Restorative effects of (+)-epicatechin in a rodent model of aging induced muscle atrophy: underlying mechanisms.

Sarcopenia is a progressive and generalized age-related skeletal muscle (SkM) disorder characterized by the accelerated loss of muscle mass (atrophy) and function. SkM atrophy is associated with increased incidence of falls, functional decline, frailty and mortality. In its early stage, SkM atrophy is associated with increased pro-inflammatory cytokine levels and proteasome-mediated protein degradation. These processes also link to the activation of atrophy associated factors and signaling pathways for which, there is a lack of approved pharmacotherapies. The objective of this study, was to characterize the capacity of the flavanol (+)-epicatechin (+Epi) to favorably modulate SkM mass and function in a rat model of aging induced sarcopenia and profile candidate mechanisms. Using 23 month old male Sprague-Dawley rats, an 8 weeks oral administration of the +Epi (1 mg per kg per day in water by gavage) was implemented while control rats only received water. SkM strength (grip), treadmill endurance, muscle mass, myofiber area, creatine kinase, lactate dehydrogenase, troponin, α-actin, tumor necrosis factor (TNF)-α and atrophy related endpoints (follistatin, myostatin, NFκB, MuRF 1, atrogin 1) were quantified in plasma and/or gastrocnemius. We also evaluated effects on insulin growth factor (IGF)-1 levels and downstream signaling (AKT/mTORC1). Treatment of aged rats with +Epi, led to significant increases in front paw grip strength, treadmill time and SkM mass vs. controls as well as beneficial changes in makers of myofiber integrity. Treatment significantly reversed adverse changes in plasma and/or SkM TNF-α, IGF-1, atrophy and protein synthesis related endpoints vs. controls. In conclusion, +Epi has the capacity to reverse sarcopenia associated detrimental changes in regulatory pathways leading to improved SkM mass and function. Given these results and its recognized safety and tolerance profile, +Epi warrants consideration for clinical trials.

Effects of aging and type 2 diabetes on cardiac structure and function: Underlying mechanisms.

We characterized long-term changes in cardiac structure and function in a high-fat diet/streptozotocin mouse model of aging and type 2 diabetes mellitus (T2D) and examined how the intersection of both conditions alters plasma metabolomics. We also evaluated the possible roles played by oxidative stress, arginase activity and pro-inflammatory cytokines. C57BL/6 male mice (13-month-old) were used. Control animals (n = 13) were fed regular chow for 10 months (aged group). T2D animals (n = 25) were provided a single injection of streptozotocin and fed a high fat diet for 10 months. In select endpoints, young animals were used for comparison. To monitor changes in left ventricular (LV) structure and function, echocardiography was used. At the terminal study (23 months), blood was collected and hearts processed for biochemical or histological analysis. Echo yielded diminished diastolic function with aging and T2D. LV fractional shortening and ejection fraction decreased with T2D by 16 months peaking at 23 months. Western blots noted increases in fibronectin and type I collagen with aging/T2D and greater levels with T2D in α-smooth muscle actin. Increases in plasma and/or myocardial protein carbonyls, arginase activity and pro-inflammatory cytokines occurred with aging and T2D. Untargeted metabolomics and cheminformatics revealed differences in the plasma metabolome of T2D vs. aged mice while select classes of lipid metabolites linked to insulin resistance, were dysregulated. We thus, document changes in LV structure and function with aging that in select endpoints, are accentuated with T2D and link them to increases in OS, arginase activity and pro-inflammatory cytokines.

Improving Cardiovascular Risk in Postmenopausal Women with an (-)-Epicatechin-Based Nutraceutical: A Randomly Assigned, Double-Blind vs. Placebo, Proof-of-Concept Trial.

BACKGROUND: Age-adjusted rates of cardiovascular disease (CVD) are higher in men than in women. CVD risk-factor outcomes are underrecognized, underestimated, and undertreated in women because the clinical expressions in women differ from those of men. There are no universally accepted recommendations on what to do in women when the values of fasting glucose, blood pressure, and lipids are only slightly altered or at borderline values. We reported the positive effects on CVD risk markers using cacao by-products, showing that alternative approaches can be used to prevent cardiovascular disease in women. The objective was to evaluate the changes in lipoprotein subfractions induced by three months of treatment with an epicatechin-enriched cacao supplement. METHODS: A double-blind, placebo-controlled proof-of-concept study was developed to evaluate the effects of 3 months of treatment with an (-)-epicatechin-enriched cacao supplement on lipoprotein subfractions. RESULTS: The usual screening workshop for postmenopausal women could be insufficient and misleading. Assessing the effect of a (-)-epicatechin-enriched cacao supplement employing a lipoprotein subfractionation profile analysis suggests a decrease in cardiovascular risk. CONCLUSIONS: A simple, low-cost, safe (-)-epicatechin-enriched cacao supplement product can improve the cardiovascular risk in postmenopausal women.

