Early prevention by L-Arginine attenuates coronary atherosclerosis in a model of hypercholesterolemic animals; no positive results for treatment

<p>Abstract</p> <p>Background</p> <p>Endothelial dysfunction (ED) is an independent predictor of cardiovascular events. ED is also a reversible disorder, and nitric oxide donors like L-arginine may promote this process. Despite the positive results from several studies, there are some studies that have shown that L-arginine administration did not improve endothelium-dependent dilation or the inflammatory state of patients. In this study the early and the late effects of L-arginine on coronary fatty streak formation and ED biomarkers were considered in hypercholesterolemic rabbits.</p> <p>Methods</p> <p>36 white male rabbits randomly assigned in 3 groups. Rabbits were fed 1% high-cholesterol diet (LP group, n = 15), or high-cholesterol diet with oral L-arginine (3% in drinking water) (EP group, n = 15) or standard diet (control group, n = 6) for 4 weeks (phase I). Afterward, all animals were fed normal diet for 4 weeks (phase II). In the second phase, L-arginine was discontinued for EP group and was begun for LP group. The plasma levels of lipids, von Willebrand factor (vWF), and nitrite were compared before and after 4 and 8 weeks of experiment. Coronary fatty streak formation was measure after 4 and 8 weeks of experiment.</p> <p>Results</p> <p>The plasma levels of lipids were increased significantly in both groups of LP and EP after phase I. The hypercholesterolemia induced significant increased vWF release in LP group. The L-arginine supplementation led to significant plasma nitrite increment in EP group. The vWF in LP group was higher than other groups (p < 0.05). By the end of phase II, despite of start of L-arginine supplementation for LP group and L-arginine discontinuation in EP group, there were significantly more fatty streaks lesions in LP group coronary arteries than EP group. Furthermore, L-arginine supplementation did not result in significant nitrite increment in LP group.</p> <p>Conclusion</p> <p>Early prevention by L-arginine may be helpful to prevent the ED, but our study did not suggest the treatment. It seems reasonable to consider ED-aside from control the cardiovascular risk factors in primary prevention of atherosclerosis and its clinical outcomes before development of irreversible vascular damage.</p

Crosstalk between Peroxisome Proliferator-Activated Receptors andToll-Like Receptors: A Systematic Review

As one of the four major families of pattern recognition receptors (PRRs), toll like receptors (TLRs)are crucial and important components of the innate immune system. Peroxisome proliferatoractivatedreceptors (PPARs) with three isoforms are transcription factors classified as a subfamilyof nuclear receptor proteins, and are of significant regulatory activity in cellular differentiation,development, metabolism, and tumorigenesis. It is well established that PPARs agonists displayanti-inflammatory effects through inhibition of the nuclear factor-kappa B (NF-κB) pathway, akey regulator of immune and inflammatory responses, in a sense that TLRs signaling pathwaysare mainly toward activation of NF-κB. Through a systematic review of previous studies, weaimed to address and clarify the reciprocal interaction between TLRs and PPARs in hope to findalternative therapeutic approaches for inflammatory diseases. Among the available scientificdatabase, 31 articles were selected for this review. A comprehensive review of this databaseconfirms the presence of a cross-talk between PPARs and TLRs, indicating that not onlyPPARs stimulation may affect the expression level of TLRs via several mechanisms leading tomodulating TLRs activities, but also TLRs have the potential to moderate the expression of PPARs.We, therefore, conclude that, as a key regulator of the innate immune system, the interactionbetween PPARs and TLRs is a potential therapeutic target in disease treatment

The role of microRNA-30a and downstream snail1 on the growth and metastasis of melanoma tumor

Objective(s): Growing evidences have indicated microRNAs as modulators of tumor development and aggression. On the other hand, a phenomenon known as epithelial-mesenchymal transition (EMT) that indicates a transient phase from epithelial-like features to mesenchymal phenotype is a key player in tumor progression.  In this study, we aimed to assess the potential impacts of miR-30a-5p as an inhibitor of melanoma progression and metastasis.Materials and Methods: MiR-30a-5p was transfected into B16-F10 melanoma cells. Then, the B16-F10 cells were injected subcutaneously or intravenously (IV) in to C57BL/6 mice. Then, the mice were euthanized and tumor size, tumor weight, snail1 protein expression and nodules in the lungs were evaluated.Results: The migration of cancerous cells was significantly suppressed in vitro following the ectopic presentation of miR-30a-5p into B16-F10 melanoma cells. Furthermore, the metastatic behavior of the neoplastic cells was further suppressed in a xenograft mouse model of melanoma as observed with limited lung infiltration. We also found that transfected miR-30a-5p into melanoma cells could decrease snail1 and N-cadherin expression. Conclusion: MiR-30a-5p may represent an effective therapeutic target for the management of melanoma and other snail-overexpressing neoplasms

