Causal relationship between depression and hypercholesterolemia: A bidirectional 2-sample Mendelian randomization study.

Although observational studies have found both a positive and negative association between depression and hypercholesterolemia, the findings are mixed and contradictory. To our knowledge, this is the first study that employs the bidirectional Mendelian randomization (MR) and multivariable MR analysis with extensive genome-wide association studies (GWAS) data to examine the causal effect between depression and hypercholesterolemia. Using summary statistics obtained from GWAS of individuals with European ancestry, we utilize a bidirectional 2-sample MR approach to explore the potential causal association between hypercholesterolemia and depressive symptoms. Multivariable Mendelian randomization analysis was used to examine whether the direct causal effect of depression on the risk of hypercholesterolemia can be affected by traits associated with the increased risk of hypercholesterolemia. This MR analysis utilized inverse variance weighted (IVW), MR-Egger regression, weighted mode, and weighted median methods. Data on the summary level of depression were acquired from a GWAS that involved 500,199 participants. We used summary GWAS datasets for hypercholesterolemia including 206,067 participants. We also used another GWAS databases of hypercholesterolemiat (n = 463,010) to validate our results. By utilizing IVW, it was discovered that there is a possibility of a 31% rise in the risk of hypercholesterolemia due to depression (OR = 1.31, 95% CI = 1.10-1.57, P = .002). We found a consistent causal effect of depression on hypercholesterolemia from the IVW analyses using different hypercholesterolemia datasets. After adjustment of smoking, physical activity, and obesity, there remains significant causal relationship between depression and hypercholesterolemia (OR = 1.25, 95% CI = 1.01-1.54, P = .040). However, we did not find any evidence indicating that hypercholesterolemia leads to depression in the opposite direction. Directional pleiotropy was not observed in the MR-Egger regression analysis. Additionally, the MR-PRESSO analysis validated these discoveries. Neither the leave-one-out sensitivity test nor the funnel plots revealed any outliers. In both the unadjusted and adjusted estimates, depression has a consistent direct causal effect on hypercholesterolemia. Our study has led to an improved comprehension of the causal connections between hypercholesterolemia and depression, which could aid in the prevention and treatment of hypercholesterolemia.

The rs17782313 polymorphism near MC4R gene confers a high risk of obesity and hyperglycemia, while PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder: a systematic review and meta-analysis.

Background: The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory. Methods: Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran's Q-statistic test and Begg's test were employed to identify heterogeneity among studies and publication bias, respectively. Results: Fifty studies (58,716 subjects) and 51 studies (18,660 subjects) were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/m2, 95% confidence interval [95% CI] = 0.12 to 0.29 kg/m2, p < 0.001), waist circumference (SMD = 0.14 cm, 95% CI = 0.06 to 0.23 cm, p < 0.001) and blood glucose (SMD = 0.09 mg/dL, 95% CI = 0.02 to 0.16 mg/dL, p = 0.01) than the TT homozygotes. Regarding the rs8192678 polymorphism, no significant associations with the indexes of obesity, glucometabolic disorder and dyslipidemia were detected. However, significant correlations between the rs8192678 polymorphism and multiple glucometabolic indexes were observed in subgroup analyses stratified by sex, age, ethnicity and health status. Conclusion: The meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022373543.

Polymorphisms of Fat Mass and Obesity-Associated Gene in the Pathogenesis of Child and Adolescent Metabolic Syndrome.

Childhood metabolic syndrome (MetS) is prevalent around the world and is associated with a high likelihood of suffering from severe diseases such as cardiovascular disease later in adulthood. MetS is associated with genetic susceptibility that involves gene polymorphisms. The fat mass and obesity-associated gene (FTO) encodes an RNA N6-methyladenosine demethylase that regulates RNA stability and molecular functions. Human FTO contains genetic variants that significantly contribute to the early onset of MetS in children and adolescents. Emerging evidence has also uncovered that FTO polymorphisms in intron 1, such as rs9939609 and rs9930506 polymorphisms, are significantly associated with the development of MetS in children and adolescents. Mechanistic studies reported that FTO polymorphisms lead to aberrant expressions of FTO and the adjacent genes that promote adipogenesis and appetite and reduce steatolysis, satiety, and energy expenditure in the carriers. The present review highlights the recent observations on the key FTO polymorphisms that are associated with child and adolescent MetS with an exploration of the molecular mechanisms underlying the development of increased waist circumference, hypertension, and hyperlipidemia in child and adolescent MetS.

