Relationship of microvascular complications and healthy lifestyle with all-cause and cardiovascular mortality in women compared with men with type 2 diabetes.

BACKGROUND: Sex differences exist in the prevalence of microvascular disease (MVD) and healthy-lifestyle adherence. Whether MVD and healthy lifestyles are associated with mortality risk similarly for women and men who have type 2 diabetes mellitus (T2DM) remains unknown. METHODS: The present study included 9992 women and 15,860 men with T2DM from the UK Biobank. MVDs included retinopathy, peripheral neuropathy, and chronic kidney disease. Healthy lifestyle factors consisted of ideal BMI, nonsmoking, healthy diet, regular exercise, and appropriate sleep duration. Sex-specific hazard ratios (HRs) of mortality associated with the MVDs or healthy lifestyles were calculated and women-to-men ratio of HRs (RHR) were further estimated, after multivariable adjustment for potential confounders. RESULTS: During a median of 12.7 years of follow-up, 4346 (1202 in women) all-cause and 1207 (254 in women) CVD deaths were recorded. The adjusted HRs (95% CI) of all-cause mortality for 1 additional increment of the MVDs were 1.71 (1.55, 1.88) for women and 1.48 (1.39, 1.57) for men, with an RHR of 1.16 (1.03, 1.30). The corresponding RHR was 1.36 (1.09, 1.69) for cardiovascular mortality. Adhering to a healthy lifestyle (≥4 vs. ≤1 lifestyle factor) was associated with an approximately 60%-70% lower risk of all-cause and cardiovascular mortality without sex differences (P-interaction >0.70). Furthermore, as compared with having no MVD and an unfavorable lifestyle, having ≥2 MVDs but a favorable lifestyle was not associated with a higher risk of all-cause mortality either in women (HR = 0.88; 95% CI: 0.49, 1.60) or in men (HR = 0.95; 95% CI: 0.64, 1.40), similarly when considering cardiovascular mortality. CONCLUSIONS: In T2DM, while MVDs are more strongly associated with mortality risk in women than in men, adhering to a favorable lifestyle is associated with a substantially lower risk of mortality and may eliminate the detrimental impact of MVDs in both sexes.

Microvascular burden and long-term risk of stroke and dementia in type 2 diabetes mellitus.

OBJECTIVE: To examine the associations between microvascular disease (MVD) and risk of stroke, dementia, and their major subtypes among individuals with type 2 diabetes mellitus (T2DM). METHODS: We included 26,173 participants with T2DM from the UK Biobank who had no known stroke or dementia at baseline. MVD burden was reflected by the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidential intervals (CIs) of stroke and dementia associated with overall MVD burden and individual MVD. RESULTS: During a median follow-up of 11.5 years, 1103 incident stroke (964 ischemic and 269 hemorrhagic stroke) and 813 incident dementia (312 Alzheimer's disease and 304 vascular dementia) cases were identified. The risk of stroke, dementia, and their major subtypes all increased with an increasing number of MVD (all P-trend <0.001). The adjusted HRs (95 % CIs) comparing three with no MVD were 5.03 (3.16, 8.02) for all stroke, 4.57 (2.75, 7.59) for ischemic stroke, and 6.60 (2.65, 16.43) for hemorrhagic stroke. The corresponding estimates were 4.28 (2.33, 7.86) for all-cause dementia, 6.96 (3.02, 16.01) for Alzheimer's disease, and 3.81 (1.40, 10.42) for vascular dementia. Among the three MVD, chronic kidney disease showed the strongest associations with both stroke subtypes, while peripheral neuropathy was most strongly associated with both dementia subtypes. CONCLUSIONS: Risk of stroke, dementia, and their major subtypes increased with an increasing number of MVD. The associations of individual MVD with stroke and dementia varied substantially by types of MVD.

