The Potential Relationship Between Serum Irisin Concentration With Inflammatory Cytokines, Oxidative Stress Biomarkers, Glycemic Indices and Lipid Profiles in Obese Patients With Type 2 Diabetes Mellitus: A Pilot Study.

Objectives: Diabetes mellitus is a serious health-treated problem identified by disorders such as insulin resistance, dyslipidemia, and inflammation. Irisin, a newly discovered myokine/adipokine, is involved in metabolic homeostasis. The present study was carried out to investigate the potential relationship between serum irisin with inflammatory cytokines, oxidative stress biomarkers, glycemic indices, and lipid profiles in obese patients with type 2 diabetes mellitus. Methodology: This analytical cross-sectional study was conducted on 62 participants (n=32 obese participants with diabetes, n=30 participants with normal weight). The participants answered a demographic questionnaire. Serum irisin, glycemic indices, lipid profiles, inflammatory cytokines and oxidative stress biomarkers were measured using standard methods. The difference between groups was assessed by independent-sample t-test or by a non-parametric equivalent. For qualitative variables, the Chi-Square test was used. Pearson rho coefficient was used to determine the potential relationship between irisin and inflammatory cytokines, oxidative stress biomarkers, glycemic indices, and lipid profiles. A p<0.05 was defined as significant. Results: The median (IQR) age of the obese participants with diabetes was 54.0 years (52.2-60.7) and in the normal weight group was 38.0 years (30.0-47.2) (p<0.001). About 78% and 60% of participants in the obese with diabetes and the normal weight groups were females (p>0.05), respectively. Significant differences were observed in serum irisin levels between the two groups, with lower levels (218.74 ng/mL, [144.98-269.26]) noted in the obese with diabetes group compared to the normal weight group (266.68 ng/mL, [200.64-336.57]) with a p=0.024. There was a substantial difference between the two groups regarding IL-6, TNF-α, and hs-CRP (p<0.05). IL-6 had a moderate negative correlation with irisin in obese patients with T2DM (r=-0.478, p=0.006). Conclusion: Irisin concentration was detected to be lower in obese people with diabetes. A negative relationship was detected between irisin and IL-6. Considering emerging evidence about the beneficial functions of irisin in improving metabolic abnormalities, designing future studies with greater sample sizes that will validate these results is needed.

The effects of vitamins and dietary pattern on epigenetic modification of non-communicable diseases.

Background: Non-communicable diseases (NCDs) have received more attention because of high prevalence and mortality rate. Besides genetic and environmental factors, the epigenetic abnormality is also involved in the pathogenesis of NCDs. Methylation of DNA, chromatin remodeling, modification of histone, and long non-coding RNAs are the main components of epigenetic phenomena. Methodology: In this review paper, the mechanistic role of vitamins and dietary patterns on epigenetic modification was discussed. All papers indexed in scientific databases, including PubMed, Scopus, Embase, Google Scholar, and Elsevier were searched during 2000 - 2021 using, vitamins, diet, epigenetic repression, histones, methylation, acetylation, and NCDs as keywords. Results: The components of healthy dietary patterns like Mediterranean and dietary approaches to stop hypertension diets have a beneficial effect on epigenetic hemostasis. Both quality and quantity of dietary components influence epigenetic phenomena. A diet with calorie deficiency in protein content and methyl-donor agents in a long time, with a high level of fat, disrupts epigenetic hemostasis and finally, causes genome instability. Also, soluble and insoluble vitamins have an obvious role in epigenetic modifications. Most vitamins interact directly with methylation, acetylation, and phosphorylation pathways of histone and DNA. However, numerous indirect functions related to the cell cycle stability and genome integrity have been recognized. Conclusion: Considering the crucial role of a healthy diet in epigenetic homeostasis, adherence to a healthy dietary pattern containing enough levels of vitamin and avoiding the western diet seems to be necessary. Having a healthy diet and consuming the recommended dietary level of vitamins can also contribute to epigenetic stability.

Exploration of meteorin-like peptide (metrnl) predictors in type 2 diabetic patients: the potential role of irisin, and other biochemical parameters.

