glutathione

摘要： Ferroptosis is a recently discovered form of iron-dependent cell death,which occurs during the pathological process of various central nervous system diseases or injuries,including secondary spinal cord injury.Selenium has been shown to promote neurological function recovery after cerebral hemorrhage by inhibiting ferroptosis.However,whether selenium can promote neurological function recovery after spinal cord injury as well as the underlying mechanism remain poorly understood.In this study,we injected sodium selenite(3μL,2.5μM)into the injury site of a rat model of T10 vertebral contusion injury 10 minutes after spinal cord injury modeling.We found that sodium selenite treatment greatly decreased iron concentration and levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal.Furthermore,sodium selenite increased the protein and mRNA expression of specificity protein 1 and glutathione peroxidase 4,promoted the survival of neurons and oligodendrocytes,inhibited the proliferation of astrocytes,and promoted the recovery of locomotive function of rats with spinal cord injury.These findings suggest that sodium selenite can improve the locomotive function of rats with spinal cord injury possibly through the inhibition of ferroptosis via the specificity protein 1/glutathione peroxidase 4 pathway.

摘要： Aim: Glutathione (GSH) is an antioxidant, protecting cell against toxicity of reactive oxygen species (ROS). Data showed that GSH might play roles in malignancy including ovarian cancer (OC), and, thus, we attempted to determine the clinical significance of GSH and effects of erastin (an inhibitor of GSH synthesis) in OC. Methods: OC tissues were taken from 41 OC patients, and cancer-tissue GSH level was measured with GSH Assay Kit. Survival curves were carried out by the Kaplan-Meier method and evaluated using the log-rank test. Multivariable Cox proportional hazard risk regression model was performed to screen the independent factor affecting the prognosis of OC patients. In vitro effect of erastin was studied using OC cell lines. Cell viability, GSH levels and whole (cytosolic and lipid) ROS production were assessed. Results: Patients with high OC-tissue-GSH levels had an apparently lower progression free survival (PFS) and overall survival (OS) compared with those with low GSH levels. The GSH levels were independent factors for predicting the PFS and OS. The basal ROS level was inversely proportional to GSH levels in OC cell lines. The basal GSH levels were important for estimating the sensitivity to erastin. Reduction of intracellular GSH levels increased whole ROS, which caused cell deaths. Conclusions: Data suggested that the GSH levels could be a candidate of prognostic biomarkers and that erastin might be worth studying as a new therapeutic drug in OC.

摘要： A simple and reliable strategy was proposed to engineer the glutathione grafted graphene oxide/ZnO nanocomposite(glutathione-GO/ZnO)as electrode material for the high-performance piroxicam sensor.The prepared glutathione-GO/ZnO nanocomposite was well characterized by X-ray diffraction(XRD),Fourier transform infrared spectrum(FTIR),X-ray photoelectron spectroscopy(XPS),field emission scanning electron microscopy(FE-SEM),cyclic voltammetry(CV),electrochemical impedance spectroscopy(EIS)and differential pulse voltammetry(DPV).The novel nanocomposite modified electrode showed the highest electrocatalytic activity towards piroxicam(oxidation potential is 0.52 V).Under controlled experimental parameters,the proposed sensor exhibited good linear responses to piroxicam concentrations ranging from 0.1 to 500 μM.The detection limit and sensitivity were calculated as 1.8 μM and 0.2 μA/μM·cm^(2),respectively.Moreover,it offered excellent selectivity,reproducibility,and long-term stability and can effectively ignore the interfering candidates commonly existing in the pharmaceutical tablets and human fluids even at a higher concentration.Finally,the reported sensor was successfully employed to the direct determination of piroxicam in practical samples.

摘要： Serine metabolism is becoming more and more important in a variety of cancers.This paper reviews the discovery of serine synthesis pathway and its imbalance in cancer,and the recent research results on serine metabolism in cancer,and also discuss on how serine metabolism plays a role in cancer.

摘要： BACKGROUND Endothelial dysfunction,a hallmark of diabetes,is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications.However,the underlying mechanisms are still not fully understood.Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and irondependent lipid peroxidation.Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases,the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear.AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms.METHODS Human umbilical vein endothelial cells(HUVECs)were treated with high glucose(HG),interleukin-1β(IL-1β),and ferroptosis inhibitor,and then the cell viability,reactive oxygen species(ROS),and ferroptosis-related marker protein were tested.To further determine whether the p53-xCT(the substrate-specific subunit of system Xc-)-glutathione(GSH)axis is involved in HG and IL-1βinduced ferroptosis,HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β.Cell viability,ROS,and ferroptosis-related marker protein were then assessed.In addition,we detected the xCT and p53 expression in the aorta of db/db mice.RESULTS It was found that HG and IL-1βinduced ferroptosis in HUVECs,as evidenced by the protective effect of the ferroptosis inhibitors,Deferoxamine and ferrostatin-1,resulting in increased lipid ROS and decreased cell viability.Mechanistically,activation of the p53-xCT-GSH axis induced by HG and IL-1βenhanced ferroptosis in HUVECs.In addition,a decrease in xCT and the presence of deendothelialized areas were observed in the aortic endothelium of db/db mice.CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.