Quercetin improved hepatic circadian rhythm dysfunction in middle-aged mice fed with vitamin D-deficient diet

We aimed to determine whether quercetin is capable of improving circadian rhythm and metabolism disorder under vitamin D-deficient condition. Middle-aged mice were randomly divided into four groups, namely, control (CON), vitamin D-deficient diet (VDD), quercetin (Q), and quercetin intervention in vitamin D-deficient diet (VDQ), with a total of 12 weeks’ intervention. Mice were sacrificed at zeitgeber time1 (ZT1) and ZT13 time points. At ZT1, circadian locomotor output cycle kaput (CLOCK) protein expression from VDD, Q, and VDQ groups; CRY1 from Q group; and CRY2 from VDD group were significantly lower compared to CON group. The mRNA expression of Sirt1, Bmal1, Clock, Cry1, and Cry2 in VDQ groups, also Bmal1, Clock, and Cry1 from Q group, were significantly decreased compared to CON group. At ZT13, compared to CON group, fasting insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were higher in VDD group; BMAL1 was significantly increased, while CLOCK and CRY1 protein were significantly decreased from VDD group; CLOCK protein from VDQ group was significantly higher compared to CON, VDD, and Q groups, and also, BMAL1 protein expression from VDQ group was elevated compared to CON group. The mRNA expression of Bmal1, Clock, Per2, Cry1, and Cry2 in VDQ groups were significantly increased compared to CON groups. The mRNA expression of Bmal1 from VDQ group was decreased compared to both VDD and Q group. In conclusion, vitamin D-deficient diet resulted in a disordered liver circadian rhythm, and quercetin improved the hepatic circadian desynchronization. Quercetin supplementation might be effective for balancing circadian rhythm under vitamin D-deficient condition. (AU)

Quercetin improved hepatic circadian rhythm dysfunction in middle-aged mice fed with vitamin D-deficient diet

We aimed to determine whether quercetin is capable of improving circadian rhythm and metabolism disorder under vitamin D-deficient condition. Middle-aged mice were randomly divided into four groups, namely, control (CON), vitamin D-deficient diet (VDD), quercetin (Q), and quercetin intervention in vitamin D-deficient diet (VDQ), with a total of 12 weeks’ intervention. Mice were sacrificed at zeitgeber time1 (ZT1) and ZT13 time points. At ZT1, circadian locomotor output cycle kaput (CLOCK) protein expression from VDD, Q, and VDQ groups; CRY1 from Q group; and CRY2 from VDD group were significantly lower compared to CON group. The mRNA expression of Sirt1, Bmal1, Clock, Cry1, and Cry2 in VDQ groups, also Bmal1, Clock, and Cry1 from Q group, were significantly decreased compared to CON group. At ZT13, compared to CON group, fasting insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were higher in VDD group; BMAL1 was significantly increased, while CLOCK and CRY1 protein were significantly decreased from VDD group; CLOCK protein from VDQ group was significantly higher compared to CON, VDD, and Q groups, and also, BMAL1 protein expression from VDQ group was elevated compared to CON group. The mRNA expression of Bmal1, Clock, Per2, Cry1, and Cry2 in VDQ groups were significantly increased compared to CON groups. The mRNA expression of Bmal1 from VDQ group was decreased compared to both VDD and Q group. In conclusion, vitamin D-deficient diet resulted in a disordered liver circadian rhythm, and quercetin improved the hepatic circadian desynchronization. Quercetin supplementation might be effective for balancing circadian rhythm under vitamin D-deficient condition. (AU)

Silver nanoparticles induce iron accumulation-associated cognitive impairment via modulating neuronal ferroptosis.

Silver nanoparticles (AgNPs) are widely used in daily life and medical fields owing to their unique physicochemical properties. Daily exposure to AgNPs has become a great concern regarding their potential toxicity to human beings, especially to the central nervous system. Ferroptosis, a newly recognized programmed cell death, was recently reported to be associated with the neurodegenerative process. However, whether and how ferroptosis contributes to AgNPs-induced neurotoxicity remain unclear. In this study, we investigated the role of ferroptosis in neurotoxic effects induced by AgNPs using in vitro and in vivo models. Our results showed that AgNPs induced a notable dose-dependent cytotoxic effect on HT-22 cells and cognitive impairment in mice as indicated by a decline in learning and memory and brain tissue injuries. These findings were accompanied by iron overload caused by the disruption of the iron transport system and activation of NCOA4-mediated autophagic degradation of ferritin. The excessive free iron subsequently induced GSH depletion, loss of GPX and SOD activities, differential expression of Nrf2 signaling pathway elements, down-regulation of GPX4 protein and production of lipid peroxides, initiating ferroptosis cascades. The mitigating effects of ferrostatin-1 and deferoxamine on iron overload, redox imbalance, neuronal cell death, impairment of mice learning and memory, Aß deposition and synaptic plasticity reduction suggested ferroptosis as a potential molecular mechanism in AgNPs-induced neurotoxicity. Taken together, these results demonstrated that AgNPs induced neuronal cell death and cognitive impairment with Aß deposition and reduction of synaptic plasticity, which were mediated by ferroptosis caused by iron-mediated lipid peroxidation. Our study provides new insights into the underlying mechanisms of AgNPs-induced neurotoxicity and predicts potential preventive strategies.

