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Li J, Zhang Q, Chen H, Xu D, Chen Z, Wen Y. Role of Heme Oxygenase-1 in Dual Stress Response of Herbicide and Micronutrient Fe in Arabidopsis thaliana. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:13499-13509. [PMID: 36223430 DOI: 10.1021/acs.jafc.2c04039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Increasingly intensive agricultural practices are leading not only to herbicide contamination but also to nutritional stress on nontarget plants. This study evaluated the role of heme oxygenase-1 (HO-1) in the dual stress response of herbicide dichlorprop and micronutrient Fe in Arabidopsis thaliana. Our results revealed that co-treatment with 20 μM zinc protoporphyrin (a specific inhibitor of HO-1) reduced the activity of HO-1 by 21.6%, Fe2+ content by 19.8%, and MDA content by 20.0%, reducing abnormal iron aggregation and oxidative stress in response to the herbicide compared to treatment with (R)-dichloroprop alone, which has herbicidal activity. Thus, free Fe2+ released from HO-1 mediated dichlorprop-induced oxidative stress in the Fenton reaction and affected aberrant Fe aggregation, which also had an enantioselective effect. This study contributes to an in-depth understanding of the toxicity mechanism of herbicides under nutrient stresses, thus providing new strategies to control the environmental risks of herbicides.
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Affiliation(s)
- Jun Li
- MOE Key Laboratory of Environmental Remediation & Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qiushui Zhang
- MOE Key Laboratory of Environmental Remediation & Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
| | - Hui Chen
- College of Science and Technology, Ningbo University, Ningbo 315211, China
| | - Dongmei Xu
- Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, College of Biological and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China
| | - Zunwei Chen
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts 02115, United States
| | - Yuezhong Wen
- MOE Key Laboratory of Environmental Remediation & Ecosystem Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China
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Beta-Carotene Affects the Effects of Heme Oxygenase-1 in Isolated, Ischemic/Reperfused Rat Hearts: Potential Role of the Iron. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27093039. [PMID: 35566389 PMCID: PMC9101800 DOI: 10.3390/molecules27093039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 11/16/2022]
Abstract
Beta-carotene (BC) is a well-known antioxidant. However, increasing evidence shows that under severe oxidative conditions, BC can become pro-oxidant, an effect that may be enhanced in the presence of iron (II). In our earlier studies, we observed that despite increasing heme oxygenase-1 (HO-1) levels in the heart, the protective effects of BC have been lost when it was used at a high concentration. Since iron releases from heme as a consequence of HO-1 activity, we hypothesized that the application of an iron-chelator (IC) would reverse the lost cardiac protection associated with an elevated HO-1 level. Thus, in the present study, we investigated the effects of desferrioxiamine (DFO) in isolated, ischemic/reperfused rat hearts after long-term treatment with vehicle or high-dose (HD) BC. Vehicle or 150 mg/bw kg daily doses of BC were administered to the rats for 4 weeks, and then their hearts were removed and subjected to 30 min of global ischemia (ISA) followed by 120 min of reperfusion (REP). During the experiments, cardiac function was registered, and at the end of the REP period, infarct size (IS) and HO-1 expression were measured. The results show that DFO treatment alone during REP significantly ameliorated postischemic cardiac function and decreased IS, although HO-1 expression was not increased significantly. In hearts isolated from BC-treated rats, no cardioprotective effects, despite an elevated HO-1 level, were observed, while DFO administration after ISA resulted in a mild improvement in heart function and IS. Our results suggest that iron could have a role whether BC exerts antioxidant or pro-oxidant effects in ISA/REP-injured hearts.
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Liu W, Lu L, Pan H, He X, Zhang M, Wang N, Zhu J, Yi H, Tang S. Haem oxygenase-1 and haemopexin gene polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity in China. Pharmacogenomics 2022; 23:431-441. [PMID: 35470713 DOI: 10.2217/pgs-2022-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Objective: To assess whether the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) might be influenced by haem oxygenase-1 (HMOX1) and haemopexin (HPX) gene polymorphisms. Methods: A dynamic anti-tuberculosis treatment cohort was constructed, and the 1:4 matched nested case-control study was analysed. Eight single nucleotide polymorphisms (SNPs) of the two genes were selected for genotyping and Bonferroni correction was performed to correct for multiple comparison. Results: Overall, 7.8% of patients developed ATDH. SNP rs1807714 in the HMOX1 gene had decreased effects on the risk of moderate and severe hepatotoxicity under the dominant and additive models, and hepatocellular injury under the additive model. SNP rs2682099 in the HPX gene had increased effects on the risk of moderate and severe hepatotoxicity under the recessive model. However, these associations disappeared after Bonferroni correction. Conclusion: HMOX1 and HPX gene polymorphisms might not be associated with susceptibility to ATDH in the Chinese population.
