While the Bushen Yizhi Formula can treat Alzheimer’s disease(AD),the yet to be ascertained specific mechanism of action was explored in this work.Methods:Different concentrations of the Bushen Yizhi Formula and amylo...While the Bushen Yizhi Formula can treat Alzheimer’s disease(AD),the yet to be ascertained specific mechanism of action was explored in this work.Methods:Different concentrations of the Bushen Yizhi Formula and amyloid-beta peptide(Aβ)were used to treat rat pheochromocytoma cells(P12)and human neuroblastoma cells(SH-SY5Y).Cell morphological changes were observed to determine the in vitro cell damage.Cell Counting Kit(CCK)-8 assay and flow cytometry were employed to identify cell viability and apoptosis/cell cycle,respectively.Western blotting and immunohistochemistry were employed to measure the expressions of endoplasmic reticulum stress(ERS)-related proteins(GRP78 and CHOP),p-IRE1α,IRE1α,ASK1,p-JNK,JNK,Bax,Bcl-2,XBP-1,and Bim.Fura 2-acetoxymethyl ester(Fura-2/AM)was used to determine the intracellular calcium(Ca^(2+))concentration.Also,an AD model was constructed by injecting Aβinto the CA1 area of the hippocampus in Sprague Dawley rats.AD model rats were gavaged with different concentrations of Bushen Yizhi Formula for 14 consecutive days.The Morris water maze experiment was conducted to test the learning and memory of rats.Hematoxylin&Eosin(H&E)and Terminal-deoxynucleotidyl Transferase(TdT)-mediated dUTP Nick-End Labeling(TUNEL)staining were done to determine histopathological changes in the brain.Results:Bushen Yizhi Formula relieved the Aβ-induced effects including cell injury,decreased viability,increased apoptosis,G0/G1 phase cell cycle arrest,upregulation of GRP78,CHOP,p-IRE1α,p-JNK,Bax,XBP-1 and Bim,as well as down-regulation of Bcl-2.These results were also seen with IRE1αsilencing.While Aβsuppressed the learning and memory abilities of rats,the Bushen Yizhi Formula alleviated these effects of Aβ.Brain nerve cell injury induced by Aβcould also be treated with Bushen Yizhi Formula.Conclusion:Bushen Yizhi Formula could influence ERS through the IRE1αsignaling pathway to achieve its therapeutic effects on AD.展开更多
Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the m...Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.展开更多
Recent findings have implicated inflammatory responses in the central nervous system in a variety of neuropsychiatric and neurodegenerative diseases,and the understanding and control of immunological responses could b...Recent findings have implicated inflammatory responses in the central nervous system in a variety of neuropsychiatric and neurodegenerative diseases,and the understanding and control of immunological responses could be a major factor of future therapeutic strategies for neurological disorders.Microglia,derived from myelogenous cells,respond to a number of stimuli and make immune responses,resulting in a prominent role as cells that act on inflammation in the central nervous system.Fractalkine(FKN or CX3CL1)signaling is an important factor that influences the inflammatory response of microglia.The receptor for FKN,CX3CR1,is usually expressed in microglia in the brain,and therefore the inflammatory response of microglia is modified by FKN.Reportedly,FKN often suppresses inflammatory responses in microglia and activation of its receptor may be effective in the treatment of inflammatory neurological disorders.However,it has also been suggested that inflammatory responses facilitated by FKN signaling aggravate neurological disorders.Thus,further studies are still required to resolve the conflicting interpretation of the protective or deleterious contribution of microglial FKN signaling.Yet notably,regulation of FKN signaling has recently been shown to be beneficial in the treatment of human diseases,although not neurological diseases.In addition,a CX3CR1 inhibitor has been developed and successfully tested in animal models,and it is expected to be in human clinical trials in the future.In this review,I describe the potential therapeutic consideration of microglial CX3CR1 dynamics through altered FKN signaling.展开更多
1-methyl-4-phenylpyridinium ion （MPP^＋） induces endoplasmic reticulum stress and activates caspase-12 in PC12 cells, leading to neuronal apoptosis. However, the underlying molecular mechanism remains unknown. The p...1-methyl-4-phenylpyridinium ion （MPP^＋） induces endoplasmic reticulum stress and activates caspase-12 in PC12 cells, leading to neuronal apoptosis. However, the underlying molecular mechanism remains unknown. The present study investigated the regulatory effects of nerve growth factor （Akt activator） and lithium chloride （glycogen synthase kinase-3β inhibitor） on the endoplasmic reticulum stress signaling pathway. The results revealed that MPP＋ induced expression of Bip and C/EBP homologous protein. The upregulation of Bip and C/EBP homologous protein, as well as the decreased pro-caspase-12 level induced by MPP^＋ were inhibited by pretreatment of the nerve growth factor or lithium chloride. These results suggest that the phosphatidylinositol 3 kinase-Aktglycogen synthase kinase-3β pathway is involved in MPP-induced endoplasmic reticulum stress.展开更多