Secondhand smoke exposure and risk of dementia in non-smokers: A population-based cohort study.

Background Large population-based prospective studies are necessary to provide clarification on the associations of panoramic secondhand smoking burden, including prenatal and postnatal secondhand smoke (SHS) exposure, with the risk of developing dementia. Methods Our study comprised a sample of 353,756 dementia-free individuals from the UK Biobank who were non-smokers, had data on the exposure of maternal smoking as well as SHS exposure in daily life, which was quantified in terms of hours per week (h/wk), and whether they lived with household smokers. Multivariable Cox regression models were utilized to analyze the independent and joint associations of maternal smoking and daily life SHS exposure with dementia risk. Results During a median follow-up of 11.8 years, 4,113 participants developed dementia. Compared with those who lived in the environment without smokers, multivariable-adjusted HRs (95% CIs) were 1.11 (1.02, 1.20) and 1.31 (1.13, 1.52) for those who exposed to SHS for >0 but ≤4 h/wk and >4 h/wk, respectively, and was 1.25 (1.13, 1.39) for those who lived with smokers in the household. A positive history of maternal smoking was associated with a modestly higher risk of dementia (HR=1.07; 95% CI: 1.01, 1.15). Furthermore, compared with participants with neither history of maternal smoking nor exposure to SHS, a particularly higher risk of dementia was observed among those with both exposures (HR = 1.48; 95% CI: 1.18, 1.86). Additionally, the HR (95% CI) was 1.32 (1.10, 1.59) when comparing participants with a history of maternal smoking who lived with smokers in their households with those who had neither exposures. Conclusions Having a history of maternal smoking, longer exposure to SHS, and living with smokers in the household were each associated with an increased risk of developing dementia. Individuals who were simultaneously exposed to maternal smoking and SHS or lived with household smokers had a particularly higher dementia risk.

Effects of intensive glycemic control on microvascular outcomes in type 2 diabetes mellitus are modified by long-term HbA1c variability: A post hoc analysis of the ACCORD trial.

AIMS: To assess the impact of long-term visit-to-visit variability in HbA1c on microvascular outcomes in type 2 diabetes mellitus (T2DM), and its influence on the effects of intensive glycemic control. METHODS: Included were participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) who had at least three measurements of HbA1c prior to new-onset microvascular outcomes, namely nephropathy, retinopathy and neuropathy. Variability in HbA1c was defined as the coefficient of variation (CV) across HbA1c measurements obtained from enrollment to the transition from intensive to standard glycemic therapy. RESULTS: During a median of 22,005, 23,121, and 13,080 person-years of follow-up, 2,905 nephropathy, 2,655 retinopathy, and 1,974 neuropathy cases were recorded, respectively. Median CV (IQR) was 7.91 % (5.66 %-10.76 %) in the standard treatment group and 9.79 % (7.32 %-13.35 %) in the intensive treatment group. In the standard treatment group, lower HbA1c-CV (the first versus the second quartile) was associated with a higher risk of all microvascular outcomes, while higher HbA1c-CV (the fourth quartile) was associated with a higher risk of nephropathy only. In the intensive treatment group, only higher HbA1c-CV was associated with a higher risk of developing the microvascular outcomes. Intensive therapy reduced all microvascular outcomes among individuals with lower HbA1c-CV, but increased the risk among those with the highest HbA1c-CV (all P values for interaction < 0.0001). For example, hazard ratios (95 % CI) of retinopathy comparing intensive with standard treatments were 0.65 (0.56-0.75), 0.84 (0.71-0.98), 0.97 (0.82-1.14) and 1.28 (1.08-1.53) across the lowest to the highest quartiles of HbA1c variability. CONCLUSIONS: The effects of intensive glycemic control on microvascular outcomes in T2DM appear to be modified by the variability of HbA1c during the treatment process, suggesting the significance of dynamic monitoring of HbA1c levels and timely adjustments to the therapeutic strategy among individuals with a high HbA1c variability.

Quercetin improved hepatic circadian rhythm dysfunction in middle-aged mice fed with vitamin D-deficient diet.

