Effects and safety of resveratrol supplementation in older adults: A comprehensive systematic review.

Resveratrol (RSV) has garnered significant attention in recent years due to its potential benefits against chronic diseases. However, its effects and safety in older adults have not been comprehensively studied. This study aimed to determine the effects and safety of RSV supplementation in older adults. MEDLINE/PubMed, Scopus, and Web of Science databases were comprehensively searched for eligible studies. Studies were enrolled if they were randomized clinical trials and had incorporated RSV supplementation for older adults. Two independent authors conducted the literature search, and eligibility was determined according to the PICOS framework. Study details, intervention specifics, and relevant outcomes were collected during the data collection. The Cochrane RoB-2 tool was used to evaluate the risk of bias. This review included 10 studies. The combination of RSV and exercise improved exercise adaptation and muscle function in healthy older adults and physical performance and mobility measures in individuals with functional limitations. RSV showed potential neuroprotective effects in patients with Alzheimer's disease. In overweight individuals, RSV demonstrated a positive impact on cognitive function, but it increased some biomarkers of cardiovascular disease risk at high doses. In older adults with diabetes and those with peripheral artery disease (PAD), RSV was not more effective than placebo. No study reported significant adverse events following RSV treatment. RSV can improve various health parameters in age-related health conditions. However, the optimal dosage, long-term effects, and potential interactions with medications still need to be investigated through well-designed RCTs.

Vitamin C supplementation lowers advanced glycation end products (AGEs) and malondialdehyde (MDA) in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled clinical trial.

This study evaluated how daily vitamin C administration impacts systemic oxidative stress and inflammation and its safety in T2D patients. This randomized, double-blinded, placebo-controlled, parallel-arm clinical trial included 70 patients with T2D. They were allocated to receive either 500 mg/day of vitamin C or a matching placebo for 8 weeks. Of the 70 subjects assigned to the trial, 57 were included in the statistical analysis (vitamin C: n = 32, placebo: n = 25). Inflammatory and oxidative markers, including advanced glycation end products (AGEs), malondialdehyde (MDA), advanced oxidation protein products (AOPP), oxidized low-density lipoprotein (ox-LDL), highly sensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and ferric reducing ability of plasma (FRAP) were measured at baseline and the end of the trial. In addition, vitamin C tolerance was evaluated. A nutritionist visited all participants for a standard diabetic regimen. Following vitamin C supplementation, the serum levels of MDA (p-value < .001) and AGEs (p-value = .002) demonstrated a significant decrease after controlling for multiple confounders, including age, blood pressure, waist circumference, HbA1C, TG, and LDL-C, while no significant changes were observed for AOPP (p-value = .234) and ox-LDL (p-value = .480). The FRAP showed an increasing trend as an antioxidant marker but was not statistically significant (p-value = .312). The hs-CRP and TNF-α had no significant changes (p-value: .899 and .454, respectively). Also, no major adverse events were observed. Vitamin C supplementation may be beneficial in reducing AGEs and MDA in patients with T2D.

Eight Weeks of Vitamin C Supplementation Restores the Lost Correlation between Serum Leptin and C-reactive Protein (CRP) in Patients with Type 2 Diabetes; A Randomized, Double-blind, Parallel-group, Placebo-controlled Clinical Trial.

OBJECTIVE: Inflammation is a well-described factor in the pathophysiology of type 2 diabetes mellitus (DM), which has been a suspect in the alteration of correlations between CRP and leptin in patients with type 2 DM. AIM: This study aimed to show the effect of vitamin C as an antioxidant on the correlation of the serum levels of C-reactive protein (CRP) and leptin in patients with type 2 DM. METHODS: We recruited 70 patients with longstanding T2DM and randomly assigned them into two groups; one received 500 mg/day of vitamin C, and the other received a placebo for eight weeks. Both groups were matched regarding baseline characteristics such as age, gender, weight, and diabetic medications. RESULTS: Out of 70 individuals, 57 participants were left in the study. After eight weeks of follow-up, leptin level was significantly increased in the Vitamin C group (MD = 3.48 change = 24%, p-value = 0.001) but did not change in the placebo group. Other markers such as Fasting plasma glucose, HbA1c, Creatinine, uric acid, Urea, cholesterol, HDL, LDL, TG, AST, ALT, insulin, and CRP did not significantly change in both groups (p value > 0.05). The significant changes in the leptin level among the vitamin C group also remained after controlling for age, BMI, Blood pressure (BP), Triglyceride (TG), and cholesterol. Also, the correlation between serum CRP and leptin became significant in the vitamin C group after eight weeks of follow-up but not in the placebo group. (rs = 0.730, p < 0.001 vs. rs = 0.286, p-value = 0.266 in placebo group). CONCLUSION: This study shows vitamin C can restore CRP-leptin correlation in patients with type 2 diabetes and increase serum leptin levels. More studies are needed to clarify the mechanism of this restoration. CLINICAL TRIAL REGISTRATION NUMBER: IRCT20160811029306N1.

