USP18 Curbs the Progression of Metabolic Hypertension by Suppressing JAK/STAT Pathway.

Hypertension is a pathological state of the metabolic syndrome that increases the risk of cardiovascular disease. Managing hypertension is challenging, and we aimed to identify the pathogenic factors and discern therapeutic targets for metabolic hypertension (MHR). An MHR rat model was established with the combined treatment of a high-sugar, high-fat diet and ethanol. Histopathological observations were performed using hematoxylin-eosin and Sirius Red staining. Transcriptome sequencing was performed to screen differentially expressed genes. The role of ubiquitin-specific protease 18 (USP18) in the proliferation, apoptosis, and oxidative stress of HUVECs was explored using Cell Counting Kit-8, flow cytometry, and enzyme-linked immunosorbent assays. Moreover, USP18 downstream signaling pathways in MHR were screened, and the effects of USP18 on these signaling pathways were investigated by western blotting. In the MHR model, total cholesterol and low-density lipoprotein levels increased, while high-density lipoprotein levels decreased. Moreover, high vessel thickness and percentage of collagen were noted along with increased malondialdehyde, decreased superoxide dismutase and catalase levels. The staining results showed that the MHR model exhibited an irregular aortic intima and disordered smooth muscle cells. There were 78 differentially expressed genes in the MHR model, and seven hub genes, including USP18, were identified. USP18 overexpression facilitated proliferation and reduced apoptosis and oxidative stress in HUVECs treated with Ang in vitro. In addition, the JAK/STAT pathway was identified as a USP18 downstream signaling pathway, and USP18 overexpression inhibited the expression of JAK/STAT pathway-related proteins. Conclusively, USP18 restrained MHR progression by promoting cell proliferation, reversing apoptosis and oxidative stress, and suppressing the JAK/STAT pathway.

Consumption of combined fructose and sucrose diet exacerbates oxidative stress, hypertrophy and CaMKIIδ oxidation in hearts from rats with metabolic syndrome.

The prevalence of the metabolic syndrome (MetS) and its cardiac comorbidities as cardiac hypertrophy (CH) have increased considerably due to the high consumption of carbohydrates, such as sucrose and/or fructose. We compared the effects of sucrose (S), fructose (F) and their combination (S + F) on the development of MetS in weaned male Wistar rats and established the relationship between the consumption of these sugars and the degree of cardiac CH development, oxidative stress (OS) and Calcium/calmodulin-dependent protein kinase type II subunit delta oxidation (ox-CaMKIIδ). 12 weeks after the beginning of treatments with S, F or S + F, arterial pressure was measured and 8 weeks later (to complete 20 weeks) the animals were sacrificed and blood samples, visceral adipose tissue and hearts were obtained. Biochemical parameters were determined in serum and cardiac tissue to evaluate the development of MetS and OS. To evaluate CH, atrial natriuretic peptide (ANP), CaMKIIδ and ox-CaMKIIδ were determined by western blot and histological studies were performed in cardiac tissue. Our data showed that chronic consumption of S + F exacerbates MetS-induced CH which is related with a higher OS and ox-CaMKIIδ.

Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice.

Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I-induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Assessment of the relationship between serum uric acid levels and liver enzymes activity in Bangladeshi adults.

Serum uric acid (SUA) level has been suggested to be associated with cardiovascular disease, diabetes and metabolic syndrome. However, little is known about the relationship between SUA and liver enzymes activity in the general population. The present study aimed to assess the relationship between SUA and serum liver enzymes in an adult population in Bangladesh. In this cross-sectional study, a total of 410 blood samples were collected from apparently healthy adults aged > 18 years. SUA, liver enzymes, lipid profile and other biochemical markers were measured in the collected samples by using standard methods. Multinomial logistic regression model was used to assess the relationship between SUA and elevated levels of liver enzymes among the participants. Overall, the prevalence of hyperuricemia was 30.1% with 32.2% in male and 18.6% in female participants. About 33% of the participants had at least one or more elevated levels of liver enzymes. The mean level of SUA was significantly higher in males (389.3 ± 96.9 µmol/L) than in the female (290.4 ± 89.8 µmol/L) subjects (p < 0.001). There was a significant difference in the mean levels of serum ALT and GGT between the male (34.5 ± 16.0 U/L and 26.7 ± 19.5 U/L, respectively) and female (25.0 ± 13.0 U/L and 19.5 ± 13.2 U/L, respectively) participants (p < 0.001 and p < 0.01, respectively). An increasing trend was observed in the mean levels of serum ALT and GGT across the SUA quartile groups (p < 0.001 and p < 0.01, respectively). SUA showed a positive and significant correlation with serum ALT (p < 0.001) and GGT (p < 0.01). In further statistical analysis after adjustment for potential confounders, SUA showed an independent and significant association with serum ALT and GGT in all regression models. In conclusion, SUA was strongly associated with serum levels of ALT and GGT after adjustment for potential confounders. More prospective studies are needed to clarify the complex relationship between SUA and liver enzymes in the general population.

