Journal articles on the topic 'Reversed heme'
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1
Reidl, J., and J. J. Mekalanos. "Lipoprotein e(P4) is essential for hemin uptake by Haemophilus influenzae." Journal of Experimental Medicine 183, no. 2 (February 1, 1996): 621–29. http://dx.doi.org/10.1084/jem.183.2.621.
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Heme uptake is a common means of iron and porphyrin acquisition by many pathogenic bacteria. The genus Haemophilus includes several important pathogenic bacterial species that characteristically require hemin-, protoporphyrin-, or heme-substituted proteins as essential growth factors under aerobic conditions. However, the mechanism of heme transport is not understood for Haemophilus. We have cloned a DNA fragment from H. influenzae that allows an Escherichia coli hemA mutant to employ exogenous hemin or protoporphyrin IX as sole sources of porphyrin. DNA sequencing of the cloned DNA fragment suggested that a previously characterized gene (hel) encoding an antigenic, outer membrane lipoprotein e(P4) was responsible for the complementation activity. Construction of hel insertion mutations in strain H. influenzae Rd demonstrated that hel is essential for growth under aerobic conditions but not under anaerobic conditions. The aerobic growth defect of hel mutants could be reversed by providing exogenous hemin in the presence of outer membrane. The analysis of hybrids between e(P4) and beta-lactamase demonstrated that a domain of e(P4) near its NH2' terminus was required for its function in hemin use. Within this domain is a short amino acid sequence that displays similarity to H. influenzae hemin binding protein HbpA, hemin-binding motifs present in eukaryotic transcription activator heme-activated protein, and the heme containing proteins hemoglobin (alpha-chain) and cytochrome C3, suggesting that this region may be involved in hemin binding and/or transport.
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Qian, XiaoWei, Hao Cheng, and XinZhong Chen. "Transient receptor potential melastatin 2–mediated heme oxygenase-1 has a role for bacterial clearance by regulating autophagy in peritoneal macrophages during polymicrobial sepsis." Innate Immunity 25, no. 8 (September 19, 2019): 530–38. http://dx.doi.org/10.1177/1753425919875796.
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Our previous study indicated an important protective role of transient receptor potential melastatin 2 (TRPM2) in controlling bacterial clearance in macrophages during polymicrobial sepsis by regulating heme oxygenase-1. Autophagy is necessary for macrophages to kill invasive bacteria. In the present study, TRPM2 knockout (KO) mice show decreased heme oxygenase-1 and autophagy in peritoneal macrophages after caecal ligation and puncture surgery. Caecal ligation and puncture-induced autophagy in peritoneal macrophages is dependent on heme oxygenase-1. TRPM2 KO mice treated with heme oxygenase-1 inducer before caecal ligation and puncture significantly increase autophagy of peritoneal macrophages, bacterial clearance rate and survival rate. In addition, TRPM2 KO mice treated with heme oxygenase-1 inducer before caecal ligation and puncture significantly attenuate organ injury and systemic inflammation. These improvements are reversed by autophagy inhibitor. Therefore, our findings suggest that TRPM2-mediated heme oxygenase-1 has a role for bacterial clearance possibly by regulating autophagy in peritoneal macrophages during polymicrobial sepsis.
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Steiner, Alexandre A., Eduardo Colombari, and Luiz G. S. Branco. "Carbon monoxide as a novel mediator of the febrile response in the central nervous system." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 277, no. 2 (August 1, 1999): R499—R507. http://dx.doi.org/10.1152/ajpregu.1999.277.2.r499.
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Heme oxygenase catalyzes the metabolism of heme to biliverdin, free iron, and carbon monoxide (CO), which has been shown to be an important neuromodulatory agent. Recently, it has been demonstrated that lipopolysaccharide (LPS) can induce the enzyme heme oxygenase in glial cells. Therefore, the present study was designed to test the hypothesis that central CO plays a role in LPS-induced fever. Colonic body temperature (Tb) was measured in awake, unrestrained rats (basal Tb= 36.8 ± 0.2°C). Intracerebroventricular injection of zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG; 75 nmol), a heme oxygenase inhibitor, caused no significant change in Tb, indicating that the central heme oxygenase pathway plays no tonic role in Tb under the experimental conditions used. Intraperitoneal injections of LPS (50–100 μg/kg) evoked dose-dependent increases in Tb. Intracerebroventricular injection of ZnDPBG in febrile rats attenuated LPS-induced fever (thermal index with ZnDPBG = 1.1 ± 0.2°C, thermal index with vehicle = 2.3 ± 0.4°C), suggesting that the central heme oxygenase pathway plays a role in fever generation. The antipyretic effect of ZnDPBG could be reversed by intracerebroventricular administration of heme-lysinate or CO-saturated saline. Collectively, our data indicate that CO arising from heme oxygenase may play an important role in fever generation by acting on the central nervous system.
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Liu, Yunfeng, Fangmiao Jing, Woelsung Yi, Avital Mendelson, Patricia Shi, Ronald Walsh, David F. Friedman, et al. "HO-1hi patrolling monocytes protect against vaso-occlusion in sickle cell disease." Blood 131, no. 14 (April 5, 2018): 1600–1610. http://dx.doi.org/10.1182/blood-2017-12-819870.
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Key Points SCD patients with a recent VOC episode have lower frequencies and numbers of HO-1hi patrolling monocytes. Heme-driven SCD vaso-occlusion is exacerbated in mice lacking patrolling monocytes and reversed following patrolling monocyte transfer.
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Mikhael, Marc, Sameer Apte, Shan Soe-Lin, and Prem Ponka. "Nitrogen Monoxide Inhibits Heme Synthesis In Reticulocytes." Blood 116, no. 21 (November 19, 2010): 4252. http://dx.doi.org/10.1182/blood.v116.21.4252.4252.
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Abstract Abstract 4252 Anemia of chronic disease (ACD) is a condition that often manifests in patients with chronic immune activation due to chronic infections, autoimmune disorders, cancer and other diseases. The pathogenesis of ACD is complex and involves inefficient erythropoietin production, immune-mediated inhibition of erythropoiesis, and retention of iron in hemoglobin-processing macrophages. During their development, erythroid cells are closely associated with macrophages. In inflammatory conditions, activated macrophages generate large quantities of the gaseous molecule, nitric oxide (NO), which has numerous effects on iron metabolism. In this study, we explored the possibility that NO affects iron metabolism in erythroid cells. We treated reticulocytes with the NO donors, sodium nitroprusside (SNP) and S-Nitroso-N-acetyl-D,L-penicillamine (SNAP). We show that NO inhibits 59Fe incorporation from 59Fe-transferrin into reticulocytes and their heme. Significantly, 5-aminolevulinic acid (ALA, the product of ALA synthase, which catalyzes the first step of heme synthesis) reversed the SNP-mediated decrease in 59Fe incorporation into heme but not the cellular 59Fe uptake. In addition, SNP treatment led to an increase in eIF2α phosphorylation (which is known to occur in heme-deficient cells) and decreased globin translation. Importantly, the addition of ALA to SNP-treated reticulocytes prevented the effect of SNP on eIF2α phosphorylation and reversed globin synthesis inhibition. This indicates that in SNP treated reticulocytes, the phosphorylation of eIF2α and inhibition of globin synthesis occur indirectly, via NO's effect on erythroid-specific ALA synthase (ALA-S2). These results led us to conclude that NO has two distinct effects on reticulocytes, namely: a decrease in ALA-S2 activity and a decrease in transferrin-mediated iron uptake. The profound impact of NO on heme synthesis, iron uptake and globin translation in reticulocytes raises the possibility that NO production by macrophages could also contribute to ACD. Disclosures: No relevant conflicts of interest to declare.
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Hodge, M. R., G. Kim, K. Singh, and M. G. Cumsky. "Inverse regulation of the yeast COX5 genes by oxygen and heme." Molecular and Cellular Biology 9, no. 5 (May 1989): 1958–64. http://dx.doi.org/10.1128/mcb.9.5.1958-1964.1989.
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The COX5a and COX5b genes encode divergent forms of yeast cytochrome c oxidase subunit V. Although the polypeptide products of the two genes are functionally interchangeable, it is the Va subunit that is normally found in preparations of yeast mitochondria and cytochrome c oxidase. We show here that the predominance of subunit Va stems in part from the differential response of the two genes to the presence of molecular oxygen. Our results indicate that during aerobic growth, COX5a levels were high, while COX5b levels were low. Anaerobically, the pattern was reversed; COX5a levels dropped sevenfold, while those of COX5b were elevated sevenfold. Oxygen appeared to act at the level of transcription through heme, since the addition of heme restored an aerobic pattern of transcription to anaerobically grown cells and the effect of anaerobiosis on COX5 transcription was reproduced in strains containing a mutation in the heme-biosynthetic pathway (hem1). In conjunction with the oxygen-heme response, we determined that the product of the ROX1 gene, a trans-acting regulator of several yeast genes controlled by oxygen, is also involved in COX5 expression. These results, as well as our observation that COX5b expression varied significantly in certain yeast strains, indicate that the COX5 genes undergo a complex pattern of regulation. This regulation, especially the increase in COX5b levels anaerobically, may reflect an attempt to modulate the activity of a key respiratory enzyme in response to varying environmental conditions. The results presented here, as well as those from other laboratories, suggest that the induction or derepression of certain metabolic enzymes during anaerobiosis may be a common and important physiological response in yeast cells.
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Hodge, M. R., G. Kim, K. Singh, and M. G. Cumsky. "Inverse regulation of the yeast COX5 genes by oxygen and heme." Molecular and Cellular Biology 9, no. 5 (May 1989): 1958–64. http://dx.doi.org/10.1128/mcb.9.5.1958.
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The COX5a and COX5b genes encode divergent forms of yeast cytochrome c oxidase subunit V. Although the polypeptide products of the two genes are functionally interchangeable, it is the Va subunit that is normally found in preparations of yeast mitochondria and cytochrome c oxidase. We show here that the predominance of subunit Va stems in part from the differential response of the two genes to the presence of molecular oxygen. Our results indicate that during aerobic growth, COX5a levels were high, while COX5b levels were low. Anaerobically, the pattern was reversed; COX5a levels dropped sevenfold, while those of COX5b were elevated sevenfold. Oxygen appeared to act at the level of transcription through heme, since the addition of heme restored an aerobic pattern of transcription to anaerobically grown cells and the effect of anaerobiosis on COX5 transcription was reproduced in strains containing a mutation in the heme-biosynthetic pathway (hem1). In conjunction with the oxygen-heme response, we determined that the product of the ROX1 gene, a trans-acting regulator of several yeast genes controlled by oxygen, is also involved in COX5 expression. These results, as well as our observation that COX5b expression varied significantly in certain yeast strains, indicate that the COX5 genes undergo a complex pattern of regulation. This regulation, especially the increase in COX5b levels anaerobically, may reflect an attempt to modulate the activity of a key respiratory enzyme in response to varying environmental conditions. The results presented here, as well as those from other laboratories, suggest that the induction or derepression of certain metabolic enzymes during anaerobiosis may be a common and important physiological response in yeast cells.
