Empagliflozin and sacubitril/valsartan reverse methotrexate cardiotoxicity by repressing oxidative stress and hypoxia in heart embryonic H9c2 cardiomyocytes - the role of morphology of mitochondria observed on electron microscopy.

OBJECTIVE: Oxidative stress and hypoxia play an important role in the pathogenesis of various cardiovascular diseases. We aimed to evaluate the effectiveness of sacubitril/valsartan (S/V) and Empagliflozin (EMPA) on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 rat embryonic cardiomyocyte cells. MATERIALS AND METHODS: BH9c2 cardiomyocyte cells were treated with methotrexate (MTX) (10-0.156 µM), empagliflozin (EMPA; 10-0.153 µM) and sacubitril/valsartan (S/V; 100-1.062 µM) for 24, 48 and 72 h. The half maximum inhibitory concentration (IC50) and half maximum excitation concentration (EC50) values of MTX, EMPA and S/V were determined. The cells under investigation were exposed to 2.2 µM MTX before treatment with 2 µM EMPA and 25 µM S/V. The cell viability, lipid peroxidation, oxidation of proteins and antioxidant parameters were measured while morphological changes were also observed by transmission electron microscopy (TEM). RESULTS: The results showed that treatment with 2 µM EMPA, 25 µM S/V or their combination produced a protective effect against the reduction in cell viability caused by 2.2 µM MTX.  While HIF-1α levels plunged to their lowest with S/V treatment, oxidant parameters dipped, and antioxidant parameters soared to their highest level with S/V and EMPA combination treatment. A negative correlation was found between HIF-1α and total antioxidant capacity in the S/V treatment group. CONCLUSIONS: A significant decrease in HIF-1α and oxidant molecules together with an enhancement in antioxidant molecules and normalization of the mitochondria morphology as observed on electron microscopy in S/V and EMPA-treated cells were detected. Although S/V and EMPA have both protective effects against cardiac ischemia and oxidative damage, this effect may be increased more with S/V treatment alone compared to combined treatment.

Ranolazine exhibits anti-inflammatory and antioxidant activities in H9c2 cardiomyocytes.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of ranolazine on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 cardiomyocyte cells. MATERIALS AND METHODS: We have assessed the effects of increasing concentrations of methotrexate (MTX) and ranolazine on proliferation of H9c2 rat cardiomyocyte cells by MTT assay. Malondialdehyde (MDA) protein oxidation [advanced oxidation protein products (AOPPs)], lipid hydroperoxide (LOOH) and xanthine oxidase (XO) activity as oxidative stress markers and HIF-1α levels increased and total thiol (T-SH), catalase (CAT) activity and total antioxidant capacity (TAC) antioxidant capacity markers decreased in MTX-treated cells compared to control cells. RESULTS: Oxidative stress markers decreased, and antioxidant capacity markers increased in cells treated with ranolazine alone compared to control cells. For all parameters, we showed that the levels of oxidant, antioxidant markers and HIF-1α in cells treated with MTX and ranolazine together reached the level of the control group, and ranolazine reversed the oxidative damage caused by MTX. CONCLUSIONS: The cell viability increased the levels of oxidant and prooxidant markers and decreased the levels of antioxidant markers decreased in H9c2 cardiomyocytes induced by oxidative stress. These results suggest that ranolazine may protect the cardiomyocytes from MTX-induced oxidative damage. The effects of ranolazine could result from its antioxidant properties.

The role of laparoscopic sleeve gastrectomy on inflammatory parameters in morbidly obese patients.

BACKGROUND: Obesity is an excessive increase in body fat mass and triggers chronic inflammation which causes increased fat accumulation in the visceral fat tissue. The aim of this study was to analyze serum zinc (Zn), Zn-alpha 2 glycoprotein (ZAG), peroxisome proliferator-activated receptor-γ (PPAR-γ) and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) levels in morbidly obese patients before and after laparoscopic sleeve gastrectomy (LSG) and determine the association between alteration in body mass index (BMI), the % Excess Weight Loss (% EWL) and the biochemical parameters. METHODS: Thirty healthy individuals as a control group and 30 morbidly obese patients who had undergone LSG were enrolled in this study. Routine anthropometric and laboratory biochemical parameters in venous blood samples of groups at baseline and 1 and 12 months after LSG were recorded. RESULTS: Significant weight loss was achieved at 1 and 12 months after LSG. At baseline serum ZAG and PPAR-γ levels were lower, while NF-кB levels were higher in morbidly obese patients compared with the control group. Serum ZAG and PPAR-γ levels increased while NF-кB levels decreased 1 month and 12 months after LSG. Decreased %EWL was negatively correlated with changes in NF-кB, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), fasting plasma glucose and insulin at 12 months after LSG in morbidly obese patients. However, %EWL was positively correlated with changes in ZAG. CONCLUSIONS: Obesity was associated with down-regulated serum ZAG and PPAR-γ levels while up-regulated serum NF-кB. Our findings suggest that LSG ameliorates upregulating PPAR-γ expression, thereby inhibiting NF-κB-mediated inflammation by weight loss.