Effect of carbohydrate restriction on body weight in overweight and obese adults: a systematic review and dose-response meta-analysis of 110 randomized controlled trials.

Introduction: Carbohydrate-restricted diets are one of the most effective dietary interventions for weight loss. However, the optimum carbohydrate intake for implementing the most effective weight-loss interventions is still being discussed. We aimed to determine the optimum carbohydrate intake for short- and long-term weight loss in adults with overweight and obesity. Methods: We searched PubMed, Scopus, Web of Science, and CENTRAL from inception to May 2021 for randomized controlled trials examining the effect of a carbohydrate-restricted diet (≤45% of energy intake) as compared to a control diet (carbohydrate intake >45% of energy intake) on body weight in adults with overweight/obesity. A random-effects dose-response meta-analysis was conducted to calculate the mean difference for each 10% decrease in carbohydrate intake at the 6-month follow-up (1 to 6 months), 12-month follow-up (6 to 12 months), and follow-up longer than 12 months. The shape of the dose-dependent effects was also evaluated. The certainty of the evidence was rated using the GRADE approach. The minimal clinically important difference (MCID) threshold was defined as 5% weight loss (equal to 4.39 kg). Results: A total of 110 trials were selected for the present meta-analysis. In the linear dose-response meta-analysis, each 10% decrease in carbohydrate intake reduced body weight by 0.64 kg (95% CI: -0.79 to -0.49; n = 101 trials with 4,135 participants, high-certainty evidence) at the 6-month follow-up and by 1.15 kg (95% CI: -1.61 to -0.69; 42 trials with 2,657 participants, moderate-certainty evidence) at the 12-month follow-up. Non-linear dose-response meta-analyses indicated a monotonic reduction in body weight with the decrease in carbohydrate intake, with the greatest reduction at 5% at the 6-month follow-up (mean difference 5%: -3.96 kg, 95% CI: -4.92 to -3.00) and 10% at the 12-month follow-up (mean difference 10%: -6.26 kg, 95% CI: -10.42 to -2.10). At follow-up longer than 12 months, dose-response analyses suggested a non-linear effect, wherein carbohydrate intakes higher than 40% and lower than 30% were not effective for weight loss. Discussion: Carbohydrate restriction is an effective dietary strategy for important weight loss in adults with overweight and obesity. At 6-month and 12-month follow-ups, body weight decreased proportionally, more than the MCID threshold, along with the decrease in carbohydrate intake. At follow-up longer than 12 months, there was a non-linear effect, with the greatest reduction at 30% carbohydrate intake. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022315042.

Effects of probiotic/synbiotic supplementation on body weight in patients with diabetes: a systematic review and meta-analyses of randomized-controlled trials.

OBJECTIVE: The aim of the present study was to assess the effect of probiotic/synbiotic supplementation on anthropometric measures in adults with diabetes, independent of body weight. METHODS: PubMed, Scopus, Web of Sciences and the Cochrane Library were searched for randomized controlled trials (RCTs) up until December 14, 2022. The effect sizes were pooled using an inverse-variance random-effects model. The methodological quality of studies as well as the quality of evidence was assessed using standard tools. RESULTS: Thirty-two RCTs met the established inclusion criteria. Overall, compared with the respective control groups, probiotic/synbiotic supplementation resulted in a significant reduction in body weight (weighted mean difference [WMD]: -0.50 kg; 95% CI: -0.83, -0.17; I2 = 79.8%, n = 27 studies]), body mass index (WMD: -0.24 kg/m2; 95% CI: -0.39, -0.09; I2 = 85.7%, n = 30 studies), and waist circumference (WMD: -0.90 cm; 95% CI: -1.13, -0.52; I2 = 0%, n = 11 studies). However, hip circumference and waist to hip ratio were not significantly improved. CONCLUSIONS: Our analysis revealed that probiotic/synbiotic supplementation may assist with weight management in patients with diabetes, especially when consumed at higher doses, in younger adults, and in participants with obesity. However, more studies are needed to elucidate the anti-obesity effects of specific strains of probiotics/synbiotics.

Resveratrol may mildly improve renal function in the general adult population: A systematic review and meta-analysis of randomized controlled clinical trials.

