Lessons Learned from a Global Perspective of Coronavirus Disease-2019.

Coronavirus disease-2019 has impacted the world globally. Countries and health care organizations across the globe responded to this unprecedented public health crisis in a varied manner in terms of public health and social measures, vaccination development and rollout, the conduct of research, developments of therapeutics, sharing of information, and in how they continue to deal with the widespread aftermath. This article reviews the various elements of the global response to the pandemic, focusing on the lessons learned and strategies to consider during future pandemics.

Effects of supplementing a healthy diet with pecan nuts or extra-virgin olive oil on inflammatory profile of patients with stable coronary artery disease: a randomised clinical trial.

The consumption of nuts and extra-virgin olive oil has been associated with suppression of inflammatory pathways that contribute to atherosclerosis, but its role on the modulation of the inflammatory profile in patients with established coronary artery disease (CAD) is unclear. The aim of this study was to evaluate the effects of adding pecan nuts or extra-virgin olive oil to a healthy diet on inflammatory markers in patients with stable CAD. In this randomised clinical trial, 204 patients were enrolled to three study groups: sixty seven to control group (CG: healthy diet), sixty eight to pecan nuts group (PNG: 30 g/d of pecans + healthy diet) and sixty nine to extra-virgin olive oil group (OOG: 30 ml/d of extra-virgin olive oil + healthy diet). High-sensitivity C-reactive protein (hs-CRP, in mg/l), fibrinogen (mg/dl), IL 2, 4, 6, 10 (pg/ml) and interferon-γ (IFN-γ, in pg/ml), IL-6/IL-10, IL-2/IL-4 and IFN-/γIL-4 ratios were evaluated at baseline and after the follow-up (12 weeks). As main results, after adjustment for sex, statin used and relative body weight variation, there were no differences between groups regarding inflammatory markers at the end of the study. IL-6 levels (primary outcome) were reduced in 12 weeks when compared with baseline in all study groups (CG: difference: -0·593 (se = 0·159) pg/dL; PNG: difference: -0·335 (se = 0·143) pg/dl; OOG: IL-6 difference: -0·325 (se = 0·143) pg/dl). In conclusion, there was no significant effect of including pecan nuts or extra virgin olive oil to a healthy diet on inflammatory markers in individuals with CAD.

Effect of pecan nuts and extra-virgin olive oil on glycemic profile and nontraditional anthropometric indexes in patients with coronary artery disease: a randomized clinical trial.

BACKGROUND/OBJECTIVES: The influence of cardioprotective foods on nontraditional indexes related to dysglycemia and body fat distribution is unknown in individuals with coronary artery disease (CAD). This study aimed to evaluate the effect of a healthy diet supplemented with pecan nuts or extra-virgin olive oil on glycemic profile and adipose tissue dysfunction assessed by anthropometric indexes in patients with stable CAD. SUBJECTS/METHODS: In a randomized, pragmatic, parallel clinical trial lasting 12 weeks, 204 individuals were allocated to three interventions: a healthy diet (control group [CG], n = 67), a healthy diet plus 30 g/day of pecan nuts (pecan nut group [PNG], n = 68), or a healthy diet plus 30 mL/day of extra-virgin olive oil (olive oil group [OOG], n = 69). Triglyceride-glucose (TyG) index (primary outcome) and other markers of glycemic profile were evaluated, and nontraditional anthropometric indexes as well. Diet quality was assessed according to the Alternate Healthy Eating Index (mAHEI). RESULTS: After adjustment for baseline values, use of antidiabetic drugs and insulin, there were no differences in both glycemic and anthropometric profiles according to groups at the end of the study. PNG improved the quality of the diet in comparison to other groups (final mAHEI scores: CG: 19 ± 7.5; PNG: 26 ± 8; OOG: 18.9 ± 6; P < 0.001). CONCLUSIONS: There was no difference regarding glycemic and anthropometric parameters according to interventions in patients with stable CAD. However, adding pecan nuts to a healthy diet may improve its quality. Further studies must be conducted considering dietary interventions on secondary cardiovascular prevention setting. CLINICAL TRIALS IDENTIFIER NUMBER: NCT02202265. First Posted: July 2014; Last Update: September 2020.

