Publications by authors named "Wenhua Ling"

184 Publications

Gut microbiota, inflammation, and molecular signatures of host response to infection.

J Genet Genomics 2021 May 3. Epub 2021 May 3.

College of Life Sciences, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China. Electronic address:

Gut microbial dysbiosis has been linked to many noncommunicable diseases. However, little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection. Here, we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers, which have recently been identified as molecular signatures predicting the progression of the COVID-19. We demonstrate that in our cohort of 990 healthy individuals without infection, this proteomic risk score is positively associated with proinflammatory cytokines mainly among older, but not younger, individuals. We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals. Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation. Overall, our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals. These results may provide novel insights into the cross-talk between gut microbiota and host immune system.
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http://dx.doi.org/10.1016/j.jgg.2021.04.002DOI Listing
May 2021

Associations between Adherence to Four A Priori Dietary Indexes and Cardiometabolic Risk Factors among Hyperlipidemic Patients.

Nutrients 2021 Jun 24;13(7). Epub 2021 Jun 24.

School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518106, China.

Little is known about which currently available a priori dietary indexes provide best guidance for reducing cardiometabolic risk factors (CMRF) among hyperlipidemic patients. This study was designed to compare the associations between four a priori dietary indexes, including Diet Balance Index (DBI-16), Chinese Healthy Eating Index (CHEI), Mediterranean Diet Score (MDS) and Dietary Approaches to Stop Hypertension (DASH) and CMRF among hyperlipidemic patients. A total of 269 participants were enrolled into the cross-sectional study. DBI-16, CHEI, MDS, and DASH scores were calculated using established methods. CMRF was measured using standard methods. DBI-total scores (DBI-TS) were inversely associated with triglyceride concentrations and TC:HDL-C ratio, and positively associated with HDL-C and ApoA1 concentrations (all < 0.05), while the results for DBI-low bound scores (DBI-LBS) were opposite. DBI-high bound scores (DBI-HBS) and DASH scores were positively and inversely associated with glucose concentrations, respectively (both < 0.05). Higher diet quality distance (DQD) was positively associated with higher TC, LDL-C and ApoB concentrations, and TC:HDL-C and LDL-C:HDL-C ratios, and lower HDL-C and ApoA1 concentrations and ApoA1:ApoB ratio (all < 0.05). CHEI scores were inversely associated with triglyceride concentrations ( = 0.036). None of the dietary indexes was associated with blood pressures. DBI-16 provided most comprehensive evaluations of the overall diet quality and balance for optimizing cardiometabolic health among hyperlipidemic individuals.
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http://dx.doi.org/10.3390/nu13072179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308401PMC
June 2021

Association between plasma S-adenosylmethionine and risk of mortality in patients with coronary artery disease: A cohort study.

Am J Clin Nutr 2021 Jun 30. Epub 2021 Jun 30.

Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.

Background: S-adenosylmethionine (SAM) as methyl donors participates in methylation and is converted into S-adenosylhomocysteine (SAH), which is a precursor of homocysteine. Increased plasma SAH and homocysteine are associated with increased risk of cardiovascular disease. However, the relation of plasma SAM with cardiovascular risk is still unclear.

Objectives: To determine the relation between plasma SAM and risk of mortality among patients with coronary artery disease (CAD).

Methods: Baseline plasma SAM concentrations were measured in 1553 patients with CAD from the Guangdong Coronary Artery Disease Cohort between October 2008 and December 2011. Proportional hazards Cox analyses were performed to ascertain associations between SAM and risk of all-cause and cardiovascular mortality.

Results: After a median follow-up of 9.2 (IQR: 8.5-10.2) y, of 1553 participants, 321 had died, including 227 deaths from cardiovascular diseases. Patients in the lowest quartile of SAM concentrations had a higher risk of all-cause death (HR, 1.59; 95% CI: 1.14, 2.21) and cardiovascular death (HR, 2.14; 95% CI: 1.41, 3.27) than those in the highest quartile in multivariable adjusted analysis. Each 1-SD decrease in the SAM concentration remained associated with a 42% greater risk of total death (HR, 1.42; 95% CI: 1.23, 1.64) and a 66% higher risk of cardiovascular death (HR, 1.66; 95% CI: 1.37, 2.01) after fully adjusting for other cardiovascular risk factors. Furthermore, each 1-SD decrease in plasma SAM/SAH ratio, as the methylation index, was also inversely associated with the risk of all-cause (HR, 1.80; 95% CI: 1.42, 2.29) and cardiovascular mortality (HR, 1.68; 95% CI: 1.29, 2.19) in fully adjusted analyses.

Conclusions: Our data show a significant inverse relation between plasma SAM and risk of mortality in patients with CAD after adjustment for homocysteine, SAH, and other cardiovascular disease risk factors.
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http://dx.doi.org/10.1093/ajcn/nqab210DOI Listing
June 2021

Are the different MAFLD subtypes based on the inclusion criteria correlated with all-cause mortality?

J Hepatol 2021 Jun 18. Epub 2021 Jun 18.

Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.06.013DOI Listing
June 2021

Epigenetic regulation of TXNIP-mediated oxidative stress and NLRP3 inflammasome activation contributes to SAHH inhibition-aggravated diabetic nephropathy.

Redox Biol 2021 09 5;45:102033. Epub 2021 Jun 5.

Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China. Electronic address:

S-adenosylhomocysteine (SAH) is hydrolyzed by SAH hydrolase (SAHH) to homocysteine and adenosine. Increased plasma SAH levels were associated with disturbed renal function in patients with diabetes. However, the role and mechanism of SAHH in diabetic nephropathy is still unknown. In the present study, we found that inhibition of SAHH by using its inhibitor adenosine dialdehyde (ADA) accumulates intracellular or plasma SAH levels and increases high glucose-induced podocyte injury and aggravates STZ-induced diabetic nephropathy, which is associated with Nod-like receptor protein 3 (NLRP3) inflammasome activation. Inhibition or knockout of NLRP3 attenuates SAHH inhibition-aggravated podocyte injury and diabetic nephropathy. Additionally, SAHH inhibition increases thioredoxin-interacting protein (TXNIP)-mediated oxidative stress and NLRP3 inflammasome activation, but these effects were not observed in TXNIP knockout mice. Mechanistically, SAHH inhibition increased TXNIP by inhibiting histone methyltransferase enhancer of zeste homolog 2 (EZH2) and reduced trimethylation of histone H3 lysine 27 and its enrichment at promoter of early growth response 1 (EGR1). Moreover, EGR1 is activated and enriched at promoters of TXNIP by SAHH inhibition and is essential for SAHH inhibition-induced TXNIP expression. Inhibition of EGR1 protected against SAHH inhibition-induced NLRP3 inflammasome activation and oxidative stress and diabetic nephropathy. Finally, the harmful effects of SAHH inhibition on inflammation and oxidative stress and diabetic nephropathy were also observed in heterozygote SAHH knockout mice. These findings suggest that EZH2/EGR1/TXNIP/NLRP3 signaling cascade contributes to SAHH inhibition-aggravated diabetic nephropathy. Our study firstly provides a novel insight into the role and mechanism of SAHH inhibition in diabetic nephropathy.
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http://dx.doi.org/10.1016/j.redox.2021.102033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209273PMC
September 2021

Egg consumption associated with all-cause mortality in rural China: a 14-year follow-up study.

