MSI-XGNN: an explainable GNN computational framework integrating transcription- and methylation-level biomarkers for microsatellite instability detection.

Microsatellite instability (MSI) is a hypermutator phenotype caused by DNA mismatch repair deficiency. MSI has been reported in various human cancers, particularly colorectal, gastric and endometrial cancers. MSI is a promising biomarker for cancer prognosis and immune checkpoint blockade immunotherapy. Several computational methods have been developed for MSI detection using DNA- or RNA-based approaches based on next-generation sequencing. Epigenetic mechanisms, such as DNA methylation, regulate gene expression and play critical roles in the development and progression of cancer. We here developed MSI-XGNN, a new computational framework for predicting MSI status using bulk RNA-sequencing and DNA methylation data. MSI-XGNN is an explainable deep learning model that combines a graph neural network (GNN) model to extract features from the gene-methylation probe network with a CatBoost model to classify MSI status. MSI-XGNN, which requires tumor-only samples, exhibited comparable performance with two well-known methods that require tumor-normal paired sequencing data, MSIsensor and MANTIS and better performance than several other tools. MSI-XGNN also showed good generalizability on independent validation datasets. MSI-XGNN identified six MSI markers consisting of four methylation probes (EPM2AIP1|MLH1:cg14598950, EPM2AIP1|MLH1:cg27331401, LNP1:cg05428436 and TSC22D2:cg15048832) and two genes (RPL22L1 and MSH4) constituting the optimal feature subset. All six markers were significantly associated with beneficial tumor microenvironment characteristics for immunotherapy, such as tumor mutation burden, neoantigens and immune checkpoint molecules such as programmed cell death-1 and cytotoxic T-lymphocyte antigen-4. Overall, our study provides a powerful and explainable deep learning model for predicting MSI status and identifying MSI markers that can potentially be used for clinical MSI evaluation.

Dietary fibre intake and risk of prediabetes in China: results from the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) Cohort Study.

High dietary fibre intake has been associated with a lower risk of diabetes, but the association of dietary fibre with prediabetes is only speculative, especially in China, where the supportive data from prospective studies are lacking. This study aimed to examine the association between dietary fibre intake and risk of incident prediabetes among Chinese adults. We performed a prospective analysis in 18 085 participants of the Tianjin Chronic Low-grade Systemic Inflammation and Health cohort study who were free of diabetes, prediabetes, cancer and CVD at baseline. Dietary data were collected using a validated 100-item FFQ. Prediabetes was defined based on the American Diabetes Association diagnostic criteria. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95 % CI. During 63 175 person-years of follow-up, 4139 cases of incident prediabetes occurred. The multivariable HR of prediabetes for the highest v. lowest quartiles were 0·85 (95 % CI 0·75, 0·98) (P for trend = 0·02) for total dietary fibre, 0·84 (95 % CI 0·74, 0·95) (P for trend < 0·01) for soluble fibre and 1·05 (95 % CI 0·93, 1·19) (P for trend = 0·38) for insoluble fibre. Fibre from fruits but not from cereals, beans and vegetables was inversely associated with prediabetes. Our results indicate that intakes of total dietary fibre, soluble fibre and fibre derived from fruit sources were associated with a lower risk of prediabetes.

The association between daily yogurt consumption and serum lipid profiles in the general adult population: the TCLSIH cohort study.

The purpose of this cross-sectional study is to determine the association between yogurt consumption and lipid profiles in the general Chinese population. In this cross-sectional study, a total of 26,824 participants were included from Tianjin, China. Lipid profiles were determined by automated biochemical analyser. Yogurt consumption frequency was assessed by a validated food frequency questionnaire. Analysis of covariance was used to determine the association between daily yogurt consumption and lipid profiles. In the final multivariate model, daily yogurt consumption was negatively associated with triglyceride (TG) (p for trend <0.001) and positively associated with high density lipoprotein cholesterol (HDL-C) (p for trend = 0.02). There were no significant differences (p for trend >0.05) between daily yogurt consumption and total cholesterol (TC) or low density lipoprotein cholesterol (LDL-C). Results suggested that higher daily yogurt consumption was negatively correlated with TG and positively correlated with HDL-C in the general Chinese population.

