Short-chain fatty acid concentrations in the incidence and risk-stratification of colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: The beneficial role of gut microbiota and bacterial metabolites, including short-chain fatty acids (SCFAs), is well recognized, although the available literature around their role in colorectal cancer (CRC) has been inconsistent. METHODS: We performed a systematic review and meta-analysis to examine the associations of fecal SCFA concentrations to the incidence and risk of CRC. Data extraction through Medline, Embase, and Web of Science was carried out from database conception to June 29, 2022. Predefined inclusion/exclusion criteria led to the selection of 17 case-control and six cross-sectional studies for quality assessment and analyses. Studies were categorized for CRC risk or incidence, and RevMan 5.4 was used to perform the meta-analyses. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model. Studies lacking quantitation were included in qualitative analyses. RESULTS: Combined analysis of acetic, propionic, and butyric acid revealed significantly lower concentrations of these SCFAs in individuals with a high-risk of CRC (SMD = 2.02, 95% CI 0.31 to 3.74, P = 0.02). Additionally, CRC incidence was higher in individuals with lower levels of SCFAs (SMD = 0.45, 95% CI 0.19 to 0.72, P = 0.0009), compared to healthy individuals. Qualitative analyses identified 70.4% of studies reporting significantly lower concentrations of fecal acetic, propionic, butyric acid, or total SCFAs in those at higher risk of CRC, while 66.7% reported significantly lower concentrations of fecal acetic and butyric acid in CRC patients compared to healthy controls. CONCLUSIONS: Overall, lower fecal concentrations of the three major SCFAs are associated with higher risk of CRC and incidence of CRC.

Effects of vitamin D supplementation on advanced glycation end products signaling pathway in T2DM patients: a randomized, placebo-controlled, double blind clinical trial.

BACKGROUND: Several researches have recommended vitamin D possible health benefits on diabetic complications development, but a few number of studies have been accomplished on the molecular and cellular mechanisms. Certain cellular pathways modification and also some transcription factors activation may protect cells from hyperglycemia condition induced damages. This study purpose was to determine the vitamin D supplementation effect on some key factors [advanced glycation end products (AGEs) signaling pathway] that were involved in the diabetic complications occurrence and progression for type-2 diabetes participants. METHODOLOGY: 48 type-2 diabetic patients (T2DM) randomly divided into two groups (n = 24 per group), receiving: 100-µg vitamin D or placebo for 3 months. At this study beginning and the end, the receptor expression for advanced glycation end products (RAGE) and glyoxalase I (GLO1) enzyme from peripheral blood mononuclear cells (PBMCs) and AGEs and tumor necrosis factor-α (TNF-α) serum levels were measured by the use of real-time PCR and ELISA methods, respectively. RESULTS: This study results demonstrated that vitamin D supplementation could down-regulate RAGE mRNA [fold change = 0.72 in vitamin D vs. 0.95 in placebo) P = 0.001)]. In addition, no significant changes were observed for GLO1 enzyme expression (P = 0.06). This study results also indicated that vitamin D serum level significantly increased in vitamin D group (P < 0.001). Moreover, AGES and TNF-α serum levels significantly reduced in vitamin D group, but they were remained unchanged in the placebo group. CONCLUSION: In conclusion, vascular complications are more frequent in diabetic patients, and vitamin D treatment may prevent or delay the complications onset in these patients by AGEs serum level and RAGE gene expression reducing.Trial registration NCT03008057. Registered December 2016.

DHA-enriched fish oil upregulates cyclin-dependent kinase inhibitor 2A (P16INK) expression and downregulates telomerase activity without modulating effects of PPARγ Pro12Ala polymorphism in type 2 diabetic patients: A randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVE: The present study investigated the effects of docosahexaenoic acid (DHA)-enriched fish oil supplement on telomerase activity, mRNA expression of P16INK, IL-6, and TNF-α considering Pro12Ala polymorphism in the PPARγ gene. METHODS/DESIGN: In this double-blind randomized controlled trial, 72 PPARγ Pro12Ala polymorphism genotyped type 2 diabetic patients aged 30-70 years were randomly assigned to receive 2.4 gr of DHA-enriched fish oil or a placebo for 8 weeks. Genotyping of the Pro12Ala polymorphism in the PPARγ gene was assessed using polymerase chain reaction-restriction length polymorphism (PCR-RFLP), telomerase activity in the peripheral blood mononuclear cell (PBMC) was measured using PCR-ELISA based on the telomeric repeat amplification protocol (TRAP), and changes in the mRNA expression of P16, IL-6, and TNF-α were measured using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In the DHA group, telomerase activity was decreased (p = 0.001) during the intervention. In addition, between-group comparisons showed significant differences in the changes in telomerase activity (p = 0.003) and P16 mRNA expression (p = 0.028) and non-significant differences in TNF-α and IL-6 mRNA expression. The gene*DHA interaction could not affect changes in P16, IL-6, or TNF-α mRNA expression or in telomerase activity in PBMC. DISCUSSION: Short-time DHA-enriched fish oil supplementation caused increased levels of P16 expression and a decline in telomerase activity compared with the control group without modulating the effects of Pro12Ala polymorphism on the PPARγ gene. Because of the positive correlation between P16 activity and cellular senescence, the possibility of senescence stimulation by DHA is proposed.

