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.

Advances in the Properties of Incomptine A: Cytotoxic Activity and Downregulation of Hexokinase II in Breast Cancer Cell Lines.

Breast cancer treatments are limited by the cancer subtype and its selectivity towards tumor cells, hence the importance of finding compounds that increase the survival of healthy cells and target any subtype. Incomptine A (IA) is a sesquiterpene lactone with demonstrated cytotoxic activity. In this study, through in vitro assays, it was observed that IA has similar cytotoxic activity between the subtypes triple negative, HER2+, and luminal A of the breast cancer cell lines. IA cytotoxic activity is higher in cancer than in nontumorigenic cells, and its selectivity index for cancer cells is more than that of the drug doxorubicin. Molecular docking and its in silico comparison with the 2-Deoxyglucose inhibitor suggest that IA could bind to Hexokinase II (HKII), decreasing its expression. Since we did not find changes in the expression of the glycolytic pathway, we suppose that IA could affect the antiapoptotic function of HKII in cancer cells. The IA-HKII union would activate the voltage-gated anion channel 1 (VDAC1), resuming apoptosis. Therefore, we suggest that IA could be used against almost any subtype and that its cytotoxic effect could be due to the reactivation of apoptosis in breast cancer cells.

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.

(-)-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.

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.

Early hyperbaric oxygen therapy improves survival in a model of severe sepsis.

Sepsis is a major clinical challenge, with therapy limited to supportive interventions. Therefore, the search for novel remedial approaches is of great importance. We addressed whether hyperbaric oxygen therapy (HBOT) could improve the outcome of sepsis using an acute experimental mouse model. Sepsis was induced in male CD-1 mice by cecal ligation and puncture (CLP) tailored to result in 80-90% mortality within 72 h of the insult. After CLP, mice were randomized into two groups receiving HBOT or not at different times after the initial insult or subjected to multiple HBOT treatments. HBOT conditions were 98% oxygen pressurized to 2.4 atmospheres for 1 h. HBOT within 1 h after CLP resulted in 52% survival in comparison with mice that did not receive the treatment (13% survival). Multiple HBOT at 1 and 6 h or 1, 6, and 21 h displayed an increase in survival of >50%, but they were not significantly different from a single treatment after 1 h of CLP. Treatments at 6 or 21 h after CLP, excluding the 1 h of treatment, did not show any protective effect. Early HBO treatment did not modify bacterial counts after CLP, but it was associated with decreased expression of TNF-α, IL-6, and IL-10 expression in the liver within 3 h after CLP. The decrease of cytokine expression was reproduced in cultured macrophages after exposure to HBOT. Early HBOT could be of benefit in the treatment of sepsis, and the protective mechanism may be related to a reduction in the systemic inflammatory response.

High Flavonoid Cocoa Supplement Ameliorates Plasma Oxidative Stress and Inflammation Levels While Improving Mobility and Quality of Life in Older Subjects: A Double-Blind Randomized Clinical Trial.

BACKGROUND: The age-related decline in mass, strength, and performance of skeletal muscle is associated with loss of independence, falls risk, disability, institutionalization, and death. METHODS: To determine whether a cocoa supplement enriched in flavonoids can improve plasma markers of oxidative stress and inflammation, physical performance and frailty in middle-aged and older subjects, we conducted a two-phase, randomized, double-blind, clinical trial. The initial study included 60 subjects (55- to 70-year-old) allocated into placebo (P), highly alkalinized (no-flavonoid; NF), or flavonoid-rich natural cocoa (F) beverage groups. The follow-up study included 74 older subjects (65- to 90-year-old) randomly distributed into NF or F groups. Subjects were instructed to consume the beverages once/day for up to 12-weeks. A comprehensive (aging relevant) set of end points were assessed, which included mean change in blood plasma metabolic and oxidative stress indicators, in physical performance tests and quality of life (QoL). RESULTS: In the initial study, the F group showed improved glycemia, triglyceridemia, High-density lipoprotein cholesterol, Low-density lipoprotein cholesterol, triglyceridemia/HDL index, and oxidative markers. Performance on the Up and Go test, skeletal muscle index, and quality of life also improved. In the follow-up study, F treatment was associated with significant improvements in metabolic, oxidative stress, and inflammatory endpoints and positive effects on physical performance, frailty indicators, and quality of life (F vs. NF group). CONCLUSIONS: Regular flavonoids consumption positively affects blood oxidative stress and inflammation end points, cardiometabolic risk markers, physical performance, and quality of life. The sum of such effects may help to mitigate the extent of frailty development in the elderly people. TRIAL REGISTRATION: NCT03585868.

