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Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT1and AT2receptors. For that reason, the aim of this work was to study the gene and protein expression of AT1and AT2receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60 mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT1receptors than normotensive rats while the AT2expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT1and AT2receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT1and AT2receptors. However, the overexpression of AT2could be associated with the reduction in the response to Ang II in the early stage of diabetes. [ABSTRACT FROM AUTHOR]

Numerous studies indicate that intrauterine growth restriction (IUGR) can predispose individuals to metabolic syndrome (MetS) in adulthood. Several reports have demonstrated that pharmacological concentrations of biotin have therapeutic effects on MetS. The present study investigated the beneficial effects of prenatal biotin supplementation in a rat model of intrauterine caloric restriction to prevent cardiometabolic risk in adult female offspring fed fructose after weaning. Female rats were exposed to a control (C) diet or global caloric restriction (20%) (GCR), with biotin (GCRB) supplementation (2 mg/kg) during pregnancy. Female offspring were exposed to 20% fructose (F) in drinking water for 16 weeks after weaning (C, C/F, GCR/F, and GCRB/F). The study assessed various metabolic parameters including Lee's index, body weight, feed conversion ratio, caloric intake, glucose tolerance, insulin resistance, lipid profile, hepatic triglycerides, blood pressure, and arterial vasoconstriction. Results showed that GCR and GCRB dams had reduced weights compared to C dams. Offspring of GCRB/F and GCR/F dams had lower body weight and Lee's index than C/F offspring. Maternal biotin supplementation in the GCRB/F group significantly mitigated the adverse effects of fructose intake, including hypertriglyceridemia, hypercholesterolemia, hepatic steatosis, glucose and insulin resistance, hypertension, and arterial hyperresponsiveness. This study concludes that prenatal biotin supplementation can protect against cardiometabolic risk in adult female offspring exposed to postnatal fructose, highlighting its potential therapeutic benefits.

Currently, it is known that angiotensin II (AngII) induces inflammation, and an AT 1 R blockade has anti-inflammatory effects. The use of an AT 1 receptor antagonist promotes the inhibition of the secretion of multiple proinflammatory cytokines in macrophages, as well as a decrease in the concentration of reactive oxygen species. The aim of this study was to determine the effect of AT 1 receptor gene silencing on the modulation of cytokines (e.g., IL-1β, TNF-α, and IL-10) in THP-1 macrophages and the relation to the gene expression of NF-κB., Materials and Methods: We evaluated the gene expression of PPAR-γ in THP-1 macrophages using PMA (60 ng/mL). For the silencing, cells were incubated with the siRNA for 72 h and telmisartan (10 µM) was added to the medium for 24 h. After that, cells were incubated during 1 and 24 h, respectively, with Ang II (1 µM). The gene expression levels of AT 1 R, NF-κB, and cytokines (IL-1β, TNF-α, and IL-10) were measured by RT-qPCR., Results: We observed that silencing of the AT 1 receptor causes a decrease in the expression of mRNA of proinflammatory cytokines (IL-1β and TNF-α), NF-κB, and PPAR-γ., Conclusions: We conclude that AT 1 R gene silencing is an alternative to modulating the production of proinflammatory cytokines such as TNF-α and IL-1β via NF-κB in macrophages and having high blood pressure decrease.

Aims: The aim of this study was to develop a possible treatment for pulmonary arterial hypertension., Background: Pulmonary arterial hypertension (PAH) is a rare disease characterised by a pulmonary arterial pressure greater than 20 mmHg. One of the factors that contribute to PAH is an increase in the production of endothelin-1, a polypeptide that increases vascular resistance in the pulmonary arteries, leading to increased pulmonary arterial pressure and right ventricular hypertrophy., Objective: The objective of this study was to design, synthesize, and evaluate two siRNAs directed against endothelin-1 in a rat model of PAH induced with monocrotaline., Methods: Wistar rats were administered monocrotaline (60 mg/kg) to induce a PAH model. Following two weeks of PAH evolution, the siRNAs were administered, and after two weeks, right ventricular hypertrophy was evaluated using the RV/LV+S ratio, blood pressure, weight, and relative expression of ECE-1 (Endothelin-converting enzyme-1) mRNA (messenger RNA) by RT-PCR (real-time PCR)., Results: The monocrotaline group showed an increase in the hypertrophy index and in ECE-1 mRNA, as well as a significant decrease in weight compared to the control group, while in the monocrotaline + siRNA group, a significant decrease was observed in the relative expression of ECE-1 mRNA, as well as in right ventricular hypertrophy., Conclusions: Based on the above information, we conclude that the administration of siRNAs directed to ECE-1 decreases the damage associated with PAH., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Asthma is one of the most common chronic non-communicable diseases worldwide, characterized by variable airflow limitation secondary to airway narrowing, airway wall thickening, and increased mucus resulting from chronic inflammation and airway remodeling. Current epidemiological studies reported that hypovitaminosis D is frequent in patients with asthma and is associated with worsening the disease and that supplementation with vitamin D 3 improves asthma symptoms. However, despite several advances in the field, the molecular mechanisms of asthma have yet to be comprehensively understood. MicroRNAs play an important role in controlling several biological processes and their deregulation is implicated in diverse diseases, including asthma. Evidence supports that the dysregulation of miR-21, miR-27b, miR-145, miR-146a, and miR-155 leads to disbalance of Th1/Th2 cells, inflammation, and airway remodeling, resulting in exacerbation of asthma. This review addresses how these molecular mechanisms explain the development of asthma and its exacerbation and how vitamin D 3 may modulate these microRNAs to improve asthma symptoms.