We aimed to determine whether quercetin is capable of improving circadian rhythm and metabolism disorder under vitamin D-deficient condition. Middle-aged mice were randomly divided into four groups, namely, control (CON), vitamin D-deficient diet (VDD), quercetin (Q), and quercetin intervention in vitamin D-deficient diet (VDQ), with a total of 12 weeks' intervention. Mice were sacrificed at zeitgeber time1 (ZT1) and ZT13 time points. At ZT1, circadian locomotor output cycle kaput (CLOCK) protein expression from VDD, Q, and VDQ groups; CRY1 from Q group; and CRY2 from VDD group were significantly lower compared to CON group. The mRNA expression of Sirt1, Bmal1, Clock, Cry1, and Cry2 in VDQ groups, also Bmal1, Clock, and Cry1 from Q group, were significantly decreased compared to CON group. At ZT13, compared to CON group, fasting insulin and homeostasis model assessment-insulin resistance (HOMA-IR) were higher in VDD group; BMAL1 was significantly increased, while CLOCK and CRY1 protein were significantly decreased from VDD group; CLOCK protein from VDQ group was significantly higher compared to CON, VDD, and Q groups, and also, BMAL1 protein expression from VDQ group was elevated compared to CON group. The mRNA expression of Bmal1, Clock, Per2, Cry1, and Cry2 in VDQ groups were significantly increased compared to CON groups. The mRNA expression of Bmal1 from VDQ group was decreased compared to both VDD and Q group. In conclusion, vitamin D-deficient diet resulted in a disordered liver circadian rhythm, and quercetin improved the hepatic circadian desynchronization. Quercetin supplementation might be effective for balancing circadian rhythm under vitamin D-deficient condition.

Associations of dietary advanced glycation end products with liver steatosis via vibration controlled transient elastography in the United States: a nationwide cross-sectional study.

PURPOSE: Large population-based studies for the associations between dietary advanced glycation end products (dAGEs) intake and liver steatosis remain lacking. It is necessary to clarify the relationship of dAGEsintake with liver steatosis through the National Health and Nutrition Survey (NHANES). METHODS: A total of 5856 participants in the NHANES 2017-2018 were included. The dietary AGEs intake, including ε-(carboxymethyl)lysine(CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of ultra-performance LC-tandem MS dietary AGEs database and two 24-h dietary recall interviews. Liver steatosis was assessed by controlled attenuation parameter via transient elastography. Logistic regression model was adopted to explore the relationships between dAGEs intake and hepatic steatosis. RESULTS: Compared with individuals of total dAGEs, CML, MG-H1 in the lowest tertile, those in the highest tertile had highest risk of hepatic steatosis, and the corresponding odds radios(ORs) (95% confidence interval(CI)) were 1.37 (1.01, 1.84), 1.36 (1.04,1.78) and 1.40 (1.06, 1.85), respectively. Subgroups analysis found that the positive association between dAGEs, CML, CEL and MG-H1 and hepatic steatosis appeared stronger in subjects with obesity and those with abnormal waist circumference (WC). CONCLUSION: There was a positive correlation between dAGEs, CML, MG-H1, and hepatic steatosis, and this association mainly existed in subjects with obesity and those with abnormal WC. Dietary AGEs restriction might be of high priority for subjects with obesity for the prevention of fatty liver disease. Further longitudinal studies are required to confirm the causal associations and explore the potential mechanisms.

The relationships between plasma advanced glycation end products level and cognitive function in middle-aged and elderly Chinese subjects.

OBJECTIVES: To determine the relationships between circulating representative advanced glycation end products (AGEs) and cognitive performance in middle-aged and elderly Chinese adults. METHOD: A cross-sectional study with 1834 participants were included. Cognitive performance was assessed using the Mini-Mental State Examination (MMSE). Plasma free AGEs including Nε-carboxymethyl-L-lysine (CML), Nε-(1-carboxyethyl) lysine (CEL), S-carboxymethyl-L-cysteine (CMC) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Multivariate adjusted linear and logistic regression analysis were used to explore the associations between plasma AGEs and cognitive function. RESULTS: The prevalence of mild cognitive impairment (MCI) was 17.94%. Plasma CMC and MG-H1 level were negatively associated with MMSE score (ß = -0.42, p < 0.001 for all) in the multivariate linear regression analysis. In the multivariate logistic regression analysis, compared to the lowest tertile, participants within the highest tertile of CMC and MG-H1 had increased risk of MCI [ORs (95% CI): 1.62 (1.21-2.17), P trend <0.001, and ORs (95% CI): 1.30 (0.97-1.76), P trend = 0.069, respectively]. In addition, the weighted quantile sum (WQS) index was negatively associated with MMSE (ß = -0.48, P < 0.001) and increased risk of MCI [ORs (95% CI): 1.35 (1.20-1.52), P < 0.001]. CONCLUSION: Combined exposure of plasma free AGEs including CML, CEL, CMC and MG-H1 were associated with increased risk of cognitive impairment. Plasma CMC and MG-H1 might the main contributors for cognitive impairment, while further longitudinal studies are required to verify the associations.

