Antifibrotic Effects of (ㅡ)-Epicatechin on High Glucose Stimulated Cardiac Fibroblasts

Alejandra Garate-Carrillo,Israel Ramirez-Sanchez,Justina Nguyen,Julisa Gonzalez,Guillermo Ceballos,Francisco Villarreal 한국식품영양과학회 2021 Journal of medicinal food Vol.24 No.11

Cardiac fibrosis is one of the hallmarks of a diabetic cardiomyopathy. When activated, cardiac fibroblasts (CFs) increase the production of extracellular matrix proteins. Transforming growth factor (TGF)-β1 is known to mediate cardiac fibrosis through the SMAD pathway. High glucose (HG = 25 mM) cell culture media can activate CFs using TGF-β1. There is a need to identify effective antifibrotic agents. Studies in animals indicate that treatment with (−)-epicatechin (Epi) appears capable of reducing myocardial fibrosis. Epi binds to G-protein coupled estrogen receptor (GPER) and activates downstream pathways. We evaluated the potential of Epi to mitigate the development of a profibrotic phenotype in HG stimulated CFs. CF primary cultures were isolated from young male rats and were exposed for up to 48 h HG media and treated with vehicle or 1 μM Epi. Relevant profibrotic end points were measured by the use of various biochemical assays. HG exposure of CFs increased TGF-β1 protein levels by ∼15%, fibronectin ∼25%, urea levels ∼60%, proline incorporation ∼70%, and total collagen ∼15%. Epi treatment was able to significantly block HG induced increases in TGF-β1, fibronectin, urea, proline, and total collagen protein levels. GPER levels were reduced by HG and restored in CFs treated with Epi an effect associated with the activation (i.e., phosphorylation) of c-Src. Epi treatment also reverted SMAD levels. Altogether, results demonstrate that CFs cultured in HG acquire a profibrotic phenotype, which is blocked by Epi an effect, likely mediated at least, in part, by GPER effects on the SMAD/TGF-β1 pathway.

Beneficial Effects of Flavonoids on Skeletal Muscle Health: A Systematic Review and Meta-Analysis

Levy Munguı´a,Cristian Gonza´lez,Andre´s Portilla,Eduardo Meaney,Francisco Villarreal,Nayelli Na´jera,Guillermo Ceballos 한국식품영양과학회 2022 Journal of medicinal food Vol.25 No.5

Skeletal muscle (SkM) is a highly dynamic tissue that responds to physiological adaptations or pathological conditions, and SkM mitochondria play a major role in bioenergetics, regulation of intracellular calcium homeostasis, pro-oxidant/antioxidant balance, and apoptosis. Flavonoids are polyphenolic compounds with the ability to modulate molecular pathways implicated in the development of mitochondrial myopathy. Therefore, it is pertinent to explore its potential application in conditions such as aging, disuse, denervation, diabetes, obesity, and cancer. To evaluate preclinical and clinical effects of flavonoids on SkM structure and function. We performed a systematic review of published studies, with no date restrictions applied, using PubMed and Scopus. The following search terms were used: “flavonoids” OR “flavanols” OR “flavones” OR “anthocyanidins” OR “flavanones” OR “flavan-3-ols” OR “catechins” OR “epicatechin” OR “(−)-epicatechin” AND “skeletal muscle.” The studies included in this review were preclinical studies, clinical trials, controlled clinical trials, and randomized-controlled trials that investigated the influence of flavonoids on SkM health. Three authors, independently, assessed trials for the review. Any disagreement was resolved by consensus. The use of flavonoids could be a potential tool for the prevention of muscle loss. Their effects on metabolism and on mitochondria function suggest their use as muscle regulators.

Obesity and Cardiovascular Risk Improvement Using Cacao By-Products in a Diet-Induced Obesity Murine Model

Isabel Hidalgo,Alicia Ortiz,Marı´a Sanchez-Pardo,Leticia Gardun˜o-Siciliano,Marcela Herna´ndez-Ortega,Francisco Villarreal,Eduardo Meaney,Nayelli Najera,Guillermo Manuel Ceballos 한국식품영양과학회 2019 Journal of medicinal food Vol.22 No.6

