Quantitative proteomics study of carnosine effect in an animal model of Western diet-induced nonalcoholic fatty liver disease.

The nonalcoholic fatty liver disease (NAFLD), which is closely related to westernized dietary (WD) patterns, displays a rising epidemiological and economic burden. Since there is no pharmacological therapy approved for this disease, mechanistic studies are warranted. In this work, we investigated the action of carnosine (CAR), a natural dipeptide with several protection roles against oxidative stress in the liver of NAFLD rats. NAFLD was induced by WD-rich sugars and fat, verifying the histological evidence of steatosis. As intraperitoneal administration of CAR reversed liver steatosis, the protein profiles of NAFLD liver and CAR NAFLD liver were evaluated by label-free proteomics approach. A total of 2531 proteins were identified and the 230 and 276 were significantly up- and downregulated, respectively, by CAR treatment of NAFLD rats and involved in fundamental pathways such as oxidative stress and lipid metabolism. Perilipin 2 and apolipoprotein E, components of the plasma membrane of vesicle, resulted in highly downregulated in the CAR-treated NAFLD liver. The advanced bioanalytical approach demonstrated the efficacy of CAR in overcoming the main symptoms of NAFLD, ameliorating the steatosis in the liver.

Effects of carnosine supplementation on markers for the pathophysiological development of metabolic dysfunction-associated steatotic liver disease in a diet-induced model.

Consumption of diets high in sugar and fat is related to the development of Metabolic dysfunction-associated steatotic liver disease (MASLD). Carnosine (CAR) is a dipeptide with antioxidant and anti-inflammatory action and has been studied for treating diseases. This work aimed to evaluate the effects of CAR on diet-induced MASLD in rats. Male Wistar rats were distributed into 2 groups (17 weeks): normocaloric (Co, n = 12), and hypercaloric diet rich in lipids and simple carbohydrates (MASLD, n = 12). After, the animals were redistributed to begin the treatment with CAR (4 weeks): Co (n = 6), Co + CAR (n = 6), MASLD (n = 6), and MASLD + CAR (n = 6), administered intraperitoneally (250 mg/kg). Evaluations included nutritional, hormonal and metabolic parameters; hepatic steatosis, inflammatory and oxidative markers. MASLD group had a higher adiposity index, systolic blood pressure, glucose, plasma and liver triglycerides and cholesterol, insulin, hepatic steatosis, oxidative markers, and lower PPAR-α (Peroxisome Proliferator-activated receptor α), compared to the Co. CAR attenuated plasma and hepatic triglyceride and cholesterol levels, hepatic steatosis, CD68+ macrophages, and hepatic oxidative markers, in addition to increasing HDL cholesterol levels and PPAR-α, compared to the untreated MASLD group. CAR acts in importants pathophysiological processes of MASLD and may be a therapeutic compound to control the disease.

Effects of glyphosate exposure on western diet-induced non-alcoholic fatty liver disease in mice.

We evaluated whether glyphosate promotes western diet (WD)-induced non-alcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed WD and received intragastrical glyphosate (0.05, 5 or 50 mg/kg) for 6 months. Glyphosate did not promote WD-induced obesity, hypercholesterolemia, glucose intolerance, hepatic steatosis, and fibrosis. Nonetheless, the higher dose (50 mg) enhanced hepatic CD68+ macrophage density, p65, TNF-α, and IL-6 protein levels. Furthermore, this dose decreased hepatic Nrf2 levels, while enhancing lipid peroxidation in the liver and adipose tissue. Hepatic transcriptome revealed that glyphosate at 50 mg upregulated 212 genes and downregulated 731 genes. Genes associated with oxidative stress and inflammation were upregulated, while key cell cycle-related genes were downregulated. Our results indicate that glyphosate exposure - in a dose within the toxicological limits - impairs hepatic inflammation/redox dynamics in a NAFLD microenvironment.

Sildenafil attenuates oxidative stress and endothelial dysfunction in lead-induced hypertension.

