Pharmacological Targeting of Heme Oxygenase-1 in Osteoarthritis

Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. Here, we review the protective role of HO-1 in OA with a focus on the regulatory mechanisms that mediate HO-1 activity.

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Heme Oxygenase-1 in Central Nervous System Malignancies

Journal of Clinical Medicine ◽

10.3390/jcm9051562 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1562 ◽

Cited By ~ 3

Author(s):

Giuseppe Sferrazzo ◽

Michelino Di Rosa ◽

Eugenio Barone ◽

Giovanni Li Volti ◽

Nicolò Musso ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Tumors ◽

Heme Oxygenase ◽

Biological Effects ◽

Redox Homeostasis ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Childhood Malignancies ◽

Pediatric Solid Tumors

Central nervous system tumors are the most common pediatric solid tumors and account for 20–25% of all childhood malignancies. Several lines of evidence suggest that brain tumors show altered redox homeostasis that triggers the activation of various survival pathways, leading to disease progression and chemoresistance. Among these pathways, heme oxygenase-1 (HO-1) plays an important role. HO-1 catalyzes the enzymatic degradation of heme with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin. The biological effects of HO-1 in tumor cells have been shown to be cell-specific since, in some tumors, its upregulation promotes cell cycle arrest and cellular death, whereas, in other neoplasms, it is associated with tumor survival and progression. This review focuses on the role of HO-1 in central nervous system malignancies and the possibility of exploiting such a target to improve the outcome of well-established therapeutic regimens. Finally, several studies show that HO-1 overexpression is involved in the development and resistance of brain tumors to chemotherapy and radiotherapy, suggesting the use of HO-1 as an innovative therapeutic target to overcome drug resistance. The following keywords were used to search the literature related to this topic: nuclear factor erythroid 2 p45-related factor 2, heme oxygenase, neuroblastoma, medulloblastoma, meningioma, astrocytoma, oligodendroglioma, glioblastoma multiforme, and gliomas.

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Trilobatin Protects Cardiomyocytes from Hypoxia/ Reperfusion Injury by Regulating the Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:133-138 ◽

2020 ◽

Vol 19 (2) ◽

pp. 133-138

Author(s):

Wenyu Chen ◽

Hui He

Keyword(s):

Heme Oxygenase ◽

Molecular Mechanisms ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Cellular Injury ◽

Nuclear Factor ◽

Oxygen Species ◽

H9c2 Cells ◽

Natural Plant ◽

Induced Changes

Trilobatin is a natural plant-derived glycosylated flavonoid that has been shown to exhibit multiple beneficial pharmacologic activities including protection of heart against H/R-induced cardiomyocyte injury. However, the molecular mechanisms underlying protection from H/R-induced cardiomyocyte injury remain unknown. Using H9C2 cells as a model, we examined the effect of trilobatin on H/R-induced cellular injury, apoptosis, and generation of reactive oxygen species. The results showed that trilobatin protected H9C2 cells not only from cell death and apoptosis, but also counteracted H/R-induced changes in malondialdehyde, superoxide dismutase, glutathione, and glutathione peroxidase. The evaluation of the mechanism underlying the effect of trilobatin on protection from H/R-induced cellular injury suggested changes in the regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

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Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases

Current Pharmaceutical Design ◽

10.2174/1381612824666180717160623 ◽

2018 ◽

Vol 24 (20) ◽

pp. 2283-2302 ◽

Cited By ~ 9

Author(s):

Vivian B. Neis ◽

Priscila B. Rosa ◽

Morgana Moretti ◽

Ana Lucia S. Rodrigues

Keyword(s):

Neurodegenerative Diseases ◽

Heme Oxygenase ◽

Therapeutic Potential ◽

Redox Homeostasis ◽

Antioxidant Defenses ◽

Heme Oxygenase 1 ◽

Physiological Conditions ◽

And Oxidative Stress ◽

Defensive Mechanism

Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review.

