scholarly journals A novel mechanism of heme degradation to biliverdin studied by QM/MM and QM calculations

2018 ◽  
Vol 47 (25) ◽  
pp. 8283-8291 ◽  
Author(s):  
Fatemeh Sadat Alavi ◽  
Mahin Gheidi ◽  
Mansour Zahedi ◽  
Nasser Safari ◽  
Ulf Ryde
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Iron Homeostasis ◽  
Heme Degradation

Heme degradation by heme oxygenase enzymes is important for maintaining iron homeostasis and prevention of oxidative stress.

Abstract P338: Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Hibba Chaudhry ◽  
Alexandra Nichols ◽  
Komal Sodhi ◽  
Krithika Srikanthan ◽  
Athar Nawab
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Iron Homeostasis ◽  
Transmembrane Protein ◽  
Low Grade ◽  
Obese Mice ◽  
Liver Iron ◽  
Cellular Iron ◽  
Cobalt Protoporphyrin ◽  
Stress Response System

Hepcidin, a phase II reactant secreted by hepatocytes, regulates cellular iron levels by increasing internalization of ferroportin- a transmembrane protein facilitating egress of cellular iron. Chronic low-grade inflammatory states, such as obesity, have been shown to increase oxidative stress and enhance hepcidin secretion from hepatocytes and macrophages. Heme-heme oxygenase (HO) is a stress response system, the induction of which reduces oxidative stress thereby abating patho-physiological conditions such as obesity and metabolic syndrome.8 week old male obese (ob) mice and their age- and sex-matched lean mice were used as controls. CoPP was administered intraperitoneally once a week (3 mg/kg) for 6 weeks to obese mice. CoPP plus stannous mesoporphyrin (SnMP) was administered intraperitoneally three times a week (20 mg/kg) for 6 weeks. We investigated the effects of HO-1 induction on hepatic hepcidin levels and on iron homeostasis in tissues from lean and obese mice. Obese mice exhibited hyperglycemia along with increased levels of pro-inflammatory cytokines (MCP-1, IL-6, p<0.05), oxidative stress and increased hepatic hepcidin levels (p<0.05). Enhancement of hepcidin was reflected in the reduced expression of ferroportin in obese mice (p<0.05). Further, our results showed attenuation of insulin receptor phosphorylation and attenuation of metabolic regulators including pAMPK, pAKT and pLKB1. Cobalt protoporphyrin (CoPP)-induced HO-1 up-regulation in obese mice and reversed these pathophysiological alterations (p<0.05) while attenuating hepatic hepcidin levels and enhancing ferritin expression. These effects of CoPP were prevented in obese mice concurrently exposed to an inhibitor of HO (SnMP) (p<0.05). Taken together, our results highlight a modulatory effect of HO on iron homeostasis mediated through the suppression of hepatic hepcidin in conjunction with the rescue of cellular ferritin levels. Therefore, these findings may prove an effective strategy in treating the metabolic consequences of obesity including alteration of liver iron homeostasis.

scholarly journals Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Nitin Puri ◽  
Yevgeniy Arefiev ◽  
Robert Chao ◽  
David Sacerdoti ◽  
Hibba Chaudry ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Iron Homeostasis ◽  
Transmembrane Protein ◽  
Low Grade ◽  
Obese Mice ◽  
Cellular Iron ◽  
Cobalt Protoporphyrin ◽  
Stress Response System ◽  
Metabolic Regulators

Hepcidin, a phase II reactant secreted by hepatocytes, regulates cellular iron levels by increasing internalization of ferroportin-a transmembrane protein facilitating egress of cellular iron. Chronic low-grade inflammatory states, such as obesity, have been shown to increase oxidative stress and enhance hepcidin secretion from hepatocytes and macrophages. Heme-heme oxygenase (HO) is a stress response system which reduces oxidative stress. We investigated the effects of HO-1 induction on hepatic hepcidin levels and on iron homeostasis in hepatic tissues from lean and obese mice. Obese mice exhibited hyperglycemia (p<0.05); increased levels of proinflammatory cytokines (MCP-1, IL-6,p<0.05); oxidative stress (p<0.05); and increased hepatic hepcidin levels (p<0.05). Enhancement of hepcidin was reflected in the reduced expression of ferroportin in obese mice (p<0.05). However, this effect is accompanied by a significant decline in ferritin expression. Additionally, there are reduced insulin receptor phosphorylation and attenuation of metabolic regulators pAMPK, pAKT, and pLKB1. Cobalt protoporphyrin- (CoPP-) induced HO-1 upregulation in obese mice reversed these alterations (p<0.05), while attenuating hepatic hepcidin levels. These effects of CoPP were prevented in obese mice concurrently exposed to an inhibitor of HO (SnMP) (p<0.05). Our results highlight a modulatory effect of HO on iron homeostasis mediated through the suppression of hepatic hepcidin.

scholarly journals Chlamydomonas reinhardtii LFO1 Is an IsdG Family Heme Oxygenase