8
Alvarado, Gerardo, Attila Tóth, Éva Csősz, Gergő Kalló, Katalin Dankó, Zoltán Csernátony, Ann Smith, et al. "Heme-Induced Oxidation of Cysteine Groups of Myofilament Proteins Leads to Contractile Dysfunction of Permeabilized Human Skeletal Muscle Fibres." International Journal of Molecular Sciences 21, no. 21 (October 31, 2020): 8172. http://dx.doi.org/10.3390/ijms21218172.
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Heme released from red blood cells targets a number of cell components including the cytoskeleton. The purpose of the present study was to determine the impact of free heme (20–300 µM) on human skeletal muscle fibres made available during orthopedic surgery. Isometric force production and oxidative protein modifications were monitored in permeabilized skeletal muscle fibre segments. A single heme exposure (20 µM) to muscle fibres decreased Ca2+-activated maximal (active) force (Fo) by about 50% and evoked an approximately 3-fold increase in Ca2+-independent (passive) force (Fpassive). Oxidation of sulfhydryl (SH) groups was detected in structural proteins (e.g., nebulin, α-actinin, meromyosin 2) and in contractile proteins (e.g., myosin heavy chain and myosin-binding protein C) as well as in titin in the presence of 300 µM heme. This SH oxidation was not reversed by dithiothreitol (50 mM). Sulfenic acid (SOH) formation was also detected in the structural proteins (nebulin, α-actinin, meromyosin). Heme effects on SH oxidation and SOH formation were prevented by hemopexin (Hpx) and α1-microglobulin (A1M). These data suggest that free heme has a significant impact on human skeletal muscle fibres, whereby oxidative alterations in structural and contractile proteins limit contractile function. This may explain and or contribute to the weakness and increase of skeletal muscle stiffness in chronic heart failure, rhabdomyolysis, and other hemolytic diseases. Therefore, therapeutic use of Hpx and A1M supplementation might be effective in preventing heme-induced skeletal muscle alterations.
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Ahmad, Mansoor, Xiangmin Zhao, Melissa R. Kelly, Sharath Kandhi, Oscar Perez, Nader G. Abraham, and Michael S. Wolin. "Heme oxygenase-1 induction modulates hypoxic pulmonary vasoconstriction through upregulation of ecSOD." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 4 (October 2009): H1453—H1461. http://dx.doi.org/10.1152/ajpheart.00315.2009.
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Endothelium-denuded bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving removing a superoxide-derived hydrogen peroxide-mediated relaxation. BPA organ cultured for 24 h with 0.1 mM cobalt chloride (CoCl2) to increase the expression and activity of heme oxygenase-1 (HO-1) is accompanied by a decrease in 5 μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to KCl in BPA was not affected by increases in HO-1, but the hypoxic pulmonary vasoconstriction (HPV) response was decreased. Organ culture with a HO-1 inhibitor (10 μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Treatment of HO-1-induced BPA with extracellular catalase resulted in reversal of the attenuation of HPV without affecting the force development to KCl. Increasing intracellular peroxide scavenging with 0.1 mM ebselen increased force development to KCl and partially reversed the decrease in HPV seen on induction of HO-1. HO-1 induction increases extracellular (ec) superoxide dismutase (SOD) expression without changing Cu,Zn-SOD and Mn-SOD levels. HO-1-induced BPA rings treated with the copper chelator 10 mM diethyldithiocarbamate to inactivate ecSOD and Cu,Zn-SOD showed increased superoxide and decreased peroxide to levels equal to non-HO-1-induced rings, whereas the addition of SOD to freshly isolated BPA rings attenuated HPV similar to HO-1 induction with CoCl2. Therefore, HO-1 induction in BPA increases ecSOD expression associated with enhanced generation of peroxide in amounts that may not be adequately removed during hypoxia, leading to an attenuation of HPV.
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Iwadate, Reiko, Yoko Satoh, Yukino Watanabe, Hiroshi Kawai, Naomi Kudo, Yoichi Kawashima, Tadahiko Mashino, and Atsushi Mitsumoto. "Impairment of heme biosynthesis induces short circadian period in body temperature rhythms in mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 1 (July 1, 2012): R8—R18. http://dx.doi.org/10.1152/ajpregu.00019.2011.
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It has been demonstrated that the function of mammalian clock gene transcripts is controlled by the binding of heme in vitro. To examine the effects of heme on biological rhythms in vivo, we measured locomotor activity (LA) and core body temperature (Tb) in a mouse model of porphyria with impaired heme biosynthesis by feeding mice a griseofulvin (GF)-containing diet. Mice fed with a 2.0% GF-containing diet (GF2.0) transiently exhibited phase advance or phase advance-like phenomenon by 1–3 h in terms of the biological rhythms of Tbor LA, respectively (both, P < 0.05) while mice were kept under conditions of a light/dark cycle (12 h:12 h). We also observed a transient, ∼0.3 h shortening of the period of circadian Tbrhythms in mice kept under conditions of constant darkness ( P < 0.01). Interestingly, the observed duration of abnormal circadian rhythms in GF2.0 mice lasted between 1 and 3 wk after the onset of GF ingestion; this finding correlated well with the extent of impairment of heme biosynthesis. When we examined the effects of therapeutic agents for acute porphyria, heme, and hypertonic glucose on the pathological status of GF2.0 mice, it was found that the intraperitoneal administration of heme (10 mg·kg−1·day−1) or glucose (9 g·kg−1·day−1) for 7 days partially reversed (50%) increases in urinary δ-aminolevulinic acids levels associated with acute porphyria. Treatment with heme, but not with glucose, suppressed the phase advance (-like phenomenon) in the diurnal rhythms ( P < 0.05) and restored the decrease of heme ( P < 0.01) in GF2.0 mice. These results suggest that impairments of heme biosynthesis, in particular a decrease in heme, may affect phase and period of circadian rhythms in animals.
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Santucci, Roberto, Jan Mintorovitch, Ioannis Constantinidis, James D. Satterlee, and Franca Ascoli. "CD studies on the reversed heme orientation in monomeric Glycera dibranchiata hemoglobins." Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 953 (January 1988): 201–4. http://dx.doi.org/10.1016/0167-4838(88)90025-8.
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Yang, Liming, Shuo Quan, and Nader G. Abraham. "Retrovirus-mediated HO gene transfer into endothelial cells protects against oxidant-induced injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 1 (July 1, 1999): L127—L133. http://dx.doi.org/10.1152/ajplung.1999.277.1.l127.
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Heme oxygenase (HO)-1 is a stress protein that has been implicated in defense mechanisms against agents that may induce oxidative injury, such as endotoxins, heme, and cytokines. Overexpression of HO-1 in cells might, therefore, protect against oxidative stress produced by certain agents, specifically heme, by catalyzing its degradation to bilirubin, which by itself has antioxidant properties. We report for the first time the successful transduction of human HO-1 gene into rat lung microvessel endothelium using replication-defective retroviral vector. Cells transduced with human HO-1 gene exhibited a 2.1-fold increase in HO-1 protein level, which was associated with a 2.3-fold elevation in enzyme activity compared with that in nontransduced cells. The cGMP content in transduced endothelial cells was increased by 2.9-fold relative to that in nontransduced cells. Moreover, human HO-1 gene-transduced endothelial cells acquired substantial resistance to toxicity produced by exposure to heme and H2O2compared with that in nontransduced cells. The protective effect of enhancement of HO-1 activity against heme and H2O2was reversed by pretreatment with stannic mesoporphyrin, a competitive inhibitor of HO. These data demonstrate that the induction of HO-1 in response to injurious stimuli represents an important mechanism for moderating the severity of cell damage. Regulation of HO activity in this manner may have clinical applications.
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Santos, Daniel Garcia, Jesse Eisenberg, Matthias Schranzhofer, and Prem Ponka. "Studies on Heme Oxygenase 1 During Erythroid Differentiation." Blood 116, no. 21 (November 19, 2010): 4254. http://dx.doi.org/10.1182/blood.v116.21.4254.4254.
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Abstract Abstract 4254 Heme is indispensable for the function of all aerobic cells as a prosthetic group of innumerable proteins. However, “free heme” (uncommitted) can initiate the formation of free radicals and cause lipid peroxidation, which can lead to cellular damage and tissue injury. Therefore, the rate of heme biosynthesis and catabolism must be well balanced by tight control mechanisms. The highest amounts of organismal heme (75-80%) are present in circulating red blood cells (RBC), whose precursors synthesize heme with rates that are at least one order of magnitude higher (on the per cell basis) than those in the liver – the second most active heme producer in the body. The degradation of heme is exclusively carried out by heme oxygenases 1 and 2 (HO1 and HO2), which catalyze the rate-limiting step in the oxidative degradation of heme. Although the heme-inducible HO isoform, HO1, has been extensively studied in hepatocytes and many other non-erythroid cells, virtually nothing is known about the expression of HO1 in developing RBC. Similarly, it is unknown whether HO1 plays any role in erythroid cell development under physiological or pathophysiological conditions. Using both a murine erythroleukemia cell line (MEL) and primary erythroid cells isolated from mouse fetal livers, we have demonstrated that during erythroid differentiation HO1 is up-regulated at both mRNA and protein levels. This increase in HO1 can be prevented by succinylacetone (SA), an inhibitor of heme synthesis that blocks 5-aminolevulinic acid dehydratase. These data suggest that in developing RBC, in addition to the continuous assembly of heme with globin chains, there is an increase in levels of uncommitted heme, which upregulates HO1 expression. Additionally, we have shown that down-regulation of HO1 via siRNA increased hemoglobinization in differentiating MEL cells. In contrast, induction of HO1 expression by NaAsO2 reduced the hemoglobinization of MEL cells. This effect could be reversed to control levels by the addition of HO1 inhibitor tin-protophorphyrin (SnPP). These results show that in differentiating erythroid cells the balance between levels of heme and HO1 have to be tightly regulated to maintain hemoglobinization at appropriate levels. Our results lead us to propose that disturbances in HO1 expression could play a role in some pathophysiological conditions such as thalassemias. Disclosures: No relevant conflicts of interest to declare.
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Khitan, Zeid, Mohit Harsh, Komal Sodhi, Joseph I. Shapiro, and Nader G. Abraham. "HO-1 Upregulation Attenuates Adipocyte Dysfunction, Obesity, and Isoprostane Levels in Mice Fed High Fructose Diets." Journal of Nutrition and Metabolism 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/980547.
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Background.Fructose metabolism is an unregulated metabolic pathway and excessive fructose consumption is known to activate ROS. HO-1 is a potent antioxidant gene that plays a key role in decreasing ROS and isoprostanes. We examined whether the fructose-mediated increase in adipocyte dysfunction involves an increase in isoprostanes and that pharmacological induction of HO-1 would decrease both isoprostane levels and adipogenesis.Methods and Results.We examined the effect of fructose, on adipogenesis in human MSCs in the presence and absence of CoPP, an inducer of HO-1. Fructose increased adipogenesis and the number of large lipid droplets while decreasing the number of small lipid droplets (P<0.05). Levels of heme and isoprostane in fructose treated MSC-derived adipocytes were increased. CoPP reversed these effects and markedly increased HO-1 and the Wnt signaling pathway. The high fructose diet increased heme levels in adipose tissue and increased circulating isoprostane levels (P<0.05versus control). Fructose diets decreased HO-1 and adiponectin levels in adipose tissue. Induction of HO-1 by CoPP decreased isoprostane synthesis (P<0.05versus fructose).Conclusion.Fructose treatment resulted in increased isoprostane production and adipocyte dysfunction, which was reversed by the increased expression of HO-1.
