👤 Islam Khalili

Growing evidence suggests that resveratrol possesses neuroprotective properties against arsenic toxicity. This study investigated whether resveratrol could ameliorate arsenic-induced depression-like behaviors in male Naval Medical Research Institute (NMRI) mice and explored potential molecular mechanisms. Mice were exposed to arsenic (50 mg/L in drinking water) for 4 weeks and treated with resveratrol (10 or 20 mg/kg). Behavioral assessments included the hole-board test (HBT) for exploratory behavior, and the sucrose splash test (SST), tail suspension test (TST), and forced swim test (FST) for depression-like behaviors. The mRNA levels of Bdnf, Creb1, and Dvl1 in the brain were analyzed by qRT-PCR. Arsenic exposure induced significant depression-like behaviors, characterized by decreased grooming in SST and increased immobility in TST and FST. Resveratrol treatment prevented these behavioral alterations and exhibited intrinsic antidepressant effects in naïve mice, with dose-dependent reductions in immobility time (FST) and increased grooming (SST). Notably, resveratrol (20 mg/kg) enhanced rearing frequency in naïve mice and decreased it in the arsenic-treated mice. At the molecular level, arsenic downregulated Bdnf expression, while resveratrol restored its levels. In contrast, no significant changes in Creb1 and Dvl1 expression were observed. These findings indicate that resveratrol mitigates arsenic-induced depression-like behaviors primarily through the modulation of Bdnf-dependent pathways, independent of Creb1 and Dvl1. These results position resveratrol as a potential antidepressant and underscore its therapeutic promise for mood disorders associated with environmental toxicant exposure. Show less

High intake of dietary n-3 polyunsaturated fatty acids (PUFA) is associated with a decreased risk of ulcerative colitis (UC) and Crohn's disease (CD). However, results have been heterogeneous suggesting that genetic variations in PUFA metabolism may modify this risk. We conducted a case-control study nested within 2 prospective cohorts, the Nurses' Health Study (NHS) and NHS II. Among women providing blood (n = 62,437) or buccal cells (n = 59,543) for genotyping, we confirmed new diagnoses of CD or UC. Dietary intake was assessed 4 years before diagnosis. Confirmed cases were matched 1:2 to controls. Subjects were genotyped for single nucleotide polymorphisms at CYP4F3, FADS1, and FADS2 loci. Conditional logistic regression models examined the interaction between genotype, n3:n6 PUFA intake and risk of CD and UC. Our study included 101 CD and 139 UC patients matched to 495 controls. On multivariable analysis, high intake of n3:n6 PUFA (above median) demonstrated a trend toward reduced risk of UC (Odds ratio [OR] 0.71, 95% confidence interval [CI], 0.47-1.09, P = 0.11). High n3:n6 PUFA intake was associated with a reduced risk of UC in individuals with the GG/AG genotype at a single nucleotide polymorphism in CYP4F3 (OR 0.57, 95% CI, 0.32-0.99) but not those with the AA genotype (OR 0.95, 95% CI, 0.47-1.93) (P-interaction = 0.049). No gene-diet interactions were noted for CD. The association between dietary n3:n6 PUFA intake and risk of UC may be modified variants at CYP4F3. Further gene-environment studies of the association between diet and IBD risk are warranted. Show less

Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 × 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 × 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk. Show less

The WNT signaling is deregulated in most human colorectal cancers (CRC). Promoter methylation has been proposed as an alternative mechanism to inactivate genes in tumors. To gain insight into the methylation silencing of the WNT pathway during colorectal carcinogenesis, we examined the aberrant methylation profile of four genes, APC, Axin1, Axin2, and GSK3β in an unselected series of 112 sporadic colorectal tumors by methylation specific PCR. It has been suggested that the Axin2 C148T SNP is associated with the risk of developing certain types of cancers. To assess the contribution of Axin2 SNP to CRC susceptibility, we examined the Axin2 C148T genotype in CRC patients and 170 healthy controls by PCR-RFLP. The frequency of CRCs with at least one gene methylated was 18.75%. Promoter methylation of Axin2 and APC genes was detected in 7.1 and 11.9% of tumors, respectively. No aberrant methylation was found in Gsk3β and Axin1 gene in these tumor series. The methylation status of APC had no significant association with clinical parameters. But, promoter methylation of Axin2 was sex-related, occurring more frequently in females (P = 0.002). The frequency of Axin2 C148T genotypes were similar in patients and controls. Moreover, we observed no association between the Axin2 SNP and risk of CRC in patients stratified by age, sex, and smoking status. However, the heterozygote CT genotype was associated with a reduced CRC risk in distal patients compared with proximal patients (OR = 0.3; 95% CI 0.1-0.9, P = 0.04). Our findings indicate that Axin1 and GSK3β methylation play a minor role in colorectal carcinogenesis. Show less