C Allele of the PPARδ+294T>C Polymorphism Confers a Higher Risk of Hypercholesterolemia, but not Obesity and Insulin Resistance: A Systematic Review and Meta-Analysis.

The relationships of the PPARα Leu162Val and PPARδ+294 T>C polymorphisms with metabolic indexes have been reported to be inconsistent and even contradictory. The meta-analysis was conducted to clarify the relationships between the two variants and the indexes of obesity, insulin resistance, and blood lipids. PubMed, Google Scholar, Embase, and Cochrane Library were searched for eligible studies. Standardized mean difference with 95% confidence interval was calculated to estimate the differences in the metabolic indexes between the genotypes of the Leu162Val and+294 T>C polymorphisms. Heterogeneity among studies was assessed by Cochran's x2-based Q-statistic test. Publication bias was identified by using Begg's test. Forty-one studies (44 585 subjects) and 33 studies (23 018 subjects) were identified in the analyses for the Leu162Val and+294 T>C polymorphisms, respectively. C allele carriers of the+294 T>C polymorphism had significantly higher levels of total cholesterol and low-density lipoprotein cholesterol than TT homozygotes in the whole population. Notably, C allele carriers of the+294 T>C polymorphism had significantly higher levels of triglycerides and total cholesterol in East Asians, but lower levels of triglycerides in West Asians than TT homozygotes. Regarding the Leu162Val polymorphism, it was found that Val allele carriers had significantly higher levels of blood glucose than Leu/Leu homozygotes only in European Caucasians. The meta-analysis demonstrates that C allele of the+294 T>C polymorphism in PPARδ gene confers a higher risk of hypercholesterolemia, which may partly explain the relationship between this variant and coronary artery disease.

Minor alleles of FTO rs9939609 and rs17817449 polymorphisms confer a higher risk of type 2 diabetes mellitus and dyslipidemia, but not coronary artery disease in a Chinese Han population.

Background: Relationships of the polymorphisms in fat mass and obesity-associated gene (FTO) and peroxisome proliferator-activated receptor delta gene (PPARD) with metabolic-related diseases remain to be clarified. Methods: One thousand three hundred and eighty-one subjects were enrolled. Metabolic-related diseases including obesity, dyslipidemia, hyperhomocysteinemia, hyperuricemia, hypertension, type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) were defined based on diagnostic criteria. FTO rs9939609 and rs17817449, and PPARD rs2016520 and rs2267668 polymorphisms were genotyped by using polymerase chain reaction-restricted fragment length polymorphism method. Results: Patients with T2DM or dyslipidemia had a higher frequency of AA, AT or AA + AT genotypes as well as A allele of FTO rs9939609 polymorphism than those free of T2DM or dyslipidemia (P ≤ 0.04 for all). Patients with T2DM or dyslipidemia had a higher frequency of GG, GT or GG + GT genotypes as well as G allele of FTO rs17817449 polymorphism than those free of T2DM or dyslipidemia (P ≤ 0.03 for all). Multivariate logistic regression analyses showed that FTO rs9939609 and rs17817449 polymorphisms were independently associated with T2DM as well as dyslipidemia after adjustment for age, sex, smoking and other metabolic diseases. FTO rs9939609 and rs17817449 polymorphisms were not associated with obesity, hyperhomocysteinemia, hyperuricemia, hypertension and CAD. Obese or T2DM carriers of the AA or AT genotype of the FTO rs9939609 polymorphism had a higher prevalence of dyslipidemia compared to non-obese or non-T2DM carriers of the AA or AT genotype (P = 0.03 for both). Among the carriers of GG or GT genotype of the FTO rs17817449 polymorphism, the prevalence of dyslipidemia in obese patients was higher than that in non-obese subjects (P < 0.01). PPARD rs2016520 and rs2267668 polymorphisms were not correlated with any of the metabolic-related diseases in the study population. Conclusion: Minor alleles of FTO rs9939609 and rs17817449 polymorphisms confer a higher risk of T2DM and dyslipidemia, and the risk is further increased among obese individuals. PPARD rs2016520 and rs2267668 polymorphisms are not associated with metabolic-related diseases.