Unmasking of oestrogen-dependent changes in left ventricular structure and function in aged female rats: a potential model for pre-heart failure with preserved ejection fraction.

KEY POINTS: Heart failure with preserved ejection fraction (HFpEF) is seen more frequently in older women; risk factors include age, hypertension and excess weight. No female animal models of early stage remodelling (pre-HFpEF) have examined the effects that the convergence of such factors have on cardiac structure and function. In this study, we demonstrate that ageing can lead to the development of mild chamber remodelling, diffuse fibrosis and loss of diastolic function. The loss of oestrogens further aggravates such changes by leading to a notable drop in cardiac output (while preserving normal ejection fraction) in the presence of diffuse fibrosis that is more predominant in endocardium and is accompanied by papillary fibrosis. Excess weight did not markedly aggravate such findings. This animal model recapitulates many of the features recognized in older, female HFpEF patients and thus, may serve to examine the effects of candidate therapeutic agents. ABSTRACT: Two-thirds of patients with heart failure with preserved ejection fraction (HFpEF) are older women, and risk factors include hypertension and excess weight/obesity. Pathophysiological factors that drive early disease development (before heart failure ensues) remain obscure and female animal models are lacking. The study evaluated the intersecting roles of ageing, oestrogen depletion and excess weight on altering cardiac structure/function. Female, 18-month-old, Fischer F344 rats were divided into an aged group, aged + ovariectomy (OVX) and aged + ovariectomy + 10% fructose (OVF) in drinking water (n = 8-16/group) to induce weight gain. Left ventricular (LV) structure/function was monitored by echocardiography. At 22 months of age, animals were anaesthetized and catheter-based haemodynamics evaluated, followed by histological measures of chamber morphometry and collagen density. All aged animals developed hypertension. OVF animals increased body weight. Echocardiography only detected mild chamber remodelling with ageing while intraventricular pressure-volume loop analysis showed significant (P < 0.05) decreases vs. ageing in stroke volume (13% OVX and 15% for OVF), stroke work (34% and 52%) and cardiac output (29% and 27%), and increases in relaxation time (10% OVX) with preserved ejection fraction. Histology indicated papillary and interstitial fibrosis with ageing, which was higher in the endocardium of OVX and OVF groups. With ageing, ovariectomy leads to the loss of diastolic and global LV function while preserving ejection fraction. This model recapitulates many cardiovascular features present in HFpEF patients and may help understand the roles that ageing and oestrogen depletion play in early (pre-HFpEF) disease development.

Synthesis of novel (-)-epicatechin derivatives as potential endothelial GPER agonists: Evaluation of biological effects.

