Background The insecticide exposure has been linked to Parkinson's disease (PD). In the present study, we used a most widely used cell line in study of PD, the SH‐SY5Y cells, to investigate mechanisms of chlorpyrifos (CPF) induced cell toxicity and the possible roles of cell pyroptosis and oxidative stress in SH‐SY5Y cells, as well as role of miR‐181/SIRT1/PGC‐1α/Nrf2 signaling pathway in this process. Methods SH‐SY5Y cells were treated with different concentrations of CPF. Cell viability was measured using CCK‐8 assay. Cell pyroptosis was determined by immunofluorescence of caspase‐1 and TUNEL assay. The miR‐181 (has‐miR‐181‐5p) level was determined by qRT‐PCR. Expression of SIRT1, PGC‐1α, Nrf2, and pyroptosis related proteins NLRP3, caspase‐1, IL‐1β, and IL‐18 was determined by both qRT‐PCR and Western blotting. Results Cell viability was found to be decreased with the increased CPF concentrations. The pyroptosis related proteins, ROS levels, as well as level of caspase‐1 and the TUNEL positive cells were all significantly up‐regulated by CPF. Meanwhile, expression of miR‐181 and pyroptosis proteins was also enhanced, while the SIRT1/PGC‐1α/Nrf2 signaling was inhibited by CPF. Knockdown of Nrf2 significantly up‐regulated the expression of pyroptosis related proteins, ROS level, caspase‐1, and the TUNEL positive cells, while over‐expression of Nrf2 resulted in opposite results. The expression of PGC‐1α and Nrf2 was significantly down‐regulated when SIRT1 was inhibited, while over‐expressed SIRT1 led to increased PGC‐1α and Nrf2 levels. Besides, miR‐181 promoted the CPF induced activation of pyroptosis and oxidative stress, as well as down‐regulated SIRT1/PGC‐1α/Nrf2 signaling, while inhibition of miR‐181 led to opposite results. Conclusions Chlorpyrifos could inhibit cell proliferation, activate cell pyroptosis and increase susceptibility on oxidative stress‐induced toxicity by elevating miR‐181 through down‐regulation of the SIRT1/PGC‐1α/Nrf2 pathway in human neuroblastoma SH‐SY5Y cells. This study might give deeper insights for mechanisms of CPF induced toxicity and might give some novel research targets for PD treatment.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death in neonates with no effective treatments. Recent advancements in hydrogen (H2) gas offer a promising therapeutic approach for ischemia reperfusion injury; however, the impact of this approach for HIE remains a subject of debate. We assessed the therapeutic effects of H2 gas on HIE and the underlying molecular mechanisms in a rat model of neonatal hypoxic-ischemic brain injury (HIBI). H2 inhalation significantly attenuated neuronal injury and effectively improved early neurological outcomes in neonatal HIBI rats as well as learning and memory in adults. This protective effect was associated with initiation time and duration of sustained H2 inhalation. Furthermore, H2 inhalation reduced the expression of Bcl-2-associated X protein (BAX) and caspase-3 while promoting the expression of Bcl-2, nuclear factor erythroid-2-related factor 2, and heme oxygenase-1 (HO-1). H2 activated extracellular signal-regulated kinase and c-Jun N-terminal protein kinase and dephosphorylated p38 mitogen-activated protein kinase (MAPK) in oxygen-glucose deprivation/reperfusion (OGD/R) nerve growth factor-differentiated PC12 cells. Inhibitors of MAPKs blocked H2-induced HO-1 expression. HO-1 small interfering RNA decreased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and sirtuin 1 (SIRT1) and reversed the protectivity of H2 against OGD/R-induced cell death. These findings suggest that H2 augments cellular antioxidant defense capacity through activation of MAPK signaling pathways, leading to HO-1 expression and subsequent upregulation of PGC-1α and SIRT-1 expression. Thus, upregulation protects NGF-differentiated PC12 cells from OGD/R-induced oxidative cytotoxicity. In conclusion, H2 inhalation exerted protective effects on neonatal rats with HIBI. Early initiation and prolonged H2 inhalation had better protective effects on HIBI. These effects of H2 may be related to antioxidant, antiapoptotic, and anti-inflammatory responses. HO-1 plays an important role in H2-mediated protection through the MAPK/HO-1/PGC-1α pathway. Our results support further assessment of H2 as a potential therapeutic for neurological conditions in which oxidative stress and apoptosis are implicated.
Introduction:Major depressive disorder (MDD) is a mental disorder caused by the combination of genetic, environmental, and psychological factors. Over the years, a number of genes potentially associated with MDD have been identified. However, in many cases, the role of these genes and their relationship in the etiology and development of MDD remains unclear. Under such situation, a systems biology approach focusing on the function correlation and interaction of the candidate genes in the context of MDD will provide useful information on exploring the molecular mechanisms underlying the disease. Methods:We collected genes potentially related to MDD by screening the human genetic studies deposited in PubMed (https ://www.ncbi.nlm.nih.gov/pubmed). The main biological themes within the genes were explored by function and pathway enrichment analysis.Then, the interaction of genes was analyzed in the context of protein-protein interaction network and a MDD-specific network was built by Steiner minimal tree algorithm. Results:We collected 255 candidate genes reported to be associated with MDD from available publications. Functional analysis revealed that biological processes and biochemical pathways related to neuronal development, endocrine, cell growth and/or survivals, and immunology were enriched in these genes. The pathways could be largely grouped into three modules involved in biological procedures related to nervous system, the immune system, and the endocrine system, respectively. From the MDD-specific network, 35 novel genes potentially associated with the disease were identified. Conclusion:By means of network-and pathway-based methods, we explored the molecular mechanism underlying the pathogenesis of MDD at a systems biology level. Results from our work could provide valuable clues for understanding the molecular features of MDD. K E Y W O R D Smajor depressive disorder, network analysis, pathway cross talk 2 of 16 | FAN et Al.
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