The novel type II toxin-antitoxin PacTA modulates Pseudomonas aeruginosa iron homeostasis by obstructing the DNA-binding activity of Fur.

Type II toxin-antitoxin (TA) systems are widely distributed in bacterial and archaeal genomes and are involved in diverse critical cellular functions such as defense against phages, biofilm formation, persistence, and virulence. GCN5-related N-acetyltransferase (GNAT) toxin, with an acetyltransferase activity-dependent mechanism of translation inhibition, represents a relatively new and expanding family of type II TA toxins. We here describe a group of GNAT-Xre TA modules widely distributed among Pseudomonas species. We investigated PacTA (one of its members encoded by PA3270/PA3269) from Pseudomonas aeruginosa and demonstrated that the PacT toxin positively regulates iron acquisition in P. aeruginosa. Notably, other than arresting translation through acetylating aminoacyl-tRNAs, PacT can directly bind to Fur, a key ferric uptake regulator, to attenuate its DNA-binding affinity and thus permit the expression of downstream iron-acquisition-related genes. We further showed that the expression of the pacTA locus is upregulated in response to iron starvation and the absence of PacT causes biofilm formation defect, thereby attenuating pathogenesis. Overall, these findings reveal a novel regulatory mechanism of GNAT toxin that controls iron-uptake-related genes and contributes to bacterial virulence.

Total Glucosides of Paeony Attenuates Ulcerative Colitis via Inhibiting TLR4/NF-κB Signaling Pathway.

The therapeutic effects and mechanisms of action of total glucosides of paeony (TGP) in treating ulcerative colitis remain to be clarified. Mouse model of ulcerative colitis was treated with TGP and the indexes including scores of disease activity index, gross morphologic damage and histological damage, and inflammatory and oxidative stress markers were determined. Patients with ulcerative colitis received TGP capsule therapy and the indexes including efficacy of colonoscopy and histology, scores of Ulcerative Colitis Activity Index (UCAI) and Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and inflammatory parameters were assessed. The expressions of toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) were measured in colonic tissues of mice and patients. TGP treatment significantly increased weight, decreased scores of disease activity index, gross morphologic damage and histological damage, and reduced the levels of tumor necrosis factor-α, interleukin-1ß, malondialdehyde and myeloperoxidase in mouse model. Patients treated with TGP capsule had significantly higher relief rates of diarrhea, abdominal pain, and bloody purulent stool, decreased UCAI and increased SIBDQ scores, and lower levels of erythrocyte sedimentation rate, C-reactive protein and CD4+/CD8+ T-cell ratio than those patients with routine therapy. The overall response rate of TGP capsule was significantly higher than that of routine therapy. TGP treatment significantly suppressed the expressions of TLR4 and NF-κB in colonic tissues of both mouse model and patients with UC. TGP shows a good therapeutic effect on ulcerative colitis in animals and human patients, and the underlying mechanisms may be related to the inhibition of TLR4/NF-κB signaling by TGP.

G Allele of the rs1801282 Polymorphism in PPARγ Gene Confers an Increased Risk of Obesity and Hypercholesterolemia, While T Allele of the rs3856806 Polymorphism Displays a Protective Role Against Dyslipidemia: A Systematic Review and Meta-Analysis.