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Affiliation(s)
- Wenpei Liu
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Lihuan Lu
- Department of Tuberculosis, The Second People's Hospital of Changshu, Changshu, 215500, China
| | - Hongqiu Pan
- Department of Tuberculosis, The Third People's Hospital of Zhenjiang Affiliated to Jiangsu University, Zhenjiang, 212021, China
| | - Xiaomin He
- Department of Infectious Disease, The People's Hospital of Taixing, Taixing, 225400, China
| | - Meiling Zhang
- Department of Infectious Disease, The Jurong Hospital Affiliated to Jiangsu University, Jurong, 212400, China
| | - Nannan Wang
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Jia Zhu
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Honggang Yi
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Shaowen Tang
- Department of Epidemiology & Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
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Bouvier ML, Fehsel K, Schmitt A, Meisenzahl-Lechner E, Gaebel W, von Wilmsdorff M. Sex-dependent effects of long-term clozapine or haloperidol medication on red blood cells and liver iron metabolism in Sprague Dawley rats as a model of metabolic syndrome. BMC Pharmacol Toxicol 2022; 23:8. [PMID: 35033194 PMCID: PMC8760835 DOI: 10.1186/s40360-021-00544-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 12/23/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Patients with liver diseases often have some form of anemia. Hematological dyscrasias are known side effects of antipsychotic drug medication and the occurrence of agranulocytosis under clozapine is well described. However, the sex-dependent impact of clozapine and haloperidol on erythrocytes and symptoms like anemia, and its association with hepatic iron metabolism has not yet been completely clarified. Therefore, in the present study, we investigated the effect of both antipsychotic drugs on blood parameters and iron metabolism in the liver of male and female Sprague Dawley rats. METHODS After puberty, rats were treated orally with haloperidol or clozapine for 12 weeks. Blood count parameters, serum ferritin, and liver transferrin bound iron were determined by automated counter. Hemosiderin (Fe3+) was detected in liver sections by Perl's Prussian blue staining. Liver hemoxygenase (HO-1), 5'aminolevulinate synthase (ALAS1), hepcidin, heme-regulated inhibitor (HRI), cytochrome P4501A1 (CYP1A1) and 1A2 (CYP1A2) were determined by Western blotting. RESULTS We found anemia with decreased erythrocyte counts, associated with lower hemoglobin and hematocrit, in females with haloperidol treatment. Males with clozapine medication showed reduced hemoglobin and increased red cell distribution width (RDW) without changes in erythrocyte numbers. High levels of hepatic hemosiderin were found in the female clozapine and haloperidol medicated groups. Liver HRI was significantly elevated in male clozapine medicated rats. CYP1A2 was significantly reduced in clozapine medicated females. CONCLUSIONS The characteristics of anemia under haloperidol and clozapine medication depend on the administered antipsychotic drug and on sex. We suggest that anemia in rats under antipsychotic drug medication is a sign of an underlying liver injury induced by the drugs. Changing hepatic iron metabolism under clozapine and haloperidol may help to reduce these effects of liver diseases.
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Affiliation(s)
- Marie-Luise Bouvier
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstraße 2, 40629, Düsseldorf, Germany.
| | - Karin Fehsel
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstraße 2, 40629, Düsseldorf, Germany
| | - Andrea Schmitt
- Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians University Munich, Nußbaumstrasse 7, 80336, Munich, Germany.,Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovidio Pires de Campos 785, São Paulo, SP, 05453-010, Brazil
| | - Eva Meisenzahl-Lechner
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstraße 2, 40629, Düsseldorf, Germany
| | - Wolfgang Gaebel
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstraße 2, 40629, Düsseldorf, Germany
| | - Martina von Wilmsdorff
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstraße 2, 40629, Düsseldorf, Germany
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Feng X, Wang S, Sun Z, Dong H, Yu H, Huang M, Gao X. Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice. Front Endocrinol (Lausanne) 2021; 12:626390. [PMID: 33679620 PMCID: PMC7930496 DOI: 10.3389/fendo.2021.626390] [Citation(s) in RCA: 202] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/06/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Ferroptosis is a recently identified iron-dependent form of cell death as a result of increased reactive oxygen species (ROS) and lipid peroxidation. In this study, we investigated whether ferroptosis aggravated diabetic nephropathy (DN) and damaged renal tubules through hypoxia-inducible factor (HIF)-1α/heme oxygenase (HO)-1 pathway in db/db mice. METHODS Db/db mice were administered with or without ferroptosis inhibitor Ferrostatin-1 treatment, and were compared with db/m mice. RESULTS Db/db mice showed higher urinary albumin-to-creatinine ratio (UACR) than db/m mice, and Ferrostatin-1 reduced UACR in db/db mice. Db/db mice presented higher kidney injury molecular-1 and neutrophil gelatinase-associated lipocalin in kidneys and urine compared to db/m mice, with renal tubular basement membranes folding and faulting. However, these changes were ameliorated in db/db mice after Ferrostatin-1 treatment. Fibrosis area and collagen I were promoted in db/db mouse kidneys as compared to db/m mouse kidneys, which was alleviated by Ferrostatin-1 in db/db mouse kidneys. HIF-1α and HO-1 were increased in db/db mouse kidneys compared with db/m mouse kidneys, and Ferrostatin-1 decreased HIF-1α and HO-1 in db/db mouse kidneys. Iron content was elevated in db/db mouse renal tubules compared with db/m mouse renal tubules, and was relieved in renal tubules of db/db mice after Ferrostatin-1 treatment. Ferritin was increased in db/db mouse kidneys compared with db/m mouse kidneys, but Ferrostatin-1 reduced ferritin in kidneys of db/db mice. Diabetes accelerated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS formation in mouse kidneys, but Ferrostatin-1 prevented ROS formation derived by NADPH oxidases in db/db mouse kidneys. The increased malondialdehyde (MDA) and the decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GSH-Px) were detected in db/db mouse kidneys compared to db/m mouse kidneys, whereas Ferrostatin-1 suppressed MDA and elevated SOD, CAT, and GSH-Px in db/db mouse kidneys. Glutathione peroxidase 4 was lower in db/db mouse kidneys than db/m mouse kidneys, and was exacerbated by Ferrostatin-1 in kidneys of db/db mice. CONCLUSIONS Our study indicated that ferroptosis might enhance DN and damage renal tubules in diabetic models through HIF-1α/HO-1 pathway.
