Hyperbaric oxygenation applied before or after mild or hard stress: effects on the redox state in the muscle tissue.

The mechanism is unclear for the reported protective effect of hyperbaric oxygen preconditioning against oxidative stress in tissues, and the distinct effects of hyperbaric oxygen applied after stress. The trained mice were divided into three groups: the control, hyperbaric oxygenation preconditioning, and hyperbaric oxygenation applied after mild (fasting) or hard (prolonged exercise) stress. After preconditioning, we observed a decrease in basal levels of nitric oxide, tetrahydrobiopterin, and catalase despite the drastic increase in inducible and endothelial nitric oxide synthases. Moreover, the basal levels of glutathione, related enzymes, and nitrosative stress only increased in the preconditioning group. The control and preconditioning groups showed a similar mild stress response of the endothelial and neuronal nitric oxide synthases. At the same time, the activity of all nitric oxide synthase, glutathione (GSH) in muscle, declined in the experimental groups but increased in control during hard stress. The results suggested that hyperbaric oxygen preconditioning provoked uncoupling of nitric oxide synthases and the elevated levels of GSH in muscle during this study, while hyperbaric oxygen applied after stress showed a lower level of GSH but higher recovery post-exercise levels in the majority of antioxidant enzymes. We discuss the possible mechanisms of the redox response and the role of the nitric oxide in this process.

Role of Sulfur Compounds in Garlic as Potential Therapeutic Option for Inflammation and Oxidative Stress in Asthma.

Asthma is a chronic inflammatory disease in the airways with a multifactorial origin but with inflammation and oxidative stress as related pathogenic mechanisms. Garlic (Allium sativum) is a nutraceutical with different biological properties due to sulfur-containing natural compounds. Studies have shown that several compounds in garlic may have beneficial effects on cardiovascular diseases, including those related to the lungs. Therefore, it is possible to take advantage of the compounds from garlic as nutraceuticals for treating lung diseases. The objective of this article is to review the biological properties of the sulfur compounds present in garlic for the treatment of asthma, as well as the cellular mechanisms involved. Here, we discuss the potential therapeutic effects of garlic compounds in the modulation of inflammation and oxidative stress, as well as its antibiotic and antiviral activities for identifying and testing potential treatment options for asthma management.

Global longitudinal strain is superior to ejection fraction for detecting myocardial dysfunction in end-stage renal disease with hyperparathyroidism.

BACKGROUND: The estimation of left ventricular ejection fraction (LVEF) by 2D echocardiography (2D-ECHO) is the most used tool to assess LV systolic function (LVSF). Global longitudinal strain (GLS) has recently been suggested as a superior method for several evaluations. This study explored the association and prevalence of LV systolic dysfunction (LVSD) by using these methods in patients with end-stage renal disease (ESRD) and severe hyperparathyroidism (SHPTH); both associated with cardiovascular events (CEs). AIM: To evaluate the myocardial function in patients with ESRD and SHPTH by using the GLS and LVEF measured through conventional 2D-ECHO. METHODS: In 62 patients with ESRD and SHPTH, asymptomatic, and without a history of CEs, LVSF was evaluated by 2D-ECHO, obtaining the EF, by the Simpson biplane method, and GLS by speckle tracking. RESULTS: The total patients with ESRD had a preserved LVEF (> 50%) but abnormal GLS (< 13.55%). Additionally, multivariate analysis showed an independent association of GLS and serum parathyroid hormone (PTH), LV mass index, and hemoglobin. Also, PTH was independently associated with lateral e' wave and tricuspid regurgitation velocity. CONCLUSION: In patients with SHPTH linked to ESRD, the use of GLS by 2D-ECHO is a more sensitive tool than LVEF for detecting LVSD.

Anti-Inflammatory Effect of Allicin Associated with Fibrosis in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, TNF-α, NFκB p65, Iκß, TGF-ß, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-ß were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1ß, and Cd68 in the lung. In addition, TGF-ß, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-ß. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.

Cannabidiol-mediated RISK PI3K/AKT and MAPK/ERK pathways decreasing reperfusion myocardial damage.