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Shen, Hui-Hui, Cheng-Jie Wang, Xin-Yan Zhang, Yan-Ran Sheng, Shao-Liang Yang, Zi-Meng Zheng, Jia-Lu Shi, Xue-Min Qiu, Feng Xie, and Ming-Qing Li. "HIF1A-induced heme oxygenase 1 promotes the survival of decidual stromal cells against excess heme-mediated oxidative stress." Reproduction 163, no. 1 (January 1, 2022): 33–43. http://dx.doi.org/10.1530/rep-21-0314.
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Heme oxygenase 1 (HO-1, encoded by the HMOX1 gene) is the rate-limiting enzyme that catalyzes heme degradation, and it has been reported to exert antioxidative effects. Recently, decidualization has been reported to confer resistance to environmental stress signals, protecting against oxidative stress. However, the effects and regulatory mechanism of HO-1 in decidual stromal cells (DSCs) during early pregnancy remain unknown. Here, we verified that the levels of HO-1 and heme in DSCs are increased compared with those in endometrial stromal cells. Additionally, the upregulation of HIF1A expression led to increased HMOX1 expression in DSCs possibly via nuclear factor erythroid 2-related factor (encoded by the NFE2L2 gene). However, addition of the competitive HO-1 inhibitor zinc protoporphyrin IX resulted in an increase in HIF1A expression. Hydrogen peroxide (H2O2) induced the production of reactive oxygen species (ROS), decreased the cell viability of DSCs in vitro, and upregulated the level of heme. As an HO-1 inducer, cobalt protoporphyrin IX decreased ROS production and significantly reversed the inhibitory effect of H2O2 on cell viability. More importantly, patients with unexplained spontaneous abortion had low levels of HO-1 that were insufficient to protect against oxidative stress. This study suggests that the upregulation of HO-1 expression via HIF1A protects DSCs against excessive heme-mediated oxidative stress. Furthermore, the excessive oxidative stress injury and impaired viability of DSCs associated with decreased HO-1 expression should be associated with the occurrence and/or development of spontaneous abortion.
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Miler, Eliana A., Silvana I. Nudler, Fernanda A. Quinteros, Jimena P. Cabilla, Sonia A. Ronchetti, and Beatriz H. Duvilanski. "Cadmium induced-oxidative stress in pituitary gland is reversed by removing the contamination source." Human & Experimental Toxicology 29, no. 10 (March 2, 2010): 873–80. http://dx.doi.org/10.1177/0960327110362703.
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Cadmium (Cd2+) is one of the most important environmental contaminants and acts as an endocrine disruptor. Previously, we have demonstrated that the simultaneous administration of Cd2+ and melatonin (Mel) in drinking water impaired metal-induced oxidative stress in rat anterior pituitary gland. The aim of this study was to investigate if a treatment started after the toxic manifestations of Cd 2+ became evident could reverse the effects of the metal. Animals exposed to Cd2+ (5 parts per million [ppm], 30 days) were treated with Mel or without the metal during the next 1 or 2 months. Cd2+ exposure increased the expression of heme oxygenase-1 (HO-1), a biomarker of oxidative stress, and an a posteriori Mel treatment reversed oxidative stress induced by Cd2+. This effect was also observed 1 month after metal removal. The Cd2+-induced increase in metallothionein-1 (MT-1) and nitric oxide synthase 1 (NOS1) expression were also reversed by metal removal. In addition, serum prolactin and luteinizing hormone levels affected by Cd 2+ exposure were normalized. Considering that the manifestations of Cd2+ intoxication become evident only after a certain period of metal accumulation, these results show that metal removal is enough to reverse Cd2+ effects in anterior pituitary gland and bring to light the relevance of moving away the individual from the contamination source.
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Kashyap, Purna C., Kyoung Moo Choi, Nirjhar Dutta, David R. Linden, Joseph H. Szurszewski, Simon J. Gibbons, and Gianrico Farrugia. "Carbon monoxide reverses diabetic gastroparesis in NOD mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 6 (June 2010): G1013—G1019. http://dx.doi.org/10.1152/ajpgi.00069.2010.
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Diabetic gastroparesis is associated with increased oxidative stress attributable to loss of upregulation of heme oxygenase-1 (HO1), with resultant damage to interstitial cells of Cajal and delayed gastric emptying. These changes can be reversed by induction of HO1. HO1 catalyzes the breakdown of heme into iron, biliverdin and, carbon monoxide (CO). The aim of this study was to determine whether inhalation of CO can mimic the protective effects of HO1. Nonobese diabetic (NOD) mice with delayed gastric emptying were treated with CO inhalation. Serum malondialdehyde was measured as a marker of oxidative stress. Gastric emptying of solids was measured using a [13C]octanoic acid breath test. Kit expression levels were determined in immunoblots of protein extracted from the external muscle layers of the gastric body and antrum. The effect of CO on oxidative stress and gastric emptying was also determined in the presence of HO activity inhibitor chromium mesoporphyrin. CO inhalation reduced oxidative stress, restored Kit expression and reversed delayed gastric emptying in diabetic NOD mice with delayed gastric emptying. CO inhalation maintained this effect in the presence of the HO activity inhibitor, chromium mesoporphyrin, also resulting in restoration of the delay in gastric emptying. CO inhalation mimics the protective effect of upregulation of HO1 and decreased oxidative stress, increased Kit expression, and restored delay in gastric emptying. This effect of CO was independent of HO activity, suggesting that its effects were downstream of HO1. CO represents a potential therapeutic option for treatment of diabetic gastroparesis.
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Doran, John D., and Bruce C. Hill. "Effect of diethyl pyrocarbonate modification on spectral and steady-state kinetic properties of bovine heart cytochrome oxidase." Biochemistry and Cell Biology 70, no. 7 (July 1, 1992): 565–72. http://dx.doi.org/10.1139/o92-087.
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The histidine-specific reagent diethyl pyrocarbonate has been used to chemically modify bovine heart cytochrome oxidase. Thirty-two of sixty-seven histidine residues of cytochrome oxidase are accessible to modification by diethyl pyrocarbonate. Effects on the Soret and α bands of the heme spectrum indicate disturbance in the environment of one or both of the heme groups. However, diethyl pyrocarbonate modification does not alter the 830-nm absorbance band, suggesting that the environment of CuA is unchanged. Maximal modification of cytochrome oxidase by diethyl pyrocarbonate results in loss of 85–90% of the steay-state electron transfer activity, which can be reversed by hydroxylamine treatment. However, modification of the first 20 histidines does not alter either activity or the heme spectrum, but only when 32 residues have been modified are the activity and heme spectral changes complete. The steady-state kinetic profile of fully modified oxidase is monophasic; the phase corresponding to tight cytochrome c binding and low turnover is retained, whereas the high turnover phase is abolished. Proteoliposomes incorporated with modified oxidase have a 65% lower respiratory control ratio and 40% lower proton pumping stoichiometry than liposomes containing unmodified oxidase. These results are discussed in terms of a redox-linked proton pumping model for energy coupling via cytochrome oxidase.Key words: cytochrome oxidase, histidine modification, electron transfer, proton pumping, diethyl pyrocarbonate.
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Martínez-Sernández, Victoria, Mercedes Mezo, Marta González-Warleta, María J. Perteguer, Laura Muiño, Esteban Guitián, Teresa Gárate, and Florencio M. Ubeira. "The MF6p/FhHDM-1 Major Antigen Secreted by the Trematode Parasite Fasciola hepatica Is a Heme-binding Protein." Journal of Biological Chemistry 289, no. 3 (November 26, 2013): 1441–56. http://dx.doi.org/10.1074/jbc.m113.499517.
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Blood-feeding parasites have developed biochemical mechanisms to control heme intake and detoxification. Here we show that a major antigen secreted by Fasciola hepatica, previously reported as MF6p, of unknown function (gb|CCA61804.1), and as FhHDM-1, considered to be a helminth defense molecule belonging to the family of cathelicidin-like proteins (gb|ADZ24001.1), is in fact a heme-binding protein. The heme-binding nature of the MF6p/FhHDM-1 protein was revealed in two independent experiments: (i) immunopurification of the secreted protein·heme complexes with mAb MF6 and subsequent analysis by C8 reversed-phase HPLC and MS/MS spectrometry and (ii) analysis of the binding ability of the synthetic protein to hemin in vitro. By immunohistochemistry analysis, we have observed that MF6p/FhHDM-1 is produced by parenchymal cells and transported to other tissues (e.g. vitellaria and testis). Interestingly, MF6p/FhHDM-1 is absent both in the intestinal cells and in the lumen of cecum, but it can be released through the tegumental surface to the external medium, where it binds to free heme molecules regurgitated by the parasite after hemoglobin digestion. Proteins that are close analogs of the Fasciola MF6p/FhHDM-1 are present in other trematodes, including Clonorchis, Opistorchis, Paragonimus, Schistosoma, and Dicrocoelium. Using UV-visible spectroscopy and immunoprecipitation techniques, we observed that synthetic MF6p/FhHDM-1 binds to hemin with 1:1 stoichiometry and an apparent Kd of 1.14 × 10−6m−1. We also demonstrated that formation of synthetic MF6p/FhHDM-1·hemin complexes inhibited hemin degradation by hydrogen peroxide and hemin peroxidase-like activity in vitro. Our results suggest that MF6p/FhHDM-1 may be involved in heme homeostasis in trematodes.
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Gómez-Manzo, S., J. L. Chavez-Pacheco, M. Contreras-Zentella, M. E. Sosa-Torres, R. Arreguín-Espinosa, M. Pérez de la Mora, J. Membrillo-Hernández, and J. E. Escamilla. "Molecular and Catalytic Properties of the Aldehyde Dehydrogenase of Gluconacetobacter diazotrophicus, a Quinoheme Protein Containing Pyrroloquinoline Quinone, Cytochrome b, and Cytochrome c." Journal of Bacteriology 192, no. 21 (August 27, 2010): 5718–24. http://dx.doi.org/10.1128/jb.00589-10.
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ABSTRACT Several aldehyde dehydrogenase (ALDH) complexes have been purified from the membranes of acetic acid bacteria. The enzyme structures and the chemical nature of the prosthetic groups associated with these enzymes remain a matter of debate. We report here on the molecular and catalytic properties of the membrane-bound ALDH complex of the diazotrophic bacterium Gluconacetobacter diazotrophicus. The purified ALDH complex is a heterodimer comprising two subunits of 79.7 and 50 kDa, respectively. Reversed-phase high-pressure liquid chromatography (HPLC) and electron paramagnetic resonance spectroscopy led us to demonstrate, for the first time, the unequivocal presence of a pyrroloquinoline quinone prosthetic group associated with an ALDH complex from acetic acid bacteria. In addition, heme b was detected by UV-visible light (UV-Vis) spectroscopy and confirmed by reversed-phase HPLC. The smaller subunit bears three cytochromes c. Aliphatic aldehydes, but not formaldehyde, were suitable substrates. Using ferricyanide as an electron acceptor, the enzyme showed an optimum pH of 3.5 that shifted to pH 7.0 when phenazine methosulfate plus 2,6-dichlorophenolindophenol were the electron acceptors. Acetaldehyde did not reduce measurable levels of the cytochrome b and c centers; however, the dithionite-reduced hemes were conveniently oxidized by ubiquinone-1; this finding suggests that cytochrome b and the cytochromes c constitute an intramolecular redox sequence that delivers electrons to the membrane ubiquinone.