Synthetic Pyridoindole and Rutin Affect Upregulation of Endothelial Nitric Oxide Synthase and Heart Function in Rats Fed a High-Fat-Fructose Diet.

Metabolic syndrome (MetS) belongs to the serious health complications expanding in cardiovascular diseases, obesity, insulin resistance, and hyperglycemia. In this study, hypertriacylglycerolemic rats fed a high-fat-fructose diet (HFFD) were used as an experimental model of MetS to explore the effect of tested compounds. Effects of a new prospective pyridoindole derivative coded SMe1EC2 and the natural polyphenol rutin were tested. Endothelial nitric oxide synthase (NOS3) and nuclear factor kappa B (NF-?B) expression were assessed in the left ventricle immunohistochemically and left ventricle activity was monitored in isolated perfused rat hearts. NOS3 activity in the left ventricle decreased markedly as a result of a HFFD. NOS3 expression was upregulated by both substances. NF-?B expression was increased in the MetS group in comparison to control rats and the expression further increased in the SMe1EC2 treatment. This compound significantly improved the coronary flow in comparison to the control group during reperfusion of the heart followed after ischemia. Further, it tended to increase left ventricular systolic pressure, heart product, rate of maximal contraction and relaxation, and coronary flow during baseline assessment. Moreover, the compound SMe1EC2 decreased the sensitivity of hearts to electrically induced ventricular fibrillation. Contrary to this rutin decreased coronary flow in reperfusion. Present results suggest that despite upregulation of NOS3 by both substances tested, pyridoindole SMe1EC2 rather than rutin could be suitable in treatment strategies of cardiovascular disorders in MetS-like conditions.

Association between pregravid liver enzyme levels and gestational diabetes in twin pregnancies: a secondary analysis of national cohort study.

Multiple pregnancies are prone to gestational diabetes mellitus (GDM). This study investigated the association between pregravid liver enzyme levels and the development of GDM in a twin pregnancy. Women who had the National Health Screening Examination and delivered their twin babies within one year were enrolled. Pregravid liver enzyme levels were divided into high and low level. Risks for developing GDM by high levels of liver enzymes were analyzed, in subgroups by pregravid obesity or metabolic syndrome. Among the 4348 twin pregnancies, 369 women (8.5%) developed GDM not requiring insulin treatment (GDM - IT), and 119 women (2.7%) developed GDM requiring insulin treatment(GDM + IT). High levels of pregravid GGT and ALT were related to risks of GDM + IT not only in women with obesity or metabolic syndrome (odds ratio[OR] 6.348, 95% confidence interval [CI] 2.579-15.624 and OR 6.879, 95% CI 2.232-21.204, respectively), but also in women without obesity (OR 3.05, 95% CI 1.565-5.946) or without metabolic syndrome (OR 3.338, 95% CI 1.86-5.992), compared to in women with low levels of those. However, there were no significant associations in the pregravid ALT and GGT levels and risks for development of GDM - IT, unrelated to pregravid obesity or metabolic syndrome. Therefore, this study suggests that women with high levels of pregravid GGT and ALT need to recognize their increased risk of GDM + IT, regardless of pregravid obesity or MetS, when they get pregnant twin.

Liver Enzymes and Their Association with Some Cardiometabolic Diseases: Evidence from a Large Kurdish Cohort.