Consumption of Preserved Egg Is Associated with Modestly Increased Risk of Nonalcoholic Fatty Liver Disease in Chinese Adults.

BACKGROUND: Although preserved egg is a traditional Chinese delicacy widely consumed in China and Southeast Asian countries, whether habitual preserved egg consumption is associated with nonalcoholic fatty liver disease (NAFLD) remains unknown. OBJECTIVES: This study aimed to examine the association between preserved egg consumption and risk of NAFLD in a cohort of Chinese adults. METHODS: This prospective cohort study included 15,883 participants aged 19-88 y (58% women) from the TCLSIH (Tianjin Chronic Low-grade Systemic Inflammation and Health) cohort study who were free of liver diseases, cancer, and cardiovascular disease at baseline. Preserved egg consumption was assessed using an FFQ at baseline. NAFLD was diagnosed by transabdominal sonography during an annual health examination. Multivariable Cox proportional hazards regression models were used to calculate HRs and 95% CIs across categories of preserved egg consumption. RESULTS: During 56,002 person-years of follow-up, 3683 first incident cases of NAFLD were recorded. After adjustment for sociodemographic characteristics, lifestyle risk factors, total energy intake, egg intake, and eating patterns, the multivariable HRs (95% CIs) of incident NAFLD according to categories of preserved egg consumption were 1.00 (reference) for never, 1.05 (0.98, 1.14) for <1 time/wk, 1.09 (0.96, 1.24) for 1 time/wk, and 1.26 (1.09, 1.46) for ≥2 times/wk (P-trend < 0.01). The results were robust to a series of sensitivity analyses. CONCLUSIONS: Habitual preserved egg consumption is associated with a modestly higher risk of NAFLD among the Chinese adult population. The mechanism underlying this association warrants further research.This trial was registered at www.umin.ac.jp/ctr/ as UMIN000027174.

Association between consumption frequency of honey and non-alcoholic fatty liver disease: results from a cross-sectional analysis based on the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) Cohort Study.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Recent evidence has suggested the protective effects of honey consumption against the metabolic syndrome, but the association between honey intake and NAFLD is still unclear. We investigated how the consumption frequency of honey was associated with NAFLD in the general population. This was a cross-sectional study of 21 979 adults aged 20-90 years. NAFLD was diagnosed based on the ultrasound-diagnosed fatty liver without significant alcohol intake and other liver diseases. Diet information, including consumption frequency of honey, was assessed by a validated 100-item FFQ. OR with 95 % CI were calculated by the binary logistic regression model, adjusting for confounding factors identified by the directed acyclic graph. Overall, 6513 adults (29·6 %) had NAFLD. Compared with participants consuming ≤1 time/week of honey, the multivariable OR of NAFLD were 0·86 (95 % CI 0·77, 0·97) for 2-6 times/week and 1·10 (95 % CI 0·95, 1·27) for ≥1 times/d (Pfor trend = 0·90). The results were generally similar in subgroups of BMI at a cut-point of 24·0 kg/m2 (Pfor interaction = 0·10). In this large-scale study, consuming honey 2-6 times/week was inversely associated with NAFLD, whereas consuming honey ≥1 times/d had no association with NAFLD. These results need replication in other large-scale prospective studies.

Riboflavin deficiency alters cholesterol homeostasis partly by reducing apolipoprotein B100 synthesis in HepG2 cells.

