Vitamin E alleviates pyraclostrobin-induced toxicity in zebrafish (Danio rerio) and its potential mechanisms.

Strobilurin fungicides (SFs) are commonly used in agriculture worldwide and frequently detected in aquatic environments. High toxicity of SFs to aquatic organisms has caused great concerns. To explore whether vitamin E (VE) can relieve the toxicity caused by pyraclostrobin (PY), zebrafish were exposed to PY with or without VE supplementation. When co-exposure with VE (20 µM), the 96 h-LC50 values of PY to zebrafish embryos, adult, and the 24 h-LC50 value of PY to larvae increased from 43.94, 58.36 and 38.16 µg/L to 64.72, 108.62 and 72.78 µg/L, respectively, indicating that VE significantly decreased the toxicity of PY to zebrafish at different life stages. In addition, VE alleviated the deformity symptoms (pericardial edema and brain damage), reduced speed and movement distance, and decreased heart rate caused by 40 µg/L PY in zebrafish larvae. Co-exposure of PY with VE significantly reduced PY-caused larval oxidative stress and immunotoxicity via increasing the activities of superoxide dismutase, catalase and level of glutathione, as well as reducing the malondialdehyde production and the expression levels of Nrf2, Ucp2, IL-8, IFN and CXCL-C1C. Meanwhile, the expression levels of gria4a and cacng4b genes, which were inhibited by PY, were significantly up-regulated after co-exposure of PY with VE. Moreover, co-exposure with VE significantly reversed the increased mitochondrial DNA copies and reduced ATP content caused by PY in larvae, but had no effect on the expression of cox4i1l and activity of complex III that reduced by PY, suggesting VE can partially improve PY-induced mitochondrial dysfunction. In conclusion, the potential mechanisms of VE alleviating PY-induced toxicity may be ascribed to decreasing the oxidative stress level, restoring the functions of heart and nervous system, and improving the immunity and mitochondrial function in zebrafish.

Single-cell analysis reveals the immune heterogeneity and interactions in lungs undergoing hepatic ischemia-reperfusion.

Hepatic ischemia-reperfusion IR (HIR) is an unavoidable pathophysiological process during liver transplantation, resulting in systematic sterile inflammation and remote organ injury. Acute lung injury (ALI) is a serious complication after liver transplantation with high postoperative morbidity and mortality. However, the underlying mechanism is still unclear. To assess the phenotype and plasticity of various cell types in the lung tissue microenvironment after HIR at the single-cell level, single-cell RNA sequencing (scRNA-seq) was performed using the lungs from HIR-induced mice. In our results, we identified 23 cell types in the lungs after HIR and found that this highly complex ecosystem was formed by subpopulations of bone marrow-derived cells that signaled each other and mediated inflammatory responses in different states and different intervals. We described the unique transcriptional profiles of lung cell clusters and discovered two novel cell subtypes (Tspo+Endothelial cells and Vcan+ monocytes), as well as the endothelial cell-immune cell and immune cell-T cell clusters interactome. In addition, we found that S100 calcium binding protein (S100a8/a9), specifically and highly expressed in immune cell clusters of lung tissues and exhibited detrimental effects. Finally, the cellular landscape of the lung tissues after HIR was established, highlighting the heterogeneity and cellular interactions between major immune cells in HIR-induced lungs. Our findings provided new insights into the mechanisms of HIR-induced ALI and offered potential therapeutic target to prevent ALI after liver transplantation.

Dexmedetomidine had neuroprotective effects on hippocampal neuronal cells via targeting lncRNA SHNG16 mediated microRNA-10b-5p/BDNF axis.

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, is a commonly used anesthetic drug in surgical procedures. Previous studies have indicated that DEX exerts neuroprotective effects while the detailed mechanism has not been fully elucidated. Here, we aim to study the role of lncRNA SHNG16 in DEX-induced brain protection and its underlying molecular mechanism. The rats underwent middle cerebral artery occlusion (MCAO) surgery and oxygen-glucose deprivation (OGD)-treated HT22 hippocampal neurons were treated with DEX, respectively. CCK8 was used to evaluate cell viability. sh-SHNG16 as well as miR-10b-5p mimics were transfected into hippocampal neurons to further explore the bio-function of SNHG16 and miR-10b-5p in vitro. Furthermore, the interactions between SHNG16 and miR-10b-5p, miR-10b-5p and BDNF gene were confirmed by dual-luciferase report assay. Our data revealed that DEX attenuated neurological damage of the MCAO rats and also increased the cell viability of the neurons significantly. Besides, expression of SHNG16 and BDNF were both downregulated while miR-10b-5p was upregulated in MCAO brain tissues or OGD treated neurons. DEX inhibited miR-10b-5p expression but increased SHNG16 and BDNF levels with a dosage effect. After transfection with sh-SHNG16 or miR-10b-5p mimics, the expression of BDNF protein was downregulated, accompanied with decreased neuron viability. Dual-luciferase assay showed that SHNG16 targeted on miR-10b-5p, which also could bind directly to the 3'-UTR sites of BDNF and negatively regulate its expression. In conclusion, DEX exerts neuroprotective in ischemic stroke via improving neuron damage, the underlying mechanism may be upregulating SHNG16 and BDNF via sponging miR-10b-5p.

Src is Implicated in Hepatic Ischemia Reperfusion-Induced Hippocampus Injury and Long-Term Cognitive Impairment in Young Mice via NMDA Receptor Subunit 2A Activation.

Hepatic ischemia reperfusion (HIR) has been found to induce hippocampus injury and cognitive dysfunction. The N-methyl-d-aspartate (NMDA) receptor subunit 2A (NR2A) is an important factor mediating excitotoxicity and neurons injury, and autophosphorylation of Src can up-regulate tyrosine phosphorylation of NR2A to improve its activity. However, the role of Src and NR2A in HIR-induced hippocampus injury in young mice remains unknown. In this study, we found that serum biomarkers of brain injury (S100ß and NSE) increased significantly and reached highest after reperfusion of 3 days which had the same trend with the levels of p-Src and p-NR2A. Interactions between Src and NR2A or PSD95 were increased after HIR. Hippocampal neuron apoptosis was increased, and long-term cognitive impairment was found after reperfusion of 1 month. Inhibition of Src and NR2A with PP2 and NVP-AAM077 respectively not only down-regulated the levels of p-Src and p-NR2A, but also ameliorated hippocampal neurons apoptosis and long-term cognitive impairment after HIR. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-6 were increased after reperfusion of 3 days, while PP2 and NVP-AAM077 treatment didn't attenuate the changes. And no difference was found in serum TNF-α, IFN-γ, IL-6 concentrations as well as the levels of Src, p-Src, NR2A, p-NR2A, PSD95 among the four groups after reperfusion of 1 month. In summary, HIR can lead to hippocampus injury and long-term cognitive dysfunction, and Src-PSD95-NR2A pathway plays an important role in the process.