Background: The relationships between the rs1801282 and rs3856806 polymorphisms in nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) gene and obesity indexes as well as serum lipid levels have been extensively investigated in various studies, but the results were inconsistent and even contradictory. Methods: PubMed, Google Scholar, Embase, Cochrane Library, Web of Science, Wanfang, CNKI and VIP databases were searched for eligible studies. The random-effTPDEects model was used, and standardized mean difference (SMD) with 95% confidence interval (CI) was calculated to estimate the differences in obesity indexes and serum lipid levels between the subjects with different genotypes in a dominant model. Heterogeneity among studies was assessed by Cochran's x2-based Q-statistic test. Publication bias was identified by using Begg's test. Results: One hundred and twenty studies (70,317 subjects) and 33 studies (18,353 subjects) were identified in the analyses for the rs1801282 and rs3856806 polymorphisms, respectively. The G allele carriers of the rs1801282 polymorphism had higher levels of body mass index (SMD = 0.08 kg/m2, 95% CI = 0.04 to 0.12 kg/m2, p < 0.001), waist circumference (SMD = 0.12 cm, 95% CI = 0.06 to 0.18 cm, p < 0.001) and total cholesterol (SMD = 0.07 mmol/L, 95% CI = 0.02 to 0.11 mmol/L, p < 0.01) than the CC homozygotes. The T allele carriers of the rs3856806 polymorphism had lower levels of low-density lipoprotein cholesterol (SMD = -0.09 mmol/L, 95% CI = -0.15 to -0.03 mmol/L, p < 0.01) and higher levels of high-density lipoprotein cholesterol (SMD = 0.06 mmol/L, 95% CI = 0.02 to 0.10 mmol/L, p < 0.01) than the CC homozygotes. Conclusions: The meta-analysis suggests that the G allele of the rs1801282 polymorphism confers an increased risk of obesity and hypercholesterolemia, while the T allele of the rs3856806 polymorphism displays a protective role against dyslipidemia, which can partly explain the associations between these polymorphisms and cardiovascular disease. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier [CRD42022319347].

Neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and monocyte to lymphocyte ratio in depression: A meta-analysis.

BACKGROUND: The possible associations between depression and neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) have been evaluated in numerous studies. But the results were still controversial. METHODS: The WEB OF SCIENCE, PUBMED, EMBASE, and COCHRANE LIBRARY databases were searched for eligible studies. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to assess the differences in NLR, PLR, and MLR levels between depressed patients and controls. RESULTS: Two thousand five hundred and eighty cases and 2664 controls, 1393 cases and 1370 controls, 744 cases and 765 controls were identified in the meta-analyses for NLR, PLR, and MLR, respectively. The pooled analyses showed that depressed subjects had significantly higher levels of NLR than healthy controls (SMD = 0.33, 95% CI = 0.15-0.15, P < 0.001). Sensitivity analysis and publication bias test confirmed the result. Subgroup analyses suggested that the association between depression and NLR could be affected by country, study design, and antidepressant treatment. While no significant difference of PLR (SMD = 0.13, 95% CI = -0.04-0.31, P = 0.140) and MLR (SMD = 0.02, 95% CI = -0.24-0.28, P = 0.892) values was found between depressed subjects and controls. LIMITATIONS: High heterogeneity was noted across studies. CONCLUSIONS: The present meta-analysis supported the hypothesis that depression is associated with inflammation, and NLR can be used as an indicator of depression. Further large-scale studies are warranted, especially those that evaluate PLR or MLR in depression.

PPARγ Gene Polymorphisms, Metabolic Disorders, and Coronary Artery Disease.

Being activated by endogenous and exogenous ligands, nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) enhances insulin sensitivity, promotes adipocyte differentiation, stimulates adipogenesis, and has the properties of anti-atherosclerosis, anti-inflammation, and anti-oxidation. The Human PPARγ gene (PPARG) contains thousands of polymorphic loci, among them two polymorphisms (rs10865710 and rs7649970) in the promoter region and two polymorphisms (rs1801282 and rs3856806) in the exonic region were widely reported to be significantly associated with coronary artery disease (CAD). Mechanistically, PPARG polymorphisms lead to abnormal expression of PPARG gene and/or dysfunction of PPARγ protein, causing metabolic disorders such as hypercholesterolemia and hypertriglyceridemia, and thereby increasing susceptibility to CAD.

The Association between COMT Val158Met Polymorphism and the Post-Traumatic Stress Disorder Risk: A Meta-Analysis.