Glycine is a non-essential amino acid with many functions and effects. Glycine can bind to specific receptors and transporters that are expressed in many types of cells throughout an organism to exert its effects. There have been many studies focused on the anti-inflammatory effects of glycine, including its abilities to decrease pro-inflammatory cytokines and the concentration of free fatty acids, to improve the insulin response, and to mediate other changes. However, the mechanism through which glycine acts is not clear. In this review, we emphasize that glycine exerts its anti-inflammatory effects throughout the modulation of the expression of nuclear factor kappa B (NF-κB) in many cells. Although glycine is a non-essential amino acid, we highlight how dietary glycine supplementation is important in avoiding the development of chronic inflammation.

Asthma is a heterogeneous entity encompassing distinct endotypes and varying phenotypes, characterized by common clinical manifestations, such as shortness of breath, wheezing, and variable airflow obstruction. Two major asthma endotypes based on molecular patterns are described: type 2 endotype (allergic-asthma) and T2 low endotype (obesity-related asthma). Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides in length, currently involved in many diverse biological functions, such as chromatin remodeling, gene transcription, protein transport, and microRNA processing. Despite the efforts to accurately classify and discriminate all the asthma endotypes and phenotypes, if long noncoding RNAs could play a role as biomarkers in allergic asthmatic and adolescent obesity-related asthma, adolescents remain unknown. To compare expression levels of lncRNAs: HOTAIRM1, OIP5-AS1, MZF1-AS1, and GAS5 from whole blood of Healthy Adolescents (HA), Obese adolescents (O), allergic asthmatic adolescents (AA) and Obesity-related asthma adolescents (OA). We measured and compared expression levels from the whole blood of the groups mentioned above through RT-q-PCR. We found differentially expressed levels of these lncRNAs between the groups of interest. In addition, we found a discriminative value of previously mentioned lncRNAs between studied groups. Finally, we generated an interaction network through bioinformatics. Expression levels of OIP5-AS1, MZF1-AS1, HOTAIRM1, and GAS5 in whole blood from the healthy adolescent population, obese adolescents, allergic asthma adolescents, and obesity-related asthma adolescents are differently expressed. Moreover, these lncRNAs could act as molecular biomarkers that help to discriminate between all studied groups, probably through molecular mechanisms with several genes and miRNAs implicated.

A higher Th17-immune response characterises obesity and obesity-related asthma phenotype. Nevertheless, obesity-related asthma has a more significant Th17-immune response than obesity alone. Retinoid-related orphan receptor C (RORC) is the essential transcription factor for Th17 polarisation. Previous studies have found that adolescents with obesity-related asthma presented upregulation of RORC , IL17A , and TNFA . However, the mechanisms that cause these higher mRNA expression levels in this asthmatic phenotype are poorly understood. Methylation directly regulates gene expression by adding a methyl group to carbon 5 of dinucleotide CpG cytosine. Thus, we evaluated the relationship between RORC , IL17A , and TNFA methylation status and mRNA expression levels to investigate a possible epigenetic regulation. A total of 102 adolescents (11-18 years) were studied in the following four groups: 1) healthy participants (HP), 2) allergic asthmatic participants (AAP), 3) obese participants without asthma (OP), and 4) non-allergic obesity-related asthma participants (OAP). Real-time qPCR assessed the methylation status and gene expression levels in peripheral blood leukocytes. Remarkably, the OAP and AAP groups have lower promoter methylation patterns of RORC , IL17A , and TNFA than the HP group. Notably, the OAP group presents lower RORC promoter methylation status than the OP group. Interestingly, RORC promoter methylation status was moderately negatively associated with gene expression of RORC ( r s = -0.39, p < 0.001) and IL17A ( r s = -0.37, p < 0.01), respectively. Similarly, the promoter methylation pattern of IL17A was moderately negatively correlated with IL17A gene expression ( r s = -0.3, p < 0.01). There is also a moderate inverse relationship between TNFA promoter methylation status and TNFA gene expression ( r s = -0.3, p < 0.01). The present study suggests an association between lower RORC , IL17A , and TNFA gene promoter methylation status with obesity-related asthma and allergic asthma. RORC, IL17A , and TNFA gene promoter methylation patterns are moderately inversely correlated with their respective mRNA expression levels. Therefore, DNA methylation may regulate ROR C, IL17A , and TNF gene expression in both asthmatic phenotypes., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Background: Chronic or low-grade inflammation is a process where various immune cells are recruited from the periphery into adipose tissue. This event gives rise to localised inflammation, in addition to having a close interaction with cardiometabolic pathologies where the mediation of orphan receptors is observed. The aim of this study was to analyse the participation of the orphan receptors GPR21, GPR39, GPR82 and GPR6 in a chronic inflammatory process in 3T3-L1 cells. The 3T3-L1 cells were stimulated with TNF-α (5 ng/mL) for 60 min as an inflammatory model. Gene expression was measured by RT-qPCR., Results: We showed that the inflammatory stimulus of TNF-α in adipocytes decreased the expression of the orphan receptors GPR21, GPR26, GPR39, GPR82 and GPR6, which are related to low-grade inflammation., Conclusions: Our results suggest that GPR21 and GPR82 are modulated by glycine, it shows a possible protective role in the presence of an inflammatory environment in adipocytes, and they could be a therapeutic target to decrease the inflammation in some diseases related to low-grade inflammation such as diabetes, obesity and metabolic syndrome.