In the production of chocolate, only cocoa seeds are used, generating by-products that are generally discarded, increasing the risk of environmental contamination. Given fiber, carbohydrates, proteins, and flavonoid content the use of cacao pod husks can generate nutraceutical products for human consumption. In contrast, obesity represents a major public health problem worldwide. Cacao derivatives are able to modulate overweight and lipid disorders. The objective of present work was to prepare and characterize products using cacao by-products and analyze their effects on altered cardiometabolic risk markers in an obesity model induced by high fat diet and fructose ingestion in rats. The effects of a pellet and extracts made with outer pod husk and kernel husk for 5 weeks were analyzed in an obesity rat model. The treatments significantly decreased body weight by 39%, systolic blood pressure by 27%, triglycerides by 55%, total cholesterol by 24%, low-density lipoprotein cholesterol by 37%, and the triglycerides/high-density lipoprotein ratio by 54%. Cacao by-products improved the metabolic function of obese animals, without causing secondary effects

Effects of Cacao By-Products and a Modest Weight Loss Intervention on the Concentration of Serum Triglycerides in Overweight Subjects: Proof of Concept

Perla Leon-Flores,Nayelli Najera,Elizabeth Perez,Blanca Pardo,Fiacro Jimenez,Dylan Diaz-Chiguer,Francisco Villarreal,Isabel Hidalgo,Guillermo Ceballos,Eduardo Meaney 한국식품영양과학회 2020 Journal of medicinal food Vol.23 No.7

Therapeutic approaches to decrease serum triglyceride (TG) concentrations are not successful mainly due to poor adherence or adverse effects of therapies. In consequence, the search for new low-cost and safer therapeutic alternatives is mandatory. Dark chocolate and cacao have shown promising results improving lipid profiles. Recently, using cacao by-products to reduce elevated cardiometabolic risk markers in an animal model of obesity induced by a high-fat diet and fructose, we showed that TGs, low-density lipoprotein cholesterol, and the TG/high-density lipoprotein (HDL) ratio decreased, suggesting that cacao by-products improved the metabolic function of obese animals. Based on these results, as a proof of concept, a blinded placebo-controlled study was implemented to explore the effects of cacao by-products on anthropometric and biochemical variables in a group of overweight subjects participating in a program composed of reduced-calorie-diet counseling plus a simple aerobic exercise plan. The results showed that counseling induced weight and abdominal circumference reductions in both groups. TGs did not change in the control group; however, TG decreased significantly by 54.9 mg/dL (27.9%) in the experimental group. The TG/HDL cholesterol ratio changed markedly (1.5) in the experimental group. The results reported suggest the use of cacao by-products as an alternative for the treatment of hypertriglyceridemia.

(−)-Epicatechin Ameliorates Cardiac Fibrosis in a Female Rat Model of Pre-Heart Failure with Preserved Ejection Fraction

Moises Bustamante-Pozo,Israel Ramirez-Sanchez,Alejandra Garate-Carrillo,Bruce Ito,Viridiana Navarrete,Moises Haro,Ricardo Garcia,Nancy Carson,Guillermo Ceballos,Francisco Villarreal 한국식품영양과학회 2022 Journal of medicinal food Vol.25 No.8

One of the most abundant flavonoids present in cacao is (−)-epicatechin (Epi) and this flavanol has been linked to the cardiovascular health promoting actions of cocoa products. We previously demonstrated that Epi reduces infarct size in rodent models of ischemia/reperfusion and permanent coronary occlusion. Reduced infarct size was associated with decreased left ventricular (LV) oxidative stress (OS) and indicators of inflammation factors, which foster myocardial fibrosis. In this study, we examine the antifibrotic actions of Epi in an aging female rat model of pre-heart failure with preserved ejection fraction (pre-HFpEF) as well as its potential to mitigate plasma levels of OS, proinflammatory/profibrotic cytokines, and improve passive and active LV function. Epi treatment [1 mg/(kg·d)] was provided daily by gavage from 21 to 22 months of age, whereas controls received water. A Millar catheter was used to assess hemodynamic function. Subsequently, hearts were arrested in diastole, a balloon inserted into the LV and passive pressure–volume curves generated. Fixed LV sections were processed for collagen area fraction quantification using Sirius Red staining. Treatment with Epi did not lead to detectable changes in LV contractile function. However, passive LV pressure volume curves were significantly right shifted with Epi. Collagen area fraction values indicated that Epi treatment significantly reduces LV fibrosis. Epi also significantly reduced plasma OS markers and levels of profibrotic and proinflammatory cytokines. In conclusion, Epi reduces cardiac fibrosis in an aged, female rat model of pre-HFpEF, which correlates with significant reductions in OS and cytokine levels in the absence of changes in LV contractile function.