Human endogenous retroviruses(HERVs)are remnants of retroviral infections in human germline cells from millions of years ago.Among these,ERVW-1(also known as HERV-W-ENV,ERVWE1,or ENVW)encodes the envelope protein of t...Human endogenous retroviruses(HERVs)are remnants of retroviral infections in human germline cells from millions of years ago.Among these,ERVW-1(also known as HERV-W-ENV,ERVWE1,or ENVW)encodes the envelope protein of the HERV-W family,which contributes to the pathophysiology of schizophrenia.Additionally,neuropathological studies have revealed cell death and disruption of iron homeostasis in the brains of individuals with schizophrenia.Here,our bioinformatics analysis showed that differentially expressed genes in the human prefrontal cortex RNA microarray dataset(GSE53987)were mainly related to ferroptosis and its associated pathways.Clinical data demonstrated significantly lower expression levels of ferroptosis-related genes,particularly Glutathione peroxidase 4(GPX4)and solute carrier family 3 member 2(SLC3A2),in schizophrenia patients compared to normal controls.Further in-depth analyses revealed a significant negative correlation between ERVW-1 expression and the levels of GPX4/SLC3A2 in schizophrenia.Studies indicated that ERVW-1 increased iron levels,malondialdehyde(MDA),and transferrin receptor protein 1(TFR1)expression while decreasing glutathione(GSH)levels and triggering the loss of mitochondrial membrane potential,suggesting that ERVW-1 can induce ferroptosis.Ongoing research has shown that ERVW-1 reduced the expression of GPX4 and SLC3A2 by inhibiting their promoter activities.Moreover,Ferrostatin-1(Fer-1),the ferroptosis inhibitor,reversed the iron accumulation and mitochondrial membrane potential loss,as well as restored the expressions of ferroptosis markers GSH,MDA,and TFR1 induced by ERVW-1.In conclusion,ERVW-1 could promote ferroptosis by downregulating the expression of GPX4 and SLC3A2,revealing a novel mechanism by which ERVW-1 contributes to neuronal cell death in schizophrenia.展开更多
Objective: To evaluate the antioxidation of dihydrobiopterin reductase and to explore the effect of A278C mutation of the quinoid dihydropteridine reductase(QDPR) gene on its antioxidant activity. Methods: First, plas...Objective: To evaluate the antioxidation of dihydrobiopterin reductase and to explore the effect of A278C mutation of the quinoid dihydropteridine reductase(QDPR) gene on its antioxidant activity. Methods: First, plasmids with different genes(wild and mutant QDPR) were constructed. After gene sequencing, they were transfected into human kidney cells(HEK293T). Then, the intracellular production of reactive oxygen species(ROS) and tetrahydrobiopterin(BH4) was detected after cells were harvested. Activations of nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4), glutathione peroxidase 3(GPX3), and superoxide dismutase 1(SOD1) were analyzed to observe the oxidative stress after transfection. The expression of the neuronal nitric oxide synthase(n NOS) gene was analyzed by semiquantitative reverse-transcription polymerase chain reaction(RT-PCR). We also detected the activation of transforming growth factor β1(TGF-β1) by enzyme-linked immunosorbent assay(ELISA) to observe the connection of TGF-β1 and oxidative stress. Results: The exogenous wild-type QDPR significantly decreased the expression of n NOS, NOX4, and TGF-β1 and induced the expression of SOD1 and GPX3, but the mutated QDPR lost this function and resulted in excessive ROS production. Our data also suggested that the influence on the level of BH4 had no significant difference between mutated and the wild-type QDPR transfection. Conclusions: Wild-type QDPR played an important role in protecting against oxidative stress, but mutant QDPR failed to have these beneficial effects.展开更多
Numerous theories of how and why aging occurs have been postulated but a definitive comprehensive explanation remains elusive. Attempts to unravel genetic details of aging resulted in the identification of a yeast gen...Numerous theories of how and why aging occurs have been postulated but a definitive comprehensive explanation remains elusive. Attempts to unravel genetic details of aging resulted in the identification of a yeast gene known as Sir2 as a modulator of life span. Identification and characterization of mammalian Sir2 homologs followed and has catapulted aging research to exciting new levels. This review begins with basic definitions of aging and then describes some of the most common theories of the aging process. The review presents information related to the initial discovery of the Sirtuins and summarizes some of the recent advances in defining roles for Sirtuin family members. SIRT6 is discussed in greater detail because it is one of the best characterized of the mammalian Sirtuins and seems to be one of the most important in the aging process and metabolic regulation.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82272321 and 81971943)Fundamental Research Funds for the Central Universities(2042023kf0230)the Stanley Foundation from the Stanley Medical Research Institute(SMRI),United States(No.06R-1366).