Correlation of Biomarkers of Endothelial Injury and Inflammation to Outcome in Hospitalized COVID-19 Patients.

COVID-19 can trigger an intense systemic inflammation and prothrombotic state, leading to a rapid and disproportionate deterioration of lung function. An effective screening tool is essential to identify the patients at risk for severe disease. This observational study was conducted on hospitalized patients with moderate and severe COVID-19 pneumonia in a general hospital in Mexico City between 1 March 2021 and 15 March 2021. Serum samples were analyzed to explore the role of biomarkers of inflammation, coagulation, oxidative stress, and endothelial damage with the severity of the disease. Our results demonstrated that Syndecan-1 and nitrites/nitrates showed a high correlation in severely ill patients. In conclusion, COVID-19 patients with elevated levels of SDC-1 were associated with severe disease. This molecule can potentially be used as a marker for the progression or severity of COVID-19. Preservation of glycocalyx integrity may be a potential treatment for COVID-19.

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

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.

(-)-Epicatechin Is a Biased Ligand of Apelin Receptor.

(-)-Epicatechin (EC) is part of a large family of biomolecules called flavonoids and is widely distributed in the plant kingdom. Several studies have shown the beneficial effects of EC consumption. Many of these reported effects are exerted by activating the signaling pathways associated with the activation of two specific receptors: the G protein-coupled estrogen receptor (GPER), a transmembrane receptor, and the pregnane X receptor (PXR), which is a nuclear receptor. However, the effects of EC are so diverse that these two receptors cannot describe the complete phenomenon. The apelin receptor or APLNR is classified within the G protein-coupled receptor (GPCR) family, and is capable of activating the G protein canonical pathways and the ß-arrestin transducer, which participates in the phenomenon of receptor desensitization and internalization. ß-arrestin gained interest in selective pharmacology and mediators of the so-called "biased agonism". With molecular dynamics (MD) and in vitro assays, we demonstrate how EC can recruit the ß-arrestin in the active conformation of the APLN receptor acting as a biased agonist.

Multi-omics study identifies novel signatures of DNA/RNA, amino acid, peptide, and lipid metabolism by simulated diabetes on coronary endothelial cells.

Coronary artery endothelial cells (CAEC) exert an important role in the development of cardiovascular disease. Dysfunction of CAEC is associated with cardiovascular disease in subjects with type 2 diabetes mellitus (T2DM). However, comprehensive studies of the effects that a diabetic environment exerts on this cellular type are scarce. The present study characterized the molecular perturbations occurring on cultured bovine CAEC subjected to a prolonged diabetic environment (high glucose and high insulin). Changes at the metabolite and peptide level were assessed by Liquid Chromatography-Mass Spectrometry (LC-MS2) and chemoinformatics. The results were integrated with published LC-MS2-based quantitative proteomics on the same in vitro model. Our findings were consistent with reports on other endothelial cell types and identified novel signatures of DNA/RNA, amino acid, peptide, and lipid metabolism in cells under a diabetic environment. Manual data inspection revealed disturbances on tryptophan catabolism and biosynthesis of phenylalanine-based, glutathione-based, and proline-based peptide metabolites. Fluorescence microscopy detected an increase in binucleation in cells under treatment that also occurred when human CAEC were used. This multi-omics study identified particular molecular perturbations in an induced diabetic environment that could help unravel the mechanisms underlying the development of cardiovascular disease in subjects with T2DM.

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

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.

Is it possible to treat nonalcoholic liver disease using a flavanol-based nutraceutical approach? Basic and clinical data.

