Biochemistry, Genetics and Molecular Biology › Molecular Biology

Heme Oxygenase-1 and Carbon Monoxide

Works Count: 32538

Wikipedia

Description

This cluster of papers focuses on the research related to heme oxygenase and carbon monoxide, highlighting their roles in inflammation modulation, cytoprotection, oxidative stress, vascular biology, neuroprotection, and therapeutic applications. The papers cover a wide range of topics including the molecular mechanisms, signaling pathways, and potential therapeutic interventions involving heme oxygenase-1 and carbon monoxide.

Keywords

Heme Oxygenase-1; Carbon Monoxide; Inflammation; Cytoprotection; Bilirubin; Therapeutic Applications; Oxidative Stress; Vascular Biology; Neuroprotection; Apoptosis

Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible.

1986-01-01

M D Maines , G M Trakshel , R. Krishnan Kutty

The present report describes, for the first time, the identification of two constitutive forms of heme oxygenase, designated as HO-1 and HO-2, in rat liver microsomal fractions.HO-1 was purified to … The present report describes, for the first time, the identification of two constitutive forms of heme oxygenase, designated as HO-1 and HO-2, in rat liver microsomal fractions.HO-1 was purified to homogeneity and exhibited a specific activity of up to 4000 nmol of bilirubinlmg of proteinh.HO-2 was partially purified to a specific activity of 250 nmol of bilirubin] mg of proteinlh.In the native state, the relative activity of HO-2 surpassed that of HO-1 by 2-3-fold.HOWever, a remarkable difference existed in the regulatory mechanism(s) for the production of the two enzyme forms.Whereas the activity of HO-1 was increased up to 100-fold in response to cobalt, cadmium, hematin, phenylhydr~ine, and bromobenzene, that of HO-2 was fully refractory to these agents.The two forms differed in their apparent K,,,, thermolability, ammonium sulfate precipitation, antigenicity, electrophoretic mobility under nondenaturing conditions, and chromatographic behavior.Specifically, for HO-1 the apparent K,value was 0.24 PM, whereas that for HO-2 was 0.67 PM.HO-2 preparation was more susceptible to heat inactivation; nearly 65% activity was retained by HO-1 preparation after exposure to 60 'C for 10 min, whereas under the same conditions only about 25% of HO-2 activity was retained.When subjected to ammonium sulfate precipitation the bulk of HO-1 activity precipitated between 0 and 35% saturation, whereas that of HO-2 was precipitated between 35 and 65% saturation.The two forms appeared as immunologically different entities, in so far as a crossreactivity between antibody raised against HO-1 in rabbit and HO-2 could not be detected.Similarities were observed in respect to cofactor requirements for activity, sensitivity to inhibitors, as well as their reactivity towards the substrates used in this study, Le. hematin, hematoheme, and cytochrome c.Specifically both forms of the enzyme required NADPH-cytochrome c (P-450) reductase, NADPH or NADH, and O2 for activity, and reactions were inhibited by KCN, NaNa, and CO.Both forms cleaved the tetrapyrrole molecule exclusively at the a-meso bridge to form biliverdin IXa isomer.HO-1 and HO-2 utilized hematin and hematoheme as substrates but not intact cytochrome c.During the past few years the microsomal heme oxygenase

Carbon Monoxide Poisoning

1998-11-26

Armin Ernst , Joseph D. Zibrak

Carbon monoxide intoxication continues to be one of the most common causes of morbidity due to poisoning in the United States.1,2 It may be intentional or accidental, and exposure may … Carbon monoxide intoxication continues to be one of the most common causes of morbidity due to poisoning in the United States.1,2 It may be intentional or accidental, and exposure may be lethal. Approximately 600 accidental deaths due to carbon monoxide poisoning are reported annually in the United States,3 and the number of intentional carbon monoxide–related deaths is 5 to 10 times higher.1 The rate of accidental death caused by carbon monoxide from motor vehicles is higher in the northern United States and peaks during the winter months.4 The intentional deaths occur year-round without significant peaks.1 The severe winter of . . .

The Carbon Monoxide-binding Pigment of Liver Microsomes

1964-07-01

Tsuneo Omura , Ryo Sato

Microsomal Heme Oxygenase

1969-12-01

R Tenhunen , Harvey S. Marver , Rudi Schmid

Abstract This study characterizes microsomal heme oxygenase, a previously undescribed enzyme which catalyzes the oxidation of heme at the α-methene bridge to form biliverdin. This step is then coupled with … Abstract This study characterizes microsomal heme oxygenase, a previously undescribed enzyme which catalyzes the oxidation of heme at the α-methene bridge to form biliverdin. This step is then coupled with soluble NADPH-dependent biliverdin reductase to form bilirubin; microsomal heme oxygenase is rate-limiting in this pathway. By all analytical criteria, the product of this reaction is bilirubin. Most, if not all, of the bilirubin is of the IX α configuration, which is the sole isomeric form of bilirubin occurring physiologically. Heme oxygenase is localized specifically to the microsomal fraction, has an absolute and stoichiometric requirement for NADPH and molecular oxygen, generates carbon monoxide in amounts equimolar to bilirubin, and is inhibited by carbon monoxide. These and other data suggest that this enzyme is a mixed function oxygenase. The enzyme is most active with protohemin IX or methemalbumin; substrates with less activity are methemoglobin, the α and β chains of hemoglobin, deuterohemin IX, coprohemin I, and the hemoglobin-haptoglobin complex, in this order. Oxyhemoglobin, carboxyhemoglobin, myoglobin, and free porphyrins are not acted upon by the enzyme. The apparent Km for protohemin IX is 5.0 µm, and for the other substrates ranges from 4.5 to 5.1 µm. Sodium dodecyl sulfate, lipase, phospholipase, trypsin, potassium cyanide, sodium azide, and p-hydroxymercuribenzoate inhibit the enzyme. The kinetics and tissue distribution of this enzyme suggest that it is of major importance in the physiological degradation of hemoglobin and other hemoproteins to bile pigment.

HEMOGLOBIN CATABOLISM

1957-11-01

Gordon C. Mills

Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway

2000-04-01

Leo E. Otterbein , Fritz H. Bach , Jawed Alam +6 more

Ferritin: a cytoprotective antioxidant strategem of endothelium.

1992-09-01

G. Balla , HS Jacob , József Balla +5 more

Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome.We have shown that heme, a hydrophobic … Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome.We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H20z).In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products.This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin.After 16 h heme oxygenase and ferritin have increased approximately SO-fold and 10-fold, respectively.Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant.Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration.Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis.Conversely, a sitedirected mutant of ferritin (heavy chain Glu" 4 Lys; Hisas + Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant.We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.Aerobic organisms are well endowed with enzymatic oxidant defense systems which protect against direct assault by activated oxygen species such as superoxide and hydrogen peroxide (H202).However, much of the cellular damage caused by activated oxygen involves the collaboration of intracellular iron.For example, the amount of Hz02 required to kill Stuphylococcus uureus decreases 1,000-fold if the bacteria R 0 1 HL33793, R32, HL28935, and R 0 1 AI25625.The costs of

View PDF Chat

The heme synthesis and degradation pathways: role in oxidant sensitivity

2000-01-01

Stefan W. Ryter , Rex M. Tyrrell

Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease

1992-10-01

William J. Welch

Bilirubin Is an Antioxidant of Possible Physiological Importance

1987-02-27

Roland Stocker , Yorihiro Yamamoto , Antony F. McDonagh +2 more

Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is shown here that … Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is shown here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than α-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.

Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury.