Therapeutic effects of resveratrol and Omega-3 in mice atherosclerosis: focus on histopathological changes.

BACKGROUND: Resveratrol and omega-3 have been shown to prevent atherosclerosis. However, histopathological changes and their comparison have not been studied well. This study investigated the therapeutic effects of resveratrol and omega-3 in experimental atherosclerosis of mice. METHODS: We divided sixty 6-week-old male C57BL/6 mice into six groups and followed for 10 weeks: (1) standard diet, (2) atherogenic diet, (3) atherogenic diet along with resveratrol from the start of the sixth week, (4) atherogenic diet along with omega-3 from the start of the sixth week, (5) standard diet along with resveratrol from the start of the sixth week, (6) standard diet along with omega-3 from the start of the sixth week. RESULTS: The mice fed on an atherogenic diet had a larger fat area and a thicker aortic wall thickness than mice fed on a standard diet. The use of omega-3 and resveratrol in the mice with an atherogenic diet resulted in a significantly reduced fat area (p-value = 0.003), and resveratrol had a significantly higher effect. Omega-3 or resveratrol induced a significant reduction in aortic wall thickness in mice on an atherogenic diet, and there was no significant difference between them. Among the mice with a standard diet, this study did not observe any significant changes in the fat area or the aortic wall thickness with the consumption of omega-3 or resveratrol. CONCLUSIONS: Resveratrol and omega-3 had a regressive and therapeutic role in atherosclerosis, with a more significant effect in favor of resveratrol.

Oxidative stress and antioxidant markers in patients with alopecia areata: A comparative cross-sectional study.

Background Alopecia areata is a chronic inflammatory skin disease. Oxidative stress may contribute to the pathogenesis of this condition. Aim To evaluate the serum oxidative stress markers and antioxidant capacity in patients with alopecia areata. Methods This cross-sectional study was performed on 40 patients with alopecia areata and 40 healthy controls. The fasting blood sugar, C-reactive protein, lipid profile, and serum oxidative markers, including advanced glycation end products and advanced oxidation protein products, were measured in this study. Also, antioxidant enzymes, including paraoxonase-1, lecithin-cholesterol acyltransferase and serum ferric-reducing antioxidant power, were determined. Results The serum levels of advanced glycation end products and advanced oxidation protein products were significantly higher in patients with alopecia areata, compared to the controls (P < 0.001), whereas the levels of ferric-reducing antioxidant power, paraoxonase-1 and lecithin-cholesterol acyltransferase were significantly lower in patients with alopecia areata, compared to the controls (P < 0.001). The mean fasting blood sugar level was significantly higher in patients with alopecia areata, compared to the controls. The ferric reducing antioxidant power level was significantly associated with the percentage of hair loss (P = 0.01, r = 0.4) and the serum C-reactive protein level (P = 0.03, r = -0.3) in patients with alopecia areata. Limitations Since the current study had a cross-sectional design, no cause-effect relationship was established between alopecia areata and oxidative stress. The sample size of our study was also small. Conclusion Based on the present results, the oxidant-antioxidant enzymatic system is impaired in alopecia areata due to the increased oxidative products and decreased antioxidant activity.

Neutrophil Gelatinase-Associated Lipocalin and Retinol-Binding Protein-4 as Biomarkers for Diabetic Kidney Disease.