BACKGROUND： Studies have demonstrated that β-amyloid peptide （Aβ）, a characteristic pathological product of Alzheimer＇s disease （AD）, results in neuronal endoplasmic reticulum stress （ERS）. However, the mech...BACKGROUND： Studies have demonstrated that β-amyloid peptide （Aβ）, a characteristic pathological product of Alzheimer＇s disease （AD）, results in neuronal endoplasmic reticulum stress （ERS）. However, the mechanisms of traditional Chinese medicine against ERS in AD are poorly understood. OBJECTIVE： To measure expression levels of protective proteins （GRP78 and GRP94） of ER molecular partners and pro-apoptotic Caspase-12 ER membrane expression following application of traditional Chinese medicine natural cerebrolysin （NC） to treat Aβ1-40-induced ERS. DESIGN, TIME AND SETTING： A parallel-controlled study was performed at the Institute of Integrated Western and Traditional Chinese Medicine, Shenzhen Hospital of Southern Medical University between September 2006 and November 2008. MATERIALS： Sprague Dawley male rats, 6-8 weeks old, were used to harvest tibial and femoral bone marrow. Isolation and purification of mesenchymal stem cells （MSCs） were established from the whole bone marrow by removing non-adherent cells in primary and passage cultures. Aβ1-40 was provided by Sigma, USA. NC was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. NC was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yinxingye （Ginkgo Leaf） in a proportion of 1 ： 2： 2. Following conventional water extraction technology, an extract （1 ： 20） was prepared. Six adult, male, New Zealand rabbits underwent intragastric administration of NC extract （0.976 g/kg per day） for 1 month to prepare NC-positive serum, and the remaining 6 rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： A total of 500 nmol/L Aβ1-40 was used to establish ERS models of primary cultured MSCs. AD cell models were incubated with different doses of NC-positive serum （2.5%, 5%, and 10%）. MSCs treated with normal blank serum served as normal blank controls. MAIN OUTCOME MEASURES： Reverse transcription-polymerase chain reaction and fluorescent immunocytochemistry were respectively used to measure mRNA and protein expression levels of GRP78, GRP94, and Caspase-12 in MSCs. RESULTS： Following Aβ1-40 exposure, mRNA and protein expression levels of GRP78 and GRP94, as well as Caspase-12, significantly increased （P 〈 0.05）, suggesting successful establishment of ERS models. Following NC-positive serum application, mRNA and protein expression levels of GRP78 and GRP94 in MSCs significantly increased （P 〈 0.05 or P 〈 0.01）. However, mRNA and protein expression levels of Caspase-12 significantly decreased （P 〈 0.05, or P 〈 0.01） compared with the ERS model group. These effects were dose-dependent. CONCLUSION： NC downregulated Caspase-12 expression and upregulated GRP78 and GRP94 expression in MSCs in a dose-dependent manner under the state of Aβ1-40-induced ERS.展开更多
To investigate the effects of oxidative stress on substantia nigra neuronal degeneration and death in patients with Parkinson＇s disease, we treated neuroblastoma cells （SK-N-SH） and glioma cells with Fenton＇s reag...To investigate the effects of oxidative stress on substantia nigra neuronal degeneration and death in patients with Parkinson＇s disease, we treated neuroblastoma cells （SK-N-SH） and glioma cells with Fenton＇s reagent, iron chelating agent, neuromelanin and dopamine melanin. We investigated the changes in expression of nine oxidative stress-related genes and proteins. The levels of mRNAs for heme-oxygenase-1 and glutathione S-transferase-ml were significantly reduced in SK-N-SH cells exposed to oxidative stress, and increased in glial cells treated with deferoxamine. These results revealed that SK-N-SH neurons react sensitively to oxidative stress, which implies different outcomes between these two types of cells in the substantia nigra. Moreover, the influences of neuromelanin and dopamine melanin on cell function are varied, and dopamine melanin is not a good model for neuromelanin.展开更多
设 M 是连通的、可定向的、完备的3维 C~∞黎曼流形,C:M→S^4(1)是从 M 列4维单位球面 S^4(1)中的等距浸入.主曲率 h_1,h_2,h_3满足 h_1=h_2=R(常数).本文证明了:浸入或者是全脐的,或者是无脐点的;若浸入是全脐的.或无脐点且 h_3为常数,...设 M 是连通的、可定向的、完备的3维 C~∞黎曼流形,C:M→S^4(1)是从 M 列4维单位球面 S^4(1)中的等距浸入.主曲率 h_1,h_2,h_3满足 h_1=h_2=R(常数).本文证明了:浸入或者是全脐的,或者是无脐点的;若浸入是全脐的.或无脐点且 h_3为常数,则 M 可完全确定:若 h_3不是常数,则 M 微分同胚于 E^4中环准超环面.展开更多
Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in...Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine （6-OHDA）-induced PD rats, DMT1 with the iron responsive element （IRE, DMTI＋IRE）, but not DMT1 without IRE （DMTI-IRE）, was up- regulated, suggesting that increased DMTI＋IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMTl＋IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein （IRP） 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-indueed DMTI＋IRE up-regulation. Pre- treatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-indueed oxidative stress. Increased DMTI＋IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMTI＋IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in ag- gravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.展开更多