1996-07-01

Augustine M.K. Choi , J Alam

Accumulating evidence suggests that oxidative stress plays a central role in the pathogenesis of many pulmonary diseases including adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia, and interstitial pulmonary fibrosis. … Accumulating evidence suggests that oxidative stress plays a central role in the pathogenesis of many pulmonary diseases including adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia, and interstitial pulmonary fibrosis. The morbidity and mortality of these diseases remain high even with optimal medical management. In our attempts to devise new therapies for these disorders, it is crucial to improve our understanding of the basic mechanism(s) of oxidant-induced lung injury. A major line of investigation seeks to characterize the cellular and molecular responses of the lung to oxidant insults. Much progress has been made in our understanding of the role of the "classic" antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) in mediating the lung's resistance against oxidant lung injury. However, it is becoming clear that other oxidant-induced gene products may also play vital roles in the lung's adaptive and/or protective response to oxidative stress. One such stress-response protein is heme oxygenase-1, HO-1. Since the identification of HO-1 in 1968, many of the studies involving this enzyme were understandably focused on the regulation and function of HO-1 in heme metabolism. This emphasis is self-evident as HO-1 catalyzes the first and rate-limiting step in heme degradation. Interestingly, however, evidence accumulated over the past 25 years demonstrates that HO-1 is induced not only by the substrate heme but also by a variety of non-heme inducers such as heavy metals, endotoxin, heat shock, inflammatory cytokines, and prostaglandins. The chemical diversity of HO-1 inducers led to the speculation that HO-1, besides its role in heme degradation, may also play a vital function in maintaining cellular homeostasis. Further support for this hypothesis was provided by Tyrrell and colleagues who showed in 1989 that HO-1 is also highly induced by a variety of agents causing oxidative stress. Subsequently, many investigators have focused their attention on the function and regulation of HO-1 in various in vitro and in vivo models of oxidant-mediated cellular and tissue injury. The magnitude of HO-1 induction after oxidative stress and the wide distribution of this enzyme in systemic tissues coupled with the intriguing biological activities of the catalytic byproducts, carbon monoxide, iron, and bilirubin, makes HO-1 a highly attractive and interesting candidate stress-response protein which may play key role(s) in mediating protection against oxidant-mediated lung injury. This review will focus on the current understanding of the physiological significance of HO-1 induction and the molecular regulation of HO-1 gene expression in response to oxidative stress. We hope that this discussion will stimulate interest and investigations into a field which is still largely uncharted in the pulmonary research community.

Heme-Containing Oxygenases

1996-01-01

Masanori Sono , Mark P. Roach , Eric D. Coulter +1 more

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHeme-Containing OxygenasesMasanori Sono, Mark P. Roach, Eric D. Coulter, and John H. DawsonView Author Information Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina … ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHeme-Containing OxygenasesMasanori Sono, Mark P. Roach, Eric D. Coulter, and John H. DawsonView Author Information Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208 Cite this: Chem. Rev. 1996, 96, 7, 2841–2888Publication Date (Web):November 7, 1996Publication History Received1 May 1996Revised13 August 1996Published online7 November 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/cr9500500https://doi.org/10.1021/cr9500500research-articleACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views13686Altmetric-Citations2122LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Bioinorganic chemistry,Monomers,Oxides,Oxygen,Peptides and proteins Get e-Alerts

Carbon Monoxide: a Putative Neural Messenger

1993-01-15

Ajay Verma , David J. Hirsch , Charles E. Glatt +2 more

Carbon monoxide, an activator of guanylyl cyclase, is formed by the action of the enzyme heme oxygenase. By in situ hybridization in brain slices, discrete neuronal localization of messenger RNA … Carbon monoxide, an activator of guanylyl cyclase, is formed by the action of the enzyme heme oxygenase. By in situ hybridization in brain slices, discrete neuronal localization of messenger RNA for the constitutive form of heme oxygenase throughout the brain has been demonstrated. This localization is essentially the same as that for soluble guanylyl cyclase messenger RNA. In primary cultures of olfactory neurons, zinc protoporphyrin-9, a potent selective inhibitor of heme oxygenase, depletes endogenous guanosine 3′,5′-monophosphate (cGMP). Thus, carbon monoxide, like nitric oxide, may be a physiologic regulator of cGMP. These findings, together with the neuronal localizations of heme oxygenase, suggest that carbon monoxide may function as a neurotransmitter.

Mechanisms of Cell Death in Oxidative Stress

2006-11-20

Stefan W. Ryter , Hong Pyo Kim , Alexander Hoetzel +4 more

Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. … Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-κB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviolet-A and ionizing radiations, and cigarette smoke. Additionally ROS generated in the lung and other organs as the result of high oxygen therapy or ischemia/reperfusion can stimulate cell death pathways associated with tissue damage. Cells have evolved numerous survival pathways to counter proapoptotic stimuli, which include activation of stress-related protein responses. Among these, the heme oxygenase-1/carbon monoxide system has emerged as a major intracellular antiapoptotic mechanism.

Biliverdin reductase: A major physiologic cytoprotectant

2002-11-27

David E. Barañano , Mahil Rao , Christopher D. Ferris +1 more

Bilirubin, an abundant pigment that causes jaundice, has long lacked any clear physiologic role. It arises from enzymatic reduction by biliverdin reductase of biliverdin, a product of heme oxygenase activity. … Bilirubin, an abundant pigment that causes jaundice, has long lacked any clear physiologic role. It arises from enzymatic reduction by biliverdin reductase of biliverdin, a product of heme oxygenase activity. Bilirubin is a potent antioxidant that we show can protect cells from a 10,000-fold excess of H 2 O 2 . We report that bilirubin is a major physiologic antioxidant cytoprotectant. Thus, cellular depletion of bilirubin by RNA interference markedly augments tissue levels of reactive oxygen species and causes apoptotic cell death. Depletion of glutathione, generally regarded as a physiologic antioxidant cytoprotectant, elicits lesser increases in reactive oxygen species and cell death. The potent physiologic antioxidant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxidant, is itself oxidized to biliverdin and then recycled by biliverdin reductase back to bilirubin. This redox cycle may constitute the principal physiologic function of bilirubin.

View PDF Chat

Hypoxia and Inflammation

2011-02-16

Holger K. Eltzschig , Peter Carmeliet

This review deals with emerging evidence of an association between systemic or local hypoxia and inflammation in a variety of diseases. The evidence points to new ways of treating inflammatory … This review deals with emerging evidence of an association between systemic or local hypoxia and inflammation in a variety of diseases. The evidence points to new ways of treating inflammatory disorders or conditions such as certain cancers with intralesional hypoxia.

View PDF Chat

Reduced stress defense in heme oxygenase 1-deficient cells

1997-09-30

Kenneth D. Poss , Susumu Tonegawa

Stressed mammalian cells up-regulate heme oxygenase 1 (Hmox1; EC 1.14.99.3 ), which catabolizes heme to biliverdin, carbon monoxide, and free iron. To assess the potential role of Hmox1 in cellular … Stressed mammalian cells up-regulate heme oxygenase 1 (Hmox1; EC 1.14.99.3 ), which catabolizes heme to biliverdin, carbon monoxide, and free iron. To assess the potential role of Hmox1 in cellular antioxidant defense, we analyzed the responses of cells from mice lacking functional Hmox1 to oxidative challenges. Cultured Hmox1 −/− embryonic fibroblasts demonstrated high oxygen free radical production when exposed to hemin, hydrogen peroxide, paraquat, or cadmium chloride, and they were hypersensitive to cytotoxicity caused by hemin and hydrogen peroxide. Furthermore, young adult Hmox1 −/− mice were vulnerable to mortality and hepatic necrosis when challenged with endotoxin. Our in vitro and in vivo results provide genetic evidence that up-regulation of Hmox1 serves as an adaptive mechanism to protect cells from oxidative damage during stress.

View PDF Chat

Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications

2006-04-01

Stefan W. Ryter , Jawed Alam , Augustine M.K. Choi

The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) … The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.

Free heme toxicity and its detoxification systems in human

2005-04-08

Sanjay Kumar , Uday Bandyopadhyay

Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice

2002-03-01

Tzong‐Shyuan Lee , Lee‐Young Chau

Heme oxygenase: A novel target for the modulation of inflammatory response

1996-01-01

Dean Willis , Adrian Moore , Ronnie O. Frederick +1 more

Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite.

1989-01-01

Stephen M. Keyse , Rex M. Tyrrell

We have shown that UVA (320-380 nm) radiation, hydrogen peroxide, and sodium arsenite induce a stress protein of approximately 32 kDa in human skin fibroblasts. The synthesis and cloning of … We have shown that UVA (320-380 nm) radiation, hydrogen peroxide, and sodium arsenite induce a stress protein of approximately 32 kDa in human skin fibroblasts. The synthesis and cloning of cDNA from arsenite-induced mRNA populations have now allowed us to unequivocally identify the 32-kDa protein as heme oxygenase. By mRNA analysis we have shown that the heme oxygenase gene is also induced in cultured human skin fibroblasts by UVA radiation, hydrogen peroxide, cadmium chloride, iodoacetamide, and menadione. The known antioxidant properties of heme catabolites taken together with the observation of a high level of induction of the enzyme in cells from an organ not involved in hemoglobin breakdown strongly supports the proposal that the induction of heme oxygenase may be a general response to oxidant stress and constitutes an important cellular defense mechanism against oxidative damage.