OBJECTIVE: According to reports, liver enzymes might play a role in the incidence and development of cardiometabolic diseases such as metabolic syndrome (MetS), hypertension (HTN), and cardiovascular diseases (CVD). We conducted a study to investigate this hypothesis among the Iranian Kurdish population. METHODS: We analyzed data from the baseline phase of the Ravansar noncommunicable disease (RaNCD) cohort. The association between liver enzymes (ALT, AST, ALT/AST ratio, GGT, and ALP) with cardiometabolic disease risk factors was investigated by multiple linear regression. The odds ratio of cardiometabolic diseases in each quartile category of liver enzyme concentration was estimated using multivariable logistic regression. RESULTS: The mean age of participants was 47.3 ± 4.1 years (48.1 years in males and 51.8 years in females). In the adjusted model, all enzymes were positively associated with MetS, HTN, and CVD risk factors except for the ALT/AST ratio with SBP and DBP. In the adjusted model, subjects in the fourth quartile for GGT, ALT/AST ratio, ALT, ALP, and AST had 3.29-, 2.94-, 2.45-, 2.00-, and 1.19-fold increased risk for MetS compared with subjects in the first quartile. Increased levels of GGT and ALP were positively associated with the risk of HTN (ORs = 1.33, 95%CI = 1.03-1.71 for GGT; ORs = 1.32, 95%CI = -1.68 for ALP). An increased GGT level was significantly associated with CVD (ORs = 1.54, 95%CI = 1.03-1.68). Within the normal range quartile, ALT had a significant correlation with the incidence of MetS. CONCLUSION: According to the present study, the levels of liver enzymes could be considered for early diagnosis of MetS, HTN, and CVD.

Effects of exercise type and intensity on visfatin and the metabolic syndrome in obesity / Efectos del tipo de ejercicio y de la intensidad en la visfatina y el síndrome metabólico en la obesidad / Efeitos do tipo de exercício e da intensidade na visfatina e a síndrome metabólica na obesidade

ABSTRACT Objective: Visfatin may regulate a variety of physiological functions and it has great potential to significantly enhance our knowledge of the treatment of metabolic syndrome. Metabolic syndrome (MS) refers to metabolic abnormalities, such as abdominal obesity, dyslipidemia, high low-density cholesterol, high blood pressure and diabetes, and physical activity is an important factor for the management of MS. Therefore, the purpose of this study is to investigate the effects of visfatin on MS and MS risk factors through differences in aerobic exercise intensity and exercise type based on the premise of the same amount of exercise (energy expenditure of 400 kcal per day). Method: Thirty two obese, middle-aged women were randomly assigned to exercise intensity groups VO2max 50% (MAE, n=8) and VO2max 80% (VAE, n=8) and to type of exercise groups VO2max 50% + TRX (MARE, n=8) and VO2max 80% + TRX (VARE, n=8). The exercise program was performed 5 times a week. The data was analyzed using two-way repeated measures ANOVA and post-hoc tests within groups with LSD. Results: Body weight (p<.01 and p<.001) and % body fat (p<.05 and p<.01) significantly decreased in all groups and visfatin only increased significantly after exercise in the VARE group (p<.05). TG, glucose, and waist circumstance (p<.05, p<.01, and p<.001) significantly decreased in all groups and HDL-C (p<.05) only increased significantly after exercise only in the MARE group. Conclusion: These results suggest that, in spite of differences in exercise intensity and exercise type, exercise is effective in improving obesity and MS risk factors, but further research is needed on the exact mechanisms of visfatin. Level of evidence I; Therapeutic Studies Investigating the Results of Treatment .

