To investigate whether single nucleotide polymorphisms in maf protein K (MAFK), which encodes the MAFK, lead to increased susceptibility to ulcerative colitis in the Japanese population. METHODSThis case control study...To investigate whether single nucleotide polymorphisms in maf protein K (MAFK), which encodes the MAFK, lead to increased susceptibility to ulcerative colitis in the Japanese population. METHODSThis case control study examined the associations between MAFK single nucleotide polymorphisms (rs4268033 G>A, rs3735656 T>C and rs10226620 C>T) and ulcerative colitis susceptibility in 174 patients with ulcerative colitis (UC) cases, and 748 subjects without no lower abdominal symptoms, diarrhea or hematochezia (controls). In addition, as the second controls, we set 360 subjects, who have an irregular bowel movement without abnormal lower endoscopic findings (IBM controls). RESULTSThe genotype frequency of rs4268033 AA and allelic frequency of the rs4268033A allele were significantly higher in the UC cases than in both controls (P = 0.0005 and < 0.0001, P = 0.015 and 0.0027 vs controls and IBM controls, respectively). Logistic regression analysis after adjustment for age and gender showed that the rs4268033 AA and rs3735656 CC genotypes were significantly associated with susceptibility to UC development (OR = 2.63, 95%CI: 1.61-4.30, P = 0.0001 and OR = 1.81; 95%CI: 1.12-2.94, P = 0.015, respectively). Similar findings were observed by the comparison with IBM controls. In addition, the rs4268033 AA genotype was significantly associated with all phenotypes of UC except early onset. There was no significant association between rs10226620 and ulcerative colitis. CONCLUSIONOur results provide the first evidence that MAFK genetic polymorphisms are significantly associated with susceptibility to UC development. In particular, rs4268033 is closely associated with an increased risk for the development of UC.展开更多
Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase,followed by partial self-recovery,and ultimately an equilibrium stat...Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase,followed by partial self-recovery,and ultimately an equilibrium state of neurological dysfunction.Ferroptosis is a crucial pathological process in many neurodegenerative diseases;however,its role in chro nic compressive spinal cord injury remains unclear.In this study,we established a chronic compressive spinal cord injury rat model,which displayed its most severe behavioral and electrophysiological dysfunction at 4 wee ks and partial recovery at 8 weeks after compression.Bulk RNA sequencing data identified enriched functional pathways,including ferroptosis,presynapse,and postsynaptic membrane activity at both 4 and 8 wee ks following chro nic compressive spinal co rd injury.Tra nsmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression.Ferro ptosis activity was negatively correlated with behavioral score.Immunofluorescence,quantitative polymerase chain reaction,and western blotting showed that expression of the anti-ferroptosis molecules,glutathione peroxidase 4(GPX4) and MAF BZIP transcription factor G(MafG),in neuro ns was suppressed at 4 weeks and upregulated at 8 weeks following spinal co rd compression.There was a positive correlation between the expression of these two molecules,suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury.In conclusion,our study determined the genome-wide expression profile and fe rroptosis activity of a consistently compressed spinal cord at different time points.The results showed that anti-fe rroptosis genes,specifically GPX4 and MafG,may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury.These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.展开更多
Small Maf转录因子(sMafs),即MafF、MafG、MafK,一组含有碱性亮氨酸拉链结构的高度同源性蛋白,由于其自身缺乏转录激活域,在体内主要与Cap‘n’Collar蛋白及Bach蛋白形成异源二聚体,以及自身之间形成同源二聚体发挥作用。氧化应激和炎...Small Maf转录因子(sMafs),即MafF、MafG、MafK,一组含有碱性亮氨酸拉链结构的高度同源性蛋白,由于其自身缺乏转录激活域,在体内主要与Cap‘n’Collar蛋白及Bach蛋白形成异源二聚体,以及自身之间形成同源二聚体发挥作用。氧化应激和炎症反应是神经系统疾病中的共同特征,并在神经损伤、神经认知、神经发育及其他神经功能中具有损伤性的作用。sMafs在氧化应激和炎症反应中起着保护作用,本文现就sMafs在神经系统疾病中的抗氧化、抗炎以及其在神经损伤、认知、发育及其他的作用机制作一综述。展开更多
Glutathione(GSH),a tripeptide that is present in all mammalian tissues,is especially highly concentrated in the liver.GSH synthesis occurs via two adenosine triphosphate(ATP)-requiring enzymatic steps:the first is rat...Glutathione(GSH),a tripeptide that is present in all mammalian tissues,is especially highly concentrated in the liver.GSH synthesis occurs via two adenosine triphosphate(ATP)-requiring enzymatic steps:the first is rate-limiting,catalyzed by glutamate-cysteine ligase,generates g-glutamylcysteine from gluta-mate and cysteine;the second is catalyzed by GSH synthetase,generates GSH from g-glutamylcysteine and glycine.GSH defends against oxidative stress,participates in detoxification of xenobiotics,de-termines the redox status of the cell,and regulates vital processes such as growth and apoptosis.Hepatic GSH plays a central role in the interorgan GSH homeostasis because sinusoidal efflux of hepatic GSH determines plasma GSH level.In liver diseases GSH homeostasis is perturbed by multiple mechanisms.Hepatic GSH biosynthesis is impaired in cholestatic liver injury,endotoxemia,and fibrotic injury largely because the expression of the GSH synthetic enzymes falls.Lower hepatic GSH level further exacerbates and perpetuates ongoing liver injury.However,in hepatocellular carcinoma GSH synthetic enzymes are upregulated and this may play a role in chemoresistance.This review focuses on the current under-standing of hepatic GSH synthesis in health and disease.展开更多
