Nutrition & Metabolism

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Background Hypertension, a well-known risk factor, contributes to millions of deaths from cardiovascular and renal diseases worldwide. However, evidence on the association between frequency of dairy product consumption and hypertension is inconsistent. Methods The data for the present study are from the Tongxiang baseline dataset of the China Kadoorie Biobank prospective study. A total of 53,916 participants aged 30–79 years were included in the final analysis. Multivariable logistic regression was utilized to evaluate the association of dairy product consumption with hypertension, and multiple linear regression was conducted to assess the association of dairy product consumption with systolic and diastolic blood pressure. Results Of the 53,916 participants, 2.6% reported consuming dairy products weekly, and 44.4% had prevalent hypertension. After adjusting for socio-demographic status, lifestyle factors, BMI, waist circumference, sleep duration and snoring, when compared with participants who never consumed dairy products, the odds ratios (95% CI) for hypertension among those consuming dairy products less than once per week, and ≥ 1 time per week were 0.85 (0.77–0.95) and 0.74 (0.65–0.84), respectively. The corresponding odds ratios (95% CI) for men were 0.85 (0.71–1.02) and 0.75 (0.61–0.92), respectively (Ptrend = 0.001), and for women were 0.88 (0.76–1.01) and 0.77 (0.65–0.91), respectively. (Ptrend < 0.001). Conclusions In this large epidemiological study, higher frequency of dairy product consumption is associated with significantly lower odds of hypertension among Chinese adults.
 
Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D) in patients with SIBO with diarrhea predominant (SIBO-D, orange) and with constipation predominant (SIBO-C, grey); median with boxes represent I and III quartiles, and error bars represent the minimum and maximum values. Differences between groups were analyzed by U Manna-Whitney's test; n = 40 in both groups; *** p < 0.001
Lactulose hydrogen breath test (LHBT) in patients with low mood scores with chronic diarrhea (SIBO-D) and chronic constipation (SIBO-C) before (blue) and after rifaximin treatment (red); bars represent mean, error bars represent standard deviation. Differences in both groups before and after treatment were tested by Wilcoxon signed-rank test; n = 40 in both groups; *** p < 0.001
Ratio between urinary levels of A tryptophan and 5-hydroxyaminoacetic acid (TRP/5-HIAA) and B tryptophan and L-kynurenine (TRP/KYN) in patients with low mental mood with chronic diarrhea (SIBO-D) and chronic constipation (SIBO-C) before (blue) and after rifaximin treatment (red); boxes represent mean, error bars represent standard deviation. Differences in both groups before and after treatment were evaluated by Wilcoxon signed-rank test; n = 40 in both groups; *** p < 0.001. Schemes follow the same formatting
Urinary levels of A tryptophan (TRP), B 5-hydroxyaminoacetic acid (5-HIAA), C L-kynurenine (KYN), D xanthurenic acid (XA) and E quinolinic acid (QA) expressed in milligram per gram of creatinine (mg/gCr) in patients with low mental mood with chronic diarrhea (SIBO-D) and chronic constipation (SIBO-C) before (blue) and after rifaximin treatment (red); bars represent mean, error bars represent standard deviation. Differences in both groups before and after treatment were examined by Wilcoxon signed-rank test; n = 40 in both groups; *** p < 0.001
The Hamilton Anxiety Rating Scale (HAM-A) A, and the Hamilton Depression Rating Scale (HAM-D) B in patients with small intestinal bacterial overgrowth with diarrhea predominant (SIBO-D) and with constipation predominant (SIBO-C) before (blue) and after rifaximin treatment (red); bars represent mean, error bars represent standard deviation. Differences in both groups before and after treatment were examined by Wilcoxon signed-rank test; n = 40 in both groups; *** p < 0.001
Background: Optimal composition of intestinal bacteria is an essential condition for good health. Excessive growth of these bacteria can cause various ailments. The aim of this study was to assess the mental state and gastrointestinal complaints of patients with small intestinal bacterial overgrowth (SIBO) in relation to tryptophan metabolism and rifaximin treatment. Methods: 120 subjects, aged 23-61 years, were enrolled in the study, and divided into 3 groups, 40 individuals each: healthy subjects (Controls), patients with SIBO and chronic diarrhea (SIBO-D), and with chronic constipation (SIBO-C). The lactulose hydrogen breath test (LHBT) was performed to diagnose SIBO. The mental state of patients was assessed using the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D). L-tryptophan (TRP) and its metabolites: 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), xanthurenic acid (XA) and quinolinic acid (QA) were measured in urine by liquid-chromatography-tandem mass spectrometry and related to creatinine level. Patients with SIBO were recommended to take rifaximin for 10 days at daily dose 1200 mg, and this cycle was repeated in subsequent two months. Results: Mild and moderate anxiety, as well as mild depression were diagnosed in all SIBO patients. Changes in TRP metabolism were also observed in these patients. Specifically, an increase in the activity of the serotonin pathway of TRP metabolism in the group SIBO-D was observed. The SIBO-C patients showed an increase in the concentration of KYN, XA and QA. 5-HIAA/TRP and KYN/TRP ratios significantly decreased in group SIBO-D, and KYN and QA levels decreased in group SIBO-C after treatment with rifaximin. The levels of anxiety and depression decreased in both groups. Conclusion: Rifaximin treatment of SIBO patients ameliorated their mood disorders and gastrointestinal aliments underlined by changes in tryptophan metabolism. Trial registration Retrospectively registered (if applicable).
 
Aim This study aimed to examine the effect of lunches with different caloric contents (Study 1) and nutrient balances (Study 2) on dinner-induced postprandial glucose fluctuation. Methods Energy trial (Study 1): Thirteen healthy young participants (n = 10 men, n = 3 women) were investigated to determine the effects of different caloric intakes at lunch on glucose level variability. The study was comprised of four trials (no lunch, low lunch, standard lunch, and high-energy lunch). Energy balance trial (Study 2): Fourteen healthy young adults (n = 8 men, n = 6 women) were investigated to determine the effect of different nutrient balances during lunch on glucose level variability. The study consisted of four trials (standard, protein-rich, fat-rich, and carbohydrate-rich). In studies 1 and 2, each trial was spaced at least 24 full hours apart, and breakfast and dinner were tested as meals. The mealtimes for each trial were then aligned. Continuous glucose monitoring was used to assess the blood glucose fluctuations. Results Study 1: The no-lunch (95% CI 95.5–149.7) and low-energy lunch (95% CI 90.8–143.1) trials had significantly higher values in the incremental area under the curve (iAUC) of postprandial blood glucose at dinner compared to the standard (95% CI 55.4–90.0) and high-energy lunch (95% CI 29.3–54.6) trials (P = 0.006, P = 0.001 vs. none), (P = 0.004, P = 0.001 vs. low-energy trial). Study 2: A significantly higher postprandial blood glucose iAUC for dinner was found in the fat-rich trial (95% CI 58.5–114.0) than that in the protein-rich (95% CI 25.6–63.9) and standard (95% CI 25.6–112.4) trials, (P = 0.006, P = 0.035 vs. fat-rich trial). Conclusions Our findings indicate that skipping lunch and low-calorie or high-lipid intake increased postprandial blood glucose levels after dinner.
 
Effects of HENS on biochemical parameters including: insulin (A), blood sugar (B), HOMA-IR (C) and QUICKI (D). Values are presented as means ± SD. HOMA-IR: homeostatic model assessment-insulin resistance, QUICKI: quantitative insulin sensitivity check index, NC: normal control, DC: Diabetic control, HENS: hydroalcoholic extract of N. sativa seeds. *P-value obtained using one-way ANOVA
Comparison of the effect of HENS on total oxidant status (TOS) (A), Malondialdehyde (MDA) (B), and total antioxidant status (TAS) (C) in the study groups
Comparison of mRNA fold changes in Nrf2-liver (A), FGF21-liver (B), Nrf2-pancreas (C), FGF-pancreas (D) and β-Kloto-pancreas (E) gene expression levels in the study groups.
Comparison of mRNA fold changes in PDX1 (A) and MafA (B) gene expression levels in pancreatic tissue in the study groups
Morphological assessment of pancreatic tissue; H&E staining. Magnification × 100 and × 400. A Normal control group with the normal tissue structure; B Diabetic control group with vacuolated cells, inflamed appearance, and reduced cell density; C HENS-200 group with a slight decrease in cell density and inflammation in the islets of Langerhans; D HENS-400 group with normal cell size and histological structure
Introduction Nigella sativa (N. sativa), one of the most commonly used medicinal herbs with antioxidant properties, increases blood insulin levels and lowers fasting blood sugar. Nuclear Erythroid Factor-Related Factor 2 (Nrf2) and Fibroblast Growth Factor 21 (FGF21) are two antioxidant factors that are increased by oxidative stress and hyperglycemia. The present study investigated how hydroalcoholic extract of N. sativa seed (HENS) increases blood insulin levels, taking into account changes in antioxidant factors and expression of insulin transcription factors. Materials and methods Two groups of male diabetic wistar rats were treated orally with HESN at doses of 200 and 400 mg/kg-body weight for one month. Fasting blood sugar (FBS) and insulin were measured using standard kits by photometric and ELISA methods, respectively. The expression levels of the Nrf2, FGF21 and β-Klotho genes as well as the insulin gene-stimulating transcription factors of MafA and PDX-1 were evaluated using real-time PCR. Oxidative stress was assessed by assessing serum total oxidation status (TOS), malondialdehyde (MDA), and total antioxidant capacity (TAC). Results HSEN showed a significant reducing effect on FBS and oxidative biomarkers and an increasing effect on serum insulin levels in treated diabetic rats compared to untreated diabetics (P < 0.05). The elevated levels of NRF2 and FGF21 in the liver and pancreas of the diabetic control group were significantly reduced after treatment with both HESN doses (P < 0.05). Following the ameliorative effects of HENS on pancreatic tissue and the reduction of oxidative stress, the expression level of MafA and PDX1 genes approached the level of these factors in healthy rats (P < 0.05). Conclusion This study showed the therapeutic effects of HENS on diabetic pancreas by reducing oxidative stress and tissue damage, modifying the expression levels of PDX-1 and MafA genes, and regulating insulin secretion and blood glucose levels.
 
Associations between eating speed and body fat distribution among different age groups
Background Eating speed has been reported to be associated with energy intake, body weight, waist circumference (WC), and total body fat. However, no study has explored the association between eating speed and body fat distribution, especially its difference among different age or body mass index (BMI) groups. Methods 4770 participants aged 18–80 years were recruited from the baseline survey of the Lanxi Cohort Study. They were categorized into three groups according to meal duration. Linear regression analyses were performed among all participants and separately by age group and obesity status to evaluate the associations of WC and total and regional fat mass percentages (FM%) with eating speed. Results After adjusting for confounding factors, eating slowly was significantly related to lower WC, lower total, trunk, and android FM%, lower android-to-gynoid fat mass ratio, and higher leg and gynoid FM%. After stratification by age or obesity status, the associations were especially prominent among participants aged 18–44 years or those with BMI < 24 kg/m ² . No significant trends were found for participants aged 65–80 years or those who were overweight/obese. Conclusions Eating slowly is closely related with better fat distribution among Chinese adults, especially for those aged 18–44 years and those with BMI < 24 kg/m ² . If confirmed prospectively, it might be a potential efficient approach to improve fat distribution.
 
Brown adipocyte regulation by exogenous agents. Thyroid hormones act on thermogenesis through interaction with their Thyroid receptors (TR) and the G-protein-coupled receptor (GPCR). TRα promotes an increase in adrenergic signaling while TRβ acts to stimulate uncoupling protein 1 (UCP1). β3 receptor (β3-AR) is expressed constitutively on the surface of the adipocyte and acts to regulate the transcription and activation of genes related to mitochondrial biogenesis, brown adipocyte differentiation, and lipid storage. This receptor can be activated through cold, which is the main mechanism for activating browning, agonist drugs, or diet. Chronic exposure to cold and food intake, such as curcumin and fish oil, promotes thermogenesis by releasing catecholamines from the central nervous system (CNS) that bind to β-AR, thus initiating a signaling cascade. An increase in the concentration of cAMP is elicited which consequently leads to the enhanced activity of protein kinase A (PKA) which promotes the cAMP-response element-binding protein (CREB). This pathway is related to the transcription of thermogenic genes such as peroxisome proliferator-activated receptor γ (PPARγ), Type II iodothyronine deiodinase (DIO2), PR domain containing 16 (PRDM16), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and Cell death-inducing DNA fragmentation factor-like effector A (CIDEA). The other dietary components can participate in the induction of browning through the modulation of the gut microbiota promoting the increase of the expression of thermogenic genes. The release of growth factor 21 (FGF21) is mediated by the practice of physical exercises and physiological changes. FGF21 will interact with its FGFR receptor and that activation induces a self-phosphorylation of the FGFR that mediates the activation of pathways related to increased expression of UCP1
The impact of circadian rhythm and different diets on the WAT browning modulation. The secretion of melatonin, a circadian rhythm regulating neurohormone, is mediated by the release of Norepinephrine (NE), which binds to β-adrenergic receptors. Adrenergic activation is one of the main mechanisms of WAT browning induction and BAT activation. Intermittent fasting (IF) associates with weight reduction, improved metabolic status due to increased glycemic tolerance, decreased white adipocyte hypertrophy and AT inflammation, and augmented expression of thermogenic genes (such as UCP1) and recruitment of beige adipocytes. IF is also modulates the intestinal microbiome composition and diversity, a shift closely related to the induction of browning in the WAT. Caloric restriction (CR) is also associated with weight loss, promotes greater recruitment of beige adipocytes through the participation of M2 macrophage and eosinophil infiltration and in WAT. Finally, obesity-inducing diets correlate with increased lipid accumulation, WAT unhealthy expansion and dysregulation. Abnormal expansion of WAT promotes ER stress, greater induction of adipose cell apoptosis and inflammation through NF-κB transcription factor activation and increased pro-inflammatory cytokines secretion
WAT browning transcriptional regulation. The transcriptional regulation of the WAT beiging process involves the action of a plethora of specific proteins and nucleic acids. This orchestra of trans-acting factors modulates genes associated with oxidative capacity, mitochondrial biogenesis and non-shivering thermogenesis. While the action of some factors, such as PGC-1α, IRF4, PRDM16, ZFP516, EHMT1 and RNAs, copes with WAT browning, TLE3, ZFP423, and the NuRD complex, another set of RNAs e others inhibit this process, favoring adipogenesis and white adipocyte differentiation
Adipose tissues are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. Although white adipose tissue and brown adipose tissue are currently considered key endocrine organs, they differ functionally and morphologically. The existence of the beige or brite adipocytes, cells displaying intermediary characteristics between white and brown adipocytes, illustrates the plastic nature of the adipose tissue. These cells are generated through white adipose tissue browning, a process associated with augmented non-shivering thermogenesis and metabolic capacity. This process involves the upregulation of the uncoupling protein 1, a molecule that uncouples the respiratory chain from Adenosine triphosphate synthesis, producing heat. β-3 adrenergic receptor system is one important mediator of white adipose tissue browning, during cold exposure. Surprisingly, hyperthermia may also induce beige activation and white adipose tissue beiging. Physical exercising copes with increased levels of specific molecules, including Beta-Aminoisobutyric acid, irisin, and Fibroblast growth factor 21 (FGF21), which induce adipose tissue browning. FGF21 is a stress-responsive hormone that interacts with beta-klotho. The central roles played by hormones in the browning process highlight the relevance of the individual lifestyle, including circadian rhythm and diet. Circadian rhythm involves the sleep–wake cycle and is regulated by melatonin, a hormone associated with UCP1 level upregulation. In contrast to the pro-inflammatory and adipose tissue disrupting effects of the western diet, specific food items, including capsaicin and n-3 polyunsaturated fatty acids, and dietary interventions such as calorie restriction and intermittent fasting, favor white adipose tissue browning and metabolic efficiency. The intestinal microbiome has also been pictured as a key factor in regulating white tissue browning, as it modulates bile acid levels, important molecules for the thermogenic program activation. During embryogenesis, in which adipose tissue formation is affected by Bone morphogenetic proteins that regulate gene expression, the stimuli herein discussed influence an orchestra of gene expression regulators, including a plethora of transcription factors, and chromatin remodeling enzymes, and non-coding RNAs. Considering the detrimental effects of adipose tissue browning and the disparities between adipose tissue characteristics in mice and humans, further efforts will benefit a better understanding of adipose tissue plasticity biology and its applicability to managing the overwhelming burden of several chronic diseases.
 