RESUMEN Objetivo: La visfatina puede regular diversas funciones fisiológicas y tiene gran potencial para mejorar significativamente nuestro conocimiento sobre el tratamiento del síndrome metabólico. El síndrome metabólico (SM) se refiere a anormalidades metabólicas, como obesidad abdominal, dislipidemia, colesterol de baja densidad elevado, hipertensión y diabetes, siendo la actividad física un factor importante para el manejo del SM. Siendo así, el objetivo de este estudio es investigar los efectos de la visfatina sobre los factores de riesgo de SM por medio de diferencias de la intensidad de ejercicios aeróbicos y del tipo de ejercicio, con base en la premisa de misma cantidad de ejercicio (gasto energético de 400 kcal por día). Método: Treinta y dos mujeres obesas de media edad fueron aleatoriamente designadas para grupos de intensidad de ejercicio con VO2máx de 50% (EAM, n = 8) y VO2máx de 80% (EAV, n = 8) y grupos con VO2máx de 50% + ERC (EARM, n = 8) y VO2máx de 80% + ERC (EARV, n = 8). El programa de ejercicios fue realizado cinco veces por semana. Los datos fueron analizados con ANOVA de dos vías con medidas repetidas y tests post-hoc en los grupos con DMS. Resultados: El peso corporal (p < 0,01 y p < 0,001) y porcentual de grasa corporal (p < 0,05 y p < 0,01) disminuyeron significativamente en todos los grupos y la visfatina sólo aumentó significativamente después del ejercicio en el grupo EARV (p < 0,05). Los triglicéridos, la glucosa y la circunferencia de la cintura (p < 0,05, p < 0,01 e p < 0,001) disminuyeron significativamente en todos los grupos y el HDL-C (p < 0,05) sólo aumentó significativamente después del ejercicio sólo en el grupo EARM. Conclusión: Esos resultados sugieren que, a pesar de las diferencias de intensidad y tipo de los ejercicios, los mismos son eficaces para mejorar la obesidad y los factores de riesgo del SM, por ende, son necesarias más investigaciones sobre los mecanismos exactos de la visfatina. Nivel de Evidencia I; Estudios terapéuticos - Investigación de los resultados del tratamiento .

RESUMO Objetivo: A visfatina pode regular diversas funções fisiológicas e tem grande potencial para aprimorar significativamente nosso conhecimento sobre o tratamento da síndrome metabólica. A síndrome metabólica (SM) refere-se a anormalidades metabólicas, como obesidade abdominal, dislipidemia, colesterol de baixa densidade elevado, hipertensão e diabetes, sendo a atividade física um fator importante para o manejo da SM. Assim sendo, o objetivo deste estudo é investigar os efeitos da visfatina sobre os fatores de risco de SM por meio de diferenças da intensidade de exercícios aeróbicos e do tipo de exercício, com base na premissa de mesma quantidade de exercício (gasto energético de 400 kcal por dia). Método: Trinta e duas mulheres obesas de meia-idade foram randomicamente designadas para grupos de intensidade de exercício com VO2máxde 50% (EAM, n = 8) e VO2máxde 80% (EAV, n = 8) e grupos com VO2máxde 50% + ERC (EARM, n = 8) e VO2máxde 80% + ERC (EARV, n = 8). O programa de exercícios foi realizado 5 vezes por semana. Os dados foram analisados com ANOVA de duas vias com medidas repetidas e testes post-hoc nos grupos com DMS. Resultados: O peso corporal (p < 0,01 e p < 0,001) e percentual de gordura corporal (p < 0,05 e p < 0,01) diminuíram significativamente em todos os grupos e a visfatina só aumentou significativamente depois do exercício no grupo EARV (p < 0,05). Triglicérides, glicose e circunferência da cintura (p < 0,05, p < 0,01 e p < 0,001) diminuíram significativamente em todos os grupos e o HDL-C (p < 0,05) só aumentou significativamente depois o exercício apenas no grupo EARM. Conclusão: Esses resultados sugerem que, apesar das diferenças de intensidade e tipo dos exercícios, eles são eficazes para melhorar a obesidade e os fatores de risco da SM, porém, são necessárias mais pesquisas sobre os mecanismos exatos da visfatina. Nível de Evidência I; Estudos terapêuticos - Investigação dos resultados do tratamento .

Gamma-glutamyl transpeptidase elevation is associated with metabolic syndrome, hepatic steatosis, and fibrosis in patients with nonalcoholic fatty liver disease: A community-based cross-sectional study.

