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heme oxygenase-1 induction by hemin protects liver cells from ischemia/reperfusion injury in cirrhotic rats

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World Journal of Gastroenterology 2007年第40期13卷 5384-5390页

作者： Hui Xue Hua Guo Ying-Chao Li Zhi-Ming Hao Department of Gastroenterology The First Affiliated Hospital Xi'an Jiaotong University Medical College Xi'an 710061 Shaanxi Province China

AIM： To investigate the potential protective effect of HO-1 on cirrhotic liver cells in rats.METHODS： Male Wistar rats included in the current study were randomly divided into 5 groups as follows： normal （N） group; liver cirrhotic （LC） group; sham （S） group; I/R group and I/R ＋ hemin group. The model for inducing liver cirrhosis in rats was established according to a previously published protocol. Following this the segmental hepatic ischemia reperfusion operation was carried out. The rats were treated with 30 l^mol/kg hemin （HO-1 inducer, ferric portoporphyrin IX chloride） i.p. or 0.9% NaCI （control） 24 h and 12 h before hepatic ischemia for 30 min or sham laparotomy. Blood was collected for serum enzymatic measurement 6 and 12 h after reperfusion or sham laparotomy. HO-1, NF-κB and caspase-3 expressions were assessed by immunohistochemical analysis.RESULTS： The expressions of proteins are inversely correlated to the gray values. HO-1 expression in the I/R ＋ hemin group was increased significantly than I/R group at 6 h and 12 h after hepatic I/R （6 h： 112.0± 8.3 vs 125.1± 5.7, P 〈 0.01; 12 h： 120.8± 11.0 vs 132.4 ± 6.2, P 〈 0.01）. Hemin improved serum manganese superoxide dismutase （MnSOD）（6 h： 131.3 ± 17.6 vs 107.0 ± 13.9, P 〈 0.01; 12 h： 141.4 ：E 12.5 vs 118.3± 10.2, P 〈 0.01）, lessened liver cell injury, decreased caspase-3（6 h： 166.7 ± 8.1 vs 145.5 ± 14.6, P 〈 0.01; 12 h： 172.8± 3.8 vs 148.0 ±6.5, P 〈 0.01） and NF-κB expression （6 h： 150.2 ± 8.6 vs 139.7 ±6.0, P 〈 0.01; 12 h： 151.1 ± 5.9 vs 148.1± 5.3, P 〉 0.05） and serum alanine aminotransferase （ALT）（6 h： 413.3± 104.1 vs 626.8 ±208.2, P 〈 0.01; 12 h： 322.2 ± 98.8 vs 425.8 ± 115.4, P 〈 0.05）, aspartate aminotransferase （AST）（6 h： 665.2 ± 70.1 vs 864.3± 70.4, P 〈 0.01; 12 h： 531.1 ± 98.6 vs 664.4± 115.6, P 〈 0.01）, malondialdehyde （MDA） levels （6 h： 11.1 ± 2.17 vs 13.5 ±2.01, P 〈 0.01; 12 h： 9.36 ±1.10 vs 10.8 ± 1.62, P 〈 0.05） in the I/R ＋ hemin group when compared with the I/R group.CONCLUSION： These

关键词： heme oxygenase-1 Ischemia reperfusion Caspase-3 Nuclear factor-κB Liver cirrhosis

heme oxygenase-1 prevents liver fibrosis in rats by regulating the expression of PPAR_γ and NF-_κB

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World Journal of Gastroenterology 2012年第14期18卷 1680-1688页

作者： Hui Yang Long-Feng Zhao Zhong-Fu Zhao Yan Wang Jing-Jing Zhao Li Zhang Department of Infectious Diseases the First AffiliatedHospital of Shanxi Medical University Taiyuan 030001 ShanxiProvince China Institute of Hepatopathy Changzhi MedicalCollege Changzhi 046000 Shanxi Province China