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Affiliation(s)
- Xiaomeng Feng
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- *Correspondence: Xiaomeng Feng, ; Xia Gao,
| | - Shuo Wang
- Department of Infectious Diseases, Beijing Traditional Chinese Medical Hospital, Capital Medical University, Beijing, China
| | - Zhencheng Sun
- Department of Osteology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Hengbei Dong
- Department of Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Haitian Yu
- Education Division, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Mengxiu Huang
- Department of Hepatobiliary, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xia Gao
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
- *Correspondence: Xiaomeng Feng, ; Xia Gao,
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SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis. Cells 2020; 9:cells9112510. [PMID: 33233553 PMCID: PMC7699810 DOI: 10.3390/cells9112510] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/14/2022] Open
Abstract
Background: Sirtuin 3 (SIRT3) has a crucial role in the cardiovascular diseases. Our previous study revealed that SIRT3 knockout (SIRT3KO) promoted cardiac pericyte–fibroblast transition. In this study, we investigated the involvement of pericyte and iron in angiotensin II (Ang-II)-mediated renal fibrosis in the SIRT3KO mice. Methods and Results: NG2-DsRed mice and NG2-DsRed-SIRT3 knockout (SIRT3KO) mice were infused with saline or Ang-II (1000 ng/kg/min) for 4 weeks. Renal fibrosis, iron content and reactive oxygen species (ROS) were measured. Masson’s trichrome staining showed that SIRT3KO enhanced Ang-II-induced renal fibrosis. Immunostaining showed that Ang-II treatment increased the number of NG2-DsRed+ cells in the kidney, and SIRT3KO further enhanced NG2-DsRed+ cells. Moreover, SIRT3KO promoted pericyte differentiation into fibroblasts as evidenced by co-staining NG2-DsRed/FSP-1. Furthermore, DsRed/FSP-1+ and DsRed/transforming growth factor-β1 (TGF-β1)+ fibroblasts were elevated by SIRT3KO after Ang-II infusion. Ang-II-induced collagen I and TGF-β1 expression was also enhanced in the SIRT3KO mice. SIRT3KO significantly exacerbated Ang-II-induced iron accumulation. This was accompanied by an increase in acetyl-p53, HO-1 and FPN expression. Further, SIRT3KO sensitized Ang-II-induced upregulation of p47phox and gp91phox together with increased ROS formation in the kidney. Conclusion: Our study suggests that SIRT3 deficiency sensitized Ang-II-induced renal fibrosis by the mechanisms involved in promoting differentiation of pericytes into fibroblasts, exacerbating iron overload and accelerating NADPH oxidase-derived ROS formation.
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Helal MG, El-Kashef DH. Krill oil alleviates oxidative stress, iron accumulation and fibrosis in the liver and spleen of iron-overload rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2020; 27:3950-3961. [PMID: 31823254 DOI: 10.1007/s11356-019-06983-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 11/06/2019] [Indexed: 06/10/2023]
Abstract
Krill oil (KO) is a recent supplement which is rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids are found in both krill oil and fish oil. In krill oil, they esterified to phospholipids, but in fish oil, they are esterified to triacylglycerols. The target of this study was to investigate whether KO could help against iron overload-induced toxicity in liver and spleen. Rats were randomly assigned into 3 categories: control rats, rats received iron in a drinking water for 8 weeks followed by either vehicle or KO (40 mg/kg) treatment for an extra 8 weeks. Extent of hepatic and splenic injury was assessed via biochemical, histopathological and immunohistochemical evaluations. KO effectively improved the microscopic features of liver and spleen. Moreover, it decreased the increased levels of serum transaminases, ALP, LDH, iron, and ferritin and increased albumin serum level as well. In addition, it restored the balance between oxidants and antioxidants in the hepatic and splenic tissues. Furthermore, it decreased HO-1 levels, upregulated the production of Nrf2, and limited the expression of MMP9. These findings altogether suggest that KO might be a new candidate for treatment of iron overload-induced toxicity. Graphical abstract Graphical abstract.
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Affiliation(s)
- Manar G Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Dalia H El-Kashef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
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Atwa A, Hegazy R, Mohsen R, Yassin N, Kenawy S. Protective Effects of the Third Generation Vasodilatory Βeta - Blocker Nebivolol against D-Galactosamine - Induced Hepatorenal Syndrome in Rats. Open Access Maced J Med Sci 2017; 5:880-892. [PMID: 29362613 PMCID: PMC5771289 DOI: 10.3889/oamjms.2017.173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 08/27/2017] [Accepted: 11/25/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND: Renal dysfunction is very common in patients with advanced liver cirrhosis and portal hypertension. The development of renal failure in the absence of clinical, anatomical or pathological causes renal of failure is termed hepatorenal syndrome (HRS). AIM: The present study was constructed to investigate the possible protective effects of nebivolol (Nebi) against D-galactosamine (Gal)-induced HRS in rats. MATERIAL AND METHODS: Rats were treated with Nebi for ten successive days. On the 8th day of the experiment, they received a single dose of Gal. Serum levels of Cr, BUN, Na+ and K+ as well as AST, ALT, total bilirubin (TB), NH3 and endothelin-1 (ET-1) were determined following Gal administration. Moreover, renal and liver contents of MDA, GSH, F2-isoprostanes (F2-IPs), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-B (NF-κB), total nitric oxide (NO), in addition to activities of caspase-3 (Cas-3), heme oxygenase-1 (HO-1), inducible and endothelial NO synthase (iNOS and eNOS) enzymes were also assessed. Finally, histopathological examination was performed. RESULTS: Nebi attenuated Gal-induced renal and hepatic dysfunction. It also decreased the Gal-induced oxidative stress and inflammatory recruitment. CONCLUSION: Results demonstrated both nephroprotective and hepatoprotective effects of Nebi against HRS and suggested a role of its antioxidant, anti-inflammatory, anti-apoptotic and NO-releasing properties.