Adaptations in GLUT4 Expression in Response to Exercise Detraining Linked to Downregulation of Insulin-Dependent Pathways in Cardiac but not in Skeletal Muscle Tissue.

Insulin resistance is associated with cardiometabolic risk factors, and exercise training can improve insulin-mediated glucose uptake. However, few studies have demonstrated the reversibility of exercise-induced benefits. Thus, the authors examine the time-response effects of exercise training and detraining on glucose transporter 4 (GLUT4) content, insulin-dependent and insulin-independent pathways in cardiac and gastrocnemius muscle tissues of spontaneously hypertensive rats. Thirty-two male spontaneously hypertensive rats, 4 months old, were assigned to (n = 8/group): T (exercise training: 10-week treadmill exercise, 50-70% maximum effort capacity, 1 hr/day, 5 days/week); D2 (exercise training + 2-day detraining), D4 (exercise training + 4-day detraining); and S (no exercise). The authors evaluated insulin resistance, maximum effort capacity, GLUT4 content, p-IRS-1Tyr1179, p-AS160Ser588, p-AMPKα1Thr172, and p-CaMKIIThr286 in cardiac and gastrocnemius muscle tissues (Western blot). In response to exercise training, there were improvements in insulin resistance (15.4%; p = .010), increased GLUT4 content (microsomal, 29.4%; p = .012; plasma membrane, 27.1%; p < .001), p-IRS-1 (42.2%; p < .001), p-AS160 (60.0%; p < .001) in cardiac tissue, and increased GLUT4 content (microsomal, 29.4%; p = .009; plasma membrane, 55.5%; p < .001), p-IRS-1 (28.1%; p = .018), p-AS160 (76.0%; p < .001), p-AMPK-α1 (37.5%; p = .026), and p-CaMKII (30.0%; p = .040) in the gastrocnemius tissue. In D4 group, the exercise-induced increase in GLUT4 was reversed (plasma membrane, -21.3%; p = .027), p-IRS1 (-37.1%; p = .008), and p-AS160 (-82.6%; p < .001) in the cardiac tissue; p-AS160 expression (-35.7%; p = .034) was reduced in the gastrocnemius. In conclusion, the cardiac tissue is more susceptible to exercise adaptations in the GLUT4 content and signaling pathways than the gastrocnemius muscle. This finding may be explained by particular characteristics of insulin-dependent and insulin-independent pathways in the muscle tissues studied.

Physical training prior to myocardial infarction potentializes stem cell therapy, SDF-1/CXCR4 axis activation and inhibits the vasoconstrictor response in hypertensive rats.

Stem cell therapy is a promising strategy for recovering of injured cardiac tissue after acute myocardial infarction. The effects promoted by preventive physical training, beneficial for regeneration, are not yet understood on stem cell homing. In the present study, we evaluated the effect of preventive physical training on cell homing activation and associated mechanisms after acute myocardial infarction and therapy with adipose-derived stem cells in spontaneously hypertensive rats (SHR). Forty female SHR were allocated in sedentary (S), sedentary SHAM (S-SHAM), sedentary AMI (S-AMI), sedentary with cell therapy (S-ICT), aerobically trained (T), trained SHAM (T-SHAM), trained AMI (T-AMI) and trained with cell therapy (S-ICT) groups. Cell therapy was performed through the infusion of 2 × 105 ADSC/0.05 mL at the moment of AMI. Molecular markers of cell homing (SDF-1/CXCR4), inflammatory response (myeloperoxidase and cardiac expression of iNOS, gp91phox and NFkB), vasoconstrictor agents (Ang II and ET-1) and an angiogenesis inducer (VEGF) were measured. Functional capacity and echocardiographic parameters were also evaluated. Preventive physical training associated with cell therapy was able to reduce left ventricle ejection fraction losses in infarcted animals. Results demonstrated activation of the SDF-1/CXCR4 axis by physical training, besides a reduction in vasoconstrictor and systemic inflammatory responses. Physical training prior to AMI was able to induce a cardioprotective effect and optimize the reparative mechanism of cell therapy in an animal model of hypertension.

Leishmanicidal and antichemotactic activities of icetexanes from Salvia uliginosa Benth.