Riboflavin deficiency led to lower blood cholesterol level and higher content of hepatic cholesterol in rats and the mechanisms are not clarified yet. We hypothesized that riboflavin deficiency might alter cholesterol homeostasis via apolipoprotein B100, one of the important proteins in cholesterol transport. To test this hypothesis, HepG2 cells were cultured in riboflavin-deficient media for 4 days to develop riboflavin deficiency. Compared to riboflavin-sufficient cells, the mRNA (0. 37 ± 0.04 vs 1.03 ± 0.29 relative expression level, n = 3) and protein expressions of apolipoprotein B100 (intracellular: 173.7 ± 14.4 vs 254.8 ± 47.2 µg/mg protein; extracellular: 93.8 ± 31.1 vs 161.6 ± 23.9 µg/mg protein; n = 3) were significantly reduced in riboflavin-deficient cells (P < 0.05). Endoplasmic reticulum oxidoreductin 1 and protein disulfide isomerase, two enzymes involved in the oxidative folding of apolipoprotein B100, were also lower remarkably in expression at both mRNA and protein levels. Meanwhile, intracellular cholesterol was increased (256.3 ± 17.1 µM/g protein vs 181.4 ± 23.9 µM/g protein, n = 4) and extracellular cholesterol decreased (110.0 ± 23.2 µM/g protein vs 166.2 ± 34.6 µM/g protein, n = 4) significantly in riboflavin-deficient cells (P < 0.05). Very low-density lipoprotein was also diminished (29.0 ± 6.1 µM/g protein vs 67.0 ± 11.0 µM/g protein, n = 4) in the culture media (P < 0.05). These findings suggest that riboflavin deficiency alters cholesterol homeostasis partly by reducing apolipoprotein B100 synthesis in HepG2 cells.

Association between edible mushroom intake and the prevalence of newly diagnosed non-alcoholic fatty liver disease: results from the Tianjin Chronic Low-Grade Systemic Inflammation and Health Cohort Study in China.

Animal studies have suggested that mushroom intake can alleviate non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory and antioxidant properties. However, the association between mushroom intake and NAFLD is unknown in humans. We aimed to investigate the association of mushroom intake with NAFLD among Chinese adults. This is a cross-sectional study of 24 236 adults (mean (standard deviation) age: 40·7 (sd 11·9) years; 11 394 men (47·0 %)). Mushroom intake was assessed via a validated FFQ. Newly diagnosed NAFLD was identified based on the results of annual health examinations, including ultrasound findings and a self-reported history of the disease. Multiple logistic models were used to examine the association between mushroom intake and NAFLD. The prevalence of newly diagnosed NAFLD was 19·0 %. Compared with those consuming mushrooms less frequently (≤1 time/week), the fully adjusted OR of newly diagnosed NAFLD were 0·95 (95 % CI 0·86, 1·05) for those consuming 2-3 times/week and 0·76 (95 % CI 0·63, 0·92) for those consuming ≥4 times/week (Pfor trend = 0·01). The inverse association was consistent in subgroups defined by age, sex and BMI. In conclusion, higher mushroom intake was significantly associated with lower prevalence of NAFLD among Chinese adults. Future research is required to understand the causal association between mushroom intake and NAFLD.

Associations between honey consumption and prehypertension in adults aged 40 years and older.

Background: Honey has been shown to have multiple positive effects on human health. However, data on the associations of honey consumption with prehypertension are scarce. The aim of this study was to investigate whether honey consumption is associated with prehypertension in a Chinese population. Method: A cross-sectional study was conducted in 4,561 individuals aged ≥40 years. A validated 100-item semi-quantitative food frequency questionnaire was used to assess honey consumption. Blood pressure was measured at least twice by trained nurses. Multiple logistic regression models were used to explore the associations between honey consumption and prehypertension. Results: After adjustment for potential confounders, the odds ratios and 95% confidence intervals of prehypertension across increasing frequency of honey consumption were 1.00 (reference) for almost never, 1.17 (0.96, 1.41) for ≤6 times/week, and 1.25 (0.86, 1.84) for ≥7 times/week in men (P for trend = 0.09); 1.00 (reference) for almost never, 0.76 (0.62, 0.92) for ≤6 times/week, and 0.84 (0.63, 1.12) for ≥7 times/week in women (P for trend = 0.055), respectively. Conclusion: Our results showed that light-to-moderate intake of honey was associated with lower prevalence of prehypertension in women, but not men. Future studies are required to confirm these associations.