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Affiliation(s)
- Ahmed Atwa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Egypt
| | - Rehab Hegazy
- Department of Pharmacology, Medical Division, National Institution Research, Giza, Egypt
| | - Rania Mohsen
- Departement of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Neamat Yassin
- Department of Pharmacology, Medical Division, National Institution Research, Giza, Egypt
| | - Sanaa Kenawy
- Departement of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Decreased hepatic iron in response to alcohol may contribute to alcohol-induced suppression of hepcidin. Br J Nutr 2016; 115:1978-86. [PMID: 27080262 DOI: 10.1017/s0007114516001197] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatic Fe overload has often been reported in patients with advanced alcoholic liver disease. However, it is not known clearly whether it is the effect of alcohol that is responsible for such overload. To address this lacuna, a time-course study was carried out in mice in order to determine the effect of alcohol on Fe homoeostasis. Male Swiss albino mice were pair-fed Lieber-DeCarli alcohol diet (20 % of total energy provided as alcohol) for 2, 4, 8 or 12 weeks. Expression levels of duodenal and hepatic Fe-related proteins were determined by quantitative PCR and Western blotting, as were Fe levels and parameters of oxidative stress in the liver. Alcohol induced cytochrome P4502E1 and oxidative stress in the liver. Hepatic Fe levels and ferritin protein expression dropped to significantly lower levels after 12 weeks of alcohol feeding, with no significant effects at earlier time points. This was associated, at 12 weeks, with significantly decreased liver hepcidin expression and serum hepcidin levels. Protein expressions of duodenal ferroportin (at 8 and 12 weeks) and divalent metal transporter 1 (at 8 weeks) were increased. Serum Fe levels rose progressively to significantly higher levels at 12 weeks. Histopathological examination of the liver showed mild steatosis, but no stainable Fe in mice fed alcohol for up to 12 weeks. In summary, alcohol ingestion by mice in this study affected several Fe-related parameters, but produced no hepatic Fe accumulation. On the contrary, alcohol-induced decreases in hepatic Fe levels were seen and may contribute to alcohol-induced suppression of hepcidin.
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Lee JC, Kim IH, Park JH, Ahn JH, Cho JH, Cho GS, Tae HJ, Chen BH, Yan BC, Yoo KY, Choi JH, Lee CH, Hwang IK, Cho JH, Kwon YG, Kim YM, Won MH. Ischemic preconditioning protects hippocampal pyramidal neurons from transient ischemic injury via the attenuation of oxidative damage through upregulating heme oxygenase-1. Free Radic Biol Med 2015; 79:78-90. [PMID: 25483558 DOI: 10.1016/j.freeradbiomed.2014.11.022] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 11/05/2014] [Accepted: 11/25/2014] [Indexed: 01/17/2023]
Abstract
Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic injury by activating specific mechanisms. In this study, we tested the hypothesis that IPC attenuates postischemic neuronal death via heme oxygenase-1 (HO-1). Animals used in this study were randomly assigned to 4 groups; sham-operated group, ischemia-operated group, IPC plus (+) sham-operated group and IPC+ischemia-operated group. IPC was induced by subjecting gerbils to 2min of ischemia followed by 1 day of recovery. A significant loss of neurons was observed in pyramidal neurons of the hippocampal CA1 region (CA1) in the ischemia-operated groups at 5 days postischemia. In the IPC+ischemia-operated groups, CA1 pyramidal neurons were well protected. The level of HO-1 protein and its activity increased significantly in the CA1 of the IPC+sham-operated group, and the level and activity was maintained in all the time after ischemia-reperfusion compared with the ischemia-operated groups. HO-1 immunoreactivity was induced in the CA1 pyramidal neurons in both IPC+sham-operated- and IPC+ischemia-operated groups. We also found that levels or immunoreactivities of superoxide anion, 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal were significantly decreased in the CA1 of both IPC+sham-operated- and IPC+ischemia-operated groups. Whereas, treatment with zinc protoporphyrin IX (a HO-1 inhibitor) into the IPC+ischemia-operated groups did not preserve the IPC-mediated increase of HO-1 and lost beneficial effects of IPC by inhibiting ischemia-induced DNA damage and lipid peroxidation. In brief, IPC protects CA1 pyramidal neurons from ischemic injury by upregulating HO-1, and we suggest that the enhancement of HO-1 expression by IPC may be a legitimate strategy for a therapeutic intervention of cerebral ischemic damage.
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Affiliation(s)
- Jae-Chul Lee
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - In Hye Kim
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - Joon Ha Park
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - Ji Hyeon Ahn
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - Jeong-Hwi Cho
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - Geum-Sil Cho
- Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, South Korea
| | - Hyun-Jin Tae
- Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 200-702, South Korea
| | - Bai Hui Chen
- Department of Physiology, College of Medicine, Hallym University, Chuncheon 200-702, South Korea
| | - Bing Chun Yan
- Institute of Integrative Traditional & Western Medicine & Medical College, Yangzhou University, Yangzhou 225-001, China
| | - Ki-Yeon Yoo
- Department of Oral Anatomy, College of Dentistry, Gangneung-Wonju National University, Gangneung 210-702, South Korea
| | - Jung Hoon Choi
- Department of Anatomy, College of Veterinary Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - Choong Hyun Lee
- Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan 330-714, South Korea
| | - In Koo Hwang
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, South Korea
| | - Jun Hwi Cho
- Department of Emergency Medicine, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea
| | - Young-Guen Kwon
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea
| | - Young-Myeong Kim
- Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
| | - Moo-Ho Won
- Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, South Korea.
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Pretorius E, Kell DB. Diagnostic morphology: biophysical indicators for iron-driven inflammatory diseases. Integr Biol (Camb) 2014; 6:486-510. [PMID: 24714688 DOI: 10.1039/c4ib00025k] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Most non-communicable diseases involve inflammatory changes in one or more vascular systems, and there is considerable evidence that unliganded iron plays major roles in this. Most studies concentrate on biochemical changes, but there are important biophysical correlates. Here we summarize recent microscopy-based observations to the effect that iron can have major effects on erythrocyte morphology, on erythrocyte deformability and on both fibrinogen polymerization and the consequent structure of the fibrin clots formed, each of which contributes significantly and negatively to such diseases. We highlight in particular type 2 diabetes mellitus, ischemic thrombotic stroke, systemic lupus erythematosus, hereditary hemochromatosis and Alzheimer's disease, while recognizing that many other diseases have co-morbidities (and similar causes). Inflammatory biomarkers such as ferritin and fibrinogen are themselves inflammatory, creating a positive feedback that exacerbates disease progression. The biophysical correlates we describe may provide novel, inexpensive and useful biomarkers of the therapeutic benefits of successful treatments.