Amyloid beta(Aβ)-induced neurotoxicity and oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease(AD).ZL006 is shown to reduce over-produced nitric oxide and oxidative stress in ischemic...Amyloid beta(Aβ)-induced neurotoxicity and oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease(AD).ZL006 is shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke by interrupting the interaction of neuronal nitric oxide synthase and postsynaptic density protein 95.However,few studies are reported on the role of ZL006 in AD.To investigate whether ZL006 exerted neuroprotective effects in AD,we used Aβ1–42 to treat primary cortical neurons and N2a neuroblastoma cells as an in vitro model of AD.Cortical neurons were incubated with ZL006 or dimethyl sulfoxide for 2 hours and treated with Aβ1–42 or NH3·H2O for another 24 hours.The results of cell counting Kit-8(CCK-8)assay and calcein-acetoxymethylester/propidium iodide staining showed that ZL006 pretreatment rescued the neuronal death induced by Aβ1–42.Fluorescence and western blot assay were used to detect oxidative stress and apoptosis-related proteins in each group of cells.Results showed that ZL006 pretreatment decreased neuronal apoptosis and oxidative stress induced by Aβ1–42.The results of CCK8 assay showed that inhibition of Akt or NF-E2-related factor 2(Nrf2)in cortical neurons abolished the protective effects of ZL006.Moreover,similar results were also observed in N2a neuroblastoma cells.ZL006 inhibited N2a cell death and oxidative stress induced by Aβ1–42,while inhibition of Akt or Nrf2 abolished the protective effect of ZL006.These results demonstrated that ZL006 reduced Aβ1–42-induced neuronal damage and oxidative stress,and the mechanisms might be associated with the activation of Akt/Nrf2/heme oxygenase-1 signaling pathways.展开更多
The mitogen-activated protein kinase（MAPK） signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, transformation and death. Mitogen-activated protein kinase phosp...The mitogen-activated protein kinase（MAPK） signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, transformation and death. Mitogen-activated protein kinase phosphatase 1（MKP1） has an inhibitory effect on the p38 MAPK and JNK pathways, but it is unknown whether it plays a role in Aβ-induced oxidative stress and neuronal inflammation. In this study, PC12 cells were infected with MKP1 sh RNA, MKP1 lentivirus or control lentivirus for 12 hours, and then treated with 0.1, 1, 10 or 100 μM amyloid beta 42（Aβ42）. The cell survival rate was measured using the cell counting kit-8 assay. MKP1, tumor necrosis factor-alpha（TNF-α） and interleukin-1β（IL-1β） m RNA expression levels were analyzed using quantitative real time-polymerase chain reaction. MKP1 and phospho-c-Jun N-terminal kinase（JNK） expression levels were assessed using western blot assay. Reactive oxygen species（ROS） levels were detected using 2′,7′-dichlorofluorescein diacetate. Mitochondrial membrane potential was measured using flow cytometry. Superoxide dismutase activity and malondialdehyde levels were evaluated using the colorimetric method. Lactate dehydrogenase activity was measured using a microplate reader. Caspase-3 expression levels were assessed by enzyme-linked immunosorbent assay. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase d UTP nick end labeling method. MKP1 overexpression inhibited Aβ-induced JNK phosphorylation and the increase in ROS levels. It also suppressed the Aβ-induced increase in TNF-α and IL-1β levels as well as apoptosis in PC12 cells. In contrast, MKP1 knockdown by RNA interference aggravated Aβ-induced oxidative stress, inflammation and cell damage in PC12 cells. Furthermore, the JNK-specific inhibitor SP600125 abolished this effect of MKP1 knockdown on Aβ-induced neurotoxicity. Collectively, these results show that MKP1 mitigates Aβ-induced apoptosis, oxidative stress and neuroinflammation by inhibiting the JNK signaling pathway, thereby playing a neuroprotective role.展开更多
The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurre...The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).展开更多
Because neurons are susceptible to oxidative damage and thioredoxin reductase 1 is extensively distributed in the central nervous system and has antioxidant properties, we speculated that the enzyme may be involved in...Because neurons are susceptible to oxidative damage and thioredoxin reductase 1 is extensively distributed in the central nervous system and has antioxidant properties, we speculated that the enzyme may be involved in the pathogenesis of Parkinson＇s disease. A Parkinson＇s disease model was produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into C57BL/6 mice. Real-time reverse transcription-PCR, western blot analysis and colorimetric assay showed that the levels of thioredoxin reductase 1 mRNA and protein were decreased, along with a significant reduction in thioredoxin reductase activity, in the midbrain of Parkinson＇s disease mice compared with normal mice. Immunohistochemical staining revealed that the number of thioredoxin reductase 1-positive neurons in the substantia nigra pars compacta of Parkinson＇s disease mice was significantly decreased compared with normal mice. These experimental findings suggest that the expression of thioredoxin reductase 1 in the substantia nigra pars compacta of Parkinson＇s disease mice is significantly decreased, and that the enzyme may be associated with disease onset.展开更多
Aim： To examine whether a relationship exists between glutathione S-transferase Mu-1 （GSTM1） gene polymorphism and the susceptibility of sperm and seminal plasma from patients with idiopathic infertility to oxidati...Aim： To examine whether a relationship exists between glutathione S-transferase Mu-1 （GSTM1） gene polymorphism and the susceptibility of sperm and seminal plasma from patients with idiopathic infertility to oxidative stress. Methods： Fifty-two men with idiopathic infertility and 60 healthy fertile men were recruited to this study. GSTM1 gene polymorphism was determined by polymerase chain reaction （PCR） and both the infertile and control individuals were divided into GSTM1 null and GSTM1 positive groups according to their GSTM1 gene structure. We compared reactive oxygen species （ROS） generation, malondialdehyde （MDA）, protein carbonyls and glutathione （GSH） concentrations, and