Diabetes is a disease that leads to proliferative diabetic retinopathy (PDR), which is associated with an increase of new vessels formation due to an overexpression of angiogenic factors, such as angiopoietin 2 (ANGPT2). The aim of this work was to design a siRNA targeting ANGPT2 to decrease the retinal neovascularization associated with PDR. Adult male Wistar rats weighing 325-375 g were used. Diabetes was induced by a single dose of streptozotocin (STZ, 60 mg/kg i.p.). The siRNAs were designed, synthesised, and administered intravitreally at the beginning of diabetes induction (t 0 ), and after 4 weeks of diabetes evolution (t 4 ), subsequently evaluated the retinal neovascularization (junctions and lacunarity) and ANGPT2 expression in the retina by RT-PCR, after 4 weeks of the siRNAs administration. The results showed that the administration of STZ produced significant increases in blood glucose levels, retinal neovascularization (augmented junctions and lower lacunarity), and ANGPT2 expression, while the administration of the ANGPT2-siRNAs at different groups (t 0 and t 4 ) reduces the junctions and increases the lacunarity in diabetic rats. Therefore, we conclude that the administration of siRNAs targeting ANGPT2 could be an option to decrease the retinal neovascularization associated with PDR and halt the progression of blindness caused by diabetes.

Orphan receptors have unknown endogenous ligands, are expressed in different tissues, and participate in various diseases such as diabetes, hypertension and cancer. We studied the expression profiles of GPR21, GPR39, GPR135 and GPR153 orphan receptors in several tumour tissues. Cervical, breast, skin, prostate, and astrocytoma tissues were analysed for orphan receptor gene expression using Real time PCR analysis. GPR39 is over-expressed in cervical and prostate cancer tissues, and GPR21 and GPR135 receptors are significantly decreased in cervical, breast, skin, prostate, and astrocytoma tissues, when compared with healthy human fibroblasts. In conclusion, GPR21 and GPR135 receptor gene expression is reduced in cancerous tissues. GPR39 may have a role in the development and evolution of cervical and prostate cancer. These data suggest these receptors may be alternative molecules for new diagnostic approaches, and the design of novel therapeutics against oncological pathologies.

Hypertension is a disease, which in spite of existing treatments continues to have high morbidity and mortality, which suggests that there are other mechanisms involved in this pathology. In this sense, the orphan receptors are G protein-coupled receptor associated with various pathologies such as GPR99 which has been linked to mice develop left ventricular hypertrophy induced by blood pressure overload while GPR107 with patients with idiopathic pulmonary arterial hypertension. For this reason, the aim of this work was to study if the expression of the orphan receptors GPR99 and GPR107 are modified by arterial hypertension. Male SHR and WKY rats of 6-8 and 10-12 weeks old were used. The weight, systolic blood pressure and heart rate were measured, as well as the mRNA of the receptors GPR99 and GPR107 in the aorta, kidney, heart and brain by RT-PCR, also was realized an in silico analysis to predict which G protein could be coupled the orphan receptor GPR107. Our results showed that receptors GPR99 and GPR107 are expressed in the analyzed tissues and their expression profile tends to change at different ages and with the development of hypertension, for the other hand, the bioinformatics analysis for GPR107 showed that is coupled to Gi protein. Therefore, we do not rule out that GPR99 and GPR107 could be involved in the pathophysiology of hypertension and could be used as targets therapeutic in hypertension.

Obesity is associated with a unique non-T2 asthma phenotype, characterised by a Th17 immune response. Retinoid-related orphan receptor C (RORC) is the master transcription factor for Th17 polarisation. We investigated the association of TNFA, IL17A, and RORC mRNA expression levels with the non-T2 phenotype. We conducted a cross-sectional study in adolescents, subdivided as follows: healthy (HA), allergic asthma without obesity (AA), obesity without asthma (OB), and non-allergic asthma with obesity (NAO). TNFA, IL17A, and RORC mRNA expression in peripheral blood leukocytes were assessed by RT-PCR. NAO exhibited higher TNFA mRNA expression levels than HA or OB, as well as the highest IL17A and RORC mRNA expression levels among the four groups. The best biomarker for discriminating non-allergic asthma among obese adolescents was RORC mRNA expression levels (area under the curve: 0.95). RORC mRNA expression levels were associated with the non-T2 asthma phenotype, hinting at a therapeutic target in obesity-related asthma., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Non-allergic asthma caused by obesity is a complication of the low-grade chronic inflammation inherent in obesity. Consequently, the serum concentrations of adipokines such as retinol-binding protein 4 (RBP4) and plasminogen activator inhibitor-1 (PAI-1) increase. No gold standard molecule for the prediction of non-allergic asthma among obese patients has been identified., Objective: To evaluate RBP4 and PAI-1 as prognostic biomarkers of non-allergic asthma caused by obesity., Methods: A cross-sectional study between four groups of adolescents: (1) healthy (n = 35), (2) allergic asthma without obesity (n = 28), (3) obesity without asthma (n = 33), and (4) non-allergic asthma with obesity (n = 18)., Results: RBP4 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (39.2 ng/mL [95% confidence interval (CI): 23.8-76.0] vs. 23.5 ng/mL [95% CI: 3.2-33.5], p < 0.01), and PAI-1 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (21.9 ng/mL [95% CI: 15.7-26.5] vs. 15.9 ng/mL [95% CI: 9.4-18.2], p < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated that the serum RBP4 cut-off value was >42.78 ng/mL, with an area under the ROC curve (AUC) of 0.741 (95% CI: 0.599-0.853, p = 0.001), considered acceptable. The PAI-1 cut-off value was >12.0 ng/mL, with an AUC of 0.699 (95% CI: 0.554-0.819, p = 0.008), considered fair., Conclusions: RBP4 may be useful to predict non-allergic asthma among obese adolescents in clinical practice., Competing Interests: The authors report no conflicts of interest.