Age and Gender are vital determinants for the micronutrient demands of normal indviduals. Among these micronutrients are vitamins that are required in small amounts for optimum metabolism, homeostasis, and a healthy lifestyle, acting as coenzymes in several biochemical reactions. The majority of previous studies have examined such issues that relates to a specific vitamin or life stage, with the majority merely reporting the effect of either excess or deficiency. Vitamins are classified into water-soluble and fat-soluble components. The fat-soluble vitamins include vitamins (A, D, E, and K). Fat-soluble vitamins were found to have an indisputable role in an array of physiological processes such as immune regulation, vision, bone and mental health. Nonetheless, the fat-soluble vitamins are now considered a prophylactic measurement for a multitude of diseases such as autism, rickets disease, gestational diabetes, and asthma. Herein, in this review, a deep insight into the orchestration of the four different fat-soluble vitamins requirements is presented for the first time across the human life cycle beginning from fertility, pregnancy, adulthood, and senility with an extensive assessment ofthe interactions among them and their underlying mechanistic actions. The influence of sex for each vitamin is also presented at each life stage to highlight the different daily requirements and effects.
 
Background The ketogenic diet (KD) has anti-tumor and anti-diabetic effects in addition to its anti-epileptic role. It could also improve cardiac function and attenuate neurological insult. However, the effect of KD on blood perfusion or tissue recovery after ischemia remains largely unknown. Thus, we observed blood flow and ischemic tissue recovery following hind limb ischemia (HLI) in mice. Methods C57 mice were fed with either a KD or normal diet (ND) for 2 weeks, before inducing hind limb ischemia, blood perfusion of ischemic limb tissue was observed at 0, 7, and 21 days post operation. Results KD not only decreased blood perfusion of ischemic limb tissue but also delayed muscle recovery after ischemia, induced muscle atrophy of non-ischemic tissue compared to mice fed with ND. Furthermore, KD delayed wound healing at the surgical site and aggravated inflammation of the ischemic tissue. At the cellular level, KD altered the metabolic status of limb tissue by decreasing glucose and ketone body utilization while increasing fatty acid oxidation. Following ischemia, glycolysis, ketolysis, and fatty acid utilization in limb tissue were all further reduced by KD, while ketogenesis was mildly increased post KD in this mice model. Conclusion The KD may cause impaired tissue recovery after ischemia and possible muscle atrophy under a prolonged diet. Our results hint that patients with limb ischemia should avoid ketogenic diet.
 
Flow chart of participant recruitment
Demographics of the surveillance subjects
Background Long-term, excessively high sodium consumption can lead to increased blood pressure, which is a major risk factor for cardiovascular disease. Therefore, we aimed to analyze the dietary sodium intake and food sources to understand the epidemiological characteristics associated with potentially influencing variables in adults from Shanghai. Methods Residents aged 15 years and above were randomly selected using multi-stage stratified random sampling in Shanghai. Over 3 days, family condiments were weighed for each 24-h day, and recall surveys were conducted for the same timeframe regarding sodium intake during the spring, summer, autumn, and winter seasons. Results The median sodium intake for residents aged 15 years and above was 4.3 g/d in Shanghai, where 55.1% was obtained from cooking salt, 13.2% from sodium condiments, and 22.2% from pre-packaged food. There were no significant differences in total sodium intake or main sources of sodium intake between different seasons. The sodium intake of rural residents > suburban residents > urban residents ( P < 0.05). The logistic regression demonstrated that compared to the rural, the people living in urban and suburban consumed less sodium. Compared to the 18–44, the people aged 45–59 and ≥ 60 consumed more sodium ( P < 0.05). Conclusions Sodium intake is high in Shanghai. The absolute amount of cooking salt is low in Shanghai, and the possibility of further reduction is very little under the existing dietary habit. Limiting high sodium condiments and pre-packaged food is the new key to controlling salt intake in the future.
 
Background Altered lipid profiles are frequently present in cancer, and it is necessary to elucidate the role of changed lipid profiles in hepatocellular carcinoma (HCC). We conducted this study to investigate the changed lipid profile in HCC tissues and discover some remarkably changed lipid components, and to explore the function of changed lipid components in HCC development. Methods Gas chromatography/mass spectrometer (GC/MS analysis) was employed to measure the abundance of fatty acids between HCC tissues and adjacent noncancerous tissues. The proliferative ability of HCC cells was determined by Cell Counting Kit-8 and EdU assays. Transwell and wound healing assays were employed to determine the migratory ability of HCC cells. Protein expression was assessed by western blot assay. Results GC/MS analysis revealed that alpha-linolenic acid was present at lower levels in HCC tissues than that in the adjacent noncancerous tissues. Alpha-linolenic acid inhibited the proliferation, migration and invasion of HCC cells in vitro. Western blotting showed that alpha-linolenic acid treatment increased Farnesoid X receptor expression and decreased β-catenin and cyclinD1 expression. Conclusions Alpha-linolenic acid suppresses HCC progression through the FXR/Wnt/β-catenin signaling pathway. Rational use of alpha-linolenic acid may prevent the occurrence of liver cancer in the future.
 
Partial spearman correlations between baseline metabolic traits and C-peptide. HbA1c glycosylated hemoglobin, HDL-C high-density lipoprotein cholesterol, HOMA-IR homoeostatic model assessment‐insulin resistance, hs-CRP high-sensitivity C-reactive protein, LDL-C low-density lipoprotein cholesterol, TG triglycerides, WHR waist–hip ratio. P values were calculated using partial spearman regression with adjustment for maternal age, gestational age, education, parity, smoking status, alcohol consumption, physical activity, pre-pregnancy BMI, family history of diabetes, history of GDM, and GDM status. There were positive correlations of C-peptide with fasting insulin, homeostatic model of insulin resistance, leptin, fasting blood glucose, triglycerides, glycosylated hemoglobin, waist–hip ratio, systolic blood pressure, and low-density lipoprotein cholesterol, and negative correlations with high-density lipoprotein cholesterol and adiponectin, demonstrating an adverse metabolic profile associated with C-peptide
Receiver operator characteristic curves for early-pregnancy fasting biomarkers of glucose metabolism in gestational diabetes mellitus prediction. (A) Comparation of models based on conventional predictive factors and conventional predictive factors plus C-peptide (Difference: 0.03; P = 0.008); (B) Comparation of models with (1) conventional predictive factors and C-peptide, (2) conventional predictive factors and FBG, (3) conventional predictive factors, FBG, and C-peptide. Conventional predictive factors included maternal age, gestational age, pre-pregnancy body mass index, physical activity, parental history of diabetes mellitus, and history of GDM. AUC area under receiver operator characteristic curve, CI confidence interval, FBG fasting blood glucose, GDM gestational diabetes mellitus
Objective To examine the association of early-pregnancy serum C-peptide with incident gestational diabetes mellitus (GDM) and the predictive ability of maternal C-peptide for GDM. Methods A nested case–control study of 332 GDM cases and 664 controls was established based on the Tongji-Shuangliu Birth Cohort. The GDM cases and controls were matched at 1:2 on maternal age (± 3 years) and gestational age (± 4 weeks). Multivariable conditional logistic regression was applied to assess the association of C-peptide with risk of GDM. Partial Spearman’s correlation coefficients were estimated for the correlations between C-peptide and multiple metabolic biomarkers. C-statistics were calculated to assess the predictive ability of early-pregnancy C-peptide for GDM. Results Of 996 pregnant women, median maternal age was 28.0 years old and median gestational age was 11.0 weeks. After adjustment for potential confounders, the odds ratio of GDM comparing the extreme quartiles of C-peptide was 2.28 (95% confidence interval, 1.43, 3.62; P for trend < 0.001). Partial correlation coefficients ranged between 0.07 and 0.77 for the correlations of C-peptide with fasting insulin, homeostatic model of insulin resistance, leptin, fasting blood glucose, triglycerides, glycosylated hemoglobin, waist–hip ratio, systolic blood pressure, and low-density lipoprotein cholesterol ( P ≤ 0.025), and were − 0.11 and − 0.17 for high-density lipoprotein cholesterol and adiponectin ( P < 0.001). Serum C-peptide slightly improved the predictive performance of the model with conventional predictive factors (0.66 vs. 0.63; P = 0.008). Conclusion While the predictive value for subsequent GDM should be validated, early-pregnancy serum C-peptide may be positively associated with risk of GDM.
 
Background Hypercholesterolemia and gut microbiota dysbiosis are associated with the risk of cardiovascular diseases. Hawthorn fruits has shown to be cardioprotective and hypocholesterolemic. However, no studies to date have studied the biological activity of hawthorn seed oil (HSO). The present study was to investigate if HSO could favourably reduce plasma cholesterol and modulate gut microbiota in hypercholesterolemia hamsters. Methods Golden Syrian hamsters (age, 8 weeks) were randomly divided into five groups (n = 8, each) and fed one of the following five diets, namely a non-cholesterol diet, a high cholesterol diet containing 0.15% cholesterol (HCD); a HCD diet with addition of 4.75% HSO (LHSO), a HCD diet with addition of 9.5% HSO (HHSO), a HCD diet with addition of 0.50% cholestyramine as positive control diet. After 6-week dietary intervention, plasma lipids, inflammatory markers, atherosclerosis plaque, hepatic and fecal lipids were quantified. Microbiota in fresh feces were analysed by sequencing 16S rRNA genes, while RT-PCR and Western blot analyses were employed to quantify the expression of genes involved in cholesterol homeostasis. Results HSO at a dose of 9.5% HSO could decrease plasma cholesterol and non-HDL-cholesterol by 15%. Additionally, both HSO experimental groups also suppressed mRNA of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMG-CoA-R). Supplementation of HSO at 4.75% could significantly increase the excretion of fecal acidic sterols, accompanied by elevation of short-chain fatty acid levels in feces. The analyses of gut microbiome indicated that HSO supplementation could selectively alter the genera abundance of gut bacteria that were correlated with cholesterol metabolism including unclassified_f__Christensenellaceae, Ruminococcaceae_NK4A214_ group, norank_o_Gastranaerophilales, Faecalibaculum, Peptococcus, norank_f__Clostridiales_vadinBB60_group and Ruminococcus_2. Conclusions HSO supplementation was able to decrease plasma cholesterol by favourably modulating gut microbiota composition and gut-derived metabolites associated with cholesterol regulation. Graphical Abstract
 
Flow diagram for the study population
Abstract Background Leptin is a peptide hormone secreted by adipose tissue and is an important determinant of obesity and its complications. The purpose of this study was to establish sex- and body mass index (BMI)-specific reference intervals for serum leptin in a Chinese population and investigate the factors influencing leptin concentrations. Methods Fasting serum leptin levels were assayed in 469 men and 773 women from randomly sampled Chinese residents. Blood glucose, insulin, hemoglobin A1c (HbA1c), liver enzymes, blood lipid profiles, creatinine, and uric acid (UA) levels were measured. Pearson’s correlation coefficient and multiple linear regression analyses were used to estimate the relationship between serum leptin level and other variables. The reference intervals were determined by the 2.5th and 97.5th percentiles. Results The mean ± standard deviation serum leptin level was much higher in women (20.92 ± 12.96 ng/mL) than in men (6.45 ± 5.53 ng/mL). The reference interval of serum leptin was 0.33–19.85 ng/mL in men and 3.60–54.86 ng/mL in women. The specific reference intervals of serum leptin in men with BMI of 20 to
 
Purpose Salvianolic acid B (Sal B) possesses strong anti-inflammatory and antioxidant activity. This study aims to explore the underlying mechanism of Sal B to improve the obesity-related osteoarthritis (OA). Methods C57BL/6 J male mice were fed with a normal control diet (NCD), a high fat diet (HFD), or HFD with Sal B (25 mg/kg), and mouse body weights and osteoarticular inflammatory factor levels were examined. Mouse chondrogenic cell line ATDC5 were transfected with lncRNA KCNQ1 overlapping transcript 1 small hairpin RNA (KCNQ1OT1 shRNA), miR-128-3p mimic or Sirtuin-1 small interfering RNA (SIRT1 siRNA), then stimulated with Palmitic acid (PA) followed by the treatment of Sal B. Then, inflammatory response, apoptosis, and autophagy of ATDC5 cells in different groups were detected. Results Sal B reduced the body weight, decreased the levels of inflammatory markers, and improved cartilage damage in OA mice fed with HFD. KCNQ1OT1 was downregulated in OA mice fed with HFD, and PA-stimulated ATDC5 cells. Sal B protected ATDC5 cells against PA-mediated inflammation, apoptosis, and the inhibition of autophagy, while knockdown of KCNQ1OT1 reversed these results. KCNQ1OT1 was found to be functioned as a ceRNA to bind and downregulate the expression of miR-128-3p that was upregulated in PA-induced cells. Furthermore, SIRT1 was verified as a target of miR-128-3p. MiR-128-3p overexpression reversed the effects of Sal B on inflammatory response, apoptosis, and autophagy in PA-stimulated cells, and knockdown of SIRT1 displayed the similar results. Conclusion Sal B exerted a chondroprotective effect by upregulating KCNQ1OT1, which indicates Sal B can used for a therapeutic agent in obesity-related OA.
 