BACKGROUND: Several species of Salvia are used as medicinal plants around the world. Biological activities of isolated compounds have been described, being diterpenes frequently responsible for the effects. PURPOSE: Isolation of diterpenes from Salvia uliginosa Benth. and evaluation of the antichemotactic and leishmanicidal activities of the isolated compounds. STUDY DESIGN: To isolate diterpenes from S. uliginosa and evaluate their antichemotactic and leishmanicidal activities in vitro. METHODS: The exudate of S. uliginosa was obtained by rapidly dipping the aerial parts in dichloromethane. The compounds were isolated by repeated column chromatography over silica gel. The effects on L. amazonensis growth, survival, DNA degradation, ROS generation, as well as the antichemotactic activity and cytotoxicity of the compounds towards human erythrocytes and macrophages were evaluated. RESULTS: A novel icetexane diterpene, isoicetexone (IsoICT) along with the known diterpenes icetexone (ICT), and 7-acetoxy-6,7-dihydroicetexone were isolated from the dichloromethane surface exudate of S. uliginosa. The structures were elucidated using NMR and MS experiments, and by comparison with previously reported data. IsoICT and ICT at low concentrations caused completely inhibition of neutrophils migration in vitro. In addition, IsoICT and ICT showed high leishmanicidal activity against L. amazonensis, induced ROS production in parasites and presented low cytotoxicity against macrophages and human erythrocytes, and moderate to high selectivity index. CONCLUSION: These data indicated that IsoICT and ICT exhibit potent antichemotactic and leishmanicidal effects. Further studies are needed in order to evaluate the in vivo activities as well as the toxicity of the compounds.

The homing of bone marrow stem cells is differentially activated in ischemic and valvular heart diseases and influenced by beta-blockers.

BACKGROUND: Cell homing is the mechanism by which an injury releases signaling molecules that cause recruitment, proliferation, migration and differentiation of progenitor cells. Stromal derived factor-1 (SDF-1) and its receptor CXCR4 are key molecules involved in homing and little is known about their activation in cardiopathies. Here, we assessed the homing activation status of bone marrow cells (BMC) concerning the SDF-1 and CXCR4 expression in ischemic (IHD) and valvular (VHD) heart diseases. METHODS: The SDF-1 and inflammatory profile were analyzed by ELISA from plasma obtained bone marrow of ischemic heart patients (IHD, n = 41), valvular heart patients (VHD, n = 30) and healthy controls (C, n = 9). Flow cytometry was used to evaluate CXCR4 (CD184) expression on the surface of bone marrow cells, and the CXCR4 expression was estimated by real-time quantitative PCR. RESULTS: The SDF-1 levels in the groups IHD, VHD and control were, respectively, 230, 530 and 620 pg/mL (P = 0.483), and was decreased in VHD patients using beta-blockers (263 pg/mL) when compared with other (844 pg/mL) (P = 0.023). Compared with IHD, the VHD group showed higher CXCR4 (P = 0.071) and CXCR7 (P = 0.082) mRNA expression although no difference in the level of CXCR4+ bone marrow cells was found between groups (P = 0.360). CONCLUSION: In conclusion, pathophysiological differences between IHD and VHD can affect the molecules involved in the activation of homing. In addition, the use of beta-blockers appears to interfere in this mechanism, a fact that should be considered in protocols that use BMC.

Impact of flaxseed and soy nuts as dietary supplements on lipid profile, insulin sensitivity, and GLUT4 expression in ovariectomized rats.

We assessed the effects of a diet with flaxseed or soy nuts versus estradiol on the lipid profile, insulin sensitivity, and glucose transporter type 4 (GLUT4) expression in ovariectomized female rats. Forty-four female Wistar rats (90 days old) underwent ovariectomy and were divided into 4 groups: C (standard diet), E (standard diet + subcutaneous 17ß-estradiol pellets), L (standard diet + flaxseed + subcutaneous placebo pellets), and S (standard diet + soy nuts + subcutaneous placebo pellets). Customized diets and the insertion of pellets were started 21 days after ovariectomy and were continued for another 21 days. We measured body mass, insulin tolerance, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and GLUT4 (in cardiac and adipose tissues). We found a lower body mass and a lower Lee index in group E and a trend toward improved insulin sensitivity in group S (p = 0.066). Groups L and S showed a better lipid profile when compared with group C. Microsomal GLUT4 increased in group L (in cardiac and adipose tissues), and plasma membrane GLUT4 increased in groups E, L, and S (in both tissues). We conclude that flaxseed and soy nuts as dietary supplements improve lipid profile and increase GLUT4 expression.