Metabolic syndrome (MS) has been related with alterations in expression levels of orphan G protein coupled receptors (GPCRs) such as GPR21 and GPR82, which could be involved in some of the elements that characterizes the metabolic syndrome. The aim of this work was to evaluate changes in GPR21 and GPR82 receptors expression in two models of metabolic syndrome: one genetic (Zucker rats), and the other based on a diet (70% fructose for 9 weeks). GPR21 and GPR82 gene expressions were evaluated in brain, heart, aorta, liver and kidney by RT-qPCR. Rats with a high fructose diet, as well as obese Zucker rats, showed initial stages of pancreatic damage and alterations in some biochemical parameters related to the model consistent with the classification of MS. GPR21 and GPR82 receptors expressed in all tissues. The expression of GPR21 decreased in heart, aorta and kidney, but in liver the expression was different: decreased in diet model and increased in genetic model. In contrast, GPR82 expression depended of tissue and metabolic syndrome model. The results highlight the possible role of GPR21 and GPR82 receptors in the development MS. We conclude that the expression of GPR21 and GPR82 in different tissues is related with MS and depend of the origin of the syndrome, so they could be a therapeutic target for that syndrome.

Diabetes and hypertension can coexist and exacerbate each other. In the early stages of diabetes, there is a decreased vascular response of the sympathetic nervous system (SNS), probably due to lower expression of α 1 -adrenoceptors; however, it is unclear how diabetes in advanced stages changes the functionality of the SNS, especially the expression of α 1 -adrenoceptors. Thus, the aim of this work was to analyse the functional response to phenylephrine, a selective α 1 -adrenoceptor agonist, and the expression of α 1 -adrenoceptors in chronic diabetes and hypertension. Male SHR and WKY rats aged 10-12 weeks were administered either streptozotocin (60 mg/kg i.p.) or a vehicle (control group). Eight weeks after administration, dose-response curves to phenylephrine were generated and the gene and protein expression of α 1 -adrenoceptor subtypes (α 1A -, α 1B - and α 1D -adrenoceptors) in the heart and aorta were measured. The response to phenylephrine was diminished in hypertensive rats and in normotensive diabetic rats. The coexistence of both diabetes and hypertension produced an even smaller response to phenylephrine than that observed for each condition separately. In the heart and aorta of diabetic rats, no changes in α 1A -, α 1B - or α 1D -adrenoceptor mRNA expression were observed; however, protein expression was increased, mainly for the α 1D -adrenoceptor. Hypertension increased mRNA and protein expression of α 1 -adrenoceptors in a tissue-dependent manner. The coexistence of both diabetes and hypertension produced differences in the regulation of mRNA and protein expression (increase or decrease) in both the heart and aorta. In conclusion, diabetes, hypertension and the coexistence of both pathologies impairs the in vivo response to phenylephrine. However, the differences in α 1A -, α 1B - and α 1D -adrenoceptor expression cannot explain the reduced response to the agonist. This should be further explored in future experiments., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Obesity in adolescents is considered a major public health problem; combined interventional approaches such as omega-3 supplementation with lifestyle intervention (LI) might exert synergistic effects and exceed the impact of each individual strategy. The purpose of the present study was to evaluate if the supplementation of omega-3 with LI could improve metabolic and endothelial abnormality in obese adolescents with hypertriglyceridemia. The study involved sixty-nine adolescents with normal weight and seventy obese adolescents with hypertriglyceridemia. All obese adolescents were applied to LI and randomly assigned to omega-3 supplementation or placebo group for 12 weeks. The obese adolescents with hypertriglyceridemia presented increased levels of leptin, retinol binding protein 4 (RBP4), selectin E (sE) and asymmetric dimethylarginine (ADMA) and decreased levels of adiponectin compared with control subjects. After 12-week intervention, omega-3 supplementation with LI decreased significantly in triglycerides, HOMA, leptin, RBP4, ADMA and sE. Moreover, omega-3 with LI displayed a significant reduction in triglycerides, ADMA and sE in comparison with LI alone. In subjects with omega-3 combined with LI assessed by multivariate regression model, the reduction in triglycerides was the only independent determinant of the decrease in ADMA. The reductions in triglycerides and HOMA were significantly contributed to the changes in sE. Our data indicated that omega-3 combined with LI in short duration significantly improved dyslipidemia, insulin resistance, abnormality of adipokines, endothelial dysfunction in comparison of LI alone, indicating the combined approach is an effective clinical and applicable strategy to control metabolic abnormality and decrease the risks of cardiovascular diseases in obese adolescents., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cardiovascular complications are the main cause of mortality in patients with diabetes, these have been associated with changes in function and expression of receptors coupled to G proteins (GPCR), which include orphan receptors which some of them tend to modify in diabetes, although others are not known, such as GPR135. For this reason, the objective of this work was to study the expression of the orphan receptor GPR135 in brain, heart, kidney, aorta, lung, spleen and liver of diabetic rats, as well as its function by the administration of siRNA (small interfering RNA) and curves to isoproterenol. Our results showed that GPR135 is expressed in all tissues analyzed and its expression is modified due to diabetes, we also observed that the responses to isoproterenol increase in diabetic rats administered with siRNA. Therefore, we conclude that the orphan receptor GPR135 is expressed in different tissues and its expression tends to be modified due to diabetes, besides that it is functional and that it seems to be coupled to Gi/o protein which has negative chronotropic and inotropic effects, therefore, we do not rule out that it participates in the cardiovascular complications associated with diabetes.