Higher dietary advanced glycation products intake is associated with increased risk of dementia, independent from genetic predisposition.

BACKGROUND: Dietary advanced glycation end products (AGEs) might exert adverse effects on cognition. The associations between dietary AGEs and long-term risk of dementia are yet to be assessed in large population studies. We aimed to explore whether elevated dietary AGEs intake is associated with increased risk of dementia, and whether this association might be affected by genetic risk. METHODS: A prospective cohort study, which included a total of 93,830 participants (aged≥ 50 years) free from dementia at baseline of the UK Biobank study (2006-2010) and had at least two 24-h dietary assessments and were followed up until 2021. Dietary AGEs, including Nε-(1-Carboxyethyl)-l-lysine (CEL), Nε-(carboxymethyl) lysine (CML), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated via averaged data from the multiple 24-h food assessments according to the ultra-performance LC-tandem MS based dAGEs database. Incidence of all-cause dementia was ascertained through hospital inpatient and mortality records. Multivariable Cox regression models were utilized to estimate hazards ratios (HRs) and 95% confidence interval (CI) of dementia risk associated with dietary AGEs. RESULTS: During a median follow-up of 11.9 years, 728 participants developed dementia. In multivariable adjusted model, when comparing the highest with the lowest tertile of intake level, HRs (95% CI) of dementia were 1.43 (1.16, 1.76) for total AGEs Z score, 1.53 (1.25, 1.89) for CEL, 1.27 (1.03, 1.56) for CML and 1.24 (1.02, 1.52) for MG-H1 (all P trend<0.01). There was no significant interaction between dietary AGEs intake, genetic risk and APOE ε4 carrier status for dementia. CONCLUSIONS: Higher intakes of dietary AGEs including CEL, CML and MG-H1 were associated with a higher risk of dementia, independent from genetic risk, highlighting the significance of dietary AGEs restriction for dementia prevention.

Assessment of knowledge, attitudes, practices, and risk perceptions regarding COVID-19: a cross-sectional study from China.

Aim: To analyze the level of knowledge, attitudes, practices, and risk perception regarding COVID-19 among Chinese residents 1.5 years after the pandemic. Subject and methods: A cross-sectional study was carried out with both online and paper questionnaires. We included a variety of covariates that were characteristic-related factors such as age, gender, education level, and retirement status, as well as those closely associated with risk perception regarding COVID-19. Results: Participants (n = 3588), 53.49 ± 18.88 years old, from two provinces of China, of which 44.7% were male and 52.03% had a high school or greater level of education, answered the questions. More than 90% of participants had adequate background knowledge about COVID-19 and agreed or even strongly agreed with many attitude items related to the government's role in diagnosis, treatment, and dealing with COVID-19 infections. About three fifths of the participants reported fear of contracting COVID-19, but only a minority (18.63%) felt they were more susceptible than others. Respondents aged 45 years or younger were more likely to fear contracting the virus than those older than 45 years (adjusted OR = 1.464, 95% CI 1.196 to 1.794, P = 0.0002). High education level (adjusted OR = 1.503, 95% CI 1.187 to 1.904, P = 0.0007) and non-retired status (adjusted OR = 1.679, 95% CI 1.354 to 2.083, P < 0.0001) were associated with a higher perception of susceptibility to infection than others. Moreover, respondents who were not retired had a significantly reduced practice score (adjusted OR = 1.554, 95% CI 1.261 to 1.916, P < 0.0001). Age, retirement status, and education level were also associated with knowledge, attitude, and practice level. Conclusion: Our findings suggest that the public generally has trust in the COVID-19 vaccine and the government with regard to COVID-19 in China. We recommend that high-risk groups of communities, such as elders and patients with chronic diseases, be given greater consideration in the outbreaks. Health education campaigns combined with workplace preventive intervention should be aimed at improving COVID-19 knowledge and beliefs in order to encourage more optimistic attitudes and to maintain safe practices.

