scholarly journals The Protective Effect of Heme Oxygenase-1 on Liver Injury Caused by DON-Induced Oxidative Stress and Cytotoxicity

Toxins ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 732
Author(s):  
Zitong Meng ◽  
Liangliang Wang ◽  
Yuxiao Liao ◽  
Zhao Peng ◽  
Dan Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Antioxidant Enzyme ◽  
Cell Line ◽  
Heme Oxygenase ◽  
Toxic Effects ◽  
Heme Oxygenase 1 ◽  
Repair System ◽  
Damage Repair

Deoxynivalenol (DON) is a kind of Fusarium toxin that can cause a variety of toxic effects. Oxidative stress and DNA damage play a critical role in the toxicity of DON. However, previous studies focused more on acute toxicity in vivo/vitro models and lacked subchronic toxicity study in vivo. The potentially harmful effect of DON given at doses comparable to the daily human consumption in target organs, especially the liver, which is the main detoxification organ of DON, is also still not fully understood. Otherwise, Heme Oxygenase-1 (HO-1) has also reduced cell damage under the DON condition according to our previous study. Therefore, we used a rodent model that mimicked daily human exposure to DON and further explored its mechanism of toxic effects on liver tissue and Hepa 1–6 cell line. We also used adeno-associated virus (AAV)-modified HO-1 expressing by tail vein injection and constructed lentivirus-Hepa 1–6 cell line for mimicking HO-1 protective ability under the DON condition. The main results showed that both 30 d and 90 d exposures of DON could cause low-grade inflammatory infiltration around hepatic centrilobular veins. The reactive oxygen species (ROS) and 8-hydroxy-2 deoxyguanosine (8-OHdG) increased during DON exposure, indicating oxidation stress and DNA damage. Significantly, AAV-mediated liver-specific overexpression of HO-1 reduced DON-induced liver damage and indirectly protected the abilities of antioxidant enzyme/DNA damage repair system, while AAV-mediated silence of HO-1 produced the opposite effect. In addition, we found that overexpression of HO-1 could enhance autophagy and combined it with an antioxidant enzyme/DNA damage repair system to inhibit DON-induced hepatocyte damage. Altogether, these data suggest that HO-1 reduces the oxidative stress and DNA damage caused by DON sub-chronic exposure through maintaining DNA repair, antioxidant activity, as well as autophagy.

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

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
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.

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

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e64372 ◽  
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

scholarly journals Early heme oxygenase 1 induction delays tumour initiation and enhances DNA damage repair in liver macrophages of Mdr2−/− mice

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Roja Barikbin ◽  
Laura Berkhout ◽  
Julia Bolik ◽  
Dirk Schmidt-Arras ◽  
Thomas Ernst ◽  
...  
Keyword(s):  
Dna Damage ◽  
Heme Oxygenase ◽  
Dna Damage Repair ◽  
Heme Oxygenase 1 ◽  
Liver Macrophages ◽  
Damage Repair ◽  
Tumour Initiation

Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat

2019 ◽  
Vol 133 (1) ◽  
pp. 117-134 ◽  
Author(s):  
Pamela L. Martín ◽  
Paula Ceccatto ◽  
María V. Razori ◽  
Daniel E.A. Francés ◽  
Sandra M.M. Arriaga ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Bile Flow ◽  
Driving Forces ◽  
Membrane Lipids ◽  
Ex Vivo ◽  
Heme Oxygenase 1 ◽  
Canalicular Transporters

Abstract We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous BR levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6 and 8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert-butylhydroperoxide (tBuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by tBuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background.

scholarly journals Overexpression of Heme Oxygenase-1 in Mesenchymal Stem Cells Augments Their Protection on Retinal Cells In Vitro and Attenuates Retinal Ischemia/Reperfusion Injury In Vivo against Oxidative Stress

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Li Li ◽  
GaiPing Du ◽  
DaJiang Wang ◽  
Jin Zhou ◽  
Guomin Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Retinal Ischemia ◽  
Heme Oxygenase 1