To potentially identify proteins that interact (i.e. bind) and may contribute to mediate (-)-epicatechin (Epi) responses in endothelial cells we implemented the following strategy: 1) synthesis of novel Epi derivatives amenable to affinity column use, 2) in silico molecular docking studies of the novel derivatives on G protein-coupled estrogen receptor (GPER), 3) biological assessment of the derivatives on NO production, 4) implementation of an immobilized Epi derivative affinity column and, 5) affinity column based isolation of Epi interacting proteins from endothelial cell protein extracts. For these purposes, the Epi phenol and C3 hydroxyl groups were chemically modified with propargyl or mesyl groups. Docking studies of the novel Epi derivatives on GPER conformers at 14 ns and 70 ns demostrated favorable thermodynamic interactions reaching the binding site. Cultures of bovine coronary artery endothelial cells (BCAEC) treated with Epi derivatives stimulated NO production via Ser1179 phosphorylation of eNOS, effects that were attenuated by the use of the GPER blocker, G15. Epi derivative affinity columns yielded multiple proteins from BCAEC. Proteins were electrophoretically separated and inmmunoblotting analysis revealed GPER as an Epi derivative binding protein. Altogether, these results validate the proposed strategy to potentially isolate and identify novel Epi receptors that may account for its biological activity.

A pilot study on clinical pharmacokinetics and preclinical pharmacodynamics of (+)-epicatechin on cardiometabolic endpoints.

We reported that (-)-epicatechin can stimulate mitochondria biogenesis and improve metabolism. However, preliminary studies indicate that the (+) stereoisomer form may be more potent. We evaluated in a preliminary manner, the pharmacokinetics (PK) and initial safety analysis of (+)-epicatechin ((+)-Epi) in healthy and pre-diabetic subjects. Using a mouse model of diet-induced obesity and insulin resistance, we also evaluated the metabolic effects of (+)-Epi vs. (+)-catechin (Cat) to determine class effects. In the Phase I PK study, subjects were provided a single incremental oral dose of (+)-Epi (10, 30 or 100 mg). For the PD study, subjects were provided a single 30 mg dose per day for 7 days. Blood samples were collected and safety measures were performed. Incremental doses of (+)-Epi increase the half-life of blood metabolites from 1.2-4.9 h. The compound was well tolerated and no adverse effects were reported. Seven day dosing of pre-diabetic subjects led to tendencies for reductions in circulating levels of tumor necrosis factor-α and monocyte chemoattractant protein-1, which returned to baseline by 7 days after treatment. In animals, 2 weeks of oral dosing (0.003, 0.01, 0.03, 0.1 and 0.3 mg kg-1 day-1) dose dependently improved metabolism-related endpoints (weight gain, glucose, cholesterol, triglyceride, with thresholds as low as 0.01 mg kg-1 day-1). Cat yielded no effects at 0.1 mg kg-1 day-1. Results indicate that (+)-Epi evidences a favorable PK and safety profile. Using a pre-clinical model, the compound positively modulates metabolism, which may link to mitochondrial effects. Effects are not due to general antioxidant actions, as Cat yielded no effects.

Effects of a natural extract of Aronia Melanocarpa berry on endothelial cell nitric oxide production.

The effects of acute and chronic treatment with Aronia extracts on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation in bovine coronary artery endothelial cells were investigated. Acute time-course and concentration-response experiments were performed to determine the time and concentration at which Aronia induced maximal NO synthesis and eNOS phosphorylation. The findings indicate that relatively low concentrations (0.1 µg/mL) of Aronia extract significantly induced NO synthesis and eNOS phosphorylation after 10 min of treatment. Increased sensitivity of eNOS and a significant increase in NO synthesis resulted from longer-term stimulation with Aronia (48 hr) and an acute re-treatment of the cells (10 min). PRACTICAL APPLICATIONS: These in vitro results may be translated into potential future clinical applications where Aronia extracts may be used for prevention and coadjuvant treatment of cardiovascular diseases via increases in endothelial NO synthesis and related improvements in vascular functions. Given the dose-response effect of Aronia extract in vitro and metabolism of polyphenols that occurs in humans, dose-response studies would be necessary to define the optimal daily amount to be consumed.

Beneficial effects of dark chocolate on exercise capacity in sedentary subjects: underlying mechanisms. A double blind, randomized, placebo controlled trial.

