Isoflavone ME-344 Disrupts Redox Homeostasis and Mitochondrial Function by Targeting Heme Oxygenase 1

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.

Download Full-text

Pharmacological Targeting of Heme Oxygenase-1 in Osteoarthritis

Antioxidants ◽

10.3390/antiox10030419 ◽

2021 ◽

Vol 10 (3) ◽

pp. 419

Author(s):

Yohei Sanada ◽

Sho Joseph Ozaki Tan ◽

Nobuo Adachi ◽

Shigeru Miyaki

Keyword(s):

Heme Oxygenase ◽

Redox Homeostasis ◽

Synovial Fibroblasts ◽

Protective Role ◽

Joint Disease ◽

Heme Oxygenase 1 ◽

Transcriptional Level ◽

Related Factor ◽

Mobility Limitations ◽

Therapeutic Implications

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.

Download Full-text

Electroacupuncture Relieves Hippocampal Injury by Heme Oxygenase-1 to Improve Mitochondrial Function

Journal of Surgical Research ◽

10.1016/j.jss.2021.12.013 ◽

2022 ◽

Vol 273 ◽

pp. 15-23

Author(s):

Rui Mu ◽

Na Li ◽

Jian-bo Yu ◽

Li-rong Gong ◽

Shu-an Dong ◽

...

Keyword(s):

Heme Oxygenase ◽

Mitochondrial Function ◽

Heme Oxygenase 1

Download Full-text

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.

Download Full-text

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions

Biomolecules ◽

10.3390/biom11040589 ◽

2021 ◽

Vol 11 (4) ◽

pp. 589

Author(s):

Valeria Consoli ◽

Valeria Sorrenti ◽

Salvo Grosso ◽

Luca Vanella

Keyword(s):

Carbon Monoxide ◽

Heme Oxygenase ◽

Redox Homeostasis ◽

Transformation Products ◽

Antioxidant Response ◽

Heme Oxygenase 1 ◽

Ferrous Ions ◽

Biliverdin Reductase ◽

Rate Limiting Step

Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system.

Download Full-text

Role of ATM in Oxidative Stress-mediated c-Jun Phosphorylation in Response to Ionizing Radiation and CdCl2

Journal of Biological Chemistry ◽

10.1074/jbc.m004517200 ◽

2001 ◽

Vol 276 (15) ◽

pp. 11783-11790 ◽

Cited By ~ 47

Author(s):

Sung A. Lee ◽

Anatoly Dritschilo ◽

Mira Jung

Keyword(s):

Oxidative Stress ◽

Ionizing Radiation ◽

Heme Oxygenase ◽

Redox Homeostasis ◽

Heme Oxygenase 1 ◽

Second Phase ◽

Radiation Induced ◽

Factor C ◽

And Control

Ionizing radiation-induced phosphorylation of the transcription factor c-Jun is impaired in cells derived from individuals with ataxia telangiectasia (AT), in which theATMgene is mutated. We demonstrate here that ATM modulates c-Jun phosphorylation following exposure to ionizing radiation as well as treatment with CdCl2, a potent pro-oxidant. Exposure of AT and control fibroblasts to CdCl2induced a biphasic increase in c-Jun phosphorylation on serine residues 63 and 73, with the extent of the second phase being markedly greater in AT cells than in control cells. Heme oxygenase-1, a marker of oxidative stress, was also significantly induced in AT fibroblasts. Expression of recombinant ATM in AT fibroblasts, however, reduced the extent of the effects of CdCl2on both c-Jun phosphorylation and heme oxygenase-1 induction. Our data suggest that ATM contributes to oxidative stress-mediated signaling that leads to c-Jun phosphorylation by acting as a sensor of ionizing radiation-induced oxidative stress and by modulating intracellular redox homeostasis.

Download Full-text