Fe(Ⅱ)/α-ketoglutarate(αKG)-dependent oxygenases catalyze the oxidative modification of various molecules,from DNA,RNA,and proteins to primary and secondary metabolites.They also catalyze a variety of biochemical re...Fe(Ⅱ)/α-ketoglutarate(αKG)-dependent oxygenases catalyze the oxidative modification of various molecules,from DNA,RNA,and proteins to primary and secondary metabolites.They also catalyze a variety of biochemical reactions,including hydroxylation,halogenation,desaturation,epoxidation,cyclization,peroxidation,epimeriza-tion,and rearrangement.Given the versatile catalytic capability of such oxygenases,numerous studies have been conducted to characterize their functions and elucidate their structure-function relationships over the past few decades.Amino acids,particularly nonproteinogenic amino acids,are considered as important building blocks for chemical synthesis and components for natural product biosynthesis.In addition,the Fe(Ⅱ)/αKG-dependent oxy-genase superfamily includes important enzymes for generating amino acid derivatives,as they efficiently modify various free-standing amino acids.The recent discovery of new Fe(Ⅱ)/αKG-dependent oxygenases and the repur-posing of known enzymes in this superfamily have promoted the generation of useful amino acid derivatives.Therefore,this study will focus on the recent progress achieved from 2019 to 2022 to provide a clear view of the mechanism by which these enzymes have expanded the repertoire of free amino acid oxidative modifications.展开更多
Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord ...Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord injury is still unclea r. In this study,a rat model of spinal cord injury was established using the heavy o bject impact method,and the rats were then treated with Biochanin A(40 mg/kg) via intrape ritoneal injection for 14 consecutive days.The res ults showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal co rd tissue injury,reduced inflammation and oxidative stress in spinal cord neuro ns,and reduced apoptosis and pyroptosis.In addition,Biochanin A inhibited the expression of inflammasome-related proteins(ASC,NLRP3,and GSDMD)and the Toll-like receptor 4/nuclear factor-κB pathway,activated the Nrf2/heme oxygenase 1 signaling pathway,and increased the expression of the autophagy markers LC3 Ⅱ,Beclin-1,and P62.Moreove r,the therapeutic effects of Biochanin A on early post-s pinal cord injury were similar to those of methylprednisolone.These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways.These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage.展开更多
Background: Tumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis. In thi...Background: Tumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis. In this study, we examined the pan-cancer prognostic significance of oxygen-sensing genes from the 2-oxoglutarate-dependent oxygenase family. Methods: A multi-cohort, retrospective study of transcriptional profiles of 20,752 samples of 25 types of cancer was performed to identify pan-cancer prognostic signatures of 2-oxoglutarate-dependent oxygenase gene family (a family of oxygen-dependent enzymes consisting of 61 genes). We defined minimal prognostic gene sets using three independent pancreatic cancer cohorts (n = 681). We identified two signatures, each consisting of 5 genes. The ability of the signa-tures in predicting survival was tested using Cox regression and receiver operating characteristic (ROC) curve analyses. Results: Signature 1 (KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7) and signature 2 (KDM3A, P4HA1, ASPH, PLOD1, PLOD2) were associated with good and poor prognosis. Signature 1 was prognostic in 8 cohorts representing 6 cancer types (n = 2627): bladder urothelial carcinoma (P = 0.039), renal papillary cell carcinoma (P = 0.013), liver cancer (P = 0.033 and P = 0.025), lung adenocarcinoma (P = 0.014), pancreatic adenocarcinoma (P < 0.001 and P = 0.040), and uterine corpus endometrial carcinoma (P < 0.001). Signature 2 was prognostic in 12 cohorts representing 9 cancer types (n = 4134): bladder urothelial carcinoma (P = 0.039), cervical squamous cell carcinoma and endocervical adenocar-cinoma (P = 0.035), head and neck squamous cell carcinoma (P = 0.038), renal clear cell carcinoma (P = 0.012), renal papillary cell carcinoma (P = 0.002), liver cancer (P < 0.001, P < 0.001), lung adenocarcinoma (P = 0.011), pancreatic adenocarcinoma (P = 0.002, P = 0.018, P < 0.001), and gastric adenocarcinoma (P = 0.004). Multivariate Cox regression confirmed independent clinical relevance of the signatures in these cancers. ROC curve analyses confirmed superior performance of the signatures to current tumor staging benchmarks. KDM8 was a potential tumor suppressor down- regulated in liver and pancreatic cancers and an independent prognostic factor. KDM8 expression was negatively correlated with that of cell cycle regulators. Low KDM8 expression in tumors was associated with loss of cell adhesion phenotype through HNF4A signaling. Conclusion: Two pan-cancer prognostic signatures of oxygen-sensing genes were identified. These genes can be used for risk stratification in ten diverse cancer types to reveal aggressive tumor subtypes.展开更多
The fatty alk(a/e)ne biosynthesis pathway found in cyanobacteria gained tremendous attention in recent years as a promising alternative approach for biofuel production. Cyanobacterial aldehyde-deformylating oxygena...The fatty alk(a/e)ne biosynthesis pathway found in cyanobacteria gained tremendous attention in recent years as a promising alternative approach for biofuel production. Cyanobacterial aldehyde-deformylating oxygenase (cADO), which catalyzes the conversion of Cn fatty aldehyde to its corresponding Cn-1 alk(ale)ne, is a key enzyme in that pathway. Due to its low activity, alk(a/e)ne production by cADO is an inefficient process. Previous biochemical and structural investi. gations of cADO have provided some information on its catalytic reaction. However, the details of its cata- lytic processes remain unclear. Here we report five crystal structures of cADO from the Synechococcus elongates strain PCC7942 in both its iron-free and iron-bound forms, representing different states during its catalytic process. Structural comparisons and functional enzyme assays indicate that Giu144, one of the iron-coordinating residues, plays a vital role in the catalytic reaction of cADO. Moreover, the helix where Glu144 resides exhibits two distinct conformations that correlates with the different binding states of the di-iron center in cADO structures. Therefore, our results provide a structural explanation for the highly labile feature of cADO di-iron center, which we pro- posed to be related to its low enzymatic activity. On the basis of our structural and biochemical data, a possible catalytic process of cADO was proposed, which could aid the design of cADO with improved activity.展开更多
Angucyclines are one of the largest families of aromatic polyketides with various chemical structures and bioactivities.Decades of studies have made it easy for us to depict the picture of their early biosynthetic pat...Angucyclines are one of the largest families of aromatic polyketides with various chemical structures and bioactivities.Decades of studies have made it easy for us to depict the picture of their early biosynthetic pathways.Two families of oxygenases,the FAD-dependent oxygenases and the ring opening oxygenases,contribute to the formation of some unique skeletons of atypical angucyclines.The FAD-dependent oxygenases involved in the biosynthetic gene clusters of typical angucyclines catalyze two hydroxylation reactions at C-12 and C-12b of prejadomycin,while their homolog JadH in jadomycin gene cluster catalyze the C-12 hydroxylation and 4a,12b-dehydration reactions of prejadomycin,which leads to the production of dehydrorabelomycin,a common intermediate during the biosynthesis of atypical angucyclines.Ring opening oxygenases of a unique family of oxygenases catalyze the oxidative CeC bond cleavage reaction of dehydrorabelomycin,followed by different rearrangement reactions,resulting in the formation of the various chemical skeletons of atypical angucyclines.These results suggested that the functional differentiation of these oxygenases could apparently enrich the sources of aromatic polyketides with greater structure diversities.展开更多
CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebr...CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.展开更多
The activation of heme oxygenase-1(HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catab...The activation of heme oxygenase-1(HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide(CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection.In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload(with signs of a chronic hepatitis) and iron deficiency anemia(with paradoxical increased levels of ferritin).Hypoxia induces HO-1 expression in multiple rodent,bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types(endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.展开更多
