Complexation of the Antihypertensive Drug Olmesartan with Zn: In Vivo Antihypertensive and Cardiac Effects.

This study is based on the premise that the application of chemical synthesis strategies to structurally modify commercial drugs by complexation with biometals is a valid procedure to improve their biological effects. Our purpose is to synthesize a compound with greater efficacy than the original drug, able to enhance its antihypertensive and cardiac pharmacological activity. Herein, the structure of the coordination compound of Zn(II) and the antihypertensive drug olmesartan, [Zn(Olme)(H2O)2] (ZnOlme), is presented. After 8 weeks of treatment in SHR male rats, ZnOlme displayed a better blood pressure-lowering activity compared with olmesartan, with a noticeable effect even in the first weeks of treatment, while ZnCl2 showed similar results than the control. ZnOlme also reduced left ventricle (LV) weight and left ventricle/tibia length ratio (LV/TL), posterior wall thickness (PWT), and intraventricular septum in diastole (IVSd) suggesting its potential to prevent LV hypertrophy. Besides, ZnOlme reduced interstitial fibrosis (contents of collagen types I and III, responsible for giving rigidity and promoting vascular elasticity, respectively). The recovery of heart function was also evidenced by fractional shortening (diastolic left ventricular/systolic left ventricular) diameter determinations. Furthermore, ZnOlme increased the antioxidant capacity and prevented cardiac oxidative stress: it enhanced the reduction of reactive oxygen species generation, exerted a significant decrease in lipid peroxidation and enhanced glutathione contents in heart tissues compared to the control, Zn, and olmesartan treatments. Our results demonstrate that continuous oral administration of ZnOlme causes a better antihypertensive effect and grants enhancement of cardioprotection through antioxidant activity, in combination with hemodynamic improvement.

Improvement of the cardiovascular effect of methyldopa by complexation with Zn(II): Synthesis, characterization and mechanism of action.

BACKGROUND: the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(H2O)2]·H2O (ZnMD) provide a promising alternative pathway to improve the biological properties of MD. METHODS: ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl2 were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91phox and p47phox) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis. RESULTS: The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment. CONCLUSION: Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.

Abrupt Photoperiod Changes Differentially Modulate Hepatic Antioxidant Response in Healthy and Obese Rats: Effects of Grape Seed Proanthocyanidin Extract (GSPE).

Disruptions of the light/dark cycle and unhealthy diets can promote misalignment of biological rhythms and metabolic alterations, ultimately leading to an oxidative stress condition. Grape seed proanthocyanidin extract (GSPE), which possesses antioxidant properties, has demonstrated its beneficial effects in metabolic-associated diseases and its potential role in modulating circadian disruptions. Therefore, this study aimed to assess the impact of GSPE administration on the liver oxidant system of healthy and diet-induced obese rats undergoing a sudden photoperiod shift. To this end, forty-eight photoperiod-sensitive Fischer 344/IcoCrl rats were fed either a standard (STD) or a cafeteria diet (CAF) for 6 weeks. A week before euthanizing, rats were abruptly transferred from a standard photoperiod of 12 h of light/day (L12) to either a short (6 h light/day, L6) or a long photoperiod (18 h light/day, L18) while receiving a daily oral dose of vehicle (VH) or GSPE (25 mg/kg). Alterations in body weight gain, serum and liver biochemical parameters, antioxidant gene and protein expression, and antioxidant metabolites were observed. Interestingly, GSPE partially ameliorated these effects by reducing the oxidative stress status in L6 through an increase in GPx1 expression and in hepatic antioxidant metabolites and in L18 by increasing the NRF2/KEAP1/ARE pathway, thereby showing potential in the treatment of circadian-related disorders by increasing the hepatic antioxidant response in a photoperiod-dependent manner.

Rhythm and ROS: Hepatic Chronotherapeutic Features of Grape Seed Proanthocyanidin Extract Treatment in Cafeteria Diet-Fed Rats.