文摘To investigate whether single nucleotide polymorphisms in maf protein K (MAFK), which encodes the MAFK, lead to increased susceptibility to ulcerative colitis in the Japanese population. METHODSThis case control study examined the associations between MAFK single nucleotide polymorphisms (rs4268033 G>A, rs3735656 T>C and rs10226620 C>T) and ulcerative colitis susceptibility in 174 patients with ulcerative colitis (UC) cases, and 748 subjects without no lower abdominal symptoms, diarrhea or hematochezia (controls). In addition, as the second controls, we set 360 subjects, who have an irregular bowel movement without abnormal lower endoscopic findings (IBM controls). RESULTSThe genotype frequency of rs4268033 AA and allelic frequency of the rs4268033A allele were significantly higher in the UC cases than in both controls (P = 0.0005 and < 0.0001, P = 0.015 and 0.0027 vs controls and IBM controls, respectively). Logistic regression analysis after adjustment for age and gender showed that the rs4268033 AA and rs3735656 CC genotypes were significantly associated with susceptibility to UC development (OR = 2.63, 95%CI: 1.61-4.30, P = 0.0001 and OR = 1.81; 95%CI: 1.12-2.94, P = 0.015, respectively). Similar findings were observed by the comparison with IBM controls. In addition, the rs4268033 AA genotype was significantly associated with all phenotypes of UC except early onset. There was no significant association between rs10226620 and ulcerative colitis. CONCLUSIONOur results provide the first evidence that MAFK genetic polymorphisms are significantly associated with susceptibility to UC development. In particular, rs4268033 is closely associated with an increased risk for the development of UC.
文摘Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase,followed by partial self-recovery,and ultimately an equilibrium state of neurological dysfunction.Ferroptosis is a crucial pathological process in many neurodegenerative diseases;however,its role in chro nic compressive spinal cord injury remains unclear.In this study,we established a chronic compressive spinal cord injury rat model,which displayed its most severe behavioral and electrophysiological dysfunction at 4 wee ks and partial recovery at 8 weeks after compression.Bulk RNA sequencing data identified enriched functional pathways,including ferroptosis,presynapse,and postsynaptic membrane activity at both 4 and 8 wee ks following chro nic compressive spinal co rd injury.Tra nsmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression.Ferro ptosis activity was negatively correlated with behavioral score.Immunofluorescence,quantitative polymerase chain reaction,and western blotting showed that expression of the anti-ferroptosis molecules,glutathione peroxidase 4(GPX4) and MAF BZIP transcription factor G(MafG),in neuro ns was suppressed at 4 weeks and upregulated at 8 weeks following spinal co rd compression.There was a positive correlation between the expression of these two molecules,suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury.In conclusion,our study determined the genome-wide expression profile and fe rroptosis activity of a consistently compressed spinal cord at different time points.The results showed that anti-fe rroptosis genes,specifically GPX4 and MafG,may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury.These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.
文摘Glutathione(GSH),a tripeptide that is present in all mammalian tissues,is especially highly concentrated in the liver.GSH synthesis occurs via two adenosine triphosphate(ATP)-requiring enzymatic steps:the first is rate-limiting,catalyzed by glutamate-cysteine ligase,generates g-glutamylcysteine from gluta-mate and cysteine;the second is catalyzed by GSH synthetase,generates GSH from g-glutamylcysteine and glycine.GSH defends against oxidative stress,participates in detoxification of xenobiotics,de-termines the redox status of the cell,and regulates vital processes such as growth and apoptosis.Hepatic GSH plays a central role in the interorgan GSH homeostasis because sinusoidal efflux of hepatic GSH determines plasma GSH level.In liver diseases GSH homeostasis is perturbed by multiple mechanisms.Hepatic GSH biosynthesis is impaired in cholestatic liver injury,endotoxemia,and fibrotic injury largely because the expression of the GSH synthetic enzymes falls.Lower hepatic GSH level further exacerbates and perpetuates ongoing liver injury.However,in hepatocellular carcinoma GSH synthetic enzymes are upregulated and this may play a role in chemoresistance.This review focuses on the current under-standing of hepatic GSH synthesis in health and disease.