View PDF Chat

The therapeutic potential of carbon monoxide

2010-09-01

Roberto Motterlini , Leo E. Otterbein

Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage.

2003-04-01

Ning Li , Constantinos Sioutas , Arthur Cho +7 more

The objectives of this study were to determine whether differences in the size and composition of coarse (2.5-10 micro m), fine (< 2.5 microm), and ultrafine (< 0.1 microm) particulate … The objectives of this study were to determine whether differences in the size and composition of coarse (2.5-10 micro m), fine (< 2.5 microm), and ultrafine (< 0.1 microm) particulate matter (PM) are related to their uptake in macrophages and epithelial cells and their ability to induce oxidative stress. The premise for this study is the increasing awareness that various PM components induce pulmonary inflammation through the generation of oxidative stress. Coarse, fine, and ultrafine particles (UFPs) were collected by ambient particle concentrators in the Los Angeles basin in California and used to study their chemical composition in parallel with assays for generation of reactive oxygen species (ROS) and ability to induce oxidative stress in macrophages and epithelial cells. UFPs were most potent toward inducing cellular heme oxygenase-1 (HO-1) expression and depleting intracellular glutathione. HO-1 expression, a sensitive marker for oxidative stress, is directly correlated with the high organic carbon and polycyclic aromatic hydrocarbon (PAH) content of UFPs. The dithiothreitol (DTT) assay, a quantitative measure of in vitro ROS formation, was correlated with PAH content and HO-1 expression. UFPs also had the highest ROS activity in the DTT assay. Because the small size of UFPs allows better tissue penetration, we used electron microscopy to study subcellular localization. UFPs and, to a lesser extent, fine particles, localize in mitochondria, where they induce major structural damage. This may contribute to oxidative stress. Our studies demonstrate that the increased biological potency of UFPs is related to the content of redox cycling organic chemicals and their ability to damage mitochondria.

View PDF Chat

Isolation and Characterization of a cDNA from the Rat Brain that Encodes Hemoprotein Heme Oxygenase‐3

1997-07-01

William K. McCoubrey , Tony Jun Huang , Mahin D. Maines

Two isozymes of heme oxygenase (HO), HO‐1 or HSP32 and the constitutive form HO‐2, have been characterized to date. We report the discovery of a third protein species and refer … Two isozymes of heme oxygenase (HO), HO‐1 or HSP32 and the constitutive form HO‐2, have been characterized to date. We report the discovery of a third protein species and refer to it as HO‐3. HO‐3 is the product of a single transcript of ≈2.4 kb and can encode a protein of ≈33 kDa. The HO‐3 transcript is found in the spleen, liver, thymus, prostate, heart, kidney, brain and testis and is the product of a single‐copy gene. The predicted amino acid structure of HO‐3 differs from both HO‐1 (HSP32) and HO‐2 but is closely related to HO‐2 (≈90%). Escherichia coli expressed and purified HO‐3 protein does not cross react with polyclonal antibodies to either rat HO‐1 or HO‐2, is a poor heme catalyst, and displays hemoprotein spectral characteristics. The predicted protein has two heme regulatory motifs that may be involved in heme binding. These motifs and the hemoprotein nature of HO‐3 suggest a potential regulatory role for the protein in cellular processes which are heme‐dependent.

View PDF Chat

Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress

2000-04-01

Roberto Motterlini , Roberta Foresti , Rekha Bassi +1 more

Oxidative damage in Alzheimer's

1996-07-01

Mark A. Smith , George Perry , Peggy L. Richey +4 more

Nrf2, a Cap'n'Collar Transcription Factor, Regulates Induction of the Heme Oxygenase-1 Gene

1999-09-01

Jawed Alam , Daniel P. Stewart , Cheri Touchard +3 more

Stress response elements, which mediate induction of the mouse heme oxygenase-1 (HO-1) gene by several agents, resemble the binding site for the activator protein-1 (Jun/Fos), Maf, and Cap'n'Collar/basic leucine zipper … Stress response elements, which mediate induction of the mouse heme oxygenase-1 (HO-1) gene by several agents, resemble the binding site for the activator protein-1 (Jun/Fos), Maf, and Cap'n'Collar/basic leucine zipper (CNC-bZIP) families of proteins. In L929 fibroblasts, significant activation of an HO-1 enhancer-reporter fusion gene was observed only with the CNC-bZIP class of proteins with Nrf2 exhibiting the highest level of trans-activation, between 25- and 30-fold. To further examine the role of this factor in HO-1 gene regulation, a dominant-negative mutant, Nrf2M, was generated and conditionally expressed in L929 cells. The mutant protein was detected in cytoplasmic and nuclear fractions but did not affect cell growth. Under conditions of Nrf2M overexpression, HO-1 mRNA accumulation in response to heme, cadmium, zinc, arsenite, and tert-butylhydroquinone was inhibited by 85–95%. In contrast, overexpression of a dominant-negative mutant of c-Jun decreased L929 cell growth but did not inhibit HO-1 gene activation. Nrf2 does not homodimerize, but CNC-bZIP·small Maf protein heterodimers and Nrf2·Jun protein complexes are proposed to function as trans-activators. Co-expression of Jun proteins or p18, however, had no significant affect or inhibited Nrf2-mediated trans-activation. Taken together, these results implicate Nrf2 in the induction of the HO-1 gene but suggest that the Nrf2 partner in this function is a factor other than p18 or Jun proteins.

View PDF Chat

Heme oxygenase-1: unleashing the protective properties of heme

2003-07-16

Leo E. Otterbein , Miguel P. Soares , Kenichiro Yamashita +1 more

Heme oxygenase 1 is required for mammalian iron reutilization

1997-09-30

Kenneth D. Poss , Susumu Tonegawa

The majority of iron for essential mammalian biological activities such as erythropoiesis is thought to be reutilized from cellular hemoproteins. Here, we generated mice lacking functional heme oxygenase 1 (Hmox1; … The majority of iron for essential mammalian biological activities such as erythropoiesis is thought to be reutilized from cellular hemoproteins. Here, we generated mice lacking functional heme oxygenase 1 (Hmox1; EC 1.14.99.3 ), which catabolizes heme to biliverdin, carbon monoxide, and free iron, to assess its participation in iron homeostasis. Hmox1-deficient adult mice developed an anemia associated with abnormally low serum iron levels, yet accumulated hepatic and renal iron that contributed to macromolecular oxidative damage, tissue injury, and chronic inflammation. Our results indicate that Hmox1 has an important recycling role by facilitating the release of iron from hepatic and renal cells, and describe a mouse model of human iron metabolic disorders.

View PDF Chat

Hyperbaric Oxygen for Acute Carbon Monoxide Poisoning

2002-10-03

Lindell K. Weaver , Ramona O. Hopkins , Karen J. Chan +6 more

Patients with acute carbon monoxide poisoning commonly have cognitive sequelae. We conducted a double-blind, randomized trial to evaluate the effect of hyperbaric-oxygen treatment on such cognitive sequelae. Patients with acute carbon monoxide poisoning commonly have cognitive sequelae. We conducted a double-blind, randomized trial to evaluate the effect of hyperbaric-oxygen treatment on such cognitive sequelae.