Whether renal health biomarkers can benefit from resveratrol supplements is unknown. Thus, we conducted a systematic review and meta-analysis to summarize evidence from randomized controlled trials investigating the effect of resveratrol supplementation on renal health biomarkers. We hypothesized that resveratrol supplementation is associated with improved renal health biomarkers. Four electronic databases, including PubMed, Scopus, and Institute for Scientific Information Web of Science, and Cochrane Central, were searched for relevant articles up to February 2023. The pooled effect sizes were estimated using a random effects model and expressed as weighted mean difference (WMD) and 95% CI. In total, 32 articles were eligible for inclusion in the current meta-analysis. The pooled results indicated that resveratrol significantly decreased blood urea nitrogen (weighted mean difference [WMD]= -0.84 mg/dL; 95% CI, -1.48 to -0.20; P = .01; I2 = 64.4%) and creatinine levels (WMD = -1.90 µmol/L; 95% CI, -3.59 to -0.21; P = .03; I2= 52.1%), and increased glomerular filtration rate (WMD = 7.58 mL/min/1.73 m2; 95% CI, 5.25-9.91; P < .001; I2 = 0%). The favorable change of blood urea nitrogen was significant in studies with short follow-up duration (12 weeks or less), with lower doses of resveratrol (less than 500 mg/d), and those conducted in patients with diabetes. However, higher doses of resveratrol are needed to observe significant reductions in creatinine. No significant change was observed in albumin, total protein, and uric acid concentrations. This meta-analysis provides a low certainty of evidence indicating a mild renal protective effect of resveratrol in adults. Further high-quality evidence in patients with impaired renal function and estimates of mortality risk in these patients is required before resveratrol can be advocated as an adjuvant therapy.

The effect of resveratrol supplementation on biomarkers of liver health: A systematic review and meta-analysis of randomized controlled trials.

This study aimed to evaluate the effect of resveratrol on liver biomarkers in adult participants, using systematic review and meta-analysis of randomized controlled trials. PubMed, Scopus, Web of Science and Cochran Library was searched, up to October 2021. The pooled effects were calculated using a random-effects model and expressed as weighted mean difference and 95% confidence interval. The methodological quality of studies as well as certainty of evidence were assessed by standard tools. Thirty-seven relevant trials were found. Although overall analysis found no significant change, subgroup analysis showed a significant improvement in alanine aminotransferase (ALT; -7.79 U/L) and glutamyl transferase (-6.0 U/L) in patients with liver disorders, and ALT (-2.22 U/L) in younger adults; however, high-dose supplementation (>1,000 mg/day) appeared to increase alkaline phosphatase concentration (+5.07 U/L). ALT also increased in older adults (+2.33 U/L) following resveratrol supplementation. We found resveratrol did not have a significant effect on liver health in the general population. However, resveratrol could be effective in patients with liver disorders. Our findings also suggest that high-dose resveratrol administration and supplementation in older adults should be performed with caution. Further high-quality clinical trials are also needed to firmly establish the clinical efficacy of resveratrol.

Upregulation of RIPK1 implicates in HEK 293T cell death upon transient transfection of A53T-α-synuclein.

BACKGROUND: Alpha-synuclein (α-SN) is the central protein in synucleinopathies including Parkinson's disease. Nevertheless, the molecular mechanisms through which α-SN leads to neuronal death remain unclear. METHODS: To elucidate the relationship between α-SN and apoptosis, some indicators of the intrinsic and extrinsic apoptotic cell death were assessed in normal and a stable HEK293T cell line expressing firefly luciferase after transfection with the wild-type (WT) and A53T mutant α-SN. RESULTS: Opposite to WT-α-SN, overexpression of A53T-α-SN resulted in enhanced expression of almost two fold for RIPK1 (93.0 %), FADD (45 %), Caspase-8, and Casp-9 activity (52.0 %) in measured time. Transfection of both WT-α-SN and A53T-α-SN showed an increase in the Casp-3/Procasp-3 ratio (WT: 60.5 %; A53T: 41.0 %), Casp-3 activity (WT: 65.0 %; A53T: 20.5 %), and a decrease in luciferase activity (WT: 50 %; A53T: 34.8 %). Overexpression of A53T-α-SN brought about with more cell death percentage compared to WT-α-SN within 36 h. No significant alteration in cytochrome c and reactive oxygen species release into cytosol were observed for both WT-α-SN and A53T-α-SN. CONCLUSION: Altogether, these findings highlight the link between disease related mutants of α-SN (like A53T-α-SN) in triggering of RIPK1-dependent extrinsic apoptotic pathway in cell death during neurodegeneration.

