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Heme Oxygenase-1 in Kidney Health and Disease
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Pu Duann, Elias A. Lianos, Pei-Hui Lin
Heme oxygenase (HO) is the rate limiting enzyme catalyzing oxidative cleavage, with electrons delivered from NADPH via cytochrome P450 reductase (CPR), of the porphyrin ring of heme into equimolar by-products of ferrous iron (Fe2+), carbon monoxide (CO) and biliverdin (2) (Figure 1). Biliverdin is quickly converted by biliverdin reductase (BVR) into bilirubin which is ultimately expelled from body (11). Three different isoforms of heme oxygenase (HO) have been reported in mammalian, including the inducible HO-1 (encoded by HMOX1 gene) (12), the homeostatic low level and constitutively active HO-2 isoform (encoded by HMOX2 gene) (13), and the non-enzymatic HO-3 originally identified in rat brain (14). Based on phylogenic alignment, HO-3 evolved as a splicing variant from the HO-2 gene which binds heme but is deprived of catalytic activity (15). Both HO-1 and HO-2 are ubiquitously expressed and catalytically active. HO-2 is present in relatively high concentration in the brain, testis, and vascular endothelial cells (16,17), while HO-1 is more widely distributed. HO-1 is abundant in tissues rich with its substrate heme expression, such as muscle, erythroid-phagocytic system (liver and bone marrow) and spleen where abundant heme was released from senescent RBC processing and hemoglobin recycling for new heme synthesis (18,19).
Micronutrients for the Prevention and Improvement of the Standard Therapy for Parkinson’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
The levels of markers of oxidative damage and vitamin E were measured in 211 patients with PD and 135 healthy controls. The results showed that leukocyte 8-hydroxyguanosine and plasma malondialdehyde (MDA) were elevated, whereas erythrocyte glutathione peroxidase and plasma vitamin E levels were reduced in PD patients compared to the control subjects.118,119 Reduced glutathione levels were observed in the substantia nigra of the autopsied brain samples of PD patients indicating the presence of high oxidative stress.120–122 Reduced glutathione can impair mitochondrial function. Isofurans are products of lipid peroxidation and their formation is favored in the presence of high oxygen tension. The levels of Isofurans but not F2-isoprostane are elevated in the autopsied samples of the substantia nigra of PD patients.123 Heme oxygenase-1 (HO-1) is a cellular stress protein expressed in brain and other tissues, and becomes elevated in response to increased oxidative stress. The expression of HO-1 is upregulated in the autopsied samples of the substantia nigra of PD brain.124 The antioxidant capacity in the autopsied substantia nigra of PD brain was lower than control subjects.125 It has been reported that the NADH dehydrogenase activity in the platelets of PD patients were lowered compared to healthy age- and gender-matched controls, whereas the activity of succinate dehydrogenase was similar in both groups.126
Free-Radical Toxicity in Amyotrophic Lateral Sclerosis
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
Merit E. Cudkowicz, Robert H. Brown, Richard A. Smith
Free radicals are highly reactive and typically short-lived. It is difficult to measure their levels directly. Accordingly, several biochemical parameters are used to gauge indirectly the extent of oxidative damage to various cellular constituents; these include markers of oxidative damage to DNA, proteins, and lipids. Oxidative damage to DNA results in chemical changes in constituent bases. One that can be readily measured is 8-hydroxy-2-deoxyguanosine (OH8dG) (Ames 1987). Protein oxidation can be quantitated by measuring protein carbonyl groups in plasma and tissue (Floyd and Carney 1992; Halliwell and Aruoma 1995). 3-Nitrotyrosine is a marker for protein oxidation mediated by peroxynitrite (Schulz et al. 1995). Malondialehyde is a biochemical marker of lipid peroxidation (Gutteridge and Halliwell 1990). The enzyme heme oxygenase-1 (HO-1) is induced by oxidative stress (Dwyer, Nishimura, and Lu 1995); elevated HO-1 levels are thus often interpreted as evidence of oxidative toxicity.