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Tai, Yueh-Hua, Ru-Yin Tsai, Shinn-Long Lin, Chun-Chang Yeh, Jhi-Joung Wang, Pao-Luh Tao, and Chih-Shung Wong. "Amitriptyline Suppresses Neuroinflammation-dependent Interleukin-10-p38 Mitogen-activated Protein Kinase-Heme Oxygenase-1 Signaling Pathway in Chronic Morphine-infused Rats." Anesthesiology 110, no. 6 (June 1, 2009): 1379–89. http://dx.doi.org/10.1097/aln.0b013e31819fccd5.
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Background This study explores the underlying mechanism of the antiinflammatory effect of amitriptyline in chronic morphine-infused rats. Methods Male Wistar rats were implanted with two intrathecal catheters. One catheter was for the continuous infusion of saline, amitriptyline (15 microg/h), morphine (15 microg/h), p38 mitogen-activated protein kinase inhibitor SB203580 (0.5 microg/h), morphine plus amitriptyline, or morphine plus amitriptyline plus SB203580 for 5 days. The other catheter was used for daily intrathecal injection of anti-interleukin-10 (IL-10) antibody or heme oxygenase-1 inhibitor zinc protoporphyrin for 5 days. Results Amitriptyline/morphine coinfusion upregulated IL-10 protein expression in microglia; this was not observed in morphine-infused rats. Anti-IL-10 antibody effectively neutralized the amitriptyline-induced IL-10 expression in chronic morphine-infused rats. In addition, coinfusion of amitriptyline restored the antinociceptive effect of morphine (a 4.8-fold right-shift of the morphine dose-response curve compared to a 77.8-fold right-shift in its absence), and the injection of anti-IL-10 antibody or coinfusion of SB203580 partially reversed the effect of amitriptyline on the antinociceptive effect of morphine in morphine-infused rats (a 17.9-fold and 15.1-fold right-shift in morphine dose-response curves). Anti-IL-10 antibody and SB203580 significantly inhibited the amitriptyline-induced p38 mitogen-activated protein kinase and heme oxygenase-1 expression and the associated antiinflammatory effect of amitriptyline. Daily injection of zinc protoporphyrin also demonstrated that it reverses the effect of amitriptyline in morphine's antinociception and antiinflammation in chronic morphine-infused rats. Conclusions These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.
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Yang, Ying, and Tianwei Gao. "Alantolactone Suppresses Inflammation and Oxidative Stress in Doxorubicin Induced H9c2 Cells." Current Topics in Nutraceutical Research 20, no. 3 (March 22, 2022): 581–87. http://dx.doi.org/10.37290/ctnr2641-452x.20:581-587.
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Use of alantolactone in traditional Chinese medicine has been reported in a wide variety of diseases. To explore the role of alantolactone in chronic heart failure, its effect on doxorubicin treated H9c2 cells as a model was examined. The results of our studies show doxorubicin treatment decreased cell viability, enabled induction of secretion of proinflammatory cytokines, increased expression of malondialdehyde and decreased expression of superoxide dismutase, and enabled downregulation of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 pathways. Furthermore, all the reported effects of doxorubicin were reversed by alantolactone. In conclusion, alantolactone exhibits anti-inflammatory and antioxidative effects on doxorubicin treated H9c2 cells through activation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and inactivation of nuclear factor-kappa B pathway. Therefore, alantolactone might be a potential agent for the prevention of doxorubicin induced chronic heart failure.
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Park, Yunsoo, Hwa Sun Ryu, Ji Sung Kim, Ju Young Kim, Yong Guk Kim, Min Ji Pyo, Mi Jeong Park, et al. "Tussilagone inhibits dendritic cell functions via up-regulating heme oxygenase-1 expression (THER5P.833)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 200.12. http://dx.doi.org/10.4049/jimmunol.192.supp.200.12.
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Abstract Sesquiterpenoid tussilagone (TUS) has a variety of pharmacological activities. In this study, the effects of TUS on dendritic cell (DC) functions and the underlying mechanisms were investigated. TUS inhibited lipopolysaccharide (LPS)-induced activation of DCs, which was proved by the decreases of surface molecule expression, cytokine production, antigen uptake, migration, and allogenic T cell activation. TUS inhibited LPS-induced activation of NF-kB, MAPKs, and IRF-3 signalings. However, TUS did not directly inhibit kinase activities of IRAK4, IRAK1, TAK1 and IKK, suggesting that signaling molecules downstream from toll-like receptor (TLR) 4 might not be the direct targets of TUS. Instead, TUS activated heme oxygenase-1 (HO-1), which was a rate-limiting enzyme involved in heme degradation to immunosuppressive products, such as carbon monoxide and biliverdin. HO-1 antagonist reversed the inhibitory activity of TUS in DCs. Taken together, this study suggests that TUS might be an inducer of HO-1, which indirectly inhibits TLR signalings and functional activation of LPS-treated DCs
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Mingone, Christopher J., Mansoor Ahmad, Sachin A. Gupte, Joseph L. Chow, and Michael S. Wolin. "Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 3 (March 2008): H1244—H1250. http://dx.doi.org/10.1152/ajpheart.00846.2007.
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This study examines in endothelium-denuded bovine pulmonary arteries the effects of increasing heme oxygenase-1 (HO-1) activity on relaxation and soluble guanylate cyclase (sGC) activation by nitric oxide (NO). A 24-h organ culture with 0.1 mM cobalt chloride (CoCl2) or 30 μM Co-protoporphyrin IX was developed as a method of increasing HO-1 expression. These treatments increased HO-1 expression and HO activity by approximately two- to fourfold and lowered heme levels by 40–45%. Induction of HO-1 was associated with an attenuation of pulmonary arterial relaxation to the NO-donor spermine-NONOate. The presence of a HO-1 inhibitor 30 μM chromium mesoporphyrin during the 24-h organ culture (but not acute treatment with this agent) reversed the attenuation of relaxation to NO seen in arteries co-cultured with agents that increased HO-1. Relaxation to isoproterenol, which is thought to be mediated through cAMP, was not altered in arteries with increased HO-1. Inducers of HO-1 did not appear to alter basal sGC activity in arterial homogenates or expression of the β1-subunit of sGC. However, the increase in activity seen in the presence of 1 μM spermine-NONOate was attenuated in homogenates obtained from arteries with increased HO-1. Since arteries with increased HO-1 had decreased levels of superoxide detected by the chemiluminescence of 5 μM lucigenin, superoxide did not appear to be mediating the attenuation of relaxation to NO. These data suggest that increasing HO-1 activity depletes heme, and this is associated with an attenuation of pulmonary artery relaxation and sGC activation responses to NO.
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Yan, Xue-Tao, Xiang-Hu He, Yan-Lin Wang, Zong-Ze Zhang, and Jun-Jiao Tang. "Transduced PEP-1-Heme Oxygenase-1 Fusion Protein Attenuates Lung Injury in Septic Shock Rats." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/6403861.
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Oxidative stress and inflammation have been identified to play a vital role in the pathogenesis of lung injury induced by septic shock. Heme oxygenase-1 (HO-1), an effective antioxidant and anti-inflammatory and antiapoptotic substance, has been used for the treatment of heart, lung, and liver diseases. Thus, we postulated that administration of exogenous HO-1 protein transduced by cell-penetrating peptide PEP-1 has a protective role against septic shock-induced lung injury. Septic shock produced by cecal ligation and puncture caused severe lung damage, manifested in the increase in the lung wet/dry ratio, oxidative stress, inflammation, and apoptosis. However, these changes were reversed by treatment with the PEP-1-HO-1 fusion protein, whereas lung injury in septic shock rats was alleviated. Furthermore, the septic shock upregulated the expression of Toll-like receptor 4 (TLR4) and transcription factor NF-κB, accompanied by the increase of lung injury. Administration of PEP-1-HO-1 fusion protein reversed septic shock-induced lung injury by downregulating the expression of TLR4 and NF-κB. Our study indicates that treatment with HO-1 protein transduced by PEP-1 confers protection against septic shock-induced lung injury by its antioxidant, anti-inflammatory, and antiapoptotic effects.
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Camaschella, Clara, Alessandro Campanella, Luigia De Falco, Loredana Boschetto, Roberta Merlini, Laura Silvestri, Sonia Levi, and Achille Iolascon. "The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload." Blood 110, no. 4 (August 15, 2007): 1353–58. http://dx.doi.org/10.1182/blood-2007-02-072520.
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Abstract Inherited microcytic-hypochromic anemias in rodents and zebrafish suggest the existence of corresponding human disorders. The zebrafish mutant shiraz has severe anemia and is embryonically lethal because of glutaredoxin 5 (GRLX5) deletion, insufficient biogenesis of mitochondrial iron-sulfur (Fe/S) clusters, and deregulated iron-regulatory protein 1 (IRP1) activity. This leads to stabilization of transferrin receptor 1 (TfR) RNA, repression of ferritin, and ALA-synthase 2 (ALAS2) translation with impaired heme synthesis. We report the first case of GLRX5 deficiency in a middle-aged anemic male with iron overload and a low number of ringed sideroblasts. Anemia was worsened by blood transfusions but partially reversed by iron chelation. The patient had a homozygous (c.294A>G) mutation that interferes with intron 1 splicing and drastically reduces GLRX5 RNA. As in shiraz, aconitase and H-ferritin levels were low and TfR level was high in the patient's cells, compatible with increased IRP1 binding. Based on the biochemical and clinical phenotype, we hypothesize that IRP2, less degraded by low heme, contributes to the repression of the erythroblasts ferritin and ALAS2, increasing mitochondrial iron. Iron chelation, redistributing iron to the cytosol, might relieve IRP2 excess, improving heme synthesis and anemia. GLRX5 function is highly conserved, but at variance with zebrafish, its defect in humans leads to anemia and iron overload.
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Nagai, Masako, Yukifumi Nagai, Yayoi Aki, Kiyohiro Imai, Yoshinao Wada, Shigenori Nagatomo, and Yasuhiko Yamamoto. "Effect of Reversed Heme Orientation on Circular Dichroism and Cooperative Oxygen Binding of Human Adult Hemoglobin†." Biochemistry 47, no. 2 (January 2008): 517–25. http://dx.doi.org/10.1021/bi7015519.
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Yan, He, and Huan Gao. "Tangeretin Improves Anxiety-Like Behaviors in a Rat Model of Post-Traumatic Stress Disorder." Current Topics in Nutraceutical Research 20, no. 2 (December 15, 2021): 370–76. http://dx.doi.org/10.37290/ctnr2641-452x.20:370-376.
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Post-traumatic stress disorder often contributes to various anxiety-like behaviors. The single prolonged stress was used to induce anxiety-like behaviors of rats. In this model, using an elevated plus maze test, we observed that tangeretin treatment reversed the decrease in the number of open arms entries, the percentage of time spent in open arms with no change in the number of closed arms entries, and percentage of time spent in closed arms in rats subjected to single prolonged stress. Furthermore, in an open field test, tangeretin treatment reversed the decrease in the number of crossing and time spent in the center field with no change in the activities in the peripheral regions. Diminution in serotonin in different parts of brain of rats with post-traumatic stress disorder was reversed by tangeretin. At the molecular level, tangeretin treatment increased the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase 1, and oxidoreductase-1 that was reduced in the post-traumatic stress disorder group in a dose-dependent manner. In conclusion, these studies have shown for the first time that tangeretin relieves anxiety-like behaviors in rats with post-traumatic stress disorder by activating nuclear factor erythroid 2-related factor 2 signaling pathway.