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Lisa J. Lojek ◽  
Allison J. Farrand ◽  
Jennifer H. Wisecaver ◽  
Crysten E. Blaby-Haas ◽  
Brian W. Michel ◽  
...  
Keyword(s):  
Chlamydomonas Reinhardtii ◽  
Heme Oxygenase ◽  
Iron Homeostasis ◽  
Degradation Products ◽  
Family Members ◽  
Content Type ◽  
Catalytic Residues ◽  
Heme Oxygenases ◽  
Heme Degradation ◽  
Domains Of Life

ABSTRACT This work establishes a protein in the freshwater alga Chlamydomonas reinhardtii as an IsdG family heme oxygenase. This protein, LFO1, exhibits predicted secondary structure and catalytic residues conserved in IsdG family members, in addition to a chloroplast localization sequence. Additionally, the catabolite that results from the degradation of heme by LFO1 is distinct from that of other heme degradation products. Using LFO1 as a seed, we performed phylogenetic analysis, revealing that the IsdG family is conserved in all domains of life. Additionally, C. reinhardtii contains two previously identified HO-1 family heme oxygenases, making C. reinhardtii the first organism shown to contain two families of heme oxygenases. These data indicate that C. reinhardtii may have unique mechanisms for regulating iron homeostasis within the chloroplast. Heme is essential for respiration across all domains of life. However, heme accumulation can lead to toxicity if cells are unable to either degrade or export heme or its toxic by-products. Under aerobic conditions, heme degradation is performed by heme oxygenases, enzymes which utilize oxygen to cleave the tetrapyrrole ring of heme. The HO-1 family of heme oxygenases has been identified in both bacterial and eukaryotic cells, whereas the IsdG family has thus far been described only in bacteria. We identified a hypothetical protein in the eukaryotic green alga Chlamydomonas reinhardtii, which encodes a protein containing an antibiotic biosynthesis monooxygenase (ABM) domain consistent with those associated with IsdG family members. This protein, which we have named LFO1, degrades heme, contains similarities in predicted secondary structures to IsdG family members, and retains the functionally conserved catalytic residues found in all IsdG family heme oxygenases. These data establish LFO1 as an IsdG family member and extend our knowledge of the distribution of IsdG family members beyond bacteria. To gain further insight into the distribution of the IsdG family, we used the LFO1 sequence to identify 866 IsdG family members, including representatives from all domains of life. These results indicate that the distribution of IsdG family heme oxygenases is more expansive than previously appreciated, underscoring the broad relevance of this enzyme family. IMPORTANCE This work establishes a protein in the freshwater alga Chlamydomonas reinhardtii as an IsdG family heme oxygenase. This protein, LFO1, exhibits predicted secondary structure and catalytic residues conserved in IsdG family members, in addition to a chloroplast localization sequence. Additionally, the catabolite that results from the degradation of heme by LFO1 is distinct from that of other heme degradation products. Using LFO1 as a seed, we performed phylogenetic analysis, revealing that the IsdG family is conserved in all domains of life. Additionally, C. reinhardtii contains two previously identified HO-1 family heme oxygenases, making C. reinhardtii the first organism shown to contain two families of heme oxygenases. These data indicate that C. reinhardtii may have unique mechanisms for regulating iron homeostasis within the chloroplast.

Pharmacological study on the possible involvement of a Nrf2 -Heme oxygenase pathways in anti-cataract activity of fisetin

2020 ◽  
Vol 10 (1) ◽  
pp. 14-19
Author(s):  
Krishna Reddy BV ◽  
Avinash Kumar Reddy G ◽  
Sujitha V ◽  
Manasa A
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Pharmacological Study ◽  
World Population ◽  
Central Feature ◽  
Beneficial Effects ◽  
Radical Production ◽  
Anti Oxidant ◽  
Diabetic Population ◽  
Oxidant Status

DM otherwise diabetes is now a days an epidemic with the percentage of patient population rising to almost 10% of the world population. Out of all the DM complications, cataract leads the way contributing to disabilities to about 60% of diabetic population. But the pathogenesis of DM cataract is still a half-understood area of medicine there by posing a problem in the therapy. The data that we have till now gives us enough evidence to advocate the oxidative stress has a major role for the pathogenesis of DM complications like DMnephropathy, DMneuropathy, and cardiac hypertrophy, which suggests the oxidative stress is a central feature of diabetes. In the current research, the pharmacological evaluation of Fisetin for its DM based anti-cataract property was performed. This research concentrates to estimate the possible involvement of Nrf-2 / heme oxygenase (HO)-pathway in the observed therapeutic effect, if any. The data obtained in this study also indicate that the observed beneficial effects mainly due to activation of Nrf2/HO-1 pathway. These effects probably result in increased tissue anti-oxidant status as well as decreased free radical production, which ultimately responsible for the observed beneficial effects of Fisetin against hyperglycemia-induced cataract.

scholarly journals Novel Insights into the Regulatory Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 in Oxidative Stress and Inflammation of Human Fetal Membranes