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Affiliation(s)
- Etheresia Pretorius
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag x323, Arcadia 0007, South Africa.
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12
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Espinoza A, Morales S, Arredondo M. Effects of acute dietary iron overload in pigs (Sus scrofa) with induced type 2 diabetes mellitus. Biol Trace Elem Res 2014; 158:342-52. [PMID: 24699828 DOI: 10.1007/s12011-014-9944-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Accepted: 03/12/2014] [Indexed: 01/29/2023]
Abstract
Epidemiological studies have reported an association between high iron (Fe) levels and elevated risk of developing type 2 diabetes mellitus (T2D). It is believed that the formation of Fe-catalyzed hydroxyl radicals may contribute to the development of diabetes. Our goal was to determine the effect of a diet with a high Fe content on type 2 diabetic pigs. Four groups of piglets were studied: (1) control group, basal diet; (2) Fe group, basal diet with 3,000 ppm ferrous sulfate; (3) diabetic group (streptozotocin-induced type 2 diabetes) with basal diet; (4) diabetic/Fe group, diabetic animals/3,000 ppm ferrous sulfate. For 2 months, biochemical and hematological parameters were evaluated. Tissue samples of liver and duodenum were obtained to determine mRNA relative abundance of DMT1, ferroportin (Fpn), ferritin (Fn), hepcidin (Hpc), and transferrin receptor by qRT-PCR. Fe group presented increased levels of hematological (erythrocytes, hematocrit, and hemoglobin) and iron parameters. Diabetic/Fe group showed similar behavior as Fe group but in lesser extent. The relative abundance of different genes in the four study groups yielded a different expression pattern. DMT1 showed a lower expression in the two iron groups compared with control and diabetic animals, and Hpc showed an increased on its expression in Fe and diabetic/Fe groups. Diabetic/Fe group presents greater expression of Fn and Fpn. These results suggest that there is an interaction between Fe nutrition, inflammation, and oxidative stress in the diabetes development.
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MESH Headings
- Analysis of Variance
- Animals
- Blood Glucose/metabolism
- C-Reactive Protein/metabolism
- Cation Transport Proteins/genetics
- Cholesterol/blood
- Cholesterol, LDL/blood
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Diet
- Duodenum/drug effects
- Duodenum/metabolism
- Ferritins/genetics
- Ferrous Compounds/administration & dosage
- Ferrous Compounds/metabolism
- Gene Expression/drug effects
- Hepcidins/genetics
- Iron Overload/metabolism
- Iron Overload/physiopathology
- Iron, Dietary/administration & dosage
- Iron, Dietary/metabolism
- Liver/drug effects
- Liver/metabolism
- Male
- Receptors, Transferrin/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Sus scrofa
- Time Factors
- Triglycerides/blood
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Affiliation(s)
- A Espinoza
- Micronutrient laboratory, Nutrition Institute and Food Technology (INTA), University of Chile, El Líbano 5524, Macul, Santiago, Chile
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Wang QM, Du JL, Duan ZJ, Guo SB, Sun XY, Liu Z. Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation. World J Gastroenterol 2013; 19:2921-2934. [PMID: 23704825 PMCID: PMC3660817 DOI: 10.3748/wjg.v19.i19.2921] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Revised: 03/08/2013] [Accepted: 03/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of the heme oxygenase (HO)-1/carbon monoxide system on iron deposition and portal pressure in rats with hepatic fibrosis induced by bile duct ligation (BDL).
METHODS: Male Sprague-Dawley rats were divided randomly into a Sham group, BDL group, Fe group, deferoxamine (DFX) group, zinc protoporphyrin (ZnPP) group and cobalt protoporphyrin (CoPP) group. The levels of HO-1 were detected using different methods. The serum carboxyhemoglobin (COHb), iron, and portal vein pressure (PVP) were also quantified. The plasma and mRNA levels of hepcidin were measured. Hepatic fibrosis and its main pathway were assessed using Van Gieson’s stain, hydroxyproline, transforming growth factor-β1 (TGF-β1), nuclear factor-E2-related factor 2 (Nrf2), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1).
RESULTS: Serum COHb and protein and mRNA expression levels of HO-1 and Nrf2 were increased in the BDL group compared with the Sham group and were much higher in the CoPP group. The ZnPP group showed lower expression of HO-1 and Nrf2 and lower COHb. The levels of iron and PVP were enhanced in the BDL group but were lower in the ZnPP and DFX groups and were higher in the CoPP and Fe groups. Hepcidin levels were higher, whereas superoxide dismutase levels were increased and malonaldehyde levels were decreased in the ZnPP and DFX groups. The ZnPP group also showed inhibited TGF-β1 expression and regulated TIMP-1/MMP-2 expression, as well as obviously attenuated liver fibrosis.
CONCLUSION: Reducing hepatic iron deposition and CO levels by inhibiting HO-1 activity though the Nrf2/Keap pathway could be helpful in improving hepatic fibrosis and regulating PVP.
