Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons. Between 12 and 20% of inherited cases and approximately 1-2% of all cases are caused by mutations in the gene encoding dismutase 1 (SOD1). Mutant SOD1 A4V (alanine to valine) induces endoplasmic reticulum (ER) stress, which is increasingly implicated as a pathway to motor neuron degeneration and death in ALS. However, it remains unclear how ER stress is induced by mutant SOD1 A4V. Previous studies have established that it is induced early in pathophysiology and it precedes the formation of mutant SOD1 inclusions. SOD1 contains four cysteine residues, two of which form an intra-subunit disulphide bond involving Cys-57 and Cys-146. The remaining two cysteines, Cys-6 and Cys-111, remain unpaired and have been implicated in mutant SOD1 aggregation. In this study, we examined the relationship between the SOD1 A4V cysteine residues and aggregation, ER stress induction and toxicity. We report here that mutation of Cys-6 and Cys-111 in mutant SOD1 A4V, but not Cys-57 or Cys-146, ameliorates ER stress, inclusion formation and apoptosis in neuronal cell lines. These results imply that protein misfolding, induced by Cys-6 and Cys-111, is required for these pathological events in neuronal cells.Down syndrome (DS) is the most common form of mental disability of genetic etiology. Nondisjunction of chromosome 21 is the leading cause of the syndrome. In general, free trisomy 21 cases originate from missegregation in maternal meiosis. Several reports have suggested an association between genetic variants in genes encoding folate metabolizing enzymes and the predisposition to chromosome missegregation. We have conducted a case-control study of 109 DS case mothers (MDS) and 248 control mothers (CM) to assess the association between DHFR del19bp polymorphism and an increased risk of bearing a DS child. Genomic DNA was extracted from buccal cells, and molecular analysis of DHFR del19pb polymorphism was performed by polymerase chain reaction (PCR). Both MDS and CM allelic and genotypic distributions were in Hardy-Weinberg equilibrium. The frequency of DHFR del19pb-mutated allele was 0.54 in MDS and 0.46 in CM. Overall analysis showed that the mutant allele was borderline associated with DS risk (OR 1.38; 95% CI 1.00-1.89; P = 0.05) and a weak positive association for del/del and/or wt/del genotypes of DHFR del19pb polymorphism compared to homozygous wt/wt genotype was identified (OR = 1.75; 95% CI 1.01-3.03; P = 0.05). When we have analyzed data stratified by age, there is an increased risk of bearing a DS child associated with the polymorphic allele (OR = 1.49; 95% CI 1.03-2.16; P = 0.03), suggesting that DHFR del 19-bp polymorphism could be an independent risk factor for DS in women aged less then 40 years old.Intervertebral disc degeneration (IVDD) is considered to be the fundamental cause of the occurrence and development of lumbar disc herniation (LDH). The degeneration of IVDD is mainly caused by the participation of inflammatory factors. Thus, it is of great significance to analyze the pathogenesis of IVDD, which may guide clinical prevention and treatment of LDH. Our current study aims to identify the role of miR-495-3p in LDH and to further unravel the underlying mechanisms. Results in the current study showed that TNF-α treatment markedly inhibited cell viability of HNPC, increased the IL-1β level, and decreased the mRNA level of miR-495-3p in HNPC in a time-dependent manner.  https://www.selleckchem.com/products/abt-199.html  Up-regulation of miR-495-3p promoted cell proliferation and inhibited inflammation and apoptosis in TNF-α-induced HNPCs. To investigate the underlying molecular mechanism through which miR-495-3p regulates TNF-α-induced inflammation and apoptosis in HNPCs, we explored the possible target gene of miR-495-3p. Bioinformatics analysis indicated that IL5RA, which is an important gene for TNF-α-induced HNPC injury, was also a target gene of miR-495-3p. A luciferase reporter assay was applied to test and verify the direct target association between miR-495-3p and IL5RA. The results discovered that down-regulation of miR-495-3p markedly reversed the anti-apoptosis and anti-inflammation of sh-IL5RA. In short, the present study evaluated the roles of miR-495-3p and IL5RA in IVDD development and progression. All the data indicated that miRNA-495-3p may play a protective role via inhibiting inflammation and apoptosis in human nucleus pulposus cells by targeting IL5RA pathway. Therefore, miRNA-495-3p may be a potential agent for LDH, and our study may provide a novel strategy in LDH treatment.Alzheimer's disease (AD) is a serious neuropathologic disease characterized by aggregation of amyloid-β (Aβ) peptide. Aβ-mediated oxidative stress and neuroinflammation play crucial role in the development of AD. Engeletin is a flavononol glycoside that possesses anti-inflammatory effect. However, the effects of engeletin on AD have not been investigated. In the present study, we investigated the role of engeletin in AD using an in vitro AD model. Murine microglia BV-2 cells were stimulated with Aβ1-42 (5 μM) for 24 h to induce oxidative stress and inflammation. Our results showed that treatment with engeletin suppressed Aβ1-42-induced viability reduction and lactate dehydrogenase (LDH) release in BV-2 cells. Engeletin attenuated Aβ1-42-induced oxidative stress in BV-2 cells, as proved by decreased production of reactive oxygen species (ROS) and malonaldehyde (MDA) and increased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Aβ1-42-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were inhibited by engeletin treatment. Besides, engeletin inhibited Aβ1-42-induced production and mRNA levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6). Engeletin enhanced Aβ1-42-induced activation of Kelch-like ECH-associated protein 1 (Keap1)/nuclear transcription factor E2-related factor 2 (Nrf2) signaling pathway in BV-2 cells. Inhibition of Keap1/Nrf2 signaling pathway reversed the inhibitory effects of engeletin on Aβ1-42-induced oxidative stress and inflammation in BV-2 cells. Taken together, engeletin attenuated Aβ1-42-induced oxidative stress and inflammation in BV-2 cells via regulating the of Keap1/Nrf2 pathway. These findings indicated that engeletin might be served as a therapeutic agent for the treatment of AD.