BACKGROUND: Genetic factors were suggested to have influence on the development of post-traumatic stress disorder (PTSD). The possible association between catechol-O-methyltransferase (COMT) Val158Met polymorphism and PTSD has been evaluated in several studies. But the results were still controversial. Therefore, we conduct this meta-analysis to address these issues. METHODS: The PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between COMT Val158Met polymorphism and PTSD. RESULTS: Five articles including 6 studies with 893 cases and 968 controls were finally included in the present meta-analysis. The pooled analyses did not demonstrate a significant association between the COMT Val158Met polymorphism and PTSD in any of the selected genetic models: allele model (OR = 1.13, 95% CI: 0.97-1.31), dominant model (OR = 1.17, 95% CI: 0.93-1.46), recessive model (OR = 1.44, 95% CI: 0.78-2.66), and additive model (OR = 1.54, 95% CI: 0.85-2.80). Subgroup analyses suggested that the Hardy-Weinberg equilibrium status of genotype distributions could influence the relationship of COMT Val158Met polymorphism and PTSD. CONCLUSIONS: The present meta-analysis suggested that the COMT Val158Met polymorphism may not be associated with the PTSD risk. Further large-scale and population-representative studies are warranted to evaluate the impact of the COMT Val158Met polymorphism on the risk of PTSD.

rs10865710 polymorphism in PPARG promoter is associated with the severity of type 2 diabetes mellitus and coronary artery disease in a Chinese population.

BACKGROUND: Relationship between polymorphisms in peroxisome proliferator-activated receptor gamma (PPARG) and progression of type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) remains to be clarified. METHODS: 635 subjects were divided into T2DM, CAD, T2DM complicated with CAD (T2DM/CAD) and control groups according to diagnostic criteria. The rs10865710 and rs3856806 polymorphisms were genotyped, and the severity of T2DM and CAD was evaluated for all subjects. RESULTS: In patients with T2DM, G allele carriers of rs10865710 polymorphism had significantly higher levels of glucose, triglycerides, apolipoprotein B (ApoB) and lipoprotein (a) (Lp(a)) than non-carriers, T allele carriers of rs3856806 polymorphism had significantly higher levels of glucose, low-density lipoprotein cholesterol (LDL-C), ApoB and Lp(a) than non-carriers. In patients with CAD, G allele carriers of rs10865710 polymorphism had significantly higher levels of total cholesterol (TC), ApoB and Lp(a) than non-carriers, T allele carriers of rs3856806 polymorphism had significantly higher levels of body mass index, blood pressure, TC, LDL-C and ApoB than non-carriers. Patients with one or two G alleles of rs10865710 polymorphism had significantly higher levels of Gensini scores and more diseased coronary branches than those patients without CAD. The rs3856806 polymorphism was not associated with CAD severity, but it was found to be significantly associated with T2DM/CAD, T allele frequency was significantly higher in T2DM/CAD group than that in T2DM/CAD-free group. CONCLUSIONS: The rs10865710 and rs3856806 polymorphisms in PPARG are significantly associated with glucose levels in patients with T2DM. The rs10865710 polymorphism is significantly associated with the severity of CAD, which is possibly mediated by hyperlipidaemia and hyperglycaemia.

Associations of the Polymorphisms in ADIPOQ with Circulating Levels of Adiponectin and Lipids: A Meta-Analysis.

The relationships between the rs266729, rs1501299, and rs2241766 polymorphisms in adiponectin gene (ADIPOQ) and circulating levels of adiponectin and lipids remain to be clarified. Databases including PubMed and Embase were searched for eligible studies. The random-effects model was used, and standardized mean difference (SMD) with 95% confidence interval (CI) was calculated to estimate the differences in circulating levels of adiponectin and lipids between the subjects with different genotypes. A total of 12 810, 17 319, and 21 361 subjects were identified in the analyses for the rs266729, rs1501299, and rs2241766 polymorphisms, respectively. G allele carriers of the rs266729 polymorphism had lower levels of adiponectin (SMD=-0.28, 95% CI=-0.43 to-0.12) and high-density lipoprotein cholesterol (HDL-C) (SMD=-0.10, 95% CI=-0.17 to-0.02) than CC homozygotes; T allele carriers of the rs1501299 polymorphism had higher levels of adiponectin (SMD=0.21, 95% CI=0.05 to 0.36) and HDL-C (SMD=0.09, 95% CI=0.04 to 0.15) and lower levels of triglycerides (SMD=-0.06, 95% CI=-0.12 to-0.01) than GG homozygotes; G allele carriers of the rs2241766 polymorphism had lower levels of adiponectin (SMD=-0.18, 95% CI=-0.31 to-0.05) and HDL-C (SMD=-0.12, 95% CI=-0.20 to-0.04) than TT homozygotes. This meta-analysis suggests that the rs266729, rs1501299, and rs2241766 polymorphisms of ADIPOQ are significantly associated with circulating levels of adiponectin and lipids, which may partly explain the associations between these polymorphisms and coronary artery disease.