OBJECTIVES: Meteorin-like peptide (Metrnl), the newly discovered adipokines involves in glucose and lipid metabolism and energy homeostasis. The aim of the present study was to explore the potential predictors of Metrnl by emphasizing the Irisin, glycemic indices, and lipid profile biomarkers in type 2 diabetic patients. METHODS: This cross-sectional study was carried out on 32 obese types 2 diabetic patients, 31 healthy obese, and 30 healthy normal weight people between August 2020 and March 2021. Serum Metrnl and Irisin, fasting blood glucose (FBS), fasting insulin (FI), fasting insulin (FI), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), HbA1c and eAG levels were measured in a standard manner. To assay insulin resistance and insulin sensitivity, the homeostatic model assessment insulin resistance (HOMA-IR) and quantitative check index (QUICKI) model were used. Quantile regression analysis with the backward elimination method was used to explore predictors. The significant level was defined as p<0.05. RESULTS: Between variables entered into the model, only the group item showed to be the main predictor of Metrnl in type 2 diabetic patients. Besides, the serum level of Irisin was lower in diabetic patients, and a significant difference was detected between obese diabetic patients and the normal weight group (p=0.024). CONCLUSIONS: Given the multi-causality of diabetes and also the possible therapeutic role of Metrnl in the management of type 2 diabetic patients' abnormalities, designing future studies are needed to discover other predictors of Metrnl and the related mechanisms of Metrnl in the management of diabetes.

Regulation of NLRP3 inflammasome by zinc supplementation in Behçet's disease patients: A double-blind, randomized placebo-controlled clinical trial.

BACKGROUND: Overproduction of NLRP3 inflammasome complex is one of the causes of Behcet's disease's (BD) auto-inflammatory nature. The aim of current study was to examine the effect of zinc supplementation on NLRP3 inflammasome expression; as well as clinical manifestations of BD. METHODS: In this double-blind parallel placebo-controlled randomized clinical trial, 50 BD patients were randomly allocated into either zinc gluconate (30 mg/day elemental zinc) or placebo groups for 12 weeks. The mRNA expression of NLRP3 and caspase-1 in the leukocytes, serum level of zinc and IL-1ß, anthropometric measures, and clinical manifestations of patients were collected at pre- and post-intervention phase. The Iranian Behçet's disease dynamic activity measure (IBDDAM) was scored to measure the treatment effect using the calculation of number needed to treat (NNT). Analysis of covariance was performed to obtain the corresponding effect sizes. RESULTS: Zinc gluconate led to a significant improvement in genital ulcer (P = 0.019). Zinc supplementation decreased NLRP3 and caspase-1 genes expression compared with placebo group (baseline-adjusted P-value = 0.046 for NLRP3 and P-value = 0.003 for caspase-1), even after adjustment for the effect of confounding factors (baseline- and confounders-adjusted P-value = 0.032 for NLRP3 and P-value = 0.004 for caspase-1). Baseline and confounders adjusted effect size demonstrated that zinc was effective in reducing the serum level of IL-1ß (P = 0.046). The NNT [95 %CI] for the rate of IBDDAM improvement was 3 [1.7-8.5]. CONCLUSIONS: Zinc gluconate supplementation (30 mg/day) for a 3-month period can be considered as an adjuvant therapy in alleviating inflammation and genital ulcer among BD patients.

Immunomodulatory and clinical responses to zinc gluconate supplementation in patients with Behçet's disease: A double-blind, randomized placebo-controlled clinical trial.