Polyphenols play a key role in the modulation of circadian rhythms, while the cafeteria diet (CAF) is able to perturb the hepatic biological rhythm and induce important ROS production. Consequently, we aimed to elucidate whether grape seed proanthocyanidin extract (GSPE) administration recovers the CAF-induced hepatic antioxidant (AOX) misalignment and characterize the chronotherapeutic properties of GSPE. For this purpose, Fischer 344 rats were fed a standard diet (STD) or a CAF and concomitantly treated with GSPE at two time-points (ZT0 vs. ZT12). Animals were euthanized every 6 h and the diurnal rhythms of hepatic ROS-related biomarkers, hepatic metabolites, and AOX gene expression were examined. Interestingly, GSPE treatment was able to recover the diurnal rhythm lost due to the CAF. Moreover, GSPE treatment also increased the acrophase of Sod1, as well as bringing the peak closer to that of the STD group. GSPE also corrected some hepatic metabolites altered by the CAF. Importantly, the differences observed at ZT0 vs. ZT12 due to the time of GSPE administration highlight a chronotherapeutic profile on the proanthocyanin effect. Finally, GSPE could also reduce diet-induced hepatic oxidative stress not only by its ROS-scavenging properties but also by retraining the circadian rhythm of AOX enzymes.

Metabolism disturbance by light/dark cycle switching depends on the rat health status: the role of grape seed flavanols.

Changes in light/dark cycles and obesogenic diets are related to the disruption of circadian rhythms and metabolic disorders. Grape seed flavanols have shown beneficial effects on metabolic diseases and, recently, a circadian system modulation has been suggested to mediate their health-enhancing properties. Therefore, the aim of this study was to evaluate the grape seed (poly)phenol extract (GSPE) effects in healthy and obese rats after a light/dark cycle disruption. Forty-eight rats were fed a standard (STD) or cafeteria (CAF) diet for 6 weeks under STD conditions of a light/dark cycle (12 h light per day, L12). Then, animals were switched to a long (18 h light per day, L18) or short (6 h light per day, L6) photoperiod and administered a vehicle (VH) or GSPE (25 mg kg-1) for 1 week. The results showed changes in serum lipids and insulin and metabolomic profiles dependent on the photoperiod and animal health status. GSPE administration improved serum parameters and increased the Nampt gene expression in CAF rats and modified the metabolomic profile in a photoperiod-dependent manner. Metabolic effects of light/dark disturbance depend on the health status of the rats, with diet-induced CAF-induced obese rats being more affected. Grape seed flavanols improve the metabolic status in a photoperiod-dependent manner and their effects on the circadian system suggest that part of their metabolic effects could be mediated by their action on biological rhythms.

Sweet treats before sleep disrupt the clock system and increase metabolic risk markers in healthy rats.

AIM: Biological rhythms are endogenously generated natural cycles that act as pacemakers of different physiological mechanisms and homeostasis in the organism, and whose disruption increases metabolic risk. The circadian rhythm is not only reset by light but it is also regulated by behavioral cues such as timing of food intake. This study investigates whether the chronic consumption of a sweet treat before sleeping can disrupt diurnal rhythmicity and metabolism in healthy rats. METHODS: For this, 32 Fischer rats were administered daily a low dose of sugar (160 mg/kg, equivalent to 2.5 g in humans) as a sweet treat at 8:00 a.m. or 8:00 p.m. (ZT0 and ZT12, respectively) for 4 weeks. To elucidate diurnal rhythmicity of clock gene expression and metabolic parameters, animals were sacrificed at different times, including 1, 7, 13, and 19 h after the last sugar dose (ZT1, ZT7, ZT13, and ZT19). RESULTS: Increased body weight gain and higher cardiometabolic risk were observed when sweet treat was administered at the beginning of the resting period. Moreover, central clock and food intake signaling genes varied depending on snack time. Specifically, the hypothalamic expression of Nampt, Bmal1, Rev-erbα, and Cart showed prominent changes in their diurnal expression pattern, highlighting that sweet treat before bedtime disrupts hypothalamic control of energy homeostasis. CONCLUSIONS: These results show that central clock genes and metabolic effects following a low dose of sugar are strongly time-dependent, causing higher circadian metabolic disruption when it is consumed at the beginning of the resting period, that is, with the late-night snack.