HMOX1 Promotes Ferroptosis Induced by Erastin in Lens Epithelial Cell through Modulates Fe2+ Production
Published in Current Eye Research, 2023
Shengjie Liao, Mi Huang, Yanli Liao, Chao Yuan
HMOX1 could metabolize heme into carbon monoxide, iron, and biliverdin. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. To observe which by-products mediate the synergistic effect with erastin, CORM2, FeSO4, and bilirubin were added into HMOX1 knock-out cell medium with erastin. Figure 6(A) showed that CORM2 and bilirubin could not aggravate the cytotoxic effect of erastin in HMOX1 knock-out cells. Adding FeSO4 increase the sensitivity of the HLECs to erastin significantly. Then HMOX1 expression vector or empty vector were transiently transfected into HMOX1 knock-out cells, and cell viability and iron level were detected after 24 h treatment of erastin. Figure 6(B) showed that HMOX1 overexpression significantly decreased cell viability after erastin treatment. Indeed, total iron level increased when cells transfected with HMOX1 expression vector which could further increase after erastin treatment (Figure 6(C)). These data implied that iron liberated from heme by HMOX1 is a pivotal by-product that mediates the sensitivity elevation of erastin in HLECs.
Indomethacin: an exploratory study of antiviral mechanism and host-pathogen interaction in COVID-19
Published in Expert Review of Anti-infective Therapy, 2022
Nishant Shekhar, Harpinder Kaur, Phulen Sarma, Ajay Prakash, Bikash Medhi
Heme-oxygenase-1 (HMOX1) is the inducible isoform of heme-oxygenases (HO) that causes oxidative heme cleavage to biliverdine, carbon monoxide, and ferrous iron discharge, It has a regulatory role in intravascular inflammation activity [38]. Datillo (2020) using various studies, including Renieris (2020) explained that fatal SARS-CoV-2 infection leads to a very low level of serum H2S level in contrast to recovered cases [39,40]. In his model, Datillo proposed that SARS-CoV-2 infection downregulates HO-1 which leads to reduced heme breakdown, low CO concentration, which leads to low serum H2S concentration (HO-1/CO/H2S axis). Indomethacin is reported to consequently upregulate HO-1 levels in gastric mucosal cells of rats, according to Aburaya et al. (2006) [41]. In another gastric mucosal cell line study of rats, indomethacin was observed to reduce the indomethacin-induced mitochondrial oxidative stress (MOS) due to upregulation of HO-1 and prevention of MOS proinflammation [42]. These results point out the protective mechanism of HO-1 in response to oxidative stress and indomethacin-induced injury rather than directly modulating the HO-1 expression. The interaction of Orf3a with the HMOX1 gene might be associated with inhibition of HO-1 expression in SARS-CoV-2 infection since there is stated downregulation of HO-1 in SARS-CoV-2 affected individuals according to Datillo (2020). However, the effect of indomethacin in inducing HO-1 expression in SARS-CoV-2 infected patients remains undetermined.
Potential of Müller Glia for Retina Neuroprotection
Published in Current Eye Research, 2020
Karen Eastlake, Joshua Luis, G Astrid Limb
HO-1, also known as heat shock protein 32 (HSP32) forms another defence mechanism against oxidative stress. As indicated by its alternative name, HO-1 has a heat shock regulatory element. It also has additional regulatory elements in the promoter region. These elements bind to their respective inducers and cause transcription of the gene.89 HO-1 is inducible by a wide range of stimuli known to cause oxidative stress, such as hyperoxia, hypoxia, heat shock, endotoxins, cytokines and nitric oxide. HO-1 is involved in the heme catabolism and acts by cleaving the heme ring at the alpha methene bridge to produce the biologically active end products biliverdin, CO and ferrous ion.89 Various studies have demonstrated that the HO-1/CO system exhibits potent anti-oxidative, antiapoptotic, anti-inflammatory and cytoprotective activities against ischaemia-reperfusion injury, indicating a potential therapeutic use of these molecules to treat diseases associated with this type of injury.89 The transcription of HO-1 is regulated by NRF2 as evidenced in the Nrf2 knockout mice, which shows elevated oxidative stress that leads to RPE degeneration.90 Müller glia has been shown to express HO-1 protein, and its production is significantly upregulated upon exposure to advanced lipoxidation end products,91 suggesting that these products trigger a neuroprotective response by Müller cells within the retina.