The effect of Batroxobin on spatial memory disorder of left temporal ischemic rats and the expression of HSP32 and HSP70 were investigated with Morri`s water maze and immunohistochemistry methods. The results show... The effect of Batroxobin on spatial memory disorder of left temporal ischemic rats and the expression of HSP32 and HSP70 were investigated with Morri`s water maze and immunohistochemistry methods. The results showed that the mean reaction time and distance of temporal ischemic rats in searching a goal were significantly longer than those of the sham-operated rats and at the same time HSP32 and HSP70 expression of left temporal ischemic region in rats was significantly increased as compared with the sham-operated rats. However, the mean reaction time and distance of the Batroxobin-treated rats were shorter and they used normal strategies more often and earlier than those of ischemic rats. The number of HSP32 and HSP70 immune reactive cells of Batroxobin-treated rats was also less than that of the ischemic group. In conclusion, Batroxobin can improve spatial memory disorder of temporal ischemic rats; and the down-regulation of the expression of HSP32 and HSP70 is probably related to the attenuation of ischemic injury.展开更多
基金supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology,Japan(JSPS KAKENHI Grant No.JP16H06443,JP20KK013,and JP20H00490)Japan Science and Technology Agency(JST SICORP Grant No.JPMJSC1701)+2 种基金the New Energy and Industrial Technology Development Organization(NEDO,Grant No.JPNP20011)Japan Agency for Medical Research and Development(AMED)(Grant No.JP21ak0101164)H.T.is a recipient of the JSPS Postdoctoral Fellowship for Foreign Researchers(ID No.P18404).
文摘Fe(Ⅱ)/α-ketoglutarate(αKG)-dependent oxygenases catalyze the oxidative modification of various molecules,from DNA,RNA,and proteins to primary and secondary metabolites.They also catalyze a variety of biochemical reactions,including hydroxylation,halogenation,desaturation,epoxidation,cyclization,peroxidation,epimeriza-tion,and rearrangement.Given the versatile catalytic capability of such oxygenases,numerous studies have been conducted to characterize their functions and elucidate their structure-function relationships over the past few decades.Amino acids,particularly nonproteinogenic amino acids,are considered as important building blocks for chemical synthesis and components for natural product biosynthesis.In addition,the Fe(Ⅱ)/αKG-dependent oxy-genase superfamily includes important enzymes for generating amino acid derivatives,as they efficiently modify various free-standing amino acids.The recent discovery of new Fe(Ⅱ)/αKG-dependent oxygenases and the repur-posing of known enzymes in this superfamily have promoted the generation of useful amino acid derivatives.Therefore,this study will focus on the recent progress achieved from 2019 to 2022 to provide a clear view of the mechanism by which these enzymes have expanded the repertoire of free amino acid oxidative modifications.
基金supported by the National Natural Science Foundation of China,Nos.LY20H090018(to XL)and LY20H060008(to HS).
文摘Previous studies have shown that Biochanin A,a flavonoid compound with estrogenic effects,can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury;howeve r,its effect on spinal cord injury is still unclea r. In this study,a rat model of spinal cord injury was established using the heavy o bject impact method,and the rats were then treated with Biochanin A(40 mg/kg) via intrape ritoneal injection for 14 consecutive days.The res ults showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal co rd tissue injury,reduced inflammation and oxidative stress in spinal cord neuro ns,and reduced apoptosis and pyroptosis.In addition,Biochanin A inhibited the expression of inflammasome-related proteins(ASC,NLRP3,and GSDMD)and the Toll-like receptor 4/nuclear factor-κB pathway,activated the Nrf2/heme oxygenase 1 signaling pathway,and increased the expression of the autophagy markers LC3 Ⅱ,Beclin-1,and P62.Moreove r,the therapeutic effects of Biochanin A on early post-s pinal cord injury were similar to those of methylprednisolone.These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways.These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage.
