Browsing by Author "Zhang, Xi"
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Item Associations between Benign Cutaneous Nevi and Risk of Type 2 Diabetes Mellitus in Men and Women: Results from Two Prospective Cohort Studies(Office of the Vice Chancellor for Research, 2015-04-17) Dai, Hongji; Sun, Qi; Zhang, Xi; Manson, JoAnn E.; Hu, Frank B.; Song, YiqingABSTRACT Objective: Previous studies suggest that the number of cutaneous nevi and type 2 diabetes mellitus (T2DM) are both associated with endogenous sex hormone levels. However, no prospective studies have specifically examined the relationship between the number of benign cutaneous nevi and T2DM. Research Design and Methods: We prospectively examined the associations between the number of nevi and risk of T2DM among 23,748 men (1986-2010) from the Health Professionals Follow-up Study (HPFS) and 67,050 women (1989-2010) from the Nurses' Health Study (NHS). Information on the numbers of melanocytic nevi on arms and the incidence of T2DM was collected by validated questionnaires. Results: During 1,831,118 person-years of follow-up, we documented 8748 incident cases of T2DM. After adjustment for age, BMI, and other diabetes risk factors, the number of nevi was significantly associated with increased risk of T2DM. Multivariable-adjusted HRs (95% CIs) for <1, 1-5, 6-14, and ≥15 nevi were 1.00 (reference), 1.02 (0.92, 1.14), 1.10 (0.87, 1.38), and 1.70 (1.22, 2.36), respectively, for men (P trend = 0.03) and 1.00 (reference), 1.15 (1.09, 1.21), 1.25 (1.11, 1.40), and 1.70 (1.38, 2.09), respectively, for women (P trend = 0.019). This positive association remained consistent across subgroups of participants. Conclusions: Mole count may represent a novel marker for development of T2DM in men and women, indicating a unique nevus development-related mechanism, possibly due to altered levels or functions of endogenous steroid sex hormones, in the pathogenesis of T2DM. Further studies are warranted to clarify the relationship of nevogenesis and T2DM and underlying mechanisms.Item Associations of Muscle Mass and Strength with All-Cause Mortality among US Older Adults(Lippincott, Williams & Wilkins, 2018-03) Li, Ran; Xia, Jin; Zhang, Xi; Gathirua-Mwangi, Wambui Grace; Guo, Jianjun; Li, Yufeng; McKenzie, Steve; Song, Yiqing; Epidemiology, School of Public HealthINTRODUCTION: Recent studies suggested that muscle mass and muscle strength may independently or synergistically affect aging-related health outcomes in older adults; however, prospective data on mortality in the general population are sparse. METHODS: We aimed to prospectively examine individual and joint associations of low muscle mass and low muscle strength with all-cause mortality in a nationally representative sample. This study included 4449 participants age 50 yr and older from the National Health and Nutrition Examination Survey 1999 to 2002 with public use 2011 linked mortality files. Weighted multivariable logistic regression models were adjusted for age, sex, race, body mass index (BMI), smoking, alcohol use, education, leisure time physical activity, sedentary time, and comorbid diseases. RESULTS: Overall, the prevalence of low muscle mass was 23.1% defined by appendicular lean mass (ALM) and 17.0% defined by ALM/BMI, and the prevalence of low muscle strength was 19.4%. In the joint analyses, all-cause mortality was significantly higher among individuals with low muscle strength, whether they had low muscle mass (odds ratio [OR], 2.03; 95% confidence interval [CI], 1.27-3.24 for ALM; OR, 2.53; 95% CI, 1.64-3.88 for ALM/BMI) or not (OR, 2.66; 95% CI, 1.53-4.62 for ALM; OR, 2.17; 95% CI, 1.29-3.64 for ALM/BMI). In addition, the significant associations between low muscle strength and all-cause mortality persisted across different levels of metabolic syndrome, sedentary time, and LTPA. CONCLUSIONS: Low muscle strength was independently associated with elevated risk of all-cause mortality, regardless of muscle mass, metabolic syndrome, sedentary time, or LTPA among US older adults, indicating the importance of muscle strength in predicting aging-related health outcomes in older adults.Item Associations of Nutritional, Environmental, and Metabolic Biomarkers with Diabetes-Related Mortality in U.S. Adults: The Third National Health and Nutrition Examination Surveys between 1988–1994 and 2016(MDPI, 2022-06-24) Zhang, Xi; Ardeshirrouhanifard, Shirin; Li, Jing; Li, Mingyue; Dai, Hongji; Song, Yiqing; Epidemiology, School of Public HealthBackground: Nutritional, environmental, and metabolic status may play a role in affecting the progression and prognosis of type 2 diabetes. However, results in identifying prognostic biomarkers among diabetic patients have been inconsistent and inconclusive. We aimed to evaluate the associations of nutritional, environmental, and metabolic status