Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.

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TGF-β2 silencing to target biliary-derived liver diseases

Gut ◽

10.1136/gutjnl-2019-319091 ◽

2020 ◽

Vol 69 (9) ◽

pp. 1677-1690 ◽

Cited By ~ 4

Author(s):

Anne Dropmann ◽

Steven Dooley ◽

Bedair Dewidar ◽

Seddik Hammad ◽

Tatjana Dediulia ◽

...

Keyword(s):

Liver Disease ◽

Transforming Growth Factor Beta ◽

Liver Tissue ◽

Liver Diseases ◽

Transforming Growth Factor ◽

Early Stage ◽

Inflammatory Cells ◽

Mechanistic Explanation ◽

Primary Biliary Cholangitis ◽

Cholestatic Liver Disease

ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.ResultsTgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

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Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

Infection and Immunity ◽

10.1128/iai.01598-14 ◽

2014 ◽

Vol 82 (8) ◽

pp. 3113-3126 ◽

Cited By ~ 12

Author(s):

Sumanta Dey ◽

Somnath Mazumder ◽

Asim Azhar Siddiqui ◽

M. Shameel Iqbal ◽

Chinmoy Banerjee ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Function ◽

Heme Oxygenase ◽

Tissue Injury ◽

Parasite Clearance ◽

Plasmodium Yoelii ◽

Heme Oxygenase 1 ◽

Zinc Protoporphyrin ◽

Suitable Model ◽

Hepatocyte Apoptosis

ABSTRACTThe liver efficiently restores function after damage induced during malarial infection once the parasites are cleared from the blood. However, the molecular events leading to the restoration of liver function after malaria are still obscure. To study this, we developed a suitable model wherein mice infected withPlasmodium yoelii(45% parasitemia) were treated with the antimalarial α/β-arteether to clear parasites from the blood and, subsequently, restoration of liver function was monitored. Liver function tests clearly indicated that complete recovery of liver function occurred after 25 days of parasite clearance. Analyses of proinflammatory gene expression and neutrophil infiltration further indicated that hepatic inflammation, which was induced immediately after parasite clearance from the blood, was gradually reduced. Moreover, the inflammation in the liver after parasite clearance was found to be correlated positively with oxidative stress and hepatocyte apoptosis. We investigated the role of heme oxygenase 1 (HO-1) in the restoration of liver function after malaria because HO-1 normally renders protection against inflammation, oxidative stress, and apoptosis under various pathological conditions. The expression and activity of HO-1 were found to be increased significantly after parasite clearance. We even found that chemical silencing of HO-1 by use of zinc protoporphyrin enhanced inflammation, oxidative stress, hepatocyte apoptosis, and liver injury. In contrast, stimulation of HO-1 by cobalt protoporphyrin alleviated liver inflammation and reduced oxidative stress, hepatocyte apoptosis, and associated tissue injury. Therefore, we propose that selective induction of HO-1 in the liver would be beneficial for the restoration of liver function after parasite clearance.

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Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients

Journal of Hepatology ◽

10.1016/j.jhep.2004.11.040 ◽

2005 ◽

Vol 42 (4) ◽

pp. 585-591 ◽

Cited By ~ 93

Author(s):

Lucia Malaguarnera ◽

Roberto Madeddu ◽

Elisabetta Palio ◽

Nicolò Arena ◽

Mariano Malaguarnera

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Heme Oxygenase ◽

Fatty Liver Disease ◽

Heme Oxygenase 1 ◽

Alcoholic Fatty Liver ◽

And Oxidative Stress ◽

Alcoholic Fatty Liver Disease

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Faculty Opinions recommendation of Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089363.542588 ◽

2007 ◽

Author(s):

William Welch

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Heme Oxygenase ◽

Heme Oxygenase 1

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PS-074 Heme Oxygenase-1 Gene Promoter Polymorphism And Insulin Resistance Are Associated With Susceptibility To Non-alcoholic Fatty Liver Disease In Children

Archives of Disease in Childhood ◽

10.1136/archdischild-2014-307384.371 ◽

2014 ◽

Vol 99 (Suppl 2) ◽

pp. A138.3-A139

Author(s):