Eur J Public Health 2021 Jul;31(3):613-618

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.

Background: Dietary recommendations regarding egg intake remain controversial topic for public health. We hypothesized that there was a positive association between egg consumption and all-cause mortality.

Methods: To test this hypothesis, we enrolled 9885 adults from a community-based cohort in Anhui Province, China during 2003-05. Egg consumption was assessed by food questionnaire. Stratified analyses were performed for age, sex, body mass index (BMI), blood pressure, smoking, drinking and laboratory tests.

Results: After an average follow-up of 14.1 years, 9444 participants were included for analysis. A total of 814 deaths were recorded. Participants' BMI and lipid profile had no significantly difference between three egg consumption groups. BMI was 21.6±2.7 of the whole population, especially BMI>24 was only 17.3%. A bivariate association of egg consumption >6/week with increased all-cause mortality was observed compared with ≤6/week (RR: 1.35, 95% CI: 1.05, 1.73, P = 0.018). A significant interaction was observed for BMI ≥ 21.2 kg/m2 vs. BMI<21.2 kg/m2 (P for interaction: 0.001). No other significant interactions were found.

Conclusions: In this study, consuming >6 eggs/week increased risk of all-cause mortality, even among lean participants, especially who with BMI ≥ 21.2 kg/m2. Eggs are an easily accessible and constitute an affordable food source in underdeveloped regions. Consuming <6 eggs/week may be the most suitable intake mode.
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http://dx.doi.org/10.1093/eurpub/ckaa250DOI Listing
July 2021

Hepatic fibroblast growth factor 21 is involved in mediating functions of liraglutide in mice with dietary challenge.

Hepatology 2021 Apr 13. Epub 2021 Apr 13.

Div. of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Canada.

Background And Aims: Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by GLP-1-based diabetes drugs. As GLP-1 receptor (GLP-1R) is unlikely expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse-hepatocytes; determine the involvement of GLP-1R, and clarify whether FGF21 mediates certain functions of the GLP-1R agonist liraglutide.

Approaches And Results: Liver FGF21 expression was assessed in mice with daily liraglutide injection for 3 days, or in mouse primary hepatocytes (MPH) with direct liraglutide treatment. Effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high fat diet (HFD)-fed mice, in comparison with the DPP-4 inhibitor sitagliptin. Animal studies were also performed in Glp1r mice and hepatic FGF21 knockout (lFgf21-KO) mice. In wild-type mice with RNA-seq and qRT-PCR, we observed liraglutide-stimulated hepatic Fgf21 expression, and the lack of Glp1r expression in mouse liver. In MPH, liraglutide did not stimulate Fgf21. In HFD-induced obese mice, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, while their effect on reducing body-weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide-treated but not sitagliptin-treated mice. In HFD-fed Glp1r mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21-KO mice on dietary challenge, body-weight gain attenuation and lipid homeostatic effects of liraglutide was lost or significantly reduced.

Conclusions: We suggest that liraglutide-stimulated hepatic Fgf21 expression may require GLP-1R expressed in extra-hepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding on function of GLP-1-based drugs in nonalcoholic fatty liver disease (NAFLD).
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http://dx.doi.org/10.1002/hep.31856DOI Listing
April 2021

Isoflavone biomarkers are inversely associated with atherosclerosis progression in adults: a prospective study.

Am J Clin Nutr 2021 Jul;114(1):203-213

Department of Epidemiology, Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China.

Background: Many studies have examined associations between dietary isoflavones and atherosclerosis, but few used objective biomarkers.

Objectives: We examined the associations of isoflavone biomarkers (primary analyses) and equol production (secondary analyses) with the progression of carotid intima-media thickness (cIMT), and whether inflammation, systolic blood pressure (SBP), blood lipids, and sex hormone-binding globulin (SHBG) mediated these associations, in Chinese adults.

Methods: This 8.8-y prospective study included 2572 subjects (40-75 y old) from the GNHS (Guangzhou Nutrition and Health Study; 2008-2019). The concentrations of daidzein, genistein, and equol were assayed by an HPLC-tandem MS in serum (n = 2572) at baseline and in urine (n = 2220) at 3-y intervals. The cIMT of the common carotid artery (CCA) and bifurcation segment were measured by B-mode ultrasound every 3 y, and the progressions of cIMT ( ∆cIMT) were estimated using the regression method.

Results: Multivariable linear mixed-effects models (LMEMs) and ANCOVA revealed that subjects with higher serum isoflavones tended to have lower increases of CCA-cIMT. The mean ± SEM differences in 8.8-y ∆CCA-cIMT between extreme tertiles of serum isoflavones were -17.1 ± 8.4, -20.6 ± 8.3, and -23.3 ± 10.4 μm for daidzein, total isoflavone, and equol (P-trends < 0.05), respectively. LMEMs showed that the estimated yearly changes (95% CIs) (μm/y) in CCA-IMT were -2.0 (-3.8, -0.3), -1.9 (-3.6, -0.1), and -2.1 (-3.8, -0.3) in the highest (compared with the lowest) tertile of daidzein, genistein, and total isoflavones, respectively (P-interaction < 0.05). Path analyses indicated that the serum equol-atherosclerosis association was mediated by increased SHBG and decreased SBP. Similar beneficial associations were observed in the secondary analyses.

Conclusions: Serum isoflavones and equol exposure were associated with reduced cIMT progression, mediated by SHBG and SBP.
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http://dx.doi.org/10.1093/ajcn/nqab008DOI Listing
July 2021

Resveratrol enhances trans-intestinal cholesterol excretion through selective activation of intestinal liver X receptor alpha.

Biochem Pharmacol 2021 04 23;186:114481. Epub 2021 Feb 23.

Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, PR China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou 510080, PR China. Electronic address:

Resveratrol (RSV) is a dietary polyphenol with well-documented cardio-protective activity, but its effects on blood cholesterol levels remain to be established. Due to its poor bioavailability, tissue accumulation of RSV is extremely low except for that in the small intestine. In the present study, we aimed to investigate the dose-dependent effects of RSV on blood cholesterol levels and the involvement of small intestine in the cholesterol-lowering impacts of RSV. Mice were administrated with RSV at various doses with high-fat diet (HFD) or high-fat and high-cholesterol diet (HCD) for 12 weeks. The fecal neutral sterol contents were analyzed, and intestinal perfusion test was performed. An enteric barrier model using Caco-2 cells was established. We observed that RSV reduced blood cholesterol levels in a dose-dependent manner in mice fed with HFD or HCD. Further investigation revealed that RSV administration increased the bile acid pool size but did not affect cholesterol consumption or de novo cholesterol synthesis. Interestingly, RSV promoted trans-intestinal cholesterol excretion (TICE) by 2-fold in the intestinal perfusion test. In addition, RSV upregulated the expressions of ATP-binding cassette sub-family G member 5 or 8 (Abcg5/8) and ATP-binding cassette sub-family B member 1a or 1b (Abcb1a/b) by up to 8 times in the duodenum mucosa but not in the liver. RSV also significantly downregulated the expression of intestinal Niemann-Pick C1-Like 1 (Npc1l1). Knock-down of liver X receptor alpha (LXRα) but not Sirt1 by siRNA significantly blocked RSV-induced cholesterol excretion in Caco-2 cells. In conclusion, RSV could decrease circulating cholesterol levels through enhancing TICE and limiting cholesterol absorption via selective activation of intestinal LXRα.
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http://dx.doi.org/10.1016/j.bcp.2021.114481DOI Listing
April 2021

Protocatechuic Acid Protects Platelets from Apoptosis via Inhibiting Oxidative Stress-Mediated PI3K/Akt/GSK3β Signaling.