Retinal ischemia/reperfusion (I/R) injury, involving several ocular diseases, seriously threatens human ocular health, mainly treated by attenuating I/R-induced oxidative stress. Currently, mesenchymal stem cells (MSCs) could restore I/R-injured retina through paracrine secretion. Additionally, heme oxygenase-1 (HO-1) could ameliorate oxidative stress and thus retinal apoptosis, but the expression of HO-1 in MSC is limited. Here, we hypothesized that overexpression of HO-1 in MSC (MSC-HO-1) may significantly improve their retina-protective potentials. The overexpression of HO-1 in MSC was achieved by lentivirus transduction. Then, MSC or MSC-HO-1 was cocultured with retinal ganglion cells (RGC-5) in H2O2-simulated oxidative condition and their protection on RGC-5 was systemically valuated in vitro. Compared with MSC, MSC-HO-1 significantly attenuated H2O2-induced injury of RGC-5, including decrease in cellular ROS level and apoptosis, activation of antiapoptotic proteins p-Akt and Bcl-2, and blockage of proapoptotic proteins cleaved caspase 3 and Bax. In retinal I/R rats model, compared with control MSC, MSC-HO-1-treated retina significantly retrieved its structural thickness, reduced cell apoptosis, markedly attenuated retinal oxidative stress level, and largely regained the activities of typical antioxidant enzymes, SOD and CAT. Therefore, it could be concluded that overexpression of HO-1 provides a promising strategy to enhance the MSC-based therapy for I/R-related retinal injury.

Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats

2011 ◽  
Vol 301 (5) ◽  
pp. R1540-R1548 ◽  
Author(s):  
Francisca Rodriguez ◽  
Bernardo Lopez ◽  
Cayetano Perez ◽  
Francisco J. Fenoy ◽  
Isabel Hernandez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Heme Oxygenase ◽  
Oral Treatment ◽  
Diabetic Rats ◽  
Renal Hemodynamics ◽  
Heme Oxygenase 1 ◽  
Acute Administration ◽  
Sprague Dawley

Heme oxygenase-1 (HO-1) is induced by oxidative stress and plays an important role in protecting the kidney from oxidant-mediated damage in the streptozotocin (STZ) rat model of type-1 diabetes mellitus (DM-1). HO-derived metabolites, presumably carbon monoxide (CO), mediate vasodilatory influences in the renal circulation, particularly in conditions linked to elevated HO-1 protein expression or diminished nitric oxide (NO) levels. We tested the hypothesis that diabetes increases oxidative stress and induces HO-1 protein expression, which contributes to regulate renal hemodynamics in conditions of low NO bioavailability. Two weeks after the induction of diabetes with STZ (65 mg/kg iv), Sprague-Dawley rats exhibited higher renal HO-1 protein expression, hyperglycemia, and elevated renal nitrotyrosine levels than control normoglycemic animals. In anesthetized diabetic rats, renal vascular resistance (RVR) was increased, and in vivo cortical NO levels were reduced ( P < 0.05) compared with control animals. Acute administration of the HO inhibitor Stannous mesoporphyrin (SnMP; 40 μmol/kg iv) did not alter renal hemodynamics in control rats, but greatly decreased glomerular filtration rate and renal blood flow, markedly increasing RVR in hyperglycemic diabetic rats. Chronic oral treatment with the SOD mimetic tempol prevented the elevation of nitrotyrosine, the HO-1 protein induction, and the increases in RVR induced by SnMP in the diabetic group, without altering basal NO concentrations or RVR. Increasing concentrations of a CO donor (CO-releasing molecule-A1) on pressurized renal interlobar arteries elicited a comparable relaxation in vessels taken from control or diabetic animals. These results suggest that oxidative stress-induced HO-1 exerts vasodilatory actions that partially maintain renal hemodynamics in uncontrolled DM-1.