View PDF Chat

Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia

1997-02-01

Patricia Lee , Bing‐Hua Jiang , Beek Yoke Chin +4 more

Exposure of rats to hypoxia (7% O2) markedly increased the level of heme oxygenase-1 (HO-1) mRNA in several tissues. Accumulation of HO-1 transcripts was also observed after exposure of rat … Exposure of rats to hypoxia (7% O2) markedly increased the level of heme oxygenase-1 (HO-1) mRNA in several tissues. Accumulation of HO-1 transcripts was also observed after exposure of rat aortic vascular smooth muscle (VSM) cells to 1% O2, and this induction was dependent on gene transcription. Activation of the mouse HO-1 gene by all agents thus far tested is mediated by two 5′-enhancer sequences, SX2 and AB1, but neither fragment was responsive to hypoxia in VSM cells. Hypoxia-dependent induction of the chloramphenicol acetyltransferase (CAT) reporter gene was mediated by a 163-bp fragment located approximately 9.5 kilobases upstream of the transcription start site. This fragment contains two potential binding sites for hypoxia-inducible factor 1 (HIF-1). A role for HIF-1 in HO-1 gene regulation was established by the following observations: 1) HIF-1 specifically bound to an oligonucleotide spanning these sequences, 2) mutation of these sequences abolished HIF-1 binding and hypoxia-dependent gene activation in VSM cells, 3) hypoxia increased HIF-1α and HIF-1β protein levels in VSM cells, and 4) hypoxia-dependent HO-1 mRNA accumulation was not observed in mutant hepatoma cells lacking HIF-1 DNA-binding activity. Taken together, these data demonstrate that hypoxia induces HO-1 expression in animal tissues and cell cultures and implicate HIF-1 in this response. Exposure of rats to hypoxia (7% O2) markedly increased the level of heme oxygenase-1 (HO-1) mRNA in several tissues. Accumulation of HO-1 transcripts was also observed after exposure of rat aortic vascular smooth muscle (VSM) cells to 1% O2, and this induction was dependent on gene transcription. Activation of the mouse HO-1 gene by all agents thus far tested is mediated by two 5′-enhancer sequences, SX2 and AB1, but neither fragment was responsive to hypoxia in VSM cells. Hypoxia-dependent induction of the chloramphenicol acetyltransferase (CAT) reporter gene was mediated by a 163-bp fragment located approximately 9.5 kilobases upstream of the transcription start site. This fragment contains two potential binding sites for hypoxia-inducible factor 1 (HIF-1). A role for HIF-1 in HO-1 gene regulation was established by the following observations: 1) HIF-1 specifically bound to an oligonucleotide spanning these sequences, 2) mutation of these sequences abolished HIF-1 binding and hypoxia-dependent gene activation in VSM cells, 3) hypoxia increased HIF-1α and HIF-1β protein levels in VSM cells, and 4) hypoxia-dependent HO-1 mRNA accumulation was not observed in mutant hepatoma cells lacking HIF-1 DNA-binding activity. Taken together, these data demonstrate that hypoxia induces HO-1 expression in animal tissues and cell cultures and implicate HIF-1 in this response.

View PDF Chat

Oxidative mechanisms in the toxicity of metal ions

1995-02-01

S.J. Stohs

Antioxidant activity of albumin-bound bilirubin.

1987-08-01

Roland Stocker , Alexander N. Glazer , B N Ames

Bilirubin, when bound to human albumin and at concentrations present in normal human plasma, protects albumin-bound linoleic acid from peroxyl radical-induced oxidation in vitro. Initially, albumin-bound bilirubin (Alb-BR) is oxidized … Bilirubin, when bound to human albumin and at concentrations present in normal human plasma, protects albumin-bound linoleic acid from peroxyl radical-induced oxidation in vitro. Initially, albumin-bound bilirubin (Alb-BR) is oxidized at the same rate as peroxyl radicals are formed and biliverdin is produced stoichiometrically as the oxidation product. On an equimolar basis, Alb-BR successfully competes with uric acid for peroxyl radicals but is less efficient in scavenging these radicals than vitamin C. These results show that 1 mol of Alb-BR can scavenge 2 mol of peroxyl radicals and that small amounts of plasma bilirubin are sufficient to prevent oxidation of albumin-bound fatty acids as well as of the protein itself. The data indicate a role for Alb-BR as a physiological antioxidant in plasma and the extravascular space.

View PDF Chat

Pharmacological and Clinical Aspects of Heme Oxygenase

2008-03-01

Nader G. Abraham , Attallah Kappas

This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The … This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.

Toxicology of Hydrogen Sulfide

1992-04-01

R. J. Reiffenstein , William C. Hulbert , Steven Roth

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed … Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More

Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency

1999-01-01

Akihiro Yachie , Yo Niida , Taizo Wada +6 more

The first known human case of heme oxygenase-1 (HO-1) deficiency is presented in this report. The patient is a six-year-old boy with severe growth retardation. He has been suffering from … The first known human case of heme oxygenase-1 (HO-1) deficiency is presented in this report. The patient is a six-year-old boy with severe growth retardation. He has been suffering from persistent hemolytic anemia characterized by marked erythrocyte fragmentation and intravascular hemolysis, with paradoxical increase of serum haptoglobin and low bilirubin. An abnormal coagulation/fibrinolysis system, associated with elevated thrombomodulin and von Willebrand factor, indicated the presence of severe, persistent endothelial damage. Electron microscopy of renal glomeruli revealed detachment of endothelium, with subendothelial deposition of an unidentified material. Iron deposition was noted in renal and hepatic tissue. Immunohistochemistry of hepatic tissue and immunoblotting of a cadmium-stimulated Epstein-Barr virus–transformed lymphoblastoid cell line (LCL) revealed complete absence of HO-1 production. An LCL derived from the patient was extremely sensitive to hemin-induced cell injury. Sequence analysis of the patient's HO-1 gene revealed complete loss of exon-2 of the maternal allele and a two-nucleotide deletion within exon3 of the paternal allele. Growth retardation, anemia, iron deposition, and vulnerability to stressful injury are all characteristics observed in recently described HO–1 targeted mice. This study presents not only the first human case of HO-1 deficiency but may also provide clues to the key roles played by this important enzyme in vivo.

View PDF Chat

Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element

2003-04-25

Elisabeth Abidemi Balogun , Martha Hoque , Pengfei Gong +5 more

The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the … The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2-Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2-Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.

View PDF Chat

Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications

1988-07-01

Mahin D. Maines

In biological systems oxidation of heme is carried out by two isozymes of the microsomal heme oxygenase, HO-1 and HO-2. HO-1 is the commonly known heme oxygenase, the activity of … In biological systems oxidation of heme is carried out by two isozymes of the microsomal heme oxygenase, HO-1 and HO-2. HO-1 is the commonly known heme oxygenase, the activity of which can be induced by up to 100-fold in response to a wide variety of stimuli (metals, heme, hormones, etc.). HO-2 was only recently discovered, and the isozyme appears to be uninducible. The two forms are products of two different genes and differ in their tissue expression. The primary structure of HO-1 and an HO-2 fragment of 91 amino acid residues show only 58% homology, but share a region with 100% secondary structure homology. This region is believed to be the catalytic site. Most likely, HO-1 gene is regulated in the same manner as metallothione in the gene. HO-1 has a heat shock regulatory element, and possibly many promoter elements, which bind to respective inducers and cause transcription of the gene. In vivo induction of HO-1 activity in the liver is accompanied by decreases in the total P-450 levels and, in a reconstituted system, cytochrome P-450b heme can be quantitatively converted to biliverdin by HO-1 and HO-2. The enzyme activity is inhibited in vivo for extended periods subsequent to binding of Zn- and Sn- protoporphyrins. This property appears useful for the suppression of bilirubin production. The metalloporphyrins, however, are not innocuous and cause major disruptions in cellular metabolism. In this review recent findings on heme oxygenase are highlighted.

Heme oxygenase: colors of defense against cellular stress

2000-12-01

Leo E. Otterbein , Augustine M.K. Choi

The discovery of the gaseous molecule nitric oxide in 1987 unraveled investigations on its functional role in the pathogenesis of a wide spectrum of biological and pathological processes. At that … The discovery of the gaseous molecule nitric oxide in 1987 unraveled investigations on its functional role in the pathogenesis of a wide spectrum of biological and pathological processes. At that time, the novel concept that an endogenous production of a gaseous substance such as nitric oxide can impart such diverse and potent cellular effects proved to be very fruitful in enhancing our understanding of many disease processes including lung disorders. Interestingly, we have known for a longer period of time that there exists another gaseous molecule that is also generated endogenously; the heme oxygenase (HO) enzyme system generates the majority if not all of the endogenously produced carbon monoxide. This enzyme system also liberates two other by-products, bilirubin and ferritin, each possessing important biological functions and helping to define the uniqueness of the HO enzyme system. In recent years, interest in HO has emerged in numerous disciplines including the central nervous system, cardiovascular physiology, renal and hepatic systems, and transplantation. We review the functional role of HO in lung biology and its real potential application to lung diseases.

