrolün çeşitli konsantrasyonları kullanılarak, ER-stres yolağı ve bu yolağın indükledği apoptotik yolak incelenmiştir. Bulgular: PA doz ve süre bağımlı olarak ER-stres yolağını aktive etmiştir. Bu yolak, apoptotik bir yolağın da aktivasyonuna neden olmuştur. Resveratrol, PA ile indüklenen ER-stresi azaltmakla birlikte, apoptozu da inhibe etmiştir. Bununla birlikte, PA hücresel oksidatif stresin artmasına neden olurken, resveratrol antioksidan etkinik sergilemiştir. Sonuç: Sonuçlarımız, H9c2 hücrelerinde PA ile indüklenen ERstresin azaltılmasında ve apoptozun inhibe edilmesinde resveratrolün etkili olduğunu göstermiştir.Introduction: Endoplasmic reticulum (ER) stress is involved in the pathophysiology of obesity but little is known about the role of ER-stress on obesity-induced cardiovascular diseases. Material and Methods: This study was designed to examine the effect of resveratrol, a natural polyphenolic compound, on palmitic acid-induced ER-stress in H9c2 cell lines. ER-stress was induced by various concentration of PA in different time manner in H9c2 cell lines. Effects of resveratrol on ER-stress and apoptosis pathways were examined in this model. Results: PA activated ER-stress pathway in a dose- and timedependent manner. Indeed, apoptotic pathway was activated in the cells by PA. Resveratrol not only alleviated ER-stress but also inhibited apoptosis. On the other hand, PA increased oxidative stress in the cells which was alleviated by resveratrol. Conclusion: Our results suggest that, resveratrol play a role in alleviating ER-stress and inhibiting apoptosis in H9c2 cell lines

Selective inhibition of the NLRP3 inflammasome protects against acute ethanol-induced cardiotoxicity in an FBXL2-dependent manner

Binge drinking exerts cardiac toxicity through various mechanisms, including oxidative stress and inflammation. NLRP3 inflammasomes possess both pro- and anti-inflammatory properties, although the role of NLRP3 in ethanol-induced cardiotoxicity remains unknown. This study is designed to examine the role of NLRP3 inflammasome in acute ethanol cardiotoxicity and the underlying mechanisms of action. Nine- to twelve-week-old adult male C57BL/6 mice are administered with ethanol (1.5 g/kg, twice daily, i.p.) for 3 days. A cohort of control and ethanol-challenged mice are treated with the NLRP3 inhibitor MCC950 (10 mg/kg/day, i.p., days 1 and 3). Myocardial geometry and function are monitored using echocardiography and cardiomyocyte edge-detection techniques. Levels of NLRP3 inflammasome, mitophagy and apoptosis are evaluated by western blot analysis and immunofluorescence techniques. Acute ethanol challenge results in abnormally higher cardiac systolic function, in conjunction with deteriorated cardiac diastolic function and cardiomyocyte contractile function. Levels of NLRP3 inflammasome and apoptosis are elevated, and mitophagy flux is blocked (elevated Pink1-Parkin and LC3B along with diminished p62 and Rab7) in mice receiving acute ethanol challenge. Although MCC950 does not elicit a notable effect on myocardial function, apoptosis or inflammasome activation in the absence of ethanol exposure, it effectively rescues acute ethanol cardiotoxicity, as manifested by restored myocardial and cardiomyocyte functional homeostasis, suppressed NLRP3 inflammasome activation and apoptosis, and improved mitophagy flux. Our data further suggest that FBXL2, an E3 ubiquitin ligase associated with mitochondrial homeostasis and mitophagy, is destabilized due to proteasomal degradation of caspase-1 by ethanol-induced hyperactivation of NLRP3-caspase-1 inflammasome signaling, resulting in mitochondrial injury and apoptosis. These findings denote a role for NLRP3 inflammasome in acute ethanol exposure-induced cardiotoxicity in an FBXL2-dependent manner and the therapeutic promise of targeting NLRP3 inflammasome for acute ethanol cardiotoxicity