with disease progression and prognosis among diabetic patients. Methods: In a nationally representative sample in the NHANES III (The Third National Health and Nutrition Examination Survey, 1988−1994), we analyzed available data on 44 biomarkers among 2113 diabetic patients aged 20 to 90 years (mean age: 58.2 years) with mortality data followed up through 2016. A panel of 44 biomarkers from blood and urine specimens available from NHANES III were included in this study and the main outcomes as well as the measures are mortalities from all-causes. We performed weighted logistic regression analyses after controlling potential confounders. To assess incremental prognostic values of promising biomarkers beyond traditional risk factors, we compared c-statistics of the adjusted models with and without biomarkers, separately. Results: In total, 1387 (65.2%) deaths were documented between 1988 and 2016. We observed an increased risk of all-cause mortality associated with higher levels of serum C-reactive protein (p for trend = 0.0004), thyroid stimulating hormone (p for trend = 0.04), lactate dehydrogenase (p for trend = 0.02), gamma glutamyl transferase (p for trend = 0.02), and plasma fibrinogen (p for trend = 0.03), and urine albumin (p for trend < 0.0001). In contrast, higher levels of serum sodium (p for trend = 0.005), alpha carotene (p for trend = 0.006), and albumin (p for trend = 0.005) were associated with a decreased risk of all-cause mortality. In addition, these significant associations were not modified by age, sex, or race. Inclusion of thyroid stimulating hormone (p = 0.03), fibrinogen (p = 0.01), and urine albumin (p < 0.0001), separately, modestly improved the discriminatory ability for predicting all-cause mortality among diabetic patients. Conclusions: Our nationwide study findings provide strong evidence that some nutritional, environmental, and metabolic biomarkers were significant predictors of all-cause mortality among diabetic patients and may have potential clinical value for improving stratification of mortality risk.Item Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration(Wiley, 2020-08-04) Sun, Ling; Zhang, Jie; Chen, Wenfeng; Chen, Yun; Zhang, Xiaohui; Yang, Mingjuan; Xiao, Min; Ma, Fujun; Yao, Yizhou; Ye, Meina; Zhang, Zhenkun; Chen, Kai; Chen, Fei; Ren, Yujun; Ni, Shiwei; Zhang, Xi; Yan, Zhangming; Sun, Zhi-Rong; Zhou, Hai-Meng; Yang, Hongqin; Xie, Shusen; Haque, M. Emdadul; Huang, Kun; Yang, Yufeng; Medical and Molecular Genetics, School of MedicineHow complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in Parkinson's disease (PD) is largely unclear. Here, we applied frequent gene co‐expression analysis on human patient substantia nigra‐specific microarray datasets to identify potential novel disease‐related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin‐remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent aging‐dependent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Furthermore, down‐regulation of SMARCA4 specifically in the dopaminergic neurons prevented shortening of life span caused by α‐synuclein and LRRK2. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK‐ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in Drosophila in vivo. Down‐regulation of SMARCA4 or drug inhibition of MEK/ERK also mitigated mitochondrial defects in PINK1 (a PD‐associated gene)‐deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in normal aging and a broad range of age‐related disorders including PD.Item Biomarker of Magnesium Status in Response to Mg Supplementation: A Dose- and Time-Response Meta-analysis of Randomized Controlled Trials(Office of the Vice Chancellor for Research, 2015-04-17) Zhang, Xi; Song, YiqingABSTRACT Background: Magnesium is a cofactor for hundreds of human enzymes and magnesium deficiency has been associated with cardiometabolic disorders. Although a panel of magnesium biomarkers are used to assess magnesium status, their relative predictive values or clinical usefulness in response to magnesium supplementation remain unclear. Objective: We quantitatively evaluated time- and dose-response relation of magnesium biomarkers from available randomized controlled trials (RCTs) of magnesium supplementation. Methods: We systematically identified RCTs assessing magnesium biomarkers’ responses after oral magnesium supplementation through search on MEDLINE and Cochrane Library up to November 2014. We calculated the pooled weight mean differences (WMDs) of biomarkers levels between treatment and placebo group after supplementation. A dose- and time-response meta-analysis was conducted to quantitatively compare the usefulness of biomarkers in assessing magnesium status. Results: This meta-analysis included 44 RCTs of magnesium supplementation that examined a total of 38 biomarkers of magnesium status. Total magnesium concentrations