Clinical Diagnosis of Chikungunya Infection: An Essential Aid in a Primary Care Setting Where Serological Confirmation Is Not Available.

BACKGROUND: Chikungunya virus (CHIKV) diagnosis has become a challenge for primary care physicians in areas where the Zika virus and/or Dengue virus are present. Case definitions for the three arboviral infections overlap. METHODS: A cross-sectional analysis was carried out. A bivariate analysis was made using confirmed CHIKV infection as the outcome. Variables with significant statistical association were included in an agreement consensus. Agreed variables were analyzed in a multiple regression model. The area under the receiver operating characteristic (ROC) curve was calculated to determine a cut-off value and performance. RESULTS: 295 patients with confirmed CHIKV infection were included. A screening tool was created using symmetric arthritis (4 points), fatigue (3 points), rash (2 points), and ankle joint pain (1 point). The ROC curve identified a cut-off value, and a score ≥ 5.5 was considered positive for identifying CHIKV patients with a sensibility of 64.4% and a specificity of 87.4%, positive predictive value of 85.5%, negative predictive value of 67.7%, area under the curve of 0.72, and an accuracy of 75%. CONCLUSION: We developed a screening tool for CHIKV diagnosis using only clinical symptoms as well as proposed an algorithm to aid the primary care physician.

Effect of the structural modification of Candesartan with Zinc on hypertension and left ventricular hypertrophy.

Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT1 receptor), reducing oxidative stress and intracellular calcium flux, a mechanism implied in cell contraction. These results were accompanied by the reduction of the contractile capacity of mesangial cells. In vivo experiments showed that the complex causes a significant decrease in systolic blood pressure after 8 weeks of treatment in spontaneously hypertensive rats (SHR). The reduction of heart hypertrophy was evidenced by echocardiography, the histologic cross-sectional area of cardiomyocytes, collagen content, the B-type natriuretic peptide (BNP) marker and connective tissue growth factor (CTGF) and the matrix metalloproteinase 2 (MMP-2) expression. Besides, the complex restored the redox status. In this study, we demonstrated that the complexation with Zn(II) improves the antihypertensive and cardiac effects of the parental drug.

Grape Seed Proanthocyanidins Modulate the Hepatic Molecular Clock via MicroRNAs.

SCOPE: Circadian rhythm is an endogenous and self-sustained timing system, responsible for the coordination of daily processes in 24-h timescale. It is regulated by an endogenous molecular clock, which is sensitive to external cues as light and food. This study has previously shown that grape seed proanthocyanidins extract (GSPE) regulates the hepatic molecular clock. Moreover, GSPE is known to interact with some microRNAs (miRNAs). Therefore, the aim of this study is to evaluate if the activity of GSPE as modulator of hepatic clock genes can be mediated by miRNAs. METHODS AND RESULTS: 250 mg kg-1 of GSPE is administered to Wistar rats before a 6-h jet lag and sacrificed at different time points. GSPE modulated both expression of Bmal1 and miR-27b-3p in the liver. Cosinor-based analysis reveals that both Bmal1 and miR-27b-3p expression follow a circadian rhythm, a negative interaction between them, and the role of GSPE adjusting the hepatic peripheral clock via miRNA. Additionally, in vitro studies show that Bmal1 is sensitive to GSPE (25 mg L-1 ). However, this effect is independent of miR-27b-3p. CONCLUSION: miRNA regulation of peripheral clocks via GSPE may be part of a complex mechanism that involves the crosstalk with the central system rather than a direct effect.