AIM:To investigate the effects of heme oxygenase(HO)-1 on liver fibrosis and the expression of peroxisome proliferator-activated receptor gamma(PPARγ) and nuclear factor-kappa B(NF-κB) in ***:Sixty Wistar rats were used to construct liver fibrosis models and were randomly divided into 5 groups:group A(normal,untreated),group B(model for 4 wk,untreated),group C(model for 6 wk,untreated),group D [model for 6 wk,treated with zinc protoporphyrin Ⅸ(ZnPP-Ⅸ) from week 4 to week 6],group E(model for 6 wk,treated with hemin from week 4 to week 6).Next,liver injury was assessed by measuring serum alanine aminotransferase(ALT),aspartate aminotransferase(AST) and albumin *** degree of hepatic fibrosis was evaluated by measuring serum hyaluronate acid(HA),type Ⅳ collagen(Ⅳ-C) and by histological ***(Hyp) content in the liver homogenate was *** expres-sion levels of alpha-smooth muscle actin(α-SMA) in liver tissue were measured by real-time quantitative polymerase chain reaction(RT-PCR).The expression levels of PPARγ and NF-κB were determined by RT-PCR and Western ***:The expression of HO-1 increased with the development of *** of HO-1 by hemin significantly attenuated the severity of liver injury and the levels of liver fibrosis as compared with inhibition of HO-1 by ZnPP-Ⅸ.The concentrations of serum ALT,AST,HA and Ⅳ-C in group E decreased compared with group C and group D(P < 0.01).Amount of Hyp and α-SMA in the liver tissues in group E decreased compared with group C(0.62 ± 0.14 vs 0.84 ± 0.07,1.42 ± 0.17 vs 1.84 ± 0.17,respectively,P < 0.01) and group D(0.62 ± 0.14 vs 1.11 ± 0.16,1.42 ± 0.17 vs 2.56 ± 0.37,respectively,P < 0.01).The expression of PPARγ at levels of transcription and translation decreased with the development of fibrosis especially in group D;and it increased in group E compared with groups C and D(0.88 ± 0.15 vs 0.56 ± 0.19,0.88 ± 0.15 vs 0.41 ± 0.11,respectively,P < 0.01).The expr

关键词： heme oxygenase-1 Peroxisome proliferator-activated receptor gamma Nuclear factor-kappa B Liver fibrosis Hemin

heme oxygenase-1 system and gastrointestinal inflammation:A short review

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World Journal of Gastroenterology 2011年第38期17卷 4283-4288页

作者： Xiao Zhu Wen-Guo Fan Dong-Pei Li Hsiangfu Kung Marie CM Lin Cancer Institute Affiliated Tumor Hospital Guangzhou Medical University Guangzhou 510095 Guangdong Province China Institute of Biochemistry and Molecular Biology Guangdong Medical College Dongguan 523808 GuangdongProvince China Guanghua School of Stomatology Sun Yat-sen University Guangzhou 510080 Guangdong Province China Zhongshan School of Medicine Sun Yat-sen University Guangzhou 510080 Guangdong Province China Li Ka Shing Institute of Medical Sciences theChinese University of Hong Kong Shatin Hong Kong China Department of Surgery Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong China

heme oxygenase-1(HO-1) system catalyzes heme to biologically active products:carbon monoxide,biliverdin/bilirubin and free *** is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes.A growing body of evidence indicates that HO-1 activation may play an important protective role in acute and chronic inflammation of gastrointestinal *** review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal inflammation studied to *** ability to upregulate HO-1 by pharmacological means or using gene therapy may offer therapeutic strategies for gastrointestinal inflammation in the future.

关键词： heme oxygenase-1 Gastrointestinal inflammation

heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats

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World Journal of Gastroenterology 2007年第25期13卷 3478-3486页

作者： Matthias Froh Lars Conzelmann Peter Walbrun Susanne Netter Reiner Wiest Michael D Wheeler Mark Lehnert Takehiko Uesugi Jurgen Scholmerich Ronald G Thurman Department of Internal Medicine University of Regensburg Germany Department of Urology University of Mainz Germany Department of Pharmacology University of North Carolina United States

AIM： To investigate the effects of heme oxygenase-1 （HO-1） against oxidant-induced injury caused by bile duct ligation （BDL）.METHODS： Either cobalt protoporphyrin （CoPP）, a HO-1 inducer, or saline were injected intraperitoneally in male SD-rats. Three days later, BDL or sham-operations were performed. Rats were sacrificed 3 wk after BDL and livers were harvested for histology. Fibrosis was evaluated by sirius red staining and image analysis. Alpha-smooth muscular actin, which indicates activation of stellate cells, was detected by immunohistochemical staining, and q/tokine and collagen- Iα （Col- I α） mRNA expression was detected using RNase protection assays.RESULTS： Serum alanine transaminase increased 8-fold above normal levels one day after BDL. Surprisingly, enzyme release was not reduced in rats receiving CoPP. Liver fibrosis was evaluated 3 wk after BDL and the sirius red-positive area was found to be increased to about 7.8%. However, in CoPP pretreated rats sirius redpositive areas were increased to about 11.7% after BDL. Collagen-1 α and TGF-β mRNA increased significantly by BDL. Again, this effect was increased by HO-1 overexpression.CONCLUSION： Hepatic fibrosis due to BDL is not reduced by the HO-1 inducer CoPP. In contrast, HO-1 overexpression increases liver injury in rats under conditions of experimental chronic cholestasis.