Thromb Haemost 2021 Jul 5;121(7):931-943. Epub 2021 Feb 5.

Department of Nutrition and Food Safety, School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong Province, China.

Oxidative stress plays crucial roles in initiating platelet apoptosis that facilitates the progression of cardiovascular diseases (CVDs). Protocatechuic acid (PCA), a major metabolite of anthocyanin cyanidin-3-O-β-glucoside (Cy-3-g), exerts cardioprotective effects. However, underlying mechanisms responsible for such effects remain unclear. Here, we investigate the effect of PCA on platelet apoptosis and the underlying mechanisms in vitro. Isolated human platelets were treated with hydrogen peroxide (HO) to induce apoptosis with or without pretreatment with PCA. We found that PCA dose-dependently inhibited HO-induced platelet apoptosis by decreasing the dissipation of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and decreasing phosphatidylserine exposure. Additionally, the distributions of Bax, Bcl-xL, and cytochrome mediated by HO in the mitochondria and the cytosol were also modulated by PCA treatment. Moreover, the inhibitory effects of PCA on platelet caspase-3 cleavage and phosphatidylserine exposure were mainly mediated by downregulating PI3K/Akt/GSK3β signaling. Furthermore, PCA dose-dependently decreased reactive oxygen species (ROS) generation and the intracellular Ca concentration in platelets in response to HO. N-Acetyl cysteine (NAC), a ROS scavenger, markedly abolished HO-stimulated PI3K/Akt/GSK3β signaling, caspase-3 activation, and phosphatidylserine exposure. The combination of NAC and PCA did not show significant additive inhibitory effects on PI3K/Akt/GSK3β signaling and platelet apoptosis. Thus, our results suggest that PCA protects platelets from oxidative stress-induced apoptosis through downregulating ROS-mediated PI3K/Akt/GSK3β signaling, which may be responsible for cardioprotective roles of PCA in CVDs.
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http://dx.doi.org/10.1055/s-0040-1722621DOI Listing
July 2021

Friend or foe? ACE2 inhibitors and GLP-1R agonists in COVID-19 treatment.

Obes Med 2021 Mar 6;22:100312. Epub 2021 Jan 6.

Div. of Advanced Therapeutic, Toronto General Hospital Research Institute, University Health Network, Canada.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a pandemic since WHO made the statement on March 11, 2020. The infection is causing a high mortality in old people, especially those with obesity, type 2 diabetes (T2D) or cardiovascular diseases (CVD). Extra cautions are needed in the treatment of those patients. The CVD drugs ACEIs and ARBs, as well as the T2D drugs GLP-1R agonists, were shown to activate angiotensin-converting enzyme 2 (ACE2) expression in experimental animals. Elevated ACE2 expression may accelerate virus entrance into the host cells during the infection for its replication. However, expression of the soluble ACE2, may neutralize the virus to limit the infection and replication. Given that obese, diabetes and CVD patients often take those medicines in the treatment and prevention of blood pressure and glucose elevation, it remains to be determined whether those medicines represent friend or foe in the treatment of COVID-19. We suggest that retrospective studies should be conducted to determine the exact impact of those medicines in obese, diabetic, or CVD patients who had COVID-19. Results obtained will provide guidance whether those drugs can be utilized in COVID-19 patients with obesity, diabetic, or CVD.
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http://dx.doi.org/10.1016/j.obmed.2020.100312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785422PMC
March 2021

Lactucopicrin Inhibits Cytoplasmic Dynein-Mediated NF-κB Activation in Inflammated Macrophages and Alleviates Atherogenesis in Apolipoprotein E-Deficient Mice.

Mol Nutr Food Res 2021 02 22;65(4):e2000989. Epub 2021 Jan 22.

Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, P. R. China.

Scope: Nuclear factor-κB (NF-κB) activation in macrophages aggravates atherosclerosis. Dietary plant secondary metabolites including sesquiterpene lactone lactucopicrin target multiple organs. This study is focused on the impact of lactucopicrin on NF-κB activation in inflammed macrophages and atherogenesis in a mouse model of atherosclerosis.

Methods And Results: In LPS-stimulated mouse bone marrow-derived macrophages, lactucopicrin inhibits NF-κB activation, and concomitantly represses the expression of IL-1β, IL-6, and tumor necrosis factor-alpha. This effect is not due to modulation of the inhibitor of NF-κB kinases (IKK) α/β/γ and NF-κB inhibitor α, and NF-κB/p65 DNA binding activity. Instead, the lactucopicrin effect is reliant on the inhibition of cytoplasmic dynein-mediated p65 transportation, a prerequisite step for p65 nuclear translocation. In high-fat diet-fed apolipoprotein E-deficient mice, lactucopicrin consumption dose-dependently reduces plaque area, inhibits plaque macrophage accumulation, attenuates plaque macrophage NF-κB activation, and reduces both plaque and serum inflammatory burden. However, lactucopicrin consumption does not affect the levels of serum lipids and anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor beta).

Conclusion: Dietary lactucopicrin inhibits atherogenesis in mice likely by its anti-inflammatory property. These findings suggest that dietary supplementation with lactucopicrin is a promising strategy to inhibit atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.1002/mnfr.202000989DOI Listing
February 2021

Plasma Magnesium Concentrations and Risk of Incident Cancer in Adults with Hypertension: A Nested Case-Control Study.

Ann Nutr Metab 2020 3;76(5):304-312. Epub 2020 Dec 3.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.

Objective: The association between plasma magnesium and risk of incident cancer remains inconclusive in previous studies. We aimed to investigate the prospective relationship of baseline plasma magnesium concentrations with the risk of incident cancer and to examine possible effect modifiers.

Methods: A nested case-control study with 228 incident cancer cases and 228 matched controls was conducted using data from the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013. Study outcomes included incident cancer and its subtypes.