Carbon monoxide intoxication: An updated review

2007-08-28

Leon D. Prockop , Rossitza Chichkova

THE HEME OXYGENASE SYSTEM:A Regulator of Second Messenger Gases

1997-04-01

Mahin D. Maines

▪ Abstract The heme oxygenase (HO) system consists of two forms identified to date: the oxidative stress–inducible protein HO-1 (HSP32) and the constitutive isozyme HO-2. These proteins, which are different … ▪ Abstract The heme oxygenase (HO) system consists of two forms identified to date: the oxidative stress–inducible protein HO-1 (HSP32) and the constitutive isozyme HO-2. These proteins, which are different gene products, have little in common in primary structure, regulation, or tissue distribution. Both, however, catalyze oxidation of heme to biologically active molecules: iron, a gene regulator; biliverdin, an antioxidant; and carbon monoxide, a heme ligand. Finding the impressive heme-degrading activity of brain led to the suggestion that “HO in brain has functions aside from heme degradation” and to subsequent exploration of carbon monoxide as a promising and potentially significant messenger molecule. There is much parallelism between the biological actions and functions of the CO- and NO-generating systems; and their regulation is intimately linked. This review highlights the current information on molecular and biochemical properties of HO-1 and HO-2 and addresses the possible mechanisms for mutual regulatory interactions between the CO- and NO-generating systems.

Reactive species mechanisms of cellular hypoxia-reoxygenation injury

2002-02-01

Chuanyu Li , Robert M. Jackson

Exacerbation of hypoxic injury after restoration of oxygenation (reoxygenation) is an important mechanism of cellular injury in transplantation and in myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes. Cellular … Exacerbation of hypoxic injury after restoration of oxygenation (reoxygenation) is an important mechanism of cellular injury in transplantation and in myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes. Cellular hypoxia and reoxygenation are two essential elements of ischemia-reperfusion injury. Activated neutrophils contribute to vascular reperfusion injury, yet posthypoxic cellular injury occurs in the absence of inflammatory cells through mechanisms involving reactive oxygen (ROS) or nitrogen species (RNS). Xanthine oxidase (XO) produces ROS in some reoxygenated cells, but other intracellular sources of ROS are abundant, and XO is not required for reoxygenation injury. Hypoxic or reoxygenated mitochondria may produce excess superoxide (O[Formula: see text]) and release H 2 O 2 , a diffusible long-lived oxidant that can activate signaling pathways or react vicinally with proteins and lipid membranes. This review focuses on the specific roles of ROS and RNS in the cellular response to hypoxia and subsequent cytolytic injury during reoxygenation.

Carbon monoxide poisoning — a public health perspective

2000-04-01

James A. Raub , M. Mathieu-Nolf , Neil B. Hampson +1 more

Mechanisms of Cell Protection by Heme Oxygenase-1

2010-01-08

Raffaella Gozzelino , Viktória Jeney , Miguel P. Soares

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe(2+), carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed … Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe(2+), carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism underlying this cytoprotective effect relies on the ability of HO-1 to catabolize free heme and prevent it from sensitizing cells to undergo programmed cell death. This cytoprotective effect inhibits the pathogenesis of a variety of immune-mediated inflammatory diseases.

View PDF Chat

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

2005-12-01

Lingyun Wu , Rui Wang

Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed … Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed by the enzyme heme oxygenase (HO). Inducible HO (HO-1) and constitutive HO (HO-2) are mostly recognized for their roles in the oxidation of heme and production of CO and biliverdin, whereas the biological function of the third HO isoform, HO-3, is still unclear. The tissue type-specific distribution of these HO isoforms is largely linked to the specific biological actions of CO on different systems. CO functions as a signaling molecule in the neuronal system, involving the regulation of neurotransmitters and neuropeptide release, learning and memory, and odor response adaptation and many other neuronal activities. The vasorelaxant property and cardiac protection effect of CO have been documented. A plethora of studies have also shown the importance of the roles of CO in the immune, respiratory, reproductive, gastrointestinal, kidney, and liver systems. Our understanding of the cellular and molecular mechanisms that regulate the production and mediate the physiological actions of CO has greatly advanced. Many diseases, including neurodegenerations, hypertension, heart failure, and inflammation, have been linked to the abnormality in CO metabolism and function. Enhancement of endogenous CO production and direct delivery of exogenous CO have found their applications in many health research fields and clinical settings. Future studies will further clarify the gasotransmitter role of CO, provide insight into the pathogenic mechanisms of many CO abnormality-related diseases, and pave the way for innovative preventive and therapeutic strategies based on the physiologic effects of CO.

Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis

2000-10-02

Sophie Brouard , Leo E. Otterbein , Josef Anrather +4 more

Heme oxygenase 1 (HO-1) inhibits apoptosis by regulating cellular prooxidant iron. We now show that there is an additional mechanism by which HO-1 inhibits apoptosis, namely by generating the gaseous … Heme oxygenase 1 (HO-1) inhibits apoptosis by regulating cellular prooxidant iron. We now show that there is an additional mechanism by which HO-1 inhibits apoptosis, namely by generating the gaseous molecule carbon monoxide (CO). Overexpression of HO-1, or induction of HO-1 expression by heme, protects endothelial cells (ECs) from apoptosis. When HO-1 enzymatic activity is blocked by tin protoporphyrin (SnPPIX) or the action of CO is inhibited by hemoglobin (Hb), HO-1 no longer prevents EC apoptosis while these reagents do not affect the antiapoptotic action of bcl-2. Exposure of ECs to exogenous CO, under inhibition of HO-1 activity by SnPPIX, substitutes HO-1 in preventing EC apoptosis. The mechanism of action of HO-1/CO is dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) signaling transduction pathway. Expression of HO-1 or exposure of ECs to exogenous CO enhanced p38 MAPK activation by TNF-α. Specific inhibition of p38 MAPK activation by the pyridinyl imidazol SB203580 or through overexpression of a p38 MAPK dominant negative mutant abrogated the antiapoptotic effect of HO-1. Taken together, these data demonstrate that the antiapoptotic effect of HO-1 in ECs is mediated by CO and more specifically via the activation of p38 MAPK by CO.

View PDF Chat

The emerging role of reactive oxygen and nitrogen species in redox biology and some implications for plasma applications to medicine and biology

2012-06-13

David B. Graves

Reactive oxygen species (ROS) and the closely related reactive nitrogen species (RNS) are often generated in applications of atmospheric pressure plasmas intended for biomedical purposes. These species are also central … Reactive oxygen species (ROS) and the closely related reactive nitrogen species (RNS) are often generated in applications of atmospheric pressure plasmas intended for biomedical purposes. These species are also central players in what is sometimes referred to as 'redox' or oxidation–reduction biology. Oxidation–reduction biochemistry is fundamental to all of aerobic biology. ROS and RNS are perhaps best known as disease-associated agents, implicated in diabetes, cancer, heart and lung disease, autoimmune disease and a host of other maladies including ageing and various infectious diseases. These species are also known to play active roles in the immune systems of both animals and plants and are key signalling molecules, among many other important roles. Indeed, the latest research has shown that ROS/RNS play a much more complex and nuanced role in health and ageing than previously thought. Some of the most potentially profound therapeutic roles played by ROS and RNS in various medical interventions have emerged only in the last several years. Recent research suggests that ROS/RNS are significant and perhaps even central actors in the actions of antimicrobial and anti-parasite drugs, cancer therapies, wound healing therapies and therapies involving the cardiovascular system. Understanding the ways ROS/RNS act in established therapies may help guide future efforts in exploiting novel plasma medical therapies. The importance of ROS and RNS to plant biology has been relatively little appreciated in the plasma biomedicine community, but these species are just as important in plants. It appears that there are opportunities for useful applications of plasmas in this area as well.