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Liu, Xiao-Ming, Gary B. Chapman, Kelly J. Peyton, Andrew I. Schafer, and William Durante. "Antiapoptotic Action of Carbon Monoxide on Cultured Vascular Smooth Muscle Cells." Experimental Biology and Medicine 228, no. 5 (May 2003): 572–75. http://dx.doi.org/10.1177/15353702-0322805-30.
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Vascular smooth muscle cells (SMCs) generate carbon monoxide (CO) from the degradation of heme by the enzyme heme oxygenase. Because recent studies indicate that CO influences the properties of vascular SMCs, we examined whether this diatomic gas regulates apoptosis in vascular SMCs. Treatment of cultured rat aortic SMCs with a cytokine cocktail consisting of interleukin-1β (5 ng/ml), tumor necrosis factor-α (20 ng/ml), and interferon-γ (200 U/ml) for 48 hr stimulated apoptosis, as demonstrated by DNA laddering, caspase-3 activation, and annexin V staining. However, the exogenous addition of CO (200 ppm) completely blocked cytokine-mediated apoptosis. The antiapoptotic action of CO was partially reversed by the soluble guanylate cyclase inhibitor, H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μM). In contrast, the p38 mitogen-activated protein kinase inhibitor, SB203580 (10 μM), had no effect on SMC apoptosis. These findings indicate that CO is a potent inhibitor of vascular SMC apoptosis and that it blocks apoptosis, in part, by activating the cGMP signaling pathway. The ability of CO to inhibit vascular SMC apoptosis may play a critical role in attenuating lesion formation at sites of arterial damage.
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Chitambar, CR, and Z. Zivkovic. "Inhibition of hemoglobin production by transferrin-gallium." Blood 69, no. 1 (January 1, 1987): 144–49. http://dx.doi.org/10.1182/blood.v69.1.144.144.
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Abstract Recent clinical trials evaluating gallium nitrate as a chemotherapeutic agent have reported the development of microcytic hypochromic anemia in patients treated with this agent. Because gallium is known to bind avidly to transferrin, we examined the effect of transferrin-gallium (Tf-Ga) on hemoglobin production by Friend erythroleukemia cells in vitro. Cellular hemoglobin production, as assessed by benzidine staining, cellular hemoglobin content, and 59Fe incorporation into heme, was significantly decreased following exposure of cells to Tf-Ga. Tf-Ga led to an early decrease in cellular 59Fe incorporation even before changes in hemoglobin production were detected. A marked increase in cellular transferrin receptor expression occurred following exposure of cells to Tf-Ga. Tf-Ga inhibition of hemoglobin production could be reversed and hemoglobin production could be restored to normal by addition to the media of either transferrin-iron (Tf-Fe) or iron- pyridoxal isonicotinoyl hydrazone, a compound capable of supplying iron directly to reticulocytes for heme synthesis without transferrin as a mediator. These studies provide an explanation for the development of anemia in patients treated with gallium nitrate and suggest that gallium's mechanism of chemotherapeutic action includes inhibition of cellular iron incorporation.
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Chitambar, CR, and Z. Zivkovic. "Inhibition of hemoglobin production by transferrin-gallium." Blood 69, no. 1 (January 1, 1987): 144–49. http://dx.doi.org/10.1182/blood.v69.1.144.bloodjournal691144.
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Recent clinical trials evaluating gallium nitrate as a chemotherapeutic agent have reported the development of microcytic hypochromic anemia in patients treated with this agent. Because gallium is known to bind avidly to transferrin, we examined the effect of transferrin-gallium (Tf-Ga) on hemoglobin production by Friend erythroleukemia cells in vitro. Cellular hemoglobin production, as assessed by benzidine staining, cellular hemoglobin content, and 59Fe incorporation into heme, was significantly decreased following exposure of cells to Tf-Ga. Tf-Ga led to an early decrease in cellular 59Fe incorporation even before changes in hemoglobin production were detected. A marked increase in cellular transferrin receptor expression occurred following exposure of cells to Tf-Ga. Tf-Ga inhibition of hemoglobin production could be reversed and hemoglobin production could be restored to normal by addition to the media of either transferrin-iron (Tf-Fe) or iron- pyridoxal isonicotinoyl hydrazone, a compound capable of supplying iron directly to reticulocytes for heme synthesis without transferrin as a mediator. These studies provide an explanation for the development of anemia in patients treated with gallium nitrate and suggest that gallium's mechanism of chemotherapeutic action includes inhibition of cellular iron incorporation.
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Alexandreanu, Iulia C., and David M. Lawson. "Heme Oxygenase in the Rat Anterior Pituitary: Immunohistochemical Localization and Possible Role in Gonadotropin and Prolactin Secretion." Experimental Biology and Medicine 228, no. 1 (January 2003): 64–69. http://dx.doi.org/10.1177/153537020322800109.
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The objectives of this study were to determine if heme oxygenase (HO), which catalyzes the degradation of heme and the formation of carbon monoxide (CO), is localized in the rat anterior pituitary and, if so, to determine if hemin (a substrate for HO) or chromium mesoporphyrin (CrMP) (an inhibitor of HO), alter pituitary gonadotropin and prolactin secretion. For localization of HO, sections of anterior pituitaries obtained from mature Holtzman Sprague-Dawley rats in different stages of the estrous cycle were immunostained for two of the HO isoforms, HO-1 and HO-2. The immunostaining for the inducible HO isoform (HO-1) was limited to discrete populations of pituitary cells, whereas the constitutive isoform (HO-2) had a more widespread distribution. The afternoon surge of leutinizing hormone (LH) in the plasma of ovariectomized, estradiol-treated rats was advanced by 2 hr after 7 days of treatment with CrMP (4 μM/kg), and this effect was reversed when hemin (30 μM/kg) was coadministered with CrMP. The afternoon follicle-stimulating hormone (FSH) surge was not affected by either treatment. In contrast, the afternoon prolactin (PRL) surge was completely blocked or delayed by CrMP treatment, and this effect was not reversed by hemin. In vitro perifusion of pituitary explants with CrMP also significantly reduced PRL release compared with secretion from untreated explants. In vitro gonadotropin-releasing hormone (GnRH)-stimulated FSH secretion was significantly increased from pituitary explants of ovariectomized, estradiol-treated rats treated in vivo with hemin but was unaffected by CrMP treatment, whereas GnRH-stimulated LH release was not affected by hemin but was increased by CrMP treatment. In conclusion, this study demonstrates that HO exists in the rat anterior pituitary gland, and that a substrate and an inhibitor of this enzyme alter the secretion of gonadotropins and PRL.
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Motterlini, R., and V. W. Macdonald. "Cell-free hemoglobin potentiates acetylcholine-induced coronary vasoconstriction in rabbit hearts." Journal of Applied Physiology 75, no. 5 (November 1, 1993): 2224–33. http://dx.doi.org/10.1152/jappl.1993.75.5.2224.
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Cell-free hemoglobin (Hb) preparations have been shown to alter vascular tone in vitro and in vivo. The high affinity of Hb for nitric oxide, the putative endothelium-derived relaxing factor (EDRF), may be primarily responsible for this activity, but the contribution of tissue-damaging oxygen-derived free radicals has not been established. We investigated the effects of human Hb interdimerically cross-linked with bis-(3,5-dibromosalicyl)fumarate (alpha alpha Hb) on the coronary vasomotor response to acetylcholine (ACh) in isolated perfused rabbit hearts. Infusion of 0.1 g/dl alpha alpha Hb altered the dose-dependent response to ACh, decreasing the calculated IC50 (ACh concn at which coronary pressure is 50% of its maximal value) from 3.96 +/- 0.34 to 0.85 +/- 0.06 microM (P < 0.01). This augmented sensitivity to ACh was only partially reversed upon washout of alpha alpha Hb (IC50 1.93 +/- 0.13 microM). Simultaneous infusion of 60 microM deferoxamine mesylate with alpha alpha Hb attenuated this response (IC50 decreased from 3.86 +/- 0.27 to 1.73 +/- 0.38 microM), which was completely reversed after removal of alpha alpha Hb (IC50 3.41 +/- 0.17 microM). NG-nitro-L-arginine methyl ester (50 microM) and cross-linked cyanomethemoglobin (CNmet alpha alpha Hb, 0.1 g/dl) induced a significant (P < 0.05) increase in ACh-induced vasoconstriction accompanied by a reduction in myocardial functions in the same range as that caused by alpha alpha Hb. Infusion of deferoxamine mesylate (60 microM) with CNmet alpha alpha Hb completely prevented the reduction in IC50 elicited by the infusion of CNmet alpha alpha Hb alone. These data demonstrate that alpha alpha Hb can alter coronary vasomotor responsiveness and suggest the involvement of at least two mechanisms, one that is related to an accessible ferrous heme and is reversible and another that does not require an open heme site and is irreversible.
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Chang, Tuanjie, Lingyun Wu, and Rui Wang. "Inhibition of vascular smooth muscle cell proliferation by chronic hemin treatment." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 3 (September 2008): H999—H1007. http://dx.doi.org/10.1152/ajpheart.01289.2007.
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Hemin, an oxidized form of heme, is an essential regulator of gene expression and cell cycle progression. Our laboratory previously reported ( 34 ) that chronic hemin treatment of spontaneously hypertensive rats reversed the eutrophic inward remodeling of small peripheral arteries. Whether long-term treatment of cultured vascular smooth muscle cells (VSMCs) with hemin alters the proliferation status of these cells has been unknown. In the present study, hemin treatment at 5 μM for 4, 7, 14, and 21 days significantly inhibited the proliferation of cultured rat aortic VSMCs (A-10 cells) by arresting cells at G0/G1 phases so as to decelerate cell cycle progression. Heme oxygenase (HO) activity and inducible HO-1 protein expression were significantly increased by hemin treatment. HO inhibitor tin protoporphyrin IX (SnPP) abolished the effects of hemin on cell proliferation and HO activity. Interestingly, hemin-induced HO-1 expression was further increased in the presence of SnPP. Hemin treatment had no significant effect on the expression of constitutive HO-2. Expression of p21 protein and the level of reactive oxygen species (ROS) were decreased by hemin treatment, which was reversed by application of SnPP. After removal of hemin from culture medium, inhibited cell proliferation and increased HO-1 expression in VSMCs were returned to control level within 1 wk. Transfection with HO-1 small interfering RNA significantly knocked down HO-1 expression and decreased HO activity, but had no effect on HO-2 expression, in cells treated with or without hemin for 7 days. The inhibitory effect of hemin on cell proliferation was abolished in HO-1 silenced cells. It is concluded that induction of HO-1 and, consequently, increased HO activity are responsible for the chronic inhibitory effect of hemin on VSMC proliferation. Changes in the levels of p21 and ROS might also participate in the cellular effects of hemin.