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Wang QM, Duan ZJ, Du JL, Guo SB, Sun XY, Liu Z. Heme oxygenase/carbon monoxide pathway inhibition plays a role in ameliorating fibrosis following splenectomy. Int J Mol Med 2013; 31:1186-94. [PMID: 23525258 DOI: 10.3892/ijmm.2013.1309] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 02/22/2013] [Indexed: 11/06/2022] Open
Abstract
Splenectomy is a recognized therapy for liver cirrhosis with splenomegaly, since it decreases free iron concentration that accompanies the destruction of red blood cells. Heme oxygenase (HO)-1 and its by-products, iron and carbon monoxide (CO), play crucial roles in hepatic fibrosis. The aim of the present study was to determine whether splenectomy in cirrhotic rats induced by bile duct ligation (BDL), through the HO/CO pathway, could slow down the development of liver fibrosis. Male Sprague-Dawley rats were divided randomly into the sham, BDL, splenectomy, Fe, zinc protoporphyrin (Znpp) and cobalt protoporphyrin (Copp) treatment groups, for inhibiting and inducing HO-1 expression. The level of HO-1 was detected by western blot analysis and reverse transcription-polymerase chain reaction. Serum carboxyhemoglobin (COHb), iron and portal vein pressure (PVP) were also quantified. Liver iron was measured by atomic absorption spectrometry with acetylene-air flame atomization. HO-1 and α-smooth muscle actin (α-SMA) were localized by immunohistochemistry. Liver and spleen iron were visualized by Perls' Prussian blue staining. Hepatic fibrosis was assessed using hematoxylin and eosin (H&E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum transforming growth factor-β1 (TGF-β1). The results showed that liver, spleen and serum levels of HO-1, COHb and iron were greatly enhanced in the BDL group compared with the sham group; they were reduced following splenectomy and Znpp treatment, but were elevated in the Copp and Fe groups. Hydroxyproline, TGF-β1, α-SMA, PVP and malonaldehyde levels were lower in the splenectomy and Znpp groups compared to BDL, while higher levels were observed in the Copp and Fe-treated groups. Our study shows that splenectomy reduces iron and CO levels in part by reducing HO-1 expression, and it decreases portal pressure and slightly decreases hepatic fibroproliferation.
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Affiliation(s)
- Qiu-Ming Wang
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
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Transient increase of free iron in rat livers following hemorrhagic-traumatic shock and reperfusion is independent of heme oxygenase 1 upregulation. Shock 2012; 36:501-9. [PMID: 21841538 DOI: 10.1097/shk.0b013e318231822d] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Hemorrhagic-traumatic shock (HTS) followed by reperfusion induces heme oxygenase (HO) 1. Free iron (Fe2+) may cause oxidative stress, if not adequately sequestered. We aimed to characterize HO-1-mediated effects on Fe2+ levels in liver and transferrin-bound iron (TFBI) in plasma following HTS, including laparotomy, bleeding, and inadequate and adequate reperfusion. Anesthetized rats showed upregulated HO-1 mRNA at 40 min after HTS, which was followed by increased HO activity at 3 h after shock. Fe2+ levels were transiently increased at 40 min after shock, a time point when HO activity was not affected yet. Levels of plasma TFBI were higher in HTS animals, showing the highest levels at 40 min after shock, and decreased thereafter. In addition, we modulated HO activity 6 h before HTS by administering an inhibitor (zinc-protoporphyrin IX) or an activator (hemin) of HO. At 18 h after HTS in all shock groups, HO activity was increased, the highest being in the hemin-pretreated group. The zinc-protoporphyrin IX-treated HTS animals showed increased HO-1 mRNA and Fe2+ levels in the liver compared with the untreated HTS animals. Transferrin-bound iron levels were affected by pharmacological modulation before shock. All animals undergoing HTS displayed increased TFBI levels after reperfusion; however, in animals pretreated with hemin, TFBI levels increased less. Our data indicate that increase in Fe2+ levels in liver and plasma early after HTS is not mediated by HO-1 upregulation, but possibly reflects an increased mobilization from internal iron stores or increased cell damage. Thus, upregulation of HO activity by hemin does not increase Fe2+ levels following HTS and reperfusion.
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Heme oxygenase-1 induction restores high-blood-flow-dependent remodeling and endothelial function in mesenteric arteries of old rats. J Hypertens 2011; 29:102-12. [DOI: 10.1097/hjh.0b013e32833db36e] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Vankrunkelsven A, De Ceulaer K, Hsu D, Liu FT, De Baetselier P, Stijlemans B. Lack of galectin-3 alleviates trypanosomiasis-associated anemia of inflammation. Immunobiology 2010; 215:833-41. [PMID: 20605052 DOI: 10.1016/j.imbio.2010.05.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2010] [Accepted: 05/20/2010] [Indexed: 12/24/2022]
Abstract
A typical pathological feature associated with experimental African trypanosomiasis (Trypanosoma brucei infection in mice) is anemia of chronic disease (ACD), which is due to a sustained type 1 cytokine-mediated inflammation and hyperactivation of M1 macrophages. Galectin-3 (Gal-3) was amply documented to contribute to the onset and persistence of type 1 inflammatory responses and we herein document that this protein is strongly upregulated during T. brucei infection. We evaluated the involvement of Gal-3 in trypanosomiasis-associated anemia using galectin-3 deficient (Gal3(-/-)) mice. T. brucei infected Gal3(-/-) mice manifested significant lower levels of anemia during infection and survived twice as long as wild type mice. Moreover, such mice showed increased levels of serum IL-10 and reduced liver pathology (as evidenced by lower AST/ALT levels). In addition, there was also an increase in gene expression of iron export genes and a reduced expression of genes, which are associated with accumulation of cellular iron. Our data indicate that Gal-3 is involved in the development of inflammation-associated anemia during African trypanosomiasis, possibly due to a disturbed iron metabolism that in turn may also lead to liver malfunction.