Carbon Monoxide-Releasing Molecules

2002-02-08

Roberto Motterlini , James Clark , Roberta Foresti +3 more

Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon … Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon monoxide gas is known to dilate blood vessels in a manner similar to nitric oxide and has been recently shown to possess antiinflammatory and antiapoptotic properties. We report that a series of transition metal carbonyls, termed here carbon monoxide-releasing molecules (CO-RMs), liberate CO to elicit direct biological activities. Specifically, spectrophotometric and NMR analysis revealed that dimanganese decacarbonyl and tricarbonyldichlororuthenium (II) dimer release CO in a concentration-dependent manner. Moreover, CO-RMs caused sustained vasodilation in precontracted rat aortic rings, attenuated coronary vasoconstriction in hearts ex vivo, and significantly reduced acute hypertension in vivo. These vascular effects were mimicked by induction of HO-1 after treatment of animals with hemin, which increases endogenously generated CO. Thus, we have identified a novel class of compounds that are useful as prototypes for studying the bioactivity of CO. In the long term, transition metal carbonyls could be utilized for the therapeutic delivery of CO to alleviate vascular- and immuno-related dysfunctions. The full text of this article is available at http://www.circresaha.org.

Ferroptosis as a target for protection against cardiomyopathy

2019-01-28

Xuexian Fang , Hao Wang , Dan Han +7 more

Significance Nonapoptotic cell death-induced tissue damage has been implicated in a variety of diseases, including neurodegenerative disorder, inflammation, and stroke. In this study, we demonstrate that ferroptosis, a newly defined … Significance Nonapoptotic cell death-induced tissue damage has been implicated in a variety of diseases, including neurodegenerative disorder, inflammation, and stroke. In this study, we demonstrate that ferroptosis, a newly defined iron-dependent cell death, mediates both chemotherapy- and ischemia/reperfusion-induced cardiomyopathy. RNA-sequencing analysis revealed up-regulation of heme oxygenase 1 by doxorubicin as a major mechanism of ferroptotic cardiomyopathy. As a result, heme oxygenase 1 degrades heme and releases free iron in cardiomyocytes, which in turn leads to generation of oxidized lipids in the mitochondria membrane. Most importantly, both iron chelation therapy and pharmacologically blocking ferroptosis could significantly alleviate cardiomyopathy in mice. These findings suggest targeting ferroptosis as a strategy for treating deadly heart disease.

View PDF Chat

Severe oxidant hemolysis in a child with G6PD deficiency and Hb C trait

2025-06-19

Connor Cocke , Weijie Li | Blood

Association between serum bilirubin levels and carotid atherosclerosis: a systematic review and meta-analysis

2025-06-19

Bin Yan , Ying Li , Minjie Zhu +6 more | Frontiers in Endocrinology

Objective Carotid atherosclerosis (CAS) is a significant factor contributing to cardiovascular events and poses a major public health concern. There are still many controversies about the association between serum bilirubin … Objective Carotid atherosclerosis (CAS) is a significant factor contributing to cardiovascular events and poses a major public health concern. There are still many controversies about the association between serum bilirubin and CAS. This study aims to provide a systematic review and meta-analysis to examine the association between serum bilirubin levels and carotid atherosclerosis. Methods An electronic literature search was performed using PubMed, Web of Science and Embase up to December 2023. Articles were screened based on predefined inclusion criteria and assessed for risk of bias and quality of evidence utilizing the Newcastle-Ottawa Scale and GRADE tool. Pooled mean differences were calculated using a random effects model. Subgroup and meta-regression analyses were performed to identify potential sources of heterogeneity. Results Nine studies involving 7,023 participants were included in this meta-analysis. The results indicated that patients with carotid atherosclerosis exhibited lower levels of total bilirubin compared to those without (SMD -3.42, 95% CI [-5.18, -1.67]), with a statistically significant difference (z=-3.819, P &lt;0.001). Moreover, a significant inverse association was found between total bilirubin levels and the risk of carotid atherosclerosis (OR 0.79, 95% CI [0.71, 0.88], P &lt;0.001, I²=78.2%). However, substantial heterogeneity was observed (I²=98.0%, P &lt;0.001). Subgroup and meta-regression analyses indicated that sample size and the severity of carotid atherosclerotic lesions might contribute to the heterogeneity observed across studies. The GRADE assessment was low. Conclusion Lower serum bilirubin levels are associated with an increased risk of carotid atherosclerosis. This meta-analysis offers new insights into the development of diagnostic biomarkers and therapeutic targets. Further prospective cohort studies are necessary to validate our conclusions. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42023447199.

Targeting Wnt/beta-catenin signaling to attenuate short-chain chlorinated paraffins-triggered hepatocyte mitochondrial fission and subsequent pyroptosis

2025-06-17

Jing Xiao , Donglei Huang , Fengxu Wang +7 more | International Immunopharmacology

Enhancement of Hypoxia Tolerance of Gibel Carp (Carassius auratus gibelio) via a Ferroporphyrin-Rich Diet

2025-06-16

Hualiang Liang , Haifeng Mi , Kai Wang +3 more | Antioxidants

Gibel carp (Carassius auratus gibelio) were hypoxia stressed for 12 h after an 8-week FPR nutrient-enriched feeding experiment, which was to evaluate the role of FPR in hypoxic stress in … Gibel carp (Carassius auratus gibelio) were hypoxia stressed for 12 h after an 8-week FPR nutrient-enriched feeding experiment, which was to evaluate the role of FPR in hypoxic stress in gibel carp (Carassius auratus gibelio). The dissolved oxygen was reduced to a range of 0.6 ± 0.2 mg/L. Results showed that FPR supplementation could maintain the osmotic pressure equilibrium by improving the ion concentrations of plasma including Na+, Ca+ and K+, and Na+/K+-ATPase activity of liver. FPR supplementation could effectively enhance the antioxidant capacity by improving the levels of GPX, SOD, CAT, and GSH, and reduce the level of MDA. FPR supplementation could improve the core gene expressions of Nrf2 signalling pathway including nrf2, sod, ho-1, gpx, and cat. The high levels of FPR supplementation (0.04%) might had a negative effect on immunity. FPR supplementation could improve the expression levels of HIF-1 signalling pathway-related genes to adapt to hypoxia condition including hif-1α, epo, angpt1, vegf, et1, and tfr-1. These results also were supported by higher SR and number of gill mitochondria in FPR supplementation. In general, the appropriate FPR supplementation was 0.01% based on the results of this study and economic cost, which could heighten hypoxic adaptation and SR.

The Effect of Carboxyhemoglobin Concentration on Thyroid Hormones in Carbon Monoxide Poisoning

2025-06-16

Abuzer Coşkun , Burak Demirci , Burak Akın +2 more | Endocrinology research and practice.

Bilirubin: a game-changer in alzheimer’s therapy? Unveiling its neuroprotective and disease-modifying potential

2025-06-16

Ramandeep Kaur Sidhu , Yash Mittal , Khadga Raj Aran | Metabolic Brain Disease

Bilirubin may mediate the anti-inflammatory effects of aerobic exercise habits: implications for the antiatherosclerotic effects of aerobic exercise

2025-06-16

Shigemasa Tani , Yasuyuki Suzuki , Tsukasa Yagi +1 more | Coronary Artery Disease

Background Moderately elevated serum bilirubin levels and aerobic exercise effectively reduce the risk of coronary artery disease (CAD). However, the relationships among aerobic exercise, total serum bilirubin (TSB), and inflammation … Background Moderately elevated serum bilirubin levels and aerobic exercise effectively reduce the risk of coronary artery disease (CAD). However, the relationships among aerobic exercise, total serum bilirubin (TSB), and inflammation remain unclear. We investigated the associations among aerobic exercise, TSB, and inflammatory response, with TSB as a mediator of this association. Methods This cross-sectional study included 8290 participants registered at the Health Planning Center of Nihon University Hospital in 2019. We defined aerobic exercise as 30 min of sweating at least twice a week for over a year. Results In this cohort (average age, 46.7±13.0 years; 59% men), participants who undertook habitual aerobic exercise ( n =2131) had significantly higher TSB levels [0.78 (0.91/0.99) mg/dl vs. 0.74 (0.58/0.95) mg/dl, P <0.0001] than those who did not ( n =6159). Multivariable logistic regression analysis demonstrated that aerobic exercise independently predicted higher TSB levels (>50 th percentile set as the dependent variable). Participants with habitual aerobic exercise had significantly lower inflammatory blood cell components, including leukocyte, neutrophil, and platelet counts, than those who did not (all P <0.0001). The levels of these inflammatory markers significantly decreased with increasing TSB levels. Mediation analysis indicated that higher TSB levels partially mediated the association between aerobic exercise and lower counts of inflammatory markers. Conclusion Habitual aerobic exercise was associated with lower levels of inflammatory markers and higher TSB levels, which mediated the anti-inflammatory effects of aerobic exercise. These associations potentially elucidate the preventive effects of aerobic exercise on CAD risk.