BACKGROUND & AIMS: Toll-like receptor (TLR) 2 and 4 are involved in the pathogenesis of Behçet's disease (BD). The current study aimed to investigate the effect of zinc supplementation on TLR-2/4 expression and the clinical manifestations of BD. METHODS: In this double-blind placebo-controlled randomized clinical trial, 50 BD patients were randomly allocated into either zinc gluconate (30 mg/day) or placebo groups for 12 weeks. Before and after the intervention, the surface and mRNA expression level of TLR-2 and TLR-4 in the leukocytes, serum level of zinc and tumor necrosis factor-α (TNF-α), quality of life, anthropometric measures, and blood pressure of patients were collected. BD activity was studied using the nonocular Iranian Behçet's disease dynamic activity measure (IBDDAM), Behçet's disease current activity form (BDCAF), and total inflammatory activity index (TIAI) at the pre-and post-intervention phases. The effect sizes were compared between two groups using analysis of covariance. RESULTS: There were significant decrease in TLR-2 mRNA (P = 0.038) and protein expression (P = 0.034) and nonocular IBDDAM score (P = 0.046) in the zinc group compared to placebo at the endpoint. The serum level of zinc was increased in the zinc group (P < 0.001). Zinc supplementation significantly decreased the TLR-4 surface (P = 0.012) and mRNA expression (P = 0.028) within the group. However, this decrease was not significant compared to the placebo group. There was no significant difference between the two groups regarding the serum level of TNF-α, BDCAF, TIAI, quality of life, anthropometric measures, and blood pressure (P > 0.05). CONCLUSIONS: The present study revealed that zinc supplementation significantly improved nonocular IBDDAM score and TLR-2 expression in BD patients. GOV REGISTRATION NUMBER: NCT05098678.

PPAR-gamma agonists: Potential modulators of autophagy in obesity.

Autophagy pathways are involved in the pathogenesis of some obesity related health problems. As obesity is a nutrient sufficiency condition, autophagy process can be altered in obesity through AMP activated protein kinase (AMPK) inhibition. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) as the main modulator of adipogenesis process can be effective in the regulation of obesity related phenotypes. As well, it has been revealed that PPAR-gamma and its agonists can regulate autophagy in different normal or cancer cells. However, their effects on autophagy modulation in obesity have been investigated in the limited number of studies. In the current comprehensive mechanistic review, we aimed to investigate the possible mechanisms of action of PPAR-gamma on the process of autophagy in obesity through narrating the effects of PPAR-gamma on autophagy in the non-obesity conditions. Moreover, mode of action of PPAR-gamma agonists on autophagy related implications comprehensively reviewed in the various studies. Understanding the different effects of PPAR-gamma agonists on autophagy in obesity can help to develop a new approach to management of obesity.

The Effect of ω3 Fatty Acids Supplementation on Levels of PPARγ and UCP2 Genes Expression, Serum Level of UCP2 Protein, Metabolic Status, and Appetite in Elite male Athletes: Protocol for a Randomized Control Trial.

Some genetic factors may influence body composition, such as PPARγ and UCP2. PPARγ plays an important role in body fat distribution. The objective of the present study is to determine the effects of omega3 fatty acids on the gene expression of PPARγ and UCP2, levels of blood lipid profile, fat mass, and fat-free mass, and appetite. Elite male athlete volunteers of up to 36 subjects were invited to participate in this RCT. Following a public announcement, volunteers were recruited from gyms, teams, and sports medicine boards in Tabriz, Iran. Gene's expression of PPARγ and UCP2, serum levels of blood lipid profile, fat mass, and fat-free mass was collected. Data collection time points include baseline in addition to 3 weeks follow up. The study was approved by the Ethics Committee of the Tabriz University Medical of Sciences (IR.TBZMED.REC.1398.782) in October 2019 and was registered with the Iranian Registry of Clinical Trials: 20190625044008N1 on December 19, 2019. Recruitment began in July and concluded in December 2019. As of August 19, 2019, we have screened 373 volunteers. 36 were enrolled. Baseline measurements of participants were collected. After three-week of intervention, end study measurements of participants were collected. The results are expected to be released in 2021. Participants have a median age of 21.86 (±3.15). The finding of this study showed Results showed PPARγ mRNA levels, and UCP2 mRNA and protein levels increased in the omega3 group (p < 0.05), as did REE (p < 0.05). Also, differences in the sensation of hunger or satiety were significant (p < 0.05). This study could result in the effects of omega-3 fatty acids on PPARγ, and UCP2 expressions, blood lipid profiles and body composition. In addition, the results of this trial can be used as baseline information for conducting further clinical and sport nutrition studies. TRIAL REGISTRATION: The trial was registered at the Iranian registry of the clinical trial website (www.irct.ir) as IRCT20190625044008N1 (https://en.irct.ir/trial/43332), registered at (19/12/2019). HIGHLIGHTS: Omega3 fatty acids as a ligand of metabolic-related genes, have a role in energy expenditure.Omega3 supplements effect on PPARγ and UCP2 mRNA expression as regulators of energy metabolismOmega3 supplements increased REE.Omega-3 supplementation could change the changes in body composition.For athletes, omega-3 simultaneously decreased fat mass and increased fat-mass.HDL-C increased after short-term supplementation with omega-3.Increased intake of omega-3, caused increased intake of energy and protein.