This study aimed to analyze the association between elevated gamma-glutamyl transpeptidase (GGT) and metabolic syndrome (MetS), hepatic steatosis, and fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). From August 2013 to August 2018, a community-based study was conducted in the northeastern part of Taiwan. Patients who underwent abdominal ultrasonography (US) and had no history of alcoholic liver disease were included. According to a US examination showing fatty liver degree, 1566 patients with NAFLD were divided into four groups: normal GGT, isolated GGT elevation, isolated alanine aminotransferase (ALT) elevation, and both GGT and ALT elevation groups. Further 1147 participants with normal serum ALT, GGT, and the abdominal US were included as the control group. GGT levels were associated with high sensitivity C-reactive protein, lower adiponectin, diabetes mellitus, and chronic kidney disease. A stepwise increase in odds ratio (OR) for MetS was found in the normal GGT group (OR = 1.71), isolated GGT elevation group (OR = 3.06), isolated ALT elevation (OR = 4.00), and both GGT + ALT elevation group (OR = 4.17) than the control group. Linear regression analysis revealed a positive association between GGT/ALT value and hepatic steatosis degree, GGT value, and degree of hepatic fibrosis. Hence, GGT elevation is associated with MetS, hepatic steatosis, and fibrosis in patients with NAFLD.

Soluble guanylate cyclase chronic stimulation effects on cardiovascular reactivity in cafeteria diet-induced rat model of metabolic syndrome.

Metabolic syndrome is linked to an increased risk of cardiovascular complications by a mechanism involving mainly decreased nitric oxide (NO) bioavailability and impaired NO-soluble guanylate cyclase (sGC)- cyclic guanosine monophosphate (cGMP) signalling (NO-sGC-cGMP). To further develop this scientific point, this study aimed to investigate the effects of long-term treatment with BAY 41-2272 (a sGC stimulator) on cardiovascular reactivity of spontaneously hypertensive rats (SHR) as a model of metabolic syndrome. SHR were randomly divided into 3 groups: control group, cafeteria diet (CD)-fed group and CD-fed group treated daily with BAY 41-2272 (5 mg/kg) by gastric gavage for 12 weeks. In vivo measurements of body weight, abdominal circumference, blood pressure and glucose tolerance test were performed. At the end of the feeding period, ex vivo cumulative concentration-response curves were performed on isolated perfused heart (isoproterenol (0.1 nM - 1 µM)) and thoracic aorta (phenylephrine (1 nM-10 µM), acetylcholine (1 nM-10 µM), and sodium nitroprusside (SNP) (0.1 nM-0.1 µM)). We showed that chronic CD feeding induced abdominal obesity, hypertriglyceridemia, glucose intolerance and exacerbated arterial hypertension in SHR. Compared to control group, CD-fed group showed a decrease in ß-adrenoceptor-induced cardiac inotropy, in coronary perfusion pressure and in aortic contraction to phenylephrine. While relaxing effects of acetylcholine and SNP were unchanged. BAY 41-2272 long-term treatment markedly prevented arterial hypertension development and glucose intolerance, enhanced the α1-adrenoceptor-induced vasoconstriction, and restored cardiac inotropy and coronary vasodilation. These findings suggest that BAY 41-2272 may be a potential novel drug for preventing metabolic and cardiovascular complications of metabolic syndrome.

Discovery of a novel series of guanidinebenzoates as gut-restricted enteropeptidase and trypsin dual inhibitors for the treatment of metabolic syndrome.

A novel series of guanidinebenzoate enteropeptidase and trypsin dual inhibitors has been discovered and SAR studies were conducted. Optimization was focused on improving properties for gut restriction, including increased aqueous solubility, lower cellular permeability, and reduced oral bioavailability. Lead compounds were identified with efficacy in a mouse fecal protein excretion study.

Imperatorin alleviates metabolic and vascular alterations in high-fat/high-fructose diet-fed rats by modulating adiponectin receptor 1, eNOS, and p47phox expression.

