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关键词： Peptides and proteins   Genetics   Protein dynamics   Rodent models   Inhibition   Oxidative stress  

摘要： The herbicide paraquat (PQ) induces hippocampal neuronal cell loss and cognitive dysfunction after one and repeated treatment. All the mechanisms involved in these effects are not well understood. Single and repeated PQ treatment increased A beta and tau protein levels, through HSP70 and TFEB downregulation and proteasome 20S inhibition, producing cell death in primary hippocampal neurons associated with cognitive decline. Our results reveal the mechanisms through which PQ could induce the accumulation of abnormal proteins and neurodegeneration that could originate the cognitive decline produced by it and could help managing its degenerative effects.

摘要： Primary Sjogren's syndrome (pSS) is an autoimmune disease that invades lacrimal glands, salivary glands, and other exocrine glands, but its pathogenic mechanism is still unclear. CD4(+)CD8(+) double-positive T (DPT) cells have been discovered in recent years to play an important role in autoimmune diseases and viral infections, but the frequency and significance of DPT in primary Sjogren's syndrome are still unclear. This study detected the frequency of DPT in the peripheral blood of patients with pSS and detected the clinical indicators and cytokines in patients. We then analyzed the correlation between DPT and clinical indicators, cytokines, and disease activity scores. The results showed that the peripheral DPT frequency of pSS patients was significantly higher than that of healthy controls. The peripheral DPT frequency was negatively correlated with ESR, IgA, and IgG, and peripheral DPT frequency was positively correlated with anti-inflammatory cytokine IL-10. Analysis of DPT and pSS disease activity scores found that DPT frequency had a negative correlation with ESSDAI and SSDAI. This study suggests that peripheral DPT may play a protective role in pSS. The frequency of peripheral DPT cells can be used as an indicator for disease activity. Regulating the expression of peripheral DPT cells is expected to become a new strategy for treatment of pSS.

关键词： Bisphenol A   4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene   Neurotoxicity   Apoptosis   Mitochondria   ER stress   ERK1/2   Akt  

摘要： Bisphenol A (BPA) is recognized as a harmful pollutant in the worldwide. Growing studies have reported that BPA can cause adverse effects and diseases in human, and link to a potential risk factor for development of neurodegenerative diseases (NDs). 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which generated in the mammalian liver after BPA exposure, is a major active metabolite of BPA. MBP has been suggested to exert greater toxicity than BPA. However, the molecular mechanism of MBP on the neuronal cytotoxicity remains unclear. In this study, MBP exposure significantly reduced Neuro-2a cell viability and induced apoptotic events that MBP (5-15 mu M) exhibited greater neuronal cytotoxicity than BPA (50-100 mu M). The mitochondria-dependent apoptotic signals including the decrease in mitochondrial membrane potential (MMP) and the increase in cytosolic apoptosis-induced factor (AIF), cytochrome c release, and Bax protein expression were involved in MBP (10 mu M)-induced Neuro-2a cell death. Exposure of Neuro-2a cells to MBP (10 mu M) also triggered endoplasmic reticulum (ER) stress through the induction of several key molecules including glucose-regulated protein (GRP)78, C/EBP homologous protein (CHOP), X-box binding protein (XBP)-1, protein kinase R-like ER kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2 alpha), inositol-requiring enzyme(IRE)-1, activation transcription factor(AFT)4 and ATF6, and caspase-12. Pretreatment with 4-PBA (an ER stress inhibitor) and specific siRNAs for GRP78, CHOP, and XBP-1 significantly suppressed the expression of these ER stress-related proteins and the activation of caspase-12/-3/-7 in MBP-exposed Neuro-2a cells. Furthermore, MBP (10 mu M) exposure dramatically increased the activation of extracellular regulated protein (ERK)1/2 and decreased Akt phosphorylation. Pretreatment with PD98059 (an ERK1/2 inhibitor) and transfection with the overexpression of activation of Akt1 (myr-Akt1) effectively suppressed MBP-induced