ß-blockers interfere with cell homing receptors and regulatory proteins in a model of spontaneously hypertensive rats.

AIM: To examine the interference of ß-blockers with the chemokine stromal cell-derived factor-1 (SDF-1) found in cell homing receptors, C-X-C chemokine receptor type 4 (CXCR-4) and CXCR-7, and regulatory proteins of homing pathways, we administered atenolol, carvedilol, metoprolol, and propranolol for 30 days using an orogastric tube to hypertensive rats. METHOD: We collected blood samples before and after treatment and quantified the levels of SDF-1 with enzyme-linked immunosorbent assay (ELISA). On day 30 of treatment, the spontaneously hypertensive rats (SHR) were euthanized, and heart, liver, lung, and kidney tissues were biopsied. Proteins were isolated for determining the expression of CXCR-4, CXCR-7, GRK-2 (G protein-coupled receptors kinase 2), ß-arrestins (ß1-AR and ß2-AR), and nuclear factor kappa B (NFκB). RESULTS: We found that the study drugs modulated these proteins, and metoprolol and propranolol strongly affected the expression of ß1-AR (P = .0102) and ß2-AR (P = .0034). CONCLUSION: ß-blockers modulated tissue expression of the proteins and their interactions following 30 days of treatment. It evidences that this class of drugs can interfere with proteins of cell homing pathways.

Preventive Physical Training Partially Preserves Heart Function and Improves Cardiac Antioxidant Responses in Rats After Myocardial Infarction Preventive Physical Training and Myocardial Infarction in Rats.

In acute myocardial infarction (AMI), reactive oxygen species may cause irreversible damage to the heart tissue. Physical training is capable of enhancing antioxidant capacity, acting as a cardioprotective factor. We assessed the preventive effects of physical training on the antioxidant and functional responses of the heart of Wistar Kyoto rats after AMI. Wistar Kyoto rats (n = 12) were allocated to sedentary (SED) or trained (EXE-aerobic training on a treadmill) groups. Echocardiographic exams were performed 48 hr before and 48 hr after the induction of AMI. Superoxide dismutase (SOD) and catalase (CAT) activities, and total glutathione (GSH) were measured in vitro in the heart tissue. After AMI, the EXE group showed higher left ventricular shortening fraction (29%; p = .004), higher cardiac output (37%; p = .032) and reduced myocardial infarction size (16%; p = .007) than SED. The EXE group showed a higher nonenzymatic antioxidant capacity (GSH, 23%; p = .004), but the SOD and CAT activities were higher in SED (23% SOD; p = .021 and 20% CAT; p = .016). In addition, the SOD activity was positively correlated with myocardial infarction size and inversely correlated with cardiac output. Physical training partially preserved cardiac function and increased intracellular antioxidant response in cardiac tissue of animals after AMI.

VEGF gene therapy cooperatively recruits molecules from the immune system and stimulates cell homing and angiogenesis in refractory angina.

BACKGROUND: New vessels are formed in response to stimuli from angiogenic factors, a process in which paracrine signaling is fundamental. OBJECTIVE: To investigate the cooperative paracrine signaling profile in response to Vascular Endothelial Growth Factor (VEGF) gene therapy in patients with coronary artery disease (CAD) and refractory angina. METHOD: A cohort study was conducted in which plasma was collected from patients who underwent gene therapy with a plasmid expressing VEGF 165 (10) and from surgical procedure controls (4). Blood samples were collected from both groups prior to baseline and on days 3, 9 and 27 after the interventions and subjected to systemic analysis of protein expression (Interleukin-6, IL-6; Tumor Necrosis Factor-α, TNF-α; Interleukin-10, IL-10; Stromal Derived Factor-1 α, SDF-1α; VEGF; Angiopoietin-1, ANGPT-1; and Endothelin-1, ET-1) using the enzyme-linked immunosorbent assay (ELISA). RESULTS: Analysis showed an increase in proinflammatory IL-6 (p=0.02) and ET-1 (p=0.05) on day 3 after gene therapy and in VEGF (p=0.02) on day 9. A strong positive correlation was found between mobilization of endothelial progenitor cells and TNF-α on day 9 (r=0.71; p=0.03). Furthermore, a strong correlation between ß-blockers, antiplatelets, and vasodilators with SDF-1α baseline in the group undergoing gene therapy was verified (r=0.74; p=0.004). CONCLUSION: Analysis of cooperative paracrine signaling after VEGF gene therapy suggests that the immune system cell and angiogenic molecule expression as well as the endothelial progenitor cell mobilization are time-dependent, influenced by chronic inflammatory process and continuous pharmacological treatment.