In the present study, the therapeutic effects of imperatorin on metabolic and vascular alterations and possible underlying mechanisms were investigated in high-fat/high-fructose diet (HFFD)-fed rats. Male Sprague-Dawley rats were fed a high-fat diet plus 15% fructose in drinking water for 16 weeks. HFFD-fed rats were treated with imperatorin (15 or 30 mg/kg/day) for the last 4 weeks. In HFFD-fed rats, imperatorin significantly reduced obesity, hypertension, dyslipidemia, and insulin resistance. Imperatorin markedly improved vascular endothelial function and alleviated changes in vascular morphology. Furthermore, imperatorin treatment significantly increased the plasma levels of the nitric oxide metabolite and adiponectin, and upregulated adiponectin receptor 1 and endothelial nitric oxide synthase (eNOS) protein expression in the thoracic aorta. Imperatorin treatment decreased vascular superoxide anion production and downregulated aortic NADPH oxidase subunit p47phox protein expression. These findings indicated that imperatorin alleviates HFFD-induced metabolic and vascular alterations in rats. The possible underlying mechanism may involve the restoration of adiponectin receptor 1 and eNOS expression and suppression of p47phox expression.

Role of CaMKII in the regulation of fatty acids and lipid metabolism.

BACKGROUND & AIMS: Previous studies have reported the beneficial roles of the activation of calmodulin-dependent protein kinase (CaMK)II to many cellular functions associated with human health. This review aims at discussing its activation by exercise as well as its roles in the regulation of unsaturated, saturated, omega 3 fatty acids, and lipid metabolism. METHODS: A wide literature search was conducted using online database such as 'PubMed', 'Google Scholar', 'Researcher', 'Scopus' and the website of World Health Organization (WHO) as well as Control Disease and Prevention (CDC). The criteria for the search were mainly lipid and fatty acid metabolism, diabetes, and metabolic syndrome (MetS). A total of ninety-seven articles were included in the review. RESULTS: Calmodulin-dependent protein kinase activation by exercise is helpful in controlling membrane lipids related with type 2 diabetes and obesity. CaMKII regulates many health beneficial cellular functions in individuals who exercise compared with those who do not exercise. Regulation of lipid metabolism and fatty acids are crucial in the improvement of metabolic syndrome. CONCLUSIONS: Approaches that involve CaMKII could be a new avenue for designing novel and effective therapeutic modalities in the treatment or better management of metabolic diseases such as type 2 diabetes and obesity.

Associations of gamma-glutamyl transferase with cardio-metabolic diseases in people living with HIV infection in South Africa.

BACKGROUND: Gamma-glutamyl transferase (GGT) has recently been reported as a biomarker for cardiovascular (CVD) risk in general populations. We investigated the associations of GGT with cardio-metabolic diseases and CVD risk in South Africans living with HIV. METHODS: In this cross-sectional study, HIV-infected adults were randomly recruited across 17 HIV clinics in the Western Cape Province. Homeostatic model assessment for insulin resistance (HOMA-IR), hypertension, diabetes, metabolic syndrome by Joint Interim Statement criteria (JIS-MS), a ≥5% and ≥10% predicted risk for a CVD event within 10 years by the Framingham risk score (10-years-CVD risk) were computed. Associations between GGT and cardio-metabolic trait were explored using linear and binomial logistic regressions adjusted for age, gender, lifestyle behaviours and HIV-related characteristics. RESULTS: Among 709 participants (561 women, mean age 38.6 years), log-GGT was positively associated with waist circumference (ß=2.75; p<0.001), diastolic blood pressure (ß=1.65; p=0.006), total cholesterol (ß=0.21; p<0.001), low-density lipoprotein-cholesterol (ß=0.16; p<0.001), high-density lipoprotein-cholesterol and log-triglycerides (both ß=0.12; p<0.001), fasting plasma glucose (ß=0.19; p=0.031), 2-hour-post-glucose-load plasma glucose (ß=0.26; p=0.007), HOMA-IR (ß=0.13; p=0.001), log-high-sensitivity C-reactive-protein (ß=0.3; p<0.001) in linear regression analyses; with hypertension [OR=1.41 (95%CI, 1.13-1.75); p=0.001], JIS-MS [OR=1.33 (1.05-1.68); p=0.016], ≥5% 10-year-CVD risk [OR=1.55 (1.24-1.9400); p<0.001] and ≥10% 10-year-CVD risk [OR=1.56 (1.08-2.23); p=0.016] but not with diabetes [OR=1.24 (0.88-1.71), p=0.205] in logistic regression analyses. CONCLUSIONS: In this study, GGT levels were associated with cardio-metabolic variables independent of HIV specific attributes. If confirmed in longitudinal studies, GGT evaluation maybe included in CVD risk monitoring strategies in people living with HIV.