In heart failure patients the consumption of (-)-epicatechin ((-)-Epi)-rich cocoa can restore skeletal muscle (SkM) mitochondrial structure and decrease biomarkers of oxidative stress. However, nothing is known about its effects on exercise capacity and underlying mechanisms in normal, sedentary subjects. Twenty normal, sedentary subjects (∼50 years old) were randomized to placebo or dark chocolate (DC) groups and consumed 20 g of the products for 3 months. Subjects underwent before and after treatment, bicycle ergometry to assess VO2 max and work, SkM biopsy to assess changes in mitochondrial density, function and oxidative stress and blood sampling to assess metabolic endpoints. Seventeen subjects completed the trial. In the DC group (n = 9), VO2 max increased (17% increase, p = 0.056) as well as maximum work (watts) achieved (p = 0.026) with no changes with placebo (n = 8). The DC group evidenced increases in HDL levels (p = 0.005) and decreased triglycerides (p = 0.07). With DC, SkM evidenced significant increases in protein levels for LKB1, AMPK and PGC1α and in their active forms (phosphorylated AMPK and LKB1) as well as in citrate synthase activity while no changes were observed in mitochondrial density. With DC, significant increases in SkM reduced glutathione levels and decreases in protein carbonylation were observed. Improvements in maximum work achieved and VO2 max may be due to DC activation of upstream control systems and enhancement of SkM mitochondria efficiency. Larger clinical studies are warranted to confirm these observations.

The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER).

We have provided evidence that the stimulatory effects of (-)-epicatechin ((-)-EPI) on endothelial cell nitric oxide (NO) production may involve the participation of a cell-surface receptor. Thus far, such entity(ies) has not been fully elucidated. The G protein-coupled estrogen receptor (GPER) is a cell-surface receptor that has been linked to protective effects on the cardiovascular system and activation of intracellular signaling pathways (including NO production) similar to those reported with (-)-EPI. In bovine coronary artery endothelial cells (BCAEC) by the use of confocal imaging, we evidence the presence of GPER at the cell-surface and on F-actin filaments. Using in silico studies we document the favorable binding mode between (-)-EPI and GPER. Such binding is comparable to that of the GPER agonist, G1. By the use of selective blockers, we demonstrate that the activation of ERK 1/2 and CaMKII by (-)-EPI is dependent on the GPER/c-SRC/EGFR axis mimicking those effects noted with G1. We also evidence by the use of siRNA the role that GPER has on mediating ERK1/2 activation by (-)-EPI. GPER appears to be coupled to a non Gαi/o or Gαs, protein subtype. To extrapolate our findings to an ex vivo model, we employed phenylephrine pre-contracted aortic rings evidencing that (-)-EPI can mediate vasodilation through GPER activation. In conclusion, we provide evidence that suggests the GPER as a potential mediator of (-)-EPI effects and highlights the important role that GPER may have on cardiovascular system protection.

Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis.

Excess enzyme-mediated protein O-GlcNAcylation is known to occur with diabetes mellitus. A characteristic of diabetic cardiomyopathy is the development of myocardial fibrosis. The role that enhanced protein O-GlcNAcylation plays in modulating the phenotype of cardiac fibroblasts (CF) is unknown. To address this issue, rat CF were cultured in normal glucose (NG; 5 mM glucose) or high-glucose (HG; 25 mM) media for 48 h. Results demonstrate that CF cultured in HG have higher levels (~50%) of overall protein O-GlcNAcylation vs. NG cells. Key regulators of collagen synthesis such as transforming-growth factor-ß1 (TGF-ß1), SMADs 2/3, and SMAD 7 protein levels, including those of arginase I and II, were altered, leading to increases in collagen levels. The nuclear transcription factor Sp1 and arginase II evidence excess O-GlcNAcylation in HG cells. Expression in CF of an adenovirus coding for the enzyme N-acetylglucosaminidase, which removes O-GlcNAc moieties from proteins, decreased Sp1 and arginase II O-GlcNAcylation and restored HG-induced perturbations in CF back to NG levels. These findings may have important pathophysiological implications for the development of diabetes-induced cardiac fibrosis.