Proanthocyanidins Restore the Metabolic Diurnal Rhythm of Subcutaneous White Adipose Tissue According to Time-Of-Day Consumption.

Consumption of grape seed proanthocyanidin extract (GSPE) has beneficial effects on the functionality of white adipose tissue (WAT). However, although WAT metabolism shows a clear diurnal rhythm, whether GSPE consumption could affect WAT rhythmicity in a time-dependent manner has not been studied. Ninety-six male Fischer rats were fed standard (STD, two groups) or cafeteria (CAF, four groups) diet for 9 weeks (n = 16 each group). From week 6 on, CAF diet animals were supplemented with vehicle or 25 mg GSPE/kg of body weight either at the beginning of the light/rest phase (ZT0) or at the beginning of the dark/active phase (ZT12). The two STD groups were also supplemented with vehicle at ZT0 or ZT12. In week 9, animals were sacrificed at 6 h intervals (n = 4) to analyze the diurnal rhythms of subcutaneous WAT metabolites by nuclear magnetic resonance spectrometry. A total of 45 metabolites were detected, 19 of which presented diurnal rhythms in the STD groups. Although most metabolites became arrhythmic under CAF diet, GSPE consumption at ZT12, but not at ZT0, restored the rhythmicity of 12 metabolites including compounds involved in alanine, aspartate, and glutamate metabolism. These results demonstrate that timed GSPE supplementation may restore, at least partially, the functional dynamics of WAT when it is consumed at the beginning of the active phase. This study opens an innovative strategy for time-dependent polyphenol treatment in obesity and metabolic diseases.

Grape Seed Proanthocyanidins Mitigate the Disturbances Caused by an Abrupt Photoperiod Change in Healthy and Obese Rats.

Variations in the light/dark cycle and obesogenic diets trigger physiological and behavioral disorders. Proanthocyanidins, in addition to their healthy properties, have recently demonstrated a modulating effect on biological rhythms. Therefore, the aim of this study was to evaluate the administration of a grape seed proanthocyanidin-rich extract (GSPE) to mitigate the disruption caused by a sudden photoperiod change in healthy and cafeteria (CAF)-diet obese rats. For this, 48 photoperiod-sensitive Fischer 344 rats were fed standard or CAF diets for 6 weeks under a standard (12 h light/day, L12) conditions. Then, rats were switched to a long (18 h light/day, L18) or short (6 h light/day, L6) photoperiod and administered vehicle or GSPE (25 mg/kg) for 1 week. Body weight (BW) and food intake (FI) were recorded weekly. Animal activity and serum hormone concentrations were studied before and after the photoperiod change. Hormone levels were measured both at 3 h (ZT3) and 15 h (ZT15) after the onset of light. Results showed the impact of the CAF diet and photoperiod on the BW, FI, activity, and hormonal status of the animals. GSPE administration resulted in an attenuation of the changes produced by the photoperiod disruption. Specifically, GSPE in L6 CAF-fed rats reduced serum corticosterone concentration, restoring its circadian rhythm, increased the T3-to-T4 ratio, and increased light phase activity, while under L18, it decreased BW and testosterone concentration and increased the animal activity. These results suggest that GSPE may contribute to the adaptation to the new photoperiods. However, further studies are needed to elucidate the metabolic pathways and processes involved in these events.

Time-of-Day Circadian Modulation of Grape-Seed Procyanidin Extract (GSPE) in Hepatic Mitochondrial Dynamics in Cafeteria-Diet-Induced Obese Rats.