in blood (serum or plasma), RBC, and urine were significantly raised after magnesium supplementation by 0.05 mmol/l, 0.12 mmol/l, and 1.52 mmol/24h corresponding to 5.81%, 5.30%, and 28.3% increases relative to baseline magnesium levels, respectively. Our dose- and time-response meta-analyses showed that blood and urinary magnesium levels abruptly increased at the first 20-week supplementation and afterwards reached a plateau. Evidence was insufficient due to limited numbers of studies testing other potential biomarkers, including ionized Mg, muscle Mg, mononuclear Mg, intracellular Mg, IV Mg load, ultrafiltrable Mg, and fecal Mg.Item The Circulating Concentration and 24-h Urine Excretion of Magnesium Dose- and Time-Dependently Respond to Oral Magnesium Supplementation in a Meta-Analysis of Randomized Controlled Trials(Oxford, 2016-03) Zhang, Xi; Del Gobbo, Liana C.; Hruby, Adela; Rosanoff, Andrea; He, Ka; Dai, Qi; Costello, Rebecca B.; Zhang, Wen; Song, Yiqing; Epidemiology, School of Public HealthBackground: Accurate determination of Mg status is important for improving nutritional assessment and clinical risk stratification. Objective: We aimed to quantify the overall responsiveness of Mg biomarkers to oral Mg supplementation among adults without severe diseases and their dose- and time responses using available data from randomized controlled trials (RCTs). Methods: We identified 48 Mg supplementation trials (n = 2131) through searches of MEDLINE and the Cochrane Library up to November 2014. Random-effects meta-analysis was used to estimate weighted mean differences of biomarker concentrations between intervention and placebo groups. Restricted cubic splines were used to determine the dose- and time responses of Mg biomarkers to supplementation. Results: Among the 35 biomarkers assessed, serum, plasma, and urine Mg were most commonly measured. Elemental Mg supplementation doses ranged from 197 to 994 mg/d. Trials ranged from 3 wk to 5 y (median: 12 wk). Mg supplementation significantly elevated circulating Mg by 0.04 mmol/L (95% CI: 0.02, 0.06) and 24-h urine Mg excretion by 1.52 mmol/24 h (95% CI: 1.20, 1.83) as compared to placebo. Circulating Mg concentrations and 24-h urine Mg excretion responded to Mg supplementation in a dose- and time-dependent manner, gradually reaching a steady state at doses of 300 mg/d and 400 mg/d, or after ~20 wk and 40 wk, respectively (all P-nonlinearity ≤ 0.001). The higher the circulating Mg concentration at baseline, the lower the responsiveness of circulating Mg to supplementation, and the higher the urinary excretion (all P-linearity < 0.05). In addition, RBC Mg, fecal Mg, and urine calcium were significantly more elevated by Mg supplementation than by placebo (all P-values < 0.05), but there is insufficient evidence to determine their responses to increasing Mg doses. Conclusions: This meta-analysis of RCTs demonstrated significant dose- and time responses of circulating Mg concentration and 24-h urine Mg excretion to oral Mg supplementation.Item Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway(Springer Nature, 2021-07-15) Xu, Lin; Zhang, Xinge; Xin, Yue; Ma, Jie; Yang, Chenyan; Zhang, Xi; Hou, Guoqing; Dong, Xiaocheng Charlie; Sun, Zhaoli; Xiong, Xiwen; Cao, Xuan; Biochemistry and Molecular Biology, School of MedicineAlcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.Item Effects of Exercise Training on Cardiorespiratory Fitness and Biomarkers of Cardiometabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials(AMA, 2015-06-26) Lin, Xiaochen; Zhang, Xi; Guo, Jianjun; Roberts, Christian K.; McKenzie, Steve; Wu, Wen-Chih; Liu, Simin; Song, Yiqing; Department of Epidemiology, Richard M. Fairbanks School of Public HealthBACKGROUND: Guidelines recommend exercise for cardiovascular health, although evidence from trials linking exercise to cardiovascular health through intermediate biomarkers remains inconsistent. We performed a meta-analysis of randomized controlled trials to quantify the impact of exercise on cardiorespiratory fitness and a variety of conventional and novel cardiometabolic biomarkers in adults without cardiovascular disease. METHODS AND RESULTS: Two researchers selected 160 randomized controlled trials (7487 participants) based on literature searches of Medline, Embase, and Cochrane Central (January 1965 to March 2014). Data were extracted using a standardized protocol. A random-effects meta-analysis and systematic review was conducted to evaluate the effects of exercise interventions on cardiorespiratory fitness and circulating biomarkers. Exercise significantly raised absolute and relative cardiorespiratory fitness. Lipid profiles were improved in exercise groups, with lower levels of triglycerides and higher levels of high-density lipoprotein cholesterol and apolipoprotein A1. Lower levels of fasting