Myocardial ischemia continues to be the first cause of morbimortality in the world; the definitive treatment is reperfusion; however, this action causes additional damage to ischemic myocardial tissue; this forces to seek therapies of cardioprotection to reduce this additional damage. There are many cardioprotective agents; within these, cannabinoids have shown to have beneficial effects, mainly cannabidiol (CBD). CBD is a non psychoactive cannabinoid. To evaluate the effect in experimental models of CBD in myocardial ischemia reperfusion in rats, twelve-week-old male rats have been used. The animals were divides in 3 groups: control(C), ischemia reperfusion (IR) and CBD pretreatment (1/day/5mg/kg /10days). Langendorff organ isolate studies were performed, and the area of infarction was assessed with triphenyl tetrazolium, in addition to molecular analysis of AT1 and AT2 receptors and Akt and Erk proteins and their phosphorylated forms related to RISK pathways. It was observed that there is an improvement with the use of CBD increasing inotropism and cardiac lusitropism, improving considerably the cardiovascular functionality. These could be related to the reduction of the area of infarction and activation of the AT2 receptor and the RISK pathway with absence of activation of the AT2 receptor (these could relate the reduction of the infarct area and the restoration of cardiovascular function with the activation of the AT2 receptor and the RISK pathway with the absence of activation of the AT2 receptor). The use of cannabinoids was shown to have beneficial effects when used as a treatment for myocardial reperfusion damage.

Arginase inhibition by (-)-Epicatechin reverses endothelial cell aging.

Endothelial dysfunction (EnD) occurs with aging and endothelial nitric oxide (NO) production by NO synthase (NOS) can be impaired. Low NO levels have been linked to increased arginase (Ar) activity as Ar competes with NOS for L-arginine. The inhibition of Ar activity can reverse EnD and (-)-epicatechin (Epi) inhibits myocardial Ar activity. In this study, through in silico modeling we demonstrate that Epi interacts with Ar similarly to its inhibitor Norvaline (Norv). Using in vitro and in vivo models of aging, we examined Epi and Norv-inhibition of Ar activity and its endothelium-protective effects. Bovine coronary artery endothelial cells (BCAEC) were treated with Norv (10 µM), Epi (1 µM) or the combination (Epi + Norv) for 48 h. Ar activity increased in aged BCAEC, with decreased NO generation. Treatment decreased Ar activity to levels seen in young cells. Epi and Epi + Norv decreased nitrosylated Ar levels by ~25% in aged cells with lower oxidative stress (~25%) (dihydroethidium) levels. In aged cells, Epi and Epi + Norv restored the eNOS monomer/dimer ratio, protein expression levels and NO production to those of young cells. Furthermore, using 18 month old rats 15 days of treatment with either Epi (1 mg/kg), Norv (10 mg/kg) or combo, decreased hypertension and improved aorta vasorelaxation to acetylcholine, blood NO levels and tetra/dihydribiopterin ratios in cultured rat aortic endothelial cells. In conclusion, results provide evidence that inhibiting Ar with Epi reverses aged-related loss of eNOS function and improves vascular function through the modulation of Ar and eNOS protein levels and activity.

Nutraceuticals in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by the loss and obstructive remodeling of the pulmonary arterial wall, causing a rise in pulmonary arterial pressure and pulmonary vascular resistance, which is responsible for right heart failure, functional decline, and death. Although many drugs are available for the treatment of this condition, it continues to be life-threatening, and its long-term treatment is expensive. On the other hand, many natural compounds present in food have beneficial effects on several cardiovascular conditions. Several studies have explored many of the potential beneficial effects of natural plant products on PAH. However, the mechanisms by which natural products, such as nutraceuticals, exert protective and therapeutic effects on PAH are not fully understood. In this review, we analyze the current knowledge on nutraceuticals and their potential use in the protection and treatment of PAH, as well as whether nutraceuticals could enhance the effects of drugs used in PAH through similar mechanisms.

Effects of chronic inhibition of Testosterone metabolism on cardiac remodeling after ischemia/reperfusion-induced myocardial damage in gonadectomized rats.