glutathione S-transferase （GST） activity in seminal plasma and spermatozoa from infertile patients and controls with respect to GSTM1 genotype. Results： Significantly higher levels of oxidative stress and damage markers were found in idiopathic infertile men with the GSTM1 null genotype compared with those with the GSTM1 positive genotype. There was no significant difference in genotype distribution for theGSTM1 variant between the idiopathic infertile subjects and fertile subjects. Patients with the GSTM1 null genotype also had lower sperm concentrations than those with GSTM1 positive genotype. Conclusion： Our results suggest that the susceptibility of sperm and seminal plasma to oxidative stress is significantly greater in idiopathic infertile men with the GSTM1 null genotype compared with those possessing the gene. Therefore, in patients with idiopathic infertility, GSTM1 polymorphism might be an important source of variation in susceptibility of spermatozoa to oxidative damage.展开更多
Crocetin is an aglycon of carotenoid extracted by saffron stigmas (Crocus sativus L.) and known to have a potent anti-oxidative effect. Amyliod β (Aβ), hallmark of Alzheimer’s disease, is reported to have neurotoxi...Crocetin is an aglycon of carotenoid extracted by saffron stigmas (Crocus sativus L.) and known to have a potent anti-oxidative effect. Amyliod β (Aβ), hallmark of Alzheimer’s disease, is reported to have neurotoxicity partly via oxidative stress. In this study, we investigated the effect of crocetin on hippocampal HT22 cell death induced by Aβ1-42. Furthermore, to clarify the mechanism underlying the protective effects of crocetin against Aβ1-42- induced cell death, we measured reactive oxygen species (ROS) production by CM-H2DCFDA kit assay. Crocetin at 1 -10 μM protected HT22 cells against Aβ1-42-induced neuronal cell death and decreased ROS production increased by Aβ1-42. These results that crocetin has the potent neuroprotective effect against Aβ1-42-induced cytotoxicity in hippocampal cells by attenuating oxidative stress, suggest that crocetin may provide a useful therapeutic strategy against Aβ-related disorders.展开更多
To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we establishe...To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we established an in vitro transfection of human HO-1 gene into rat VSMC mediated by a retroviral vector. The results showed that the profound expression of HO-1 protein as well as HO activity was 1.8- and 2.0-fold increased respectively in the transfected cells compared to the non-transfected ones. The treatment of VSMC with different concentrations of H2O2 led to the remarkable cell damage as indicated by survival rate and LDH leakage. However, the resistance of the HO-1 transfected VSMC against H2O2 was significantly raised. This protective effect was dramatically diminished when the transfected VSMC were pretreated with ZnPP-IX, a specific inhibitor of HO, for 24 h. In addition, we found that the growth potential of the transfected cells was significantly inhibited directly by increased activity of HO-1, and this effect might be related to decreased phosphorylation of MAPK. These results suggest that the overexpression of introduced hHO-1 is potentially able to reduce the risk factors of atherosclerosis, partially due to its cellular protection against oxidative injury and to its inhibitory effect on cellular proliferation.展开更多
PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expr...PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.展开更多
基金supported by the National Natural Science Foundation of China[81904266,82004309].
文摘While the Bushen Yizhi Formula can treat Alzheimer’s disease(AD),the yet to be ascertained specific mechanism of action was explored in this work.Methods:Different concentrations of the Bushen Yizhi Formula and amyloid-beta peptide(Aβ)were used to treat rat pheochromocytoma cells(P12)and human neuroblastoma cells(SH-SY5Y).Cell morphological changes were observed to determine the in vitro cell damage.Cell Counting Kit(CCK)-8 assay and flow cytometry were employed to identify cell viability and apoptosis/cell cycle,respectively.Western blotting and immunohistochemistry were employed to measure the expressions of endoplasmic reticulum stress(ERS)-related proteins(GRP78 and CHOP),p-IRE1α,IRE1α,ASK1,p-JNK,JNK,Bax,Bcl-2,XBP-1,and Bim.Fura 2-acetoxymethyl ester(Fura-2/AM)was used to determine the intracellular calcium(Ca^(2+))concentration.Also,an AD model was constructed by injecting Aβinto the CA1 area of the hippocampus in Sprague Dawley rats.AD model rats were gavaged with different concentrations of Bushen Yizhi Formula for 14 consecutive days.The Morris water maze experiment was conducted to test the learning and memory of rats.Hematoxylin&Eosin(H&E)and Terminal-deoxynucleotidyl Transferase(TdT)-mediated dUTP Nick-End Labeling(TUNEL)staining were done to determine histopathological changes in the brain.Results:Bushen Yizhi Formula relieved the Aβ-induced effects including cell injury,decreased viability,increased apoptosis,G0/G1 phase cell cycle arrest,upregulation of GRP78,CHOP,p-IRE1α,p-JNK,Bax,XBP-1 and Bim,as well as down-regulation of Bcl-2.These results were also seen with IRE1αsilencing.While Aβsuppressed the learning and memory abilities of rats,the Bushen Yizhi Formula alleviated these effects of Aβ.Brain nerve cell injury induced by Aβcould also be treated with Bushen Yizhi Formula.Conclusion:Bushen Yizhi Formula could influence ERS through the IRE1αsignaling pathway to achieve its therapeutic effects on AD.
