Elevated Serum Copper, Zinc, Selenium, and Lowered α-Klotho Associations: Findings from NHANES 2011-2016 Dataset.

The α-Klotho is crucial for human health and longevity. However, the relationship between trace elements and α-Klotho levels needs further investigation. We aimed to explore the relationship between serum levels of selenium (Se), copper (Cu), and zinc (Zn), and serum α-Klotho levels. We analyzed 2138 samples from the 2011-2016 National Health and Nutrition Examination Survey, and the weighted linear regression, WQS, and qgcomp models were utilized to evaluate the effects of these elements on serum α-Klotho levels, individually and combined. A negative correlation was observed between serum Cu concentration and serum α-Klotho levels (ß = - 0.128, 95% CI - 0.196, - 0.059), with each increase in Cu concentration grade showing a gradual decrease in serum α-Klotho levels (Ptrend = 0.002). The WQS model exhibited a negative correlation between the combined effect of Se, Cu, and Zn and serum α-Klotho levels (ß = - 0.035, 95%CI - 0.060, - 0.010), consistently in males (ß = - 0.038 (- 0.059, - 0.017)) and in the 40-49 age group (ß = - 0.059, 95% CI - 0.119, - 0.012). The qgcomp model mirrored these findings, showing a negative correlation in the combined effect index of Se, Cu, and Zn with serum α-Klotho levels (ß = - 0.027, 95% CI - 0.047, - 0.006), consistent in females (ß = - 0.032, 95% CI - 0.061, - 0.004) and in individuals with BMI ≥ 25 (ß = - 0.030, 95% CI - 0.054, - 0.006), and in the 40-49 age group (ß = - 0.047, 95% CI - 0.088, - 0.006). Elevated serum Cu levels may be associated with lower serum α-Klotho levels. The combined effect of serum Se, Cu, and Zn shows a negative correlation with serum α-Klotho levels, with Cu contributing the most. Our findings provide significant insights into assessing the role of trace nutrients in maintaining human health.

Fluoride Induces Neurocytotoxicity by Disrupting Lysosomal Iron Metabolism and Membrane Permeability.

The detrimental effects of fluoride on neurotoxicity have been widely recorded, yet the detailed mechanisms underlying these effects remain unclear. This study explores lysosomal iron metabolism in fluoride-related neurotoxicity, with a focus on the Steap3/TRPML1 axis. Utilizing sodium fluoride (NaF)-treated human neuroblastoma (SH-SY5Y) and mouse hippocampal neuron (HT22) cell lines, our research demonstrates that NaF enhances the accumulation of ferrous ions (Fe2+) in these cells, disrupting lysosomal iron metabolism through the Steap3/TRPML1 axis. Notably, NaF exposure upregulated ACSL4 and downregulated GPX4, accompanied by reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity and increased malondialdehyde (MDA) levels. These changes indicate increased vulnerability to ferroptosis within neuronal cells. The iron chelator deferoxamine (DFO) mitigates this disruption. DFO binds to lysosomal Fe2+ and inhibits the Steap3/TRPML1 axis, restoring normal lysosomal iron metabolism, preventing lysosomal membrane permeabilization (LMP), and reducing neuronal cell ferroptosis. Our findings suggest that interference in lysosomal iron metabolism may mitigate fluoride-induced neurotoxicity, underscoring the critical role of the Steap3/TRPML1 axis in this pathological process.

TFEB ameliorates DEHP-induced neurotoxicity by activating GAL3/TRIM16 axis dependent lysophagy and alleviating lysosomal dysfunction.

Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer with known neurotoxic effects. However, the specific mechanism underlying this neurotoxicity remains unclear. This study aimed to investigate the role of lysosomal function and lysophagy in DEHP-induced neurotoxicity, with a particular focus on the regulatory role of Transcription factor EB (TFEB). To achieve this, we utilized in vitro models of DEHP-exposed SH-SY5Y cells and HT22 cells. Our findings revealed that DEHP exposure led to lysosomal damage and dysfunction. Moreover, we observed impaired autophagic degradation, characterized by elevated levels of LC3II and p62. DEHP treatment downregulated the expression of TFEB, GAL3, and TRIM16, while upregulating the expression of PARP. This led to the inhibition of GAL3/TRIM16 axis dependent lysophagy and ultimately excessive apoptosis in neuronal cells. Importantly, TFEB overexpression alleviated lysosomal dysfunction, activated lysophagy, and mitigated DEHP-induced apoptosis. Overall, our results suggest that DEHP induces not only lysosomal dysfunction, but also inhibits lysophagy through the suppression of GAL3/TRIM16 axis. Consequently, impaired clearance of damaged lysosomes occurs, culminating in neuronal apoptosis. Taken together, our findings highlight the critical role of TFEB in regulating lysophagy and lysosomal function. Furthermore, TFEB may serve as a potential therapeutic target for mitigating DEHP-induced neuronal toxicity.

Rutin mitigates fluoride-induced nephrotoxicity by inhibiting ROS-mediated lysosomal membrane permeabilization and the GSDME-HMGB1 axis involved in pyroptosis and inflammation.

Fluoride is known to induce nephrotoxicity; however, the underlying mechanisms remain incompletely understood. Therefore, this study aims to explore the roles and mechanisms of lysosomal membrane permeabilization (LMP) and the GSDME/HMGB1 axis in fluoride-induced nephrotoxicity and the protective effects of rutin. Rutin, a naturally occurring flavonoid compound known for its antioxidative and anti-inflammatory properties, is primarily mediated by inhibiting oxidative stress and reducing proinflammatory markers. To that end, we established in vivo and in vitro models. In the in vivo study, rats were exposed to sodium fluoride (NaF) throughout pregnancy and up until 2 months after birth. In parallel, we employed in vitro models using HK-2 cells treated with NaF, n-acetyl-L-cysteine (NAC), or rutin. We assessed lysosomal permeability through immunofluorescence and analyzed relevant protein expression via western blotting. Our findings showed that NaF exposure increased ROS levels, resulting in enhanced LMP and increased cathepsin B (CTSB) and D (CTSD) expression. Furthermore, the exposure to NaF resulted in the upregulation of cleaved PARP1, cleaved caspase-3, GSDME-N, and HMGB1 expressions, indicating cell death and inflammation-induced renal damage. Rutin mitigates fluoride-induced nephrotoxicity by suppressing ROS-mediated LMP and the GSDME/HMGB1 axis, ultimately preventing fluoride-induced renal toxicity occurrence and development. In conclusion, our findings suggest that NaF induces renal damage through ROS-mediated activation of LMP and the GSDME/HMGB1 axis, leading to pyroptosis and inflammation. Rutin, a natural antioxidative and anti-inflammatory dietary supplement, offers a novel approach to prevent and treat fluoride-induced nephrotoxicity.