Purpose: The aim of this study was to investigate the possible relationship among insulin resistance (IR), endothelial dysfunction, and alteration of adipokines in Mexican obese adolescents and their association with metabolic syndrome (MetS)., Materials and Methods: Two hundred and twenty-seven adolescents were classified according to the body mass index (BMI) (control: N=104; obese: N=123) and homeostasis model of the assessment-insulin resistance index (HOMA-IR) (obese with IR: N=65). The circulating concentrations of leptin, adiponectin, soluble intercellular adhesion molecule-1 (sICAM-1), and IR were determined by standard methods., Results: The obese adolescents with IR presented increased presence of MetS and higher circulating concentrations in sICAM-1 in comparison with the obese subjects without IR. The lowest concentrations of adiponectin were observed in the obese with IR. In multivariate linear regression models, sICAM-1 along with triglycerides, total cholesterol, and waist circumference was strongly associated with HOMA-IR (R 2 =0.457, P=0.008). Similarly, after adjustment for age, BMI-SDS, lipids, and adipokines, HOMA-IR remained associated with sICAM-1 (R 2 =0.372, P=0.008). BMI-SDS was mildly associated with leptin (R 2 =0.176, P=0.002) and the waist circumference was mild and independent determinant of adiponectin (R 2 =0.136, P=0.007)., Conclusions: Our findings demonstrated that the obese adolescents, particularly the obese subjects with IR exhibited increased presence of MetS, abnormality of adipokines, and endothelial dysfunction. The significant interaction between IR and endothelial dysfunction may suggest a novel therapeutic approach to prevent or delay systemic IR and the genesis of cardiovascular diseases in obese patients.

Aims: Metabolic syndrome (MS) is composed of several metabolic abnormalities that increase the risk of cardiovascular diseases and diabetes. Although there are treatments for the components of MS, this pathology maintains a high mortality, suggesting that there are other mechanisms in which orphan receptors such as GPR26 and GPR39 may be involved. For this reason, the aim of this work was to evaluate the expression of GPR26 and GPR39 orphan receptors in two models of MS (diet and genetics)., Materials and Methods: We used male Wistar rats, which received 70% fructose in drinking water for 9 weeks, and obese Zucker rats. We measured weight, blood pressure, glucose, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol to determine the MS and the expression of the orphan receptors GPR26 and GPR39 in brain, heart, aorta, liver, and kidney by RT-PCR., Results: The analysis of the expression of the orphan receptors GPR26 and GPR39 showed that the receptors are expressed in some tissues, but the expression of the GPR26 tends to decrease in the heart and aorta, whereas in the brain, no changes were observed, this receptor is not expressed in the liver and kidney of both strains. The expression of GPR39 isoforms depends on the tissue and MS model., Conclusions: We conclude that the orphan receptors GPR26, GPR39v1, and GPR39v2 are expressed in different tissues and their profile expression is dependent on the etiology of the MS.

Objective: This study was to investigate whether the metabolic abnormalities of adipokines and asymmetrical dimethylarginine (ADMA) associate with pulmonary function deficits in adolescents with obesity and asthma., Methods: This study enrolled 28 obese adolescents with asthma, 46 obese adolescents without asthma, 58 normal-weight adolescents with asthma, and 63 healthy control subjects. Serum levels of leptin, high-molecule-weight (HMW) adiponectin, retinol binding protein 4 (RBP4), asymmetrical dimethylarginine (ADMA), and pulmonary function were qualified., Results: The obese subjects had higher levels of leptin and ADMA but lower levels of HMW adiponectin than the normal-weight subjects with or without asthma. The subjects with asthma had higher levels of RBP4 than those without asthma. The obese adolescents with asthma had lowest forced expiratory lung volume in the first second (FEV 1 )/forced vital capacity (FVC) ratio among the four study groups. In all the study subjects and in the subjects with asthma alone, the FEV 1 /FVC ratio associated negatively with leptin, however, such association was rendered non-significant when adjusted for BMI. The pulmonary function deficits associated inversely with BMI percentile in the subjects with asthma. However, the decreased FEV 1 /FVC ratio was not correlated with HMW adiponectin, RBP4 or ADMA., Conclusions: Our present study confirmed obstructive pattern of pulmonary function characterized by the reduced FEV 1 /FVC ratio in the obese adolescents with asthma. These pulmonary deficits were associated inversely with the increased BMI percentile.