关键词： heme oxygenase-1 Bile duct ligation Chronic cholestasis Liver fibrosis Serum alaninetransaminase Transforming growth factor-13 Tumornecrosis factor- I ~ Type I collagen

heme oxygenase-1 system and gastrointestinal tumors

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World Journal of Gastroenterology 2010年第21期16卷 2633-2637页

作者： Marie CM Lin Hsiangfu Kung The Brain Tumor Center and Neurosurgery Division Prince of Wales HospitalThe Chinese University of Hong Kong Li Ka Shing Institute of Medical Sciences the Chinese University of Hong Kong

heme oxygenase-1(HO-1) system catabolizes heme into three products:carbon monoxide,biliverdin/bilirubin and free *** is involved in many physiological and pathophysiological processes.A great deal of data has demonstrated the roles of HO-1 in the formation,growth and metastasis of *** interest in this system by investigators involved in gastrointestinal tumors is fairly recent,and few papers on HO-1 have touched upon this *** review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal tumors studied to *** implications for possible therapeutic manipulation of HO-1 in gastrointestinal tumors are also discussed.

关键词： heme oxygenase-1 Gastrointestinal tumors

heme oxygenase-1 alleviates ischemia/reperfusion injury in aged liver

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World Journal of Gastroenterology 2005年第5期11卷 690-694页

作者： Xue-HaoWang KeWang FengZhang Xiang-ChengLi JunLi Wei-De JunGuo Xiao-FengQian YeFan TheLiverTransplantationCenteroftheFirstAffiliatedHospital NanjingMedicalUniversityNanjing210029JiangsuProvinceChina DepartmentofBiochemistry NanjingMedicalUniversityNanjing210029JiangsuProvinceChina

AIM: To investigate if ischemia/reperfusion (I/R) injury in aged liver could be alleviated by heme oxygenase-1 (HO-1).METHODS: Three groups of SD rats (16 mo old) were studied. Group 1: control donors received physiological saline 24 h before their livers were harvested; group 2: donors were pretreated with hemih 24 h before their livers were harvested; and group 3: donors received hemin 24 h before their livers were harvested and zinc protoporphyrin (ZnPP,HO-1 inhibitor) was given to recipients at reperfusion. The harvested livers were stored in University of Wisconsin solution (4 ℃) for 6 h, and then transplanted to syngeneic rats. Serum glutamic oxaloacetic transaminase (SGOT),apoptotic cells, and apoptotic gene were measured 3, 6,12, 24, 48 h after reperfusion. We measured the apoptotic index by TUNEL, determined the expression of antiapoptotic Bcl-2 and proapoptotic (caspase-3) gene products by Western ***: After 3, 6, 12, 24, and 48 h of reperfusion, the SGOT levels (584.4±85.8 u/L, 999.2±125.2 u/L, 423.4±161.3u/L, 257.8±95.8 u/L, and 122.4±26.4 u/L) in hemin group were significantly (all P＜0.05) lower than those in saline group (1082.2±101.2 u/L, 1775.2±328.3 u/L, 840.4±137.8 u/L,448.6±74.3 u/L, and 306.2±49.3 u/L). Liver HO-1 enzymatic activity correlated with beneficial effects of hemin and deleterious effects of adjunctive ZnPP treatment. Markedly less apoptotic (TUNEL+) liver cells 3, 6, 12, 24, and 48 h after reperfusion (5.16±0.73, 10.2±0.67, 9.28±0.78, 7.14±1.12,and 4.78±0.65) (P＜0.05) could be detected in hemin liver grafts, as compared to controls (7.82±1.05, 15.94±1.82,11.67±1.59, 8.28±1.09, and 6.36±0.67). We detected the increased levels of Bcl-2 (1.5-fold) expression and compared with saline controls. These differences were most pronounced at 12 h after transplantation. In contrast, an active form of proapoptotic caspase-3 (p20) protein was found to be 2.9-fold lower at 24 h in hemin-pretreated group, as compared to saline liver transpla

关键词： Aged liver Ischemia-reperfusion injury heme oxygenase-1

heme oxygenase-1 inhibits neuropathic pain in rats with diabetic mellitus

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Neural Regeneration Research 2012年第29期7卷 2305-2311页

作者： Qian Kong Kang Liu Lingxi Wu Long Wang Department of Anesthesiology Renmin Hospital of Wuhan University Wuhan 430060 Hubei Province China