The effects of testosterone on cardiovascular homeostasis are still not well understood. The objective of this work was to evaluate the effects of testosterone in the absence or presence of inhibition of Aromatase (4-hydroxyandrostenedione) and/or 5α reductase (Finasteride) enzymatic activities on the myocardial remodeling 30 days after ischemia/reperfusion (I/R) injury in gonadectomized rats. Results showed that testosterone administration to ORX rats resulted in decreased myocardial damaged area, inflammatory infiltrates and reduced MMP-3 and 13 expressions. Interestingly, Finasteride administration resulted in a greater decrease in scar tissue, inflammatory infiltrates, along with a significant decrease in MMP-3 and 13 expressions. In contrast, 4-hydroxyandrostenedione administrations increased all parameters. Our results suggest that testosterone does not have a direct effect since simultaneous inhibition of aromatase and 5α-reductase did not induce significant changes in I/R induced myocardial injury.

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.

Effect of (-)-epicatechin on the modulation of progression markers of chronic renal damage in a 5/6 nephrectomy experimental model.

AIMS: To evaluate the effects of (-)-epicatechin (Epi) in the progression of kidney damage. MATERIAL AND METHODS: We assessed the effects of Epi [0.01-20 mg/kg of body weight/day] during 14 days, in a 5/6 nephrectomy model in mice. KEY FINDINGS: Nephrectomy-induced systolic arterial hypertension was significantly reduced in a dose dependent manner with Epi treatment. Increased serum creatinine and urea were reduced almost to normal values. The concentration of tetrahydrobiopterin (BH4), used as subrogate of endothelial dysfunction, decreased in nephrectomyzed animals, Epi treatment increased BH4 levels almost reaching normal values. The expression of angiotensin II receptor (AT1-R) and NADPH oxidase-4 (NOX-4) and 3-nitrotyrosine levels increased with nephrectomy and were reduced with Epi treatment. Renal tissue morphology in the remaining tissue was conserved with Epi treatment in a dose dependent manner. SIGNIFICANCE: Chronic kidney disease (CKD) is an independent cardiovascular risk factor associated with a mortality rate 10 to 20 times higher than that of the general population. High blood pressure, endothelial dysfunction and oxidative stress are important factors determining kidney damage progression. Findings of this study indicate that Epi is able to counteract the deleterious effects of subtotal nephrectomy and the structural and functional changes in the remnant kidney tissue, decreasing the progression of CKD. These results warrant the possibility of implement clinical trials to limit the progression of CKD in humans.

The cardioprotective effects of (-)-Epicatechin are mediated through arginase activity inhibition in a murine model of ischemia/reperfusion.

The production of nitric oxide (NO) by nitric oxide synthases (NOS) depends on the bioavailability of L-arginine as NOS competes with arginase for this common substrate. As arginase activity increases, less NO is produced and adverse cardiovascular consequences can emerge. (-)-Epicatechin (EPI), the most abundant flavonoid in cacao, has been reported to stimulate endothelial and neuronal NOS expression and function leading to enhanced vascular function and cardioprotective effects. However, little is known about the effects of EPI on myocardial arginase activity. The aim of the present study was to determine if EPI is able to interact and modulate myocardial arginase and NOS expression and activity. For this purpose, in silico modeling, in vitro activity assays and a rat model of ischemia/reperfusion injury were used. In silico and in vitro results demonstrate that EPI can interact with arginase and significantly decrease its activity. In vivo, 10 days of EPI pretreatment reduces ischemic myocardium arginase expression while increasing NOS expression and phosphorylation levels. Altogether, these results may partially account for the cardioprotective effects of EPI.

Participation of COX-1 and COX-2 in the contractile effect of phenylephrine in prepubescent and old rats.