Description of a utrophin associated protein complex in lipid raft domains of human artery smooth muscle cells.

The dystrophin-associated protein complex (DAPC) is a multimeric complex that links the extracellular matrix to the actin cytoskeleton, and in some cases dystrophin can be substituted by its autosomal homologue utrophin to form the utrophin-associated protein complex (UAPC). Both complexes maintain the stability of plasma membrane during contraction process and play an important role in transmembrane signaling. Mutations in members of the DAPC are associated with muscular dystrophy and dilated cardiomyopathy. In a previous study with human umbilical cord vessels, we observed that utrophin colocalize with caveolin-1 (Cav-1) which proposed the presence of UAPC in the plasma membrane of vascular smooth muscle (VSM). In the current study, we demonstrated by immunofluorescence analysis, co-immunoprecipitation assays, and subcellular fractionation by sucrose gradients, the existence of an UAPC in lipid raft domains of human umbilical artery smooth muscle cells (HUASMC). This complex is constituted by utrophin, ß-DG, ε-SG, α-smooth muscle actin, Cav-1, endothelial nitric oxide synthase (eNOS) and cavin-1. It was also observed the presence of dystrophin, utrophin Dp71, ß-SG, δ-SG, δ-SG3 and sarcospan in non-lipid raft fractions. Furthermore, the knockdown of α/ß-DG was associated with the decrease in both the synthesis of nitric oxide (NO) and the presence of the phosphorylated (active) form of eNOS; and with a reduction in the downstream activation of some cGMP signaling transduction pathway components. Together these results show the presence of an UAPC complex in HUASMC that may participate in the activity regulation of eNOS and in the vascular function.

Cardiovascular risk factors in a Mexican middle-class urban population: The Lindavista Study. Baseline data / Factores de riesgo cardiovascular en mexicanos de clase media: el estudio Lindavista. Datos basales

Introduction and objective: The aim of this communication is to describe the cardiovascular risk factors affecting a Mexican urban middle-class population. Methods: A convenience sample of 2602 middle class urban subjects composed the cohort of the Lindavista Study, a prospective study aimed to determine if conventional cardiovascular risks factors have the same prognosis impact as in other populations. For the baseline data, several measurements were done: obesity indexes, smoking, blood pressure, fasting serum glucose, total cholesterol, HDL-c, LDL-c and triglycerides. This paper presents the basal values of this population, which represents a sample of the Mexican growing urban middle-class. Results: The mean age in the sample was 50 years; 59% were females. Around 50% of the entire group were overweighed, while around 24% were obese. 32% smoked; 32% were hypertensive with a 20% rate of controlled pressure. 6% had diabetes, and 14% had impaired fasting glucose; 66% had total cholesterol ≥ 200mg/dL; 62% showed HDL-c levels <40mg/dL; 52% triglycerides > 150 mg/dL, and 34% levels of LDL-c ≥ 160 mg/dL. Half of the population studied had the metabolic syndrome. Conclusion: These data show a population with a high-risk profile, secondary to the agglomeration of several cardiovascular risk factors.

Introducción y objetivo: el objetivo de este comunicado es describir los factores de riesgo cardiovascular en la población urbana mexicana de clase media. Métodos: La cohorte del estudio Lindavista se compone de una muestra por conveniencia de 2,602 sujetos de clase media. El estudio es prospectivo y tiene como finalidad determinar si los factores de riesgo cardiovascular tienen el mismo factor pronóstico que en otras poblaciones. Para los datos basales, se hicieron varias determinaciones: índices de obesidad, consumo de tabaco, presión arterial, glucosa, colesterol total, c-HDL, c-LDL y triglicéridos en ayuno. Resultados: La media de edad fue de 50 años; el 59% fueron mujeres. Aproximadamente el 50% de la muestra presentó sobrepeso, mientras que el 24% eran obesos. El 32% fumaban, el 32% eran hipertensos con una tasa de control del 20%. El 6% tenían diabetes y el 14% resistencia a la insulina. El 66% tuvieron colesterol total ≥ 200 mg/dl; el 62% mostraron bajos niveles de c-HDL, el 52% triglicéridos > 150 mg/dl, y el 34% niveles de c-LDL ≥ 160 mg/dl. La mitad de la muestra tenía síndrome metabólico. Conclusión: Los datos revelan una población de alto riesgo cardiovascular debido a la aglomeración de diversos factores de riesgo.