Schematic diagram of astrocyte-neuron lactate shuttle (ANLS). ACoA, acetyl-CoA; EAAT, Excitatory amino acid transporter; HK, Hexokinase; Gln, Glutamine; GLS, Glutaminase; GLUT, Glucose transporter; GlyP, Glycogen phosphorylase; GlyS, Glycogen synthase; GS, Glutamate synthase; LDH, Lactate dehydrogenase; MCT, Monocarboxylic acid transporters; PDH, Pyruvate dehydrogenase; PFK, Phosphofructokinase; PKM1, Pyruvate kinase M1; PKM2, Pyruvate kinase M2; TCA cycle, Tricarboxylic acid cycle
Putative mechanisms of lactate as a signal molecule to regulate cognition. ATP, Adenosine triphosphate; BDNF, Brain-derived neurotrophic factor; cAMP, Cyclic adenosine mono-phosphate; CREB, Cyclic AMP-responsive element-binding protein; ERK, Extracellular regulated protein kinases; Gi, Inhibitory adenylate cyclase G protein; GPR81, G protein-coupled receptor 81; HCAR1, Hydroxycarboxylic acid receptor 1; NLRP3, NLR family pyrin domain containing 3; NMDAR, N-methyl-D-aspartic acid receptor; PKA, Protein kinase A; VEGFA, Vascular Endothelial Growth Factor A; VGF, VGF nerve growth factor inducible
Exercise increases brain lactate levels in two ways, including central brain-derived and peripheral skeletal muscle-derived. GLUT 1, Glucose transporter 1; MCT, Monocarboxylic acid transporter
Lactate has previously been considered a metabolic waste and is mainly involved in exercise-induced fatigue. However, recent studies have found that lactate may be a mediator of the beneficial effects of exercise on brain health. Lactate plays a dual role as an energy supply substrate and a signaling molecule in this process. On the one hand, astrocytes can uptake circulating glucose or degrade glycogen for glycolysis to produce lactate, which is released into the extracellular space. Neurons can uptake extracellular lactate as an important supplement to their energy metabolism substrates, to meet the demand for large amounts of energy when synaptic activity is enhanced. Thus, synaptic activity and energy transfer show tight metabolic coupling. On the other hand, lactate acts as a signaling molecule to activate downstream signaling transduction pathways by specific receptors, inducing the expression of immediate early genes and cerebral angiogenesis. Moderate to high-intensity exercise not only increases lactate production and accumulation in muscle and blood but also promotes the uptake of skeletal muscle-derived lactate by the brain and enhances aerobic glycolysis to increase brain-derived lactate production. Furthermore, exercise regulates the expression or activity of transporters and enzymes involved in the astrocyte-neuron lactate shuttle to maintain the efficiency of this process; exercise also activates lactate receptor HCAR1, thus affecting brain plasticity. Rethinking the role of lactate in cognitive function and the regulatory effect of exercise is the main focus and highlights of the review. This may enrich the theoretical basis of lactate-related to promote brain health during exercise, and provide new perspectives for promoting a healthy aging strategy.
 
Literature screening process of this study
Background Diet and nutrition, as a modifiable risk factor, have been demonstrated to play a significant role in the etiology of biliary diseases, whereas few comprehensive studies have been able to evaluate the strength and quality of these evidence. This umbrella review aims to evaluate the evidence pertaining risk factors for biliary diseases in terms of diet and nutrition-related indicators. Methods An umbrella review method was adopted: evidence from observational studies up to 22 November 2021 were identified using PubMed, Web of Science, the Cochrane database, as well as manual screening. Eligible systematic reviews and meta-analyses were screened according to inclusion and exclusion criteria. The inclusion criteria were: (1) meta analysis or systematic review; (2) The theme of the study is the relationship between diet or nutrition and biliary tract diseases; (3) Summarized and reported OR, RR or HR values and corresponding 95% CI; (4) No restrictions on the use of participants and languages; (5) Only extract the data of biliary tract diseases from multiple health outcomes; (6) Only the most recent studies on the same subject were included. This study had been registered at PROSPERO (CRD42021293908). For each eligible systematic review and meta-analysis, we extracted the data of general characteristics and the main findings. The methodological quality of the meta-analyses included in our study were assessed by AMSTAR2 and the quality of evidence was evaluated by the GRADE. Results A total of 323 articles were searched, among which 24 articles with 83 unique outcomes were identified as eligible. 35 of these outcomes were downgraded in GRADE evaluation as they reported heterogeneity. In short, among 83 unique outcomes, 5 were rated as moderate, 16 as low, and the rest as very low. For the prevention of biliary tract diseases, emphasis should be placed on appropriately increasing the intake of fruits, vegetables, coffee and tea, and reducing the intake of alcohol, raw fish and foods with high nitrate. Meanwhile, weight, blood sugar and lipid levels should be controlled, and diabetes should be actively prevented and treated. Drinking is not recommended to prevent gallstones, although studies have shown that it may reduce the risk of cholecystolithiasis. Conclusions Our study summarizes the current multifaceted evidence on the relationship between dietary and nutritional indicators and biliary diseases, but the quality of all evidence was not high. Evidence from additional high-quality prospective studies are needed in the future.
 
Effects of inulin on body weight gain, adipose tissue weight, and blood glucose in mice. A Body weight gain. Control: n = 12; Inulin group: n = 12. B Glucose tolerance test. The area under the curve (AUC) over the course of 120 min in each experiment was averaged. C Ratio of the weight of epididymal (eWAT) per body weight. D Histological examination of epididymal white adipose tissues (eWAT) using hematoxylin and eosin (H&E) staining. Scale bar = 200 µm. Area of average white adipocyte size in eWAT. Control: n = 6; Inulin group: n = 6. Data are expressed as means ± SEM. *p < 0.05
Effects of inulin on respiratory quotient, and energy expenditure in mice. A O2 consumption (VO2) and CO2 production (VCO2). B Energy expenditure during light and dark cycles. C Respiratory quotient, and energy expenditure. Light and dark cycles are indicated with white and gray backgrounds, respectively. Data are expressed as means ± SEM. *p < 0.05, ***p < 0.001. Control: n = 4; Inulin group: n = 4
Immunostaining expression of UCP1 in epididymal white adipose tissue (eWAT). Scale bar = 200 µm. Data are expressed as means ± SEM. Control: n = 6; Inulin group: n = 6
Results of the metabolomics analysis of the content of jejunum, feces, and portal vein serum. Lipidomics analysis. A Concentrations of amino acids, organic acids, and short-chain fatty acids (SCFAs) in the jejunum. B Concentrations of amino acids, organic acids, and short-chain fatty acids (SCFAs) in the feces. C Concentrations of amino acids, organic acids, and short-chain fatty acids (SCFAs) in the portal vein serum. D Lipidomics analysis of epididymal white adipose tissue (eWAT). Data are expressed as means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001. Control: n = 6; Inulin group: n = 6
Aim Inulin, a soluble dietary fiber, is a source of energy for the host while the metabolites, such as short-chain fatty acids (SCFAs), produced in the gut through bacterial fermentation exerts the anti-obesity effect. In this study, we aimed to apply a metabolomics approach and clarify the role of this soluble dietary fiber on glucose and lipid metabolism under the calorie-matched condition. Materials and methods Eight-week-old male C57BL/6J mice were fed a high-fat/high-sucrose based diet containing maltodextrin or inulin for 12 weeks through calorie-matched pair feeding. We evaluated glucose tolerance, and energy expenditure using indirect calorimetry, comprehensive metabolites in the content of jejunum, feces, and portal vein serum using gas chromatography-mass spectrometry, and histological changes in the adipose tissue. Results The inulin group exhibited reduced visceral adipose tissue and smaller size of visceral adipocyte. It also exhibited improved glucose tolerance and an increase in energy expenditure. Reflecting the results of fermentation, the metabolomics analysis revealed an increase in the succinic acid and SCFA contents in both feces and portal vein serum in the inulin group. Conclusions Inulin altered the gut metabolites and reduced visceral adipose tissue, thereby resulting in improved glucose tolerance.
 
Flowchart of study
Background Taurine supplementation as a sulfur-containing amino acid may attenuate and/or alleviate diabetes-induced complications and endothelial dysfunction via its anti-inflammatory and antioxidant activities. Our purpose was to investigate the effect of Taurine supplementation on endothelial dysfunction markers, oxidative stress, inflammation, and glycemic control in patients with type 2 diabetes mellitus (T2DM). Methods In the current clinical trial, 120 patients with T2DM were randomly allocated to take either Taurine (containing 1 g Taurine, n = 60) or placebo (n = 60) three times per day for an eight-week period. Moreover, all patients were on a low-calorie diet. The primary outcome was fasting blood glucose (FBG) and endothelial markers including sera intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule (VCAM), and matrix metallopeptidase 9 (MMP-9). The secondary outcome was dietary intake, anthropometric indices, serum insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), total antioxidant capacity (TAC), tumor necrosis factor (TNF), high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), and lipid profile. Results After 8 weeks, Taurine-supplemented patients had a considerable decrease in serum insulin and HOMA-IR compared to placebo group. However, Taurine supplementation did not improve other metabolic parameters including lipid profiles, glycated hemoglobin, and fasting blood glucose (FBG). There was a significant decline in MDA, TNF, and hs-CRP levels after these eight-week period of Taurine supplementation. In addition, the Taurine group had fewer serum levels of endothelial dysfunction markers than the placebo group. Conclusions The evidence from our study revealed that Taurine supplementation significantly reduced insulin and HOMA-IR, as well as oxidative stress, inflammation, and endothelial markers in individuals with T2DM. Trial registration The protocol of the study was recorded in the Iranian Registry of Clinical Trials (IRCT20180712040438N3).
 
Characteristics of maternal exogenous DHA-rich n-3 PUFAs supplementation and geographical distributions of the subjects in this birth cohort. A showed the geographical distributions. B demonstrated maternal exogenous DHA-rich n-3 PUFAs supplementation in different districts of Beijing. Note: PUFAs: polyunsaturated fatty acids
Effects of the 26 SNPs in the fatty acid desaturases and elongases on the profiles of PUFAs in the colostrum. A presented the linkage disequilibrium (LD) between the 26 SNPs in the Fads1, Fads2, Fads3, Elvol2 and Elvol5 and fatty acid synthesis (r² × 100). B showed the profiles of n-6 PUFAs (LA, AA and AA/LA). C presented the profiles of n-3 PUFAs (ALA, EPA, DHA, EPA/ALA, DHA/ALA and DHA/EPA). Note: In the Fig. 2B and 2C, red, blue and green respectively demonstrated there were positive, negative and no significant associations between the 26 SNPs and the profiles of n-6 and n-3 PUFAs. Fads Fatty acid desaturases, Elovl Elongase of very long chain fatty acid, PUFAs Polyunsaturated fatty acids, SNPs Single nucleotide polymorphisms, LA Linoleic acid, AA Arachidonic acid, ALA α-Linolenic acid, EPA Eicosapentaenoic acid, DHA Docosahexaenoic acid
Interactions of maternal DHA-rich n-3PUFAs intake with the genotypes of significant SNPs in the fatty acid desaturases on the profiles of PUFAs in the colostrum. A presented the interactions of maternal DHA-rich n-3 PUFAs intake with Fads3/rs76996928 (T/C) on the content of LA. B presented the interactions of maternal DHA-rich n-3 PUFAs intake with Fads2/rs174598 (A/T) on the content of EPA. C and D respectively presented the interactions of maternal DHA-rich n-3 PUFAs intake with Fads1/rs174448 (A/G) on the ontents of DHA and DHA/EPA. Note: High DHA-rich n-3 PUFAs intake group was included maternal exogenous DHA-rich n-3 PUFAs supplementation at the early (S1) and middle (S2) pregnancy, Low DHA-rich n-3 PUFAs intake group was included maternal exogenous DHA-rich n-3 PUFAs supplementation at the late pregnancy (S3) and non-exogenous DHA-rich n-3 PUFAs supplementation during the whole pregnancy. PUFAs Polyunsaturated fatty acids, SNPs Single nucleotide polymorphisms, Fads Fatty acid desaturases, LA Linoleic acid, EPA Eicosapentaenoic acid, DHA Docosahexaenoic acid
Background The single nucleotide polymorphisms (SNPs) in the fatty acid desaturases and elongases might associate with the endogenous synthesis of polyunsaturated fatty acids (PUFAs). However, the related epidemiological evidence is still conflicting. So we aimed to clearly evaluate the interactions between maternal DHA-rich n-3 PUFAs supplementation and the known 26 SNPs on the profiles of PUFAs in the colostrum using a Chinese birth cohort. Methods Totally, 1050 healthy mother-infant pairs were enrolled in this study at gestational 6–8 weeks when they established their pregnancy files at Fuxing Hospital affiliated to Capital Medical University in Beijing from January to December 2018. Meanwhile, their venous blood samples were obtained for DNA extraction to detect the genotypes of SNPs in the Fads1, Fads2, Fads3, Elovl2 and Elovl5 using the Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry. Then the colostrum samples were collected to determine the profiles of PUFAs by gas chromatography. Results Maternal DHA-rich n-3 PUFAs supplementation from the early and middle pregnancy could reduce the infant BMI at birth, and impact the profiles of PUFAs in the colostrum, as higher n-3 PUFAs (EPA, DHA, DHA/ALA and DHA/EPA), lower n-6 PUFAs (AA and AA/LA) and ∑-6/n-3ΣPUFAs. Moreover, there were significant correlations between multiple SNPs and the profiles of n-6 PUFAs (rs76996928 for LA, rs174550, rs174553 and rs174609 for AA, rs174550 and rs76996928 for AA/LA) and n-3 PUFAs in the colostrum (rs174448, rs174537, rs174550, rs174553, rs174598, rs3168072, rs174455 and rs174464 for ALA, rs174550, rs174553 and rs174598 for EPA, rs174455 and rs174464 for DHA, rs174448 and rs3168072 for DHA/EPA) using the multiple linear regressions by adjusting the maternal age, gestational week, mode of delivery, infant sex and BMI at birth, and all these above significant SNPs had the cumulative effects on the profiles of PUFAs. Furthermore, the pairwise comparisons also showed the meaningful interactions between maternal DHA-rich n-3 PUFAs supplementation and related genotypes of SNPs (rs76996928 for LA, rs174598 for EPA, rs174448 for DHA and DHA/EPA) on the contents of PUFAs in the colostrum. Conclusions Results from this birth cohort study proved that the pregnant women with the following SNPs such as Fads3 rs174455 T, Fads3 rs174464 A and Fads1 rs174448 G alleles should pay more attention on their exogenous DHA supplementation from the early and middle pregnancy for the blocked endogenous synthesis. Trial registration : This study was approved by the Ethics Committee of Beijing Pediatric Research Institution, Beijing Children’s Hospital affiliated to Capital Medical University (2016–08), which was also registered at the website of http://www.chictr.org.cn/showproj.aspx?proj=4673 (No: ChiCTR-OCH-14004900).
 
