Cystatin C is a predictor for long-term All-Cause and Cardiovascular Mortality in US Adults with Metabolic Syndrome.

OBJECTIVE: This study examined the relationship between Cystatin C (CysC) levels and all-cause, CVD, and cancer mortality in US metabolic syndrome (MetS) patients. METHODS: The 1999-2002 National Health and Nutrition Examination Survey (NHANES) prospective cohort research included 1,980 MetS participants. To assess CysC levels and all-cause, CVD, and cancer mortality, fitted curves, Kaplan-Meier survival curves, cox regression analysis, and ROC curves were performed. RESULTS: During a mean follow-up of 15.3 ± 5.4 years, a total of 819 deaths occurred. The fitted and Kaplan-Meier survival curves revealed that greater CysC levels were linked to higher all-cause, CVD, and cancer mortality rates (P<0.05). After adjusting for variables, CysC level was associated with all-cause, CVD, and cancer mortality at 1.63 (1.42-1.88), 1.53 (1.19-1.95), and 1.53 (1∼2.32), respectively (P<0.05). Later tertile models showed consistent results. High CysC tertile participants showed higher risk of all-cause mortality (HR 1.87; 1.43-2.45), CVD mortality (HR 1.97, 1.15∼3.38), and cancer mortality (HR 1.72, 1.01∼2.91) compared to those in the lowest tertile (P<0.05). Subgroup studies by sex and other characteristics confirmed the findings. CysC demonstrated the higher predictive efficacy across mortality outcomes, followed by eGFR, outperforming Urea nitrogen, Creatinine, Uric acid, and CRP. CysC alone exhibited substantial predictive value for all-cause (AUC 0.773; P<0.05) and CVD mortality (AUC 0.726; P<0.05). Combining CysC with age enhanced the predictive value for all-cause mortality to 0.861 and CVD mortality to 0.771 (P<0.05). CONCLUSION: MetS patients with elevated CysC levels have a higher risk of all-cause, CVD, and cancer death. CysC may predict MetS all-cause and CVD mortality.

Association of Handgrip Strength with Hip Fracture and Falls in Community-dwelling Middle-aged and Older Adults: A 4-Year Longitudinal Study.

OBJECTIVE: Hip fracture and falls are significant health concerns. Handgrip strength (HGS) is closely associated with overall muscle strength and physical health. However, the longitudinal relationship between HGS and the risk of hip fractures and falls remains unclear, particularly regarding gender differences. This longitudinal study aimed to investigate the association between HGS and the risk of hip fracture and falls in individuals aged 45 years and above, considering gender-specific differences over a 4-year period. METHODS: This study included 10,092 participants (4471 men and 5621 women) aged 45 years and above from the China Health and Retirement Longitudinal Study (CHARLS). Incidents of hip fractures and falls were recorded during a 4-year follow-up, along with various demographic and clinical factors. Participants were categorized into five groups based on their HGS quintiles. Logistic regression models were employed to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between HGS and hip fracture/fall risk. RESULTS: During the 4-year follow-up period, 223 cases of hip fracture (2.2%) and 1831 cases of falls (18.1%) were documented. Notably, higher HGS demonstrated a strong inverse association with the risk of hip fracture in both males and females (p < 0.05). In comparison to the lowest HGS quintile, the adjusted odds ratios (ORs) for hip fracture were 0.46 (0.27-0.78) for the total population, 0.4 (0.19-0.81) for males and 0.48 (0.23-0.98) for females in the highest HGS quintile. Furthermore, a profound and statistically significant negative correlation between HGS and falls was detected (p < 0.05). The adjusted ORs for falls in the highest HGS quintile, compared to the lowest quintile, were 0.62 (0.51-0.76) in the overall population, 0.59 (0.44-0.78) in males, and 0.78 (0.62-0.99) in females. CONCLUSION: Our findings highlight the significant inverse association between HGS and the risk of hip fracture and falls in both males and females aged 45 years and above. Assessing handgrip strength may serve as a valuable tool for predicting fracture and fall risk.

Magnesium Depletion Score and Metabolic Syndrome in US Adults: Analysis of NHANES 2003-2018.