Vitamin D is related to handgrip strength in adult men aged 50 years and over: A population study from the TCLSIH cohort study.

OBJECTIVE: Handgrip strength (HGS) begins an accelerating decline around 50 years. Many of the studies performed in old adults have demonstrated a significant relationship between vitamin D and HGS, but the studies performed in participants with a broad age range have yielded conflicting results. The purpose of the study was to investigate the relationship between vitamin D and HGS using age 50 as a specific cut-off. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Totally 5102 participants (2911 males, 2191 females) from the TCLSIH Cohort. MEASUREMENTS: Serum concentration of 25-hydroxyvitamin D (25(OH)D) was measured using an enzyme immunoassay. We divided participants into quartiles according to 25(OH)D, and the ranges for increasing quartiles were as follows: (males [≥50 years]: 10.94-31.85, 31.88-43.01, 43.20-56.06, 56.20-143.0; males [<50 years]: 11.11-34.68, 34.71-46.91, 46.96-59.45, 59.50-143.7; females [≥50 years]: 7.21-30.01, 30.02-40.18, 40.21-52.44, 52.49-275.4; females [<50 years]: 5.29-28.91, 28.92-40.19, 40.20-51.90, 51.91-140.2). HGS was measured with a hydraulic hand-held dynamometer. Analysis of covariance was employed to explore the relationship. RESULTS: Among males aged above 50 years, the means (95% confidence interval) for HGS per body weight across the categories of serum 25(OH)D concentration were 0.523 (0.430-0.638), 0.545 (0.447-0.664), 0.543 (0.446-0.661), 0.546 (0.449-0.664) (Ptrend  < 0.01) after adjustment for potential confounding factors. However, no relationships were observed between serum 25(OH)D concentration and HGS in males aged below 50 years and females in the whole age range. CONCLUSIONS: Serum 25(OH)D concentration was significantly related to HGS in males aged above 50 years, independent of confounding factors. Future studies are needed to clarify the age and sex relationship between serum 25(OH)D concentration and HGS.

Association between nut consumption and non-alcoholic fatty liver disease in adults.

BACKGROUND & AIMS: Increased nut consumption has been associated with reduced inflammation, insulin resistance, and oxidative stress. Although these factors are closely involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), few studies have focused on the association between nut consumption and NAFLD in the general population. We aimed to investigate the association of nut consumption and NAFLD in an adult population. METHODS: A total of 23 915 participants from Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) Cohort Study were included in this study. Information on dietary intake was collected using a validated food frequency questionnaire. Abdominal ultrasonography was done to diagnose NAFLD. Multivariable logistic regression was used to assess the association of nut consumption with NAFLD. RESULTS: After adjusting for sociodemographic, medical, dietary, and lifestyle variables, the odds ratios (95% confidence interval) for NAFLD across categories of nut consumption were 1.00 (reference) for <1 time/week, 0.91 (0.82, 1.02) for 1 time/week, 0.88 (0.76, 1.02) for 2-3 times/week, and 0.80 (0.69, 0.92) for ≥4 times/week (P for trend < 0.01). These associations were attenuated but remained significant after further adjustment for blood lipids, glucose, and inflammation markers. CONCLUSIONS: Higher nut consumption was significantly associated with lower prevalence of NAFLD. Further prospective studies and randomized trials are required to ascertain the causal association between nut consumption and NAFLD.

The relationship between Helicobacter pylori infection and depressive symptoms in the general population in China: The TCLSIH cohort study.