文摘Background: Tumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis. In this study, we examined the pan-cancer prognostic significance of oxygen-sensing genes from the 2-oxoglutarate-dependent oxygenase family. Methods: A multi-cohort, retrospective study of transcriptional profiles of 20,752 samples of 25 types of cancer was performed to identify pan-cancer prognostic signatures of 2-oxoglutarate-dependent oxygenase gene family (a family of oxygen-dependent enzymes consisting of 61 genes). We defined minimal prognostic gene sets using three independent pancreatic cancer cohorts (n = 681). We identified two signatures, each consisting of 5 genes. The ability of the signa-tures in predicting survival was tested using Cox regression and receiver operating characteristic (ROC) curve analyses. Results: Signature 1 (KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7) and signature 2 (KDM3A, P4HA1, ASPH, PLOD1, PLOD2) were associated with good and poor prognosis. Signature 1 was prognostic in 8 cohorts representing 6 cancer types (n = 2627): bladder urothelial carcinoma (P = 0.039), renal papillary cell carcinoma (P = 0.013), liver cancer (P = 0.033 and P = 0.025), lung adenocarcinoma (P = 0.014), pancreatic adenocarcinoma (P < 0.001 and P = 0.040), and uterine corpus endometrial carcinoma (P < 0.001). Signature 2 was prognostic in 12 cohorts representing 9 cancer types (n = 4134): bladder urothelial carcinoma (P = 0.039), cervical squamous cell carcinoma and endocervical adenocar-cinoma (P = 0.035), head and neck squamous cell carcinoma (P = 0.038), renal clear cell carcinoma (P = 0.012), renal papillary cell carcinoma (P = 0.002), liver cancer (P < 0.001, P < 0.001), lung adenocarcinoma (P = 0.011), pancreatic adenocarcinoma (P = 0.002, P = 0.018, P < 0.001), and gastric adenocarcinoma (P = 0.004). Multivariate Cox regression confirmed independent clinical relevance of the signatures in these cancers. ROC curve analyses confirmed superior performance of the signatures to current tumor staging benchmarks. KDM8 was a potential tumor suppressor down- regulated in liver and pancreatic cancers and an independent prognostic factor. KDM8 expression was negatively correlated with that of cell cycle regulators. Low KDM8 expression in tumors was associated with loss of cell adhesion phenotype through HNF4A signaling. Conclusion: Two pan-cancer prognostic signatures of oxygen-sensing genes were identified. These genes can be used for risk stratification in ten diverse cancer types to reveal aggressive tumor subtypes.
基金We would like to thank Yi Han and Shengquan Liu at the Institute of Biophysics, CAS and the staffs at Shanghai Synchrotron Radiation Facility and Photo Factory, Japan, respectively, for help during X-ray data collection. We also thank Wei Shao at Beijing Center for Physical and Chemical Analysis for help with the GC analysis, Zhen Xue at Institute of Botany, CAS for providing help for the GC-QqQ- MS/MS analysis, and Hongzhi Zhang at Institute of Geographic Sciences and Natural Resources Research, CAS for technical support with the metal content analysis by ICP-OES. This work was supported by the National Basic Research Program (973 Program) (Nos. 2011CBA00902 and 2011CBA00907), Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08020302), National Natural Science Foundation of China(Grant Nos. 31021062 and 31170765), and CAS Cross and Coop- eration Team for Scientific Innovation (Y31102110A).