Vascular reactivity can be influenced by the vascular region, animal age, and pathologies present. Prostaglandins (produced by COX-1 and COX-2) play an important role in the contractile response to phenylephrine in the abdominal aorta of young rats. Although these COXs are found in many tissues, their distribution and role in vascular reactivity are not clear. At a vascular level, they take part in the homeostasis functions involved in many physiological and pathologic processes (e.g., arterial pressure and inflammatory processes). The aim of this study was to analyze changes in the contractile response to phenylephrine of thoracic/abdominal aorta and the coronary artery during aging in rats. Three groups of rats were formed and sacrificed at three distinct ages: prepubescent, young and old adult. The results suggest that there is a higher participation of prostanoids in the contractile effect of phenylephrine in pre-pubescent rats, and a lower participation of the same in old rats. Contrarily, there seems to be a higher participation of prostanoids in the contractile response of the coronary artery of older than pre-pubescent rats. Considering that the changes in the expression of COX-2 were similar for the three age groups and the two tissues tested, and that expression of COX-1 is apparently greater in older rats, COX-1 and COX-2 may lose functionality in relation to their corresponding receptors during aging in rats.

Atherosclerotic risk in middle-aged women with rheumatoid arthritis / Riesgo aterosclerótico en mujeres de mediana edad con artritis reumatoide

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease, with progressive joint destruction, leading to disability. In half of patients, mortality is associated to coronary events, caused by classical risk factors (RF) and/or the inflammatory process. Objectives: To explore the relevance of systemic inflammatory milieu in RA without the burden of traditional RF. Methods: Women with RA and free of traditional RF (n = 30) were compared against healthy women (n = 31). Body mass index, blood pressure, glycemia, serum creatinine, total cholesterol (TC), high density lipoprotein (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG) and oxidized LDL (oxLDL), erythrocyte sedimentation rate, high-sensitivity C reactive protein (hsCRP), lipid quotients for assessing risk (TC/HDLc, LDLc/HDLc, oxLDL/non HDL cholesterol, TG/HDLc), and ultrasonographic carotid intima media thickness (IMT) were estimated or measured. Results: hsCRP and oxLDL were significantly higher in RA patients. IMT values were among normality, but thickness was slightly increased in left carotid, suggesting early atherosclerotic changes. In RA patients inflammation is associated to a higher concentration of oxLDL. No atherosclerosis was proven but a slight greater thickness in left carotid foretells the development of the disease. Conclusions: In RA patients without vascular RF, a special follow up must be implemented to halt atherosclerosis development.

Antecedentes: La artritis reumatoide (AR) es una enfermedad inflamatoria crónica, con destrucción progresiva de las articulaciones, que lleva a la discapacidad. En la mitad de lospacientes, la mortalidad se asocia con eventos coronarios, causados por factores de riesgo (FR) clásicos y/o el proceso inflamatorio. Objetivo: Explorar la relevancia del medio inflamatorio sistémico en la AR sin la carga de FR tradicionales. Métodos: Las mujeres con AR, sin los FR tradicionales (n = 30) fueron comparados contra mujeres sanas (n = 31). El índice de masa corporal, presión arterial, glucemia, creatinina sérica, colesterol total (CT), lipoproteínas de alta densidad (HDL-c), colesterol de lipoproteínas de baja densidad (LDL-c), triglicéridos (TG) y LDL oxidada (LDLox), velocidad de sedimentación de los eritrocitos, proteína C reactiva de alta sensibilidad (PCR-us), cocientes de lípidos para la evaluación de riesgos (TC/HDLc, LDLc/HDLc, colesterol LDLox/noHDL, TG/HDLc), y el espesor ultrasonográfico de la capa íntima-media carotídea (IMT), fueron estimados o medidos. Resultados: hsCRP y LDLox fueron significativamente mayores en los pacientes con AR. Los valores de IMT estaban dentro de la normalidad, pero el espesor se incrementó ligeramente en la carótida izquierda, lo que sugiere cambios ateroscleróticos tempranos. En los pacientes con AR la inflamación está asociada con una mayor concentración de oxLDL. No se comprobó aterosclerosis pero un espesor ligeramente mayor en la carótida izquierda, los hace propensos a desarrollar la enfermedad. Conclusiones: En los pacientes con AR sin FR vascular, un seguimiento especial debe ser implementado para frenar el desarrollo de la aterosclerosis.