Results: When plasma magnesium concentrations were assessed as quartiles, a significantly higher incident risk of total cancer was found in participants in quartile 1 (<0.76 mmol/L; odds ratio [OR] = 2.70; 95% CI: 1.33-5.49) and quartile 4 (≥0.89 mmol/L; OR = 2.05; 95% CI: 1.12-3.76), compared with those in quartile 3 (0.83 to <0.89 mmol/L). In cancer site-specific analyses, similar trends were found for gastrointestinal cancer, esophageal cancer, gastric cancer, breast cancer, lung cancer, and other cancers. Furthermore, none of the variables, including age, sex, current smoking status, current alcohol intake, BMI, systolic blood pressure, and total cholesterol levels at baseline significantly modified the association between plasma magnesium and cancer risk.

Conclusions: Both low and high plasma magnesium concentrations were significantly associated with an increased incident risk of cancer, compared with the reference concentrations of 0.83 to <0.89 mmol/L among hypertensive adults.
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http://dx.doi.org/10.1159/000510214DOI Listing
December 2020

Dietary fruit and vegetable intake, gut microbiota, and type 2 diabetes: results from two large human cohort studies.

BMC Med 2020 12 3;18(1):371. Epub 2020 Dec 3.

Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.

Background: Little is known about the inter-relationship among fruit and vegetable intake, gut microbiota and metabolites, and type 2 diabetes (T2D) in human prospective cohort study. The aim of the present study was to investigate the prospective association of fruit and vegetable intake with human gut microbiota and to examine the relationship between fruit and vegetable-related gut microbiota and their related metabolites with type 2 diabetes (T2D) risk.

Methods: This study included 1879 middle-age elderly Chinese adults from Guangzhou Nutrition and Health Study (GNHS). Baseline dietary information was collected using a validated food frequency questionnaire (2008-2013). Fecal samples were collected at follow-up (2015-2019) and analyzed for 16S rRNA sequencing and targeted fecal metabolomics. Blood samples were collected and analyzed for glucose, insulin, and glycated hemoglobin. We used multivariable linear regression and logistic regression models to investigate the prospective associations of fruit and vegetable intake with gut microbiota and the association of the identified gut microbiota (fruit/vegetable-microbiota index) and their related fecal metabolites with T2D risk, respectively. Replications were performed in an independent cohort involving 6626 participants.

Results: In the GNHS, dietary fruit intake, but not vegetable, was prospectively associated with gut microbiota diversity and composition. The fruit-microbiota index (FMI, created from 31 identified microbial features) was positively associated with fruit intake (p < 0.001) and inversely associated with T2D risk (odds ratio (OR) 0.83, 95%CI 0.71-0.97). The FMI-fruit association (p = 0.003) and the FMI-T2D association (OR 0.90, 95%CI 0.84-0.97) were both successfully replicated in the independent cohort. The FMI-positive associated metabolite sebacic acid was inversely associated with T2D risk (OR 0.67, 95%CI 0.51-0.86). The FMI-negative associated metabolites cholic acid (OR 1.35, 95%CI 1.13-1.62), 3-dehydrocholic acid (OR 1.30, 95%CI 1.09-1.54), oleylcarnitine (OR 1.77, 95%CI 1.45-2.20), linoleylcarnitine (OR 1.66, 95%CI 1.37-2.05), palmitoylcarnitine (OR 1.62, 95%CI 1.33-2.02), and 2-hydroglutaric acid (OR 1.47, 95%CI 1.25-1.72) were positively associated with T2D risk.

Conclusions: Higher fruit intake-associated gut microbiota and metabolic alteration were associated with a lower risk of T2D, supporting the public dietary recommendation of adopting high fruit intake for the T2D prevention.
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http://dx.doi.org/10.1186/s12916-020-01842-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712977PMC
December 2020

Dose-dependent reductions in plasma ceramides after anthocyanin supplementation are associated with improvements in plasma lipids and cholesterol efflux capacity in dyslipidemia: A randomized controlled trial.

Clin Nutr 2021 Apr 15;40(4):1871-1878. Epub 2020 Oct 15.

School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Food, Nutrition, and Health, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Engineering Technology Center of Nutrition Transformation, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address:

Background & Aims: Plasma ceramides have been identified as novel risk factors for metabolic and cardiovascular diseases. We aimed to evaluate the effects of dietary anthocyanins on plasma ceramides and to disentangle whether the alterations in ceramides could be related with those in other cardiometabolic risk factors in the dyslipidemia.

Methods: In a randomized double-blinded placebo-controlled trial, 176 eligible dyslipidemia subjects were randomly assigned into four groups receiving placebo, 40, 80, or 320 mg/day anthocyanins, respectively for 12 weeks.

Results: A total of 169 subjects completed the study. After 12-week intervention, dietary anthocyanins dose-dependently reduced plasma concentrations of all six ceramide species in the dyslipidemia subjects (all P values < 0.05). Specifically, 320 mg/day anthocyanins effectively lowered plasma N-palmitoylsphingosine (Cer 16:0, mean change: -28.3 ± 41.2 versus 2.9 ± 38.2, nmol/L, P = 0.018) and N-tetracosanoylsphingosine (Cer 24:0, mean change: -157.1 ± 493.9 versus 10.7 ± 439.9, nmol/L, P = 0.002) compared with the placebo. The declines in plasma Cer 16:0 and Cer 24:0 were significantly correlated with the decreases in plasma non-high-density lipoprotein cholesterol (nonHDL-C, Spearman's r = 0.32, P = 0.040 for Cer 16:0; Spearman's r = 0.35, P = 0.026 for Cer 24:0), apolipoprotein B (Spearman's r = 0.33, P = 0.031 for Cer 16:0; Spearman's r = 0.48, P = 0.002 for Cer 24:0), and total cholesterol (Spearman's r = 0.34, P = 0.026 for Cer 16:0; Spearman's r = 0.31, P = 0.042 for Cer 24:0) after 12-week 320 mg/day anthocyanin administration. Besides, we found that anthocyanins at 320 mg/day also markedly enhanced cholesterol efflux capacity in the dyslipidemia, the changes of which were positively associated with the reductions in Cer 16:0 (Spearman's r = 0.42, P = 0.006) independent of HDL-C and apolipoprotein A-I.

Conclusions: Reductions in plasma Cer 16:0 and Cer 18:0 after 12-week anthocyanin intervention were dose-dependently associated with improvements in plasma lipids and cholesterol efflux capacity in the dyslipidemia.

Clinical Trial Registration: The study was registered at ClinicalTrials.gov with the identifier No. NCT03415503.
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http://dx.doi.org/10.1016/j.clnu.2020.10.014DOI Listing
April 2021

Effect of Anthocyanins Supplementation on Serum IGFBP-4 Fragments and Glycemic Control in Patients with Fasting Hyperglycemia: A Randomized Controlled Trial.

Diabetes Metab Syndr Obes 2020 28;13:3395-3404. Epub 2020 Sep 28.

Internal Medicine Department, BaiYun Hospital, GuangZhou, GuangDong Province, People's Republic of China.

Background: Insulin-like growth factor binding protein-4 (IGFBP-4) fragments have been shown to be associated with cardiometabolic diseases. Anthocyanins as a subgroup of natural polyphenols could have benefits on treating cardiometabolic diseases. The aim of this study was to examine the effects of purified anthocyanins on serum IGFBP-4 fragments and glycemic control in patients with fasting hyperglycemia.