insulin, homeostatic model assessment-insulin resistance, and glycosylated hemoglobin A1c were found in exercise groups. Compared with controls, exercise groups had higher levels of interleukin-18 and lower levels of leptin, fibrinogen, and angiotensin II. In addition, we found that the exercise effects were modified by age, sex, and health status such that people aged <50 years, men, and people with type 2 diabetes, hypertension, dyslipidemia, or metabolic syndrome appeared to benefit more. CONCLUSIONS: This meta-analysis showed that exercise significantly improved cardiorespiratory fitness and some cardiometabolic biomarkers. The effects of exercise were modified by age, sex, and health status. Findings from this study have significant implications for future design of targeted lifestyle interventions.Item Effects of Magnesium Supplementation on Blood Pressure: A Meta-Analysis of Randomized Double-Blind Placebo-Controlled Trials(Elsevier, 2016-08) Zhang, Xi; Li, Yufeng; Del Gobbo, Liana C.; Rosanoff, Andrea; Wang, Jiawei; Zhang, Wen; Song, Yiqing; Department of Epidemiology, Richard M. Fairbanks School of Public HealthThe antihypertensive effect of magnesium (Mg) supplementation remains controversial. We aimed to quantify the effect of oral Mg supplementation on blood pressure (BP) by synthesizing available evidence from randomized, double-blind, placebo-controlled trials. We searched trials of Mg supplementation on normotensive and hypertensive adults published up to February 1, 2016 from MEDLINE and EMBASE databases; 34 trials involving 2028 participants were eligible for this meta-analysis. Weighted mean differences of changes in BP and serum Mg were calculated by random-effects meta-analysis. Mg supplementation at a median dose of 368 mg/d for a median duration of 3 months significantly reduced systolic BP by 2.00 mm Hg (95% confidence interval, 0.43–3.58) and diastolic BP by 1.78 mm Hg (95% confidence interval, 0.73–2.82); these reductions were accompanied by 0.05 mmol/L (95% confidence interval, 0.03, 0.07) elevation of serum Mg compared with placebo. Using a restricted cubic spline curve, we found that Mg supplementation with a dose of 300 mg/d or duration of 1 month is sufficient to elevate serum Mg and reduce BP; and serum Mg was negatively associated with diastolic BP but not systolic BP (all P<0.05). In the stratified analyses, a greater reduction in BP tended to be found in trials with high quality or low dropout rate (all P values for interaction <0.05). However, residual heterogeneity may still exist after considering these possible factors. Our findings indicate a causal effect of Mg supplementation on lowering BPs in adults. Further well-designed trials are warranted to validate the BP-lowering efficacy of optimal Mg treatment.Item Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials(Springer, 2016-12) Tang, Huilin; Zhang, Xi; Zhang, Jingjing; Li, Yufeng; Del Gobbo, Liana Christine; Zhai, Suodi; Song, Yiqing; Department of Epidemiology, Richard M. Fairbanks School of Public HealthAims/hypothesis By analysing available evidence from randomised controlled trials (RCTs), we aimed to examine whether and to what extent sodium–glucose cotransporter 2 (SGLT2) inhibitors affect serum electrolyte levels in type 2 diabetes patients. Methods We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov up to 24 May 2016 for published RCTs of SGLT2 inhibitors that reported changes in serum electrolyte levels. Weighted mean differences (WMD) between each SGLT2 inhibitor and placebo were calculated using a random-effects model. Dose-dependent relationships for each SGLT2 inhibitor were evaluated using meta-regression analysis. Results Eighteen eligible RCTs, including 15,309 patients and four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin and ipragliflozin) were evaluated. In patients without chronic kidney disease, each SGLT2 inhibitor significantly increased serum magnesium levels compared with placebo (canagliflozin: WMD 0.06 mmol/l for 100 mg and 0.09 mmol/l for 300 mg; dapagliflozin: WMD 0.1 mmol/l for 10 mg; empagliflozin: WMD 0.04 mmol/l for 10 mg and 0.07 mmol/l for 25 mg; and ipragliflozin: WMD 0.05 mmol/l for 50 mg). Canagliflozin increased serum magnesium in a linear dose-dependent manner (p = 0.10). Serum phosphate was significantly increased by dapagliflozin. Serum sodium appeared to significantly differ by SGLT2 inhibitor type. No significant changes in serum calcium and potassium were observed. Findings were robust after including trials involving patients with chronic kidney disease. Conclusions/interpretation SGLT2 inhibitors marginally increased serum magnesium levels in type 2 diabetes patients indicating a drug class effect. Further investigations are required to examine the clinical significance of elevated magnesium levels in individuals with type 2 diabetes.