Cardiovascular risk factors in a Mexican middle-class urban population. The Lindavista Study. Baseline data.

INTRODUCTION AND OBJECTIVE: The aim of this communication is to describe the cardiovascular risk factors affecting a Mexican urban middle-class population. METHODS: A convenience sample of 2602 middle class urban subjects composed the cohort of the Lindavista Study, a prospective study aimed to determine if conventional cardiovascular risks factors have the same prognosis impact as in other populations. For the baseline data, several measurements were done: obesity indexes, smoking, blood pressure, fasting serum glucose, total cholesterol, HDL-c, LDL-c and triglycerides. This paper presents the basal values of this population, which represents a sample of the Mexican growing urban middle-class. RESULTS: The mean age in the sample was 50 years; 59% were females. Around 50% of the entire group were overweighed, while around 24% were obese. 32% smoked; 32% were hypertensive with a 20% rate of controlled pressure. 6% had diabetes, and 14% had impaired fasting glucose; 66% had total cholesterol ≥ 200 mg/dL; 62% showed HDL-c levels<40 mg/dL; 52% triglycerides>150 mg/dL, and 34% levels of LDL-c ≥ 160 mg/dL. Half of the population studied had the metabolic syndrome. CONCLUSION: These data show a population with a high-risk profile, secondary to the agglomeration of several cardiovascular risk factors.

Anthropometric traits, blood pressure, and dietary and physical exercise habits in health sciences students; the obesity observatory project.

BACKGROUND: Obesity and the metabolic syndrome affect a considerable segment of the population worldwide, including health professionals. In fact, several studies have reported that physicians tend to have more cardiovascular risk factors than their patients. The present cross-sectional study assessed whether the Health Sciences students had a healthier lifestyle, thus could have a more preventive attitude towards chronic diseases than the general population. MATERIALS AND METHODS: Students of the medical-biological areas were surveyed by answering a questionnaire about familiar cardiovascular risk factors, personal smoking, alcohol drinking, dietary and exercise habits. Blood pressure was also measured, along with weight, height, and abdominal circumference. RESULTS: 23.4% of the participants were overweight and 10% obese. Parental obesity was the most frequent risk factor, followed by social drinking and smoking. We found high consumption of animal derived foods, breakfast- like cereals, pastries, white bread and sweetened beverages; while low intake of fruit and vegetables were reported. More than half the sample reported to practice very little or no exercise at all. DISCUSSION AND CONCLUSIONS: We found similar or even higher rates of risk factors than the average population, that may eventually lead to the development of chronic cardiometabolic diseases. Thus we can infer that biomedical education is inefficient in inducing healthy lifestyles among biomedical students, which could have impact in their future practice as they will most probable become obese health-professionals, thus fail to effectively treat their own patients.