Beneficial effects of a flavanol-enriched cacao beverage on anthropometric and cardiometabolic risk profile in overweight subjects / Efectos beneficiosos de una bebida de cocoa enriquecida con flavanol en el perfil antropométrico y de riesgo cardiometabólico en sujetos con sobrepeso

Overweight and obesity are associated with systemic inflammation and oxidative stress which, in turn, enhance the development of cardiometabolic disruptions. Lifestyle changes and pharmacologic approaches show moderately effective results regarding overall health improvements. Evidence suggests that cacao flavonoids are associated with a reduced cardiometabolic risk, due to the modulation of molecular pathways subjacent to glucose and lipids metabolism. The aim of this study was to assess the effects of cacao flavonoids supplementation on anthropometric and cardiometabolic risk factors in overweight subjects. A double-blind, placebo-controlled, pilot clinical trial was conducted in overweight subjects with borderline criteria of metabolic syndrome. Participants were randomly assigned to either, supplement of cacao flavonoids (80 mg) or placebo, daily, for 4 weeks. Cardiometabolic variables were blood pressure, glycemia and lipid profile. Serum markers of oxidative damage (free protein carbonyls and malondialdehyde) were also analyzed. Anthropometric measurements included body weight, body mass index, waist circumference, and fat and fat-free mass. We found significant reductions in body weight (p = 0.04), waist circumference (p = 0.03), triacylglycerols (p < 0.01), TG/HDL ratio (p = 0.01), MDA (p = 0.02) and protein carbonyls (p = 0.01) in the flavonoid-supplemented group. Results from this study show that cacao flavonoids can effectively modulate anthropometric and cardiometabolic risk factors.

El sobrepeso y la obesidad están asociados con la inflamación sistémica y el estrés oxidativo, que, a su vez, incrementan el desarrollo de trastornos cardiometabólicos. Cambios en el estilo de vida y tratamientos farmacológicos muestran resultados moderadamente eficaces en relación con la mejora general de la salud. La evidencia sugiere que los flavonoides del cacao se asocian con un riesgo cardiometabólico reducido, debido a la modulación de las vías moleculares subyacentes al metabolismo de la glucosa y de los lípidos. El objetivo de este estudio fue evaluar los efectos de la suplementación de flavonoides del cacao sobre factores de riesgo cardiometabólico y antropométrico en sujetos con sobrepeso. Se llevó a cabo un ensayo clínico piloto, doble ciego y controlado con placebo en sujetos con sobrepeso y criterios limítrofes de síndrome metabólico. Los participantes fueron asignados al azar a cuatro semanas de tratamiento con suplemento oral de flavonoides de cacao (80 mg) diario o placebo. Las variables cardiometabólicas analizadas fueron presión arterial sistémica, glicemia y perfil lipídico. También se analizaron los marcadores séricos de estrés oxidativo (carbonilos proteicos libres y malondialdehído). Las medidas antropométricas incluyeron el peso corporal, índice de masa corporal, circunferencia de la cintura, masa grasa y masa libre de grasa. Se encontró una reducción significativa en el peso corporal (p = 0.04), circunferencia de la cintura (p = 0.03), triglicéridos (p < 0.01), la relación TG/HDL (p = 0.01), MDA (p = 0.02) y carbonilos (p = 0.01) en el grupo con suplemento de flavonoides. Los resultados de este estudio muestran que los flavonoides del cacao pueden modular efectivamente factores de riesgo cardiometabólico y antropométricos.

Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling.