Lactoferrin alleviates Western diet-induced cognitive impairment through the microbiome-gut-brain axis.

Lactoferrin (Lf) has been shown to benefit cognitive function in several animal models. To elucidate the underlying mechanisms, male C57BL/6J mice were randomly divided into the control (CON), Western-style diets (WD), lactoferrin (Lf), and Lf + antibiotics (AB) groups. The Lf group was intragastrically administered with Lf, and the Lf + AB group additionally drank a solution with antibiotics. After 16 weeks of intervention, Lf improved the cognitive function as indicated by behavioral tests. Lf also increased the length and curvature of postsynaptic density and upregulated the related protein expression, suggesting improved hippocampal neurons and synapses. Lf suppressed microglia activation and proliferation as revealed by immunofluorescence analysis. Lf decreased the serum levels of pro-inflammatory cytokines and downregulated their protein expressions in the hippocampus region. Lf also inhibited the activation of NF-κB/NLRP3 inflammasomes in the hippocampus. Meanwhile, Lf upregulated the expression of tight junction proteins, and increased the abundance of Bacteroidetes at phylum and Roseburia at genus, which are beneficial for gut barrier and cognitive function. The antibiotics eliminated the effects of long-term Lf intervention on cognitive impairment in the Lf + AB group, suggesting that gut microbiota participated in Lf action. Short-term Lf intervention (2 weeks) prevented WD-induced gut microbiota alteration without inducing behavioral changes, supporting the timing sequence of gut microbiota to the brain. Thus, Lf intervention alleviated cognitive impairment by inhibiting microglial activation and neuroinflammation through the microbiome-gut-brain axis.

Glomerular filtration rate estimated by differing measures and risk of all-cause mortality among Chinese individuals without or with diabetes: A nationwide prospective study.

BACKGROUND: Whether estimated glomerular filtration rates (eGFRs) by differing biomarkers are differentially associated with mortality or whether the associations differ by diabetes status remains unclear, especially in Chinese population. METHODS: We included 6995 participants without diabetes (mean age: 60.4 years) and 1543 with diabetes (mean age: 61.8 years). Each eGFR measure was divided into normal (≥90 mL/min/1.73 m2 ), modestly declined (60 to <90 mL/min/1.73 m2 ), and chronic kidney disease (CKD) (<60 mL/min/1.73 m2 ) groups. Cox proportional hazards models were used to estimate hazard ratio (HR) of all-cause mortality associated with each eGFR. RESULTS: Over a follow-up of 7 years, 677 and 215 deaths occurred among individuals without or with diabetes, respectively. Among those without diabetes, all measures of modestly declined eGFR were not associated with mortality, whereas CKD defined by eGFR cystatin C (eGFRcys) and eGFR creatinine (eGFRcr)-cys (HRs were 1.71 and 1.55, respectively) but not by eGFRcr were associated with higher risk of mortality. Among diabetes, all measures of modestly declined eGFR (HRs: 1.53, 1.56, and 2.09 for eGFRcr, eGFRcys, and eGFRcr-cys, respectively) and CKD (HRs: 2.57, 2.99, and 3.92 for eGFRcr, eGFRcys, and eGFRcr-cys, respectively) were associated with higher risk of mortality. Regardless of diabetes status, an addition of eGFRcys or eGFRcr-cys to traditional risk factors lead to a larger improvement in the prediction of all-cause mortality risk than adding eGFRcr. CONCLUSIONS: The association of eGFR with mortality risk appeared to be varied by its measures and by diabetes status among middle-aged and older Chinese, which needs to be considered in clinical practice.

Exploring the Complex Relationship between Gut Microbiota and Risk of Colorectal Neoplasia Using Bidirectional Mendelian Randomization Analysis.