Hypertension and diabetes are multifactorial diseases that frequently coexist and exacerbate each another. During the development of diabetes, the impairment of noradrenergic and renin-angiotensin systems has been reported in the response mediated by α 1 -AR and AT 1 receptors. Although their participation in the development of cardiovascular complications is still controversial, some studies have found increased or diminished response to the vasoconstrictive effect of noradrenaline or angiotensin II in a time-dependent manner of diabetes. Thus, the aim of this work was to investigate the possible changes in the expression or localization of α 1 -AR (α 1A and α 1D ) and angiotensin II receptors (AT 1 and AT 2 ) in aorta of rats after 4 weeks of the onset of diabetes. In order to be able to examine the expression of these receptors, immunofluorescence procedure was performed in tunica intima and tunica media of histological sections of aorta. Fluorescence was detected by a confocal microscopy. Our results showed that the receptors are expressed in both tunics, where adrenergic receptors have a higher density in tunica intima and tunica media of SHR compared with WKY; meanwhile, the expression of angiotensin II receptors is not modified in both groups of rats. On the other hand, the results showed that diabetes produced an increase or a decrease in the expression of receptors that is not associated to a specific type of receptor, vascular region, or strain of rat. In conclusion, diabetes and hypertension modify the expression of the receptors in tunica intima and tunica media of aorta in a different way.

Diabetes and hypertension have been associated with cardiovascular diseases and stroke. Some reports have related the coexistence of hypertension and diabetes with increase in the risk of developing vascular complications. Recently some studies have shown results suggesting that in the early stages of diabetes and hypertension exist a reduced functional response to vasopressor agents like angiotensin II (Ang II), which plays an important role in blood pressure regulation mechanism through the activation of its AT1 and AT2 receptors. For that reason, the aim of this work was to study the gene and protein expression of AT1 and AT2 receptors in aorta of diabetic SHR and WKY rats. Diabetes was induced by the administration of streptozotocin (60 mg/kg i.p.). After 4 weeks of the onset of diabetes, the protein expression was obtained by western blot and the mRNA expression by RT-PCR. Our results showed that the hypertensive rats have a higher mRNA and protein expression of AT1 receptors than normotensive rats while the AT2 expression remained unchanged. On the other hand, the combination of diabetes and hypertension increased the mRNA and protein expression of AT1 and AT2 receptors significantly. In conclusion, our results suggest that diabetes with hypertension modifies the mRNA and protein expression of AT1 and AT2 receptors. However, the overexpression of AT2 could be associated with the reduction in the response to Ang II in the early stage of diabetes.

Aims/introduction: Diabetes mellitus is a chronic degenerative disease characterized by high blood glucose levels as a result of problems in the action or insulin secretion. Although there are many treatments for this pathology, it has been associated with a high mortality rate. For this reason, it is important to try to identify new pathways that could be involved in diabetic complications. Recently, a new class of receptors has been reported, called orphan receptors because the associated ligand and signaling pathways are unknown, these receptors have been associated with certain pathologies. Therefore, the aim of this work was to study the expression of the orphan receptors GPR22 and GPR162 in heart, aorta, brain and kidney of diabetic rats., Materials and Methods: We used Wistar male rats with 10-12 weeks of age. Diabetes was induced by a single dose of streptozotocin (60 mg/kg i.p.). After four weeks, the tissue was obtained and the expression of the mRNA was measured by RT-PCR., Results: Our results showed that the orphan receptors are expressed in a different way in heart, kidney, brain and aorta of diabetic and non-diabetic rats., Conclusions: We conclude that orphan receptors could be involved in the development of diabetes complications.