(-)-Epicatechin (EPI) is cardioprotective in the setting of ischemia/reperfusion (IR) injury and doxycycline (DOX) is known to preserve cardiac structure/function after myocardial infarction (MI). The main objective of this study was to examine the effects of EPI and DOX co-administration on MI size after IR injury and to determine if cardioprotection may involve the mitigation of mitochondrial swelling. For this purpose, a rat model of IR was used. Animals were subjected to a temporary 45 min occlusion of the left anterior descending coronary artery. Treatment consisted of a single or double dose of EPI (10 mg/kg) combined with DOX (5 mg/kg). The first dose was given 15 min prior to reperfusion and the second 12 h post-MI. The effects of EPI +/- DOX on mitochondrial swelling (i.e. mPTP opening) were determined using isolated mitochondria exposed to calcium overload and data examined using isobolographic analysis. To ascertain for the specificity of EPI effects on mitochondrial swelling other flavonoids were also evaluated. Single dose treatment reduced MI size by ~46% at 48 h and 44% at three weeks. Double dosing evidenced a synergistic, 82% reduction at 3 weeks. EPI plus DOX also inhibited mitochondrial swelling in a synergic manner thus, possibly accounting for the cardioprotective effects whereas limited efficacy was observed with the other flavonoids. Given the apparent lack of toxicity in humans, the combination of EPI and DOX may have clinical potential for the treatment of myocardial IR injury.

The molecular fingerprint of human papillomavirus infection and its effect on the Langerhans cell population in squamous cell carcinomas of the genital skin.

BACKGROUND: Information is scarce about the presence of molecular alterations related to human papillomavirus (HPV) infection in squamous cell carcinomas of the genital skin and about the effect of this infection in the number of Langerhans cells present in these tumors. AIMS: To determine the presence of HPV in genital skin squamous cell carcinomas and to see the relationship between HPV infection and changes in the expression of Ki-67 antigen (Ki-67), p53 protein (p53), retinoblastoma protein (pRb) and E-cadherin and to alterations in Langerhans cell density, if any. METHODS: A descriptive, comparative, retrospective and cross-sectional study was performed with all the cases diagnosed as squamous cell carcinomas of the genital skin at the Dermatopathology Service from 2001 to 2011. The diagnosis was verified by histopathological examination. The presence of HPV was examined using chromogenic in situ hybridization, and protein expression was studied via immunohistochemical analysis. RESULTS: The 34 cases studied were verified as squamous cell carcinomas and 44.1% were HPV positive. The degree of expression of pRb was 17.50% ±14.11% (mean ± SD) in HPV-positive cases and 29.74% ±20.38% in HPV-negative cases (P = 0.0236). The degree of expression of Ki-67 was 47.67% ±30.64% in HPV-positive cases and 29.87% ±15.95% in HPV-negative cases (P = 0.0273). CONCLUSION: HPV infection was related to lower pRb expression and higher Ki-67 expression in comparison with HPV negative samples. We could not find a relationship between HPV infection and the degree of expression of p53 and E-cadherin or with Langerhans cell density.

Acute effects of an oral supplement of (-)-epicatechin on postprandial fat and carbohydrate metabolism in normal and overweight subjects.

Postprandial hyperglycemia, in particular when accompanied by excessive hypertriglyceridemia, is associated with increased cardiovascular risk, mainly in overweight or obese subjects, as it favors oxidative stress, systemic inflammation and endothelial dysfunction. Thus, treatments that favorably modulate metabolism by reducing steep increases in postprandial serum glucose and triglycerides, are of considerable interest. Evidence suggests that (-)-epicatechin (EPI) is responsible for reductions in cardiometabolic risk associated with chocolate consumption; these effects may be associated with favorable effects of EPI on postprandial metabolism. The aims of this study were to assess the effects of EPI on postprandial metabolism in normal-weight and overweight/obese subjects. Twenty adult volunteers (normal and overweight) underwent oral metabolic tolerance tests in the absence and presence of oral EPI (1 mg kg(-1)). Metabolic responses were examined using indirect calorimetry and determining blood glucose and triglycerides at 0, 2 and 4 hours after metabolic load ingestion. Results show that EPI increased postprandial lipid catabolism, as evidenced by a significant decrease in the respiratory quotient, which implies an increase in fat oxidation. The effect was associated with significantly lower postprandial plasma glucose and triglycerides concentrations. The effects were more prominent in overweight subjects. In conclusion, EPI modulates postprandial metabolism by enhancing lipid oxidation accompanied by reductions in glycemia and triglyceridemia.