摘要： BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance.

摘要： Clubroot of Chinese cabbage(Brassica rapa L.ssp.pekinensis),caused by the obligate parasite Plasmodiophora brassicae,accounts for serious yield losses.The aim of our study was to explore the phytohormone levels and metabolome changes in the roots of resistant and susceptible B.rapa genotypes at a late stage of infection,i.e.,28 days post-infection.Both genotypes showed decreased auxin levels after P.brassicae infection except for indole-3-acetic acid.Overall,the susceptible genotype had higher auxin and cytokinin levels after infection,with the exception of trans-zeatin and 3-indolebutyric acid as compared to the resistant genotype.Jasmonic acid levels declined after infection regardless of the genotype.Resistance against clubroot was evident with the increased levels of salicylic acid in the resistant genotype.The susceptible genotype had a higher number of differentially accumulated metabolites(DAMs)(262)than the resistant genotype(238)after infection.Interestingly,132 DAMs were commonly detected in both genotypes when infected with the pathogen,belonging to metabolite classes such as phenolic acids,amino acids,and derivatives,glucosinolates,organic acids,flavonoids,nucleotides and derivatives,and fatty acids.The differential metabolite analysis revealed that metabolites related to amino acid biosynthesis,fatty acid biosynthesis and elongation,glutathione metabolism,and glucosinolate metabolism were highly accumulated in the resistant genotype,suggesting their essential roles in resistance against P.brassicae infection.

摘要： Alterations in the ratio of glutathione(GSH) to glutathione disulfide(GSSG) reveal the cell living state and are associated with a variety of diseases. In this study, an Au NPs grafted nanoporous silicon chip was used for surface assisted laser desorption ionization-mass spectrometry(SALDI-MS) detection of GSH. Due to the bond interaction between thiol of GSH and Au NPs modified on the chip surfaces, GSH could be captured from the complex cellular lysate. Meanwhile, the composite nanostructures of Au NPs grafted porous silicon surface presented good desorption/ionization efficiency for GSH detection. The GSH levels in different tumor cells were successfully detected. Chip-based SALDI-MS was optimized for quantification of intracellular GSH/GSSG ratio changing under drug stimulation in liver tumor cells, GSSG was reduced to GSH by reductant of tris(2-carboxyethyl)phosphine(TCEP) and isotope-labeling GSH was as an internal standard. It was found that the increasing concentration of drug irinotecan and hypoxia culture condition caused the rapid consumption of GSH and a decrease of GSH/GSSG ratio in liver tumor cells. The developed SALDI-MS method provided a convenient way to accurately measure and rapidly monitor cellular GSH value and the ratios of GSH/GSSG.

摘要： Stress, inflammation and Plasminogen activator inhibitor 1 (PAI-1) are key mechanisms throughout the development of aging, constituting a crossroad in the most frequent pathologies that accompany it. Among metabolic processes, obesity, metabolic syndrome and type 2 diabetes mellitus are included and Alzheimer’s disease among the neurodegenerative processes. Stress is a mechanism of defense of the organism against exogenous and endogenous actions called stressors. In the case of low intensity stimuli, the organism responds with actions aimed at a physiological adaptation (Homeostasis). On the other hand, when a high intensity (experimental level) or chronic stimulus (oxidative stress) is repeated, structural and functional changes are observed in different organs with activation of the hypothalamus-pituitary-adrenal axis, the renin angiotensin system and the sympathetic nervous system, stimulating the production of hormones that release cytokines with proin-flammatory/antiinflammatory properties that play an important role in the previously mentioned pathologies, as well as a marked increase in PAI-1, a gene regulated by stress and by cytokines, with manifest action at the origin of thromboembolic disease, so frequent in aging. The objective of this review is to highlight the importance of the binomial stress and PAI-1 in aging and in the pathologies that accompany it. Because PAI-1 is part of the pathology and complications in aging, some authors suggest the study of PAI-1 inhibitors to achieve its physiological levels, as part of the treatment of these diseases.