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Heme-Mediated Activation of the Nrf2/HO-1 Axis Attenuates Calcification of Valve Interstitial Cells

Biomedicines ◽

10.3390/biomedicines9040427 ◽

2021 ◽

Vol 9 (4) ◽

pp. 427

Author(s):

Enikő Balogh ◽

Arpan Chowdhury ◽

Haneen Ababneh ◽

Dávid Máté Csiki ◽

Andrea Tóth ◽

...

Keyword(s):

Target Gene ◽

Interstitial Cells ◽

Protective Role ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Valvular Interstitial Cells ◽

Aortic Valves ◽

Antioxidant Genes ◽

Valve Interstitial Cells ◽

Nrf2 Target Gene

Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of a variety of antioxidant genes, and plays a protective role in valve calcification. Heme oxygenase-1 (HO-1), an Nrf2-target gene, is upregulated in human calcified aortic valves. Therefore, we investigated the effect of Nrf2/HO-1 axis in VIC calcification. We induced osteogenic differentiation of human VICs with elevated phosphate and calcium-containing osteogenic medium (OM) in the presence of heme. Heme inhibited Ca deposition and OM-induced increase in alkaline phosphatase and osteocalcin (OCN) expression. Heme induced Nrf2 and HO-1 expression in VICs. Heme lost its anti-calcification potential when we blocked transcriptional activity Nrf2 or enzyme activity of HO-1. The heme catabolism products bilirubin, carbon monoxide, and iron, and also ferritin inhibited OM-induced Ca deposition and OCN expression in VICs. This study suggests that heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs. The anti-calcification effect of heme is attributed to the end products of HO-1-catalyzed heme degradation and ferritin.

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Maltol inhibits the progression of osteoarthritis via the nuclear factor-erythroid 2-related factor-2/heme oxygenase-1 signal pathway in vitro and in vivo

Food & Function ◽

10.1039/d0fo02325f ◽

2021 ◽

Author(s):

Ding-Chao Zhu ◽

Yi-Han Wang ◽

Jia-Hao Lin ◽

Zhi-Min Miao ◽

Jia-Jing Xu ◽

...

Keyword(s):

Cartilage Degeneration ◽

Degenerative Joint Disease ◽

Signal Pathway ◽

Joint Disease ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Articular Cartilage Degeneration

Osteoarthritis (OA) is a common degenerative joint disease characterized by articular cartilage degeneration and inflammation. Currently, there is hardly any effective treatment for OA due to its complicated pathology and...

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Activation of Extracellular Signal–Regulated Kinase Mediates Apoptosis Induced by UropathogenicEscherichia coliToxins via Nitric Oxide Synthase: Protective Role of Heme Oxygenase–1

The Journal of Infectious Diseases ◽

10.1086/421243 ◽

2004 ◽

Vol 190 (1) ◽

pp. 127-135 ◽

Cited By ~ 25

Author(s):

Ming Chen ◽

Wenjie Bao ◽

Roman Aizman ◽

Ping Huang ◽

Olle Aspevall ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Heme Oxygenase ◽

Protective Role ◽

Heme Oxygenase 1 ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Oxide Synthase

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A Dual Role of Heme Oxygenase-1 in Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20010039 ◽

2018 ◽

Vol 20 (1) ◽

pp. 39 ◽

Cited By ~ 48

Author(s):

Shih-Kai Chiang ◽

Shuen-Ei Chen ◽

Ling-Chu Chang

Keyword(s):