Methods: A set of 121 participants with elevated fasting glucose (≥5.6 mmol/L), who were originally randomly assigned to anthocyanins (320 mg/day) or placebo groups, were included in this study. Serum IGFBP-4 fragments, fasting and postload glucose, insulin, and C-peptide after a three-hour oral glucose tolerance test (OGTT) were measured at baseline and at the end of 12 weeks.

Results: Compared with placebo, anthocyanins increased serum IGFBP-4 fragments (net change 8.33 ng/mL, 95% CI [1.2, 15.47], =0.023) and decreased fasting glucose (-0.4 mmol/L [-0.71, -0.1], =0.01), 2-hour C-peptide (-1.02 ng/mL [-1.99, -0.04], =0.041) and the 3-hour area under the curve (AUC) of C-peptide (-2.19 [-4.11, -0.27], =0.026). No other significant difference in parameters for glycemic control and insulin resistance was observed.

Conclusion: Anthocyanins supplementation for 12 weeks improved serum IGFBP-4 fragments and decreased fasting glucose and postload C-peptide in patients with fasting hyperglycemia. Further studies are needed to confirm our findings and clarify the potential mechanism.

Trial Registration: ClinicalTrials.gov, NCT02689765. Registered on 6 February 2016, https://clinicaltrials.gov/ct2/show/NCT02689765.
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http://dx.doi.org/10.2147/DMSO.S266751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532046PMC
September 2020

Associations between serum total, free and bioavailable testosterone and non-alcoholic fatty liver disease in community-dwelling middle-aged and elderly women.

Diabetes Metab 2021 May 12;47(3):101199. Epub 2020 Oct 12.

Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong Province 510080, PR China. Electronic address:

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) is considered both a cause and consequence of the metabolic syndrome (MetS). While emerging evidence has indicated that testosterone is associated with MetS, the relationship between testosterone and NAFLD in women remains unclear. Therefore, this study investigated the associations between serum testosterone levels and NAFLD prevalence risk in a community-based cross-sectional study.

Methods: A total of 2117 adult women were included in the analysis. Serum total testosterone (TT) was measured by chemiluminescence immunoassay, and other testosterone-related indices, such as concentrations and percentages of calculated free testosterone (cFT) and bioavailable testosterone (BioT), and free androgen index (FAI), were also calculated. NAFLD was diagnosed by clinical criteria. Logistic regression was used to explore these associations.

Results: There were significant differences in TT, FAI, cFT and BioT between women with and without NAFLD (all P<0.001). Multivariate logistic-regression analyses demonstrated that both absolute concentrations and percentages of cFT and BioT were positively associated with NAFLD risk prevalence in all models. Adjusted ORs (95% CI) for quartile 4 vs quartile 1 of % cFT and % BioT were 5.94 (4.29-8.22) and 5.21 (3.79-7.17) in model 2, and 4.35 (3.07-6.18) and 3.58 (2.55-5.03) in model 3 (all P<0.001 for trend). In addition, quartiles of TT, FAI, cFT and BioT were significantly correlated with degree of hepatic steatosis. ROC analysis also showed that % cFT and % BioT were more accurate for predicting NAFLD prevalence than was TT.

Conclusion: Serum cFT and BioT were positively associated with NAFLD risk, and elevated levels of cFT and BioT could be independent risk factors of NAFLD prevalence in middle-aged and elderly women.
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http://dx.doi.org/10.1016/j.diabet.2020.09.007DOI Listing
May 2021

Vitamin B and risk of diabetes: new insight from cross-sectional and longitudinal analyses of the China Stroke Primary Prevention Trial (CSPPT).

BMJ Open Diabetes Res Care 2020 10;8(1)

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China

Introduction: Previous studies in mostly Western populations have yielded conflicting findings on the association of vitamin B with diabetes risk, in part due to differences in study design and population characteristics. This study sought to examine the vitamin B-diabetes association in Chinese adults with hypertension by both cross-sectional and longitudinal analyses.

Research Design And Methods: This report included a total of 16 699 participants from the China Stroke Primary Prevention Trial, with pertinent baseline and follow-up data. Diabetes mellitus was defined as either physician-diagnosed diabetes, use of glucose-lowering drugs, or fasting blood glucose (FBG) ≥7.0 mmol/L. New-onset diabetes was defined as any new case of onset diabetes during the follow-up period or FBG ≥7.0 mmol/L at the exit visit.

Results: At baseline, there were 1872 (11.2%) patients with diabetes; less than 1.5% had clinical vitamin B deficiency (<148.0 pmol/L). Over a median follow-up period of 4.5 years, there were 1589 (10.7%) cases of new-onset diabetes. Cross-sectional analyses showed a positive association between baseline vitamin B levels and FBG levels (β=0.18, 95% CI 0.15 to 0.21) and diabetes (OR=1.16, 95% CI 1.10 to 1.21). However, longitudinal analyses showed no association between baseline vitamin B and new-onset diabetes or changes in FBG levels. Among a subset of the sample (n=4366) with both baseline and exit vitamin B measurements, we found a positive association between an increase in vitamin B and an increase in FBG.

Conclusions: In this large Chinese population of patients with hypertension mostly sufficient with vitamin B, parallel cross-sectional and longitudinal analyses provided new insight into the conflicting findings of previous studies, and these results underscore the need for future studies to consider both baseline vitamin B and its longitudinal trajectory in order to better elucidate the role of vitamin B in the development of diabetes. Such findings would have important clinical and public health implications.
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http://dx.doi.org/10.1136/bmjdrc-2020-001423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539576PMC
October 2020

Associations between plasma ceramides and mortality in patients with coronary artery disease.

Atherosclerosis 2020 12 10;314:77-83. Epub 2020 Sep 10.

Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong Province, 510080, China; Guangdong Engineering Technology Center of Nutrition Transformation, Guangzhou, Guangdong Province, 510080, China. Electronic address:

Background And Aims: The relationship between ceramides and the risk of mortality among patients with coronary artery disease (CAD) is currently relatively sparse. This prospective study aimed to clarify whether plasma ceramides are associated with greater risks of cardiovascular and all-cause mortality among CAD patients.

Methods: Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to measure plasma ceramides, C16:0, C18:0, C24:0, and C24:1, in 1704 CAD patients. Cox regression models were used to estimate the association between ceramides and the risk of cardiovascular and all-cause mortality.

Results: During the median 9.3-year follow-up, 396 all-cause deaths occurred, of which 253 were cardiovascular deaths. Plasma C16:0, C18:0 and C24:1 ceramides and their ratios with C24:0 ceramide were significantly associated with increased risk of cardiovascular and all-cause mortality. After multivariable adjusted, for 1-SD increases of C16:0/C24:0, C18:0/C24:0, and C24:1/C24:0 ratios, the risk of cardiovascular mortality increased by 27%, 35%, and 21%, and the risk of all-cause mortality increased by 29%, 28%, and 24%, respectively. Patients with higher ceramide risk score had 1.81-fold (95%CI, 1.24-2.64) and 1.95-fold (95%CI, 1.43-2.65) risk of cardiovascular and all-cause mortality, respectively, compared to patients with lower ceramide risk score. The risks of cardiovascular and all-cause mortality increased by 9% for 1-point increment in the ceramide risk score. Subgroup analyses did not substantially modify the results.