Nonalcoholic fatty liver disease (NAFLD) is characterized by a spectrum of diseases, ranging from simple steatosis to hepatocellular carcinoma. The main factors for NAFLD are closely related to obesity, insulin resistance, intestinal microbiota alterations, hyperinsulinism, low-grade systemic inflammation, nitroxidative stress, lipid peroxidation, and mitochondrial dysfunction. Currently, the treatment of NAFLD is based on diet and exercise because, to date, there is no specific pharmacological agent, already approved, that raises the need for new therapeutic strategies. Nutraceuticals, such as polyphenols, have potential beneficial effects for health. In this article, the beneficial effects of epigallocatechin-3-gallate (EGCG) and (-)-epicatechin (EC) are discussed. EGCG is the main catechin in green tea, which has shown in various studies its potential effect preventing and treating NAFLD since it has shown antihyperlipidemic, anti-inflammatory, antifibrotic, antioxidant, and improvement of liver lipid metabolism. However, it has been found that excessive consumption may cause hepatotoxicity. EC is widely distributed in nature (fruits and vegetables). This flavanol has shown many beneficial effects, including antihypertensive, anti-inflammatory, anti-hyperglycemic, antithrombotic, and antifibrotic properties. It increases mitochondrial biogenesis, and it also has effects on the regulation of synthesis and metabolism of lipids. This flavanol is a nontoxic substance; it has been classified by the United States Food and Drug Administration as harmless. The EC-induced effects can be useful for the prevention and/or treatment of NAFLD.

Restorative potential of (-)-epicatechin in a rat model of Gulf War illness muscle atrophy and fatigue.

We examined in a rat model of Gulf War illness (GWI), the potential of (-)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicle and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi partially reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function.

Validation of post-harvest antimicrobial interventions to control Shiga toxin-producing Escherichia coli (STEC) on market hog carcass surfaces.

Although swine are less associated with STEC foodborne disease outbreaks, the potential for swine to serve as a source of STEC infections in human beings cannot be disregarded. This study compared eight USDA-approved antimicrobial intervention technologies to quantify their ability to reduce STEC contamination on market hog carcasses. Hogs were harvested to provide skin-on carcass sides, and eight sides (per three replications) were inoculated with a 7-strain STEC cocktail (ca. 5 log CFU/cm2 across all external and body cavity surfaces). Each side was randomly assigned to a final pre-chill wash treatment administered in a commercial Chad carcass cabinet using a low-volume spray [3% lactic acid (lLA; 130 °F), 400 ppm peracetic acid (lPAA), or acidified 400 ppm peracetic acid (laPAA)] or a high-volume wash [ambient water (hAW), 400 ppm PAA (hPAA), 400 or 600 ppm hypobromous acid (hDBDMH), or 71 °C water (hHW)] treatment according to a randomized complete block study design. Post-treatment (after a 10-min hanging drip) and post-chilling (18 h at 2 °C) STEC reductions were compared for external skin-on surfaces and internal body cavity lean surface tissue. Post-treatment color changes were determined for lean, adipose, and skin carcass surfaces before and after chilling. When applied to the external, skin-on surface, the hHW, hPAA, and hDBDMH600 deluge washes were significantly (P ≤ 0.05) more effective than the other intervention technologies, achieving STEC reductions of 3.8, 3.4, and 3.2 log CFU/cm2, respectively. In comparison, the hAW control reduced STEC by 1.7-log CFU/cm2 on the external, skin-on surface. The carcass interventions were less effective at reducing STEC populations attached to interior body cavity (diaphragm region), with post-chill populations reduced by 0.9-2.2 log cycles, while the hAW control wash achieved a 0.6-log reduction. None of the treatments negatively impacted instrumental carcass color. While all market hog carcass interventions reduced STEC populations, larger reductions were observed when applied to the external, skin-on surface, with the largest reductions achieved by the hHW, hPAA, and hDBDMH600 deluge washes. These data equip pork processors with the information necessary to support decision-making when selecting an intervention technology.

Anticancer potential of (-)-epicatechin in a triple-negative mammary gland model.