Overweight and obesity have been associated with increase in cardiometabolic risk. Therapeutics include lifestyle changes and/or pharmacologic agents. However, such interventions are often limited by poor compliance and/or significant side effects. The consumption of certain dietary products, such as cocoa, exerts positive effects on cardiometabolic risk factors. (-)-Epicatechin (EPI), the most abundant flavonoid in cacao has been reported to replicate such effects. However its mechanisms of action have not been fully elucidated.In a rat model of high-fat diet-induced obesity and its associated cardiometabolic risk factors, we administered 1mg/kg of EPI, by gavage, for 2 weeks. Endpoints included weight-gain, glycemia, triglyceridemia, and systolic blood pressure. We also assessed food intake and fecal excretion. Mitochondrial function and structure related proteins were measured by Westerns.Obesity, hyperglycemia, hypertriglyceridemia, and systolic hypertension were developed after the administration of the high-fat diet for five weeks. EPI significantly decreased the rate of weight gain, glycemia and hypertriglyceridemia. The ratio between energy intake and excretion was not significantly modified by treatment. EPI restored the obesity-induced decreases in the levels of skeletal muscle and abdominal tissue sirtuins (SIRTs), peroxisome proliferator-activated receptor coactivator (PGC-1α), mitofilin, transcription factor A mitochondrial (TFAM), uncoupling protein 1 (UCP1), and deiodinase.EPI treatment yielded beneficial effects on high fat diet-induced endpoints thus may be considered as a potential agent for the treatment of obesity and its cardiometabolic associated abnormalities. Mechanism of action may be attributed to the modulation of cellular/mitochondrial function, thus improving overall metabolism., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the effect of a six-month lifestyle intervention on adiponectin, resistin, and two soluble forms of tumor necrosis factor-α receptor (sTNFR) in obese adolescents. A total of 54 obese adolescents aged 10 to 16 years completed the program. Twenty-four adolescents with normal weight at baseline were used as a control group. Our results demonstrated that obese adolescents had abnormal lipid profile, homeostasis model assessment (HOMA) index, adiponectin level (5.6 ± 2.7 vs. 7.6 ± 2.9 μg/mL, p = 0.005) as well as resistin level (31.0 ± 9.0 vs. 24.3 ± 8.5 ng/mL, p = 0.003), whereas levels of both sTNFRs were similar to those in normal weight subjects. After the six-month lifestyle intervention, obese adolescents had a slight but significant drop in standard deviation score-body mass index (SDS-BMI), a significant decrease in waist circumference, total cholesterol, triglycerides, HOMA index, as well as resistin, and a significant increase in adiponectin and high-density lipoprotein-cholesterol. In adolescents without decreased SDS-BMI, no change was observed in adipokines. Changes in adiponectin correlated negatively with changes in waist circumference (r = -0.275, p = 0.044). Changes in resistin correlated positively with changes in triglycerides (r = 0.302, p = 0.027). The study demonstrated the increase of resistin and the decrease of adiponectin in obese adolescents. Lifestyle intervention improved adipokine abnormalities in obese subjects.

The aim of this study was to evaluate the effect of a six-month lifestyle intervention on ghrelin and asymmetrical dimethylarginine (ADMA) in obese Mexican adolescents. A total of 65 obese Mexican adolescents aged 10-16 years completed a six-month lifestyle intervention. Anthropometric and biochemical parameters were assessed at baseline and at six months. Twenty normal-weight adolescents were also evaluated at baseline. Insulin resistance (IR) was determined by the homeostasis model assessment of IR (HOMA-IR). Ghrelin and ADMA were determined by enzyme-linked immunosorbent assay. Obese adolescents presented significantly higher triglycerides, cholesterol, glucose, insulin, HOMA-IR, and ADMA levels, while ghrelin was significantly lower. The lifestyle intervention led to a significant improvement in HOMA-IR, ghrelin, and ADMA in the whole studied obese subjects. ADMA and ghrelin levels were associated with BMI and IR components. According to the value of HOMA-IR, the obese subjects were divided into subjects with or without IR, no difference in ghrelin and ADMA was observed in these two subgroups. After intervention, the obese with IR showed increased ghrelin and decreased ADMA, while the obese without IR only showed improvement in ghrelin. The multiple linear regression analysis revealed that the changes of systolic blood pressure were the only predictor for the changes of ghrelin in the obese with IR. Our study demonstrated the increase of ADMA and the decrease of ghrelin in obese adolescents. Lifestyle intervention improved insulin resistance, decreased ADMA, and increased ghrelin in obese subjects with IR although no significant weight loss was observed.

Hypertension and diabetes have been related to noradrenergic system impairment, especially to the response mediated by alpha-1 receptors. The aim of this work was to investigate possible changes in the expression of alpha-1 adrenergic receptors in aorta and carotid arteries of Wistar Kyoto and spontaneously hypertensive rats after 4 weeks of the onset of diabetes. Our results suggest that early diabetes modifies the expression of alpha-1 adrenergic receptors in aorta and carotid arteries of both WKY and SHR strains in a different way.

Background: Obesity promotes a low-grade systemic inflammatory state that may act on the lung to exacerbate asthma. There is little information on the relationship between systemic inflammation and lung function in children and adolescents., Objectives: To explore the relationship among fibrinogen, plasminogen activator inhibitor-1 (PAI-1), lung function in adolescents with the presence of asthma, and/or obesity., Methods: Totally 178 adolescents (boys and girls) were involved; four groups were divided according to their diagnosis: non-obese and non-asthmatic controls (n = 38), non-obese asthmatics (n = 31), obese non-asthmatics (n = 62), obese asthmatics (n = 47). The levels of PAI-1 and fibrinogen were determined in blood samples. The lung function was evaluated with spirometry by measuring forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flows between 25 and75% (FEF(25-75%))., Results: Compared to healthy controls, obese adolescents with or without asthma show higher levels of fibrinogen (289.2 ± 61.5, 328.4 ± 54.9, and 324.9 ± 68.9 mg/dL, respectively), PAI-1 (36.0 ± 17.3, 53.2 ± 22.3, and 52.6 ± 24.7 ng/mL, respectively), and the reduced FEV1/FVC ratio (87.7 ± 7.7, 81.6 ± 8.6, and 81.7 ± 6.9, respectively). In the whole studied subjects, FEV1/FVC ratio shows significant inverse correlation with PAI-1 (r = -0.185), fibrinogen (r = -0.157), body mass index (BMI; r = -0.303), insulin(r = -0.198), and HOMA (r = -0.173). In the 78 asthmatic subjects, FVC correlates positively with BMI., Conclusion: Our data demonstrate that the degree of systemic inflammation and the degree of obesity in the whole studied adolescents groups correlate negatively with lung function, suggesting an obstructive pulmonary pattern. Further studies are needed to identify the pathophysiological mechanism for such association.