Grape Seed Oil Compounds: Biological and Chemical Actions for Health.

Grape seed oil is rich in phenolic compounds, fatty acids, and vitamins, with economic importance to pharmaceutical, cosmetic, and food industry. Its use as an edible oil has also been suggested, especially due to its pleasant sensory characteristics. Grape seed oil has beneficial properties for health that are mainly detected by in vitro studies, such as anti-inflammatory, cardioprotective, antimicrobial, and anticancer properties, and may interact with cellular and molecular pathways. These effects have been related to grape seed oil constituents, mainly tocopherol, linolenic acid, resveratrol, quercetin, procyanidins, carotenoids, and phytosterols. The aim of this article was to briefly review the composition and nutritional aspects of grape seed oil, the interactions of its compounds with molecular and cellular pathways, and its possible beneficial effects on health.

Molecular Properties of Red Wine Compounds and Cardiometabolic Benefits.

Wine has been used since the dawn of human civilization. Despite many health benefits, there is still a lot of discussion about the real properties of its components and its actions on cells and molecular interactions. A large part of these issues permeate the fine line between the amount of alcohol that causes problems to organic systems and the amount that could be beneficial for the health. However, even after the process of fermentation, wine conserves different organic compounds from grapes, such as polysaccharides, acids, and phenolic compounds, such as flavonoids and nonflavonoids. These substances have known anti-inflammatory and antioxidant capacities, and are considered as regulatory agents in cardiometabolic process. In this study, the main chemical components present in the wine, its interaction with molecules and biological mechanisms, and their interference with intra- and extracellular signaling are reviewed. Finally, the properties of wine that may benefit cardiovascular system are also revised.

Cell Therapy in Ischemic Heart Disease: Interventions That Modulate Cardiac Regeneration.

The incidence of severe ischemic heart disease caused by coronary obstruction has progressively increased. Alternative forms of treatment have been studied in an attempt to regenerate myocardial tissue, induce angiogenesis, and improve clinical conditions. In this context, cell therapy has emerged as a promising alternative using cells with regenerative potential, focusing on the release of paracrine and autocrine factors that contribute to cell survival, angiogenesis, and tissue remodeling. Evidence of the safety, feasibility, and potential effectiveness of cell therapy has emerged from several clinical trials using different lineages of adult stem cells. The clinical benefit, however, is not yet well established. In this review, we discuss the therapeutic potential of cell therapy in terms of regenerative and angiogenic capacity after myocardial ischemia. In addition, we addressed nonpharmacological interventions that may influence this therapeutic practice, such as diet and physical training. This review brings together current data on pharmacological and nonpharmacological approaches to improve cell homing and cardiac repair.

Integrated Transcriptomics Establish Macrophage Polarization Signatures and have Potential Applications for Clinical Health and Disease.

Growing evidence defines macrophages (Mφ) as plastic cells with wide-ranging states of activation and expression of different markers that are time and location dependent. Distinct from the simple M1/M2 dichotomy initially proposed, extensive diversity of macrophage phenotypes have been extensively demonstrated as characteristic features of monocyte-macrophage differentiation, highlighting the difficulty of defining complex profiles by a limited number of genes. Since the description of macrophage activation is currently contentious and confusing, the generation of a simple and reliable framework to categorize major Mφ phenotypes in the context of complex clinical conditions would be extremely relevant to unravel different roles played by these cells in pathophysiological scenarios. In the current study, we integrated transcriptome data using bioinformatics tools to generate two macrophage molecular signatures. We validated our signatures in in vitro experiments and in clinical samples. More importantly, we were able to attribute prognostic and predictive values to components of our signatures. Our study provides a framework to guide the interrogation of macrophage phenotypes in the context of health and disease. The approach described here could be used to propose new biomarkers for diagnosis in diverse clinical settings including dengue infections, asthma and sepsis resolution.