Conclusions: Our study documented that distinct ceramides were significantly associated with the risks of cardiovascular and all-cause mortality in CAD patients. Further studies are warranted to determine the clinical diagnostic value of distinct ceramides in identifying patients at risk of mortality.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.09.004DOI Listing
December 2020

Anthocyanins increase serum adiponectin in newly diagnosed diabetes but not in prediabetes: a randomized controlled trial.

Nutr Metab (Lond) 2020 21;17:78. Epub 2020 Sep 21.

Center for Chronic Disease Control, NanShan, Shenzhen, People's Republic of China.

Background: Epidemiological studies have suggested that adiponectin is associated with the development of insulin resistance and type 2 diabetes. This study first examined the effect of purified anthocyanins, a group of dietary flavonoids, on serum adiponectin in patients with prediabetes and newly diagnosed diabetes.

Methods: A total of 160 patients with prediabetes (n = 90) or newly diagnosed diabetes (n = 70) were randomly assigned to either the anthocyanins group or the placebo group for 12 weeks of intervention. Serum adiponectin, a set of biomarkers related to glucolipid metabolism, anthropometric parameters, dietary intake and physical activity were measured before and after intervention.

Results: Anthocyanins increased serum adiponectin compared with placebo (net change 0.46 µg/mL, 95% CI [0.03, 0.90],  = 0.038) in the subjects with newly diagnosed diabetes. No significant difference in the change in adiponectin was observed between the two groups either in the overall subjects (0.02 µg/mL [- 0.32, 0.36],  = 0.906) or in prediabetes (- 0.35 µg/mL [- 0.85, 0.16],  = 0.174). Anthocyanins also decreased fasting glucose (- 0.5 mmol/L [- 1, - 0.04],  = 0.035) in the subjects with newly diagnosed diabetes, but no such change was observed in those with prediabetes.

Conclusions: Anthocyanins supplementation for 12 weeks improved serum adiponectin and fasting glucose in patients with newly diagnosed diabetes, but not in patients with prediabetes.

Trial Registration: ClinicalTrials.gov, NCT02689765. Registered on 6 February 2016, https://clinicaltrials.gov/ct2/show/NCT02689765.
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http://dx.doi.org/10.1186/s12986-020-00498-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507266PMC
September 2020

Anthocyanins regulate serum adipsin and visfatin in patients with prediabetes or newly diagnosed diabetes: a randomized controlled trial.

Eur J Nutr 2021 Jun 15;60(4):1935-1944. Epub 2020 Sep 15.

GuangDong Province, BaiYun Hospital, YueXiu District, GuangZhou, PR China.

Background: Epidemiological studies have suggested that adipsin and visfatin are associated with the development of type 2 diabetes. This is the first study to investigate the effects of supplementation with purified anthocyanins on serum adipsin and visfatin in patients with prediabetes or newly diagnosed diabetes.

Methods: A total of 160 participants with prediabetes or newly diagnosed diabetes (40-75 years old) were given 320 mg anthocyanins or placebo daily for 12 weeks in a randomized trial. Serum adipsin, serum visfatin, lipids and glycated hemoglobin A1c (HbA1c) were measured. The areas under the curve (AUCs) for glucose, insulin and C-peptide were determined before-and after-treatment by a standard 3-h 75 g oral glucose tolerance test (OGTT).

Results: Relatively significant increases in serum adipsin (net change 0.15 µg/mL [0.03, 0.27], p = 0.018) and decreases in visfatin (-3.5 ng/mL [-6.69, -0.31], p = 0.032) were observed between the anthocyanins and placebo groups. We also observed significant improvements in HbA1c (-0.11% [-0.22, -0.11], p = 0.033), apolipoprotein A-1 (apo A-1) (0.12 g/L [0.03, 0.21], p = 0.012) and apolipoprotein B (apo B) (-0.07 g/L [-0.14, -0.01], p = 0.033) in response to the anthocyanins intervention.

Conclusion: Purified anthocyanins supplementation for 12 weeks increased serum adipsin and decreased serum visfatin in patients with prediabetes or newly diagnosed diabetes. Trial registration ClinicalTrials.gov, identifier: NCT02689765.
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http://dx.doi.org/10.1007/s00394-020-02379-xDOI Listing
June 2021

Lower adropin expression is associated with oxidative stress and severity of nonalcoholic fatty liver disease.

Free Radic Biol Med 2020 11 15;160:191-198. Epub 2020 Aug 15.

Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, PR China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, 510080, PR China. Electronic address:

Background & Aims: Adropin has been reported to be involved in metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). However, the clinical relevance of adropin expression to the histological severity of NAFLD is unclear. This study aimed to investigate adropin expression in biopsy-proven NAFLD patients.

Methods: This case-control study enrolled a total of 109 participants, including 15 normal histological controls, 26 nonalcoholic fatty liver (NAFL), 21 nonalcoholic steatohepatitis (NASH) subjects and B-ultrasound NAFLD-free normal controls matched to the cases based on age and sex (the case:control ratio was 1:1). Liver biopsies were obtained and histological characteristics were assessed. Primary murine hepatocytes were isolated from C57BL/6J mice and incubated with doses of palmitate to induce oxidative stress.

Results: The serum adropin level in NASH patients was 9.99 ± 5.51 ng/ml, significantly lower than that in B-ultrasound normal controls (22.70 ± 6.32 ng/ml), histological normal controls (21.93 ± 6.63 ng/ml) and NAFL patients (17.82 ± 6.90 ng/ml). Serum adropin levels were negatively correlated with the histological severity of NAFLD. The lower serum adropin level predicted NASH (area under the ROC curve: 87.1%). Adropin expression in serum and liver was also negatively associated with hepatic MDA and serum 8-iso-PGF2α levels. Furthermore, palmitate rather than oleate induced oxidative stress in a dose-dependent manner with a gradient decrease in adropin expression in primary murine hepatocytes. Adropin overexpression or treatment ameliorated palmitate-induced oxidative stress in hepatocytes.

Conclusions: Circulating adropin was inversely associated with the oxidative stress and histological severity of NAFLD. It may play an important role in the development of NAFLD.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.08.005DOI Listing
November 2020

Adropin regulates hepatic glucose production via PP2A/AMPK pathway in insulin-resistant hepatocytes.

FASEB J 2020 08 24;34(8):10056-10072. Epub 2020 Jun 24.

Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China.