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Affiliation(s)
- Ann Vankrunkelsven
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
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18
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Wang J, Ma H, Boor PJ, Sadagopa Ramanujam VM, Ansari G, Khan MF. Up-regulation of heme oxygenase-1 in rat spleen after aniline exposure. Free Radic Biol Med 2010; 48:513-8. [PMID: 19969074 PMCID: PMC2818702 DOI: 10.1016/j.freeradbiomed.2009.11.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Revised: 11/13/2009] [Accepted: 11/24/2009] [Indexed: 11/18/2022]
Abstract
The splenic toxicity of aniline is characterized by vascular congestion, hyperplasia, fibrosis, and the development of a variety of sarcomas in rats. However, the underlying mechanisms by which aniline elicits splenotoxic response are not well understood. Previously we have shown that aniline exposure causes oxidative damage to the spleen. To further explore the oxidative mechanism of aniline toxicity, we evaluated the potential contribution of heme oxygenase-1 (HO-1), which catalyzes heme degradation and releases free iron. Male SD rats were given 1 mmol/kg/day aniline in water by gavage for 1, 4, or 7 days, and respective controls received water only. Aniline exposure led to significant increases in HO-1 mRNA expression in the spleen (2-and 2.4-fold at days 4 and 7, respectively) with corresponding increases in protein expression, as confirmed by ELISA and Western blot analysis. Furthermore, immunohistochemical assessment of spleen showed stronger immunostaining for HO-1 in the spleens of rats treated for 7 days, confined mainly to the red pulp areas. No changes were observed in mRNA and protein levels of HO-1 after 1 day exposure. The increase in HO-1 expression was associated with increases in total iron (2.4-and 2.7-fold), free iron (1.9-and 3.5-fold), and ferritin levels (1.9-and 2.1-fold) at 4 and 7 days of aniline exposure. Our data suggest that HO-1 up-regulation in aniline-induced splenic toxicity could be a contributing pro-oxidant mechanism, mediated through iron release, and leading to oxidative damage.
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Affiliation(s)
- Jianling Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - Huaxian Ma
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - Paul J. Boor
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - V. M. Sadagopa Ramanujam
- Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, TX, USA
| | - G.A.S. Ansari
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - M. Firoze Khan
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
- Address for Correspondence: M. Firoze Khan, Ph.D., Professor, Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0438, Tel: 409-772-6881, Fax: 409-747-1763,
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Butt OI, Buehler PW, D'Agnillo F. Differential induction of renal heme oxygenase and ferritin in ascorbate and nonascorbate producing species transfused with modified cell-free hemoglobin. Antioxid Redox Signal 2010; 12:199-208. [PMID: 19659432 DOI: 10.1089/ars.2009.2798] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Abstract Heme catabolism and iron sequestration systems play an important role in regulating the response to extracellular hemoglobin (Hb). We previously reported that extracellular Hb oxidizes more readily in the circulation of guinea pigs, a nonascorbate (AA)-producing species with similar plasma and tissue antioxidant status to humans, compared to rats, an AA-producing species. To determine whether these two species exhibit differences in heme catabolism and iron sequestration at the level of the kidney, we examined heme oxygenase (HO), H- and L-ferritin expression, nonheme iron deposition, and renal AA content following transfusion with polymerized bovine hemoglobin (HbG). Both species showed similar rates of hemoglobinuria but urinary HbG was significantly more oxidized in guinea pigs. HbG enhanced HO activity in both species but appeared greater and more sustained in guinea pigs. Conversely, rats showed a greater and more rapid induction of H- and L-ferritin as well as greater iron accumulation and AA content. Furthermore, ferrous and ferric iron deposits were detected in rats while only ferric iron was observed in guinea pigs. These findings suggest significant differences in the renal handling of HbG which may be important for understanding how endogenous antioxidant defenses may modulate the renal response to extracellular Hb.
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Affiliation(s)
- Omer I Butt
- Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA
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Khan ZA, Farhangkhoee H, Barbin YP, Adams PC, Chakrabarti S. Glucose-induced regulation of novel iron transporters in vascular endothelial cell dysfunction. Free Radic Res 2009; 39:1203-10. [PMID: 16298746 DOI: 10.1080/10715760500143254] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Increased iron indices have been associated with the development of diabetes and its complications. In the present study, we have investigated the glucose-induced alteration of iron transporters, divalent metal transporter-1 (DMT-1), iron regulated transporter protein-1 (IREG-1), and transferrin receptor (TfR), in endothelial cell iron accumulation and oxidative stress. Cells were exposed to high glucose levels and subjected to gene expression, protein expression, iron measurement and assessment of oxidative stress. Our results show, for the first time, expression of DMT-1 and IREG-1 in vascular endothelial cells. Our data further indicates upregulation of DMT-1 and IREG-1 mRNA and protein in response to high levels of glucose. TfR, however, exhibited a modest decrease in response to high levels of glucose. Increased expression of DMT-1 and IREG-1 was associated with iron accumulation and oxidative stress. Furthermore, our results show differential expression of iron transporters with treatment of high glucose-exposed cells with two different iron chelators. In conclusion, our study suggests that glucose-induced alteration of iron transporters may arbitrate iron accumulation and oxidative stress in endothelial cells.
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Affiliation(s)
- Zia A Khan
- Department of Pathology, University of Western Ontario, London, Canada
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Haemolytic anaemia and alterations in hepatic iron metabolism in aged mice lacking Cu,Zn-superoxide dismutase. Biochem J 2009; 420:383-90. [PMID: 19296829 DOI: 10.1042/bj20082137] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The continuous recycling of haem iron following phagocytosis and catabolism of senescent and damaged red blood cells by macrophages is a crucial process in the maintenance of systemic iron homoeostasis. However, little is known about macrophage iron handling in haemolytic states resulting from a deficiency in antioxidant defences. Our observations indicate that the recently described chronic, but moderate regenerative, haemolytic anaemia of aged SOD1 (superoxide dismutase 1)-knockout mice is associated with red blood cell modifications and sensitivity to both intra- and extra-vascular haemolysis. In the present study, we have characterized the molecular pathways of iron turnover in the liver of Sod1-deficient mice. Despite iron accumulation in liver macrophages, namely Kupffer cells, we did not measure any significant change in non-haem liver iron. Interestingly, in Kupffer cells, expression of the rate-limiting enzyme in haem degradation, haem oxygenase-1, and expression of the iron exporter ferroportin were both up-regulated, whereas the hepcidin mRNA level in the liver was decreased in Sod1-/- mice. These results suggest that concerted changes in the hepatic expression of iron- and haem-related genes in response to haemolytic anaemia in Sod1-/- mice act to reduce toxic iron accumulation in the liver and respond to the needs of erythropoiesis.