基金supported by the Key Science and Technology Research of Henan Province,No.222102310351(to JW)Luoyang 2022 Medical and Health Guiding Science and Technology Plan Project,No.2022057Y(to JY)Henan Medical Science and Technology Research Program Province-Ministry Co-sponsorship,No.SBGJ202002099(to JY)。
文摘Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.
基金supported by a KAKENHI Grant-in-Aid for Scientific Research,No.21K09133(to KI).
文摘Recent findings have implicated inflammatory responses in the central nervous system in a variety of neuropsychiatric and neurodegenerative diseases,and the understanding and control of immunological responses could be a major factor of future therapeutic strategies for neurological disorders.Microglia,derived from myelogenous cells,respond to a number of stimuli and make immune responses,resulting in a prominent role as cells that act on inflammation in the central nervous system.Fractalkine(FKN or CX3CL1)signaling is an important factor that influences the inflammatory response of microglia.The receptor for FKN,CX3CR1,is usually expressed in microglia in the brain,and therefore the inflammatory response of microglia is modified by FKN.Reportedly,FKN often suppresses inflammatory responses in microglia and activation of its receptor may be effective in the treatment of inflammatory neurological disorders.However,it has also been suggested that inflammatory responses facilitated by FKN signaling aggravate neurological disorders.Thus,further studies are still required to resolve the conflicting interpretation of the protective or deleterious contribution of microglial FKN signaling.Yet notably,regulation of FKN signaling has recently been shown to be beneficial in the treatment of human diseases,although not neurological diseases.In addition,a CX3CR1 inhibitor has been developed and successfully tested in animal models,and it is expected to be in human clinical trials in the future.In this review,I describe the potential therapeutic consideration of microglial CX3CR1 dynamics through altered FKN signaling.
基金the National Natural Science Foundation of China, No. 30860085a grant from the Candidates of Young and Middle-Aged Academic Leaders of Yunnan Province, No. 2006PY01-07the Natural Science Foundation of Yunnan Province, No. 2007C177M
文摘1-methyl-4-phenylpyridinium ion （MPP^＋） induces endoplasmic reticulum stress and activates caspase-12 in PC12 cells, leading to neuronal apoptosis. However, the underlying molecular mechanism remains unknown. The present study investigated the regulatory effects of nerve growth factor （Akt activator） and lithium chloride （glycogen synthase kinase-3β inhibitor） on the endoplasmic reticulum stress signaling pathway. The results revealed that MPP＋ induced expression of Bip and C/EBP homologous protein. The upregulation of Bip and C/EBP homologous protein, as well as the decreased pro-caspase-12 level induced by MPP^＋ were inhibited by pretreatment of the nerve growth factor or lithium chloride. These results suggest that the phosphatidylinositol 3 kinase-Aktglycogen synthase kinase-3β pathway is involved in MPP-induced endoplasmic reticulum stress.