Introducción: La obesidad y el síndrome metabólico afectan a un segmento considerable de la población mundial, incluyendo a los profesionales de la salud. De hecho, diversos estudios han reportado que los médicos tienden a presentar más factores de riesgo cardiovascular que sus propios pacientes. El presente estudio transversal evaluó si los estudiantes del área de la salud tenían un estilo de vida más saludable y, por tanto, una mejor actitud en cuanto a la prevención de las enfermedades crónico-degenerativas, que el resto de la población. Materiales y métodos: Se encuestaron estudiantes del área medico-biológica a través de un cuestionario sobre antecedentes heredo-familiares de riesgo cardiovascular, consumo actual de tabaco y alcohol, así como hábitos alimentarios y de ejercicio físico. Se midió la presión arterial, el peos, la talla y la circunferencia abdominal. Resultados: 23.4% de los participantes presentaban sobrepeso y 10% obesidad. La obesidad paterna fue el factor de riesgo más frecuente, seguido de consumo social de alcohol y tabaquismo. Se encontró un alto consume de alimentos de origen animal, cereales industrializados y refrescos; por otra parte, se reportó un bajo consumo de verduras y frutas. Más de la mitad de la muestra refirió ser sedentario. Discusión y conclusiones: Se encontraron datos muy similares a aquéllos reportados sobre la población general, que eventualmente conducirán al desarrollo de enfermedades cardiometabólicas. Por tanto, es posible inferir que la educación biomédica no es eficiente en la inducción de un estilo de vida saludable entre los estudiantes de ciencias de la salud. Tal fenómeno podría impactar su práctica futura ya que probablemente se convertirán en profesionistas obesos, con la consecuente falla en la prevención primaria y secundaria de sus propios pacientes.

(-)-Epicatechin-induced calcium independent eNOS activation: roles of HSP90 and AKT.

Cardiovascular disease (CVD) is a leading determinant of mortality and morbidity in the world. Epidemiologic studies suggest that flavonoid intake plays a role in the prevention of CVD. Consumption of cocoa products rich in flavonoids lowers blood pressure and improves endothelial function in healthy subjects as well as in subjects with vascular dysfunction such as smokers and diabetics. The vascular actions of cocoa follow the stimulation of nitric oxide (NO). These actions can be reproduced by the administration of the cocoa flavanol (-)-epicatechin (EPI). Previously, using human endothelial cells cultured in calcium-free media, we documented EPI effects on eNOS independently of its translocation from the plasmalemma. To further define the mechanisms behind EPI-eNOS activation in Ca(2+) -deprived endothelial cells, we evaluated the effects of EPI on the eNOS/AKT/HSP90 signaling pathway. Results document an EPI-induced phosphorylation/activation of eNOS, AKT, and HSP90. We also demonstrate that EPI induces a partial AKT/HSP90 migration from the cytoplasm to the caveolar membrane fraction. Immunoprecipitation assays of caveolar fractions demonstrate a physical association between HSP90, AKT, and eNOS. Thus, under Ca(2+)-free conditions, EPI stimulates NO synthesis via the formation of an active complex between eNOS, AKT, and HSP90.

Stimulatory effects of the flavanol (-)-epicatechin on cardiac angiogenesis: additive effects with exercise.

The consumption of moderate amounts of cocoa products has been associated with reductions in the incidence of cardiovascular diseases. In animal studies, the flavanol (-)-epicatechin (Epi) yields cardioprotection. The effects may be partly due to its capacity to stimulate endothelial nitric oxide synthase (eNOS). The sustained activation of eNOS, as observed with exercise, can serve as a trigger of muscle angiogenesis via the activation of vascular endothelial growth factor (VEGF)-related events. Experiments were pursued to examine the potential of Epi to stimulate myocardial angiogenesis and determine the effects that its combined use with exercise (Ex) may trigger. Hearts obtained from a previous study were used for this purpose. Animals received 1 mg/kg of Epi or water (vehicle) via oral gavage (twice daily). Epi and/or Ex (by treadmill) was provided for 15 days. Results indicate that Ex or Epi significantly stimulate myocardial angiogenesis by ~30% above control levels. The use of Epi-Ex lead to further significant increases (to ~50%). Effects were associated with increases in protein levels and/or activation of canonical angiogenesis pathway associated events (HIF1a, VEGF, VEGFR2, PI3K, PDK, AKT, eNOS, NO, cGMP, MMP-2/-9, Src-1, and CD31). Thus, the use of Epi may represent a safe and novel means to stimulate myocardial angiogenesis.