G6PD activity contributes to the regulation of histone acetylation and gene expression in smooth muscle cells and to the pathogenesis of vascular diseases.

We aimed to determine 1) the mechanism(s) that enables glucose-6-phosphate dehydrogenase (G6PD) to regulate serum response factor (SRF)- and myocardin (MYOCD)-driven smooth muscle cell (SMC)-restricted gene expression, a process that aids in the differentiation of SMCs, and 2) whether G6PD-mediated metabolic reprogramming contributes to the pathogenesis of vascular diseases in metabolic syndrome (MetS). Inhibition of G6PD activity increased (>30%) expression of SMC-restricted genes and concurrently decreased (40%) the growth of human and rat SMCs ex vivo. Expression of SMC-restricted genes decreased (>100-fold) across successive passages in primary cultures of SMCs isolated from mouse aorta. G6PD inhibition increased Myh11 (47%) while decreasing (>50%) Sca-1, a stem cell marker, in cells passaged seven times. Similarly, CRISPR-Cas9-mediated expression of the loss-of-function Mediterranean variant of G6PD (S188F; G6PDS188F) in rats promoted transcription of SMC-restricted genes. G6PD knockdown or inhibition decreased (48.5%) histone deacetylase (HDAC) activity, enriched (by 3-fold) H3K27ac on the Myocd promoter, and increased Myocd and Myh11 expression. Interestingly, G6PD activity was significantly higher in aortas from JCR rats with MetS than control Sprague-Dawley (SD) rats. Treating JCR rats with epiandrosterone (30 mg/kg/day), a G6PD inhibitor, increased expression of SMC-restricted genes, suppressed Serpine1 and Epha4, and reduced blood pressure. Moreover, feeding SD control (littermates) and G6PDS188F rats a high-fat diet for 4 mo increased Serpine1 and Epha4 expression and mean arterial pressure in SD but not G6PDS188F rats. Our findings demonstrate that G6PD downregulates transcription of SMC-restricted genes through HDAC-dependent deacetylation and potentially augments the severity of vascular diseases associated with MetS.NEW & NOTEWORTHY This study gives detailed mechanistic insight about the regulation of smooth muscle cell (SMC) phenotype by metabolic reprogramming and glucose-6-phosphate dehydrogenase (G6PD) in diabetes and metabolic syndrome. We demonstrate that G6PD controls the chromatin modifications by regulating histone deacetylase (HDAC) activity, which deacetylates histone 3-lysine 9 and 27. Notably, inhibition of G6PD decreases HDAC activity and enriches H3K27ac on myocardin gene promoter to enhance the expression of SMC-restricted genes. Also, we demonstrate for the first time that G6PD inhibitor treatment accentuates metabolic and transcriptomic reprogramming to reduce neointimal formation in coronary artery and large artery elastance in metabolic syndrome rats.

Soluble epoxide hydrolase as a therapeutic target for obesity-induced disorders: roles of gut barrier function involved.

Emerging research supports that soluble epoxide hydrolase (sEH), an enzyme involved in eicosanoid metabolism, could be a promising target for obesity-associated disorders. The sEH enzyme is overexpressed in many tissues of obese animals. Genetic ablation or pharmacological inhibition of sEH attenuates the development of a wide range of obesity-induced disorders, including endoplasmic reticulum stress, metabolic syndrome, kidney diseases, insulin resistance, fatty liver, hepatic steatosis, inflammation, and endothelial dysfunction. Furthermore, our recent research showed that genetic ablation or inhibition of sEH attenuated obesity-induced intestinal barrier dysfunction and its resulted bacterial translocation, which is widely regarded to be a central mechanism for the pathogenesis of various obesity-induced disorders. Together, these results support that targeting sEH could be a promising strategy to reduce risks of obesity-induced disorders, at least in part through blocking obesity-induced leaky gut syndrome.

PCSK9 inhibitor effectively attenuates cardiometabolic impairment in obese-insulin resistant rats.