Major susceptibility to alterations in liver function (e.g., hepatic steatosis) in a prone environment due to circadian misalignments represents a common consequence of recent sociobiological behavior (i.e., food excess and sleep deprivation). Natural compounds and, more concisely, polyphenols have been shown as an interesting tool for fighting against metabolic syndrome and related consequences. Furthermore, mitochondria have been identified as an important target for mediation of the health effects of these compounds. Additionally, mitochondrial function and dynamics are strongly regulated in a circadian way. Thus, we wondered whether some of the beneficial effects of grape-seed procyanidin extract (GSPE) on metabolic syndrome could be mediated by a circadian modulation of mitochondrial homeostasis. For this purpose, rats were subjected to "standard", "cafeteria" and "cafeteria diet + GSPE" treatments (n = 4/group) for 9 weeks (the last 4 weeks, GSPE/vehicle) of treatment, administering the extract/vehicle at diurnal or nocturnal times (ZT0 or ZT12). For circadian assessment, one hour after turning the light on (ZT1), animals were sacrificed every 6 h (ZT1, ZT7, ZT13 and ZT19). Interestingly, GSPE was able to restore the rhythm on clock hepatic genes (Bmal1, Per2, Cry1, Rorα), as this correction was more evident in nocturnal treatment. Additionally, during nocturnal treatment, an increase in hepatic fusion genes and a decrease in fission genes were observed. Regarding mitochondrial complex activity, there was a strong effect of cafeteria diet at nearly all ZTs, and GSPE was able to restore activity at discrete ZTs, mainly in the diurnal treatment (ZT0). Furthermore, a differential behavior was observed in tricarboxylic acid (TCA) metabolites between GSPE diurnal and nocturnal administration times. Therefore, GSPE may serve as a nutritional preventive strategy in the recovery of hepatic-related metabolic disease by modulating mitochondrial dynamics, which is concomitant to the restoration of the hepatic circadian machinery.

Chronic GPER activation prevents ischemia/reperfusion injury in ovariectomized rats.

During menopause women are exposed to an increase in cardiovascular risk. G protein-coupled estrogen receptor (GPER) is known to mediate several of the protective effects of such hormones. G1 was described as a selective and synthetic agonist for GPER. The aim of the present research is to evaluate the effect of a chronic treatment with G1 in ovariectomized (OVX) rats exposed to ischemia/reperfusion (I/R). Considering the hypothesis that an impaired mitochondrial state could be involved in the alterations produced in OVX rats, other objective of this study was to investigate it in an isolated preparation. Three months old rats were assigned to undergo either bilateral ovariectomy or sham operation. The OVX rats were randomly treated during one month with either G1 or vehicle. Cardiac mitochondria from OVX rats showed a depolarized membrane potential and a decreased calcium retention capacity in comparison with Sham rats, which were prevented by chronic G1 treatment. I/R caused a higher decrease of left ventricular developed pressure and a higher increase of left ventricular end diastolic pressure in OVX compared to Sham hearts. These altered mechanical parameters were prevented by G1. The induced infarct size was significantly higher in OVX, which was reduced by G1 treatment. These results indicate that the mitochondrial state in OVX rats is impaired, accompanied by an altered mechanical response after ischemia and reperfusion injury, which was effectively prevented with chronic treatment with G1. The present study may provide further insights for the potential development of a therapy based on the GPER modulation.

Blood Pressure-Lowering Effect of Wine Lees Phenolic Compounds Is Mediated by Endothelial-Derived Factors: Role of Sirtuin 1.