BACKGROUND: Depressive symptoms are a common, debilitating, and costly public health issue. Helicobacter pylori (H pylori) infection cause changes in the normal physiological state of the gastrointestinal (GI) flora. Although the physiological state of the GI tract is closely related to mental disorders, few population studies have examined the relationship between H pylori infection and depressive symptoms in the general population. The aim of this study was to examine whether H pylori infection is related to depressive symptoms among the general adult population. MATERIALS AND METHODS: This cross-sectional study included 5558 inhabitants of Tianjin, China. H pylori infection was diagnosed with the carbon 13 breath test. Depressive symptoms were assessed using the Chinese version of 20-item Self-rating Depression Scale (SDS) with three cutoffs (45, 48, and 50) to indicate elevated depressive symptoms. Multiple logistic regression analysis were conducted to assess the association between H pylori infection and depressive symptoms. RESULTS: The prevalence of depressive symptoms (SDS ≥ 45) was 12.7% in men and 17.4% in women. In multivariable models, the odds ratios and 95% confidence interval of having depressive symptoms by H pylori infection were 1.25 (1.01-1.56), 1.46 (1.11-1.91), and 1.46 (1.05-2.06) for three cutoffs: 45, 48, and 50 in women. However, no significant difference was found between H pylori infection and depressive symptoms in men. CONCLUSIONS: This study firstly suggested that H pylori infection was related to depressive symptoms in women in the general adult population. Further prospective studies or randomized trials are required to clarify the causality.

Association of dietary patterns with depressive symptoms in Chinese postmenopausal women.

Many components in diet have regulated oxidative stress, inflammatory reaction and even balance oestrogen levels. Because these factors are closely associated with depressive symptoms in postmenopausal women, it is considered that dietary factors are able to prevent and control depressive symptoms. On the other hand, a dietary pattern that considers the correlations and synergies between foods and nutrients is expected to have a greater impact on disease risk. The aim of the present study is to evaluate whether dietary patterns are associated with depressive symptoms in Chinese postmenopausal women. A cross-sectional study of 2051 postmenopausal women (mean age: 58·8 (sd 7·4) years) was conducted in Tianjin, China. Dietary consumption was assessed by a valid self-administered FFQ. Principal component analysis was used to derive three major dietary patterns: 'healthy', 'sweets' and 'traditional Tianjin' from eighty-eight food items. Depressive symptoms were assessed using the Zung Self-Rating Depression Scale, and cut-off point of 48 indicating serious depressive symptoms. The association between quartile of dietary patterns and depressive symptoms was assessed using multiple logistic regression analysis. The multivariable-adjusted OR of having depressive symptoms for increasing quartile of dietary patterns were as follows: healthy, 1·00, 0·79 (95 % CI 0·49, 1·28), 0·62 (95 % CI 0·37, 1·04) and 0·57 (95 % CI 0·33, 0·97); sweets, 1·00, 0·75 (95 % CI 0·42, 1·3), 1·08 (95 % CI 0·64, 1·81) and 1·66 (95 % CI 1·03, 2·71); and traditional Tianjin, 1·00, 1·02 (95 % CI 0·58, 1·79), 0·96 (95 % CI 0·54, 1·71) and 2·53 (95 % CI 1·58, 4·16), respectively. The present study demonstrated that a healthy dietary pattern was inversely associated with depressive symptoms. On the contrary, greater adherence to sweets and traditional Tianjin dietary patterns was associated with a higher prevalence of depressive symptoms.

Estimated daily quercetin intake and association with the prevalence of type 2 diabetes mellitus in Chinese adults.