BACKGROUND: The association between magnesium status and metabolic syndrome remains unclear. This study aimed to examine the relationship between the kidney reabsorption-related magnesium depletion score (MDS) and metabolic syndrome among US adults. METHODS: We analyzed data from 15,565 adults participating in the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Metabolic syndrome was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report. The MDS is a scoring system developed to predict the status of magnesium deficiency that fully considers the pathophysiological factors influencing the kidneys' reabsorption capability. Weighted univariate and multivariate logistic regression were used to assess the association between MDS and metabolic syndrome. Restricted cubic spline analysis was conducted to characterize dose-response relationships. Stratified analyses by sociodemographic and lifestyle factors were also performed. RESULTS: In both univariate and multivariate analyses, higher MDS was significantly associated with increased odds of metabolic syndrome. Each unit increase in MDS was associated with approximately a 30% higher risk for metabolic syndrome, even after adjusting for confounding factors (OR 1.31; 95% CI 1.17-1.45). Restricted cubic spline graphs depicted a linear dose-response relationship across the MDS range. This positive correlation remained consistent across various population subgroups and exhibited no significant interaction by age, gender, race, adiposity, smoking status, or alcohol consumption. CONCLUSIONS: Higher urinary magnesium loss as quantified by MDS may be an independent linear risk factor for metabolic syndrome in US adults, irrespective of sociodemographic and behavioral factors. Optimizing magnesium nutritional status could potentially confer benefits to patients with metabolic syndrome.

Dietary Copper Intake and Risk of Parkinson's Disease: a Cross-sectional Study.

Copper is an essential trace element for the human body. The epidemiological evidence for the association of dietary intake of copper with the risk of Parkinson's disease (PD) is limited. We conducted an evaluation of the cross-sectional data gathered from the National Health and Nutrition Examination Surveys spanning from 2007 to 2018, which comprised a total of 17,948 participants. To discern the distinct characteristics of the participants, we performed a univariate analysis and utilized a 1:2 ratio propensity score matching method to minimize the effects of selection bias. We employed weighted univariate as well as three multivariate logistic regression models both prior to and following matching, with the aim of examining the association between dietary copper intake and PD risk. Finally, we used the restricted cubic spline (RCS) methodology in order to investigate possible non-linear relationships. Furthermore, subgroup analysis was undertaken to elicit further understanding concerning the association between copper intake and PD. A negative correlation resulted between dietary copper intake and PD risk in both univariate and multivariate logistic regression models, prior to and following matching. Our findings demonstrate that there is a nonlinear, dose-dependent relationship between copper intake and PD, according to our RCS analysis. In subgroup analysis, copper intake was identified as an important protective factor for individuals who were non-Hispanic White, unmarried, and had completed higher education. Dietary copper intake was associated with the risk of PD. Supplementation of dietary copper may have potentially beneficial effects.

17-year follow-up of association between telomere length and all-cause mortality, cardiovascular mortality in individuals with metabolic syndrome: results from the NHANES database prospective cohort study.

BACKGROUND: The relationship between leukocyte telomere length (LTL) and mortality risk in individuals with metabolic syndrome (MetS) remains poorly understood. This study aimed to investigate the association between telomere length and long-term all-cause mortality, and cardiovascular disease (CVD) mortality, in individuals with MetS in the United States. METHODS: A total of 1980 participants with MetS aged 18 years or older from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (1999-2002) were included in this cohort study. Medical records review was used to identify the cause of deaths as of December 2018. We employed Kaplan-Meier curves, fitted curves, and Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause and CVD mortality, stratified by tertiles of LTL. RESULTS: Over a median follow-up of 17.75 years of participants with metabolic syndrome, 819 deaths occurred, including 231 cardiovascular deaths. After adjusting for multiple covariates, participants with shorter telomere length had a significantly higher risk of all-cause mortality (HR, 1.33; 95% CI, 1.11-1.6) and CVD mortality (HR, 1.36; 95% CI, 0.96-1.93) compared with those in the highest tertile of telomere length. All-cause mortality (P < 0.001) and cardiovascular disease mortality (P = 0.028) followed a similar pattern across tertiles of telomere length. CONCLUSION: In individuals with MetS, shorter telomere length is associated with increased risks of death from cardiovascular disease and all causes. The underlying mechanisms and clinical implications of these findings require additional investigation.