The effects of lycopene supplementation on insulin-like growth factor-1 and insulin-like growth factor binding proteins: A systematic review of randomized controlled trials.

Lycopene has been posited to regulate insulin-like growth factor-1 (IGF-1). We aimed to conduct a systematic review of the effects of lycopene on circulating IGF-1 and insulin-like growth factor binding proteins (IGFBPs) in adults. A systematic search was carried out in PubMed, Scopus, ISI Web of Science, and the Cochrane Library databases for randomized controlled trials (RCTs), published from inception until March 2020. A total of 11 studies fulfilled the selection criteria. Eleven studies examined the effect of lycopene supplementation on IGF-1, one of which reported a significant reduction. Moreover, three, four, and ten studies were found for IGFBP-1, IGFBP-2, and IGFBP-3, respectively; where one study found a significant increase in these proteins. In conclusion, no consistent modifying effect of lycopene supplementation on IGF-1 and IGFBPs levels are evident in the literature. More research is needed to explore the effect of lycopene on IGF-1 system.

The effect of probiotics/synbiotics supplementation on renal and liver biomarkers in patients with type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.

Despite the apparent beneficial effects of probiotics/synbiotics on glucose haemostasis, lipid profile and inflammatory responses, it is not clear whether these beneficial effects also impact renal and hepatic function in diabetes. Therefore, we sought to assess the effect of probiotics/synbiotics supplementation on renal and liver biomarkers in adults with type 2 diabetes mellitus (T2DM) using a systematic review and meta-analysis of randomised controlled trials (RCT). PubMed, Scopus, Web of Science and Cochrane Library were systematically searched, up to February 2021. The pooled weighted mean difference (WMD) was estimated using a random-effects model. The methodological quality of studies, as well as certainty of evidence, was assessed using standard scales. Fifteen related trials were identified. Meta-analysis of six trials, involving 426 participants, indicated that probiotics/synbiotics supplementation reduced serum levels of creatinine (WMD = -0·10 mg/dl, 95 % CI -0·20, -0·00; P = 0·01; I 2 = 87·7 %; P-heterogeneity < 0·001), without any significant effect on blood urea nitrogen (BUN), glomerular filtration rate or microalbuminuria. No significant improvement was found on liver biomarkers following probiotics/synbiotics supplementation. The subgroup analysis showed a significant improvement in BUN when follow-up duration lasted for 12 weeks or more (WMD = -1·215 mg/dl, 95 % CI -1·933, -0·496; P = 0·001) and in creatinine levels in patients with renal dysfunction (WMD = -0·209 mg/dl, 95 % CI -0·322, -0·096; P < 0·001). Our results are insufficient to advocate the use of probiotics/synbiotics for improving renal or liver function in patients with T2DM. Indeed, due to the low certainty of evidence, these findings need to be affirmed in further high-quality RCT.

The effect of vitamin D supplementation on serum levels of fibroblast growth factor- 23: A systematic review and meta-analysis of randomized controlled trials.

Previous studies of the effect of vtamin D on serum levels of fibroblast growth factor- 23 (FGF-23) have yeilded an inconsistent findings. This systematic review and meta-analysis of randomized controlled trials (RCTs) sought to investigate the effect of vitamin D supplementation on serum levels of FGF-23. PubMed, Scopus, ISI Web of Science, and the Cochrane Library were searched, from database inception to November 2020, for RCTs that evaluated the effects of native or active vitamin D supplementation on serum levels of FGF-23 in adults. Weighted mean difference (WMD) were calculated and random effects meta-analysis was used to estimate the overall effects. Twenty-seven trials were included in the meta-analysis. Supplementation with native vitamin D (23 studies, n = 2247 participants; weighted mean difference [WMD] = 0.5 pg/mL, 95 % CI: -0.52 to 1.51, P = 0.33; I2 = 29.9 %), and active vitamin D (5 studies, n = 342 participants, WMD = 29.45 pg/mL, 95 % CI: -3.9 to 62.81, P = 0.08; I2 = 99.3%) had no significant effects on serum FGF-23 concentration. In subgroup analyses, supplementation with ergocalciferol (3 studies, n = 205 participants; WMD = 18.27 pg/mL, 95 % CI: 5.36-31.17, P = 0.006), and daily dosing regimens (9 studies, n = 1374 participants; WMD = 0.41 pg/mL, 95 % CI: 0.22 to 0.59, P < 0.001) increased serum FGF-23 levels compared to control. Overall, our findings revealed no significan effect of vitamin D supplementation on serum FGF-23 concentration. However, further high quality, large-scale studies are needed to better elucidate this relationship.