PURPOSE: Quercetin is one of potential antidiabetic substances because of its powerful antioxidant and anti-inflammatory actions. The purpose of this study is to estimate daily quercetin intake and assess the relationship between dietary quercetin intake and the prevalence of type 2 diabetes mellitus (T2DM) in a Chinese population. METHODS: Dietary intake was investigated by a validated 100-item food frequency questionnaire. Daily intakes of quercetin and nutrients were calculated accordingly. T2DM was diagnosed based on the criteria of the American Diabetes Association. Adjusted logistic regression models were used to analyze the relationship between the quartiles of quercetin intake and the prevalence of T2DM. RESULTS: The prevalences of T2DM were 8.35% in men and 4.68% in women. The main food sources of quercetin were apple, orange, and green tea. Daily intake of quercetin was 20.9 ± 2.32 mg/day (mean ± SD). After adjusting for potentially confounding factors, the odds ratios (95% CI) for T2DM across the ascending quartiles of quercetin intake were: 1.00 (reference), 0.75 (0.60-0.95), 0.76 (0.59-0.99), and 0.63 (0.51-0.94). CONCLUSIONS: The results of the present study showed that quercetin intake was inversely related to the prevalence of T2DM in the Chinese population, suggesting a protective effect of quercetin in the development of T2DM.

The relationship between red blood cell distribution width and atrial fibrillation in Asian population: A cross-sectional study.

BACKGROUND: Red blood cell distribution width (RDW) was related with increased risk of mortality and adverse cardiovascular outcomes. However, it is uncertain whether RDW is related to the prevalence of atrial fibrillation (AF) in Asian population. The aim of this study was to assess the relationship between RDW and AF in a large Chinese population. METHODS: We performed a cross-sectional study to examine the relationship between RDW and AF among 106 998 subjects who were from the Tianjin Chronic Low-grade Systemic Inflammation and Health Cohort Study. AF was diagnosed using electrocardiography, and RDW was measured using an automated hematology analyzer. Multiple logistic regression models were conducted to examine the relation between tertiles of RDW and AF. RESULTS: The overall prevalence of AF was 0.1% (129/106 998). After adjustments for potential confounding factors, the odds ratios (95% confidence intervals) of AF across increasing tertiles of RDW were 1.00 (reference), 1.08 (0.69, 1.67), and 2.65 (1.75, 4.07) (P for trend < .0001), respectively. CONCLUSIONS: The study demonstrated that elevated RDW is significantly related to higher prevalence of AF in a general Chinese population. Large prospective studies are needed to confirm this finding.

Relationship between serum levels of immunoglobulins and metabolic syndrome in an adult population: A population study from the TCLSIH cohort study.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) is a combination of metabolic disorders that increase the risk of developing cardiovascular disease, and inflammation is considered as a pathological basis for MetS. Immunoglobulins (Igs) are the major secretory products of the adaptive immune system. However, no large-scale population study has focused on a possible relationship between Igs and MetS. We designed a cross-sectional study to investigate the relationship between Igs and prevalence of MetS in a large-scale adult population. METHODS AND RESULTS: A total of 10,289 participants were recruited among residents in Tianjin, China. Metabolic syndrome was defined in accordance with the criteria of the American Heart Association scientific statements of 2009. Serum levels of Igs were determined by immunonephelometry. Multiple logistic regression models were used to assess the relationship between the quintiles of serum levels of Igs and the prevalence of MetS. The overall prevalence of MetS was 36.1%. The mean (standard deviation) values of Igs (IgG, IgE, IgM, and IgA) were 1205.7 (249.3) mg/dL, 93.1 (238.9) IU/mL, 105.7 (57.3) mg/dL, and 236.2 (97.6) mg/dL, respectively. The adjusted odds ratios (95% confidence interval) of MetS for the highest quintile of Igs (IgG, IgE, IgM, and IgA), when compared to the lowest quintile, were 0.81 (0.70, 0.95), 0.97 (0.83, 1.12), 1.13 (0.97, 1.33), and 1.52 (1.30, 1.77), respectively. CONCLUSIONS: This study demonstrated that decreased IgG and increased IgA are independently related to a higher prevalence of MetS. The results indicate that the Igs might be useful predictive factors for MetS in the general adult population.