BACKGROUND: Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis. METHODS: Summary-level data for gut microbiota and metabolites were obtained from MiBioGen, FINRISK and human metabolome consortia. Summary-level data for colorectal cancer were derived from a genome-wide association study meta-analysis. In forward Mendelian randomization (MR), we employed genetic instrumental variables (IV) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with colorectal cancer. We also used a lenient threshold for nine apriori gut microbiota taxa as secondary analyses. In reverse MR, we explored association between genetic liability to colorectal neoplasia and abundance of microbiota studied above using 95, 19, and 7 IVs for colorectal cancer, adenoma, and polyps, respectively. RESULTS: Forward MR did not find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and colorectal cancer risk. However, reverse MR supported genetic liability to colorectal adenomas was causally related with increased abundance of two taxa: Gammaproteobacteria (ß = 0.027, which represents a 0.027 increase in log-transformed relative abundance values of Gammaproteobacteria for per one-unit increase in log OR of adenoma risk; P = 7.06×10-8), Enterobacteriaceae (ß = 0.023, P = 1.29×10-5). CONCLUSIONS: We find genetic liability to colorectal neoplasia may be associated with abundance of certain microbiota taxa. It is more likely that subset of colorectal cancer genetic liability variants changes gut biology by influencing both gut microbiota and colorectal cancer risk. IMPACT: This study highlights the need of future complementary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and colorectal cancer susceptibility.

Combined Exposure to Multiple Metals and Kidney Function in a Midlife and Elderly Population in China: A Prospective Cohort Study.

[Background] Metal exposure is suspected to be correlated to kidney function. However, the combined effects of co-exposing to multiple metals, especially both toxic and protective metals, have not been completely evaluated. [Method] A prospective cohort study was conducted with the "135" cohort for the evaluation of how plasma metal levels are correlated to kidney function in a midlife and elderly community in southern China. An amount of 1368 subjects without kidney disease at baseline were enrolled in the final analysis. By using linear regression and logistic regression models, the correlation of individual metal values with renal function parameters was assessed. Measuring of the multiple metal exposure level was performed by principal component analysis (PCA). [Results] Diminished renal function, as evaluated based on fast kidney function decline, or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, was positively associated with the plasma concentrations of chromium and potassium, but it was negatively associated with selenium and iron (p < 0.05). In multiple-metal analyses, linear and logistic regression models showed that the iron and chromium exposure pattern had a protective effect on renal function, whereas the sodium and potassium exposure pattern and the cadmium and lead exposure pattern increased the risk for fast kidney function decline, and eGFR < 60 mL/min/1.73 m2. [Conclusions] Certain metals, including chromium, potassium, selenium, and iron, were correlated with kidney function in a midlife and elderly community in China. In addition, the potential combined influences of co-exposing to multiple metals were observed.

Microbiota from Exercise Mice Counteracts High-Fat High-Cholesterol Diet-Induced Cognitive Impairment in C57BL/6 Mice.

Gut microbes may be the critical mediators for the cognitive enhancing effects of exercise. Via fecal microbiota transplantation (FMT), this study is aimed at determining the mechanism of how voluntary exercise improved learning and memory ability impairment post a high-fat, high-cholesterol (HFHC) diet. The learning and memory abilities assessed via the Morris water maze in the FMT recipient group of voluntary exercising mice were improved compared to sedentary group. 16S rRNA gene sequencing results indicated that exercise-induced changes in gut microbiota distribution were transmissible, mainly in terms of elevated Lactobacillus, Lactobacillus, and Eubacterium nodatum, as well as decreased Clostrida_UCG-014 and Akkermansia after FMT. The neuroprotective effects of FMT were mainly related to the improved insulin signaling pathway (IRS2/PI3K/AKT) and mitochondrial function; inhibition of AQP4; decreased p-Tau at serine 396 and 404; increased BDNF, PSD95, and synaptophysin in the hippocampus; and also decreased HDAC2 and HDAC3 protein expressions in the nuclear and cytoplasmic fractions of the hippocampus. The findings of qRT-PCR suggested that exercise-induced gut microbes, on the one hand, elevated GPR109A and decreased GPR43 and TNF-α in the hippocampus. On the other hand, it increased GPR109A and GPR41 expressions in the proximal colon tissue. In addition, total short-chain fatty acid (SCFA), acetic acid, propionic acid, isobutyric acid, valeric acid, and isovaleric acid contents were also elevated in the cecum. In conclusion, exercise-induced alterations in gut microbiota play a decisive role in ameliorating HFHC diet-induced cognitive deficits. FMT treatment may be a new considerable direction in ameliorating cognitive impairment induced by exposure to HFHC diet.

Urine caffeine metabolites are positively associated with cognitive performance in older adults: An analysis of US National Health and Nutrition Examination Survey (NHANES) 2011 to 2014.