The effect of omega3 fatty acid supplementation on PPARγ and UCP2 expressions, resting energy expenditure, and appetite in athletes.

BACKGROUND: Omega3 fatty acids as a ligand of energy-related genes, have a role in metabolism, and energy expenditure. These effects are due to changes in the expression of peroxisome proliferator-activated receptor-gamma (PPARγ) and uncoupling protein2 (UCP2). This study evaluated the effect of omega3 supplements on PPARγ mRNA expression and UCP2 mRNA expression and protein levels, as regulators of energy metabolism, resting energy expenditure (REE), and appetite in athletes. METHODS: In a 3-week double-blind RCT in Tabriz, Iran, in 2019, 36 male athletes, age 21.86 (±3.15) y with 16.17 (±5.96)% body fat were randomized to either an intervention (2000 mg/day omega3; EPA: 360, DHA: 240) or placebo (2000 mg/day edible paraffin) groups. Appetite and REE were assessed before and after the intervention. PPARγ and UCP2 mRNA expression and UCP2 protein levels in blood were evaluated by standard methods. RESULTS: Results showed PPARγ mRNA levels, and UCP2 mRNA and protein levels increased in omega3 group (p < 0.05), as did REE (p < 0.05). Also, differences in the sensation of hunger or satiety were significant (p < 0.05). CONCLUSIONS: Our findings showed that omega3 supplementation leads to the up-regulation of PPARγ and UCP2 expressions as the indicators of metabolism in healthy athletes.

Probiotics Supplementation on Cardiac Remodeling Following Myocardial Infarction: a Single-Center Double-Blind Clinical Study.

Adverse cardiac remodeling after myocardial infarction (MI) can lead to the syndrome of heart failure (HF). Recently, changes in gut microbiota composition (dysbiosis) have appeared as a novel candidate that may be linked to the development of CR and HF. The aim of this trial was to evaluate the effects of probiotics administration on attenuating CR in patients with MI. A single-center double-blind placebo-controlled stratified randomized clinical study was conducted in 44 subjects with MI who underwent percutaneous coronary intervention (PCI). Patients were randomly assigned to take, with lunch, either a probiotic capsule containing 1.6 × 109 colony-forming unit (CFU) of bacteria (treatment group) or capsules contained inulin (control group) over 3 months. CR biomarkers (including serum procollagen III, transforming growth factor beta (TGF-ß), trimethylamine N-oxide (TMAO), and matrix metallopeptidase 9 (MMP-9)) were assessed. Echocardiography results were measured at baseline and after the intervention. Significant decreases were seen in serum TGF-ß concentrations (- 8.0 ± 2.1 vs. - 4.01 ± 1.8 pg/mL, p = 0.001) and TMAO levels (- 17.43 ± 10.20 vs. - 4.54 ± 8.7 mmol/L, p = 0.043), and there were no differences were seen in MMP-9 (- 4.1 ± 0.12 vs. - 4.01 + 0.15 nmol/mL, p = 0.443) and procollagen III levels (- 1.35 ± 0.70 vs. 0.01 + 0.3 mg/L, p = 0.392) subsequent to probiotics supplementation compared with the placebo group. Improvements in echocardiographic indices were also greater in the probiotics group as compared with that in the control group, but not at a significant level. Regression analysis revealed that baseline left ventricular ejection fraction (LVEF), and changes of procollagen III, predicted 62% of the final LVEF levels. Probiotics administration may have a beneficial effect on the cardiac remodeling process in patients with myocardial infarction. Iranian Registry of Clinical Trials (IRCT): IRCT20121028011288N15.

A comprehensive mechanistic review insight into the effects of micronutrients on toll-like receptors functions.