Cell Death ◽

Heme Oxygenase ◽

Cancer Progression ◽

Critical Role ◽

Causative Factor ◽

Protective Role ◽

Dark Side ◽

Heme Oxygenase 1 ◽

Cellular Iron

Heme oxygenase (HO)-1 is known to metabolize heme into biliverdin/bilirubin, carbon monoxide, and ferrous iron, and it has been suggested to demonstrate cytoprotective effects against various stress-related conditions. HO-1 is commonly regarded as a survival molecule, exerting an important role in cancer progression and its inhibition is considered beneficial in a number of cancers. However, increasing studies have shown a dark side of HO-1, in which HO-1 acts as a critical mediator in ferroptosis induction and plays a causative factor for the progression of several diseases. Ferroptosis is a newly identified iron- and lipid peroxidation-dependent cell death. The critical role of HO-1 in heme metabolism makes it an important candidate to mediate protective or detrimental effects via ferroptosis induction. This review summarizes the current understanding on the regulatory mechanisms of HO-1 in ferroptosis. The amount of cellular iron and reactive oxygen species (ROS) is the determinative momentum for the role of HO-1, in which excessive cellular iron and ROS tend to enforce HO-1 from a protective role to a perpetrator. Despite the dark side that is related to cell death, there is a prospective application of HO-1 to mediate ferroptosis for cancer therapy as a chemotherapeutic strategy against tumors.

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The Protective Role of Resveratrol against Arsenic Trioxide-Induced Cardiotoxicity

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/407839 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Weiqian Zhang ◽

Changming Guo ◽

Ruifeng Gao ◽

Ming Ge ◽

Yanzhu Zhu ◽

...

Keyword(s):

Arsenic Trioxide ◽

Cardiac Dysfunction ◽

Oxidative Dna Damage ◽

Antioxidant Properties ◽

Reactive Oxygen Species Generation ◽

Protective Role ◽

Natural Food ◽

Heme Oxygenase 1 ◽

Related Factor

Arsenic trioxide (As2O3) shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Unfortunately, limiting the application of this effective agent to APL patients is severe cardiotoxicity. Resveratrol, the natural food-derived polyphenolic compound, is well known for its antioxidant properties and protects the cardiovascular system. But the potential role of resveratrol against As2O3in heart via nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) is unclear. The present study evaluated the effects of pretreatment with resveratrol and As2O3on oxidative stress and cardiac dysfunction in rat. In the present study, resveratrol decreased As2O3-induced reactive oxygen species generation, oxidative DNA damage, and pathological alterations. In addition, cardiac dysfunction parameters, intracellular calcium and arsenic accumulation, glutathione redox ratio, and cAMP deficiency levels were observed in As2O3-treated rats; these changes were attenuated by resveratrol. Furthermore, resveratrol significantly prohibited the downregulation of both Nrf2 and HO-1 gene expressions that were downregulated by As2O3, whereas resveratrol did not alter As2O3-induced nitric oxide formation. Thus, the protective role of resveratrol against As2O3-induced cardiotoxicity is implemented by the maintenance of redox homeostasis (Nrf2-HO-1 pathway) and facilitating arsenic efflux. Our findings suggest coadministration with resveratrol, and As2O3might provide a novel therapeutic strategy for APL.

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6-Gingerol Ameliorates Sepsis Induced Acute Lung Injury by Regulating Nuclear Factor-κB and Nuclear-Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Signaling Pathways

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:255-260 ◽

2020 ◽

Vol 19 (3) ◽

pp. 255-260

Author(s):

Fan Yang ◽

Lu Deng ◽

MuHu Chen ◽

Ying Liu ◽

Jianpeng Zheng

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Heme Oxygenase ◽

Interleukin 1 ◽

Nuclear Factor Κb ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Alveolar Collapse ◽

Factor Α

Acute lung injury initiated systemic inflammation leads to sepsis. Septic mice show a series of degenerative changes in lungs as demonstrated by pulmonary congestion, alveolar collapse, inflammatory cell infiltration, and increased wet-todry weight in lungs. 6-Gingerol ameliorates histopathological changes and clinical outcome of the sepsis. The increase in the levels of tumor necrosis factor-α, interleukin-1 beta, interleukin-6, and interleukin-18 in septic mice were reduced by administration with 6-Gingerol. Also, 6-Gingerol attenuates sepsis-induced increase of malonaldehyde and decrease of catalase, superoxide, and glutathione. Enhanced phospho-p65, reduced nuclear factor erythropoietin-2-related factor 2, and heme oxygenase 1 in septic mice were reversed by administration with 6-Gingerol. In conclusion, 6-Gingerol demonstrates anti-inflammatory and antioxidant effects against sepsis associated acute lung injury through inactivation of nuclear factor-kappa B and activation of nuclear-factor erythroid 2-related factor 2 pathways.

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