The aim of this study was to explore urine caffeine metabolites in relation to cognitive performance among 2011-2014 National Health and Nutrition Examination Survey participants aged ≥60 years. We hypothesized that urine caffeine metabolites were positively associated with cognition in older adults. Caffeine and 14 of its metabolites were quantified in urine by use of high-performance liquid chromatography-electrospray ionization-tandem quadruple mass spectrometry with stable isotope labeled internal standards. Cognitive assessment was based on scores from the word learning and recall modules. Participants were categorized based on the quartiles of caffeine and its metabolites level. The association between caffeine metabolites and each cognitive dimension was analyzed using multiple logistic regression analysis in adjusted models. Stratification analyses by gender were also performed. For CERAD test, there was a significant association between 1-methyluric acid (OR=0.62, 95% CI: 0.42 to 0.92), 7-methylxanthine(OR=0.49, 95% CI: 0.27 to 0.89), theophylline (OR=0.52, 95% CI: 0.29 to 0.92), as well as paraxanthine (OR=0.49, 95% CI: 0.27 to 0.88) and cognitive function. For animal fluency test, there was a positive association between theophylline (TP) (OR=0.44, 95% CI: 0.22 to 0.89) and cognitive function. The trend that the risk of low cognitive function decreased with increasing concentration of 1-methylxanthine (P trend=0.0229) was also observed. Furthermore, the same trend existed for 3-methylxanthine (p trend = 0.0375) in men. In conclusion, there was a significant positive association between urine caffeine metabolites and cognitive performance in older adults, particularly for theophylline, paraxanthine and caffeine; and the association might be dependent on gender.

Trimethylamine N-oxide aggravated cognitive impairment from APP/PS1 mice and protective roles of voluntary exercise.

To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning and memory abilities, and exercise reversed TMAO induced cognitive impairment. Serum TMAO, choline, betaine and TMA were significantly elevated from TMAO group, while exercise group had decreased TMAO, betaine and TMA level. TMAO group has significantly upregulated BACE1 from both hippocampus and cortex, also increased cathepsin B, p-Tau at Ser396&Ser404, GFAP, p-NF-κB p65 in cortex, while reduced BDNF, synaptophysin and PSD95 in hippocampus, also reduced occludin and ZO-1 from cortex, and reduced occludin from colon. In contrast, BACE1 from both hippocampus and cortex, also cathepsin B and p-Tauser396 from cortex were reduced, BDNF, snaptophysin, and PSD95 from hippocampus, ZO-1 from cortex, and occludin from colon were elevated post exercise compared to TMAO group. Exercise elevated α diversity index of cecal content, and TMAO and exercise affected gut microbiota profiles differentially. In conclusion, TMAO led to gut microbiota dysbiosis, impaired gut-brain integrity, elevated neuroinflammation, Aß pathology and tau phosphorylation, disordered synaptic function; and exercise could reverse TMAO induced cognitive dysfunction via improving the above markers. The potential deleterious effects of TMAO on cognitive function need to be validated in humans, also dosages of exercise for exerting neuroprotective effects against TMAO induced cognitive impairment.

The Association Between Exposure to Air Pollution and Dementia Incidence: The Modifying Effect of Smoking.

BACKGROUND: The influence of overall air pollution on dementia risk and the potential effect modification by other risk factors remain to be clarified. METHODS: We included 459 844 UK residents who were free of dementia and had data on the exposure to particulate matter (PM)2.5, PM2.5-10, PM10, NO2, and NOx during baseline recruitment. The combined exposure to various PMs and NOx was estimated by using an air pollution score. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia were estimated by multivariable Cox models. RESULTS: During a median 11.7 years follow-up, 5 905 incident cases of all-cause dementia were identified. With the exception of PM2.5-10, all other air pollutants were separately associated with a higher risk of all-cause dementia (all p-trend < .001) with generally similar associations for dementia subtypes. An increasing air pollution score was associated with higher risks of all-cause as well as individual dementia outcomes, with adjusted HRs (95% CI) of 1.27 (1.18, 1.37) for all-cause dementia, 1.27 (1.14, 1.43) for Alzheimer's disease, and 1.35 (1.16, 1.57) for vascular dementia when comparing the highest with the lowest quartile of the score (all p-trend < .001). These associations of air pollution score with dementia and its subtypes were observed among never and former smokers but not among current smokers (all p-interaction < .030). CONCLUSION: Air pollution was associated with a higher risk of dementia among nonsmokers but not current smokers. Additional studies are required to confirm our findings and to explore the potential mechanisms underlying the possible effect modification by smoking status.