OBJECTIVES: The main aim of this work was to analyse the potential tumour growth inhibition effects of (-)-epicatechin (EC). Triple-negative breast cancer (TNBC) is an invasive form of cancer characterized by the absence of progesterone receptor, estrogen receptor and human epidermal growth factor receptor 2. Doxorubicin (DOX) is widely used for its anti-tumour activity. EC belongs to the flavanol subfamily and is a candidate molecule for the adjuvant treatment of cancer due to its antiproliferative activities. METHODS: Evaluation of EC effects and pathways involved in a model of TNBC. KEY FINDINGS: EC inhibited tumour growth as efficiently as DOX (inhibition rates of 74% and 79% for EC and DOX, respectively). The evaluation of adenosine monophosphate-activated protein kinase (AMPK) and Akt phosphorylation and mTOR expression indicates that EC modulates these pathways, resulting in the inhibition of cell proliferation. Additionally, we found an increase in the survival of EC-treated animals compared with control-treated animals. This effect was similar to the effects induced by DOX (survival rates of 44% and 30% for EC and DOX, respectively). CONCLUSION: EC has antiproliferative properties and increases survival in a model of TNBC. These effects may occur through the modulation of deregulated AMPK and Akt/mTOR signalling pathways.

Selective FPR2 Agonism Promotes a Proresolution Macrophage Phenotype and Improves Cardiac Structure-Function Post Myocardial Infarction.

Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted ß-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression. Treatment with BMS-986235 improved mouse survival, reduced left ventricular area, reduced scar area, and preserved wall thickness. Treatment increased macrophage arginase-1 messenger RNA and CD206 receptor levels indicating a proresolution phenotype. In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes.

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

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)-ß1 is known to mediate cardiac fibrosis through the SMAD pathway. High glucose (HG = 25 mM) cell culture media can activate CFs using TGF-ß1. 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-ß1 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-ß1, 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-ß1 pathway.

Stimulatory effects of (-)-epicatechin and its enantiomer (+)-epicatechin on mouse frontal cortex neurogenesis markers and short-term memory: proof of concept.

Consumption of (-)-epicatechin (Epi), a cacao flavanol improves cognition. The aim was to compare the effects of (-)-Epi or its stereoisomer (+)-Epi on mouse frontal cortex-dependent short-term working memory and modulators of neurogenesis. Three-month-old male mice (n = 7 per group) were provided by gavage either water (vehicle; Veh), (-)-Epi, at 1 mg kg-1 or (+)-Epi at 0.1 mg per kg of body weight for 15 days. After treatment, spontaneous alternation was evaluated by Y-maze. Brain frontal cortex was isolated for nitrate/nitrite measurements, Western blotting for nerve growth factor (NGF), microtubule associated protein 2 (MAP2), endothelial and neuronal nitric oxide synthase (eNOS and nNOS) and immunohistochemistry for neuronal specific protein (NeuN), doublecortin (DCX), capillary (CD31) and neurofilaments (NF200). Results demonstrate the stimulatory capacity of (-)-Epi and (+)-Epi on markers of neuronal proliferation as per increases in immunoreactive cells for NeuN (74 and 120% respectively), DCX (70 and 124%) as well as in NGF (34.4, 63.6%) and MAP2 (41.8, 63.8%). Capillary density yielded significant increases with (-)-Epi (∼80%) vs. (+)-Epi (∼160%). CD31 protein levels increased with (-)-Epi (∼70%) and (+)-Epi (∼140%). Effects correlated with nitrate/nitrite stimulation by (-)-Epi and (+)-Epi (110.2, 246.5%) and enhanced eNOS phosphorylation (Ser1177) with (-)-Epi and (+)-Epi (21.4, 41.2%) while nNOS phosphorylation only increased with (+)-Epi (18%). Neurofilament staining was increased in (-)-Epi by 135.6 and 84% with (+)-Epi. NF200 increased with (-)-Epi (116%) vs. (+)-Epi (84.5%). Frontal cortex-dependent short-term spatial working improved with (-)-Epi and (+)-Epi (15, 13%). In conclusion, results suggest that both enantiomers, but more effectively (+)-Epi, upregulate neurogenesis markers likely through stimulation of capillary formation and NO triggering, improvements in memory.

Measurement of the three-axis vibration, temperature, and relative humidity profiles of commercial transport trailers for pigs.