Toll-like receptors (TLRs) are the special proteins receptors for recognition of molecules related to the pathogens. In this way, TLRs and secreted cytokines as a result of TLRs activation are involved in the inflammation pathways. So far, in vivo and in vitro studies have demonstrated that micronutrients (vitamins & minerals) with a broad range of effects on body health, can regulate TLRs signaling pathways. Current review aimed at determining the possible mechanisms of micronutrient effects on TLRs functions. In the aspect of gene expression, micronutrients have inconsistent effects on mRNA level of TLRs which are dependent on time, dose and type of studied TLR. Also, some micronutrients affect gene expression of TLRs signaling mediators namely TLRs adaptors like Myeloid differentiation primary response 88 (MyD88). In the aspect of TLRs signaling pathways, nuclear factor-κB (NF-κB) is an important mediator which is regulated by micronutrients. Also, the regulatory effects of micronutrients on phosphorylation reactions may be effective in the activation/inactivation of TLRs signaling mediators. In addition, zinc can regulate TLRs signaling indirectly via the zinc finger proteins which have contradictory effects on TLRs cascade. In conclusion, the relationship between micronutrients and TLRs signaling is complicated and depends on some known internal, external and genetic factors like form of studied micronutrient, cell type, TLR agonist, dose and time of exposure, inflammation, apoptosis, cell cycle, and environmental factors. Some unknown factors may be effective in TLRs response and as a result additional mechanistic studies are needed to elucidate exact effect of micronutrients on TLRs signaling.

Investigation the effect of oleoylethanolamide supplementation on the abundance of Akkermansia muciniphila bacterium and the dietary intakes in people with obesity: A randomized clinical trial.

Akkermansia muciniphila bacterium is one of the inhabitant gut microbiota involving in the energy homeostasis and inhibition of the inflammations. The present study was designed to evaluate the effects of Oleoylethanolamide (OEA) supplementation on the abundance of A. muciniphila and the dietary intakes in obese people. In this randomized, double-blind, controlled clinical trial, 60 eligible obese people were selected and divided randomly into two groups including OEA group (received two capsules containing 125 mg of OEA daily) and placebo group (received two capsules containing 125 mg of starch daily). The treatment lasted for 8 weeks. Dietary intakes were evaluated according to the three -day food record and, were analyzed by the Nutritionist 4 software. In order to evaluate the changes in the abundance of A. muciniphila bacterium, faeces samples were collected at baseline and at the end of study. The targeting of the 16S rRNA gene in A. muciniphila was measured by the quantitative real-time PCR analysis. For OEA group, the energy and carbohydrate intakes decreased significantly after adjusting for baseline values and confounder factors; (p = 0.035), the amount of carbohydrate was reported as 422.25 (SD = 103.11) gr and 368.44 (SD = 99.08) gr; (p = 0.042)), before and after the treatment, respectively. The abundance of A. muciniphila bacterium increased significantly in OEA group compared to placebo group (p < 0.001). Considering the accumulating evidence identified OEA as a novel, safe, and efficacious pharmaceutical agent increasing the abundance of A. muciniphila bacterium and modifying the energy balance, therefore it is suggested to use its supplement for treatment of the obese people. However, future studies are needed to confirm the positive results obtained in this study.

Effect of pomegranate seed oil supplementation on the GLUT-4 gene expression and glycemic control in obese people with type 2 diabetes: A randomized controlled clinical trial.

Abnormality in glucose transporter type 4 (GLUT-4) function and insulin secretion are the main causes of type 2 diabetes mellitus (T2DM). Due to adverse effects of antidiabetic drugs, nowadays, nutraceuticals have been of much interest to investigators. The aim of the present study was to determine the effect of pomegranate seed oil (PSO) on the GLUT-4 gene expression and glycemic control in obese people with T2DM. This randomized clinical trial was conducted on 52 obese type 2 diabetic patients for 8 weeks in Tabriz, Iran, in 2018. Patients were divided into the intervention group (n = 26; who consumed daily three capsules containing 1 g PSO) and the placebo group (n = 26; the same amounts paraffin). GLUT-4 gene expression and glycemic indices were evaluated by standard methods. GLUT-4 gene expression was increased significantly in the PSO group. Within-group changes in fasting blood sugar (FBS) and quantitative insulin sensitivity check index were significant in the PSO group. After adjusting the age, gender, and baseline values, FBS was significantly decreased. Insulin concentration, HbA1C, HOMA-IR, and HOMA-ß did not manifest significant changes. PSO increased the GLUT-4 gene expression in diabetic patients without any side effects. However, future clinical studies are needed to confirm the obtained results.