Mitochondrial disorders as a mechanism for the development of obese Sarcopenia.

Obese sarcopenia is a severe and prevalent disease in an aging society. Compared to sarcopenia alone, the development and advanced stage of obesity sarcopenia is faster and more severe. Diagnosis of the cause of adipocyte accumulation is also more complicated; however, no effective pharmacological treatment is available. Chronic inflammation is one of the causes of sarcopenia, and obese patients, who are more likely to develop chronic inflammation, may simultaneously suffer from obesity and sarcopenia. Mitochondrial metabolic disorders have been more easily observed in the tissue cells of patients with obesity and sarcopenia. Mitochondrial metabolic disorders include abnormal mtDNA release, mitochondrial autophagy, and dynamic mitochondrial disorders. Therefore, this review will reveal the mechanism of development of obesity myasthenia gravis from the perspective of mitochondria and discuss the currently existing small-molecule drugs.

Elevated visceral adiposity index linked to improved cognitive function in middle-aged and elderly Chinese: evidence from the China health and retirement longitudinal study.

Object: Cognitive decline and obesity are major global public health issues, and their association has been widely acknowledged. The link between the visceral adiposity index (VAI) and cognitive function in the Chinese population remains uncertain. This study aims to investigate the effects of VAI levels on cognitive function in the Chinese middle-aged and elderly population. Methods: We analyzed longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) collected in 2011, 2013, 2015, and 2018. VAI levels were divided into three tertiles. Generalized estimating equation (GEE) models were used to explore the relationships between VAI levels and cognitive function, including overall cognitive scores, episodic memory, and mental status. Adjustments were made for potential confounders. Results: The study consisted of 2,677 participants. Contrary to expectations, higher VAI levels were associated with higher overall cognitive scores and improved episodic memory scores, while no significant effect was observed on mental status. The GEE models consistently indicated that higher VAI levels were associated with higher overall cognitive scores, primarily due to their association with episodic memory. Stratified analyses revealed that the VAI was associated with better cognitive function primarily in males, individuals under 60 years old, those with lower education levels, rural residents, and married individuals, mainly in relation to episodic memory. No significant interactions were observed between VAI and demographic factors. Conclusion: Our findings suggest that higher visceral adiposity is associated with slower cognitive decline in the Chinese middle-aged and elderly population, especially in its association with episodic memory. These results underline the need to further investigate the potential protective role of visceral fat in cognitive function, potentially offering new insights for interventions to enhance cognitive function and prevent dementia in this population.

The association of handgrip strength with all-cause and cardiovascular mortality: results from the National Health and Nutrition Examination Survey database prospective cohort study with propensity score matching.

Objective: To investigate the association between handgrip strength (HGS) with all-cause and cardiovascular disease (CVD) mortality in US adults. Method: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (2011-2014) with 10,470 participants. The cox regression analysis, Kaplan-Meier survival curves, fitted curves, ROC curves, and propensity score-matched analysis (PSM) with inverse probability of treatment weighting (IPTW), SMRW (PSM with repeated weights), PA (pairwise algorithm), and OW (overlap weighting) regression analysis were performed to assess the relationship between HGS and all-cause and CVD mortality. Results: The low HGSs (men <37.4 kg, women <24 kg), was found to be associated with higher all-cause and CVD mortality in a reverse J-shaped curve (p < 0.05). Adjusting for multiple covariates including age, BMI, race, education level, marriage status, smoking and alcohol use, and various comorbidities, the hazard ratio (HR) for all-cause mortality in the lowest HGS quintile 1 (Q1) was 3.45 (2.14-5.58) for men and 3.3 (1.88-5.79) for women. For CVD mortality, the HR was 2.99 (1.07-8.37) for men and 10.35 (2.29-46.78) for women. The area under the curve (AUC) for HGS alone as a predictor of all-cause mortality was 0.791 (0.768-0.814) for men and 0.780 (0.752-0.807) for women (p < 0.05), while the AUC for HGS and age was 0.851 (0.830-0.871) for men and 0.848 (0.826-0.869) for women (p < 0.05). For CVD mortality, the AUC for HGS alone was 0.785 (95% CI 0.738-0.833) for men and 0.821 (95% CI 0.777-0.865) for women (p < 0.05), while the AUC for HGS and age as predictors of all-cause mortality was 0.853 (0.861-0.891) for men and 0.859 (0.821-0.896) for women (p < 0.05). The HGS Q1 (men <37.4 kg and women <24 kg) was matched separately for PSM. After univariate, multivariate Cox regression models, PSM, IPTW, SMRW, PA, and OW analyses, women had 2.37-3.12 and 2.92-5.12 HRs with low HGS for all-cause and CVD mortality, while men had 2.21-2.82 and 2.33-2.85 for all-cause and CVD mortality, respectively (p < 0.05). Conclusion: Adults with low HGS exhibited a significantly increased risk of both all-cause and CVD mortality, regardless of gender. Additionally, low HGS served as an independent risk factor and predictor for both all-cause and CVD mortality.