The objective of this study was to collect and interpret three-axis acceleration, temperature, and relative humidity data from six locations within commercial transport trailers shipping market-weight pigs. Transport was observed in Kansas (n = 15) and North Carolina (n = 20). Prior to loading, three-axis accelerometers were affixed to six locations on the trailers: top fore (TF), top center (TC), top aft (TA), bottom fore (BF), bottom center (BC), and bottom aft (BA) compartments. Data were post-processed to calculate root-mean-square (RMS) accelerations and vibration dose values (VDV) in the vertical direction and the horizontal plane. These values were compared with exposure action values (EAV) and exposure limit values (ELV), vibration levels deemed uncomfortable and potentially dangerous to humans. Additionally, RMS and VDV were compared among the trailer compartments. The vertical RMS accelerations for all compartments exceeded the EAV for loads measured in Kansas, and for the majority of the compartments measured in North Carolina. Many compartments, specifically the BA compartment from all trips, exceeded the vertical ELV. Regardless of where the data were collected, fewer compartments exceeded the EAV in the horizontal orientation. Only BA compartments exceeded the ELV in the horizontal orientation. There were Area × Level interactions for vertical and horizontal RMS and VDV (P < 0.01). The BF compartment had a greater vertical RMS value than the TF, TC, and BC (P < 0.02) compartments, but did not differ (P = 0.06) from the TA compartment. The vertical RMS of the TA compartment did not differ from the TF, TC, and BC compartments (P > 0.13). The BF compartment had a greater (P = 0.02) vertical VDV value than the TC location, but did not differ from the other locations (P > 0.16). All other locations did not differ in vertical VDV (P > 0.12). The BF compartment had greater horizontal RMS than the TC and TA compartments (P < 0.01), but did not differ from TF and BC compartments (P > 0.12). All other compartments did not differ in horizontal RMS (P > 0.34). All compartments, aside from the BA compartment, did not differ in horizontal VDV (P > 0.19). Vibration analyses indicated the BA compartment had the greatest vertical and horizontal vibrations and a large percentage of the compartments exceed the EAV and ELV, which indicated pigs may have experienced uncomfortable trips that could cause discomfort or fatigue.

(-)-Epicatechin induces mitochondrial biogenesis and markers of muscle regeneration in adults with Becker muscular dystrophy.

INTRODUCTION: We conducted an open-label study to examine the effects of the flavonoid (-)-epicatechin in seven ambulatory adult patients with Becker muscular dystrophy (BMD). METHODS: Seven participants received (-)-epicatechin 50 mg twice per day for 8 weeks. Pre- and postprocedures included biceps brachii biopsy to assess muscle structure and growth-relevant endpoints by western blotting, mitochondria volume measurement, and cristae abundance by electron microscopy, graded exercise testing, and muscle strength and function tests. RESULTS: Western blotting showed significantly increased levels of enzymes modulating cellular bioenergetics (liver kinase B1 and 5'-adenosine monophosphate-activated protein kinase). Peroxisome proliferator-activated receptor gamma coactivator-1alpha, a transcriptional coactivator of genes involved in mitochondrial biogenesis and cristae-associated mitofilin levels, increased as did cristae abundance. Muscle and plasma follistatin increased significantly while myostatin decreased. Markers of skeletal muscle regeneration myogenin, myogenic regulatory factor-5, myoblast determination protein 1, myocyte enhancer factor-2, and structure-associated proteins, including dysferlin, utrophin, and intracellular creatine kinase, also increased. Exercise testing demonstrated decreased heart rate, maximal oxygen consumption per kilogram, and plasma lactate levels at defined workloads. Tissue saturation index improved in resting and postexercise states. DISCUSSION: (-)-Epicatechin, an exercise mimetic, appears to have short-term positive effects on tissue biomarkers indicative of mitochondrial biogenesis and muscle regeneration, and produced improvements in graded exercise testing parameters in patients with BMD.

El VIH y la opresión de los hombres seropositivos con identidades no heteronormativas en Chiapas, México / O HIV e a opressão de homens soropositivos com identidades não-heteronormativas em Chiapas, México / Aids and non-heteronormative HIV-positive men's oppression in Chiapas, Mexico

Resumen A partir de seis entrevistas a hombres con VIH (HV) con identidades no heteronormativas, este artículo explora los cambios y continuidades, después del diagnóstico, en sus sexualidades y expresiones de género. Se focalizó la atención en los condicionamientos estructurales a estas experiencias. Para el análisis, se retomaron elementos de la construcción de género de y la teoría de la estructuración. Se recurre al método de comparación constante, para formar categorías con los patrones encontrados. Los resultados destacan que la opresión estructural a las prácticas sexuales y expresiones de género, se incrementa con la agudización de necesidades materiales y de apoyo, espiritual y psicológico.