The antihypertensive effect of wine lees powder (WLPW) from a Cabernet grape variety was related to its high content in flavanols and anthocyanins compounds. This study investigates the involvement of endothelial-derived factors and SIRT1 in its bioactivity. Spontaneously hypertensive rats (SHR) were orally administered water or WLPW (125 mg/kg bw). Posteriorly, both groups were intraperitoneally administered saline, Nω-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, indomethacin, a prostacyclin synthesis inhibitor, or sirtinol, an inhibitor of sirtuins. Blood pressure (BP) was recorded before and 6 h after WLPW administration. In an additional experiment, SHR were administered water or WLPW and endothelial expressions of eNos, Sirt1, Nox4, and Et1 were determined. The BP-lowering properties of WLPW were abolished by L-NAME and partially reduced by indomethacin, demonstrating that WLPW antihypertensive effect was mediated by changes in NO availability, although prostacyclin also contributed to this activity. Moreover, BP-lowering effect was reduced by sirtinol, indicating that WLPW decreased BP in a SIRT1-dependent manner. Furthermore, WLPW upregulated eNos and Sirt1 and downregulated Nox4 and Et1 endothelial gene expression. These results evidence the vasoprotective effect of WLPW and show that its antihypertensive effect in SHR is endothelium dependent and mediated by SIRT1.

Carbonic anhydrase IX and hypoxia-inducible factor 1 attenuate cardiac dysfunction after myocardial infarction.

Myocardial infarction (MI) is one of the leading causes of death worldwide. Prognosis and mortality rate are directly related to infarct size and post-infarction pathological heart remodeling, which can lead to heart failure. Hypoxic MI-affected areas increase the expression of hypoxia-inducible factor (HIF-1), inducing infarct size reduction and improving cardiac function. Hypoxia translocates HIF-1 to the nucleus, activating carbonic anhydrase IX (CAIX) transcription. CAIX regulates myocardial intracellular pH, critical for heart performance. Our objective was to investigate CAIX participation and relation with sodium bicarbonate transporters 1 (NBC1) and HIF-1 in cardiac remodeling after MI. We analyzed this pathway in an "in vivo" rat coronary artery ligation model and isolated cardiomyocytes maintained under hypoxia. Immunohistochemical studies revealed an increase in HIF-1 levels after 2 h of infarction. Similar results were observed in 2-h infarcted cardiac tissue (immunoblotting) and in hypoxic cardiomyocytes with a nuclear distribution (confocal microscopy). Immunohistochemical studies showed an increase CAIX in the infarcted area at 2 h, mainly distributed throughout the cell and localized in the plasma membrane at 24 h. Similar results were observed in 2 h in infarcted cardiac tissue (immunoblotting) and in hypoxic cardiomyocytes (confocal microscopy). NBC1 expression increased in cardiac tissue after 2 h of infarction (immunoblotting). CAIX and NBC1 interaction increases in cardiac tissue subjected to MI for 2h when CAIX is present (immunoprecipitation). These results suggest that CAIX interacts with NBC1 in our infarct model as a mechanism to prevent acidic damage in hypoxic tissue, making it a promising therapeutic target.

Blood Pressure-Lowering Effect of Wine Lees: Dose-Response Study, Effect of Dealcoholization and Possible Mechanisms of Action.

The antihypertensive effect of wine lees (WL) has been previously evidenced. In this study, the antihypertensive properties of different doses of WL were evaluated in spontaneously hypertensive rats (SHR). In addition, the blood pressure (BP)-lowering effect of dried (dealcoholized) WL powder (WLPW) and the mechanisms involved in its functionality were investigated. Furthermore, a possible hypotensive effect of WLPW was discarded in Wistar-Kyoto (WKY) rats. The administration of WL at different doses caused a dose-dependent decrease in BP of SHR up to 5.0 mL/kg bw, exhibiting the maximum decrease at 6 h post-administration. WLPW caused a greater drop in BP than WL, showing an antihypertensive effect higher and more prolonged than the drug Captopril. Moreover, the BP-lowering effect of WLPW was specific to the hypertensive state since an undesirable hypotensive effect in normotensive WKY rats was ruled out. Finally, WLPW improved oxidative stress and increased the activity of the antioxidant endogen system of SHR. These results suggest that WLPW could be used as functional ingredient for foods or nutraceuticals to ameliorate hypertension. Nevertheless, further clinical studies are needed to evaluate its long-term antihypertensive efficiency.

ACE Inhibitory and Antihypertensive Activities of Wine Lees and Relationship among Bioactivity and Phenolic Profile.