The association between thyroid function and incidence of metabolic syndrome in euthyroid subjects: Tianjin chronic low-grade systemic inflammation and health cohort study.

OBJECTIVE: Thyroid hormones (THs) are primarily responsible for the regulation of energy homeostasis and metabolism. However, few prospective studies have assessed the association between THs and metabolic syndrome (MetS) in a general population. We therefore designed a cohort study to examine whether serum TH levels within the reference range are predictive factors for developing MetS in adults. DESIGN: Prospective cohort study. PARTICIPANTS: A prospective study (n = 6119) was performed in Tianjin, China. Participants without a history of MetS were followed up for 1 to 3 years with a median follow-up duration of 2 years. MEASUREMENTS: Serum free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels were measured by chemiluminescence immunoassay. MetS was defined in accordance with the criteria of the American Heart Association scientific statements of 2009. THs, TSH levels and MetS were assessed yearly during the follow-up. Adjusted Cox proportional hazards regression models were used to assess the associations between FT3, FT4 and TSH quintiles and MetS. RESULTS: The incidence of MetS was 17.7% (96 per 1000 person-years). In the final multivariate models, the hazard ratios (95% confidence interval) for MetS across serum FT3 quintiles were 1.00 (reference), 1.03 (0.84, 1.25), 1.14 (0.94, 1.38), 1.09 (0.90, 1.32) and 1.33 (1.11, 1.61), respectively (P for trend <.01). However, no significant associations between FT4, TSH and MetS were observed. CONCLUSIONS: This population-based prospective cohort study suggests that increased serum FT3 level, rather than FT4 and TSH, is an independent predictor for developing MetS in euthyroid subjects.

Glutathione homeostasis is significantly altered by quercetin via the Keap1/Nrf2 and MAPK signaling pathways in rats.

Previously, we showed that 0.5% quercetin simultaneously decreased serum homocysteine and glutathione (GSH) levels in rats. The aim of the present study was to investigate the effects of 0.5% quercetin on GSH metabolism, related enzymes and signal pathways in rats. Rats were fed the control diet and 0.5% quercetin-supplemented diet for 6 weeks. The results showed that quercetin reduced serum and hepatic content of GSH and the ratio of GSH and oxidized glutathione (GSSG), enhanced hepatic activity and mRNA expression of glutathione S-transferase (GST), inhibited hepatic activity and mRNA expression of glutamate cysteine ligase (GCL), and decreased hepatic glutathione reductase (GR) mRNA expression. Levels of phosphorylated p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinases (MAPKs) increased, while that of nuclear factor E2-like 2 (Nrf2) protein decreased after quercetin treatment. However, no significant hepatotoxicity was noted. We concluded that quercetin treatment altered hepatic GSH metabolism by modulating GSH metabolic enzyme activities and mRNA expression in rats, and p38, ERK1/2 MAPKs, and Nrf2 were involved in modulating GSH metabolism-related enzymes.

Effects of riboflavin deficiency and high dietary fat on hepatic lipid accumulation: a synergetic action in the development of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Riboflavin, one of water soluble vitamins, plays a role in lipid metabolism and antioxidant function. However, the effects of riboflavin deficiency on NAFLD development have not yet to be fully explored. METHODS: In the present study, an animal model of NAFLD was induced by high fat diet feeding in mice and a cellular model of NAFLD was developed in HepG2 cells by palmitic acid (PA) exposure. The effects of riboflavin deficiency on lipid metabolism and antioxidant function were investigated both in vivo and in vitro. In addition, the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) was studied in HepG2 cells using gene silencing technique. RESULTS: The results showed that riboflavin deficiency led to hepatic lipid accumulation in mice fed high fat diet. The expressions of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1) were up-regulated, whereas that of adipose triglyceride lipase (ATGL) down-regulated. Similar changes in response to riboflavin deficiency were demonstrated in HepG2 cells treated with PA. Factorial analysis revealed a significant interaction between riboflavin deficiency and high dietary fat or PA load in the development of NAFLD. Hepatic PPARγ expression was significantly upregulated in mice fed riboflavin deficient and high fat diet or in HepG2 cells treated with riboflavin deficiency and PA load. Knockdown of PPARγ gene resulted in a significant reduction of lipid accumulation in HepG2 cells exposed to riboflavin deficiency and PA load. CONCLUSIONS: There is a synergetic action between riboflavin deficiency and high dietary fat on the development of NAFLD, in which PPARγ may play an important role.