The effect of vitamin D supplementation on insulin-like growth factor-1: A systematic review and meta-analysis of randomized controlled trials.

PURPOSE: There is equivocality regarding the interaction between vitamin D and insulin-like growth factor-1 (IGF-1). Thus, the aim of this study was to elucidate the effect of vitamin D supplementation on serum levels of IGF-1 by conducting a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: PubMed, Scopus, and ISI Web of Science databases were searched up to May 2019 for RCTs that evaluated the effect of vitamin D supplementation on IGF-1 levels. Mean and standard deviation changes of IGF-1 in each treatment group were considered for analysis and pooled using random-effect model. Risk of bias for included studies was assessed by the Cochrane scale and the NutriGrade approach was applied to evaluate the quality of evidence. RESULTS: Six trials (n = 773 participants) were included in the meta-analysis. Compared with control group, vitamin D supplementation yielded no significant effect on serum level of IGF-1 (weighted mean difference [WMD] =4.66 ng/ml, 95 % CIs: -6.72 to 16.03, P = 0.42, I2 = 74.8, P-heterogeneity = 0.001). Additionally, no meaningful changes were observed in subgroup analyses. CONCLUSION: The evidence from the limited number of published trials does not convincingly show that vitamin D supplementation elicits any clinically relevant effects on IGF-1 levels. More high-quality studies are needed to reach a consensual conclusion in this area.

Conjugated CAR T cell one step beyond conventional CAR T cell for a promising cancer immunotherapy.

Cancer immunotherapy aims to enhance the immune system reactivity against tumour cells. Chimeric Antigen Receptor (CAR), presented on the surface of the T cells, specifically redirects the cell and demonstrates significant promises in treating patients with different types of haematologic malignancies. Although several cases of improvement have been reported, clinical experiences, such as excessive activity, poor control, toxicity and limited life span of conventional CAR T cells have emerged as treatment challenges associated with this therapeutic strategy. Recently, multiple switchable CAR T platforms have been made to enable better control in a dose-dependent manner, which is correlated to distinct characteristics of different switch molecules. This review aimed at a brief represention of toxicities of the CAR T cells, the obstacles facing tumour treatments especially in solid tumours, and finally providing a framework for classification of the newly developed Conjugated/Split CAR-T cell technologies to overcome difficulties. Overall, Newly developed Conjugated CAR T cells using among with soluble switch molecules seems to be as responsive as the conventional CAR T cells, yet providing many new useful options to effectively overcome limitations and significantly improve patient safety.

Mild antagonistic effect of Valproic acid in combination with AZD2461 in MCF-7 breast cancer cells.

Background: Breast cancer (BC) is a complex disease, but current treatments are not efficient enough considering increased relapse and decreased survival rate among patients. Poly (ADP-ribose) polymerase inhibitors are recently developed anticancer agents which target cells with defects in homologous recombination (HR) pathway. This study wishes to assess whether the combination of AZD2461 as a newly developed PARP1 inhibitor and valproic acid (VPA), a histone deacetylase inhibitor could effectively reduce the growth of MCF-7 cells with no fundamental DNA repair defect. Methods: Both trypan blue dye exclusion assay and MTT viability test were used to evaluate cell death. γ-H2AX levels, as a marker of DNA repair, were measured using in cell ELISA method. The Student's t-test and non-parametric analysis of variance (ANOVA) were applied for our data analyses where p-value <0.05 was considered statistically significant. Results: As calculated by CompuSyn software, IC50 values for VPA and AZD2461 were 4.89 mM and 42.83 µM respectively following 48 hours treatment. Also, the trypan blue exclusion assay results showed a concentration- and time-dependent decrease when MCF-7 cells were treated with both agents (p<0.05). Combination analysis showed a mild antagonism (CI>1.1) while γ-H2AX levels found not to be significantly increased in MCF-7 cells co-treated with VPA+AZD2461 compared to each agent alone (p=0.29). Conclusion: Our findings revealed that the combination of VPA and AZD2461 could decrease cell viability of MCF-7 cells, but it was not able to significantly increase unrepaired DNA damage sites. The mechanism responsible for drugs combination was not of synergism or addition. Determining the type of involved cell death mechanisms might be followed in further studies.