Artificial Haemoglobin: Development of Cyclodextrin-haem Complexes for Application in Biological and Medical Fields

2025-06-13

Hiroaki Kitagishi , Qiyue Mao , Atsuki Nakagami +1 more | Royal Society of Chemistry eBooks

The creation of artificial compounds that have similar functions to biomolecules is called biomimetic chemistry. Reproduction of the oxygen-binding property of haemoglobin, the most abundant iron-containing protein in the body, … The creation of artificial compounds that have similar functions to biomolecules is called biomimetic chemistry. Reproduction of the oxygen-binding property of haemoglobin, the most abundant iron-containing protein in the body, contributes to the understanding of the structure‒function relationship in haemoglobin. In addition, haemoglobin biomimetic compounds are valuable for the development of artificial blood substitutes. However, the construction of synthetic compounds that reversibly bind molecular oxygen (O2) in water as well as in vivo has long been difficult and unachievable. The construction of an inclusion complex composed of a methylated cyclodextrin (CD) dimer and an iron(ii)porphyrin haem analogue was a breakthrough in the development of artificial haemoglobin. This inclusion complex, called hemoCD, is being studied as the first aqueous artificial haemoglobin model and is expected to have practical applications as an oxygen carrier as well as an antidote for poisoning by toxic gases (CO, HCN, H2S). This chapter outlines the design strategy and biological/medical applications of the artificial haemoglobin hemoCD.

Ultrasound-controllable carbon monoxide nano-delivery systems for combined sonodynamic/gaseous therapies

2025-06-13

Chong Feng , Shuang Song , Xiaoyu Zhang +3 more | Frontiers in Bioengineering and Biotechnology

Indroduction The integration of sonodynamic therapy (SDT) and carbon monoxide (CO) presents a promising synergistic strategy in cancer therapy owing to the unique advantage of CO in SDT sensitization. However, … Indroduction The integration of sonodynamic therapy (SDT) and carbon monoxide (CO) presents a promising synergistic strategy in cancer therapy owing to the unique advantage of CO in SDT sensitization. However, the development of SDT-compatible CO-delivery nanosystems remain a substantial challenge. Methods Here, we developed an ultrastable and controllable CO nanoreservoir system through the integration of chlorine e6 (Ce6)-loaded, cancer cell membrane coating and iron carbonyl (Fe 3 CO 12 )-bridged mesoporous silica bodies (Fe 3 CO 12 -MSNs), which was specifically engineered to simultaneously achieve SDT and ultrasound (US)-responsive sustained CO release. Owing to the stabilization of Fe 3 CO 12 within the silica framework, Fe 3 CO 12 -MSNs not only decreased unwanted CO leakage during transport but also enabled US-responsive matrix degradation accompanied by sustained CO release at tumor sites, which prolongs the therapeutic window of CO and maximizes the synergy of SDT and CO therapy. Results and Discussion This nanoplatform-mediated combination therapies showed highly efficient antitumor effects and triggered a robust tumor-specific immune responses. When in combination with immune checkpoint blockers, the nanoplatform notably eradicate the breast cancer with low systematic toxicity. Overall, our work provides a promising nanoplatform with US-responsive and sustainable CO release for highly efficient and safe SDT/CO combined therapeis.

Baicalin alleviates sepsis-associated acute kidney injury through activation of the PPAR-γ/UCP1 signaling pathway

2025-06-12

Neng Bao , Mingjia Gu , Qiuju Huang +7 more | Renal Failure

This study aims to investigate the protective effect of baicalin on sepsis-associated acute kidney injury (SA-AKI) and its molecular mechanism. An SA-AKI mouse model was established via lipopolysaccharide (LPS) injection. … This study aims to investigate the protective effect of baicalin on sepsis-associated acute kidney injury (SA-AKI) and its molecular mechanism. An SA-AKI mouse model was established via lipopolysaccharide (LPS) injection. Baicalin's effects on renal function, oxidative stress, and apoptosis were evaluated using histopathology, dihydroethidium, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Bioinformatics, molecular docking, ribonucleic acid (RNA) sequencing, and Western blotting were employed to investigate the role of baicalin in regulating the peroxisome proliferator‑activated receptor‑γ (PPAR-γ)/uncoupling protein 1 (UCP1) pathway. Human kidney-2 cells were used for in vitro validation. In this study, baicalin significantly ameliorated LPS-induced acute kidney injury by modulating the PPAR-γ/UCP1 signaling pathway. Both in vivo and in vitro experiments revealed that baicalin attenuates inflammation, oxidative stress, and apoptosis while restoring mitochondrial function. RNA sequencing analysis revealed significant upregulation of PPAR-γ/UCP1 in the baicalin-treated group. Further molecular docking and molecular dynamics simulations confirmed a stable interaction between baicalin and UCP1. Validation via small interfering RNA-mediated knockdown of PPAR-γ and UCP1 revealed that inhibition of the PPAR-γ/UCP1 pathway abrogated baicalin's protective effects, highlighting the critical role of this pathway in mediating baicalin's renoprotection. Baicalin protects against SA-AKI by activating the PPAR-γ/UCP1 signaling pathway. This study provides new insights into the mechanisms through which baicalin mitigates kidney injury in sepsis, suggesting its potential as a therapeutic agent for SA-AKI.

Recombinant Expression and Purification of Plasmodium Heme Detoxification Protein in E. coli: Challenges and Discoveries

2025-06-11

Rahul Singh , Ravindra D. Makde | bioRxiv (Cold Spring Harbor Laboratory)

1.2 Abstract Heme, a toxic by-product of Plasmodium ’s proteolytic digestion of host hemoglobin, is detoxified by the malaria parasite through its conversion into hemozoin (Hz)—the malaria pigment. This detoxification … 1.2 Abstract Heme, a toxic by-product of Plasmodium ’s proteolytic digestion of host hemoglobin, is detoxified by the malaria parasite through its conversion into hemozoin (Hz)—the malaria pigment. This detoxification pathway is a key target for many antimalarial drugs, which aim to induce heme-mediated toxicity to the parasite. The Heme Detoxification Protein (HDP) plays a central role in heme-to-Hz transformation; however, its precise mechanism remains unclear, largely due to the absence of successful recombinant expression in a native, soluble form. In this study, we aimed to express HDP recombinantly in its native soluble state using an E. coli -based system. A range of strategies were employed, including expression of orthologs, consensus sequence design, fusion to solubility-enhancing partners, co-expression with molecular chaperones, and extensive construct optimization through N-terminal truncations. Despite extensive efforts, most recombinant HDP constructs were either insoluble or formed soluble aggregates. Notably, only a single construct—with a 44-residue N-terminal truncation and a C-terminal 6His tag ( HDPpf-C10 )—was successfully expressed in a soluble form. Surprisingly, HDPpf-C10, although retaining domains implicated in heme binding and transformation, exhibited no detectable heme-to-Hz transformation activity. This finding highlights the essential role of the flexible-unstructured N-terminal region in mediating both heme binding and its subsequent conversion to Hz, providing new insights into HDP function and guiding future structural and mechanistic studies.

Protective effects of minocycline, a tetracycline antibiotic, on cytokine storm and oxidative stress in acute lung injury

2025-06-03

Weiwei Yin , Bingqin Wen , Yingying Xiao +5 more | International Immunopharmacology

Interplay between inflammatory reflex and energetic metabolism in endotoxaemia: A role for haem oxygenase 1?

