Associations between the TyG index and the ɑ-Klotho protein in middle-aged and older population relevant to diabetes mellitus in NHANES 2007-2016.

BACKGROUND: The anti-aging protein Klotho has diverse functions in antioxidative stress and energy metabolism through several pathways. While it has been reported that α-Klotho is downregulated in patients with insulin resistance (IR), the association between Klotho and IR is complex and controversial. The triglyceride-glucose (TyG) index has provided a practical method for assessing IR. With this in mind, our study aimed to investigate the relationship between the TyG index and soluble α-Klotho protein levels in US populations, both with and without diabetes mellitus. METHODS: This cross-sectional study analyzed data from middle-aged and older participants in the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. The participants were divided into two groups based on their diabetes mellitus status: those with diabetes and those without diabetes. To evaluate the relationship between the TyG index and the concentration of the α-Klotho protein in each group, a series of survey-weighted multivariable linear regression models were employed. Furthermore, to examine the association between these two variables, multivariable-adjusted restricted cubic spline curves and subgroup analysis were generated. RESULTS: The study involved 6,439 adults aged 40 years or older, with a mean age of 57.8 ± 10.9 years. Among them, 1577 (24.5%) had diabetes mellitus. A subgroup analysis indicated that the presence of diabetes significantly affected the relationship between the TyG index and the α-Klotho level. After considering all covariables, regression analysis of the participants without diabetes revealed that the α-Klotho concentration decreased by 32.35 pg/ml (95% CI: -50.07, -14.64) with each one unit increase in TyG (p < 0.001). The decline in α-Klotho levels with elevated TyG was more pronounced in the female population. In patients with diabetes mellitus, a non-linear association between the TyG index and α-Klotho was observed. There was no significant correlation observed between the two when TyG index were below 9.7. However, there was an increase in klotho levels of 106.44 pg/ml for each unit increase in TyG index above 9.7 (95% CI: 28.13, 184.74) (p = 0.008). CONCLUSION: Our findings suggested that the presence of diabetes may influence the relationship between the TyG index and soluble α-Klotho. Furthermore, there seem to be sex differences in individuals without diabetes. Further studies are necessary to validate these findings.

Cubane-type tungsten-iron-sulfur clusters with a nitrogen atom in the core: terminal ligand substitutions and redox behaviors.

The lack of M-Fe-S (M = Mo or W) clusters incorporating a second period (2p) atom in the core has resulted in limited investigations and poor understanding of the physical and chemical properties of the M-Fe-S clusters closely related to the FeMo cofactor. In this work, systematic studies have been carried out to explore the chemical reactivities at the terminal ligand sites and the redox properties of a series of clusters comprising a [WFe3S3N] cubane core, based on the previously developed cluster [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]1-. Substitutions of the terminal chlorides with ethanethiolate, methanethiolate, thiophenolate, p-thiocresolate and azide occurred smoothly, while the replacement of the chlorides with carbene ligands required the reduction of the precursor into [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]2- first. The reduced cluster core could also be supported by thiophenolates as terminal ligands, but not thiolates or azides. It is remarkable that the thiophenolate ligated reduced cluster can be synthesized from the precursor [(Tp*)WFe3S3(µ3-NSiMe3)Cl3]1-via different synthetic routes, either reduction followed by substitution or substitution followed by reduction, either in situ or stepwise. This work indicates that terminal ligands contribute significantly to determine the chemical and physical properties of the clusters, even though they might affect the cluster core to a limited extent from a structural point of view, which raises the possibility of delicate control in regulating the physical/chemical properties of M-Fe-S clusters with a heteroleptic core incorporating 2p atom(s).

Alcohol Consumption and Stroke Risk in Men: A Population-Based Cohort Study in Rural Tianjin, China.

BACKGROUND: Although the protective effects of alcohol consumption against future cardiovascular disease have been published, the effects of alcohol on stroke risk remain controversial. METHOD: We assessed the effects of alcohol consumption on stroke risk in a poorly educated, low-income population in rural China. Between 1991 and 2018, a population-based cohort study was conducted in rural Tianjin, China, to examine stroke risk. All registered stroke events were clinically verified using available computed tomography or MRI scans. The stroke risk was analyzed, according to the extent of alcohol consumption, using Cox regression analyses. RESULTS: We identified 352 incident stroke events among male participants during the study period. The stroke incidences (per 100,000 person-years) were 965.3 overall, 575.9 for ischemic stroke events, 208.4 for hemorrhagic stroke events, and 181.0 for undefined stroke events. Overall, alcohol consumption provided a 32% reduction in the total stroke risk. Low-dose alcohol consumption (≤12 g/day) showed a negative association with total (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.46-0.88; p = 0.008) and ischemic (HR, 0.66; 95% CI, 0.44-0.98; p = 0.039) strokes. Alcohol consumption was not significantly associated with hemorrhagic strokes. After age stratification, alcohol consumption was protective against total and ischemic strokes in men aged ≥55 years old, with the risk of each stroke type decreasing by 46 and 49%, respectively. Low-dose alcohol consumption was inversely associated with both total and ischemic stroke risks, with the risks decreasing by 56 and 65%, respectively. Alcohol consumption was not significantly associated with strokes among men aged <55 years old. CONCLUSIONS: These findings suggest that low-dose alcohol consumption may decrease the risk of ischemic strokes among men. Even so, the adverse effects of alcohol on the liver and pancreas cannot be ignored. Additionally, the effects of alcohol consumption on stroke risk vary with age, protecting against ischemic and total strokes among males ≥55 years old. Nevertheless, recommending light drinking and its potential health benefits should not be generalized to men of all ages.