Quercetin Alleviates Insulin Resistance and Repairs Intestinal Barrier in db/db Mice by Modulating Gut Microbiota.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which seriously affects public health. Gut microbiota remains a dynamic balance state in healthy individuals, and its disorder may affect health status and even results in metabolic diseases. Quercetin, a natural flavonoid, has been shown to have biological activities that can be used in the prevention and treatment of metabolic diseases. This study aimed to explore the mechanism of quercetin in alleviating T2DM based on gut microbiota. db/db mice were adopted as the model for T2DM in this study. After 10 weeks of administration, quercetin could significantly decrease the levels of body weight, fasting blood glucose (FBG), serum insulin (INS), the homeostasis model assessment of insulin resistance (HOMA-IR), monocyte chemoattractant protein-1 (MCP-1), D-lactic acid (D-LA), and lipopolysaccharide (LPS) in db/db mice. 16S rRNA gene sequencing and untargeted metabolomics analysis were performed to compare the differences of gut microbiota and metabolites among the groups. The results demonstrated that quercetin decreased the abundance of Proteobacteria, Bacteroides, Escherichia-Shigella and Escherichia_coli. Moreover, metabolomics analysis showed that the levels of L-Dopa and S-Adenosyl-L-methionine (SAM) were significantly increased, but 3-Methoxytyramine (3-MET), L-Aspartic acid, L-Glutamic acid, and Androstenedione were significantly decreased under quercetin intervention. Taken together, quercetin could exert its hypoglycemic effect, alleviate insulin resistance, repair the intestinal barrier, remodel the intestinal microbiota, and alter the metabolites of db/db mice.

Vitamin B6 alleviates chronic sleep deprivation-induced hippocampal ferroptosis through CBS/GSH/GPX4 pathway.

Several studies have found that sleep deprivation (SD) can lead to neuronal ferroptosis and affect hippocampal function. However, there are currently no effective interventions. Vitamin B6 is a co-factor for key enzymes in the transsulfuration pathway which is critical for maintaining cell growth in the presence of cysteine deprivation. The results showed that SD inhibited cystine-glutamate antiporter light chain subunit xCT protein expression and caused cysteine deficiency, which reduced the synthesis of the glutathione (GSH) to trigger neuronal ferroptosis. Nissl staining further revealed significant neuronal loss and shrinkage in the CA1 and CA3 regions of the hippocampus in SD mice. Typical ferroptotic indicators characterized by lipid peroxidation and iron accumulation were showed in the hippocampus after sleep deprivation. As expected, vitamin B6 could alleviate hippocampal ferroptosis by upregulating the expression of cystathionine beta-synthase (CBS) in the transsulfuration pathway, thereby replenishing the intracellular deficient GSH and restoring the expression of GPX4. Similar anti-ferroptotic effects of vitamin B6 were demonstrated in HT-22 cells treated with ferroptosis activator erastin. Furthermore, vitamin B6 had no inhibitory effect on erastin-induced ferroptosis in CBS-knockout HT22 cells. Our findings suggested chronic sleep deprivation caused hippocampal ferroptosis by disrupting the cyst(e)ine/GSH/GPX4 axis. Vitamin B6 alleviated sleep deprivation-induced ferroptosis by enhancing CBS expression in the transsulfuration pathway.