The level of Hb in C group and M group before Intervention. *P < 0.05 vs C group
Weight changes of SD rats in each group. Adaptive feeding: 0-1w; Molding: 1-6w; Intervention: 6-10w
The protein expressions of CYP2R1, CYP27A1, CYP27B1, CYP24A1. n = 4, (A) CYP2R1, (B) CYP27A1, (C) CYP27B1, (D) CYP24A1; 1:C, 2:DFe, 3:LFe, 4:MFe, 5:HFe, *P < 0.05
The Immunofluorescence staining of CYP2R1, CYP27A1, CYP27B1, CYP24A1(400X). n = 3, (A) C, (B) DFe, (C) LFe, (D) MFe, (E) HFe, Scale:50 μm
Abstract Background Iron and vitamin D (VD) is essential to health. Previous studies have shown that iron homeostasis has a potential effect on VD metabolism, but the mechanism is not fully understood. Objectives To explore the relationship between VD metabolism and iron metabolism, as well as the regulatory mechanism of iron on VD metabolism. Methods 40 male rats were fed adaptively for 7 days and randomly divided into control (C, n = 6 normal diet) group and model (M, n = 24 iron deficient diet) by simple randomization, the latter was used to establish iron deficiency anemia (IDA) model. After 6 weeks of feeding, the M group was randomly divided into: iron deficiency group (DFe), low iron group (LFe), medium iron group (MFe) and high iron group (HFe) by block randomization. Different doses of iron dextran (based on iron content (100 g·bw·d)): 0, 1.1, 3.3 and 9.9 mg) were given respectively. After 4 weeks, the rats were anesthetized with 8% chloral hydrate, Blood (collected from the abdominal aorta), liver and kidney tissues were collected. The serum and tissues were separately packed and frozen at -80℃ for testing. Results The results showed that the levels of hemoglobin (Hb), red blood cell (RBC), serum iron (SI), liver iron, and kidney iron in DFe group were lower than those in the other four groups, while the levels of total iron-binding capacity (TIBC), transferrin (TF) and transferrin receptor (Tfr) in DFe group were higher than those in other groups; The serum levels of 25-(OH)D3 and 1,25-(OH)2D3 in DFe group were significantly lower than those in C group (P
 
Flow chart of the cohort study
Risk of death according to restricted cubic spline regression among participants without known diabetes. The data were adjusted for age, sex, residential area, body mass index, smoking, alcohol use, regular exercise, education, hypertension, and dyslipidaemia
Background This study aimed to examine associations between haemoglobin A1c (HbA1c) levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans. Methods Using 16 years of follow-up data from the Korean Genome and Epidemiology Study, we analysed 9294 individuals aged 40–69 years with no history of cardiovascular disease (CVD) or cancer. Participants were divided into a known diabetes group and five groups categorized by HbA1c levels (< 5.0%, 5.0–5.4%, 5.5–5.9%, 6.0–6.4%, and ≥ 6.5%). Hazard ratios (HRs) for all-cause and cause-specific mortality associated with HbA1c levels were calculated using a conventional and a time-dependent Cox proportional hazards model. Restricted cubic spline models were fitted to investigate the relationship between continuous HbA1c levels and mortality among people without known diabetes. Subgroup analyses were performed for age, sex, smoking, hypertension, liver diseases, and red blood cell counts. Results During a median follow-up period of 15.7 years, there were 944 deaths, including 185 deaths from CVD, 359 from cancer, and 125 from all external causes. Compared with participants with HbA1c levels of 5.5–5.9%, multivariate-adjusted HRs and 95% confidence intervals for all-cause death of participants with levels < 5.0%, 5.0–5.4%, 6.0–6.4%, and ≥ 6.5% and participants with known diabetes were 1.84 (1.35–2.51), 1.13 (0.95–1.34), 1.30 (1.04–1.62), 1.37 (0.97–1.93), and 2.03 (1.70–2.44), respectively. The risk of cancer mortality was significantly increased in HbA1c < 5.0% (HR, 2.21; 95% CI 1.42–3.44) and known diabetes (HR, 1.60; 95% CI 1.18–2.15). When we performed diverse subgroup analyses, low HbA1c levels at baseline were strongly associated with mortality in participants with liver diseases. Conclusions We found U-shaped associations between HbA1c levels at baseline and over time and all-cause mortality in middle-aged and older Koreans. Additionally, the risk of cancer mortality increased both in low and high HbA1c groups, but CVD mortality increased only in high HbA1c group. In particular, people with liver diseases and low HbA1c levels had a high risk of all-cause mortality. Therefore, more careful management of these groups is suggested to identify any deteriorating health conditions. Graphical abstract
 
Flow diagram of study design. VAT^, predicted values of VAT (visceral adipose tissue) mass; BMD bone mineral density; DXA dual-energy x-ray absorptiometry; FN-BMD femoral neck BMD; LS-BMD lumbar spine BMD; FA-BMD forearm BMD; MR mendelian randomization; and IV instrumental variable
Association of VAT^ with heel BMD using restricted cubic splines. Betas are indicated by solid lines and 95% CIs by shaded areas. The reference point was the median of VAT^ in men (1.65 kg) and women (0.70 kg), separately, with knots placed at the 5th, 25th, 50th, 75th, and 95th centiles of each VAT^ distribution. All models were adjusted for age, household income, lean mass, standing height, smoking status, alcohol consumption, physical activity, calcium supplement use, vitamin D supplement use, overall health rating, diabetes, cardiovascular disease, cancer, and for women, menopausal status and use of hormone replacement therapy. VAT^ predicted values of VAT (visceral adipose tissue) mass; BMD bone mineral density; and CI confidence interval
Association of VAT^ with total fracture risk using restricted cubic splines. HRs are indicated by solid lines and 95% CIs by shaded areas. The reference point was the median of VAT^ in men (1.67 kg) and women (0.69 kg), separately, with knots placed at the 5th, 25th, 50th, 75th, and 95th centiles of each VAT^ distribution. All models were adjusted for age, household income, lean mass, standing height, smoking status, alcohol consumption, physical activity, calcium supplement use, vitamin D supplement use, overall health rating, diabetes, cardiovascular disease, cancer, and for women, menopausal status and use of hormone replacement therapy. VAT^ predicted values of VAT (visceral adipose tissue) mass; HR hazard ratio; and CI confidence interval
Associations of VAT^ with heel BMD in men and women by BMI categories
Background The associations between visceral adipose tissue (VAT) and bone mineral density (BMD) or fracture have been controversial and the causality of the associations remains to be assessed. This study aimed to explore the associations of VAT^ (predicted value of VAT mass) with BMD and fracture risk in men and women, and to examine their potential causation by two-sample Mendelian randomization (MR) analyses. Methods UK Biobank is a large, population-based prospective cohort study that recruited more than 500,000 participants aged 40–69 in the United Kingdom from 2006 to 2010. In this study, we used a validated and reliable prediction model to estimate the VAT amount of the participants. On this basis, linear and nonlinear multivariable statistical models were used to explore the association of VAT^ with BMD and fracture risk in different groups of sex and BMI. In observational analyses, the multivariable linear regression model and Cox proportional-hazards model were used to assess VAT^ association with BMD and fracture risk, respectively. Inverse variance weighting was used as the main result of MR analysis. Results In 190,836 men, an inverted U-shaped association was observed between VAT^ and heel BMD (P for nonlinearity < 0.001), with a turning point of VAT^ = 1.25 kg. Per kg increase in VAT^ was associated with a 0.13 standard deviation (SD) increase in heel BMD (P = 1.5 × 10⁻¹⁶) among men with lower amounts of VAT^, and associated with a 0.05 SD decrease in heel BMD (P = 1.3 × 10⁻¹⁵) among men with higher amounts of VAT^. In 193,592 women, per kg increase in VAT^ was monotonically associated with a 0.16 SD increase in heel BMD (P = 1.2 × 10⁻¹³⁶, P for VAT^-sex interaction = 8.4 × 10⁻⁵¹). During a median follow-up of 8.2 years, VAT^ was associated with lower risks of hip fractures in the overall men and women (P for VAT^-sex interaction = 1.9 × 10⁻⁴ for total fractures; 1.5 × 10⁻⁴ for other fractures). There were significant interactions of VAT^ and BMI on heel BMD and fracture risks in men only (P for VAT^-BMI interaction = 5.9 × 10⁻³¹ for heel BMD; 2.7 × 10⁻⁴ for total fractures; 5.7 × 10⁻³ for hip fractures; 6.8 × 10⁻³ for other fractures). In two-sample MR analyses, evidence of causality was not observed between VAT^ and DXA-derived BMD or fractures. Conclusions These novel findings demonstrated gender-dependent associations of VAT^ with BMD and fracture risk, with the association in men being modified by adiposity. Evidence of causality was not observed, suggesting that the observational association of VAT^ with BMD and fracture risk could be the result of confounding.
 
Effect of chronic alcohol intake hepatic steatosis and liver injury. A Representative images of hepatic hematoxylin and eosin (H&E) and of Oil Red O staining (100× and 200×). B Quantification of lipid accumulation based on Oil red O staining (200×). C Changes of inflammation in mice liver in response to alcohol intake (n = 10 per group). PF pair-fed control group, AF alcohol-fed group
Alcohol-induced changes of lipids profiling in mice liver (n = 6 per group). A Score plot of principle component analysis (PCA) in alcohol-fed, pair-fed and quality control groups. B Score plot of orthogonal partial least squares discriminant analysis (OPLS-DA) in alcohol-fed and pair-fed control groups. C Permutation tests for OPLS-DA model. D Volcano plot showing changes of 120 lipids in mice liver after alcohol intervention. The up-regulated lipids were colored with red, the down-regulated lipids were colored with blue, and the gray plots represent lipids not significantly changed
Heatmap of the 49 significantly differential triacylglycerols (TAGs) showed apparent clustering according to alcohol-fed and pair-fed groups (n = 6 per group). Red shows higher expression and blue shows lower expression
Characteristics of the 41 up-regulated TAGs and the 8 down-regulated TAGs in response to alcohol intake, according to their total carbon number (A), unsaturation (B) and contained fatty acid (C)
Correlation between the indicators of hepatic steatosis, lipid peroxidation and inflammation and the top 25 significantly changed triacylglycerolls (TAGs). Red represents positive correlation and blue represents negative correlation. *P < 0.05
Background Alcoholic liver disease (ALD) is one of the most prevalent chronic liver disease worldwide. Alcohol-induced alterations in hepatic lipids play an important role in ALD develpoment and progression. The present study aimed to thoroughly describe the changes of lipid profiling in liver of mice with early-stage alcoholic liver disease. Methods C57BL/6J male mice aged 7-week were randomized into alcohol-fed (AF) group and pair-fed control group (PF) (n = 10 per group). The early stage of ALD was induced with Lieber-DeCarli liquid diet. The lipids profiling was analyzed by absolute quantitative lipidomics with UHPLC-QTRAP-MS/MS. Results Alcohol intake significantly increased the levels of alanine aminotransferase (ALT) in plasma, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and triacylglycerols (TAG) levels in liver. Lipidomis analyses showed that 41 TAGs were up-regulated and 8 TAGs were down-regulated in response to alcohol intake. The 8 decreased TAGs were with more double bond, longer carbon chain length and mostly contained docosahexaenoic acid (C22:6n-3) and eicosapentaenoic acid (C20:5n-3), compared with the up-regulated TAGs. Furthermore, the down-regulated TAG(56:9)_FA20:5 was inversely associated with ALT and IL-6 levels. In addition, several altered lysophosphatidylcholines (LPC), lysophosphatidylethanolamines (LPE) and hexosylceramides (HCER) were all significantly decreased in response to alcohol consumption, especially HCer(18:1/22:0), with the top reduction among all the down-regulated lipids. Conclusions These findings suggest that not only the up-regulated lipids, alcohol-induced reduction in some specific lipids might also contribute to the ALD development, especially TAG(56:9)_FA20:5 and HCer(18:1/22:0). Their physiological functions and effects on ALD development warrants further investigation.
 
Birth weight changes associated with per 3% increase in energy from dietary protein intake during pregnancy. Multilevel linear regression models were used to estimate changes and 95% CIs. Model 1 was adjusted for total energy intake, offspring sex, gestational age, and socio-demographic characteristics (including geographic area, residence, childbearing age, education, occupation, household wealth index, and parity). Model 2 was adjusted for all variables in Model 1 plus health-related characteristics (including passive smoking, alcohol drinking, antenatal check visit frequency, folate/iron supplements use, anemia, and medication use) and principal component score based on the nutrient intakes. Models were mutually adjusted for animal protein and plant protein. The black circles represent birth weight changes, and the vertical lines represent 95% CIs
Birth weight changes associated with per 3% increase in energy from major dietary protein sources during pregnancy. Multilevel linear regression models were used to estimate changes and 95% CIs. Models were adjusted for total energy intake, offspring sex, gestational age, socio-demographic characteristics (including geographic area, residence, childbearing age, education, occupation, household wealth index, and parity), health-related characteristics (including passive smoking, alcohol drinking, antenatal check visit frequency, folate/iron supplements use, anemia, and medication use), principal component score based on the nutrient intakes, and mutually adjusted for other major dietary protein sources. The black circles represent birth weight changes, and the vertical lines represent 95% CIs. *P = 0.008
Birth outcomes associated with per 3% increase in energy from major dietary protein sources during pregnancy. Multilevel logistic regression models were used to estimate ORs and 95% CIs. Models were adjusted for total energy intake, socio-demographic characteristics (including geographic area, residence, childbearing age, education, occupation, household wealth index, and parity), health-related characteristics (including passive smoking, alcohol drinking, antenatal check visit frequency, folate/iron supplements use, anemia, and medication use), principal component score based on the nutrient intakes, and mutually adjusted for other major dietary protein sources. Models for low birth weight were additionally adjusted for offspring sex and gestational age. The black boxes represent ORs, with the size inversely proportional to the variance of the logarithm of the OR, and the horizontal lines represent 95% CIs
Background Previous studies have yielded inconsistent results on the association between maternal dietary protein intake and birth weight. Moreover, little is known about the effects of dietary protein intake from different sources on fetal growth. This study aimed to investigate the associations of different dietary protein sources (total protein, animal protein, plant protein, and major dietary protein sources) during pregnancy with birth weight and the related adverse birth outcomes. Methods 7310 women were recruited using a stratified multistage random sampling method at 0–12 months (median: 3; 10–90th percentile: 0–7) after delivery in Shaanxi, China. Maternal diets were gathered by a validated FFQ and other characteristics were collected by a standard questionnaire. Multilevel linear or logistic regression models were used to estimate birth weight changes or ORs (95% CIs) for adverse birth outcomes associated with different dietary protein sources during pregnancy. Results The mean percentage of energy from total protein was 11.4% (SD 2.2), with only 27.4% of total protein derived from animal protein. Per 3% increase in energy from total protein, animal protein, and dairy protein was associated with birth weight increases of 19.4 g (95% CI 6.0–32.9), 20.6 g (4.8–36.5), and 18.2 g (4.7–31.7), respectively. Per 3% increase in energy from total protein, animal protein, and dairy protein was also associated with lower risks of low birth weight (LBW) (total protein: OR = 0.78, 95% CI 0.64–0.94; animal protein: 0.79, 0.65–0.96; dairy protein: 0.71, 0.56–0.91), small for gestational age (SGA) (total protein: 0.88, 0.79–0.98; animal protein: 0.87, 0.78–0.97; dairy protein: 0.81, 0.68–0.96), and intrauterine growth retardation (IUGR) (total protein: 0.84, 0.72–0.98; animal protein: 0.86, 0.75–0.98; dairy protein: 0.78, 0.66–0.92). We observed no associations of plant protein and other major dietary protein sources with birth weight and the above birth outcomes. The results did not change when maternal protein was substituted for fat or carbohydrate. Conclusions Among Chinese pregnant women with low intake of protein, higher intake of dietary protein, in particular animal protein and dairy protein, is associated with higher birth weight and lower risks of LBW, SGA, and IUGR.
 