Adropin as a secretory peptide has shown a protective role on the disorders of glucose and lipid metabolism. However, the role and mechanism of this peptide on the hepatic glucose production has remained unclear. Adropin knockout (KO) mice were generated to explore its effects on the enhanced hepatic glucose production in obesity. We found that compared to wild-type (WT) mice, adropin-KO mice developed the unbalanced enhanced hepatic glucose production in advance of the whole-body insulin resistance (IR) by high-fat diet (HFD). Mechanistically, adropin dissociated CREB-CRTC2 and FoxO1-PGC1α complex and reduced their binding to the promoters of G6Pase and PEPCK to decrease glucose production in IR. However, these effects were not observed in insulin-sensitive hepatocytes. Furthermore, in IR hepatocytes, dampened AMPK signaling was re-activated by adropin treatment via inhibition of PP2A. To further authenticate AMPK role in vivo, we administrated HFD-fed mice with AAV8-CA AMPKα and found that AMPK activation functionally restored the aberrant glucose production and IR induced by adropin-deficiency. This study provides evidence that adropin activates the AMPK pathway via inhibition of PP2A and decreases the liver glucose production in IR context. Therefore, adropin may represent a novel target for the prevention and treatment of diabetes.
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http://dx.doi.org/10.1096/fj.202000115RRDOI Listing
August 2020

Bisphenol A exposure induces gut microbiota dysbiosis and consequent activation of gut-liver axis leading to hepatic steatosis in CD-1 mice.

Environ Pollut 2020 Oct 29;265(Pt A):114880. Epub 2020 May 29.

Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, 510080, China. Electronic address:

Interactions between the intestine and the liver, the so-called 'gut-liver axis', play a crucial role in the onset of hepatic steatosis and non-alcoholic fatty liver disease. However, not much is known about the impact of environmental pollutants on the gut-liver axis and consequent hepatic steatosis. Bisphenol A (BPA), a widely used plasticiser, is an important environmental contaminant that affects gut microbiota. We hypothesised that BPA induces hepatic steatosis by promoting gut microbiota dysbiosis and activating the gut-liver axis. In this study, male CD-1 mice were fed with diet containing BPA (50 μg/kg body weight/day) for 24 weeks. Dietary exposure to BPA increased lipid contents and fat accumulation in the liver. Analysis of 16 S rRNA gene sequencing revealed that the diversity of gut microbiota reduced and the composition of gut microbiota was altered in the BPA-fed mice. Further, the abundance of Proteobacteria, a marker of dysbacteria, increased, whereas the abundance of Akkermansia, a gut microbe associated with increased gut barrier function and reduced inflammation, markedly decreased. Expression levels of intestinal tight junction proteins (zona occludens-1 and occludin) also decreased drastically, leading to increased intestinal permeability and elevated levels of endotoxins. Furthermore, BPA up-regulated the expression of Toll-like receptor 4 (TLR4) and phosphorylation of nuclear factor-kappa B (NF-κB) in the liver and increased the production of inflammatory cytokines, including interleukin-1β, interleukin-18, tumour necrosis factor-α, and interleukin-6. Take together, our work indicated that dietary intake of BPA induced hepatic steatosis, and this was closely related to dysbiosis of gut microbiota, elevated endotoxin levels, and increased liver inflammation through the TLR4/NF-κB pathway.
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http://dx.doi.org/10.1016/j.envpol.2020.114880DOI Listing
October 2020

Dietary Cyanidin-3-Glucoside Attenuates High-Fat-Diet-Induced Body-Weight Gain and Impairment of Glucose Tolerance in Mice via Effects on the Hepatic Hormone FGF21.

J Nutr 2020 08;150(8):2101-2111

Division of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.

Background: Dietary polyphenols including anthocyanins target multiple organs.

Objective: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G).

Methods: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2).

Results: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and β-klotho (>3-fold, P < 0.05).

Conclusions: Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21.
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http://dx.doi.org/10.1093/jn/nxaa140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398791PMC
August 2020

Association between plasma retinol levels and the risk of all-cause mortality in general hypertensive patients: A nested case-control study.

J Clin Hypertens (Greenwich) 2020 05 30;22(5):906-913. Epub 2020 Apr 30.

National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China.

To evaluate the association between plasma retinol levels with all-cause mortality and investigate the possible effect modifiers in general hypertensive patients with no previous cardiovascular disease (CVD). This case-control study was nested in the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, controlled trial conducted in 32 communities in Anhui and Jiangsu provinces in China. The current study included 617 cases of all-cause mortality and 617 controls matched on age (≤1 year), sex, treatment group, and study site. All-cause mortality was the main outcome in this analysis, which included death due to any reason. The median follow-up duration was 4.5 years. Overall, there was a U-shaped relation of plasma retinol with all-cause mortality. In the threshold effect analysis, the risk of all-cause mortality significantly decreased with the increase in plasma retinol (per 10 μg/dL increments: OR, 0.73; 95% CI: 0.61-0.87) in participants with plasma retinol <58.3 μg/dL and increased with the increase in plasma retinol (per 10 μg/dL increments: OR, 1.08; 95% CI: 1.01-1.16) in those with plasma retinol ≥58.3 μg/L. In participants with plasma retinol <58.3 μg/dL, a stronger inverse association was observed in those with higher time-averaged SBP (≥140 vs <140 mm Hg; P-interaction = .034), or higher vitamin E levels (≥11.5 [quartile 4]; vs <11.5 μg/mL; P-interaction = .013). The present study demonstrated that there was a U-shaped relationship of plasma retinol levels with the risk of all-cause mortality in general hypertensive patients, with a turning point around 58.3 μg/dL.
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http://dx.doi.org/10.1111/jch.13866DOI Listing
May 2020

Anthocyanin supplementation at different doses improves cholesterol efflux capacity in subjects with dyslipidemia-a randomized controlled trial.

Eur J Clin Nutr 2021 02 21;75(2):345-354. Epub 2020 Apr 21.

Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, Guangdong Province, PR China.

Background/objectives: Numerous clinical trials have confirmed that supplementation with purified anthocyanins has favorable effects on metabolic diseases, but the dose-response of dyslipidemia to anthocyanin supplementation remains unclear. This study aimed to investigate the effect of anthocyanin supplementation in different doses on lipid profile.

Subjects/methods: We randomly assigned 176 dyslipidemic subjects aged 35-70 to three purified anthocyanin groups (40 mg/day, n = 45; 80 mg/day, n = 42; 320 mg/day, n = 43) and a placebo group (n = 46). Anthropometric parameters, serum lipid profiles, and cholesterol efflux capacity (CEC) were measured at baseline, and at the end of 6 and 12 weeks.

Results: After 12 weeks of supplementation, significant differences in CEC (P = 0.033), high-density lipoprotein cholesterol (HDL-C) (P = 0.043), and apolipoprotein A-I (ApoA-I) (P = 0.022) were observed between four groups. Compared with placebo, 320 mg/day anthocyanin significantly increased CEC (35.8%, 95% CI: 11.5-60.2%; P = 0.004), HDL-C (0.07 mmol/L, 95% CI: 0.01-0.14; P = 0.003), and ApoA-I (0.07 g/L, 95% CI: 0.01-0.12; P = 0.008). Linear trend analysis showed that anthocyanin supplementation has a strong dose-response relationship with CEC (P = 0.002), HDL-C (P = 0.038), and ApoA-I (P = 0.023). Moreover, the enhancement of CEC showed positive correlations with the increase in HDL-C (r = 0.215, P < 0.01) and APOA-I (r = 0.327, P < 0.01).