文摘Human endogenous retroviruses(HERVs)are remnants of retroviral infections in human germline cells from millions of years ago.Among these,ERVW-1(also known as HERV-W-ENV,ERVWE1,or ENVW)encodes the envelope protein of the HERV-W family,which contributes to the pathophysiology of schizophrenia.Additionally,neuropathological studies have revealed cell death and disruption of iron homeostasis in the brains of individuals with schizophrenia.Here,our bioinformatics analysis showed that differentially expressed genes in the human prefrontal cortex RNA microarray dataset(GSE53987)were mainly related to ferroptosis and its associated pathways.Clinical data demonstrated significantly lower expression levels of ferroptosis-related genes,particularly Glutathione peroxidase 4(GPX4)and solute carrier family 3 member 2(SLC3A2),in schizophrenia patients compared to normal controls.Further in-depth analyses revealed a significant negative correlation between ERVW-1 expression and the levels of GPX4/SLC3A2 in schizophrenia.Studies indicated that ERVW-1 increased iron levels,malondialdehyde(MDA),and transferrin receptor protein 1(TFR1)expression while decreasing glutathione(GSH)levels and triggering the loss of mitochondrial membrane potential,suggesting that ERVW-1 can induce ferroptosis.Ongoing research has shown that ERVW-1 reduced the expression of GPX4 and SLC3A2 by inhibiting their promoter activities.Moreover,Ferrostatin-1(Fer-1),the ferroptosis inhibitor,reversed the iron accumulation and mitochondrial membrane potential loss,as well as restored the expressions of ferroptosis markers GSH,MDA,and TFR1 induced by ERVW-1.In conclusion,ERVW-1 could promote ferroptosis by downregulating the expression of GPX4 and SLC3A2,revealing a novel mechanism by which ERVW-1 contributes to neuronal cell death in schizophrenia.
基金supported by the National Natural Science Foundation of China(No.81130066)the International Cooperation and Exchanges of the National Natural Science Foundation of China(No.81620108031)
文摘Objective: To evaluate the antioxidation of dihydrobiopterin reductase and to explore the effect of A278C mutation of the quinoid dihydropteridine reductase(QDPR) gene on its antioxidant activity. Methods: First, plasmids with different genes(wild and mutant QDPR) were constructed. After gene sequencing, they were transfected into human kidney cells(HEK293T). Then, the intracellular production of reactive oxygen species(ROS) and tetrahydrobiopterin(BH4) was detected after cells were harvested. Activations of nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4), glutathione peroxidase 3(GPX3), and superoxide dismutase 1(SOD1) were analyzed to observe the oxidative stress after transfection. The expression of the neuronal nitric oxide synthase(n NOS) gene was analyzed by semiquantitative reverse-transcription polymerase chain reaction(RT-PCR). We also detected the activation of transforming growth factor β1(TGF-β1) by enzyme-linked immunosorbent assay(ELISA) to observe the connection of TGF-β1 and oxidative stress. Results: The exogenous wild-type QDPR significantly decreased the expression of n NOS, NOX4, and TGF-β1 and induced the expression of SOD1 and GPX3, but the mutated QDPR lost this function and resulted in excessive ROS production. Our data also suggested that the influence on the level of BH4 had no significant difference between mutated and the wild-type QDPR transfection. Conclusions: Wild-type QDPR played an important role in protecting against oxidative stress, but mutant QDPR failed to have these beneficial effects.
文摘Numerous theories of how and why aging occurs have been postulated but a definitive comprehensive explanation remains elusive. Attempts to unravel genetic details of aging resulted in the identification of a yeast gene known as Sir2 as a modulator of life span. Identification and characterization of mammalian Sir2 homologs followed and has catapulted aging research to exciting new levels. This review begins with basic definitions of aging and then describes some of the most common theories of the aging process. The review presents information related to the initial discovery of the Sirtuins and summarizes some of the recent advances in defining roles for Sirtuin family members. SIRT6 is discussed in greater detail because it is one of the best characterized of the mammalian Sirtuins and seems to be one of the most important in the aging process and metabolic regulation.