基金the National Natural Science Foundation of China, No. 30973779the National Special Planning Project for Traditional Chinese Medicine of China, No.02-03LP41the Key Program of Scientific Planning of Guangdong Province, No. 2006B35630007
文摘BACKGROUND： Studies have demonstrated that β-amyloid peptide （Aβ）, a characteristic pathological product of Alzheimer＇s disease （AD）, results in neuronal endoplasmic reticulum stress （ERS）. However, the mechanisms of traditional Chinese medicine against ERS in AD are poorly understood. OBJECTIVE： To measure expression levels of protective proteins （GRP78 and GRP94） of ER molecular partners and pro-apoptotic Caspase-12 ER membrane expression following application of traditional Chinese medicine natural cerebrolysin （NC） to treat Aβ1-40-induced ERS. DESIGN, TIME AND SETTING： A parallel-controlled study was performed at the Institute of Integrated Western and Traditional Chinese Medicine, Shenzhen Hospital of Southern Medical University between September 2006 and November 2008. MATERIALS： Sprague Dawley male rats, 6-8 weeks old, were used to harvest tibial and femoral bone marrow. Isolation and purification of mesenchymal stem cells （MSCs） were established from the whole bone marrow by removing non-adherent cells in primary and passage cultures. Aβ1-40 was provided by Sigma, USA. NC was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. NC was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yinxingye （Ginkgo Leaf） in a proportion of 1 ： 2： 2. Following conventional water extraction technology, an extract （1 ： 20） was prepared. Six adult, male, New Zealand rabbits underwent intragastric administration of NC extract （0.976 g/kg per day） for 1 month to prepare NC-positive serum, and the remaining 6 rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： A total of 500 nmol/L Aβ1-40 was used to establish ERS models of primary cultured MSCs. AD cell models were incubated with different doses of NC-positive serum （2.5%, 5%, and 10%）. MSCs treated with normal blank serum served as normal blank controls. MAIN OUTCOME MEASURES： Reverse transcription-polymerase chain reaction and fluorescent immunocytochemistry were respectively used to measure mRNA and protein expression levels of GRP78, GRP94, and Caspase-12 in MSCs. RESULTS： Following Aβ1-40 exposure, mRNA and protein expression levels of GRP78 and GRP94, as well as Caspase-12, significantly increased （P 〈 0.05）, suggesting successful establishment of ERS models. Following NC-positive serum application, mRNA and protein expression levels of GRP78 and GRP94 in MSCs significantly increased （P 〈 0.05 or P 〈 0.01）. However, mRNA and protein expression levels of Caspase-12 significantly decreased （P 〈 0.05, or P 〈 0.01） compared with the ERS model group. These effects were dose-dependent. CONCLUSION： NC downregulated Caspase-12 expression and upregulated GRP78 and GRP94 expression in MSCs in a dose-dependent manner under the state of Aβ1-40-induced ERS.
基金the National Natural Science Foundation of China, No. 30600201the Tianjin Science and Technology Committee, No. 07JCYBJC09900
文摘To investigate the effects of oxidative stress on substantia nigra neuronal degeneration and death in patients with Parkinson＇s disease, we treated neuroblastoma cells （SK-N-SH） and glioma cells with Fenton＇s reagent, iron chelating agent, neuromelanin and dopamine melanin. We investigated the changes in expression of nine oxidative stress-related genes and proteins. The levels of mRNAs for heme-oxygenase-1 and glutathione S-transferase-ml were significantly reduced in SK-N-SH cells exposed to oxidative stress, and increased in glial cells treated with deferoxamine. These results revealed that SK-N-SH neurons react sensitively to oxidative stress, which implies different outcomes between these two types of cells in the substantia nigra. Moreover, the influences of neuromelanin and dopamine melanin on cell function are varied, and dopamine melanin is not a good model for neuromelanin.
文摘设 M 是连通的、可定向的、完备的3维 C~∞黎曼流形,C:M→S^4(1)是从 M 列4维单位球面 S^4(1)中的等距浸入.主曲率 h_1,h_2,h_3满足 h_1=h_2=R(常数).本文证明了:浸入或者是全脐的,或者是无脐点的;若浸入是全脐的.或无脐点且 h_3为常数,则 M 可完全确定:若 h_3不是常数,则 M 微分同胚于 E^4中环准超环面.
基金We thank Dr Wei-dong Le for providing the MES23.5 cell line. This work was supported by grants from the National Program of Basic Research sponsored by the Ministry of Science and Tech- nology of China （2006CB500704）, the National Natural Science Foundation of China （30930036, 30770757, 30870858） and the Natural Science Fund of Shandong Province for Distinguished Young Scholars （JQ200807）.
文摘Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine （6-OHDA）-induced PD rats, DMT1 with the iron responsive element （IRE, DMTI＋IRE）, but not DMT1 without IRE （DMTI-IRE）, was up- regulated, suggesting that increased DMTI＋IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMTl＋IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein （IRP） 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-indueed DMTI＋IRE up-regulation. Pre- treatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-indueed oxidative stress. Increased DMTI＋IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMTI＋IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in ag- gravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.
基金supported by the National Natural Science Foundation of China,Nos.81671055,81971009(to XLZ)the Key Research and Development Program of Jiangsu Province of China,No.BE2016610(to YX)+3 种基金the National Key Research and Development Program of China,No.2016YFC1300504(to YX)and No.2018YFC1704405(to XLZ)Jiangsu Province Key Medical Discipline,No.ZDXKA2016020(to YX)Jiangsu Province Medical Youth Talent,No.QNRC2016024(to XLZ)Young Talent Support Program from Jiangsu Association for Science and Technology(to XLZ)。
文摘Amyloid beta(Aβ)-induced neurotoxicity and oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease(AD).ZL006 is shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke by interrupting the interaction of neuronal nitric oxide synthase and postsynaptic density protein 95.However,few studies are reported on the role of ZL006 in AD.To investigate whether ZL006 exerted neuroprotective effects in AD,we used Aβ1–42 to treat primary cortical neurons and N2a neuroblastoma cells as an in vitro model of AD.Cortical neurons were incubated with ZL006 or dimethyl sulfoxide for 2 hours and treated with Aβ1–42 or NH3·H2O for another 24 hours.The results of cell counting Kit-8(CCK-8)assay and calcein-acetoxymethylester/propidium iodide staining showed that ZL006 pretreatment rescued the neuronal death induced by Aβ1–42.Fluorescence and western blot assay were used to detect oxidative stress and apoptosis-related proteins in each group of cells.Results showed that ZL006 pretreatment decreased neuronal apoptosis and oxidative stress induced by Aβ1–42.The results of CCK8 assay showed that inhibition of Akt or NF-E2-related factor 2(Nrf2)in cortical neurons abolished the protective effects of ZL006.Moreover,similar results were also observed in N2a neuroblastoma cells.ZL006 inhibited N2a cell death and oxidative stress induced by Aβ1–42,while inhibition of Akt or Nrf2 abolished the protective effect of ZL006.These results demonstrated that ZL006 reduced Aβ1–42-induced neuronal damage and oxidative stress,and the mechanisms might be associated with the activation of Akt/Nrf2/heme oxygenase-1 signaling pathways.
