Neurotoxicity of manganese via ferroptosis induced by redox imbalance and iron overload.

Manganese (Mn) is an essential trace element for maintaining bodily functions. Excessive exposure to Mn can pose serious health risks to humans and animals, particularly to the nervous system. While Mn has been implicated as a neurotoxin, the exact mechanism of its toxicity remains unclear. Ferroptosis is a form of programmed cell death that results from iron-dependent lipid peroxidation. It plays a role in various physiological and pathological cellular processes and may be closely related to Mn-induced neurotoxicity. However, the mechanism of ferroptosis in Mn-induced neurotoxicity has not been thoroughly investigated. Therefore, this study aims to investigate the role and mechanism of ferroptosis in Mn-induced neurotoxicity. Using bioinformatics, we identified significant changes in genes associated with ferroptosis in Mn-exposed animal and cellular models. We then evaluated the role of ferroptosis in Mn-induced neurotoxicity at both the animal and cellular levels. Our findings suggest that Mn exposure causes weight loss and nervous system damage in mice. In vitro and in vivo experiments have shown that exposure to Mn increases malondialdehyde, reactive oxygen species, and ferrous iron, while decreasing glutathione and adenosine triphosphate. These findings suggest that Mn exposure leads to a significant increase in lipid peroxidation and disrupts iron metabolism, resulting in oxidative stress injury and ferroptosis. Furthermore, we assessed the expression levels of proteins and mRNAs related to ferroptosis, confirming its significant involvement in Mn-induced neurotoxicity.

Bone Marrow Mesenchymal Stem Cell Extracellular Vesicle-derived miR-27b- 3p activates the Wnt/Β-catenin Pathway by Targeting SMAD4 and Aggravates Hepatic Ischemia-reperfusion Injury.

BACKGROUND: To investigate the roles of extracellular vesicles (EVs) secreted from bone marrow mesenchymal stem cells (BMSCs) and miR-27 (highly expressed in BMSC EVs) in hepatic ischemia‒ reperfusion injury (HIRI). APPROACHES AND RESULTS: We constructed a HIRI mouse model and pretreated it with an injection of agomir-miR-27-3p, agomir-NC, BMSC-EVs or control normal PBS into the abdominal cavity. Compared with the HIRI group, HIRI mice preinjected with BMSC-EVs had significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and alleviated liver necrosis (P<0.05). However, compared with HIRI+NC mice, HIRI+miR-27b mice had significantly increased ALT and AST levels, aggravated liver necrosis, and increased apoptosis-related protein expression (P<0.05). The proliferation and apoptosis of AML-12 cells transfected with miR-27 were significantly higher than the proliferation and apoptosis of AML-12 cells in the mimic NC group (P<0.01) after hypoxia induction. SMAD4 was proven to be a miR-27 target gene. Furthermore, compared to HIRI+NC mice, HIRI+miR-27 mice displayed extremely reduced SMAD4 expression and increased levels of wnt1, ß-catenin, c-Myc, and Cyclin D1. CONCLUSION: Our findings reveal the role and mechanism of miR-27 in HIRI and provide novel insights for the prevention and treatment of HIRI; for example, EVs derived from BMSCs transfected with antimiR- 27 might demonstrate better protection against HIRI.

[Effect of High-Concentration Uric Acid on Nitric Oxide].

Uric acid (UA) is the final product of purine metabolism in human body,and its metabolic disorder will induce hyperuricemia (HUA).The occurrence and development of HUA are associated with a variety of pathological mechanisms such as oxidative stress injury,activation of inflammatory cytokines,and activation of renin-angiotensin-aldosterone system.These mechanisms directly or indirectly affect the bioavailability of endogenous nitric oxide (NO).The decrease in NO bioavailability is common in the diseases with high concentration of UA as an independent risk factor.In this review,we summarize the mechanisms by which high concentrations of UA affect the endogenous NO bioavailability,with a focus on the mechanisms of high-concentration UA in decreasing the synthesis and/or increasing the consumption of NO.This review aims to provide references for alleviating the multisystem symptoms and improving the prognosis of HUA,and lay a theoretical foundation for in-depth study of the correlations between HUA and other metabolic diseases.

BMSC-exosomes miR-25-3p Regulates the p53 Signaling Pathway Through PTEN to Inhibit Cell Apoptosis and Ameliorate Liver Ischemia‒reperfusion Injury.

BACKGROUND: Hepatic ischemia‒reperfusion injury (HIRI) is a pathological phenomenon during liver surgery, and bone marrow-mesenchymal stem cell (BMSC) exosomes (BMSC-Exos) regulate cell apoptosis and reduce ischemia‒reperfusion injury. We aimed to investigate the roles of BMSC-Exos and miR-25b-3p (enriched in BMSC-Exos) in HIRI and elucidate the underlying mechanisms. APPROACHES AND RESULTS: An HIRI mouse model was constructed and preinjected with BMSC-Exos, agomir-miR-25, agomir-miR-NC, or PBS via the tail vein. Compared with mice with HIRI, mice with HIRI preinjected with BMSC-Exos had significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and alleviated liver necrosis (P < 0.05). Quantitative hepatic transcriptomics showed that mice with HIRI preinjected with BMSC-Exos exhibited increased cell division, hematopoietic or lymphoid organ development and metabolic processes. miRNA sequencing of BMSC-Exos revealed that miR-25, which is related to I/R injury, was enriched in the exosomes. Compared with HIRI + NC mice, HIRI + miR-25b-3p mice had significantly increased miR-25b-3p expression, decreased ALT/AST levels and apoptosis-related protein expression (P < 0.05), and alleviated liver necrosis. The proliferation of AML-12 cells transfected with miR-25b-3p was significantly higher than that in the mimic NC group (P < 0.01) after hypoxia induction, and the apoptosis rate of cells was significantly lower than that in the NC group (P < 0.01). PTEN was identified as a miR-25b-3p target gene. PTEN expression was significantly diminished in miR-25b-3p-transfected AML12 cells (P < 0.05). HIRI + agomir-miR-25 mice displayed reduced PTEN expression and decreased p53 and cleaved caspase 3 levels compared to HIRI + NC mice. CONCLUSIONS: We revealed the roles and underlying mechanisms of BMSC-Exos and miR-25 in HIRI, contributing to the prevention and treatment of HIRI.