Effect of DHA-rich fish oil on PPARγ target genes related to lipid metabolism in type 2 diabetes: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: The beneficial effects of omega-3 polyunsaturated fatty acids on lipid levels are well documented. However, the related molecular mechanisms are widely unknown. Omega-3 polyunsaturated fatty acids are natural ligand for peroxisome proliferator-activated receptor γ (PPARγ). OBJECTIVE: The aim of this study was to evaluate the effect of docosahexaenoic acid (DHA)-rich fish oil supplementation on modulation of some PPARγ-responsive genes related to lipid metabolism. METHODS: Patients with type 2 diabetes were randomly assigned to consume either DHA-rich fish oil (containing 2400 mg/d fish oil; DHA: 1450 mg and eicosapentaenoic acid: 400 mg) or placebo for 8 weeks. Lipid profile and glycemic control parameters as well as the gene expression of PPARγ, liver x receptor-a, ATP-binding cassette A1, and CD36 in peripheral blood mononuclear cells were measured at baseline and after 8 weeks. RESULTS: DHA-rich fish oil supplementation resulted in decreased triglycerides (TG) level compared with placebo group, independently of the baseline value of TG (all patients (P = .003), hypertriglyceridemic subjects (P = .01), and normotriglyceridemic subjects (P = .02)). Moreover, a higher reduction in TG level was observed in hypertriglyceridemic subjects, comparing to normotriglyceridemic subjects with DHA-rich fish oil supplementation (P = .01). Other lipid parameters as well as the expression of PPARγ, liver x receptor-a, ATP-binding cassette A1, and CD36 were not affected by DHA-rich fish oil supplementation. Only in hypertriglyceridemic subjects, DHA-rich fish oil supplementation upregulated CD36 expression, compared with the placebo group (P = .01). CONCLUSIONS: DHA-rich fish oil supplementation for 8 weeks increased CD36 expression in hypertriglyceridemic subjects, which might result to higher reduction in TG level, comparing with normotriglyceridemic subjects. However, this finding should be investigated in further studies.

Docosahexaenoic Acid-Rich Fish Oil Supplementation Improves Body Composition without Influence of the PPARγ Pro12Ala Polymorphism in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: The aims of this research were to investigate (1) the impact of docosahexaenoic acid (DHA)-rich fish oil supplementation on body composition, plasma adiponectin level, and peroxisome proliferator-activated receptor γ (PPARγ) gene expression, and (2) whether the effect of DHA-rich fish oil supplementation on the aforementioned variables is modulated by PPARγ Pro12Ala polymorphism. METHODS: We genotyped PPARγ Pro12Ala polymorphism in subjects with type 2 diabetes mellitus (T2DM). Ala carriers and non-Ala carriers were randomly assigned to DHA-rich fish oil or placebo intake for 8 weeks. RESULTS: Glycemic control was not affected by the intervention. The supplementation with DHA-rich fish oil decreased waist circumference (p < 0.001), body fat mass (p = 0.01), body fat percent (p = 0.04), and viscera fat rating (p = 0.02) as well as trunk fat mass (p = 0.04). Weight, body mass index, fat-free mass, adiponectin level, and PPARγ gene expression changes showed no significant difference. No gene-diet interaction was found on body composition, adiponectin level, and PPARγ gene expression. CONCLUSIONS: DHA-rich fish oil supplementation favorably modulated body composition in patients with T2DM and could be useful to reduce visceral obesity. However, the PPARγ Pro12Ala polymorphism did not influence the changes in the desired variables.

Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population.

BACKGROUND: Germ-line mutations of RET proto-oncogene are the known cause of hereditary medullary thyroid carcinoma (MTC), which account for approximately 25% of all MTC cases and occur as multiple endocrine neoplasia type 2 syndromes. Here, we present the first comprehensive genetic screening and analysis of MTC among Iranian families. METHODS: A total of 55 patients with MTC (male to female ratio=1:1.6; average age of disease onset = 33 ± 13 years) from 53 independent families participated in this study. All of the patients had undergone total thyroidectomy between 1999 and 2006, and 51 of them were clinically characterized as apparently sporadic cases. Genomic DNA samples were obtained and following highly-specific polymerase chain reaction amplification of the 6 RET key exons (10, 11, 13, 14, 15, and 16) were subjected to direct DNA sequencing without a requirement for a purification step. RESULTS: Sequence analysis revealed that 9 (17.6%) of the apparently sporadic cases (from 8 kindreds) carried an RET germ-line mutation. Of the seven different mutations identified among all of the families studied, five were in the cysteine codons, with Cys634Arg having the highest prevalence (45.5%) among the afflicted families. Mutation carriers have an earlier age of onset (21 ± 6) versus the sporadic cases (37 ± 12). CONCLUSIONS: This is the first comprehensive genetic screening and analysis of MTC among Iranian families. The results further confirm the need and advantages of DNA sequencing for identification of hereditary MTC cases. There does not seem to be a meaningful correlation between single nucleotide polymorphism patterns and the average age of disease onset. Geographical distribution of the sporadic cases, however, shows a significant concentration toward the Northern regions of the country, noticeably the provinces situated directly to the south of the Caspian Sea.