Both gestation and diabetes mellitus (DM) are conditions associated with an increased participation of renin-angiotensin system (RAS) as well as with changes in the vascular response to angiotensin II (Ang II). We sought to establish the impact of gestational diabetes mellitus (GDM) on Ang II- induced vasoconstriction and its correlation with the expression of angiotensin II receptors (AT(1)R, AT(2) R). Female Wistar rats, virgin, or on day 3 after mating, received randomly streptozotocin (STZ) 60 mg/kgor saline ip.Streptozotocin-treated animals developed hyperglycemia (25.6 ± 1.42 mM). Ang II-induced vasoconstriction was evaluated on isolated aortas with (e+) and without (e-) endothelium and the protein expression of AT(1)R and AT(2)R was measured by western blot. Gestational diabetes mellitus significantly increased vasoconstriction with respect to all the other groups. Changes were observed only on e+ vessels. Interestingly, GDM moved AT(1)R: AT(2)R balance towards AT(1) R, while both pregnancy and diabetes towards AT(2)R expression. In conclusion, GDM increases the possibility of an hypertensive complication by an increased AT(1)R expression.

Diabetes has been related to changes in vascular responses, mainly an increase in the vasoconstrictor responses and a decrease in the vasodilator responses. The literature has now begun to study the effects of diabetes in the early stages of development; the first studies on these stages indicate that diabetes produces different changes compared to the advanced stages. For that reason, the aim of this work was to evaluate the responses to norepinephrine and dopamine on normotensive and hypertensive rats with 4 weeks of diabetes evolution. The results showed that 4 weeks of diabetes produces a decrease of the vasopressor response to both agents (norepinephrine and dopamine). These results suggest that in the early stages, there are changes that help to decrease the pressor responses and these changes could disappear in the advanced stages.

Recent studies have shown the effect of perivascular adipose tissue (PVAT) on the regulation of vascular function; however, its role in the model of metabolic syndrome remains unclear. The aim of this study was to examine the effect of losartan on PVAT-derived vascular dysfunction in fructose-induced hypertensive rats. Rats were fed with either water, 10% fructose, or 10% fructose with 10mg/kg losartan for 8 weeks. In the isolated aorta with PVAT and endothelium, contraction induced by norepinephrine (NE) was more potent in fructose-fed rats compared to control rats. Losartan normalized blood pressure, insulin resistance, and NE-induced vasoconstriction in fructose-fed rats. In the aortic rings with/without endothelium and with/without PVAT, losartan could not improve the acetylcholine-induced relaxation in fructose-fed rats. The observation suggested that losartan partly improved the PVAT-associated vascular regulation in fructose-induced hypertensive rats.

Early stages of diabetes have been related to arterial impairment in the vasoconstriction to norepinephrine. For that reason, the aim of this work was to investigate possible changes in the reactivity to angiotensin II and 5-HT in pithed rats and to evaluate the responses of aortic rings to acetylcholine and sodium nitroprussiate in streptozotocin-induced diabetes with 4 weeks evolution in both Wistar-Kyoto (WKY) and Spontaneously hypertensive rats (SHR). Our results suggest that hypertension produces a greater decrease in the vasoconstrictor response to angiotensin II and 5-HT in early stages of diabetes, while the NO-GMPc pathway could be involved such effect.

The pressor effect induced by acute hyperglycemia is not well understood, therefore, it was of interest to study the effect of intravenous glucose infusion on the mean arterial pressure of anesthetized Wistar rats. Animals received glucose (100 mg/kg/min, i.v.), mannitol or saline during 30 min, but only glucose increased the mean arterial pressure (about 40 mm Hg), plasma glucose, insulin and nitric oxide (NO). Pretreatment with reserpine or indorenate (a central antihypertensive) inhibited completely the pressor effect of glucose. Reserpine also decreased the plasma NO levels. Pretreatment with ramipril or with streptozotocin decreased the late phase of the glucose-induced pressor response and the NO levels, the latter treatment also abolishes insulin plasma concentrations. The present results suggest that the pressor effect induced by glucose has an early phase due to an increase of efferent sympathetic discharges and a delayed phase produced by the activation of the renin angiotensin system.

The pressor effect of N -nitric-l-arginine methyl ester (l-NAME) in rats has been attributed to the inhibition of the endothelial nitric oxide synthase; however, recent findings suggest that the central and sympathetic nervous systems may be also involved. In the present work, the authors attempted to study the possible central and sympathetic mechanisms involved in the pressor effect of l-NAME. They compared mean arterial pressure response during 1 h of continuous infusion of normal saline or l-NAME (0.031 mg. kg. min ) in Wistar rats treated with reserpine, adrenal medullectomy, pithing, and pithing + medullectomy. After 15-20 min infusion, a significantly greater increase of mean arterial pressure was observed in anesthetized rats with l-NAME and l-NAME + medullectomy versus rats with l-NAME + reserpine and l-NAME + pithing, and the magnitude of the difference increased further during the continuous 1-h l-NAME infusion. Adrenal medullectomy totally abolished the pressor effect of l-NAME in pithed group. The present findings suggest that the central and sympathetic nervous systems play important roles in the maintenance of the pressor effect of l-NAME, while the adrenal medulla becomes important only when the sympathetic nervous system has been suppressed.