Objects Caloric restriction (CR) is known to extend lifespan and exert a protective effect on organs, and is thus a low-cost and easily implemented approach to the health maintenance. However, there have been no studies that have systematically evaluated the metabolic changes that occur in the main tissues affected by CR. This study aimed to explore the target tissues metabolomic profile in CR mice. Methods Male C57BL/6J mice were randomly allocated to the CR group (n = 7) and control group (n = 7). A non-targeted gas chromatography–mass spectrometry approach and multivariate analysis were used to identify metabolites in the main tissues (serum, heart, liver, kidney, cortex, hippocampus, lung, muscle, and white adipose) in model of CR. Results We identified 10 metabolites in the heart that showed differential abundance between the 2 groups, along with 9 in kidney, 6 in liver, 6 in lung, 6 in white adipose, 4 in hippocampus, 4 in serum, 3 in cortex, and 2 in muscle. The most significantly altered metabolites were amino acids (AAs) (glycine, aspartic acid, l -isoleucine, l -proline, l -aspartic acid, l -serine, l -hydroxyproline, l -alanine, l -valine, l -threonine, l -glutamic acid, and l -phenylalanine) and fatty acids (FAs) (palmitic acid, 1 -monopalmitin, glycerol monostearate, docosahexaenoic acid, 16-octadecenoic acid, oleic acid, stearic acid, and hexanoic acid). These metabolites were associated with 7 different functional pathways related to the metabolism of AAs, lipids, and energy. Conclusion Our results provide insight into the specific metabolic changes that are induced by CR and can serve as a reference for physiologic studies on how CR improves health and extends lifespan.
 
Background Excessive consumption of high-fat diets is associated with disordered metabolic responses, which may lead to chronic diseases. High-fat diets containing different types of fatty acids lead to distinct alterations in metabolic responses of gut-brain axis. Methods In our study, normal male C57BL/6J mice were fed to multiple high fatty acid diets (long-chain and medium-chain saturated fatty acid, LCSFA and MCSFA group; n-3 and n-6 polyunsaturated fatty acid, n-3 and n-6 PUFA group; monounsaturated fatty acid, MUFA group; trans fatty acid, TFA group) and a basic diet (control, CON group) for 19 weeks. To investigate the effects of high-fat diets on metabolic responses of gut-brain axis in obese mice, blood lipids were detected by fast gas chromatography, and related proteins in brain and intestine were detected using Western blotting, ELISA, and immunochemistry analysis. Results All high-fat diets regardless of their fatty acid composition induced obesity, lipid disorders, intestinal barrier dysfunction, and changes in gut-brain axis related factors except basal diet in mice. For example, the protein expression of zonula occludens-1 (ZO-1) in ileum in the n-3 PUFA group was higher than that in the MCSFA group (P < 0.05). The expressions of insulin in hippocampus and leptin in ileum in the MCSFA group significantly increased, compared with other groups (all Ps < 0.05). Conclusion The high MCSFA diet had the most effect on metabolic disorders in gut-brain axis, but the high n-3 PUFA diet had the least effect on changes in metabolism.
 
Flowchart of study selection
Background An increasing number of children and adolescents are affected by metabolic syndrome (MetS). Dietary inflammatory index (DII) was associated with MetS in adult population. This study aimed to determine the associations between DII scores, MetS, and MetS components among children and adolescents. Methods Data of children and adolescents in the National Health and Nutrition Examination Survey (NHANES) database 2001–2008 were obtained. DII was calculated for each participant based on the 24-h dietary recall interview. Univariate and multivariate logistic regression were conducted to determine the associations between DII, the other study variables and abnormal MetS components. Results A total of 5,656 US children and adolescents (mean age = 15.49) in the 2001–2018 NHANES database were included. After adjusting for all confounders in the multivariate analysis, the top DII quartile was significantly and independently associated with increased odds of high blood pressure (BP) (aOR = 2.27, 95% CI: 1.02–5.07) as compared with the lowest DII quartile. DII in quartile 2, 3 or 4 were not significantly associated with increased odds of MetS, high waist circumference (WC), low high density lipoprotein-cholesterol (HDL-c), triglyceride (TG) or fasting plasma glucose (FPG) as compared with the lowest quartile. In stratified analysis by recommended physical activity level for children and adolescents, no significant association was observed between higher DII and MetS. Conclusions Among US children and adolescents, high DII is associated with prevalent high BP but not MetS. The finding may contribute to future policymaking in promoting children’s health.
 
DHM prevents diet-induced obesity. A Body weight of DIO mice during DHM administration (n = 6). B Food intake per week during the 4 weeks of the experiment (n = 8). C Fat mass and lean mass normalized by body weight (n = 5). Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01
DHM protects against metabolic dysfunction in DIO mice. A, B Intraperitoneal glucose tolerance test (n = 8). C, D Insulin tolerance test (n = 8). E Serum triglyceride level (n = 5). F Liver mass normalized by body weight (n = 5). G Representative liver H&E staining(n = 5). Scale bar = 100 μm. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001
DHM stimulates iWAT browning. A iWAT mass, epididymal WAT (eWAT) mass and BAT mass normalized by body weight (n = 5). B Representative H&E staining of iWAT (upper panel) and UCP1 immunohistochemistry (brown) (lower panel), scale bar = 100 μm. C Percentage of different adipocyte cell sizes in iWAT(n = 5). D RNA expression profiles of the brown fat marker and mitochondrial-related and fatty acid oxidation-related genes in iWAT. E PGC-1α and UCP1 protein expression in iWAT. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01
DHM induces the browning of primary adipocytes and increases mitochondrial activity. A Representative images of visual estimation and oil red O staining of primary inguinal adipocytes treated with DHM, scale bar = 100 μm. B RNA expression profiles of the brown fat marker and mitochondrial-related and fatty acid oxidation-related genes in primary inguinal adipocytes. C Western blots of PGC-1α and UCP1 protein in primary inguinal adipocytes. D, E Basal OCR in DHM-treated primary inguinal adipocytes. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001
DHM induces the browning program by upregulating IRF4/PGC-1α. A Protein levels of p-AMPK, T-AMPK, p-PKA, p-p38 MAPK, and T-p38 MAPK in iWAT. B Luciferase expression of the PGC-1α promoter in HEK293T cells. C Heatmaps representing the expression of thermogenic genes in iWAT by RNA-seq. D The IRF4 mRNA expression level in iWAT. (E) The IRF4 protein expression level in iWAT. F Luciferase expression of the IRF4 promoter in HEK293T cells. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001
Background Promoting the browning of white adipose tissue (WAT) is a promising approach for the treatment of obesity and related comorbidities because it increases energy expenditure. In this study, we investigated whether Dihydromyricetin (DHM), a flavonoid component, could ameliorate diet-induced obesity through promoting the browning of WAT. Methods Male C57BL/6 J mice were received a high-fat diet (HFD) to induce obesity and subsequently were treated with DHM (100 mg/kg/day) or vehicle for 4 weeks. The effects of DHM on weight reduction and metabolic phenotype improvement were observed in the mice. The expression of genes and protein involved in browning of WAT were assessed in inguinal WAT (iWAT) of the mice. Then, the effect of DHM on the inducing browning program was verified in adipocytes differentiated from stromal vascular fraction (SVF) cells of mouse iWAT. Finally, the mechanism by which DHM improves the browning of WAT was explored using RNA-seq and luciferase reporter assay. Results We find that DHM reduces body weight, decreases WAT mass, improves glucose and lipid metabolic disorders, and ameliorates hepatic steatosis in diet-induced obese (DIO) mice. Further studies show that DHM induces WAT browning, which is manifested by increased expression of uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and enhanced mitochondrial activity in iWAT and primary adipocytes. In addition, we also find that DHM enhances interferon regulatory factor 4 (IRF4) expression, which is a key transcriptional regulator of PGC-1α. Conclusion Our findings identify that DHM prevents obesity by inducing the browning of WAT through the upregulation of IRF4/PGC-1α, which may have potential therapeutic implications for the treatment of obesity.
 
A Pearson correlations of the associations between fat mass (%) with reserve capacity for males and females. B Partial correlation of the associations between thigh subcutaneous adipose tissue (SAT) with maximal oxygen consumption rate (OCR) for males and females adjusting for fat mass. Partial correlation value between thigh SAT and maximal OCR for all subjects was r = 0.04, p = 0.8. All variables were natural log transformed for analyses
A Pearson correlation of the association between fat mass (%) and τPCr for males and females. B Partial correlation of the association between thigh subcutaneous adipose tissue (SAT) and τPCr for males and females adjusting for fat mass. Partial correlation value between thigh SAT and τPCr for all subjects was r = − 0.38, p = 0.03. All variables were natural log transformed for analyses
Background Adiposity and mitochondrial dysfunction are related factors contributing to metabolic disease development. This pilot study examined whether in vivo and ex vivo indices of mitochondrial metabolism were differentially associated with body composition in males and females. Methods Thirty-four participants including 19 females (mean 27 yr) and 15 males (mean 29 yr) had body composition assessed by dual energy x-ray absorptiometry and magnetic resonance (MR) imaging. Monocyte reserve capacity and maximal oxygen consumption rate (OCR) were determined ex vivo using extracellular flux analysis. In vivo quadriceps mitochondrial function was measured using ³¹ P-MR spectroscopy based on post-exercise recovery kinetics (τPCr). The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin levels. Variables were log-transformed, and Pearson correlations and partial correlations were used for analyses. Results Mitochondrial metabolism was similar between sexes ( p > 0.05). In males only, higher fat mass percent (FM%) was correlated with lower reserve capacity (r = − 0.73; p = 0.002) and reduced muscle mitochondrial function (r = 0.58, p = 0.02). Thigh subcutaneous adipose tissue was inversely related to reserve capacity in males (r = − 0.75, p = 0.001), but in females was correlated to higher maximal OCR (r = 0.48, p = 0.046), independent of FM. In females, lean mass was related to greater reserve capacity (r = 0.47, p = 0.04). In all participants, insulin (r = 0.35; p = 0.04) and HOMA-IR (r = 0.34; p = 0.05) were associated with a higher τPCr. Conclusions These novel findings demonstrate distinct sex-dependent associations between monocyte and skeletal muscle mitochondrial metabolism with body composition. With further study, increased understanding of these relationships may inform sex-specific interventions to improve mitochondrial function and metabolic health.
 
Background In hospitalized patients, drug side effects usually trigger intestinal mucositis (IM), which in turn damages intestinal absorption and reduces the efficacy of treatment. It has been discovered that natural polysaccharides can relieve IM. In this study, we extracted and purified homogenous polysaccharides of Wuguchong (HPW), a traditional Chinese medicine, and explored the protective effect of HPW on 5-fluorouracil (5-FU)-induced IM. Methods and results First, we identified the physical and chemical properties of the extracted homogeneous polysaccharides. The molecular weight of HPW was 616 kDa, and it was composed of 14 monosaccharides. Then, a model of small IM induced by 5-FU (50 mg/kg) was established in mice to explore the effect and mechanism of HPW. The results showed that HPW effectively increased histological indicators such as villus height, crypt depth and goblet cell count. Moreover, HPW relieved intestinal barrier indicators such as D-Lac and diamine oxidase (DAO). Subsequently, western blotting was used to measure the expression of Claudin-1, Occludin, proliferating cell nuclear antigen, and inflammatory proteins such as NF-κB (P65), tumour necrosis factor-α (TNF-α), and COX-2. The results also indicated that HPW could reduce inflammation and protect the barrier at the molecular level. Finally, we investigated the influence of HPW on the levels of short-chain fatty acids, a metabolite of intestinal flora, in the faeces of mice. Conclusions HPW, which is a bioactive polysaccharide derived from insects, has protective effects on the intestinal mucosa, can relieve intestinal inflammation caused by drug side effects, and deserves further development and research.
 
Flowchart for the participants
Backgrounds This randomized controlled trial aimed to investigate the effects of replacing red meat with legumes in the dietary approach to stop hypertension (DASH) diet on inflammatory markers over 16 weeks in overweight and obese individuals with type 2 diabetes. Also, the modulatory effects of TCF7L2 rs7903146 variant on this effect were assessed. Methods In this trial, 300 participants with type 2 diabetes, aged 30–65 years with an identified TCF7L2 rs7903146 genotype, were studied. The participants were randomly assigned to the DASH diet or the legume-based DASH diet over 16 weeks. In the DASH diet group, the participants were instructed to follow the standard DASH diet. The legume-based DASH diet was similar to the standard DASH diet, with the exception that one serving of red meat was replaced with one serving of legumes at least five days a week. At the beginning of the study and 16-week follow-up, venous blood samples were collected from all participants who fasted for 12–14 h overnight. The serum concentration of High-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) was measured using an enzyme-linked immunosorbent assay (ELISA) kit. Also, the serum malondialdehyde (MDA) concentration was assessed based on a colorimetric method using a commercial kit. The primary outcome was the difference in hs-CRP changes between the diets. A secondary outcomes was the difference in IL-6, TNF-α, and MDA between the groups among total population and based on TCF7L2 rs7903146 risk allele (CT + TT) and non-risk allele (CC) separately. Results The hs-CRP level reduced in the legume-based DASH diet group as compared to the DASH diet group in the 16-week follow-up group. The levels of TNF-α, IL-6, and MDA reduced after the legume-based DASH diet relative to the DASH diet. Reduction of inflammatory markers was observed in both carriers of rs7903146 risk allele and non-risk allele. Conclusions Substituting one serving of red meat with one serving of legumes in DASH diet, at least five days a week, could improve the hs-CRP, TNF-α, IL-6, and MDA in participants with type 2 diabetes regardless of having rs7903146 risk or non-risk allele. Trial registration IRCT, IRCT20090203001640N17.
 