Extracellular-vesicle containing miRNA-503-5p released by macrophages contributes to atherosclerosis.

Endothelial dysfunction, and the differentiation of smooth muscle cells (SMCs) into proliferative, secretory phenotypes, are two major pathophysiological processes in atherosclerosis. SMCs have the potential to recruit macrophages in atherosclerotic plaques, in which macrophages drive inflammatory responses. In this study, we found that microRNA-503-5p (miR-503-5p) was enriched in either extracellular vesicles (EVs), secreted by oxidized low-density lipoprotein-treated macrophages, or the EVs from peripheral blood mononuclear cells of atherosclerosis patients. miR-503-5p was transferred intercellularly from macrophages to the co-cultured human coronary artery endothelial cells (HCAECs) and HCASMCs via EVs, thus reducing the proliferative and angiogenic abilities of HCAECs and accelerating the proliferative and migrating abilities of HCASMCs. Smad family members 1, 2 and 7 were negatively regulated by miR-503-5p in HCAECs and HCASMCs. miR-503-5p was verified as an enhancer of inflammatory cytokines and adhesion molecules released by macrophages, in part via the down-regulation of smad family members 1, 2 and 7. The inhibition of miR-503-5p by lentivirus reduced atherosclerotic lesion formations in the aorta of atherosclerotic mice. Our work demonstrated a miR-503-5p- and EV-mediated mechanism for macrophage communication with HCAECs and HCASMCs in atherosclerosis. miR-503-5p is pro-atherosclerotic stimuli that may be a therapeutic target for atherosclerosis treatment.

Sulfation of Quercitrin, Epicatechin and Rutin by Human Cytosolic Sulfotransferases (SULTs): Differential Effects of SULT Genetic Polymorphisms.

Radix Bupleuri is one of the most widely used herbal medicines in China for the treatment of fever, pain, and/or chronic inflammation. Quercitrin, epicatechin, and rutin, the flavonoids present in Radix Bupleuri, have been reported to display anti-inflammatory, antitumor, and antioxidant biological activities among others. Sulfation has been reported to play an important role in the metabolism of flavonoids. In this study, we aimed to systematically identify the human cytosolic sulfotransferase enzymes that are capable of catalyzing the sulfation of quercitrin, epicatechin, and rutin. Of the thirteen known human cytosolic sulfotransferases, three (cytosolic sulfotransferase 1A1, cytosolic sulfotransferase 1C2, and cytosolic sulfotransferase 1C4) displayed sulfating activity toward quercitrin, three (cytosolic sulfotransferase 1A1, cytosolic sulfotransferase 1A3, and cytosolic sulfotransferase 1C4) displayed sulfating activity toward epicatechin, and six (cytosolic sulfotransferase 1A1, cytosolic sulfotransferase 1A2, cytosolic sulfotransferase 1A3, cytosolic sulfotransferase 1B1, cytosolic sulfotransferase 1C4, and cytosolic sulfotransferase 1E1) displayed sulfating activity toward rutin. The kinetic parameters of the cytosolic sulfotransferases that showed the strongest sulfating activities were determined. To investigate the effects of genetic polymorphisms on the sulfation of quercitrin, epicatechin, and rutin, individual panels of cytosolic sulfotransferase allozymes previously prepared were analyzed and shown to display differential sulfating activities toward each of the three flavonoids. Taken together, these results provided a biochemical basis underlying the metabolism of quercitrin, epicatechin, and rutin through sulfation in humans.