Long-term high-fat diet consumption causes obese-insulin resistance and cardiac mitochondrial dysfunction, leading to impaired left ventricular (LV) function. Atorvastatin effectively improved lipid profiles in obese patients. However, inadequate reduction in low density lipoprotein cholesterol (LDL-C) level was found. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor effectively reduced LDL-C levels. We hypothesized that this PCSK9 inhibitor has a greater efficacy in attenuating cardiometabolic impairments than atorvastatin in obese-insulin resistant rats. Female rats were fed with either a high fat or normal diet for 12 weeks. High fat diet fed rats (HFD) were then divided into 3 groups and were given vehicle, atorvastatin (40 mg/kg/day; s.c.), or PCSK9 inhibitor (4 mg/kg/day; s.c.) for additional 3 weeks. The metabolic parameters, cardiac and mitochondrial function and [Ca2+]i transients were determined. HFD rats developed obese-insulin resistance as indicated by increased plasma insulin and HOMA index. Although high-fat diet fed rats treated with vehicle (HFV) rats had markedly impaired LV function as indicated by reduced %LVFS, impaired cardiac mitochondrial function, and [Ca2+]i transient regulation, these impairments were attenuated in high-fat diet fed rats treated with atorvastatin (HFA) and high-fat diet fed rats treated with PCSK9 inhibitor (HFP) rats. However, these improvements were greater in HFP rats than HFA rats. Our findings indicated that the PCSK9 inhibitor exerted greater cardioprotection than atorvastatin through improved mitochondrial function in obese-insulin resistant rats.

Roles of sarcoplasmic reticulum Ca2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model.

The intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SERCA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC20 phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 partially restored lymphatic contractile activity in MetSyn lymphatic vessel by increasing phasic contractile frequency. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.

Hydromethanolic Extracts from Adansonia digitata L. Edible Parts Positively Modulate Pathophysiological Mechanisms Related to the Metabolic Syndrome.

Metabolic syndrome includes a cluster of risk factors for many pathological conditions, including hyperglycemia, abdominal obesity, hyperlipidemia, and hypertension. Adansonia digitata L. (also known as baobab) is used in traditional African Medicine and recent studies showed that it improves the metabolism of carbohydrates and lipids. The aim of this study is to investigate the mechanisms of action associated with the beneficial effects of extracts from the edible parts of baobab (fruit pulp, leaves, raw and toasted seeds), evaluating their inhibitory activity against: alpha-amylase, alpha-glucosidase, angiotensin-converting enzyme, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, and pancreatic lipase. Baobab fruit pulp and leaf extracts resulted to be the most active ones and were then tested on the differentiation process of SW-872 human liposarcoma cells to mature adipocytes. The addition of these latter extracts did not affect triglyceride accumulation, indicating a neutral impact on this parameter. The findings here reported help to explain the growing amount of evidence on the biological properties of baobab and provide suggestions about their use in food and nutraceutical fields.

An overview of ghrelin O-acyltransferase inhibitors: a literature and patent review for 2010-2019.

INTRODUCTION: The peptide hormone ghrelin regulates physiological processes associated with energy homeostasis such as appetite, insulin signaling, glucose metabolism, and adiposity. Ghrelin has also been implicated in a growing number of neurological pathways involved in stress response and addiction behavior. For ghrelin to bind the growth hormone secretagogue receptor 1a (GHS-R1a) and activate signaling, the hormone must first be octanoylated on a specific serine side chain. This key transformation is performed by the enzyme ghrelin O-acyltransferase (GOAT), and therefore GOAT inhibitors may be useful in treating disorders related to ghrelin signaling such as diabetes, obesity, and related metabolic syndromes. AREAS COVERED: This report covers ghrelin and GOAT as potential therapeutic targets and summarizes work on GOAT inhibitors through the end of 2019, highlighting recent successes with both peptidomimetics and small molecule GOAT inhibitors as potent modulators of GOAT-catalyzed ghrelin octanoylation. EXPERT OPINION: A growing body of biochemical and structural knowledge regarding the ghrelin/GOAT system now enables multiple avenues for identifying and optimizing GOAT inhibitors. We are at the beginning of a new era with increased opportunities for leveraging ghrelin and GOAT in the understanding and treatment of multiple health conditions including diabetes, obesity, and addiction.