A novel selective therapeutic targeting heme oxygenase-1 revealed a potent antimetastatic activity in androgen-refractory human prostate cancer models

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16090-e16090
Author(s):  
M. A. Alaoui-Jamali ◽  
A. Gupta ◽  
W. A. Szarek ◽  
T. A. Bismar ◽  
R. Gheorghe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Prostate Cancer ◽  
Cell Proliferation ◽  
Heme Oxygenase ◽  
Lung Metastases ◽  
Heme Oxygenase 1 ◽  
Hormone Refractory ◽  
Novel Therapeutic

e16090 Prostate cancer is a highly prevalent disease. Despite a significant improvement in the overall survival attributed in part to early detection and introduction of novel therapeutic modalities, many cancer patients at primary diagnosis present advanced disease or experience recurrence of the cancer. The progression of prostate cancer (PCA) to hormone-refractory phenotype (HRPCA) and to metastasis is an ominous event in patients with advanced PCA. Currently, clinically available drugs for hormone refractory PCA have only marginal efficacy. In this study, we identified heme oxygenase 1 (HO-1) to be significantly upregulated in epithelial PCA cells, but not in surrounding stromal cells, from hormone refractory prostate cancer cases compared to hormone-responsive prostate cancer and to benign tissues. We validated HO-1 as a novel therapeutic target for HRPCA. Specifically, inhibition of HO-1 gene in androgen-independent and highly invasive prostate cancer cells, PC3M, decreased HO-1 activity, oxidative stress, MAPKs activation, cell proliferation, and cell migration and invasion in vitro, as well as inhibition of prostate tumor growth and lymph nodes and lung metastases in vivo. The impact of HO-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively downregulates HO-1 activity, oxidative stress, and significantly inhibits cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity in inhibiting HRPCA metastasis formation was observed when OB-24 was combined with the chemotherapy drug taxol. The molecular and potential clinical impact of OB-24 alone and in combination with taxanes on HRPCA will be discussed. [Table: see text]

scholarly journals Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW 264.7 Macrophages through Activating the Nuclear Factor Erythroid 2-Related Factor-2/Heme Oxygenase-1 Pathway

Antioxidants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 82 ◽  
Author(s):  
Da Kwon ◽  
Hee-Jae Cha ◽  
Hyesook Lee ◽  
Su-Hyun Hong ◽  
Cheol Park ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Protective Effect ◽  
Heme Oxygenase ◽  
Raw 264.7 Cells ◽  
Heme Oxygenase 1 ◽  
Raw 264.7 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Raw 264.7 Macrophages

Reactive oxygen species (ROS), products of oxidative stress, contribute to the initiation and progression of the pathogenesis of various diseases. Glutathione is a major antioxidant that can help prevent the process through the removal of ROS. The aim of this study was to evaluate the protective effect of glutathione on ROS-mediated DNA damage and apoptosis caused by hydrogen peroxide, H2O2, in RAW 264.7 macrophages and to investigate the role of the nuclear factor erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. The results showed that the decrease in the survival rate of RAW 264.7 cells treated with H2O2 was due to the induction of DNA damage and apoptosis accompanied by the increased production of ROS. However, H2O2-induced cytotoxicity and ROS generation were significantly reversed by glutathione. In addition, the H2O2-induced loss of mitochondrial membrane potential was related to a decrease in adenosine triphosphate (ATP) levels, and these changes were also significantly attenuated in the presence of glutathione. These protective actions were accompanied by a increase in the expression rate of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) and poly(ADP-ribose) polymerase cleavage by the inactivation of caspase-3. Moreover, glutathione-mediated cytoprotective properties were associated with an increased activation of Nrf2 and expression of HO-1; however, the inhibition of the HO-1 function using an HO-1 specific inhibitor, zinc protoporphyrin IX, significantly weakened the cytoprotective effects of glutathione. Collectively, the results demonstrate that the exogenous administration of glutathione is able to protect RAW 264.7 cells against oxidative stress-induced mitochondria-mediated apoptosis along with the activity of the Nrf2/HO-1 signaling pathway.

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