Activation of dsRNA-Dependent Protein Kinase R by MicroRNA-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance.

MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here we reported that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine TNFα. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated which, in turn, targeted the 3'-UTR of PPARα mRNA, impaired mitochondrial fatty acid ß-oxidation and induced mitochondrial and ER stress. More importantly, the upregulated miR-378a can directly bind to and activate the dsRNA-dependent protein kinase R (PKR) to sustain the metabolic stress. In vivo, genetic depletion of miR-378a prevented PKR activation, ameliorated inflammatory stress and insulin resistance. Counterbalancing the upregulated miR-378a using nanoparticles encapsulated with an anti-miR-378a oligonucleotide restored PPARα activity, inhibited PKR activation and ER stress, and improved insulin sensitivity in the fructose-fed mice. Conclusion: Our study delineated a novel mechanism of miRNA-378a in the pathogenesis of metabolic inflammation and insulin resistance through targeting metabolic signaling at both mRNA (e.g., PPARα) and protein (e.g., PKR) molecules. This novel finding of functional interaction between miRNAs (e.g., miR-378a) and cellular RNA binding protein(s) (e.g., PKR) is biologically significant as it greatly broadens the potential targets of miRNAs in cellular pathophysiological processes.

Activation of dsRNA-Dependent Protein Kinase R by miR-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance.

MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here, we report that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine tumor necrosis factor-α. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated, which, in turn, targeted the 3'-untranslated region of PPARα mRNA, impaired mitochondrial fatty acid ß-oxidation, and induced mitochondrial and endoplasmic reticulum stress. More importantly, the upregulated miR-378a can directly bind to and activate the double-strand RNA (dsRNA)-dependent protein kinase R (PKR) to sustain the metabolic stress. In vivo, genetic depletion of miR-378a prevented PKR activation and ameliorated inflammatory stress and insulin resistance. Counterbalancing the upregulated miR-378a using nanoparticles encapsulated with an anti-miR-378a oligonucleotide restored PPARα activity, inhibited PKR activation and ER stress, and improved insulin sensitivity in fructose-fed mice. Our study delineated a novel mechanism of miR-378a in the pathogenesis of metabolic inflammation and insulin resistance through targeting metabolic signaling at both mRNA (e.g., PPARα) and protein (e.g., PKR) molecules. This novel finding of functional interaction between miRNAs (e.g., miR-378a) and cellular RNA binding proteins (e.g., PKR) is biologically significant because it greatly broadens the potential targets of miRNAs in cellular pathophysiological processes.

Effects of ABCA1 gene polymorphisms on risk factors, susceptibility and severity of coronary artery disease.

BACKGROUND: The relationships between the rs1800976, rs4149313 and rs2230806 polymorphisms in ATP binding cassette protein A1 and severity of coronary artery disease (CAD) remain unclear. METHODS: Four hundred and forty-two patients with CAD and 217 CAD-free subjects were enrolled in this study. The rs1800976, rs4149313 and rs2230806 polymorphisms were genotyped by PCR-RFLP. Severity of CAD was evaluated by Gensini score system, number of stenotic coronary vessels and extent of coronary stenosis. RESULTS: C allele of the rs1800976 polymorphism, G allele of the rs4149313 polymorphism and A allele of the rs2230806 polymorphism were found to be risk alleles for CAD (p<0.05 for all). In patients with CAD, C allele of the rs1800976 polymorphism was associated with high levels of hypersensitive C reactive protein (hs-CRP) and cystatin c (CysC), and its frequency increased with percentiles of Gensini score, number of stenotic coronary vessels and extent of coronary stenosis (p<0.05 for all). The subjects with GA genotype of the rs4149313 polymorphism had higher levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B and hs-CRP than those with AA genotype (p<0.05 for all). The subjects with AA genotype of the rs2230806 polymorphism had higher levels of TC, LDL-C and uric acid than those with GA genotype (p<0.05 for all). No associations between the rs4149313 or rs2230806 polymorphism and severity of CAD were detected. CONCLUSIONS: The rs1800976 polymorphism is significantly associated with the occurrence and severity of CAD, which is possibly mediated by hs-CRP and CysC.