Wine lees (WL) are by-products generated in the winemaking process. The aim of this study was to investigate the angiotensin-converting enzyme inhibitory (ACEi) activity, and the blood pressure (BP) lowering effect of WL from individual grape varieties. The relationship among their activities and phenolic profiles was also studied. Three WL, from Cabernet, Mazuela, and Garnacha grape varieties, were firstly selected based on their ACEi properties. Their phenolic profiles were fully characterized by UHPLC-ESI-Q-TOF-MS. Then, their potential antihypertensive effects were evaluated in spontaneously hypertensive rats (SHR). BP was recorded before and after their oral administrations (2, 4, 6, 8, 24, and 48 h) at a dose of 5 mL/kg bw. Cabernet WL (CWL) exhibited a potent antihypertensive activity, similar to that obtained with the drug Captopril. This BP-lowering effect was related to the high amount of anthocyanins and flavanols present in these lees. In addition, a potential hypotensive effect of CWL was discarded in normotensive Wistar-Kyoto rats. Finally, the ACEi and antihypertensive activities of CWL coming from a different harvest were confirmed. Our results suggest the potential of CWL for controlling arterial BP, opening the door to commercial use within the wine industry.

Impact of gut microbiota on plasma oxylipins profile under healthy and obesogenic conditions.

BACKGROUND & AIMS: Oxylipins (OXLs) are bioactive lipid metabolites derived from polyunsaturated fatty acids (PUFAs) which act as signaling molecules and are involved in inflammatory processes such as those that occur in obesity. On the other hand, gut microbiota plays an essential role in regulating inflammatory responses. However, little is known about the potential impact of gut bacteria on OXLs metabolism. Thus, the objective of this study was to investigate the effect of gut microbiota dysbiosis on plasma oxylipins profile in healthy and diet-induced obese animals. METHODS: Eight-week-old male Wistar rats were fed with either a standard or cafeteria diet (CAF) for 5 weeks and administered an antibiotic cocktail (ABX) in the drinking water (Ampicillin: 1 g/ml, Vancomycin: 0.5 g/ml, Imipenem: 0.25 g/ml) for the last 2 weeks in order to induce gut microbiota dysbiosis. Metabolomics analysis of OXLs in plasma was performed by HPLC-MS analysis. No antibiotic treated animals were included as controls. RESULTS: Plasma OXLs profile was significantly altered due to both CAF feeding and ABX administration. ABX effect was more pronounced under obesogenic conditions. Several significant correlations between different bacteria taxa and these lipid mediators were observed. Among these, the positive correlation of Proteobacteria with LTB4, a proinflammatory OXL involved in obesity-related disorders, was especially remarkable. CONCLUSIONS: Gut microbiota plays a key role in regulating these lipid metabolites and, therefore, affecting oxylipins-mediated inflammatory processes. These results are the first evidence to our knowledge of gut microbiota impact on OXLs metabolism. Moreover, this can set the basis for developing new obesity markers based on OXLs and gut microbiota profiles.

Características clínico-radiológicas de la hiperostosis esquelética idiopática difusa en 2 centros médicos de Cali, Colombia: reporte de 24 casos / Clinical and radiological characteristics of diffuse idiopathic skeletal hyperostosis in two medical centers in Cali, Colombia: Report of 24 cases