Williams' neural stem cells: new model for insight into microRNA dysregulation.

Williams syndrome (WS) is a neurodevelopmental genetic disorder, due to a 7q11.23 hemizygous deletion. WS has a characteristic neurocognitive profile that includes intellectual disability (ID). Haploinsufficiency of some of the deleted genes is partially associated with the cognitive phenotype. The aim of this paper is to determine the differences in the microRNA (miRNA) expression in WS patients, using a neural cell model from the patients olfactory neuroepithelium (ONE), and to establish the relationship with those genes involved in neurodevelopment and neural function. To assess these goals, we made a comparative analysis of the miRNAs expression profile between WS patients and controls. Through an in silico analysis, we established potential pathways and targets associated with neural tissue. The expression profile shows 14 dysregulated miRNAs, including nervous system (NS)-rich miRNAs such as miR-125b, let-7c and miR-200. Most of these miRNAs have potential targets associated with NS functions while others have been reported to have specific neuronal functions. These data suggest that miRNAs widely contribute to the regulation of neurodevelopmental intrinsic processes, and that specific miRNAs could participate in WS neurobiology.

Effects of (-)-epicatechin and derivatives on nitric oxide mediated induction of mitochondrial proteins.

Impaired mitochondrial function represents an early manifestation of endothelial dysfunction and likely contributes to the development of cardiovascular diseases (CVD). The stimulation of mitochondrial function and/or biogenesis is seen as a means to improve the bioenergetic and metabolic status of cells and thus, reduce CVD. In this study we examined the capacity of the flavanol (-)-epicatechin and two novel derivatives to enhance mitochondrial function and protein levels in cultured bovine coronary artery endothelial cells. As nitric oxide production by endothelial cells is suspected in mediating mitochondria effects (including biogenesis), we also examined the dependence of responses on this molecule using an inhibitor of nitric oxide synthase. Results indicate that the flavanol (-)-epicatechin and derivatives are capable of stimulating mitochondrial function as assessed by citrate synthase activity as well as induction of structural (porin, mitofilin) and oxidative phosporylation protein levels (complex I and II). Effects were blocked by the use of the chemical inhibitor of the synthase thus, evidencing a role for nitric oxide in mediating these effects. The results observed indicate that the three agents are effective in enhancing mitochondria function and protein content. The effects noted for (-)-epicatechin may serve to explain the healthy effects on cardiometabolic risk ascribed to the consumption of cocoa products.

Testosterone metabolites mediate its effects on myocardial damage induced by ischemia/reperfusion in male Wistar rats.

The role of testosterone in cardiovascular (CV) homeostasis is in controversy, and the exact effects of testosterone on the cardiovascular system remain poorly understood. Testosterone is metabolized by aromatase into 17ß-estradiol and by 5α-reductase into dihydrotestosterone (DHT). Thus, identification of these metabolites in the heart may help to explain the controversy regarding the cardiovascular effects of testosterone. We analyzed the expression patterns of these testosterone-metabolizing enzymes and assessed the effect of its enzymatic activity inhibition on ischemia (40 min)/reperfusion (4h, I/R) via the left anterior descendent coronary artery in intact and gonadectomized male rats. Myocardial damage was measured as percentage of infarcted area vs. area at risk. Aromatase and 5α-reductase protein expression was found in the left ventricle of intact and orchidectomized rats. Exogenous testosterone had no effect on I/R induced myocardial damage in intact male rats, meanwhile exogenous testosterone protects against I/R injury in orchidectomized rats. However, enzymatic inhibition of aromatase increased myocardial damage in the presence of testosterone, while enzymatic inhibition of 5α-reductase significantly decreased the level of myocardial damage. Our results also showed that sub-chronic inhibition of 5α-reductase resulted in myocardial protection in both groups. Furthermore, in orchidectomized and intact male rats IV treatment with DHT induces a significant increase in the myocardial damage induced by I/R. Thus, the effect of testosterone on cardiovascular pathophysiology could be related, at least in part to changes in the balance of testosterone 5α-reduction and aromatization.