AIMS: This study was designed to evaluate the conflicting association between 2 tubular protein markers including neutrophil gelatinase-associated lipocalin (NGAL) and retinol-binding protein-4 (RBP-4) with albuminuria and glomerular filtration rate (GFR) and calculate the accuracy of the role of NGAL and RBP-4 in diagnosis of diabetic nephropathy (DN) in patients with type2 diabetes. METHODS: This is a cross-sectional study that included 133 patients with type 2 diabetes. There were 3 diabetic study groups with normoalbuminuria, moderately increased albuminuria, severely increased albuminuria, and non-diabetic control group without any renal disease. We analyzed the difference of urinary NGAL (uNGAL) and RBP-4 between nondiabetics and diabetics, as well as within the diabetic group. We also assessed the association between albuminuria and NGAL and RBP-4. RESULTS: The urinary levels of NGAL and RBP-4 were higher in patients with type 2 diabetes compared to nondiabetics as well as in albuminuric diabetics compared to nonalbuminuric patients with diabetes (p value <0.001). These 2 proteins were higher in patients with severely increased albuminuria compared to patients with moderately increased albuminuria, even after adjustment for other metabolic factors (all p < 0.01). Moreover, areas under the curve of NGAL and RBP-4 for the diagnosis of chronic kidney disease were 80.6 and 74.6%, respectively. CONCLUSION: uNGAL and RBP-4 are potential markers of tubular damage that may increase before the onset of glomerular markers such as albuminuria and GFR in patients with type 2 diabetes. Therefore, these markers can be used as complementary measurements to albuminuria and GFR in the earlier diagnosis of DN.

The Preventive Effect of L-Lysine on Lysozyme Glycation in Type 2 Diabetes.

Lysozyme is a bactericidal enzyme whose structure and functions change in diabetes. Chemical chaperones are small molecules including polyamines (e.g. spermine), amino acids (e.g. L-lysine) and polyols (e.g. glycerol). They can improve protein conformation in several stressful conditions such as glycation. In this study, the authors aimed to observe the effect of L-lysine as a chemical chaperone on structure and function of glycated lysozyme. In this study, in vitro and in vivo effects of L-lysine on lysozyme glycation were investigated. Lysozyme was incubated with glucose and/or L-lysine, followed by an investigation of its structure by electrophoresis, fluorescence spectroscopy, and circular dichroism spectroscopy and also assessment of its bactericidal activity against M. lysodeikticus. In the clinical trial, patients with type 2 diabetes mellitus (T2DM) were randomly divided into two groups of 25 (test and control). All patients received metformin and glibenclamide for a three months period. The test group was supplemented with 3 g/day of L-lysine. The quantity and activity of lysozyme and other parameters were then measured. Among the test group, L-lysine was found to reduce the advanced glycation end products (AGEs) in the sera of patients with T2DM and in vitro condition. This chemical chaperone reversed the alteration in lysozyme structure and function due to glycation and resulted in increased lysozyme activity. Structure and function of glycated lysozyme are significantly improved by l-lysine; therefore it can be considered an effective therapeutic supplementation in T2DM, decreasing the risk of infection in these patients.

Protective role of calcium ion against stress-induced osmotic fragility of red blood cells in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus can increase osmotic fragility of red blood cells. Osmotic fragility test is an index of the function of cytoskeletal proteins and of the calcium pump activity in RBC membrane. The aim of this study is to determine the effect of physiological calcium supplement on red blood cell osmotic fragility of patients with type 2 diabetes mellitus. Osmotic fragility of red cells was determined for 30 healthy subjects and 30 patients in a NaCl gradient medium. 5 mg/dl of calcium was added to media and the osmotic fragility were evaluated for RBCs of patients and healthy subjects. Comparison of patients and control group showed higher sensitivity of red cells of patients to osmotic fragility upon exposure to higher sodium chloride concentrations. Comparison of initial, fifty percent and total hemolysis showed significant difference on initial and fifty percent hemolysis between two groups (P < 0.001). In healthy subjects, Fifty percent hemolysis index showed a smaller change after addition of calcium, from 4.1 ± 0.22 to 3.9 ± 0.2 (P < 0.05). Fifty percent hemolysis index for patients significantly decreased from 4.45 ± 0.17 to 4 ± 0.17 after addition of calcium (P < 0.001). Osmotic fragility increases in patients with diabetes. The role of calcium in cell membrane integrity was more prominent in the patients with diabetes than the healthy subjects, emphasizing the role of calcium on the membrane stability. We showed for the first time that controlling calcium ion concentration in patients with diabetes could exert a protective and beneficial role against membrane-affecting conditions.

Effect of crocin on the insulin resistance and lipid profile of streptozotocin-induced diabetic rats.