Imbalance in redox status is associated with tumor aggressiveness and poor outcome in lung adenocarcinoma patients.

PURPOSE: The expression levels of human antioxidant genes (HAGs) and oxidative markers were investigated in light of lung adenocarcinoma aggressiveness and patient outcome. METHODS: We assayed in vitro the tumoral invasiveness and multidrug resistance in human lung adenocarcinoma (AdC) cell lines (EKVX and A549). Data were associated with several redox parameters and differential expression levels of HAG network. The clinicopathological significance of these findings was investigated using microarray analysis of tumor tissue and by immunohistochemistry in archival collection of biopsies. RESULTS: An overall increased activity (expression) of selected HAG components in the most aggressive cell line (EKVX cells) was observed by bootstrap and gene set enrichment analysis (GSEA). In vitro validation of oxidative markers revealed that EKVX cells had high levels of oxidative stress markers. In AdC cohorts, GSEA of microarray datasets showed significantly high levels of HAG components in lung AdC samples in comparison with normal tissue, in advanced stage compared with early stage and in patients with poor outcome. Cox multivariate regression analysis in a cohort of early pathologic (p)-stage of AdC cases showed that patients with moderate levels of 4-hydroxynonenal, a specific and stable end product of lipid peroxidation, had a significantly less survival rate (hazard ratio of 8.87) (P < 0.05). CONCLUSIONS: High levels of oxidative markers are related to tumor aggressiveness and can predict poor outcome of early-stage lung adenocarcinoma patients.

High cofilin-1 levels correlate with cisplatin resistance in lung adenocarcinomas.

High cofilin-1 levels have been shown to be an accurate prognostic biomarker in non-small cell lung cancer (NSCLC) and a predictive factor in drug resistance. Herein we explore the role of cofilin-1 in cis-diamminedichloroplatinum(II) (cisplatin) resistance. We evaluated cofilin-1 levels in intrinsically cisplatin-resistant A549 (ICR-A549) cells and determined the cisplatin toxicity in A549 cells transiently transfected and overexpressing CFL1 plasmid. Moreover, expression levels (activity) of the CFL1 gene network were analyzed in a cisplatin-resistant human lung adenocarcinoma cell panel. ICR-A549 cells, selected by challenging parental cells with 10-fold drug GI50 value, presented a sixfold increase in cisplatin GI50 value and an increased cofilin-1 immunocontent (P < 0.01). In addition, cells transfected with cofilin-1 became more resistant to cisplatin (P < 0.01). High activity of the CFL1 gene network was found in a cisplatin-resistant adenocarcinoma cell panel (P < 0.01). In vitro evidences suggest that cofilin-1 is a biological predictor of cisplatin resistance, supporting new treatment initiatives based on cofilin-1 levels to guide chemotherapeutic interventions in NSCLC patients.

High doses of vascular endothelial growth factor 165 safely, but transiently, improve myocardial perfusion in no-option ischemic disease.