Conclusions: Anthocyanin supplementation at 0-320 mg/day for 12 weeks enhances CEC in a dose-response manner in dyslipidemic subjects. Anthocyanin supplementation doses of 80-320 mg/day can improve serum HDL-C levels and HDL-induced CEC.
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http://dx.doi.org/10.1038/s41430-020-0609-4DOI Listing
February 2021

A dose-response evaluation of purified anthocyanins on inflammatory and oxidative biomarkers and metabolic risk factors in healthy young adults: A randomized controlled trial.

Nutrition 2020 06 27;74:110745. Epub 2020 Jan 27.

Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, China; Department of Nutrition, Henry Fok School of Food Science and Engineering, Shaoguan University, Shaoguan, China. Electronic address:

Objectives: Anthocyanins derived from different plant sources have been found to possess a variety of health-promoting effects, including antiinflammatory properties and protection from oxidative stress. The aim of this study was to investigate the dose-response relationship between anthocyanins and metabolic risk factors as well as inflammatory and oxidative biomarkers in healthy adult volunteers.

Methods: We conducted a randomized, double-blind, placebo-controlled trial, which included an increasing dosing schedule of 20, 40, 80, 160, and 320 mg of purified anthocyanins or placebo. Participants (n = 111) were administered either agent for 14 consecutive days.

Results: No significant differences in either baseline characteristics or daily intake of dietary nutrients were detected between the experimental and control groups. After anthocyanin supplementation, there was a significant difference in adjusted fasting plasma glucose levels. The group receiving 80 mg/d of anthocyanin had the lowest baseline-adjusted fasting plasma glucose when compared with placebo (F = 3.556, P = 0.007). Logarithmically adjusted plasma interleukin-10 levels were negatively correlated with increasing anthocyanin dose (F = 2.738, P = 0.025). Similarly, 8-iso-prostaglandin F2α levels decreased with increasing anthocyanins dose (F = 3.513, P = 0.009).

Conclusions: Taken together, our results suggest that anthocyanin supplementation at a dose greater than 80 mg/d is an effective antioxidant and antiinflammatory agent in healthy young adults.
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http://dx.doi.org/10.1016/j.nut.2020.110745DOI Listing
June 2020

Association between liver fibrosis scores and the risk of mortality among patients with coronary artery disease.

Atherosclerosis 2020 04 14;299:45-52. Epub 2020 Mar 14.

Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Technology Center of Nutrition Transformation, Guangzhou, Guangdong, 510080, China. Electronic address:

Background And Aims: Fatty liver diseases are highly prevalent in patients with coronary artery disease (CAD) and might progress to irreversible liver fibrosis. Whether baseline liver fibrosis (LF) scores are associated with long-term mortality among patients with CAD requires investigation.

Methods: The analysis was conducted based on a prospective cohort study among 3263 patients with CAD in China. Cox models were used to assess the association of baseline levels of LF scores, including non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis 4 score (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), gamma-glutamyltransferase to platelet ratio (GPR), and Forns score, with the risk of all-cause and cardiovascular mortality among CAD patients.

Results: During a median follow-up period of 7.56 (inter-quartile range: 6.86-8.31) years, 538 deaths were identified, 319 of those were due to cardiovascular diseases. Compared with patients with lowest score levels, multivariable-adjusted HRs (95% CI) for those with highest levels of NFS, FIB-4, APRI, GPR and Forns score were 2.89 (2.14-3.91), 2.84 (2.14-3.76), 1.77 (1.33-2.36), 1.47 (1.19-1.83) and 3.10 (1.88-5.11) for all-cause mortality, 3.02 (2.05-4.45), 3.34 (2.29-4.86), 1.99 (1.40-2.83), 1.80 (1.36-2.39) and 2.43 (1.28-4.61) for cardiovascular mortality, respectively. These associations were consistent when we excluded those who died within the first year of follow-up or stratified patients by different sex, age, BMI, diabetes status, metabolic syndrome status, CAD type and hsCRP level.

Conclusions: Higher LF scores are associated with increased risks of all-cause and cardiovascular mortality among CAD patients. LF scores might play a potential role in CAD prognosis prediction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.03.010DOI Listing
April 2020

Anthocyanin supplementation improves anti-oxidative and anti-inflammatory capacity in a dose-response manner in subjects with dyslipidemia.

Redox Biol 2020 05 26;32:101474. Epub 2020 Feb 26.

Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong Province, PR China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, Guangdong Province, PR China; Guangdong Engineering Technology Center of Nutrition Transformation, Guangzhou, Guangdong Province, PR China. Electronic address:

Background: Anthocyanins, one of the major plant bioactive substances, possess anti-oxidative and anti-inflammatory capacity. However, their dose-response relationship has remained unclear. The present study investigated the dose-response relationship of anthocyanins with oxidative stress and inflammation in subjects with dyslipidemia.

Design: and Participants: A total of 169 participants with dyslipidemia were randomly assigned to placebo (n = 43), anthocyanins 40 mg/day (n = 44), 80 mg/day (n = 40), or 320 mg/day (n = 42) groups. Urine 8-iso-prostaglandin F (8-iso-PGF), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malonaldehyde (MDA), total superoxide dismutase (T-SOD), UA (uric acid), interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured at baseline, at 6 weeks, and at 12 weeks.

Results: Anthocyanin supplementation (320 mg/day) for 6 weeks significantly improved T-SOD versus baseline (P < 0.05). A slight reduction in serum IL-6, TNF-α, and urine 8-iso-PGF from the baseline was observed at 12 weeks in the group receiving 40 mg/day anthocyanins. Anthocyanins (80 mg/day) significantly reduced serum IL-6 (-20%), TNF-α (-11%) and urine 8-iso-PGF (-27%) versus baseline (P < 0.05). Moreover, 320 mg/day anthocyanin supplementation reduced serum IL-6 (-40%), TNF-α (-21%), MDA (-20%) and urine 8-iso-PGF (-37%) and 8-OHdG (-36%) than 80 mg/day and 40 mg/day anthocyanins, P value < 0.05. Anthocyanin supplementation has dose-response relationships with decreased inflammatory cytokines IL-6, TNF-α and oxidative stress biomarkers 8-iso-PGF, 8-OHdG and MDA (P for trend, <0.05). Furthermore, a strong positive correlation was observed between the changes in the urine 8-iso-PGF , 8-OHdG levels and serum IL-6 levels in subjects from anthocyanin groups after 12 weeks of treatment.

Conclusions: Supplementation of anthocyanins for 12 weeks positively improved the anti-oxidative and anti-inflammatory capacity in a dose-response manner in individuals with dyslipidemia.
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http://dx.doi.org/10.1016/j.redox.2020.101474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078384PMC
May 2020
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