Punicic acid: A potential compound of pomegranate seed oil in Type 2 diabetes mellitus management.

Diabetes is one of the most prevalent diseases in the worldwide. Type 2 diabetes mellitus (T2DM), the most common form of the disease, has become a serious threat to public health and is a growing burden on global economies. Due to the unexpected adverse effects of antidiabetic medicines, the use of nutraceuticals as a complementary therapy has drawn extensive attention by investigators. In this issue, a novel nutraceutical, Punicic acid (PA)-the main ingredient of pomegranate seed oil (PSO) that has potential therapeutic effects in T2DM-has been investigated. PA is a peroxisome proliferator-activated receptor gamma agonist, and unlike synthetic ligands, such as thiazolidinediones, it has no side effects. PA exerts antidiabetic effects via various mechanisms, such as reducing inflammatory cytokines, modulating glucose homeostasis, and antioxidant properties. In this review, we discussed the potential therapeutic effects of PSO and PA and represented the related mechanisms involved in the management of T2DM.

Oleoylethanolamide Supplementation Reduces Inflammation and Oxidative Stress in Obese People: A Clinical Trial.

Purpose: Obesity as a serious public health problem worldwide, results in the incidence of many chronic diseases. Obesity has been recognized as a chronic low-grade inflammation disorder. Altered endocannabinoid system tone is also involved in the pathogenesis of obesity. The present study aimed to investigate the effects of oleoylethanolamide supplementation on inflammatory biomarkers and oxidative stress in obese people. Methods: This randomized, double-blind, placebo-controlled clinical trial was carried out on 60 healthy obese people in 2016 in Tabriz, Iran. Eligible subjects were randomly divided into intervention (received daily, two 125 mg OEA capsules) and control groups (the same amounts of starch) and treated for 8 weeks. Blood samples (5 ml) were taken in fasting state at the baseline and at the end of the study. The concentrations of MDA and TAS were measured using a spectrophotometer. A high sensitive-C reactive protein level was measured by Immunoturbidimetry assay using the commercial kit. IL-6 and TNF-α levels were assayed by the ELISA method. The differences between groups were assessed by ANCOVA and statistical significance was determined at p<0.05. Results: Analysis was done on 56 participants who continued intervention until the end of the study. A significant decrease in the IL-6 and TNF-α serum concentrations was observed in the intervention group (p<0.001). Changes in other variables were undetectable (p>0.05). Conclusion: The use of OEA as a complementary pharmacotherapy agent could be effective in improving inflammation and oxidative stress in obese people. Future studies are needed to confirm the obtained results.

The Association Between Urinary Cadmium Levels and Dietary Habits with Risk of Gastrointestinal Cancer in Tabriz, Northwest of Iran.

Cadmium (Cd) is a widespread toxic heavy metal and has long biological half-life. It has potential carcinogenic effects on multiple organ systems of human. However, no studies have evaluated the adverse effects of cadmium on incidence of cancer in gastrointestinal tract. The aim of this study was to investigate the association between urine cadmium (U-Cd) levels and risk of gastrointestinal cancer. This descriptive study was accomplished on 111 GI cancer patients as cases and 111 healthy people as control subjects from January to October in Tabriz, northwest Iran, during 2013. Cadmium in urine samples was measured by graphite furnace atomic absorption spectrophotometer (GFAAS). GI cancer patients had higher urine cadmium levels in comparison to healthy individuals (p < 0.05). The multivariate regression model manifested a significant association between the U-Cd concentrations and the risk of GI cancer (odds ratio (OR) = 1.70, 95 % CI = 1.35-2.20). Cases were 70 % more than controls at risk of cancer incidence. Our data indicates an association between U-Cd levels and GI cancer risk.