P Chang ◽

Y Lin ◽

K Liu ◽

S Yeh

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Heme Oxygenase ◽

Fatty Liver Disease ◽

Gene Promoter ◽

Promoter Polymorphism ◽

Heme Oxygenase 1 ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease ◽

Gene Promoter Polymorphism

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Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms22041514 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1514 ◽

Cited By ~ 1

Author(s):

Akihiro Yachie

Keyword(s):

Oxidative Stress ◽

Animal Models ◽

Heme Oxygenase ◽

Inflammatory Diseases ◽

Cell Types ◽

Pharmacological Intervention ◽

Heme Oxygenase 1 ◽

Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

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A polysaccharide of PFP-1 from Pleurotus geesteranus attenuates alcoholic liver diseases via Nrf2 and NF-κB signaling pathways

Food & Function ◽

10.1039/d1fo00310k ◽

2021 ◽

Author(s):

Xinling Song ◽

Wenxue Sun ◽

Wenxin Cai ◽

Le Jia ◽

Jianjun Zhang

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Liver Injury ◽

Signaling Pathways ◽

Alcoholic Liver Disease ◽

Fruiting Body ◽

Liver Diseases ◽

Alcoholic Liver Diseases

A polysaccharide named as PFP-1 was isolated from Pleurotus geesteranus fruiting body, and the potential investigations on ameliorating oxidative stress and liver injury against alcoholic liver disease (ALD) were processed...

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Resveratrol Protects C6 Astrocyte Cell Line against Hydrogen Peroxide-Induced Oxidative Stress through Heme Oxygenase 1

PLoS ONE ◽

10.1371/journal.pone.0064372 ◽

2013 ◽

Vol 8 (5) ◽

pp. e64372 ◽

Cited By ~ 80

Author(s):

André Quincozes-Santos ◽

Larissa Daniele Bobermin ◽

Alexandra Latini ◽

Moacir Wajner ◽

Diogo Onofre Souza ◽

...

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Cell Line ◽

Heme Oxygenase ◽

Heme Oxygenase 1

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Dexrazoxane does not protect against doxorubicin-induced damage in young rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00047.2003 ◽

2003 ◽

Vol 285 (2) ◽

pp. H499-H506 ◽

Cited By ~ 18

Author(s):

Stéphanie Héon ◽

Martin Bernier ◽

Nicolas Servant ◽

Stevan Dostanic ◽

Chunlei Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Weight Gain ◽

Heme Oxygenase ◽

Caspase 3 ◽

Exercise Program ◽

Female Rats ◽

Male Rats ◽

Heme Oxygenase 1 ◽

Cardiac Damage

Doxorubicin (DOX), an anticancer drug, causes a dose-dependent cardiotoxicity. Some evidence suggests that female children have an increased risk for DOX-mediated cardiac damage. To determine whether the iron chelator dexrazoxane (DXR) could reduce DOX-induced cardiotoxicity in the young, we injected day 10 neonate female and male rat pups with a single dose of saline or DOX, DXR, or DXR + DOX (20:1). We followed body weight gain with growth, measured cardiac hypertrophy after a 2-wk swim exercise program, markers of apoptosis (Bcl-2, BAX, BNIP1, caspase 3 activation), oxidative stress (heme oxygenase 1, protein carbonyl levels), the chaperone protein clusterin, and the transcriptional activator early growth response gene-1 (Egr-1) in hearts of nonexercised and exercised rats on neonate day 38. All DOX-alone and DXR + DOX-treated rats showed decreased weight gain, with female rats affected earlier than male rats. DXR-alone, DOX-alone, and DXR + DOX-treated rats had an increased heart weight-to-body weight (heart wt/body wt) ratio after the exercise program with female rats showing the largest increase in heart wt/body wt. Drug-treated females also showed increased cardiac apoptosis, as measured by the increased expression of the proapoptotic proteins BAX and BNIP1 and the appearance of caspase 3 activation products, and oxidative stress, as measured by increased heme oxygenase 1 expression, and reduced Egr-1 and clusterin expression when compared with the similarly treated male rats. We conclude that DXR preinjection did not reduce DOX-induced noncardiac and cardiac damage and that young female rats were more susceptible to DXR and DOX toxicities than age-matched male rats.

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