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

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.

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 ◽  
...  

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.


2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Li Li ◽  
GaiPing Du ◽  
DaJiang Wang ◽  
Jin Zhou ◽  
Guomin Jiang ◽  
...  

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.


Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1694-1702 ◽  
Author(s):  
Christine Chauveau ◽  
Séverine Rémy ◽  
Pierre Joseph Royer ◽  
Marcelo Hill ◽  
Séverine Tanguy-Royer ◽  
...  

Abstract Heme oxygenase-1 (HO-1) is an intracellular enzyme that degrades heme and inhibits immune responses and inflammation in vivo. In most cell types, HO-1 is inducible by inflammatory stimuli and oxidative stress. Here we demonstrate that human monocyte-derived immature dendritic cells (iDCs) and several but not all freshly isolated rat splenic DC subsets and rat bone marrow-derived iDCs, spontaneously express HO-1. HO-1 expression drastically decreases during human and rat DC maturation induced in vitro. In human tissues, iDCs also express HO-1, whereas mature DCs do not. Induction of HO-1 expression with cobalt protoporphyrin (CoPP) in human and rat DCs inhibits lipopolysaccharide (LPS)-induced phenotypic maturation and secretion of proinflammatory cytokines, resulting in the inhibition of alloreactive T-cell proliferation. CoPP-treated DCs, however, retain the ability to produce the anti-inflammatory cytokine interleukin 10 (IL-10). Reactive oxygen species induced by LPS in DCs were inhibited by induction of HO-1. In conclusion, we identify, for the first time, the capacity of HO-1 to block maturation of DCs and to inhibit proinflammatory and allogeneic immune responses while preserving IL-10 production. This novel immune function for HO-1 may be of interest for the inhibition of immune responses in autoimmune diseases, transplantation, and other conditions involving activation of the immune system. (Blood. 2005;106:1694-1702)


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16090-e16090
Author(s):  
M. A. Alaoui-Jamali ◽  
A. Gupta ◽  
W. A. Szarek ◽  
T. A. Bismar ◽  
R. Gheorghe ◽  
...  

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]


2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Václav Šmíd ◽  
Jakub Šuk ◽  
Neli Kachamakova-Trojanowska ◽  
Jana Jašprová ◽  
Petra Valášková ◽  
...  

Heme oxygenase 1 (Hmox1), a ubiquitous enzyme degrading heme to carbon monoxide, iron, and biliverdin, is one of the cytoprotective enzymes induced in response to a variety of stimuli, including cellular oxidative stress. Gangliosides, sialic acid-containing glycosphingolipids expressed in all cells, are involved in cell recognition, signalling, and membrane stabilization. Their expression is often altered under many pathological and physiological conditions including cell death, proliferation, and differentiation. The aim of this study was to assess the possible role of Hmox1 in ganglioside metabolism in relation to oxidative stress. The content of liver and brain gangliosides, their cellular distribution, and mRNA as well as protein expression of key glycosyltransferases were determined inHmox1knockout mice as well as their wild-type littermates. To elucidate the possible underlying mechanisms between Hmox1 and ganglioside metabolism, hepatoblastoma HepG2 and neuroblastoma SH-SY5Y cell lines were used forin vitroexperiments. Mice lackingHmox1exhibited a significant increase in concentrations of liver and brain gangliosides and in mRNA expression of the key enzymes of ganglioside metabolism. A marked shift of GM1 ganglioside from the subsinusoidal part of the intracellular compartment into sinusoidal membranes of hepatocytes was shown inHmox1knockout mice. Induction of oxidative stress by chenodeoxycholic acidin vitroresulted in a significant increase in GM3, GM2, and GD1a gangliosides in SH-SY5Y cells and GM3 and GM2 in the HepG2 cell line. These changes were abolished with administration of bilirubin, a potent antioxidant agent. These observations were closely related to oxidative stress-mediated changes in sialyltransferase expression regulated at least partially through the protein kinase C pathway. We conclude that oxidative stress is an important factor modulating synthesis and distribution of gangliosidesin vivoandin vitrowhich might affect ganglioside signalling in higher organisms.


Author(s):  
Sohsuke Yamada ◽  
Xin Guo ◽  
Akihide Tanimoto

The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. Recently, we generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.


2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.


RMD Open ◽  
2018 ◽  
Vol 4 (2) ◽  
pp. e000744 ◽  
Author(s):  
Kerstin Klein

The reading of acetylation marks on histones by bromodomain (BRD) proteins is a key event in transcriptional activation. Small molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins compete for binding to acetylated histones. They have strong anti-inflammatory properties and exhibit encouraging effects in different cell types in vitro and in animal models resembling rheumatic diseases in vivo. Furthermore, recent studies that focus on BRD proteins beyond BET family members are discussed.


2011 ◽  
Vol 4 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Ružena Sotníková ◽  
Jana Nedelčevová ◽  
Jana Navarová ◽  
Viera Nosáľová ◽  
Katarína Drábiková ◽  
...  

Protection of the vascular endothelium in experimental situationsOne of the factors proposed as mediators of vascular dysfunction observed in diabetes is the increased generation of reactive oxygen species (ROS). This provides support for the use of antioxidants as early and appropriate pharmacological intervention in the development of late diabetic complications. In streptozotocin (STZ)-induced diabetes in rats we observed endothelial dysfuction manifested by reduced endothelium-dependent response to acetylcholine of the superior mesenteric artery (SMA) and aorta, as well as by increased endothelaemia. Changes in endothelium-dependent relaxation of SMA were induced by injury of the nitric oxide radical (·NO)-signalling pathway since the endothelium-derived hyperpolarising factor (EDHF)-component of relaxation was not impaired by diabetes. The endothelial dysfunction was accompanied by decreased ·NO bioavailabity as a consequence of reduced activity of eNOS rather than its reduced expression. The results obtained using the chemiluminiscence method (CL) argue for increased oxidative stress and increased ROS production. The enzyme NAD(P)H-oxidase problably participates in ROS production in the later phases of diabetes. Oxidative stress was also connected with decreased levels of reduced glutathione (GSH) in the early phase of diabetes. After 10 weeks of diabetes, adaptational mechanisms probably took place because GSH levels were not changed compared to controls. Antioxidant properties of SMe1EC2 foundin vitrowere partly confirmedin vivo.Administration of SMe1EC2 protected endothelial function. It significantly decreased endothelaemia of diabetic rats and improved endothelium-dependent relaxation of arteries, slightly decreased ROS-production and increased bioavailability of ·NO in the aorta. Further studies with higher doses of SMe1EC2 may clarify the mechanism of its endothelium-protective effectin vivo.


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