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Liu, Yunfeng, Fangmiao Jing, Woelsung Yi, Avital Mendelson, Patricia Shi, Ronald Walsh, David F. Friedman, et al. "Protective Role of HO-1 Expressing CD16+ Patrolling Monocytes Against Hemolysis-Induced Endothelial Damage and Vaso-Occlusive Crisis in Sickle Cell Disease." Blood 130, Suppl_1 (December 7, 2017): 767. http://dx.doi.org/10.1182/blood.v130.suppl_1.767.767.
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Abstract Causing leukocyte activation and upregulation of adhesion molecules on endothelial cells. CD16+ monocytes, also known as endothelial patrolling monocytes, normally scavenge the damaged cells and debris from the vasculature. As compared to other monocyte subsets or immune cell types, the CD16+monocyte subset expresses higher levels of the anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme. Given the role of CD16+ monocytes as scavengers of debris on endothelial cells, we tested the hypothesis that this subset may protect SCD vasculature from the ongoing hemolytic insult through expression of high levels of HO-1. We found roughly 35% of circulating CD16+ monocytes from SCD patients expressed very high levels of HO-1 as compared to 5% in healthy controls. The HO-1hi SCD monocytes expressed significantly (30%) less TNF-a compared to HO-1lo monocytes following stimulation, consistent with anti-inflammatory effects of HO-1. We hypothesized that uptake of free hemoglobin/heme was responsible for high HO-1 expression levels in SCD CD16+ monocytes. To test this, healthy donors (HDs) or SCD patient monocytes were treated with different doses of free heme or hemolysed RBCs. We found dose-dependent HO-1 induction (five-fold at 20mM heme) in purified CD16- monocytes, but surprisingly none in CD16+ subset. However, upon co-culture with human umbilical vein endothelial cells (HUVEC), continuous or prior exposure to heme induced HO-1hi expression exclusively in CD16+ monocytes (5 fold in HD and further two fold in SCD compared to non-heme treated cocultures, p<0.001). Using imagining flow cytometric analysis, we found marked increase in uptake of heme-exposed endothelial cell-derived material by CD16+ monocytes (HD: 2% to 13% ± 3%; in SCD: 20% ± 3% to 30% ± 4%, p< 0.001) but none by CD16- monocytes. Our transwell studies demonstrated that cell-cell contact between CD16+ monocytes and heme-exposed HUVEC was required for HO-1hi expression. We found roughly 4-fold increase in expression of phosphatidylserine (PS, annexin V+), ICAM-1 and vCAM-1 on heme-treated HUVEC cells. Antibody blocking studies identified PS moieties as well as ICAM-1 as key molecules involved in monocyte-HUVEC interactions that mediated HO-1hi induction, suggesting that high levels of HO-1 expression in SCD CD16+ monocytes is in part the result of attachment to and engulfment of apoptotic, activated endothelial cells damaged by heme. SCD patients suffer from vaso-occlusive crisis (VOC), resulting from increased attachment of SCD RBCs to damaged and activated endothelium. We hypothesized that inadequate numbers or lower HO-1hi levels in CD16+ monocyte will predispose SCD patients to episodes of VOC due to decreased removal by CD16+ monocytes of damaged endothelial and sickle RBCs. Amongst SCD patients receiving chronic transfusions, we found a two-fold lower frequency of circulating CD16+ monocytes and half the numbers of CD16+HO-1hi monocytes in patients with a recent history of VOC episode as compared to those without VOC (p< 0.01); the former group also expressed higher levels of circulating sVCAM-1 (997 ± 210 vs 765 ± 236 ng/m, p=0.02), a marker of endothelial activation. To formally test the role of patrolling monocytes in endothelial damage induced by SCD RBCs and heme, we injected RBCs from Townes SCD mice alone or after 24hrs with heme into Nr4a1-knockout mice which have a selective loss of patrolling monocytes. Immunofluorescence analysis of liver vasculature showed a 3 fold increase in the activated endothelial marker, ICAM-1 within 24hrs following injection of sickle RBCs and two-fold increase in circulating sVCAM-1 levels in mice treated with sickle RBC plus heme (p <0.001). Transfer of HO-1+ patrolling monocytes (LY6Clo), but not a classical monocyte subset (LY6C+) reversed activated endothelial phenotype, indicating that patrolling monocytes can inhibit SCD-induced endothelial activation. Altogether, these data suggest that SCD patrolling monocytes remove hemolysis-damaged endothelial cells, resulting in HO-1 upregulation and dampening of vascular inflammation. Perturbations in CD16+ monocyte numbers resulting in lower local HO-1 levels can predispose SCD patients to VOC, thus identifying HO-1+ patrolling monocytes as key players in VOC pathophysiology and as therapeutic targets. Disclosures No relevant conflicts of interest to declare.
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Petrache, Irina, Leo E. Otterbein, Jawed Alam, Gordon W. Wiegand, and Augustine M. K. Choi. "Heme oxygenase-1 inhibits TNF-α-induced apoptosis in cultured fibroblasts." American Journal of Physiology-Lung Cellular and Molecular Physiology 278, no. 2 (February 1, 2000): L312—L319. http://dx.doi.org/10.1152/ajplung.2000.278.2.l312.
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Heme oxygenase (HO)-1 catalyzes the oxidative cleavage of heme to yield equimolar amounts of biliverdin, iron, and carbon monoxide. HO-1 is a stress response protein, the induction of which is associated with protection against oxidative stress. The mechanism(s) of protection is not completely elucidated, although it is suggested that one or more of the catalytic by-products provide antioxidant functions either directly or indirectly. The involvement of reactive oxygen species in apoptosis raised the question of a possible role for HO-1 in programmed cell death. Using the tetracycline-regulated expression system, we show here that conditional overexpression of HO-1 prevents tumor necrosis factor-α-induced apoptosis in murine L929 fibroblasts. Inhibition of apoptosis was not observed in the presence of tin protoporphyrin, a specific inhibitor of HO activity, and in cells overexpressing antisense HO-1. Interestingly, exogenous administration of a low concentration of carbon monoxide also prevented tumor necrosis factor-α-induced apoptosis in L929 fibroblasts. Inhibition of tumor necrosis factor-α-induced apoptosis by HO-1 overexpression was reversed by 1 H-(1,2,4)oxadiazolo(4,3- a)quinoxalin-1-one, an inhibitor of guanylate cyclase, which is a target enzyme for carbon monoxide. Taken together, our data suggest that the antiapoptotic effect of HO-1 may be mediated via carbon monoxide.
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Shiraishi, Fumie, Lisa M. Curtis, Leigh Truong, Kenneth Poss, Gary A. Visner, Kirsten Madsen, Harry S. Nick, and Anupam Agarwal. "Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis." American Journal of Physiology-Renal Physiology 278, no. 5 (May 1, 2000): F726—F736. http://dx.doi.org/10.1152/ajprenal.2000.278.5.f726.
Full textAbstract:
Heme oxygenase-1 (HO-1) is a 32-kDa microsomal enzyme that catalyzes the conversion of heme to biliverdin, releasing iron and carbon monoxide. Induction of HO-1 occurs as a protective response in cells/tissues exposed to a wide variety of oxidant stimuli. The chemotherapeutic effects of cis-diamminedichloroplatinum(II) (cisplatin), a commonly used anticancer drug, are limited by significant nephrotoxicity, which is characterized by varying degrees of renal tubular apoptosis and necrosis. The purpose of this study was to evaluate the functional significance of HO-1 expression in cisplatin-induced renal injury. Our studies demonstrate that transgenic mice deficient in HO-1 (−/−), develop more severe renal failure and have significantly greater renal injury compared with wild-type (+/+) mice treated with cisplatin. In vitro studies in human renal proximal tubule cells demonstrate that hemin, an inducer of HO-1, significantly attenuated cisplatin-induced apoptosis and necrosis, whereas inhibition of HO-1 enzyme activity reversed the cytoprotective effect. Overexpression of HO-1 resulted in a significant reduction in cisplatin-induced cytotoxicity. These studies provide a basis for future studies using targeted gene expression of HO-1 as a therapeutic and preventive modality in high-risk settings of acute renal failure.
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Kawakami, Tomoko, Nitin Puri, Komal Sodhi, Lars Bellner, Toru Takahashi, Kiyoshi Morita, Rita Rezzani, Tim D. Oury, and Nader G. Abraham. "Reciprocal Effects of Oxidative Stress on Heme Oxygenase Expression and Activity Contributes to Reno-Vascular Abnormalities in EC-SOD Knockout Mice." International Journal of Hypertension 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/740203.
Full textAbstract:
Heme oxygenase (HO) system is one of the key regulators of cellular redox homeostasis which responds to oxidative stress (ROS) via HO-1 induction. However, recent reports have suggested an inhibitory effect of ROS on HO activity. In light of these conflicting reports, this study was designed to evaluate effects of chronic oxidative stress on HO system and its role in contributing towards patho-physiological abnormalities observed in extracellular superoxide dismutase (EC-SOD, SOD3) KO animals. Experiments were performed in WT and EC-SOD(−/−)mice treated with and without HO inducer, cobalt protoporphyrin (CoPP). EC-SOD(−/−)mice exhibited oxidative stress, renal histopathological abnormalities, elevated blood pressure, impaired endothelial function, reduced p-eNOS, p-AKT and increased HO-1 expression; although, HO activity was significantly (P<0.05) attenuated along with attenuation of serum adiponectin and vascular epoxide levels (P<0.05). CoPP, in EC-SOD(−/−)mice, enhanced HO activity (P<0.05) and reversed aforementioned pathophysiological abnormalities along with restoration of vascular EET, p-eNOS, p-AKT and serum adiponectin levels in these animals. Taken together our results implicate a causative role of insufficient activation of heme-HO-adiponectin system in pathophysiological abnormalities observed in animal models of chronic oxidative stress such as EC-SOD(−/−)mice.
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Samb, Abdoulaye, Camille Taillé, Abdelhamid Almolki, Jérôme Mégret, James M. Staddon, Michel Aubier, and Jorge Boczkowski. "Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin." American Journal of Physiology-Lung Cellular and Molecular Physiology 283, no. 3 (September 1, 2002): L596—L603. http://dx.doi.org/10.1152/ajplung.00446.2001.
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Reactive oxygen species (ROS) increase the contractile response of airway smooth muscle (ASM). Heme oxygenase (HO) catabolizes heme to the powerful antioxidant bilirubin. Because HO is expressed in the airways, we investigated its effects on ASM contractility and ROS production in guinea pig trachea. HO expression was higher in the epithelium than in tracheal smooth muscle. Incubation of tracheal rings (TR) with the HO inhibitor tin protoporphyrin (SnPP IX) or the HO substrate hemin increased and decreased, respectively, ASM contractile response to carbamylcholine. The effect of hemin was reversed by SnPP and mimicked by the antioxidants superoxide dismutase (SOD) and catalase. Hemin significantly reduced the effect of carbamylcholine in rings treated with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), compared with ODQ-treated rings without hemin incubation, suggesting that the CO-guanosine 3′,5′-cyclic monophosphate pathway was not involved in the control of tracheal reactivity. SnPP and hemin increased and decreased ROS production by TR by 18 and 38%, respectively. Bilirubin (100 pM) significantly decreased TR contractility and ROS production. Hemin, bilirubin, and SOD/catalase decreased phosphorylation of the contractile protein myosin light chain, whereas SnPP significantly augmented it. These data suggest that modulation of the redox status by HO and, moreover, by bilirubin modulates ASM contractility by modulating levels of phosphorylated myosin light chain.