Lead (Pb) reduces NO bioavailability, impairs the antioxidant system, and increases the generation of reactive oxygen species (ROS). Pb-induced oxidative stress may be responsible for the associated endothelial dysfunction. Sildenafil has shown nitric oxide (NO)-independent action, including antioxidant effects. Therefore, we examined the effects of sildenafil on oxidative stress, reductions of NO and endothelial dysfunction in Pb-induced hypertension. Wistar rats were distributed into three groups: Pb, Pb + sildenafil and Sham. Blood pressure and endothelium-dependent vascular function were recorded. We also examined biochemical determinants of lipid peroxidation and antioxidant function. ROS levels, NO metabolites and NO levels in human umbilical vein endothelial cells (HUVECs) were also evaluated. Sildenafil prevents impairment of endothelium-dependent NO-mediated vasodilation and attenuates Pb-induced hypertension, reduces ROS formation, enhances superoxide dismutase (SOD) activity and antioxidant capacity in plasma and increases NO metabolites in plasma and HUVECs culture supernatants, while no changes were found on measurement of NO released from HUVECs incubated with plasma of the Pb and Pb + sildenafil groups compared with the sham group. In conclusion, sildenafil protects against ROS-mediated inactivation of NO, thus preventing endothelial dysfunction and attenuating Pb-induced hypertension, possibly through antioxidant effects.

Treatment with bergamot (Citrus bergamia) leaves extract attenuates leptin resistance in obese rats.

Low-grade chronic inflammation in obesity is associated with leptin resistance. In order to alleviate this pathological condition, bioactive compounds capable of attenuating oxidative stress and inflammation have been researched, and bergamot (Citrus bergamia) presents these properties. The aim was to evaluate the effect of bergamot leaves extract on leptin resistance in obese rats. Animals were divided into 2 groups: control diet (C, n = 10) and high sugar-fat diet (HSF, n = 20) for 20 weeks. After detecting hyperleptinemia, animals were divided to begin the treatment with bergamot leaves extract (BLE) for 10 weeks: C + placebo (n = 7), HSF + placebo (n = 7), and HSF + BLE (n = 7) by gavage (50 mg/kg). Evaluations included nutritional, hormonal and metabolic parameters; adipose tissue dysfunction; inflammatory, oxidative markers and hypothalamic leptin pathway. HSF group presented obesity, metabolic syndrome, adipose tissue dysfunction, hyperleptinemia and leptin resistance compared to control group. However, the treated group showed a decrease in caloric consumption and attenuation of insulin resistance. Moreover, dyslipidemia, adipose tissue function, and leptin levels showed an improvement. At the level of the hypothalamus, the treated group showed a reduction of oxidative stress, inflammation and modulation of leptin signaling. In conclusion, BLE properties were able to improve leptin resistance through recovery of the hypothalamic pathway.

Glibenclamide Increases Nitric Oxide Levels and Decreases Oxidative Stress in an In Vitro Model of Preeclampsia.

(1) Background: The bioavailability of nitric oxide (NO) and oxidative stress are important events related to the pathophysiology of preeclampsia (PE). In this present study, we aimed to evaluate the antioxidant effect of glibenclamide (GB) on the NO synthesis, oxidative stress, and antioxidant capacity in endothelial cells incubated with plasma from preeclamptic (PE) and normotensive pregnant women (NT). (2) Methods: Human umbilical vein endothelial cells (HUVECs) were incubated with a plasma pool from 10 NT and 10 PE pregnant women; NO/NOx quantification and ROS levels were assessed by a fluorescence compound; lipid peroxidation was evaluated employing thiobarbituric acid (TBA); and total antioxidant capacity was measured by ferric reduction ability power (FRAP) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). (3) Results: We found that endothelial cells incubated with plasma from PE showed lower NO and NOx levels compared with the NT group. However, GB treatment increased these levels, as well as the antioxidant capacity. Furthermore, a decrease was observed in ROS generation and lipid peroxidation (4) Conclusions: The GB treatment exerted a positive effect on the NO/NOx production by HUVEC incubated with plasma from NT and PE pregnant women, as well as in the reduction in oxidative stress and increase in the antioxidant capacity.