The relationship between sarcopenia and mortality in Chinese community-dwelling adults: a 7-year cohort study with propensity score matching and Mendelian randomization.

Background: Sarcopenia has been linked to adverse health outcomes, including an increased risk of mortality. This study aimed to assess the 7-year mortality risk of sarcopenia in a community-based population in China and explore the causal relationship between components of sarcopenia and any death. Methods: Data were sourced from the China Health and Retirement Longitudinal Study (CHARLS) conducted between 2011 and 2018. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Logistic regression, Kaplan-Meier (KM) survival analysis, and propensity score matching with inverse probability of treatment weighting were used. Mendelian randomization (MR) analyses, conducted using European population data, were utilized to assess causality between sarcopenia and any death. Results: The study included 9,006 participants: 3,892 had no sarcopenia, 3,570 had possible sarcopenia, 1,125 had sarcopenia, and 419 had severe sarcopenia. Over 7 years of follow-up, there were 871 deaths, including 196 with sarcopenia and 133 with severe sarcopenia. The KM curves showed that sarcopenia had a higher risk of mortality. Compared to those of no sarcopenia, the odds ratios (ORs) of sarcopenia for 7-year mortality were 1.41 (95% CI, 1.06-1.87) after adjusting for confounding variables (p < 0.05). The ORs of severe sarcopenia were 2.11 (95% CI, 1.51-2.95). Propensity score matching analysis and inverse probability of treatment weighting analysis confirmed these findings. The adjusted ORs of sarcopenia and 7-year mortality were 2.94 (95% CI, 1.6-5.39) in the 45-60 age group, 1.72 (95% CI, 1.11-2.68) in the 60-80 age group, and 5.03 (95% CI, 0.48-52.65) in the ≥80 age group. The ORs of severe sarcopenia and 7-year mortality were 6.92 (95% CI, 1.95-24.5) in the 45-60 age group, 2.59 (95% CI, 1.61-4.17) in the 60-80 age group, and 12.52 (95% CI, 1.18-133.18) in the ≥80 age group. The MR analyses, leveraging the inverse variance weighted (IVW) method, unveiled substantial causal links between low hand grip strength in individuals aged 60 and older, the usual walking pace, and mortality risk. Conclusion: This study underscores the significant impact of sarcopenia and its components on mortality risk within the Chinese population. Particularly, low hand grip strength and usual walking pace emerged as noteworthy contributors to mortality risk.

Icaritin alleviates cerebral ischemia‒reperfusion injury by regulating NMDA receptors through ERK signaling.