Time-dependent AUC values of different factors regarding body water. Notes: AUC: area under the curve, ECW/TBW: extracellular water/total body water, ECW/ICW: extracellular water/intracellular water, ICW/TBW: intracellular water/total body water, ECW: extracellular water, TBW: total body water, FFM: free fat mass, ICW: intracellular water, ACM: active cell mass
The relation of ECW/TBW and survival of cancer patients with sarcopenia. Notes: HRs of survival of cancer patients with sarcopenia relation to ECW/TBW (as continue value) were calculated using univariate Cox regression model (A) or multivariate Cox regression model (B). Each subgroup analysis adjusted for age, sex, tumor stage, tumor type, BMI, PG-SGA, and NLR if not stratified by these variables. ECW/TBW: extracellular water/total body water, PG-SGA: patient-generated subjective global assessment, NLR: neutrophil-to-lymphocyte ratio
The association between ECW/TBW (0.385–0.405) and the risk of survival of cancer patients with sarcopenia in various subgroups. Notes: HRs of survival of cancer patients with sarcopenia relation to ECW/TBW (as continue value) were calculated using multivariate Cox regression models. Each subgroup analysis adjusted for age, sex, tumor stage, tumor type, BMI, PG-SGA, and NLR. ECW/TBW: extracellular water/total body water, PG-SGA: patient-generated subjective global assessment, NLR: neutrophil-to-lymphocyte ratio
Background: Body water measured by bioelectrical impedance analysis (BIA) predicts the outcomes of many diseases. This study aimed to evaluate the relationship between body water and the prognosis of cancer patients with sarcopenia. Methods: This study employed 287 cancer patients with sarcopenia underwent BIA from a prospective multicenter study of patients with cancer in China from 2013 to 2020. The primary outcome of interest was all-cause mortality presented as the longest time to follow-up available. Eight indicators of body water [total body water, extracellular water, intracellular water, free fat mass, active cell mass, extracellular water/intracellular water, extracellular water/total body water (ECW/TBW), and intracellular water/total body water] were included in the research. Neutrophil-lymphocyte ratio (NLR) = neutrophil (× 109)/lymphocyte (× 109). The discriminatory ability and prediction accuracy of each factor were assessed using the C-index. The hazard ratios (HR) and 95% confidence intervals (CI) were calculated using the Cox proportional hazard model. Results: The median age was 65 years old, and 138 (48%) patients were men. During a mean follow-up of 46 months, 140 deaths were recorded, resulting in a rate of 204.6 events per 1000 patient-years. ECW/TBW showed the best predictive accuracy (C-index = 0.619) compared to the other indicators [p = 0.004, adjusted HR (95% CI) 1.70 (1.18,2.44)]. In the middle tertile (0.385-0.405), ECW/TBW had a strong independent negative association with patient survival [adjusted HR (95% CI) 2.88 (1.39-5.97), p = 0.004]. Patients who had a high ECW/TBW (ECW/TBW ≥ 0.395) combined with a high NLR had 3.84-fold risk of mortality (p < 0.001, 95% CI 1.99,7.38). Conclusions: ECW/TBW was better than other indicators in predicting survival of cancer patients with sarcopenia. High ECW/TBW combined with high NLR would further increase the risk of mortality. Trial registration: The Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) (Chinese Clinical Trial Registry: ChiCTR1800020329, URL of registration: http://www.chictr.org.cn/showprojen.aspx?proj=31813 ).
 
Background Hypertriglyceridemia (HTG) is one of the most important comorbidities in abnormal glucose patients. The aim of this study was to identify lncRNAs functional modules and hub genes related to triglyceride (TG) in prediabetes. Methods The study included 12 prediabetic patients: 6 participants with HTG and 6 participants with normal triglyceride (NTG). Whole peripheral blood RNA sequencing was performed for these samples to establish a lncRNA library. WGCNA, KEGG pathways analysis and the PPI network were used to construct co‐expression network, to obtain modules related to blood glucose, and to detect key lncRNAs. Meanwhile, GEO database and qRT-PCR were used to validate above key lncRNAs. Results We found out that the TCONS_00334653 and PVT1, whose target mRNA are MYC and HIST1H2BM, were downregulating in the prediabetes with HTG. Moreover, both of TCONS_00334653 and PVT1 were validated in the GEO database and qRT-PCR. Conclusions Therefore, the TCONS_00334653 and PVT1 were detected the key lncRNAs for the prediabetes with HTG, which might be a potential therapeutic or diagnostic target for the treatment of prediabetes with HTG according to the results of validation in the GEO database, qRT-PCR and ROC curves.
 
The flow diagram
Pie chart of percentage of water sources in different ways
Pie chart of percentage of water losses in different ways
Background Few studies on measuring human energy expenditure with the doubly labeled water method has been conducted in China. The sources and loss of water among human body have never been systematically evaluated. Less data can be available for the development of the recommendation on energy expenditure and water intake. The objective of this study was to determine the energy expenditure, water sources, and loss among young adults. Methods In this cross-sectional study, 25 participants were recruited. Double-labeled water was used to determine their energy expenditure. Water loss through skin evaporation and respiration of the lungs and water sources from metabolic water were calculated using corresponding formula, respectively. Water loss through excretion of urine was recorded and evaluated using “3-day, 24-h, real-time urine excretion record” method. All urine samples were collected and weighed in the 3 days. Water loss through excretion of feces was evaluated using “3-day, 24-h, real-time fecal-excretion record” method. All fecal samples were collected and tested by the direct drying method. Water sources from fluid intake were recorded by “7-day, 24-h, real-time fluid intake record” method. Water intake from food was calculated and tested by the weighing method combined with the duplicate portion method and the direct drying method in the 3 days. Results The energy expenditure of males was 2187 kcal/d, and that of females was 1987 kcal/d. The median fluid intake, water intake from food, and metabolic water were 887, 1173 and 246 mL, respectively, which accounted for 38.8%, 50.3%, and 11.2% of total water sources. There was a gender difference in the percentage of metabolic water ( Z = − 2.135, P = 0.033). The water loss through urine excretion, skin evaporation, respiration, and feces excretion was 1295, 172, 149 and 64 mL, respectively, which accounted for 76.5%, 10.3%, 9.5%, and 3.6% of the total water losses. Gender differences in the amount of water loss through respiration and skin evaporation were found ( Z = − 4.125, P < 0.001; Z = − 3.723, P < 0.001). Conclusions Energy expenditure of male was higher than that of female. The first major water sources was water intake from food in this study, and the first major water loss was urine excretion. Trial registration The study was registered on the website of Chinese clinical trial registry, and the code of identification is ChiCTR1900028746.
 
Concentration of markers and 25(OH)D3 before (1) and after 3 months of cholecalciferol supplementation (2). A leptin, p = 0.029; B TMAO, p = 0.022; C NO, p = 0.021; D VEGF-A, p = 0.024; E sST2, p = 0.065; F 25(OH)D3, p < 0.001
Suggested mechanism for the effect of vitamin D on adipose tissue
Background Vitamin D deficiency is one of the most common health issues in developed countries. Obese patients are most at risk of having serum 25-hydroxyvitamin D3 (25(OH)D3) levels that are too low due to the accumulation of vitamin D in adipose tissue. While the effects of a deficiency on the skeletal or immune system are known, the effects on the cardiovascular system are not yet clear. Our study investigates the effect of cholecalciferol supplementation in obese patients on selected biomarkers associated with cardiovascular diseases (CVDs). Methods The study enrolled 33 obese patients with insufficient 25(OH)D3 levels. For three months, the subjects supplemented with cholecalciferol at a dose of 2000 IU/day. Concentrations of nitric oxide (NO), vascular endothelial growth factor A (VEGF-A), leptin, trimethylamine N-oxide (TMAO) and soluble suppression of tumorigenicity 2 (sST2) were measured in baseline samples using ELISA (BioTek EPOCH). 25(OH)D3 levels measured on Beckman Coulter DXI 800 by chemiluminescence method. Results After supplementation, 25(OH)D3 levels increased significantly. Normal levels were achieved in most patients. A statistically significant reduction leptin and TMAO levels was observed. At the same time, NO and VEGF-A levels increased statistically significantly. Conclusion This study indicates that restoring normal 25(OH)D3 levels in obese people reduces the concentration of pro-inflammatory factors associated with cardiovascular diseases. Reducing inflammation and the potential impact on vascular reactivity leads to the conclusion that cholecalciferol supplementation in obese patients may benefit the cardiovascular system.
 
Background Hypercholesterolemia is closely associated with an increased risk of cardiovascular diseases. l -Arabinose exhibited hypocholesterolemia properties, but underlying mechanisms have not been sufficiently investigated. This study aimed to elucidate the mechanisms of l -arabinose on hypocholesterolemia involving the enterohepatic circulation of bile acids. Methods Thirty six-week-old male mice were randomly divided into three groups: the control group and the high-fat-high-sucrose diet (HFHSD)-fed group were gavaged with distilled water, and the l -arabinose-treated group were fed HFHSD and received 400 mg/kg/day l -arabinose for 12 weeks. Serum and liver biochemical parameters, serum and fecal bile acid, cholesterol and bile acid metabolism-related gene and protein expressions in the liver and small intestine were analyzed. Results l -Arabinose supplementation significantly reduced body weight gain, lowered circulating low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C) levels, and efficiently alleviated hepatic inflammation and lipid accumulations in HFHSD-fed mice. l -Arabinose inhibited cholesterol synthesis via downregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Additionally, l -arabinose might facilitate reverse cholesterol transport, evidenced by the increased mRNA expressions of low-density lipoprotein receptor (LDL-R) and scavenger receptor class B type 1 (SR-B1). Furthermore, l -arabinose modulated ileal reabsorption of bile acids mainly through downregulation of ileal bile acid-binding protein (I-BABP) and apical sodium-dependent bile acid transporter (ASBT), resulting in the promotion of hepatic synthesis of bile acids via upregulation of cholesterol-7α-hydroxylase (CYP7A1). Conclusions l -Arabinose supplementation exhibits hypocholesterolemic effects in HFHSD-fed mice primarily due to regulation of bile acid metabolism-related pathways.
 
Background Hypercatabolism often occurs in critically ill patients, and it increases infection rates and mortality in these patients. Enteral nutrition (EN) is commonly used in case of hypercatabolism. However, the effect of amount of calories in EN on hypercatabolism remains unexplored. Objective Here, we compared the effect of low-calorie, medium-calorie and high-calorie EN on hypercatabolism in the acute phase of endotoxemia, which is associated with gastrointestinal hormones and hypothalamic neuropeptide proopiomelanocortin (POMC). Methods Overall 84 adult male Sprague–Dawley rats were used for research. A set of rats were divided into 5 groups, Control (NS) and lipopolysaccharide (LPS) groups were fed a standard chow diet; LPS + L (LPS + 40 kcal/kg/day EN), LPS + M (LPS + 80 kcal/kg/day EN) and LPS + H (LPS + 120 kcal/kg/day EN) groups received EN through a gastric tube for 3 days. Another set of rats were used for parallel control experiment and divided into 5 groups: NS + F (saline + fasting) and LPS + F (LPS + fasting) groups were given no food, NS + L (saline + 40 kcal/kg/day EN), NS + M (saline + 80 kcal/kg/day EN) and NS + H (saline + 120 kcal/kg/day EN) groups received EN through a gastric tube for 3 days. Hypercatabolism was evaluated by assessing skeletal muscle protein synthesis and atrophy, insulin resistance, and corticosterone levels. Moreover, serum inflammatory factors, gastrointestinal hormones, hypothalamic ghrelin, growth hormone secretagogue receptor-1α, hypothalamic neuropeptide, and intestinal injury indicators were detected. Results Low-calorie EN effectively increased serum and hypothalamic ghrelin possibly due to slight intestinal barrier damage, thereby decreasing hypothalamic POMC expression; consequently, it alleviated rat insulin resistance, reduced blood cortisol levels and muscle atrophy, and improved the survival rate of rats in the acute phase of endotoxemia. Interestingly, with an increase in calories in enteral nutrition, the aforementioned effects did not increase. Conclusions Low-calorie EN could effectively increase gastrointestinal hormone ghrelin by reducing intestinal damage and suppressing POMC expression to ameliorate hypercatabolism when compared with medium-calorie and high-calorie EN. Therefore Low-calorie EN may be preferred for providing EN in the acute stage of endotoxemia.
 
Background L-theanine, a non-protein amino acid was found principally in the green tea, has been previously shown to exhibit potent anti-obesity property and hepatoprotective effect. Herein, we investigated the effects of L-theanine on alleviating nonalcoholic hepatic steatosis in vitro and in vivo, and explored the underlying molecular mechanism. Methods In vitro, HepG2 and AML12 cells were treated with 500 μM oleic acid (OA) or treated with OA accompanied by L-theanine. In vivo, C57BL/6J mice were fed with normal control diet (NCD), high‐fat diet (HFD), or HFD along with L-theanine for 16 weeks. The levels of triglycerides (TG), accumulation of lipid droplets and the expression of genes related to hepatocyte lipid metabolic pathways were detected in vitro and in vivo. Results Our data indicated that, in vivo, L-theanine significantly reduced body weight, hepatic steatosis, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), TG and LDL cholesterol (LDL-C) in HFD-induced nonalcoholic fatty liver disease (NAFLD) mice. In vitro, L-theanine also significantly alleviated OA induced hepatocytes steatosis. Mechanic studies showed that L-theanine significantly inhibited the nucleus translocation of sterol regulatory element binding protein 1c (SREBP-1c) through AMPK-mTOR signaling pathway, thereby contributing to the reduction of fatty acid synthesis. We also identified that L-theanine enhanced fatty acid β-oxidation by increasing the expression of peroxisome proliferator–activated receptor α (PPARα) and carnitine palmitoyltransferase-1 A (CPT1A) through AMP-activated protein kinase (AMPK). Furthermore, our study indicated that L-theanine can active AMPK through its upstream kinase Calmodulin-dependent protein kinase kinase-β (CaMKKβ). Conclusions Taken together, our findings suggested that L-theanine alleviates nonalcoholic hepatic steatosis by regulating hepatocyte lipid metabolic pathways via the CaMKKβ-AMPK signaling pathway.
 