UNLABELLED: Gene therapy can induce angiogenesis in ischemic tissues. The aim of this study was to assess safety, feasibility, and results, both clinical and on myocardial perfusion, of gene therapy in refractory angina. This was a phase I/II, prospective, temporal-controlled series, clinical trial. Thirteen patients were maintained for minimum 6 months under optimized clinical management, and then received intramyocardial injections of 2000 µg plasmid vascular endothelial growth factor 165 and were followed by single-photon emission computed tomography (SPECT), treadmill tests, Minnesota quality of life questionnaire (QOL), and New York Heart Association (NYHA) functional plus Canadian Cardiovascular Society (CCS) angina classifications. There were no deaths, early or late. During the optimized clinical treatment, we observed worsening of rest ischemia scores on SPECT (p<0.05). After treatment, there was a transitory increase in myocardial perfusion at the third-month SPECT under stress (pre-operative [pre-op] 18.38 ± 7.51 vs. 3 months 15.31 ± 7.30; p<0.01) and at the sixth month under rest (pre-op 13.23 ± 7.98 vs. 6 months: 16.92 ± 7.27; p<0.01). One year after, there were improvements in treadmill test steps (pre-op 2.46 ± 2.07 vs.12 months 4.15 ± 2.23; p<0.01) and oxygen consumption (pre-op 7.66 ± 4.47 vs.12 months 10.89 ± 4.65; p<0.05), QOL (pre-op 48.23 ± 18.35 vs.12 months 28.31 ± 18.14; p<0.01) scores, and CCS (pre-op 3 [3-3.5] vs.12 months 2 [1-2.5]; p<0.01) and NYHA (pre-op 3 [3-3] vs. 2 [2-2] vs. 12 months 2 [1-2]; p<0.01) classes. Gene therapy demonstrated to be feasible and safe in this advanced ischemic cardiomyopathy patient sample. There were improvements in clinical evaluation parameters, and a transitory increase in myocardial perfusion detectable by SPECT scintigraphy. CLINICAL TRIAL REGISTRATION: NCT00744315 http://clinicaltrials.gov/

Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats.

AIMS: Angiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. MAIN METHODS: Diabetes was induced in spontaneously-hypertensive rats (~210 g) by streptozotocin (50mg/kg). Thirty days later, animals received ramipril 15 µg/kg/day (R, n=10), or amlodipine 10mg/kg/day (A, n=8,) or water (C, n=10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF-ß1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). KEY FINDINGS: After treatments, body weight (p=0.77) and glycaemia (p=0.22) were similar among the groups. Systolic BP was similarly reduced (p<0.001) in A and R vs. C (172.4 ± 3.2; 1867 ± 3.7 and 202.2 ± 4.3 mmHg; respectively). ACE activity (C: 0.903 ± 0.086; A: 0.654 ± 0.025, and R: 0.389 ± 0.057 mU/mg), albuminuria (C: 264.8 ± 15.4; A: 140.8 ± 13.5 and R: 102.8 ± 6.7 mg/24h), and renal cortex GLUT1 content (C: 46.81 ± 4.54; A: 40.30 ± 5.39 and R: 26.89 ± 0.79 AU) decreased only in R (p<0.001, p<0.05 and p<0.001; respectively). SIGNIFICANCE: We concluded that the blockade of the renin-angiotensin system with ramipril reduced early markers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels.

GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome.

BACKGROUND: Metabolic syndrome is characterized by insulin resistance, which is closely related to GLUT4 content in insulin-sensitive tissues. Thus, we evaluated the GLUT4 expression, insulin resistance and inflammation, characteristics of the metabolic syndrome, in an experimental model. METHODS: Spontaneously hypertensive neonate rats (18/group) were treated with monosodium glutamate (MetS) during 9 days, and compared with Wistar-Kyoto (C) and saline-treated SHR (H). Blood pressure (BP) and lipid levels, C-reactive protein (CRP), interleukin 6 (IL-6), TNF-α and adiponectin were evaluated. GLUT4 protein was analysed in the heart, white adipose tissue and gastrocnemius. Studies were performed at 3 (3-mo), 6 (6-mo) and 9 (9-mo) months of age. RESULTS: MetS rats were more insulin resistant (p<0.001, all ages) and had higher BP (3-mo: p<0.001, 6-mo: p = 0.001, 9-mo: p = 0.015) as compared to C. At 6 months, CRP, IL-6 and TNF-α were higher (p<0.001, all comparisons) in MetS rats vs H, but adiponectin was lower in MetS at 9 months (MetS: 32 ± 2, H: 42 ± 2, C: 45 ± 2 pg/mL; p<0.001). GLUT4 protein was reduced in MetS as compared to C rats at 3, 6 and 9-mo, respectively (Heart: 54%, 50% and 57%; Gastrocnemius: 37%, 56% and 50%; Adipose tissue: 69%, 61% and 69%). CONCLUSIONS: MSG-treated SHR presented all metabolic syndrome characteristics, as well as reduced GLUT4 content, which must play a key role in the impaired glycemic homeostasis of the metabolic syndrome.