N-methyl-D-aspartate (NMDA) receptors are key signaling molecules that mediate excitotoxicity during cerebral ischemia. GluN2A-containing NMDA receptors, which are mostly located in the intrasynaptic region, mediate normal physiological processes and promote neuronal survival. GluN2B-containing NMDA receptors, which are mostly located in the extrasynaptic region, mediate excitotoxicity injury and promote neuronal death during ischemia. This study investigated the ability of icaritin (ICT) to protect against cerebral ischemia‒reperfusion injury (CI/RI) by regulating GluN2B-containing NMDA receptors through extracellular signaling regulatory kinases/death associated protein kinase 1 (ERK/DAPK1) signaling. A rat CI/RI model was established by transient middle cerebral artery occlusion (tMCAO). Following treatment with ICT and the ERK-specific inhibitor U0126, cerebral infarction, neurological function, and excitotoxicity-related molecule expression were assessed 24 h after reperfusion. ICT treatment significantly decreased cerebral infarct volume, improved neurological function, and regulated NMDA receptor subtype expression and ERK/DAPK1 signaling activation. The ability of ICT to increase GluN2A and postsynaptic density protein 95 (PSD95) mRNA and protein expression, inhibit GluN2B expression, and regulate DAPK1 activation was reversed after administration of the ERK-specific inhibitor U0126. These data indicated that ICT inhibited excitotoxicity injury and exerted a protective effect against CI/RI that was likely mediated by increased ERK signaling pathway activation and regulation of extrasynaptic and intrasynaptic NMDA receptor function, providing a new therapeutic target for ischemic encephalopathy.

The protective effects of melatonin in high glucose environment by alleviating autophagy and apoptosis on primary cortical neurons.

Cognitive dysfunction has been regarded as a complication of diabetes. Melatonin (MLT) shows a neuroprotective effect on various neurological diseases. However, its protective effect on cortical neurons in high glucose environment has not been reported. Our present study aims to observe the protective effect of melatonin on rat cortical neurons and its relationship with autophagy in high glucose environment. The rat primary cortical neurons injury model was induced by high glucose. The CCK-8, flow cytometry, Western blot and immunofluorescence methods were used to examine the cell viability, apoptosis rate and proteins expression. Our results showed that there were no differences in cell viability, apoptosis rate, and protein expression among the control, MLT and mannitol group. The cell viability of the glucose group was significantly lower than that of the control group, and the apoptosis rate of the glucose group was significantly higher than that of the control group. Compared with the glucose group, the glucose + melatonin group showed a significant increase in cell viability and a notable decrease in apoptosis rate. Melatonin concentration of 0.1-1 mmol/L can significantly alleviate the injury of cortical neurons caused by high glucose. Compared with the control group, the glucose group showed a significant reduction of B-cell lymphoma 2 (Bcl-2) protein expression, while remarkable elevations of Bcl2-associated X protein (Bax), cleaved Caspase-3, coiled-coil, myosin-like Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain-3B type II (LC3B-II) levels. The neurons pre-administered with melatonin obtained significantly reversed these changes induced by high glucose. The phosphorylation levels of protein kinase B (Akt), mechanistic target of rapamycin kinase (mTOR) and Unc-51 like autophagy activating kinase 1(ULK1) were decreased in the glucose group compared with the control group, whereas significant increase were observed in the glucose + MLT group, compared with the glucose group. These data indicated that melatonin has a neuroprotective effect on cortical neurons under high glucose environment, which may work by activating Akt/mTOR/ULK1 pathway and may be deeply associated with the downregulation of autophagy.

REG1A and RUNX3 Are Potential Biomarkers for Predicting the Risk of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Clinical features are traditionally used to predict DKD, yet with low diagnostic efficacy. Most of the recent biomarkers used to predict DKD are based on transcriptomics and metabolomics; however, they also should be used in combination with many other predictive indicators. The purpose of this study was thus to identify a simplified class of blood biomarkers capable of predicting the risk of developing DKD. The Gene Expression Omnibus database was screened for DKD biomarkers, and differentially expressed genes (DEGs) in human blood and kidney were identified via gene expression analysis and the Least Absolute Shrinkage and Selection Operator regression. A comparison of the area under the curve (AUC) profiles on multiple receiver operating characteristic curves of the DEGs in DKD and other renal diseases revealed that REG1A and RUNX3 had the highest specificity for DKD diagnosis. The AUCs of the combined expression of REG1A and RUNX3 in kidney (AUC = 0.929) and blood samples (AUC = 0.917) of DKD patients were similar to each other. The AUC of blood samples from DKD patients and healthy individuals obtained for external validation further demonstrated that REG1A combined with RUNX3 had significant diagnostic efficacy (AUC=0.948). REG1A and RUNX3 expression levels were found to be positively and negatively correlated with urinary albumin creatinine ratio and estimated glomerular filtration rate, respectively. Kaplan-Meier curves also revealed the potential of REG1A and RUNX3 for predicting the risk of DKD. In conclusion, REG1A and RUNX3 may serve as biomarkers for predicting the risk of developing DKD.