RESUMEN Introducción: La hiperostosis esquelética idiopática difusa (DISH, por sus siglas en inglés) es una afección caracterizada por la calcificación y la osificación progresiva de los ligamentos y las entesis. La mayoría de los pacientes permanecen asintomáticos hasta etapas avanzadas de la enfermedad, donde la limitación y el dolor son característicos. Objetivo: Describir las características demográficas, clínicas y radiológicas de los pacientes con DISH evaluados en el Centro Médico Imbanaco de Cali y en la Clínica de Artritis Temprana, en Cali, Colombia. Materiales y métodos: Es un estudio descriptivo, de corte transversal. Se revisaron los registros de pacientes diagnosticados con DISH, seguidos entre enero de 2000 y octubre de 2018. El diagnóstico se confirmó según los criterios de Resnick-Niwayama. Se encontraron 24 pacientes, todos se incluyeron para el análisis final. Resultados y discusión: En esta serie se encontraron 20 varones y 4 mujeres. La mediana de edad al diagnóstico fue de 70,5 arios (RIQ: 61,3-73,8 arios), siendo menor en las mujeres (71,5 versus 60 años; p = 0,04). La mediana de tiempo de evolución de los síntomas fue de 5 años (RIQ: 3-10 años), la duración fue menor en el grupo de las mujeres (5 versus 4 años; p = 0,20). El 54,2% tenían sobrepeso y el 20,8% eran diabéticos. El síntoma principal fue la limitación cervical. Los segmentos vertebrales (C: cervical; T: torácico; L: lumbar) más afectados por la osificación del ligamento longitudinal anterior (LLA) fueron C5-C6, T8-T10 y L1-L3. La afección periférica predominó en las crestas ilíacas. Todos los pacientes realizaron terapia física y 3 fueron sometidos a cirugía cervical. El grado de limitación funcional fue valorado en 19 pacientes a través de los cuestionarios modified Health Assessment Questionnaire (mHAQ) y Bath Ankylosing Spondylitis Functional Index (BASFI). La mediana del puntaje de ambos cuestionarios fue 2 veces más alta en las mujeres. Conclusión: La DISH fue más frecuente en varones mayores de 65 años y se asoció con enfermedades metabólicas como la obesidad y la diabetes. Aunque las diferencias no fueron significativas, los resultados sugieren que las mujeres presentan un fenotipo grave de la enfermedad explicado por el inicio temprano y curso progresivo de los síntomas, así como mayor limitación funcional medida por mHAQ y BASFI.

ABSTRACT Introduction: Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterised by calcification and progressive ossification of ligaments and entheses. Most patients remain asymptomatic until advanced stages of the disease, where limitation and pain are characteristic. Objective: To describe the demographic, clinical, and radiological characteristics of patients with DISH evaluated in the Centro Médico Imbanaco and Clínica de Artritis Temprana, in Cali, Colombia. Materials and methods: A descriptive, cross-sectional study was conducted by reviewing the records of patients diagnosed with DISH between January 2000 and October 2018. The diagnosis was confirmed according to the Resnick-Niwayama criteria. A total of 24 patients were found, and all were included for the final analysis. Results and discussion: The series included 20 men and 4 women, with a median age at diagnosis of 70.5 years (IQR 61.3-73.8 years), beinglower in women (71.5 versus 60 years; P=.04). The median time of onset of the symptoms was 5 years (IQR 3-10 years), and the duration was shorter in women (5 versus 4 years; P=.20). It was observed that 54% were overweight and 20% were diabetic. The main symptom was cervical limitation. The most affected vertebral segments due to the ossification of the anterior longitudinal ligament (ALL) were C5-C6, T8-T10 and L1-L3 (cervical C; thoracic T; lumbar L). The peripheral involvement was mainly in the iliac crests. All patients received physiotherapy, and three of them underwent cervical surgery. The degree of functional limitation was assessed in 19 patients using the mHAQ (Modified Health Assessment Questionnaire) and BASFI (Functional Ankylosing Spondylitis Functional (BASFI) questionnaires. The median score of both questionnaires was 2 times higher in women Conclusion: Diffuse idiopathic skeletal hyperostosis was more frequent in men over 65 years of age, and was associated with metabolic conditions such as obesity and diabetes. Although the differences were not significant, the results suggest that women have a more severe phenotype of the disease, explained by the early onset and progressive course of symptoms, as well as greater functional limitation measured by mHAQ and BASFI.