文摘The mitogen-activated protein kinase（MAPK） signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, transformation and death. Mitogen-activated protein kinase phosphatase 1（MKP1） has an inhibitory effect on the p38 MAPK and JNK pathways, but it is unknown whether it plays a role in Aβ-induced oxidative stress and neuronal inflammation. In this study, PC12 cells were infected with MKP1 sh RNA, MKP1 lentivirus or control lentivirus for 12 hours, and then treated with 0.1, 1, 10 or 100 μM amyloid beta 42（Aβ42）. The cell survival rate was measured using the cell counting kit-8 assay. MKP1, tumor necrosis factor-alpha（TNF-α） and interleukin-1β（IL-1β） m RNA expression levels were analyzed using quantitative real time-polymerase chain reaction. MKP1 and phospho-c-Jun N-terminal kinase（JNK） expression levels were assessed using western blot assay. Reactive oxygen species（ROS） levels were detected using 2′,7′-dichlorofluorescein diacetate. Mitochondrial membrane potential was measured using flow cytometry. Superoxide dismutase activity and malondialdehyde levels were evaluated using the colorimetric method. Lactate dehydrogenase activity was measured using a microplate reader. Caspase-3 expression levels were assessed by enzyme-linked immunosorbent assay. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase d UTP nick end labeling method. MKP1 overexpression inhibited Aβ-induced JNK phosphorylation and the increase in ROS levels. It also suppressed the Aβ-induced increase in TNF-α and IL-1β levels as well as apoptosis in PC12 cells. In contrast, MKP1 knockdown by RNA interference aggravated Aβ-induced oxidative stress, inflammation and cell damage in PC12 cells. Furthermore, the JNK-specific inhibitor SP600125 abolished this effect of MKP1 knockdown on Aβ-induced neurotoxicity. Collectively, these results show that MKP1 mitigates Aβ-induced apoptosis, oxidative stress and neuroinflammation by inhibiting the JNK signaling pathway, thereby playing a neuroprotective role.
基金This work was supported by the National Natural Science Foundation of China,Nos.81671240(to SZZ),81560220(to GHL)the Youth Science Foundation of Jiangxi Province of China,No.20151BAB215014(to GHL)Health and Family Planning Commission of Jiangxi Province of China,No.20195109(to GHL)。
文摘The expression of major histocompatibility complex class I(MHC-I),a key antigen-presenting protein,can be induced in dopaminergic neurons in the substantia nigra,thus indicating its possible involvement in the occurrence and development of Parkinson’s disease.However,it remains unclear whether oxidative stress induces Parkinson’s disease through the MHC-I pathway.In the present study,polymerase chain reaction and western blot assays were used to determine the expression of MHC-I in 1-methyl-4-phenylpyridinium(MPP+)-treated SH-SY5Y cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson’s disease mouse model.The findings revealed that MHC-I was expressed in both models.To detect whether the expression of MHC-I was able to trigger the infiltration of cytotoxic T cells,immunofluorescence staining was used to detect cytotoxic cluster of differentiation 8(CD8)+T cell infiltration in the substantia nigra of MPTP-treated mice.The results indicated that the presentation of MHC-I in dopaminergic neurons was indeed accompanied by an increase in the number of CD8+T cells.Moreover,in MPTP-induced Parkinson’s disease model mice,the genetic knockdown of endogenous MHC-I,which was caused by injecting specific adenovirus into the substantia nigra,led to a significant reduction in CD8+T cell infiltration and alleviated dopaminergic neuronal death.To further investigate the molecular mechanisms of oxidative stress-induced MHC-I presentation,the expression of PTEN-induced kinase 1(PINK1)was silenced in MPP+-treated SH-SY5Y cells using specific small interfering RNA(siRNA),and there was more presentation of MHC-I in these cells compared with control siRNA-treated cells.Taken together,MPP+-/MPTP-induced oxidative stress can trigger MHC-I presentation and autoimmune activation,thus rendering dopaminergic neurons susceptible to immune cells and degeneration.This may be one of the mechanisms of oxidative stress-induced Parkinson’s disease,and implies the potential neuroprotective role of PINK1 in oxidative stress-induced MHC-I presentation.All animal experiments were approved by the Southern Medical University Ethics Committee(No.81802040,approved on February 25,2018).