Life Psychosocial Stresses and Coronary Artery Disease.

BACKGROUND: It is hypothesized that the impacts of life events accumulate and can trigger and promote atherosclerosis in susceptible individuals. In the current study, the correlation of total life stressors during 1 year was investigated relative to coronary artery disease (CAD). METHODS: The study population consisted of 148 males and 152 females aged 35-76 years. The subjects were classified as CAD cases and controls according to the results of coronary angiography. The severity of CAD was scored on the basis of the number and the extent of lesions at coronary arteries. The stressful events of life were assessed using Holmes-Rahe Questionnaire and was presented as total psychological stress scores per year (TPSS). RESULTS: The frequency of cigarette smoking, diabetes mellitus, and hypertension was more prevalent in CAD cases than control subjects. The levels of TPSS were increased in patients with CAD compared to the controls (160.3 ± 71.3 vs. 139.8 ± 66.5, P = 0.020). TPSS was also associated positively with the levels of uric acid, erythrocytes counts, erythrocyte sedimentation rate, aspirin consumption, and negatively with high-density lipoprotein-cholesterol and apo-AI. In logistic regression analysis, TPSS correlated with the occurrence of CAD by the odds ratio of 1.773 (1.073-2.930), P = 0.025, but the association was weakened after adjustment for classical risk factors, especially hypertension. TPSS exhibited significant association with the severity of CAD [F (3,274) = 2.6, P = 0.051]. CONCLUSIONS: The results suggest that TPSS are associated with the occurrence and severity of CAD significantly, but the association is not independent.

Uric Acid and Coronary Artery Disease, Two Sides of a Single Coin: A Determinant of Antioxidant System or a Factor in Metabolic Syndrome.

INTRODUCTION: Uric acid has antioxidant activity and it is expected to protect against coronary artery disease (CAD). Contradictory, it is a component of metabolic syndrome and so a risk factor for CAD. The associations of plasma total antioxidant capacity (TAOC) and uric acid (UA) as well as other risk factors were investigated relative to the occurrence and severity of CAD. MATERIALS AND METHODS: The study population consisted of 148 males and 152 females aged 35-76 years who were classified as CAD cases and controls according to the results of coronary angiography. The severity of CAD was scored on the basis of the number and the extent of lesions at coronary arteries. The concentrations of UA and TAOC were measured by using of FRAP and enzymatic uricase methods. RESULTS: The prevalence of hypertension, cigarette smoking and diabetes mellitus was more frequent in CAD cases than controls. Patients with CAD when compared with the controls had increased levels of glucose, triglycerides, creatinine, UA, TAOC and decreased levels of HDL- cholesterol. Serum UA was high positive correlate of serum total and LDL-cholesterol, triglyceride, creatinine, BUN, bilirubin, TAOC and negative correlate of glucose and HDL-C. TAOC and its major determinant UA but not bilirubin and albumin are significantly associated with the prevalence and severity of CAD. In multivariate analysis and in the absence of hypertension, UA but not TAOC would remain and be associated with CAD by the OR of 1.57 (1.07-2.29), p=0.02. If the results adjusted for all major risk factors including hypertension, neither TAOC nor UA would remain in the regression equation. CONCLUSION: The results suggest that TAOC and UA but not bilirubin and albumin are associated with CAD significantly. But, the correlation is not independent and is attributed to the metabolic syndrome. The measurement of UA and TAOC will not improve the prognostic power beyond the classical risk factors.