Resumo Com base em seis entrevistas com homens com HIV (HH), com identidades não-heteronromativas, este estudo explora as mudanças e continuidades em sua sexualidade e expressões de gênero após o diagnóstico, focalizando as condições estruturais dessas experiências. Elementos de construção de gênero e a teoria de estruturação foram usados na análise. Usando o método de comparação constante para formar categorias com os padrões encontrados. Os resultados mostram que a opressão estrutural das práticas sexuais e expressões de gênero aumentam com o agravamento das necessidades materiais e de apoio espiritual e psicológico.

Abstract Based on six interviews with men with HIV (MH) that have non-heteronormative identities, this study explores transformations and continuities in their sexuality and gender expressions after the diagnosis. The focus was on the structural conditioning of this experience. For the analysis, elements of the construction of gender and the theory of structuring were used. The constant comparison method is used to form categories within patterns found. The results highlight that the structural oppression of sexual practices and gender expressions increases with the exacerbation of material needs and for spiritual and psychological support.

Effects of (-)-epicatechin on neuroinflammation and hyperphosphorylation of tau in the hippocampus of aged mice.

Evidence has implicated oxidative stress (OS) and inflammation as drivers of neurodegenerative pathologies. We previously reported on the beneficial effects of (-)-epicatechin (Epi) treatment on aging-induced OS and its capacity to restore modulators of mitochondrial biogenesis in the prefrontal cortex of 26-month-old male mice. In the present study using the same mouse model of aging, we examined the capacity of Epi to mitigate hippocampus OS, inflammation, hyperphosphorylation of tau protein, soluble ß-amyloid protein levels, cell survival, memory, anxiety-like behavior levels and systemic inflammation. Mice were subjected to 4 weeks of Epi treatment (1 mg kg-1 day-1) and samples of the hippocampus were obtained. Assessments of the OS markers, protein carbonyls, and malondialdehyde levels demonstrated their significant increase (∼3 fold) with aging that were partially suppressed by Epi. The protein levels of the glial fibrillary acidic protein, inflammatory factor 1 (Iba1), pro-inflammatory cytokines, interleukins (IL-1ß, IL-3, 5, 6 and 15), cyclooxygenase 2, tumor necrosis factor α, nuclear factor-activated B cells and interferon γ increase with aging and were also significantly decreased with Epi treatment. However, anti-inflammatory cytokines, IL-1ra, IL-10 and 11 decrease with aging and were restored with Epi. Epi also reversed the aging effects on the hyperphosphorylation of tau, increased soluble ß-amyloid levels (∼2 fold), cellular death (as per caspase 3 and 9 activity), and reduced nerve growth factor and triggering receptor expressed on myeloid cells 2 levels. Measures of anxiety like-behavior and memory demonstrated improvements with Epi treatment. Indicators of systemic inflammation increase with aging and Epi was capable of decreasing blood inflammatory markers. Altogether, the results show a significant capacity of Epi to mitigate hippocampus OS and inflammation leading to improved brain function.

PXR is a target of (-)-epicatechin in skeletal muscle.

(-)-Epicatechin (EC) is a flavanol that has shown numerous biological effects such as: decrease risk of cardiovascular dysfunction, metabolism regulation, skeletal muscle (SkM) performance improvement and SkM cells differentiation induction, among others. The described EC acceptor/receptor molecules do not explain the EC's effect on SkM. We hypothesize that the pregnane X receptor (PXR) can fulfill those characteristics, based on structural similitude between EC and steroidal backbone and that PXR activation leads to similar effects as those induced by EC. In order to demonstrate our hypothesis, we: 1) analyzed the possible EC and mouse PXR interaction through in silico strategies, 2) developed an EC's affinity column to isolate PXR, 3) evaluated, in mouse myoblast (C2C12 cells) the inhibition of EC-induced PXR's nucleus translocation by ketoconazole, a specific blocker of PXR and 4) analyzed the effect of EC as an activator of mouse PXR, evaluating the expression modulation of cytochrome 3a11 (Cyp3a11) gen and myogenin protein. (-)-Epicatechin interacts and activates PXR, promoting this protein translocation to the nucleus, increasing the expression of Cyp3a11, and promoting C2C12 cell differentiation through increasing myogenin expression. These results can be the base of further studies to analyze the possible participation of PXR in the skeletal muscle effects shown by EC.