文摘The fatty alk(a/e)ne biosynthesis pathway found in cyanobacteria gained tremendous attention in recent years as a promising alternative approach for biofuel production. Cyanobacterial aldehyde-deformylating oxygenase (cADO), which catalyzes the conversion of Cn fatty aldehyde to its corresponding Cn-1 alk(ale)ne, is a key enzyme in that pathway. Due to its low activity, alk(a/e)ne production by cADO is an inefficient process. Previous biochemical and structural investi. gations of cADO have provided some information on its catalytic reaction. However, the details of its cata- lytic processes remain unclear. Here we report five crystal structures of cADO from the Synechococcus elongates strain PCC7942 in both its iron-free and iron-bound forms, representing different states during its catalytic process. Structural comparisons and functional enzyme assays indicate that Giu144, one of the iron-coordinating residues, plays a vital role in the catalytic reaction of cADO. Moreover, the helix where Glu144 resides exhibits two distinct conformations that correlates with the different binding states of the di-iron center in cADO structures. Therefore, our results provide a structural explanation for the highly labile feature of cADO di-iron center, which we pro- posed to be related to its low enzymatic activity. On the basis of our structural and biochemical data, a possible catalytic process of cADO was proposed, which could aid the design of cADO with improved activity.
基金National Natural Science Foundation of China(Grants:31670800,31470176,and 31130001)Ministry of Science and Technology of China(Grants:2014CB910400).
文摘Angucyclines are one of the largest families of aromatic polyketides with various chemical structures and bioactivities.Decades of studies have made it easy for us to depict the picture of their early biosynthetic pathways.Two families of oxygenases,the FAD-dependent oxygenases and the ring opening oxygenases,contribute to the formation of some unique skeletons of atypical angucyclines.The FAD-dependent oxygenases involved in the biosynthetic gene clusters of typical angucyclines catalyze two hydroxylation reactions at C-12 and C-12b of prejadomycin,while their homolog JadH in jadomycin gene cluster catalyze the C-12 hydroxylation and 4a,12b-dehydration reactions of prejadomycin,which leads to the production of dehydrorabelomycin,a common intermediate during the biosynthesis of atypical angucyclines.Ring opening oxygenases of a unique family of oxygenases catalyze the oxidative CeC bond cleavage reaction of dehydrorabelomycin,followed by different rearrangement reactions,resulting in the formation of the various chemical skeletons of atypical angucyclines.These results suggested that the functional differentiation of these oxygenases could apparently enrich the sources of aromatic polyketides with greater structure diversities.
基金supported by the National Natural Science Foundation of China,No.81402930Natural Science Foundation of Universities in Anhui Province,No.KJ2021A0688+2 种基金National College Students Innovation and Entrepreneurship Program,No.202110367071Key projects of science and technology projects of Bengbu Medical College,No.2020byzd017512 Talents Training Program of Bengbu Medical College,No.BY51201104(all to SYD).
文摘CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.
基金Supported by Brazilian Foundation-FAPESP(Fundao deapoio à pesquisa do Estado de So Paulo),No.07/07139-3,10/02024-6 and CNPq
文摘The activation of heme oxygenase-1(HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide(CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection.In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload(with signs of a chronic hepatitis) and iron deficiency anemia(with paradoxical increased levels of ferritin).Hypoxia induces HO-1 expression in multiple rodent,bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types(endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.
文摘 The effect of Batroxobin on spatial memory disorder of left temporal ischemic rats and the expression of HSP32 and HSP70 were investigated with Morri`s water maze and immunohistochemistry methods. The results showed that the mean reaction time and distance of temporal ischemic rats in searching a goal were significantly longer than those of the sham-operated rats and at the same time HSP32 and HSP70 expression of left temporal ischemic region in rats was significantly increased as compared with the sham-operated rats. However, the mean reaction time and distance of the Batroxobin-treated rats were shorter and they used normal strategies more often and earlier than those of ischemic rats. The number of HSP32 and HSP70 immune reactive cells of Batroxobin-treated rats was also less than that of the ischemic group. In conclusion, Batroxobin can improve spatial memory disorder of temporal ischemic rats; and the down-regulation of the expression of HSP32 and HSP70 is probably related to the attenuation of ischemic injury.