基金supported by the Fundamental Research Funds for the Central Universities, No. lzujbky-2011-83Project of the International Cooperation and Communion Department of Chinese Education Ministry (46th batch)the Science Foundation of Key Laboratory of Preclinical Study for New Drugs of Gansu Province, No. GSKFKT-0804
文摘Because neurons are susceptible to oxidative damage and thioredoxin reductase 1 is extensively distributed in the central nervous system and has antioxidant properties, we speculated that the enzyme may be involved in the pathogenesis of Parkinson＇s disease. A Parkinson＇s disease model was produced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into C57BL/6 mice. Real-time reverse transcription-PCR, western blot analysis and colorimetric assay showed that the levels of thioredoxin reductase 1 mRNA and protein were decreased, along with a significant reduction in thioredoxin reductase activity, in the midbrain of Parkinson＇s disease mice compared with normal mice. Immunohistochemical staining revealed that the number of thioredoxin reductase 1-positive neurons in the substantia nigra pars compacta of Parkinson＇s disease mice was significantly decreased compared with normal mice. These experimental findings suggest that the expression of thioredoxin reductase 1 in the substantia nigra pars compacta of Parkinson＇s disease mice is significantly decreased, and that the enzyme may be associated with disease onset.
文摘Aim： To examine whether a relationship exists between glutathione S-transferase Mu-1 （GSTM1） gene polymorphism and the susceptibility of sperm and seminal plasma from patients with idiopathic infertility to oxidative stress. Methods： Fifty-two men with idiopathic infertility and 60 healthy fertile men were recruited to this study. GSTM1 gene polymorphism was determined by polymerase chain reaction （PCR） and both the infertile and control individuals were divided into GSTM1 null and GSTM1 positive groups according to their GSTM1 gene structure. We compared reactive oxygen species （ROS） generation, malondialdehyde （MDA）, protein carbonyls and glutathione （GSH） concentrations, and glutathione S-transferase （GST） activity in seminal plasma and spermatozoa from infertile patients and controls with respect to GSTM1 genotype. Results： Significantly higher levels of oxidative stress and damage markers were found in idiopathic infertile men with the GSTM1 null genotype compared with those with the GSTM1 positive genotype. There was no significant difference in genotype distribution for theGSTM1 variant between the idiopathic infertile subjects and fertile subjects. Patients with the GSTM1 null genotype also had lower sperm concentrations than those with GSTM1 positive genotype. Conclusion： Our results suggest that the susceptibility of sperm and seminal plasma to oxidative stress is significantly greater in idiopathic infertile men with the GSTM1 null genotype compared with those possessing the gene. Therefore, in patients with idiopathic infertility, GSTM1 polymorphism might be an important source of variation in susceptibility of spermatozoa to oxidative damage.
文摘Crocetin is an aglycon of carotenoid extracted by saffron stigmas (Crocus sativus L.) and known to have a potent anti-oxidative effect. Amyliod β (Aβ), hallmark of Alzheimer’s disease, is reported to have neurotoxicity partly via oxidative stress. In this study, we investigated the effect of crocetin on hippocampal HT22 cell death induced by Aβ1-42. Furthermore, to clarify the mechanism underlying the protective effects of crocetin against Aβ1-42- induced cell death, we measured reactive oxygen species (ROS) production by CM-H2DCFDA kit assay. Crocetin at 1 -10 μM protected HT22 cells against Aβ1-42-induced neuronal cell death and decreased ROS production increased by Aβ1-42. These results that crocetin has the potent neuroprotective effect against Aβ1-42-induced cytotoxicity in hippocampal cells by attenuating oxidative stress, suggest that crocetin may provide a useful therapeutic strategy against Aβ-related disorders.
基金This work was kindly supported by Na-tional Natural Science Foundation of China(No.39670308)
文摘To investigate whether the expression of exogenous heme oxygenase-1 (HO-1) gene within vascular smooth muscle cells (VSMC) could protect the cells from free radical attack and inhibit cell proliferation, we established an in vitro transfection of human HO-1 gene into rat VSMC mediated by a retroviral vector. The results showed that the profound expression of HO-1 protein as well as HO activity was 1.8- and 2.0-fold increased respectively in the transfected cells compared to the non-transfected ones. The treatment of VSMC with different concentrations of H2O2 led to the remarkable cell damage as indicated by survival rate and LDH leakage. However, the resistance of the HO-1 transfected VSMC against H2O2 was significantly raised. This protective effect was dramatically diminished when the transfected VSMC were pretreated with ZnPP-IX, a specific inhibitor of HO, for 24 h. In addition, we found that the growth potential of the transfected cells was significantly inhibited directly by increased activity of HO-1, and this effect might be related to decreased phosphorylation of MAPK. These results suggest that the overexpression of introduced hHO-1 is potentially able to reduce the risk factors of atherosclerosis, partially due to its cellular protection against oxidative injury and to its inhibitory effect on cellular proliferation.
基金support by the Ministerio Educación y CienciaMinisterio de Economía y Competitividad of Spain(until June 2013)
文摘PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.