Lipocalin-2 protects against renal ischemia/reperfusion injury in mice through autophagy activation mediated by HIF1α and NF-κb crosstalk.

Renal ischemia/reperfusion injury is a main cause of acute kidney injury (AKI) triggering an inflammatory response associated with infiltrating macrophages. Lipocalin-2 (Lcn2) levels correlate positively and protect against renal ischemia/reperfusion injury. However, the mechanisms remain unclear. The aim of study was to investigate the protective mechanisms of Lcn2 on renal ischemia/reperfusion injury. We found that Lcn2 deficiency significantly aggravated renal injury as evidenced by higher serum creatinine, more severe morphological injury, and increased tubular epithelial cell death in mice. We also observed that attenuated autophagy in Lcn2-/- mice, as autophagy markers LC3 II level was significantly decreased and p62 was increased in the Lcn2-/- mice after I/R, compared with that of wild type. Mechanistically, we found that recombinant Lcn2 attenuated hypoxia-induced apoptosis in proximal tubule epithelial cells in vitro, and downregulation of HIF-1α blunted Lcn2-induced autophagy and enhanced apoptosis. In addition, the Lcn2 attenuated NF-κb subunit p65 activation under hypoxia conditions. Thus, our findings provide a better understanding of the protective role of Lcn2 in kidney ischemia/reperfusion injury and suggest that Lcn2 may be a promising therapeutic target for treating patients with AKI.

Valsartan prevents glycerol-induced acute kidney injury in male albino rats by downregulating TLR4 and NF-κB expression.

In this study, the protective effect of valsartan against glycerol-induced acute kidney injury (AKI) in male albino rats was investigated. Valsartan is used to treat high blood pressure and congestive heart failure and can prolong lifespan following a heart attack. The rats were divided into control, AKI, AKI + valsartan 100 mg/kg bw, and AKI + valsartan 200 mg/kg bw groups. Superoxide dismutase, glutathione peroxidase, catalase, lipid peroxidation, and reduced glutathione were assessed, and histopathological, immunohistochemical and western blot analyses were performed. Valsartan supplementation in AKI rats substantially increased superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels but reduced the level of lipid peroxidation. Valsartan significantly reduced the severity of the renal tubular injury, renal lesions, and necrosis. Valsartan decreased NF-κB and TLR4 mRNA expression by >50% and their protein levels by >40%. Therefore, valsartan supplementation inhibited glycerol-induced functional and pathological damage to the kidney in a concentration-dependent manner. We propose that valsartan protects rat kidney tissue by downregulating NF-κB and TLR4 expression.

Involvement of the NF-κB signaling pathway in the renoprotective effects of isorhamnetin in a type 2 diabetic rat model.

The aim of the present study was to investigate the renoprotective effects of isorhamnetin (ISO) in type 2 diabetic rats and its effects on the nuclear factor-κB (NF-κB) signaling pathway, which is associated with diabetic nephropathy. The type 2 diabetic rat model was established by a high-fat diet plus streptozocin injection and the rats were subsequently treated with two dosages of ISO, respectively. The levels of blood glucose were determined. Urinary osteopontin, kidney injury molecule-1 (KIM-1) and albumin were measured to evaluate the renal function of the rats. Renal NF-κB signaling activity was assessed by measuring the levels of NF-κB p65, phospho-NF-κB p65, inhibitor of NF-κB (IκBα) and phospho-IκBα, and the NF-κB p65 DNA-binding activity. Downstream inflammatory mediators [tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-ß1 (TGF-ß1)] of the NF-κB signaling pathway were investigated to evaluate the renal inflammatory response. Renal levels of malondialdehyde and total superoxide dismutase were detected to access the oxidative stress. Furthermore, glomerular mesangial cells (GMCs) were treated with lipopolysaccharide and ISO. In the cellular experiment, the NF-κB signaling activity, levels of TNF-α, IL-1ß, IL-6, ICAM-1 and TGF-ß1, and oxidative stress were also investigated. The results showed that ISO decreased the levels of urinary osteopontin, KIM-1 and albumin. ISO also inhibited the NF-κB signaling activity, decreased the production of inflammatory mediators and attenuated oxidative stress in diabetic rats and GMCs. The present investigations revealed that ISO had ameliorative effects on diabetes-induced renal damage and the activity may be associated with the negative regulation of NF-κB signaling pathway.