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Zijlstra GS, Brandsma CA, Harpe MFH, Van Dam GM, Slebos DJ, Kerstjens HAM, De Boer AH, Frijlink HW. Dry powder inhalation of hemin to induce heme oxygenase expression in the lung. Eur J Pharm Biopharm 2007; 67:667-75. [PMID: 17537624 DOI: 10.1016/j.ejpb.2007.03.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2007] [Revised: 03/20/2007] [Accepted: 03/21/2007] [Indexed: 11/23/2022]
Abstract
The purpose of this study was to formulate hemin as a powder for inhalation and to show proof of concept of heme oxygenase 1 (HO-1) expression in the lungs of mice by inhalation of hemin. Hemin was spray dried from a neutralized sodium hydroxide solution. The particle size distribution of the powder was between 1 and 5 microm. Dispersion from the Twincer dry powder inhaler showed a fine particle fraction (<5 microm) of 36%. A specially designed aerosol box based on the Twincer-inhaler was used for a proof of concept study of HO-1 induction by inhalation of hemin in mice. The aerosol in the exposure chamber of the aerosol box remained aerosolized up to 5 min. A rhodamin B containing aerosol was used to show that the aerosol box gave deposition over the entire lung indicating the suitability of the model. Additionally, inhalation of hemin showed a dose dependent increase in HO-1 protein expression in the lungs. In conclusion, hemin was successfully formulated as a powder for inhalation and the inhalation model allowed controlled HO-1 expression in the lungs of mice. Future studies investigating the utility of inhaled hemin in treating disease states are warranted.
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Affiliation(s)
- G S Zijlstra
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
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Farhangkhoee H, Khan ZA, Chen S, Chakrabarti S. Differential effects of curcumin on vasoactive factors in the diabetic rat heart. Nutr Metab (Lond) 2006; 3:27. [PMID: 16848894 PMCID: PMC1543622 DOI: 10.1186/1743-7075-3-27] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2006] [Accepted: 07/18/2006] [Indexed: 01/06/2023] Open
Abstract
Background Increased oxidative stress has been associated with the pathogenesis of chronic diabetic complications, including cardiomyopathy. Recent studies indicate that curcumin, a potent antioxidant, may be beneficial in preventing diabetes-induced oxidative stress and subsequent secondary complications. We have investigated the effects of curcumin on the nitric oxide (NO) pathway in cardiac tissues and cultured cells. Methods Streptozotocin-induced diabetic rats were treated with curcumin for a period of one month. Heart tissues were then analyzed for endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) mRNA expression. Oxidative protein and DNA damage were assessed by immunohistochemical analysis of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Heart tissues were further subjected to endothelin-1 (ET-1) mRNA expression. In order to further characterize the effects of curcumin, we assayed microvascular endothelial cells (MVECs). Cultured MVECs, exposed either to glucose or glucose and varying concentrations of curcumin, were assessed for alterations of NOS expression and activation of nuclear factor-κB (NF-κB) and activating protein-1 (AP-1). Oxidative stress and ET-1 expression levels were also assayed. Results Our results indicate that one month of diabetes causes an upregulation of both eNOS and iNOS mRNA levels, and nitrotyrosine and 8-OHdG immunoreactivity in the heart. Treatment of diabetic rats with curcumin reduced eNOS and iNOS levels in association with reduced oxidative DNA and protein damage. Interestingly, curcumin further increased vasoconstrictor ET-1 in the heart. Exposure of MVECs to high glucose increased both eNOS and iNOS levels and oxidative stress. Curcumin prevented NOS alteration and oxidative stress in a dose-dependent manner which was mediated by nuclear factor-κB and activating protein-1. Exposure to curcumin also increased ET-1 levels in the MVECs. Conclusion Our studies indicate the differential effects of curcumin in vasoactive factor expression in the heart and indicate the importance of tissue microenvironment in the treatment of diabetic complications.
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Affiliation(s)
- Hana Farhangkhoee
- Department of Pathology, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Zia A Khan
- Department of Pathology, The University of Western Ontario, London, Ontario N6A 5C1, Canada
- Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Harvard Medical School, MA 02115, USA
| | - Shali Chen
- Department of Pathology, The University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Subrata Chakrabarti
- Department of Pathology, The University of Western Ontario, London, Ontario N6A 5C1, Canada
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Kirkby KA, Adin CA. Products of heme oxygenase and their potential therapeutic applications. Am J Physiol Renal Physiol 2006; 290:F563-71. [PMID: 16461755 DOI: 10.1152/ajprenal.00220.2005] [Citation(s) in RCA: 176] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Heme oxygenase 1 (HO-1) is induced in response to cellular stress and is responsible for converting the prooxidant heme molecule into equimolar quantities of biliverdin (BV), carbon monoxide (CO), and iron. BV is then converted to bilirubin (BR) by the enzyme biliverdin reductase. Experimental evidence suggests that induction of the HO system is an important endogenous mechanism for cytoprotection and that the downstream products of heme degradation, CO, BR, and BV, may mediate these powerful beneficial effects. These molecules, which were once considered to be toxic metabolic waste products, have recently been shown to have dose-dependent vasodilatory, antioxidant, and anti-inflammatory properties that are particularly desirable for tissue protection during organ transplantation. In fact, recent work has demonstrated that administration of exogenous CO, BR, or BV may offer a simple, inexpensive method to substitute for the cytoprotective effects of HO-1 in a variety of clinically applicable models. This review will attempt to summarize the relevant biochemical and cytoprotective properties of CO, BR, and BV, and will discuss emerging studies involving the therapeutic applications of these molecules in the kidney and other organ systems.
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Affiliation(s)
- Kristin A Kirkby
- The Comparative Nephrology and Transplantation Laboratory, Dept. of Small Animal Clinical Sciences, Veterinary Medical Teaching Hospital, PO Box 100126, Univ. of Florida, Gainesville, FL 32610-0126, USA
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