Difference between measured and estimated urinary iodine excretion in different periods of the day. UIE, urine iodine excretion; mUIC, median urinary iodine concentration; *Estimated urinary iodine excretion was significantly different compared to the measured urinary iodine excretion (P < 0.05) by Spearman rank correlation analysis; **Estimated urinary iodine excretion was significantly different compared to the measured urinary iodine excretion (P < 0.01) by Spearman rank correlation analysis; ***Estimated urinary iodine excretion was significantly different compared to the measured urinary iodine excretion (P < 0.001) by Spearman rank correlation analysis
Consistency between log-transformed Estimated 24-h urinary iodine excretion¹ and log-transformed Measured 24-h urinary iodine excretion in different periods of the day. UIE, urine iodine excretion; The X-axis is the mean of log-transformed estimated 24-h urinary iodine excretion¹ and log-transformed measured 24-h urinary iodine excretion; The Y-axis is the difference between log-transformed estimated 24-h urinary iodine excretion¹ and log-transformed measured 24-h urine iodine excretion; The solid black line represents the bias, and the dashed line represents the 95% range of consistency for the mean relative difference; Upper limit: upper 95% limit of consistency; lower limit: lower 95% limit of consistency
Consistency between log-transformed Estimated 24-h urinary iodine excretion⁵ and log-transformed Measured 24-h urinary iodine excretion in different periods of the day. UIE, urinary iodine excretion
Consistency of the six estimated 24-h urinary iodine excretion equations and the measured 24-h urinary iodine excretion in fasting urine. UIE, urine iodine excretion. Estimated 24 h UIE¹ for (A), Estimated 24 h UIE² for (B), Estimated 24 h UIE³ for (C), Estimated 24 h UIE⁴ for (D), Estimated 24 h UIE⁵ for (E) and Estimated 24 h UIE⁶ for (F);
Background Urinary iodine concentration (UIC) is routinely used to evaluate the population iodine status while the uniform method for the individual level assessment is uncertain. Objectives To explore the 24-h urinary iodine excretion (UIE) in five different periods of the day and the corresponding prediction equations respect by the use of creatinine-corrected UIC. Methods We collected 24-h, spot and fasting urine in five periods of the day to estimate 24-h UIE by the six different prediction equations. We compared the estimated creatinine-corrected UIC to the collected 24-h UIE and identified the most suitable equations in each period of the day. Results Among the six different prediction equations, the equation of Kawasaki T was the best to estimate the 24-h UIE by fasting urine among Chinese adults. Among the five periods of time, the equation of Knudsen N was the best to estimate the 24-h UIE in the non-morning period. Conclusion Urinary iodine status at the individual level could be estimated by different creatinine-based equations at different periods of the day.
 
CONSORT participant flow diagram
Quantification of carotid arterial plaque acquired by three-dimensional ultrasound. Philips VPQ software was used to assess plaque in 3D. A cross section of the vessel demonstrates a percent lumen reduction (stenosis) of 36% at baseline compared to 47% at month 6
Forest plot of stratified sub-analysis of percent change in stenosis. Although we found significant differences in percent increase of carotid stenosis within sub-groups, no tests for treatment arm by sub-group interactions reached p < 0.05. LC, L-carnitine. N = 157
Background L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). Methods This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm³ were randomized to placebo or 2 g L-C daily for 6 months. Results The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. Conclusions Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. Trial registration: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661.
 
Effect of weight loss and maintenance on patient-reported quality of life in MHO/MUO. A, B MHO + MUO were assigned following the IDF criteria for metabolic syndrome. C, D MHO + MUO were assigned on the basis of HOMA-IR. E, F MHO + MUO were assigned on the basis of ISIClamp. Values represent estimated marginal means with 95% confidence intervals from model with adjustment to sex, age, and randomization. *p < 0.05, **p < 0.01, ***p < 0.001 vs. T-3 in respective group. Where indicated, †/††/††† describe between-group comparisons, respectively. SF-36 Short Form (36) Health Survey, PCS physical component summary score, MCS mental component summary score
Effect of weight loss and maintenance on insulin resistance (adjusted for BMI) in MHO/MUO. MHO + MUO were assigned following the IDF criteria for metabolic syndrome. Values represent estimated marginal means with 95% confidence intervals from model with adjustment to sex, age, randomization, and BMI at all time-points. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. T-3 in respective group
Abstract Background While short-term effects of weight loss on quality of life and metabolic aspects appear to be different in metabolically healthy (MHO) and metabolically unhealthy obese (MUO), respective long-term data is still missing. Given the high relevance of long-term changes, we aimed to address these in this post-hoc analysis of the MAINTAIN trial. Methods We analyzed 143 overweight/obese subjects (BMI ≥ 27 kg/m2, age ≥ 18 years) before and after a 3-month weight loss program (≥ 8% weight loss), after a 12-month period of a randomized weight maintenance intervention (n = 121), and after another 6 months without intervention (n = 112). Subjects were retrospectively grouped into MHO and MUO by the presence of metabolic syndrome and secondarily by estimates of insulin sensitivity (HOMA-IR and ISIClamp). Quality of life (QoL), blood pressure, lipids, HOMA-IR, and ISIClamp were assessed and evaluated using mixed model analyses. Results Despite similar short- and long-term weight loss, weight loss-induced improvement of HOMA-IR was more pronounced in MUO than MHO after 3 months (MHO: 2.4[95%-CI: 1.9–2.9] vs. 1.6[1.1–2.1], p = 0.004; MUO: 3.6[3.2–4.0] vs. 2.0[1.6–2.4], p
 
High fructose directly induces endothelium-dependent dysfunctional vasodilation. In each group of experiments, the aortic rings were stimulated by fructose (0.25 mM and 2 mM) for 0.5 h, precontracted by using 10–6 M PE, and relaxed by 10–9–10–5 M Ach or SNP. Wire myograph recording the effect of fructose on concentration–response curves to the endothelium-dependent dilator Ach (A) and the endothelium-independent dilator SNP (B) in aortic rings from C57BL/6 J mice (WT). C, D The maximal response of Ach and SPN. All data are presented as the mean ± SEM (n = 6 aortic rings). C, control; Fru, fructose; Ach, acetylcholine; SNP, sodium nitroprusside; PE, phenylephrine. *P < 0. 05, **P < 0. 01 versus C
High fructose downregulates eNOS Ser177 phosphorylation resulting in a reduction in NO production. A Cell viability after stimulation with different concentrations of fructose for 24 h (n = 6). B, C NO production from MVECs after stimulation with fructose for 4 or 24 h (n = 4). D, E Western blot analysis showing the protein expression of eNOS and P-eNOS (Ser1177) in MVECs after stimulation with fructose for 8 h (n = 3). Relative protein levels of P-eNOS (Ser1177) were normalized to that of eNOS. All data are shown as the mean ± SEM. C, control. *P < 0. 05, **P < 0. 01, ***P < 0.001 versus C
High fructose affects the eNOS pathway closely related to PP2A in endothelial cells. MVECs were stimulated by fructose for 8 h. A, B Western blot analysis showing the protein expression of PP2AC and C, D P-PP2A (Tyr307) in MVECs. Relative protein levels of PP2AC and P-PP2A (Tyr307) were normalized to that of β-actin. Data are presented as the mean ± SEM (n = 3). C, control. *P < 0. 05, **P < 0. 01 versus C
PP2A inhibitor recovers high fructose-induced dysfunction mediated by NO reduction. MVECs were pretreated with or without 20 nM OA for 1 h and then stimulated with fructose. A NO production from MVECs (after pretreatment with fructose for 24 h) (n = 4). Western blot analysis showing the protein expression of eNOS, P-eNOS (Ser1177) (B, C), PP2AC, and P-PP2A (Tyr307) (D, E) in MVECs (after pretreatment with fructose for 8 h) (n = 3). Relative protein levels of P-eNOS (Ser1177) were normalized to that of eNOS, and those of P-PP2A (Tyr307) were normalized to that of PP2AC. All data are presented as the mean ± SEM. C, control; Fru, fructose. *P < 0.05, **P < 0.01 when compared with the respective control groups
Vasodilation function unchanged in the PP2A cKO mice under high fructose stimulation. A Identification of the PP2ACα cKO mice by genotyping. In each group of experiments, the aortic rings were stimulated by fructose (0.25 mM and 2 mM) for 0.5 h, precontracted by using 10–6 M PE, and relaxed by 10–9–10–5 M Ach or SNP. Wire myograph recording the effect of fructose in concentration–response curves to the endothelium-dependent dilator Ach (B) and the endothelium-independent dilator SNP (C) in aortic rings from the PP2ACαflox/flox and cKO mice. D, E The maximal response of Ach and SPN. All data are presented as the mean ± SEM (n = 5 aortic rings). C, control; Fru, fructose; Ach, acetylcholine; SNP, sodium nitroprusside; PE, phenylephrine. *P < 0. 05, **P < 0. 01 when compared with the respective control groups
Background Processed foods are popular and contain large amounts of industrial fructose, which changes people’s diet and exacerbates the negative health effects of high fructose. Several studies have shown that excessive intake of fructose has a major impact on vascular disease. However, the mechanism of the effect of high fructose on blood vessels is currently unclear. Methods The effect of fructose on the vasodilatation of isolated thoracic aortic rings was observed by using wire myography in wild-type (WT) mice. Cell viability and nitric oxide (NO) production were assessed by the corresponding kits in mouse vascular endothelial cells. The effect of fructose on endothelial nitric oxide synthase (eNOS) and protein phosphatase 2A (PP2A) and their changes in phosphorylation were detected by using Western blots. Moreover, a PP2A inhibitor (okadaic acid, OA) was used to evaluate the relationship between fructose and PP2A. Furthermore, PP2ACα endothelial-specific knockout (PP2A cKO) mice were used to detect the vasodilatation of in vitro fructose-incubated thoracic aortic rings by using wire myography. Results High fructose induced endothelium-dependent dysfunctional vasodilatation. High fructose reduced acetylcholine (Ach)-induced vasodilation but did not affect sodium nitroprusside (SNP)-induced vasodilation. Accordingly, NO production and the phosphorylation level of eNOS at serine (Ser) 1177 (P-eNOS) in vascular endothelial cells were remarkably reduced without changes in cell viability. The expression of protein phosphatase 2A catalytic subunit (PP2AC) was increased and the expression of phosphorylated PP2AC (P-PP2A, tyrosine [Tyr] 307) was significantly decreased. Nevertheless, these effects were reversed by OA. Moreover, knockout of the PP2A gene could recover the response of vessels to Ach under high fructose stimulation. Conclusions Our observations demonstrate an underlying mechanism of fructose-induced dysfunctional vasodilatation. Fructose could activate PP2A, which leads to decrease in the phosphorylation of eNOS at Ser1177 and the reduction of NO release, thus leading to the occurrence of endothelium-dependent dysfunctional vasodilatation.
 