2020 ◽  
Vol 21 (17) ◽  
pp. 6139 ◽  
Author(s):  
Ramkumar Menon ◽  
Morgan R Peltier
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Water Soluble ◽  
Fetal Membrane ◽  
Fetal Membranes ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Western Blots ◽  
Adverse Pregnancy ◽  
Nrf2 Expression

Fetal membrane dysfunction in response to oxidative stress (OS) is associated with adverse pregnancy outcomes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is one of the regulators of innate OS response. This study evaluated changes in Nrf2 expression and its downstream targets heme oxygenase (HO-1) and peroxisome proliferator-activated receptor gamma (PPARγ) in fetal membranes during OS and infection in vitro. Furthermore, we tested the roles of sulforaphane (SFN; an extract from cruciferous vegetables) and trigonelline (TRN; an aromatic compound in coffee) in regulating Nrf2 and its targets. Fetal membranes (n = 6) collected at term were placed in an organ explant system were treated with water-soluble cigarette smoke extract (CSE), an OS inducer (1:10), and lipopolysaccharide (LPS; 100 ng/mL). Nrf2 expression, expression, its enhancement by sulforaphane (SFN, 10 µM/mL) and down regulation by TRN (10uM/mL) was determined by western blots. Expression of Nrf2 response elements PPARγ (western) heme oxygenase (HO-1), and IL-6 were quantified by ELISA. CSE and LPS treatment of fetal membranes increased nrf2, but reduced HO-1 and PPARγ and increased IL-6. Co-treatment of SFN, but not with TRN, with CSE and LPS increased Nrf2 substantially, as well as increased HO-1 and PPARγ and reduced IL-6 expression. Risk factor-induced Nrf2 increase is insufficient to generate an antioxidant response in fetal membranes. Sulforaphane may enhance innate antioxidant and anti-inflammatory capacity by increasing NRF-2 expression.

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 Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

2021 ◽  
Vol 22 (15) ◽  
pp. 8253
Author(s):  
Jung-Yeon Kim ◽  
Yongmin Choi ◽  
Jaechan Leem ◽  
Jeong Eun Song
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Heme Oxygenase ◽  
Murine Model ◽  
Liver Diseases ◽  
Transforming Growth Factor ◽  
Heme Oxygenase 1 ◽  
Cholestatic Liver Disease ◽  
Hepatocyte Apoptosis ◽  
Cobalt Protoporphyrin

Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.

scholarly journals Role of hepcidin in oxidative stress and cell death of cultured mouse renal collecting duct cells: protection against iron and sensitization to cadmium

2021 ◽  
Author(s):  
Stephanie Probst ◽  
Johannes Fels ◽  
Bettina Scharner ◽  
Natascha A. Wolff ◽  
Eleni Roussa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cell Fate ◽  
Catalase Activity ◽  
Metal Ion ◽  
Iron Homeostasis ◽  
Collecting Duct ◽  
Duct Cell ◽  
Plasmid Transfection

AbstractThe liver hormone hepcidin regulates systemic iron homeostasis. Hepcidin is also expressed by the kidney, but exclusively in distal nephron segments. Several studies suggest hepcidin protects against kidney damage involving Fe2+ overload. The nephrotoxic non-essential metal ion Cd2+ can displace Fe2+ from cellular biomolecules, causing oxidative stress and cell death. The role of hepcidin in Fe2+ and Cd2+ toxicity was assessed in mouse renal cortical [mCCD(cl.1)] and inner medullary [mIMCD3] collecting duct cell lines. Cells were exposed to equipotent Cd2+ (0.5–5 μmol/l) and/or Fe2+ (50–100 μmol/l) for 4–24 h. Hepcidin (Hamp1) was transiently silenced by RNAi or overexpressed by plasmid transfection. Hepcidin or catalase expression were evaluated by RT-PCR, qPCR, immunoblotting or immunofluorescence microscopy, and cell fate by MTT, apoptosis and necrosis assays. Reactive oxygen species (ROS) were detected using CellROX™ Green and catalase activity by fluorometry. Hepcidin upregulation protected against Fe2+-induced mIMCD3 cell death by increasing catalase activity and reducing ROS, but exacerbated Cd2+-induced catalase dysfunction, increasing ROS and cell death. Opposite effects were observed with Hamp1 siRNA. Similar to Hamp1 silencing, increased intracellular Fe2+ prevented Cd2+ damage, ROS formation and catalase disruption whereas chelation of intracellular Fe2+ with desferrioxamine augmented Cd2+ damage, corresponding to hepcidin upregulation. Comparable effects were observed in mCCD(cl.1) cells, indicating equivalent functions of renal hepcidin in different collecting duct segments. In conclusion, hepcidin likely binds Fe2+, but not Cd2+. Because Fe2+ and Cd2+ compete for functional binding sites in proteins, hepcidin affects their free metal ion pools and differentially impacts downstream processes and cell fate.

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