Crocin is the only water soluble carotenoid in nature, and it has a known powerful antioxidant activity. The aim of this work was to investigate the hypoglycemic and hypolipidemic effects of crocin in streptozotocin (STZ)-induced type 2 diabetic rats. Neonatal male Wistar rats (2-5 days old) were randomly divided into five groups. Three groups were intraperitoneally injected with STZ (90 mg/kg body weight). Among them, two groups were treated with intraperitoneal injection of crocin (50 or 100 mg/kg), and the third group was treated with vehicle only. Two control groups were also considered, and one of them was treated with crocin. After 5 months, their blood and urine samples were collected, and the animals were sacrified. The results indicate a significant lower body weight (P < 0.001) and abnormal parameters in the diabetic rats compared with the normal group. An administration of both doses of crocin significantly decreased the levels of serum glucose, advanced glycation end products, triglyceride, total cholesterol, and low-density lipoprotein and increased the high-density lipoprotein in the diabetic rats. The treatments were also effective in decreasing HbA1c and microalbuminuria, as well as homeostatic model assessment for insulin resistance as a measure of insulin resistance in the diabetic rats.

Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial.

BACKGROUND & AIMS: Given the long term benefits observed with metformin use in diabetes patients, a role in modulating oxidative stress is imputable. Effects of metformin on markers of oxidative stress, antioxidant reserve, and HDL-c associated antioxidant enzymes were investigated. METHODS: In a clinical trial setting (Registered under Clinical Trials.gov Identifier no. NCT01521624) 99 medication-naïve, newly diagnosed type 2 diabetes patients were randomly assigned to either metformin or lifestyle modification. AOPP, AGE, FRAP, activities of LCAT, and PON were measured at baseline and after 12-weeks. RESULTS: Baseline values of the oxidative stress markers did not differ significantly between the two groups. In cases, after three months treatment, there was a significant reduction in AOPP (137.52 ± 25.59, 118.45 ± 38.42, p < 0.001), and AGE (69.28 ± 4.58, 64.31 ± 8.64, p = 0.002). FRAP and PON increased significantly (1060.67 ± 226.69, 1347.80 ± 251.40, p < 0.001 and 29.85 ± 23.18, 37.86 ± 27.60, p = 0.012 respectively). LCAT levels remained unchanged (45.23 ± 4.95, 46.15 ± 6.28, p = 0.439). Comparing the two groups in a final multivariate model, AOPP, FRAP, and AGE levels changed more significantly in metformin compared with lifestyle modification alone (p = 0.007, p < 0.001 and p < 0.001 respectively). Escalation in LCAT or PON activities did not differ between the two groups (p = 0.199 and 0.843 respectively). CONCLUSIONS: Use of metformin is more effective in reducing oxidative stress compared with lifestyle modification alone.

Investigation of the mechanism(s) involved in decreasing increased fibrinogen activity in hyperglycemic conditions using L-lysine supplementation.

INTRODUCTION: Fibrinogen is a plasma glycoprotein that participates in the hemostasis system. Its malfunction has been reported as a consequence of diabetic complications. In this study, the inhibitory effect of L-Lysine (Lys) on the nonenzymatic glycation of fibrinogen was investigated in both in vitro and in vivo conditions. MATERIALS AND METHODS: Fibrinogen was incubated with glucose in the presence or absence of Lys. Then, its structure was studied by fluorescence spectroscopy, circular dichroism, and electrophoresis. The Clauss method was used to determine fibrinogen activity. In addition, one of the two groups of type 2 diabetic patients receiving ordinary treatment was additionally treated with Lys for 3 months. Fibrinogen activity and some other parameters were evaluated in their plasma. RESULTS: The results indicated increases in the activity of glycated fibrinogen in both of the in vivo and in vitro experiments. Advanced glycation end products were increased by time, as shown using fluorometry in both the plasma of the diabetic patients and the incubation medium of protein with glucose. The circular dichroism spectra showed some changes in the fibrinogen secondary and tertiary structures after glycation. The electrophoretic mobility of the glycated fibrinogen changed and the cross-link formation between the fibrinogen subunits due to glycation was observed. Lys inhibited all of the mentioned fibrinogen changes both in the in vitro experiments and after its administration to the diabetic patients. CONCLUSION: Lys, as an inhibitor of protein glycation, improved fibrinogen's structure and function, both in vitro and in vivo.

The effect of hot-tub therapy on serum Hsp70 level and its benefit on diabetic rats: a preliminary report.