LArginine supplementation influenced nitrite but not nitrate and total nitrite in rabbit model of hypercholesterolemia

ABSTRACT Background: The assessment of altered nitric oxide (NO) availability is of potentially important diagnostic and prognostic significance. The present study is aimed to investigate the effect of L-arginine (as a natural NO donor) supplementation on NO metabolite in a rabbit model of hypercholesterolemia to find a reliable marker for endothelial NO production. Methods: White male rabbits (n = 30) randomly assigned to 2 groups. Rabbits were fed 1% high-cholesterol diet (HC group, n = 15), or HC diet with oral L-arginine (3% in drinking water) (HC + L-arginine group, n = 15) for 4 weeks. The serum levels of lipids, L-arginine, total NO metabolites (NOx), nitrite and nitrate were measured before and after the study. Results: In this study, Larginine supplementation led to a significant increased plasma level of L-arginine. The serum level of nitrite was significantly higher in L-arginine treated group while serum level of nitrate and NOx was significantly lower than HC group. Conclusion: As the result of our study showed, nitrite is a useful marker of endogenous endothelial NO production and although frequently used, neither nitrate nor NOx are reliable markers of acute changes in endothelial NO synthase activity

Prediction of dyslipidemia using gene mutations, family history of diseases and anthropometric indicators in children and adolescents: The CASPIAN-III study

Dyslipidemia, the disorder of lipoprotein metabolism resulting in high lipid profile, is an important modifiable risk factor for coronary heart diseases. It is associated with more than four million worldwide deaths per year. Half of the children with dyslipidemia have hyperlipidemia during adulthood, and its prediction and screening are thus critical. We designed a new dyslipidemia diagnosis system. The sample size of 725 subjects (age 14.66¿±¿2.61 years; 48% male; dyslipidemia prevalence of 42%) was selected by multistage random cluster sampling in Iran. Single nucleotide polymorphisms (rs1801177, rs708272, rs320, rs328, rs2066718, rs2230808, rs5880, rs5128, rs2893157, rs662799, and Apolipoprotein-E2/E3/E4), and anthropometric, life-style attributes, and family history of diseases were analyzed. A framework for classifying mixed-type data in imbalanced datasets was proposed. It included internal feature mapping and selection, re-sampling, optimized group method of data handling using convex and stochastic optimizations, a new cost function for imbalanced data and an internal validation. Its performance was assessed using hold-out and 4-foldcross-validation. Four other classifiers namely as supported vector machines, decision tree, and multilayer perceptron neural network and multiple logistic regression were also used. The average sensitivity, specificity, precision and accuracy of the proposed system were 93%, 94%, 94% and 92%, respectively in cross validation. It significantly outperformed the other classifiers and also showed excellent agreement and high correlation with the gold standard. A non-invasive economical version of the algorithm was also implemented suitable for low- and middle-income countries. It is thus a promising new tool for the prediction of dyslipidemiaPeer ReviewedPostprint (published version

Effect of fresh orange juice intake on physiological characteristics in healthy volunteers.