MgIG ameliorate acute alcohol induced-hepatic steatosis in zebrafish Larvae. a 5 dpf larvae were treated as indicated for 32 h and stained with whole-mount oil red O. The typical pictures of each group were shown. Arrows point to the liver. b Hepatic steatosis was defined as three or more lipid droplets deposition in liver. Bar chart indicates the percentage of larvae with steatosis (n = 97–223 each group; *P < 0.05 by one-way ANOVA).c H&E staining of paraffin sections through the livers of larvae treated as indicated. Clear cytoplasmic lipid droplets were seen in livers from larvae fed with alcohol. MgIG treatment decreased lipid droplets and ameliorated hepatic steatosis in alcohol-treated zebrafish larvae. d TC levels in the livers of zerafish larvae in each group. e TG levels in the livers of zerafish larvae in each group. (n = 50–60 each group; *P < 0.05, **P < 0.01, ***P < 0.001, by one-way ANOVA)
MgIG ameliorate acute alcohol induced-hepatic steatosis in zebrafish Larvae. a Oil red O staining of frozen sections through the livers of larvae treated as indicated. Clear lipid droplets were seen in livers from larvae fed with alcohol. MgIG and NAC treatment decreased lipid droplets and ameliorated hepatic steatosis in alcohol-treated zebrafish larvae. b Oil red O staining of frozen sections through the livers of zebrafish larvae. We categorized “Normal”, “Medium”, or “Severe” by varying degrees of lipid deposition in the livers of zebrafish by frozen liver sections. Representative images of “Normal”, “Medium”, or “Severe” were shown (× 400 magnification). c Quantification of steatosis is categorized “normal”, “medium”, or “severe”. Bar chart indicates the percentages of each category in each group, and the percentages of larvae in “normal” category is noted (n = 9–11 each group)
MgIG ameliorate acute alcohol induced-hepatomegaly in zebrafish Larvae. a Tg(lfabp10a:eGFP) zebrafish larvae were treated as indicated for 32 h and the typical pictures of each group were shown. Arrows point to the liver. Control group: 0% alcohol; EtOH group: 350 mM alcohol; EtOH + MgIG(0.1) group: 350 mM alcohol + 0.1 mg ml⁻¹ MgIG; EtOH + MgIG(0.05) group: 350 mM alcohol + 0.05 mg ml⁻¹ MgIG;EtOH + MgIG(0.01)group: 350 mM alcohol + 0.01 mg ml⁻¹ MgIG; EtOH + NAC(20) group: 350 mM alcohol + 20 µM NAC. b Images of Tg(lfabp10a:eGFP) zebrafish larvae treated with 0% alcohol, 350 mM alcohol, pre-treated with 0.1 mg ml⁻¹ MgIG, 0.05 mg ml⁻¹ MgIG, 0.01 mg ml⁻¹ MgIG, 20 µM NAC and co-exposed with 350 mM alcohol for 32 h. The morphological change of livers in zebrafish larvae were observed. Alcohol-treated larvae developed obvious hepatomegaly compared to the control group after 32 h of exposure, which was visibly ameliorated in MgIG-pretreated larvae. c The liver size was examined by image J software in zebrafish larvae exposed to 0% or 350 mM alcohol and larvae pre-treated with different concentrations of MgIG, 20 µM NAC and then co-exposed with 350 mM alcohol for 32 h. The liver size was normalized to control group. *P < 0.05, **P < 0.01, n.s.: no significant difference, by one-way ANOVA
Effect of MgIG on alcohol-induced ER stress. a The relative atf6, perk, irelα, bip and chop mRNA expression was analyzed by qRT-PCR in the livers of larvae treated with 0% or 350 mM alcohol, 0.1 mg ml⁻¹ MgIG, 350 mM alcohol + 0.1 mg ml⁻¹ MgIG. *P < 0.05, **P < 0.01, n.s.: no significant difference, by one-way ANOVA. b The expression of bip was detected by whole-mount in situ hybridization. The typical pictures of each group were shown. c Quantification of bip expression is categorized “strong”, “medium”, or “weak”. Bar chart indicates the percentages of each category in each group, and the percentages of larvae in “weak” category is noted. *P < 0.05, **P < 0.01, ***P < 0.001, n.s.: no significant difference, by Chi-Square test. d and e Protein expression of bip and chop was examined by western blot in zebrafish larvae exposed to 0% or 350 mM alcohol, 0.1 mg ml⁻¹ MgIG, or 350 mM alcohol + 0.1 mg ml⁻¹ MgIG for 32 h, the degree of protein expression was normalized to β-actin. *P < 0.05, **P < 0.01, ***P < 0.001, by one-way ANOVA
Effect of MgIG on alcohol-induced lipid metabolism dysfunction. a The relative acc1, fasn, hmgcs1, hmgcra, ppar-α, cpt-1, mtp, cd36 mRNA expression was analyzed by qRT-PCR in the livers of larvae treated with 0% or 350 mM alcohol, 0.1 mg ml⁻¹ MgIG, or 350 mM alcohol + 0.1 mg ml⁻¹ MgIG. *P < 0.05, **P < 0.01, ***P < 0.001, n.s.: no significant difference, by one-way ANOVA. b The expression of hmgcs1 was detected by whole-mount in situ hybridization. The typical pictures of each group were shown. c Quantification of hmgcs1 expression is categorized “strong”, “medium”, or “weak”. Bar chart indicates the percentages of each category in each group, and the percentages of larvae in “weak” category is noted. *P < 0.05, **P < 0.01, ***P < 0.001, n.s.: no significant difference, by Chi-Square test. d and e Protein expression of hmgcs1 was examined by western blot in larvae exposed to 0% or 350 mM alcohol, 0.1 mg ml⁻¹ MgIG, or 350 mM alcohol + 0.1 mg ml⁻¹ MgIG for 32 h, the degree of protein expression was normalized to β-actin. *P < 0.05, **P < 0.01, ***P < 0.001, by one-way ANOVA
Background Alcoholism is a well-known risk factor for liver injury and is one of the major causes of hepatic steatosis worldwide. Although many drugs have been reported to have protective effects against acute alcohol-induced hepatotoxicity, there is limited available treatment for alcoholic liver disease (ALD), indicating an urgent need for effective therapeutic options. Herein, we first reported the protective effects of magnesium isoglycyrrhizinate (MgIG) on acute alcohol-induced hepatic steatosis and its related mechanisms in a zebrafish model. Methods Alcohol was administered directly to embryo medium at 5 days post-fertilization (dpf) for up to 32 h. MgIG was given to the larvae 2 h before the administration of alcohol and then cotreated with alcohol starting at 5 dpf. Oil red O staining was used to determine the incidence of steatosis, and pathological features of the liver were assessed by hematoxylin–eosin staining. Biological indexes, total cholesterol (TC) and triacylglycerol (TG) were detected in the livers of zebrafish larvae. Morphological changes in the livers of zebrafish larvae were observed using liver-specific EGFP transgenic zebrafish (Tg(lfabp10a:eGFP)). The expression levels of critical molecules related to endoplasmic reticulum (ER) stress and lipid metabolism were detected by qRT–PCR, whole-mount in situ hybridization and western blotting. Results Alcohol-treated larvae developed hepatomegaly and steatosis after 32 h of exposure. We found that MgIG improved hepatomegaly and reduced the incidence of steatosis in a dose-dependent manner by oil red O staining and diminished deposits of alcohol-induced fat droplets by histologic analysis. Moreover, MgIG significantly decreased the levels of TC and TG in the livers of zebrafish larvae. Furthermore, the expression levels of critical genes involved in ER stress (atf6, irela, bip, chop) and the key enzymes regulating lipid metabolism (acc1, fasn, hmgcs1 and hmgcra) were significantly higher in the alcohol-treated group than in the control group. However, in the MgIG plus alcohol-treated group, the expression of these genes was markedly decreased compared with that in the alcohol-treated group. Whole-mount in situ hybridization and western blotting also showed that MgIG had an effect on the expression levels of critical genes and proteins involved in lipid metabolism and ER stress. Our results revealed that MgIG could markedly regulate these genes and protect the liver from ER stress and lipid metabolism disorders. Conclusions Our study is the first to demonstrate that MgIG could protect the liver from acute alcohol stimulation by ameliorating the disorder of lipid metabolism and regulating ER stress in zebrafish larvae.
 
Flow chart of study population. (APEC, asymptomatic physical examination cohort; FBG, fasting blood-glucose. BP, blood pressure.)
Distribution of food-specific IgG in the APEC. (A The positive rate of 14 kinds of common food. +: mildly positive, ++: moderately positive, + ++: severely positive; B The positive status of food-specific IgG in different sex; C The Distribution of food-specific IgG positive rate in different age groups (seven foods with higher positive rate)
The distribution of TG, FBG and BMI in different groups. (Median and 95% CI. A The distribution of TG, FBG and BMI in different IgG titers. B The distribution of TG, FBG and BMI in different number of IgG positive foods. −: negative, +: mildly positive, ++: moderately positive, +++: severely positive. SIPO: single food specific IgG positive, MUPO: multiple foods specific IgG positive. BMI, body mass index; FBG, fasting blood-glucose; TG, triglycerides. * means P < 0.05 and ** means P < 0.001.)
Background Although the association of food-specific IgG with the development and progression of specific diseases was shown by many studies, it is also present in the population without clinical symptoms. However, the association between food-specific IgG and physical examination outcomes in healthy people has not been studied yet. Methods An asymptomatic physical examination cohort (APEC) was selected according to the inclusion and exclusion criteria, the physical examination data were compared between IgG positive and IgG negative groups, and their odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression. Results The data of 28,292 subjects were included in the analysis. The overall IgG positive rate was up to 52.30%, mostly with mild to moderate IgG positivity. The multivariable Logistic regression showed the prevalence of hypertriglyceridemia, abnormal fasting blood glucose and overweight was lower in the IgG (+) positive group (OR 0.87, 95% CI 0.83–0.92; OR 0.93, 95% CI 0.87–0.99; OR 0.92, 95% CI 0.87–0.96) but there was a higher prevalence of thyroid disease (OR 1.09, 95% CI 1.04–1.15). Conclusion Food-specific IgG positivity was widespread in the APEC and was associated with lower prevalence of hypertriglyceridemia, abnormal fasting blood glucose and overweight. The underlying physiological mechanism merits further study.
 
Overview of the study population. NAFLD non-alcoholic fatty liver disease, SAM S-adenosylmethionine, SAH S-adenosylhomocysteine, Hcy homocysteine
Subgroup analysis for by gender, age, BMI, HOMA-IR and TG using multivariable logistic regression. The data are shown as the ORs (95% CI) in each quartile of serum A Hcy, B SAH, C SAM, D SAM/SAH levels for NAFLD
Correlation of methionine metabolites and degree of hepatic steatosis. A Univariate and B multivariate. A Univariate P values are calculated by were analyzed by Kruskal–Wallis one-way ANOVA for k samples. B serum (a) SAM, (b) SAH, (c) Hcy, (d) SAH/SAM ratio (log-transformed) were adjusted for age, gender, BMI, WHR, trunk fat ratio, physical activity, current smoking, current drinking, history of hypertension, diabetes, dyslipidemia and heart disease, HOMA-IR, AST/ALT ratio, TC, TG, HDL, LDL, UA, ALP and hsCRP. Multivariate P values are analyzed by ANCOVA
Background and project Non-alcoholic fatty liver disease (NAFLD) is viewed as the hepatic manifestation of metabolic syndrome. Methionine metabolites have been linked to metabolic syndrome and its related diseases. Whether serum methionine metabolites levels are associated with NAFLD remains unclear. The study aimed to assess the association between methionine metabolites and NAFLD. Methods This cross-sectional study included a total of 2814 individuals aged 40–75 years old. All participants underwent anthropometric measurements, laboratory tests, dietary assessment and abdominal ultrasonography. Multivariable logistic regression analysis was performed to estimate the association of methionine metabolites with NAFLD. Results Overall, 1446 with and 1368 without NAFLD were enrolled in this study. Participants with NAFLD had significantly higher serum S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and homocysteine (Hcy) levels, and a lower S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio than those without NAFLD (all P < 0.001). After adjusting multiple confounders, odds ratios (95% confidence interval) for quartile 4 versus quartile 1 of SAH, Hcy and SAM/SAH ratio were 1.65 (1.27–2.14), 1.63 (1.26–2.12) and 0.63 (0.49–0.83), respectively (all P for trend < 0.01). In addition, serum SAH, Hcy levels and SAM/SAH ratio were significantly correlated with the degree of hepatic steatosis (all P for trend < 0.001). Conclusion Elevated serum SAH, Hcy levels and lower SAM/SAH ratio may be independently associated with the presence of NAFLD in middle-aged and elder Chinese.
 
Background: This meta-analysis was performed to investigate the effects of nicotinamide adenine dinucleotide (NAD+) precursor supplementation on glucose and lipid metabolism in human body. Methods: PubMed, Embase, CENTRAL, Web of Science, Scopus databases were searched to collect clinical studies related to the supplement of NAD+ precursor from inception to February 2021. Then the retrieved documents were screened, the content of the documents that met the requirements was extracted. Meta-analysis and quality evaluation was performed detection were performed using RevMan5.4 software. Stata16 software was used to detect publication bias, Egger and Begg methods were mainly used. The main research terms of NAD+ precursors were Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN), Nicotinic Acid (NA), Nicotinamide (NAM). The changes in the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and fasting blood glucose were mainly concerned. Results: A total of 40 articles were included in the meta-analysis, with a sample of 14,750 cases, including 7406 cases in the drug group and 7344 cases in the control group. The results of meta-analysis showed that: NAD+ precursor can significantly reduce TG level (SMD = - 0.35, 95% CI (- 0.52, - 0.18), P < 0.0001), and TC (SMD = - 0.33, 95% CI (- 0.51, - 0.14), P = 0.0005), and LDL (SMD = - 0.38, 95% CI (- 0.50, - 0.27), P < 0.00001), increase HDL level (SMD = 0.66, 95% CI (0.56, 0.76), P < 0.00001), and plasma glucose level in the patients (SMD = 0.27, 95% CI (0.12, 0.42), P = 0.0004). Subgroup analysis showed that supplementation of NA had the most significant effect on the levels of TG, TC, LDL, HDL and plasma glucose. Conclusions: In this study, a meta-analysis based on currently published clinical trials with NAD+ precursors showed that supplementation with NAD+ precursors improved TG, TC, LDL, and HDL levels in humans, but resulted in hyperglycemia, compared with placebo or no treatment. Among them, NA has the most significant effect on improving lipid metabolism. In addition, although NR and NAM supplementation had no significant effect on improving human lipid metabolism, the role of NR and NAM could not be directly denied due to the few relevant studies at present. Based on subgroup analysis, we found that the supplement of NAD+ precursors seems to have little effect on healthy people, but it has a significant beneficial effect on patients with cardiovascular disease and dyslipidemia. Due to the limitation of the number and quality of included studies, the above conclusions need to be verified by more high-quality studies.
 
Mean bias, SD and 95% CI of each method compared to the gold-estimated salt intake (derived from the average of all methods), along with the slope and intercept for bias of each estimation vs. overall mean of 6 estimations
Background We aimed to estimate salt intake among an Iranian population using spot urine-based equations and a dietary-based method. Methods Adult men and women (n = 2069) were recruited from the Tehran Lipid and Glucose Study (2014–2017). Urinary sodium (Na), potassium (K), and creatinine (Cr) concentrations were measured in the morning spot urine samples. The 24-h urinary Na excretion and predicted salt intake was estimated using five equations, i.e., Kawasaki, Tanaka, Intersalt, Toft, and Whitton. A validated food frequency questionnaire (FFQ) was used to obtain dietary intake of salt. The agreement of each urinary- and FFQ-based salt estimation with the overall mean of the methods, considered as the gold standard, was assessed using the Bland–Altman method. Results Mean age of the participants was 45.6 ± 14.8 y, and 45.4% were men. Mean (SD) estimated salt intake, derived from the overall mean of the methods, was 9.0 ± 2.2 g/d (10.2 ± 2.1 and 7.9 ± 1.7 g/d in men and women, respectively). Mean bias of the estimations from the overall mean ranged from − 0.2.42 to 2.75 g/d, with the Tanaka equation having the least bias (mean bias = 0.13 ± 1.10, 95% CI − 2.37, 2.30 g/d). Tanaka estimated a mean salt intake of 8.9 g/d (range 2.1 to 18.7 g/d); accordingly, only 5.1% of participants adhered to the recommendation (< 5 g/d salt intake), whereas 26.8% and 2.4% exceeded the recommendation by 2- and threefold. Conclusion The Tanaka equation could provide a more accurate mean-population estimated salt intake from casual urinary Na concentration in our population. About 95% of the Iranian population exceeded the current recommendations of salt intake.
 
Background Parenteral nutrition (PN) may serve as a nutritional supportive therapy accompanied by oral medication, but the effect of PN on intestinal expression of drug metabolism-related genes remains unknown. Methods Twelve Bama piglets receiving PN for 14 days were used as in vivo model. Changes in intestinal drug metabolism-related genes were examined by proteomic analysis. Serum levels of fibroblast growth factor 19 (FGF19) were determined by ELISA, and the effect of FGF19 on the expression of drug metabolism-related genes was examined using murine ileum organoids. Results A total of 1063 differentially expressed proteins were identified in PN group. Of note, two drug transporters (Abcb1 and Abcc2) were significantly decreased in PN group, along with two glutathione-related drug-metabolizing enzymes, glutathione peroxidase (Gpx2) and glutathione S-transferase (Gsta1). Serum FGF19 levels were dramatically reduced in PN group. Treatment with recombinant FGF19 in vitro dose-dependently up-regulated the expression of Abcb1, Abcc2, Gpx2 and Gsta1 in organoids. Conclusion Our data indicated that intestinal drug metabolism-related genes were significantly dysregulated under PN, and some of the changed genes were attributed to gut-derived FGF19.
 
Top-cited authors
Jeff S Volek
  • The Ohio State University
Eric C Westman
  • Duke University
Stuart M Phillips
  • McMaster University
Anssi Manninen
  • Dominus Nutrition Oy
Khosrow Adeli
  • University of Toronto