PURPOSE: To carry out a preliminary study examining the efficacy of long-term hot-tub therapy (HTT) in the improvement of diabetic complications on streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Male Wistar rats were immersed mid-sternum in a circulating water bath (42 degrees C for 30 min) to obtain a core body temperature of 41 degrees C; this process was repeated three times a week for 5 months. The blood was collected every month. Multiple parameters were examined for all rats including heat shock protein (Hsp70) level, serum glucose and insulin concentrations, advanced glycation end product (AGE) and glycated haemoglobin (HbA1c) formation, lipid profile and antioxidant defence system. Additionally, the chaperoning capacity of glycated Hsp70 was evaluated based on in vitro studies in which the refolding of denatured luciferase was compared to refolding by native Hsp70. RESULTS: HTT-treated diabetic rats showed a significant improvement in lipid profile, antioxidant capacity, insulin secretion and serum Hsp70 level and a significant decrease in AGE formation compared to the untreated diabetic rats. However, HTT had a borderline significant effect on weight and fasting blood glucose. Glycated Hsp70 lost its chaperoning ability to reactivate the denatured luciferase. CONCLUSION: A decrease in complications in diabetic rats after hot-tub therapy is shown here. An increase in the extracellular Hsp70 level due to HTT was observed. This increase may serve to protect the structure of proteins (e.g. preventing AGE formation), and the observed beneficial effects may be related to it.

HbA1c negatively correlates with LCAT activity in type 2 diabetes.

AIMS: Abnormal high-density lipoproteins (HDL) metabolism is a major cardiovascular risk factor in type 2 diabetes mellitus (DM2). Lecithin:cholesterol acyltransferase (LCAT) increases HDL size by transferring 2-acyl groups from lecithin or phosphatidylethanolamine to unesterified cholesterol. The purpose of this study was to determine the independent correlates of LCAT activity in DM2 patients. METHODS: A total of 45 (male: 20) consecutive adult DM2 patients aging 50.0+/-7.0 years (range: 40-64 years) with a median diabetes duration of 4 years (range: 2-18) were studied. Exclusion criteria were: smoking, positive history of cardiovascular, thyroid, renal or liver disease, pregnancy, treatment with metformin, insulin, lipid lowering drugs, angiotensin-converting enzyme inhibitors, aspirin or antioxidant supplements. Univariate and multivariate analyses were performed. RESULTS: From a comprehensive list of variables studied, only HbA1c (rho=-0.951) and oxidized LDL (rho=-0.779) had statistically significant correlation with LCAT activity (p<0.001). These two variables were themselves strongly correlated to each other (rho=0.809, p<0.001). To eliminate potential confounding effects, we performed multivariate analysis, where HbA1c emerged as a strong independent predictor of LCAT activity (adjusted OR=-0.928, p<0.001). CONCLUSIONS: Glycemia-induced glycation of HDL decreases LCAT activity. The fact that HbA1c is an accurate measure of glycation and can therefore reflect glycated HDL levels explains the association found in the present study. In conclusion, HbA1c provides an easy-to-assess, accurate measure of LCAT activity in DM2.

Investigation of the mechanisms involved in the high-dose and long-term acetyl salicylic acid therapy of type I diabetic rats.

Diabetes mellitus has been classified as a conformational disease because of changes induced in the structure and function of proteins due to hyperglycemia. In this study, we investigated the effect of high-dose and long-term use of acetyl salicylic acid (ASA) on the streptozotocin-induced diabetic rats as a model of type I diabetes, with consideration on the structure and/or function of proteins. The N-[methylnitrosocarbamoyl]-d-glucosamine (streptozotocin)-induced diabetic rats together with the normal rats were studied for 5 months with and without receiving 100 mg/kg ASA in drinking water. All rats were investigated from different aspects such as heat shock protein (HSP) 70 level, serum glucose and insulin concentration, advanced glycated end product (AGE) and glycated hemoglobin (HbA1c) formation, lipid profile, high-density lipoprotein (HDL) functionality (paraoxonase1 and lecithin cholesterol acyltransferase activities), and the antioxidant system. In addition, the in vitro effect of ASA on the structure of albumin as a model protein was studied in the presence of glucose by spectroscopic techniques such as fluorometry and circular dichroism. The results show that ASA therapy causes a decrease in the glucose level and AGE and HbA1c formation, improves the lipid profile, HDL functionality, and the antioxidant capacity, induces serum HSP70, and overall decreases mortality of diabetic rats in comparison with the group without treatment. The conformation of glycated bovine serum albumin is different from the native form, and ASA retains the conformation of this protein similar to the native. The improving effect of ASA on diabetic rats is mostly due to its role as a chemopreventive agent in the structural conservation and protection of proteins involved in diabetes pathogenesis.