Background. Impaired endothelial function is a predictor of cardiovascular events. Orange juice (OJ) is rich in dietary flavonoids and could inhibit oxidative stress and inflammatory responses. We examined the effects of commercial (COJ) and fresh orange juice (FOJ) on endothelial function and physiological characteristics in healthy humans. Materials and Methods. Twenty-two healthy volunteers years were enrolled in a single blind randomized crossover controlled trial. The two groups consumed either COJ for the first 4 weeks and then FOJ (CFOJ, 4 weeks), or FOJ for the first 4 weeks and then COJ (FCOJ, 4 weeks). We assessed endothelial function by measuring flow-mediated dilation, serum concentrations of lipids, apolipoproteins A and B (apo A-1 and apo B), and inflammatory markers such as vascular endothelial adhesion molecule 1 (VCAM-1), E-selectin, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6. Results. Consumption of both juices decreased VCAM, hs-CRP, and E-selectin but increased apo A-1. A decline in LDL occurred in the FOJ group. There were no differences between the characteristics of two groups, with the exception of apo A-1 levels that were increased with both forms of OJ. The largest variations occurred with hs-CRP, VCAM in both groups. Conclusion. Consumption of COJ and FOJ produced beneficial effects on the physiological characteristics of healthy volunteers. Although these results could encourage the consumption of OJ, intervention studies are needed to determine the long-term effects of these types of OJ on metabolic and cardiovascular endpoints

Large-Scale Multi-Omics Studies Provide New Insights into Blood Pressure Regulation

Recent genome-wide association studies uncovered part of blood pressure’s heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressure-associated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort (n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice

Mutations of Dual Oxidase 2 (DUOX2) Gene among patients with Permanent and Transient Congenital Hypothyroidism

Objective: The prevalence of congenital hypothyroidism (CH) is high in Isfahan, Iran. In addition, it has different etiologies compared with other countries. The rate of parental consanguinity is also high in the city. Moreover, DUOX2 gene is effective in transient CH and permanent CH due to dyshormonogenesis. Therefore, the aim of this research was to investigate the mutations of DUOX2 gene in patients with transient CH and permanent CH due to dyshormonogenesis. Methodology: In this descriptive, prospective study, patients diagnosed with transient and permanent CH due to dyshormonogenesis during CH screening program were selected. Venous blood samples were obtained to determine the 3 mutations (Q36H, R376W, and D506N) of DUOX2 gene using polymerase chain reaction (PCR) method by specific primers and complementary methods such as restriction fragment length polymorphism (RFLP) and singlestrand conformation polymorphism (SSCP). Results: In this study, 25 patients with transient CH and 33 subjects with permanent CH due to dyshormonogenesis were studied. In addition, 30 children were studied as the control group. We did not find any mutations of the 3 mentioned mutations of DUOX2 gene. Conclusion: Considering the findings of the current study, further studies with other methods are required to evaluate other gene mutations such as pendrin, sodium-iodide symporter (NIS) and thyroglobuli

Effects of vitamin D-fortified low fat yogurt on glycemic status, anthropometric indexes, inflammation, and bone turnover in diabetic postmenopausal women: a rando...

Background & aims: Low levels of serum 25-hydroxy vitamin D (25(OH)D) are common in type 2 diabetic patients and cause several complications particularly, in postmenopausal women due to their senile and physiological conditions. This study aimed to assess the effects of vitamin D-fortified low fat yogurt on glycemic status, anthropometric indexes, inflammation, and bone turnover in diabetic postmenopausal women. Methods: In a randomized, placebo-controlled, double-blind parallel-group clinical trial, 59 postmenopausal women with type 2 diabetes received fortified yogurt (FY; 2000 IU vitamin D in 100 g/day) or plain yogurt (PY) for 12 weeks. Glycemic markers, anthropometric indexes, inflammatory, and bone turnover markers were assessed at baseline and after 12 weeks. Results: After intervention, in FY group (vs PY group), were observed: significant increase in serum 25(OH)D and decrease of PTH (stable values in PY); significant improvement in serum fasting insulin, HOMA-IR, HOMA-B, QUICKI, and no changes in serum fasting glucose and HbA1c (significant worsening of all indexes in PY); significant improvement in WC, WHR, FM, and no change in weight and BMI (stable values in PY); significant increase of omentin (stable in PY) and decrease of sNTX (significant increase in PY). Final values of glycemic markers (except HbA1c), omentin, and bone turnover markers significantly improved in FY group compared to PY group. Regarding final values of serum 25(OH)D in FY group, subjects were classified in insufficient and sufficient categories. Glycemic status improved more significantly in the insufficient rather than sufficient category; whereas the other parameters had more amelioration in the sufficient category. Conclusions: Daily consumption of 2000 IU vitamin D-fortified yogurt for 12 weeks improved glycemic markers (except HbA1c), anthropometric indexes, inflammation, and bone turnover markers in postmenopausal women with type 2 diabetes