A diabetes mellitus model was established through single intraperitoneal injection of streptozotocin into rats. Seven days later, model rats were intraperitoneally administered zinc protoporphyrin, a heme oxygenase-1 inducer, and cobalt protoporphyrin, a heme oxygenase-1 inhibitor, once every two days, for 5 successive weeks. After administration, the paw withdrawal mechanical threshold of diabetic mellitus rats significantly decreased, the myelin sheath of the sciatic nerve thickened or showed vacuole defects, the number of spinal dorsal horn neurons reduced, some neurons degenerated and were necrotic, and heme oxygenase-1 was visible in the cytoplasm of spinal dorsal hom neurons. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling demonstrated that the number of apoptotic neurons increased, which could be inhibited by cobalt protoporphyrin, however, zinc protoporphyrin led to an opposite effect. Our experimental findings indicate that heme oxygenase-1 attenuates neuropathic pain in diabetic mellitus rats through amelioration of peripheral neuropathy and inhibition of spinal dorsal horn neuron apoptosis.

关键词： diabetes mellitus neuropathic pain heme oxygenase-1 cobalt protoporphyrin zinc protoporphyrin neurons apoptosis peripheral nerve injury regeneration neural regeneration

Over-expression of heme oxygenase-1 Does not Protect Porcine Endothelial Cells from Human Xenoantibodies and Complement-mediated Lysis

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第1期33卷 102-106页

作者：张弛王璐钟山王筱啸向莹陈实陈刚 Institute of Organ Transplantation Ministry of Public HealthTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Urology Fujian Provincial Hospital Institute of Organ Transplantation Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Key Laboratory of Organ Transplantation Ministry of Public HealthTongji HospitalTongji Medical CollegeHuazhong University of Science and Technology

Accommodated organs can survive in the presence of anti-organ antibodies and complement. heme oxygenase-1 （HO-1） is essential to ensure accommodation in concordant xenotransplant models. However, whether induction of HO-1 over-expression could protect porcine endothelial cells （PECs） against human xenoantibodies and complement-mediated lysis and induce an in vitro accommodation is still unknown. The SV40-immortalized porcine aorta-derived endothelial cell line （iPEC） was pre-incubated with 20, 50, or 80 μmol/L of cobalt-protoporphyrins IX （CoPPIX） for 24 h, and the HO-1 expression in iPECs was analyzed by using Western blotting. CoPPIX-treated or untreated iPECs were incubated with normal human AB sera, and complement-dependent cytotoxicity （CDC） was measured by both flow cytometry and lactate dehydrogenase （LDH） release assay. In vitro treatment with CoPPIX significantly increased the expression of HO-1 in iPECs in a dose-dependent manner. Over-expression of HO-1 was successfully achieved by incubation of iPECs with either 50 or 80 μmol/L of CoPPIX. However, HO-1 over-expression did not show any protective effects on iPECs against normal human sera-mediated cell lysis. In conclusion, induction of HO-1 over-expression alone is not enough to pro- tect PECs from human xenoantibodies and complement-mediated humoral injury. Additionally, use of other protective strategies is needed to achieve accommodation in pig-to-primate xenotransplantation.

关键词： heme oxygenase-1 porcine endothelial cells complement-dependent cytotoxicity xenotransplantation

Quercetin protects against diabetic retinopathy in rats by inducing heme oxygenase-1 expression

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Neural Regeneration Research 2021年第7期16卷 1344-1350页

作者： Guang-Rui Chai Shu Liu Hong-Wei Yang Xiao-Long Chen Department of Ophthalmology Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Department of Geratology The First Affiliated Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

Quercetin is a widely-occurring flavonoid that protects against cancer, and improves memory and cardiovascular ***, whether quercetin exhibits therapeutic effects in diabetic retinopathy remains *** this study, we established a rat model of streptozocininduced diabetic ***-two hours later, the rats were intraperitoneally administered 150 mg/kg quercetin for 16 successive *** markedly increased the thickness of the retinal cell layer, increased the number of ganglion cells, and decreased the overexpression of the pro-inflammatory factors interleukin-1β, interleukin-18, interleukin-6 and tumor necrosis factor-α in the retinal tissue as well as the overexpression of high mobility group box-1 and the overactivation of the NLRP3 ***, quercetin inhibited the overexpression of TLR4 and NF-κBp65, reduced the expression of the pro-angiogenic vascular endothelial growth factor and soluble intercellular adhesion molecule-1, and upregulated the neurotrophins brain-derived neurotrophic factor and nerve growth *** injection of the heme oxygenase-1 inhibitor zinc protoporphyrin blocked the protective effect of *** findings suggest that quercetin exerts therapeutic effects in diabetic retinopathy possibly by inducing heme oxygenase-1 *** study was approved by the Animal Ethics Committee of China Medical University, China(approval No.2016 PS229K) on April 8, 2016.

关键词： angiogenesis diabetic retinopathy flavonoid heme oxygenase-1 inflammation neurotrophin quercetin repair