Genistein-3'-sodium sulfonate Attenuates Neuroinflammation in Stroke Rats by Down-Regulating Microglial M1 Polarization through α7nAChR-NF-κB Signaling Pathway.

Microglial M1 depolarization mediated prolonged inflammation contributing to brain injury in ischemic stroke. Our previous study revealed that Genistein-3'-sodium sulfonate (GSS) exerted neuroprotective effects in ischemic stroke. This study aimed to explore whether GSS protected against brain injury in ischemic stroke by regulating microglial M1 depolarization and its underlying mechanisms. We established transient middle cerebral artery occlusion and reperfusion (tMCAO) model in rats and used lipopolysaccharide (LPS)-stimulated BV2 microglial cells as in vitro model. Our results showed that GSS treatment significantly reduced the brain infarcted volume and improved the neurological function in tMCAO rats. Meanwhile, GSS treatment also dramatically reduced microglia M1 depolarization and IL-1ß level, reversed α7nAChR expression, and inhibited the activation of NF-κB signaling in the ischemic penumbra brain regions. These effects of GSS were further verified in LPS-induced M1 depolarization of BV2 cells. Furthermore, pretreatment of α7nAChR inhibitor (α-BTX) significantly restrained the neuroprotective effect of GSS treatment in tMCAO rats. α-BTX also blunted the regulating effects of GSS on neuroinflammation, M1 depolarization and NF-κB signaling activation. This study demonstrates that GSS protects against brain injury in ischemic stroke by reducing microglia M1 depolarization to suppress neuroinflammation in peri-infarcted brain regions through upregulating α7nAChR and thereby inhibition of NF-κB signaling. Our findings uncover a potential molecular mechanism for GSS treatment in ischemic stroke.

Icaritin Alleviates Glutamate-Induced Neuronal Damage by Inactivating GluN2B-Containing NMDARs Through the ERK/DAPK1 Pathway.

Excitatory toxicity due to excessive glutamate release is considered the core pathophysiological mechanism of cerebral ischemia. It is primarily mediated by N-methyl-D-aspartate receptors (NMDARs) on neuronal membranes. Our previous studies have found that icaritin (ICT) exhibits neuroprotective effects against cerebral ischemia in rats, but the underlying mechanism is unclear. This study aims to investigate the protective effect of ICT on glutamate-induced neuronal injury and uncover its possible molecular mechanism. An excitatory toxicity injury model was created using rat primary cortical neurons treated with glutamate and glycine. The results showed that ICT has neuroprotective effects on glutamate-treated primary cortical neurons by increasing cell viability while reducing the rate of lactate dehydrogenase (LDH) release and reducing apoptosis. Remarkably, ICT rescued the changes in the ERK/DAPK1 signaling pathway after glutamate treatment by increasing the expression levels of p-ERK, p-DAPK1 and t-DAPK1. In addition, ICT also regulates NMDAR function during glutamate-induced injury by decreasing the expression level of the GluN2B subunit and enhancing the expression level of the GluN2A subunit. As cotreatment with the ERK-specific inhibitor U0126 and ICT abolishes the beneficial effects of ITC on the ERK/DAPK1 pathway, NMDAR subtypes and neuronal cell survival, ERK is recognized as a crucial mediator in the protective mechanism of ICT. In conclusion, our findings demonstrate that ICT has a neuroprotective effect on neuronal damage induced by glutamate, and its mechanism may be related to inactivating GluN2B-containing NMDAR through the ERK/DAPK1 pathway. This study provides a new clue for the prevention and treatment of clinical ischemic cerebrovascular diseases.