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Fitch, C. D., and A. C. Chou. "Regulation of heme polymerizing activity and the antimalarial action of chloroquine." Antimicrobial Agents and Chemotherapy 41, no. 11 (November 1997): 2461–65. http://dx.doi.org/10.1128/aac.41.11.2461.
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Mice infected with Plasmodium berghei served as donors of erythrocytes with a high level of parasitemia for the study of ferriprotoporphyrin IX (FP) polymerization. Six hours after treatment of these mice with 3 micromol of chloroquine per 25 g of body weight, there were significant losses of heme polymerase I (HPA I). For chloroquine-susceptible (CS) P. berghei, the rate of FP polymerization decreased from 541 +/- 42 (mean +/- standard deviation; n = 12) to 51 +/- 19 (n = 8) nmol of FP polymerized per h per ml of packed erythrocytes (normalized to represent 1,000 parasites per 1,000 erythrocytes). For chloroquine-resistant (CR) P. berghei, the rate decreased from 284 +/- 19 (n = 16) to 124 +/- 11 (n = 6) nmol per h per ml. The chloroquine-induced loss of HPA I was accompanied by the accumulation of unpolymerized FP in CS P. berghei but not in CR P. berghei, which is consistent with the hypothesis that FP mediates the antimalarial action of chloroquine. Quinine treatment partially reversed the effects of chloroquine in CS P. berghei but not in CR P. berghei. Cycloheximide treatment antagonized the effects of chloroquine in both lines of parasites. To explain these findings, we propose that chloroquine, quinine, and cycloheximide perturb a regulatory process for HPA I. Furthermore, we propose that when chloroquine engages its target in the regulatory process, it initiates a chain of events which culminates in increased production, accessibility, or reactivity of a regulator (inactivator) of HPA I.
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Kumari, Namita, and Sergei A. Nekhai. "Heme and Iron Chelators Inhibit HIV-1 Through The Induction Of Heme Oxygenase 1, Ferroportin and IKBα." Blood 122, no. 21 (November 15, 2013): 2198. http://dx.doi.org/10.1182/blood.v122.21.2198.2198.
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Abstract Background Recently, HIV-1 infection was shown to be efficiently inhibited in macrophages and T-cells treated with hemin that was added extracellularly 1,2. Hemin administration to humanized transgenic mice significantly reduced HIV-1 viral load 1. Suppression of HIV-1 by hemin was mediated through the induction of (HO-1)1, via a protein kinase C-dependent pathway2. The inhibitory effect of hemin could be reversed by protoporphyrin, an HO-1 inhibitor 2. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1. We recently analyzed the role of HO-1 in protecting LPS-treated human macrophages against HIV-1 infection3. LPS-treated macrophages were negative for mature virions, expressed HO-1 and produced MIP1α, MIP1β and LD78β chemokines which led to a decreased CCR5 expression. Treatment with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) increased HIV-1 replication and decreased secretion of MIP1α, MIP1β, and LD78β chemokines. HO-1 also affects several proteins involved in cell cycle progression, and cell cycle is critical for HIV-1 progression. Hypoxia leads to induction and stabilization of HIF-1α and is inhibitory to HIV-1 replication. NF-kB is important for basal and Tat-activated HIV-1 transcription. Here we analyzed factors involved in HIV-1 transcription affected by HO-1 expression. Results HIV-1 replication was reduced in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication, suggesting that ferroportin plays a key role in the HIV-1 inhibition. Stable ferroportin knock down in THP1 cells led to the inability of hemin to inhibit HIV-1, again suggesting that ferroportin plays a key role in this process. In hemin-treated THP-1 cells, expression of p21, HIF-1α and IKBα mRNA was induced. The expression of IKBα, an inhibitor of NF-kB, reduced the level of p65 subunit of NF-kB. We obtained similar results in THP-1 cell treated with iron chelators, which also induced the expression of IKBα, HIF-1 and p21. THP-1 cells treated with hemin or iron chelators were arrested in G1 phase of cell cycle. Stable HIF-1a knockdown in promonocytic THP-1 cells increased HIV replication suggesting that HIF-1 might be a restriction factor for HIV-1. In contrast to iron chelators that inhibited enzymatic activity of CDK2 without affecting its protein level, hemin treatment reduced CDK2 expression at mRNA and protein levels. Conclusions Induction of HIF-1 regulatory pathway and iron export by ferroportin might protect hemin-treated THP-1 cells from HIV-1 infection. Additional molecular mechanisms of heme-mediated HIV-1 inhibition might also include NF-kB inhibition by IKBα and CDK2 inhibition leading to the inhibition of HIV-1 transcription. Our results point to novel therapeutics, such as the use of hemin and iron chelators, both of which are FDA approved for treatment for acute porphyries and iron overload. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. Literature 1. Devadas K, Dhawan S. Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction. J Immunol. 2006;176(7):4252-4257. 2. Devadas K, Hewlett IK, Dhawan S. Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction. J Leukoc Biol. 2010;87(5):915-924. 3. Zhou ZH, Kumari N, Nekhai S, et al. Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages. Biochem Biophys Res Commun. 2013;435(3):373-377. Disclosures: No relevant conflicts of interest to declare.
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Katada, Kazuhiro, Tomohisa Takagi, Takaya Iida, Tomohiro Ueda, Katsura Mizushima, Akifumi Fukui, Tetsuya Okayama, et al. "Role and Potential Mechanism of Heme Oxygenase-1 in Intestinal Ischemia-Reperfusion Injury." Antioxidants 11, no. 3 (March 15, 2022): 559. http://dx.doi.org/10.3390/antiox11030559.
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Intestinal ischemia-reperfusion (IR) injury is a complex, multifactorial, and pathophysiological condition with high morbidity and mortality, leading to serious difficulties in treatment, especially in humans. Heme oxygenase (HO) is the rate-limiting enzyme involved in heme catabolism. HO-1 (an inducible form) confers cytoprotection by inhibiting inflammation and oxidation. Furthermore, nuclear factor-erythroid 2-related factor 2 (Nrf2) positively regulates HO-1 transcription, whereas BTB and CNC homolog 1 (Bach1) competes with Nrf2 and represses its transcription. We investigated the role and potential mechanism of action of HO-1 in intestinal IR injury. Intestinal ischemia was induced for 45 min followed by 4 h of reperfusion in wild-type, Bach1-deficient, and Nrf2-deficient mice, and a carbon monoxide (CO)-releasing molecule (CORM)-3 was administered. An increase in inflammatory marker levels, nuclear factor-κB (NF-κB) activation, and morphological impairments were observed in the IR-induced intestines of wild-type mice. These inflammatory changes were significantly attenuated in Bach1-deficient mice or those treated with CORM-3, and significantly exacerbated in Nrf2-deficient mice. Treatment with an HO-1 inhibitor reversed this attenuation in IR-induced Bach1-deficient mice. Bach1 deficiency and treatment with CORM-3 resulted in the downregulation of NF-κB activation and suppression of adhesion molecules. Together, Bach1, Nrf2, and CO are valuable therapeutic targets for intestinal IR injury.
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Schranzhofer, Matthias, Manfred Schifrer, Bruno Galy, Matthias Hentze, Prem Ponka, and Muellner W. Ernst. "Low Cytosolic Non-Heme Iron Levels in Erythroid Cells Prevent IRP2-Mediated Ferritin Upregulation during Differentiation." Blood 110, no. 11 (November 16, 2007): 705. http://dx.doi.org/10.1182/blood.v110.11.705.705.
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Abstract Erythroid cells are the major consumers of iron in the human body. Differentiating erythroid cells shuttle the metal with very high efficiency towards mitochondria for the formation of heme. To satisfy their high iron needs, developing red blood cells (RBC) have to sustain high expression of transferrin receptor 1 (TfR) despite increasing cellular iron concentration. Moreover, synthesis of ferritin must not be activated by incoming iron, since this would represent a counterproductive storage during the phase of high iron demand. Recently we have demonstrated that during terminal differentiation primary erythroid cells satisfy their exceptionally high requirements for iron by switching to a mode where the post-transcriptional, iron-dependent regulatory system, formed by iron responsive proteins (IRP1 and IRP2) and iron responsive elements (IREs), seems to sense a low-iron state. This occurs despite a massive net increase of iron import into the cell (Schranzhofer et al., Blood107:4159, 2006). To examine the hypothesis that erythroid cells have low non-heme iron levels in their cytosol, we experimentally increased the cytosolic iron pool by either inhibiting heme biosynthesis or overloading cells with iron. Both block of heme synthesis by either succinylacetone or isonicotinic acid hydrazide (INH) or administration of ferric ammonium citrate, resulted in a clear increase in ferritin levels. This increase was directly proportional to the increase in the cellular concentration of non-heme-iron. Moreover, the effect of INH, the inhibitor of 5-aminolevulinic acid (ALA) synthase, could be reversed by the addition of ALA. Strikingly, increases in ferritin expression upon perturbation of cellular iron homeostasis strongly correlated with the loss of IRE-binding activity of IRP2 but not IRP1, as determined by mobility shift assays. This suggests that IRP2 is the major regulator of ferritin expression in erythroid cells. To further elaborate on this observation, we cultured primary erythroblasts derived from IRP1−/− and IRP2−/− mice (kindly provided by Drs. M. Hentze and B. Galy). In agreement with the published phenotype of microcytic hypochromic anemia, only erythroblasts lacking IRP2 exhibited a reduction in hemoglobinization. Moreover, only IRP2−/− cells showed a significant increase in ferritin expression, whereas developing RBC lacking IRP1 had levels of ferritin protein equal to wild type cells. We conclude that in erythroid cells efficient shuttling of incoming iron towards mitochondria and its prompt use for heme formation is important to keep the cytosol in an iron-deprived state and consequently ferritin protein levels low. This translational repression seems to be mainly achieved by IRP2. Together with the observation that surface expression of TfR was reduced in IRP2−/− erythroblasts during self renewal but not during terminal differentiation, our results suggest that not only down-regulation of TfR, but also up-regulation of ferritin may be a major factor for the anemic phenotype observed in IRP2−/− mice.
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Almolki, Abdelhamid, Camille Taillé, Gillian F. Martin, Peter J. Jose, Christine Zedda, Marc Conti, Jerome Megret, Dominique Henin, Michel Aubier, and Jorge Boczkowski. "Heme oxygenase attenuates allergen-induced airway inflammation and hyperreactivity in guinea pigs." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 1 (July 2004): L26—L34. http://dx.doi.org/10.1152/ajplung.00237.2003.
Full textAbstract:
Heme oxygenase (HO), the heme-degrading enzyme, has shown anti-inflammatory effects in several models of pulmonary diseases. HO is induced in airways during asthma; however, its functional role is unclear. Therefore, we evaluated the role of HO on airway inflammation [evaluated by bronchoalveolar lavage (BAL) cellularity and BAL levels of eotaxin, PGE2, and proteins], mucus secretion (evaluated by analysis of MUC5AC gene expression and periodic acid-Schiff staining), oxidative stress (evaluated by quantification of 4-hydroxynonenal adducts and carbonylated protein levels in lung homogenates), and airway responsiveness to histamine in ovalbumin (OVA)-sensitized and multiple aerosol OVA or saline-challenged guinea pigs (6 challenges, once daily, OVA group and control group, respectively). Airway inflammation, mucus secretion, oxidative stress, and responsiveness were significantly increased in the OVA group compared with the control group. HO upregulation by repeated administrations of hemin (50 mg/kg ip) significantly decreased airway responsiveness in control animals and airway inflammation, mucus secretion, oxidative stress, and responsiveness in OVA animals. These effects were reversed by the concomitant administration of the HO inhibitor tin protoporphyrin-IX (50 μmol/kg ip). Repeated administrations of tin protoporphyrin-IX alone significantly increased airway responsiveness in control animals but did not modify airway inflammation, mucus secretion, oxidative stress, and responsiveness in OVA animals. These results suggest that upregulation of the HO pathway has a significant protective effect against airway inflammation, mucus hypersecretion, oxidative stress, and hyperresponsiveness in a model of allergic asthma in guinea pigs.
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Elorza, Alvaro A., Brigham B. Hyde, Hanna Mikkola, Sheila Collins, and Orian S. Shirihai. "UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis." Blood 112, no. 11 (November 16, 2008): 5372. http://dx.doi.org/10.1182/blood.v112.11.5372.5372.
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Abstract UCP2, an inner membrane mitochondrial protein, has been implicated in bioenergetics and Reactive Oxygen Species (ROS) modulation. UCP2 has been previously hypothesized to function as a facilitator of heme synthesis and iron metabolism by reducing ROS production. While UCP2 has been found to be induced by GATA1 during erythroid differentiation its role in erythropoiesis in vivo or in vitro has not been reported thus far. Here we report on the study of UCP2 role in erythropoiesis and the hematologic phenotype of UCP2 deficient mouse. In vivo we found that UCP2 protein peaks at early stages of erythroid maturation when cells are not fully committed in heme synthesis and then becomes undetectable at the reticulocyte stage. Iron incorporation into heme was unaltered in erythroid cells from UCP2 deficient mice. While heme synthesis was not influenced by UCP2 deficiency, mice lacking UCP2 had a delayed recovery from chemically induced hemolytic anemia. Analysis of the erythroid lineage from bone marrow and fetal liver revealed that in the UCP2 deficient mice the R3 (CD71high/Ter119high) population was reduced by 24%. The count of BFU-E and CFU-E colonies, scored in an erythroid colony assay, was unaffected, indicating an equivalent number of early erythroid progenitor cells in both UCP2 deficient and control cells. Ex-vivo differentiation assay revealed that UCP2 deficient c-kit+ progenitor cells expansion was overall reduced by 14% with population analysis determining that the main effect is at the R3 stage. No increased rate of apoptosis was found indicating that expansion rather than cell death is being compromised. Reduced expansion of c-kit+ cells was accompanied by 30% reduction in the phosphorylated form of ERK, a ROS dependent cytosolic regulator of cell proliferation. Analysis of ROS in UCP2 null erythroid progenitors revealed altered distribution of ROS resulting in 14% decrease in cytosolic and 32% increase in mitochondrial ROS. Restoration of the cytosolic oxidative state of erythroid progenitor cells by the pro-oxidant Paraquat reversed the effect of UCP2 deficiency on cell proliferation in in vitro differentiation assays. Together, these results indicate that UCP2 is a regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.
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Kinderlerer, Anne R., Isabel Pombo Gregoire, Shahir S. Hamdulay, Faisal Ali, Rivka Steinberg, Gabriela Silva, Nadira Ali, et al. "Heme oxygenase-1 expression enhances vascular endothelial resistance to complement-mediated injury through induction of decay-accelerating factor: a role for increased bilirubin and ferritin." Blood 113, no. 7 (February 12, 2009): 1598–607. http://dx.doi.org/10.1182/blood-2008-04-152934.
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Abstract Catabolism of free heme by heme oxygenase-1 (HO-1) generates carbon monoxide, biliverdin, and free iron (Fe). These end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, antiapo-ptotic, antiproliferative, and antioxidant effects. We have identified an additional cytoprotective action, the regulation of complement activation, mediated via induction of decay-accelerating factor (DAF). Pharmacologic inhibition or short-interfering RNA (siRNA) depletion of HO-1 prevented induction of DAF expression in human endothelial cells. In contrast, HO-1 agonists hemin and cobalt protoporphyrin IX significantly increased DAF protein expression, reflecting an increase in transcription and steady-state mRNA. Adenoviral-mediated overexpression of HO-1 increased DAF expression, enhancing protection against C3 deposition and complement-mediated lysis, and this was reversed by DAF inhibitory monoclonal antibody (mAb) 1H4. Likewise, bilirubin, Fe chelation, and overexpression of heavy-chain ferritin all induced DAF expression in endothelial cells (EC). Analysis of cardiac endothelial cells isolated from Hmox1−/− mice revealed a 60% reduction in DAF expression compared with Hmox1+/+ EC, and Hmox1−/− cells showed enhanced sensitivity to complement. We propose that modulation of complement activation through induction of DAF represents an important component of the cytoprotective effects of HO-1 against vascular injury, such as that associated with posttransplant vasculopathy, allograft rejection, and ischemia reperfusion.
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Puri, Nitin, Yevgeniy Arefiev, Robert Chao, David Sacerdoti, Hibba Chaudry, Alexandra Nichols, Krithika Srikanthan, et al. "Heme Oxygenase Induction Suppresses Hepatic Hepcidin and Rescues Ferroportin and Ferritin Expression in Obese Mice." Journal of Nutrition and Metabolism 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/4964571.
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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.
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Tong, Guang, Ben Zhang, Xuan Zhou, Jinbo Zhao, Zhongchan Sun, Ye Tao, Jianming Pei, and Weida Zhang. "Kappa-Opioid Agonist U50,488H-Mediated Protection Against Heart Failure Following Myocardial Ischemia/Reperfusion: Dual Roles of Heme Oxygenase-1." Cellular Physiology and Biochemistry 39, no. 6 (2016): 2158–72. http://dx.doi.org/10.1159/000447911.
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Backgrounds/Aims: The selective κ-opioid agonist U50,488H protects heart from myocardial ischemia-reperfusion (MI/R) injury. We examined whether U50,488H is also beneficial for MI/R induced heart failure. Methods: Anesthetized male Sprague-Dawley rats were subjected to 30 min of myocardial ischemia via left anterior descending coronary artery (LAD) occlusion, followed by 4 weeks of reperfusion. Infarct size was examined by Evans blue/triphenyl tetrazolium chloride (TTC) staining. Cardiac function and remodeling were examined by echocardiography and histology. HO-1 gene transcription and expression were measured by RT-PCR and western blot. Results: Compared to vehicle-treated MI/R rats, rats administered a single dose of U50,488H at the beginning of reperfusion exhibited reduced myocardial infarct size, oxidative stress, hypertrophy, and fibrosis, improved mechanical function, and greater neovascularization. U50,488H also increased myocardial heme oxygenase (HO)-1 gene transcription and expression, while pharmacological HO-1 inhibition reversed all protective effects of U50,488H. Furthermore, U50,488H protected control cultured cardiomyoctes against simulated I/R-induced apoptosis but not cultures subjected to shRNA-mediated HO-1 knockdown. Inhibition of HO-1 in the subacute phase of reperfusion reversed the U50,488H-induced increase in neovascularization and suppression of oxidative stress. Finally, U50,488H increased Akt phosphorylation and nuclear translocation of Nrf2, a key HO-1 transcription activator, while inhibition of PI3K-Akt signaling abolished U50,488H-induced Nrf2 nuclear translocation, HO-1 upregulation, and cardioprotection. Conclusion: Activation of HO-1 expression through the PI3K-Akt-Nrf2 pathway may mediate the acute and long-term protective effects of U50,488H against heart failure by enhancing cardiomyocyte survival and neoangiogenesis and by reducing oxidative stress.
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Jimenez, Rosario, Marta Toral, Manuel Gómez-Guzmán, Miguel Romero, Manuel Sanchez, Ayman M. Mahmoud, and Juan Duarte. "The Role of Nrf2 Signaling in PPARβ/δ-Mediated Vascular Protection against Hyperglycemia-Induced Oxidative Stress." Oxidative Medicine and Cellular Longevity 2018 (June 25, 2018): 1–12. http://dx.doi.org/10.1155/2018/5852706.
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Hyperglycemia induces oxidative stress and plays a substantial role in the progression of vascular diseases. Here, we demonstrated the potentiality of peroxisome proliferator-activated receptor (PPAR)β/δ activation in attenuating high glucose-induced oxidative stress in endothelial cells and diabetic rats, pointing to the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2). HUVECs exposed to high glucose showed increased levels of reactive oxygen species (ROS) and upregulated NOX-2, NOX-4, Nrf2, and NQO-1 effects that were significantly reversed by the PPARβ/δ agonists GW0742 and L165041. Both PPARβ/δ agonists, in a concentration-dependent manner, induced transcriptional and protein upregulation of heme oxygenase-1 (HO-1) under low- and high-glucose conditions. All effects of PPARβ/δ agonists were reversed by either pharmacological inhibition or siRNA-based downregulation of PPARβ/δ. These in vitro findings were confirmed in diabetic rats treated with GW0742. In conclusion, PPARβ/δ activation confers vascular protection against hyperglycemia-induced oxidative stress by suppressing NOX-2 and NOX-4 expression plus a direct induction of HO-1; with the subsequent downregulation of the Nrf2 pathway. Thus, PPARβ/δ activation could be of interest to prevent the progression of diabetic vascular complications.
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Jia, Yiping, Paul W. Buehler, Robert A. Boykins, Richard M. Venable, and Abdu I. Alayash. "Structural Basis of Peroxide-mediated Changes in Human Hemoglobin." Journal of Biological Chemistry 282, no. 7 (December 17, 2006): 4894–907. http://dx.doi.org/10.1074/jbc.m609955200.
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Hydrogen peroxide (H2O2) triggers a redox cycle between ferric and ferryl hemoglobin (Hb) leading to the formation of a transient protein radical and a covalent hemeprotein cross-link. Addition of H2O2 to highly purified human hemoglobin (HbA0) induced structural changes that primarily resided within β subunits followed by the internalization of the heme moiety within α subunits. These modifications were observed when an equal molar concentration of H2O2 was added to HbA0 yet became more abundant with greater concentrations of H2O2. Mass spectrometric and amino acid analysis revealed for the first time that βCys-93 and βCys-112 were oxidized extensively and irreversibly to cysteic acid when HbA0 was treated with H2O2. Oxidation of further amino acids in HbA0 exclusive to the β-globin chain included modification of βTrp-15 to oxyindolyl and kynureninyl products as well as βMet-55 to methionine sulfoxide. These findings may therefore explain the premature collapse of the β subunits as a result of the H2O2 attack. Analysis of a tryptic digest of the main reversed phase-high pressure liquid chromatography fraction revealed two α-peptide fragments (α128 - α139) and a heme moiety with the loss of iron, cross-linked between αSer-138 and the porphyrin ring. The novel oxidative pathway of HbA0 modification detailed here may explain the diverse oxidative, toxic, and potentially immunogenic effects associated with the release of hemoglobin from red blood cells during hemolytic diseases and/or when cell-free Hb is used as a blood substitute.