2025-06-02

Evelin Capellari Cárnio , Luiz G.S. Branco , Fernanda Brognara +3 more | British Journal of Pharmacology

Inflammation is vital for defence against injury and infection, but excessive inflammation can lead to tissue damage and disease. The central nervous system (CNS) helps regulate immune responses through neuroendocrine … Inflammation is vital for defence against injury and infection, but excessive inflammation can lead to tissue damage and disease. The central nervous system (CNS) helps regulate immune responses through neuroendocrine pathways, such as the hypothalamic–pituitary–adrenal axis and the anti‐inflammatory reflex, which limit systemic inflammation. Immune responses require significant metabolic energy and the liver adapts by increasing glucose production and mobilizing fatty acids. This immune‐metabolic coordination is mediated by cytokines and metabolic regulators. This review explores how the anti‐inflammatory reflex modulates the interplay between inflammation and metabolism during endotoxaemia, with a focus on the haem oxygenase 1/carbon monoxide (HO1/CO) pathway. Carbon monoxide, a byproduct of HO1 activity, acts as a key signalling molecule that reduces inflammation, supports mitochondrial function and protects tissues. Understanding this pathway provides new insights into potential therapeutic strategies for treating inflammatory and metabolic disorders by targeting neuroimmune‐metabolic communication networks.

Abnormalities of Hippocampal Subfields in Individuals With Acute Carbon Monoxide Poisoning

2025-06-01

Mengyue Tang , Ting Li , Yan Deng +5 more | CNS Neuroscience & Therapeutics

To investigate alterations in hippocampal subfields in patients with acute carbon monoxide poisoning (ACMP) and explore their relationship with neurocognitive function. Forty-seven ACMP patients and 29 age- and sex-matched healthy … To investigate alterations in hippocampal subfields in patients with acute carbon monoxide poisoning (ACMP) and explore their relationship with neurocognitive function. Forty-seven ACMP patients and 29 age- and sex-matched healthy controls (HCs) were recruited. All ACMP patients underwent carboxyhemoglobin (COHb) assessment at admission and acquired MRI scans within 3 days post-exposure. Cognitive functions were assessed using the mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA), and activities of daily living were evaluated using the Functional Independence Measure (FIM) and Barthel Index (BI). Differences in hippocampal volume between groups were analyzed using Analysis of Covariance (ANCOVA), and correlations with cognitive and functional scores were evaluated. After follow-up, 27.66% (13/47) of ACMP patients developed Delayed Encephalopathy After Carbon Monoxide Poisoning (DEACMP). The COHb concentration was significantly higher in the DEACMP group (median 17.70% vs. 11.95%, z = -2.225, p = 0.026) compared to the Recovery group. The cognitive function scores, delayed memory-related sub-items scores derived from cognitive assessments, and activities of daily living scores in the DEACMP group were lower than those in the Recovery group (all p < 0.05). The ACMP group showed significant volume reduction in the bilateral whole hippocampus, cornu ammonis (CA) cornu ammonis 3, CA4, GC.ML.DG, Moleculat_layer, and right subiculum compared to HCs. The right subiculum and right CA4 volumes were smaller in the DEACMP group than in the Recovery group. The ROC curve analysis indicated that the combination of COHb concentration, MoCA, and FIM scores had good predictive value for DEACMP(the area under the ROC curve = 0.887, p < 0001). Correlation analysis showed that MoCA-delayed recall was positively associated with the volume of the left CA1 subfield (r = 0.357, p = 0.020), and MMSE-delayed recall was positively associated with the volume of the left presubiculum (r = 0.323, p = 0.037). This study is the first to report specific hippocampal subfield alterations in ACMP patients, suggesting their potential as non-invasive markers of hippocampal injury. The hippocampal subfields may contribute to the development of DEACMP by modulating cognitive processes. These findings may improve understanding of the neurological impact of hypoxic injuries in human subject research.

ZnCl2 smoke-induced acute lung injury: mechanism and prevention

2025-06-01

Yabin Li , Yingbao Sun , Wanmei Wang +4 more | Toxicology and Applied Pharmacology

Curcumin-loaded Nanoparticles for Renal ischemia-reperfusion injuries: Triple-play of redox homeostasis accommodation, lipid metabolism regulation, and nuclear magnetic tracing

2025-06-01

Ning Wang , Xiaochang Xue , Zhibo Zhang +5 more | Materials Today Bio

Dysregulation of Mitochondrial Iron Regulators as a Basis of Iron-Mediated Retinal Degeneration in Rats

2025-06-01

Devyani Sharma , Tapas Chandra Nag , Ashutosh Bansal +3 more | Neurotoxicity Research

Normal physiologic carboxyhemoglobinemia of neonate masquerading as carbon monoxide poisoning

2025-06-01

Jan Hagemann , Andrew Kozminski , Sarah Miller +2 more | The American Journal of Emergency Medicine

Protective Effects of Chrysin Against Diclofenac‐Induced Nephrotoxicity in Rats via Attenuation of Oxidative Stress, Apoptosis and Endoplasmic Reticulum Stress

2025-06-01

Cüneyt Çağlayan , İzzettin Ekinci , Cihan Gür +3 more | Journal of Biochemical and Molecular Toxicology

ABSTRACT Diclofenac (DCL) is a broadly prescribed non‐steroidal anti‐inflammatory drug (NSAID) for pain management and has been linked to nephrotoxicity despite its therapeutic benefits. This study provides new insights into … ABSTRACT Diclofenac (DCL) is a broadly prescribed non‐steroidal anti‐inflammatory drug (NSAID) for pain management and has been linked to nephrotoxicity despite its therapeutic benefits. This study provides new insights into the palliative impacts of chrysin (CH) against DCL‐induced kidney damage by modulating oxidative injury, endoplasmic reticulum (ER) stress and apoptosis. The rats were divided into five groups: the control group (Group 1), CH‐only group (50 mg/kg, Group 2), DCL‐only group (50 mg/kg, Group 3), DCL + CH (25 mg/kg, Group 4), and DCL + CH (50 mg/kg, Group 5). DCL injection led to significant renal damage marked by elevated serum urea, creatinine and malondialdehyde (MDA) levels, reduced glutathione (GSH) concentration, and decreased activities of antioxidant enzymes (glutathione peroxidase, superoxide dismutase and catalase). The mRNA expression levels of Ho‐1 and Nrf2 were also suppressed. Additionally, DCL treatment triggered apoptosis as evidenced by increased expression of Bax and caspase‐3 alongside decreased Bcl‐2 expression. Furthermore, DCL induced ER stress was confirmed by upregulation of Perk , Ire1 , Atf‐6 , and Grp78 transcription levels. Also, it was demonstrated that DCL treatment upregulated Mmp2 and Mmp9 levels. Treatment with CH significantly mitigated these adverse effects suggesting that CH effectively protects DCL‐induced kidney toxicity by targeting multiple pathways. In summary, this study highlights the importance of CH as a promising therapeutic agent for alleviating kidney damage associated with DCL toxicity.

Carbon monoxide ameliorates the progression of bleomycin-induced pulmonary fibrosis through manipulating macrophage reprogramming

2025-05-30

Chunyu Guo , Cheng Zhang , Zhengmei Xia +5 more | Free Radical Biology and Medicine

Prenatal alcohol exposure promotes nerve injury-induced pathological pain following morphine treatment via NLRP3-mediated peripheral and central proinflammatory immune actions.

2025-05-30

Shahani Noor , Andrea A Pasmay , Ariana N Pritha +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Adverse in-utero conditions may exert a lifelong impact on neuroimmune function. Our prior work showed that prenatal alcohol exposure (PAE) increases pathological pain sensitivity (allodynia) following peripheral sciatic nerve injury. … Adverse in-utero conditions may exert a lifelong impact on neuroimmune function. Our prior work showed that prenatal alcohol exposure (PAE) increases pathological pain sensitivity (allodynia) following peripheral sciatic nerve injury. While the immune mechanism(s) of PAE-induced immune dysfunction are poorly understood, prior studies implicated the involvement of Toll-like receptor 4 (TLR4) and the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasomes. Interestingly, emerging data suggest a surprising overlap of spinal glial proinflammatory activation via the TLR4-NLRP3-interleukin (IL)-1β axis due to opioid treatment in nerve-injured non-PAE rodents. Considering this preclinical evidence, we explored whether PAE poses a risk factor in creating proinflammatory immune bias consequent to opioid (morphine) exposure. We hypothesized that under nerve injury conditions, PAE may interact with morphine, promoting peripheral and CNS proinflammatory factors in a NLRP3-dependent manner. Using a minor nerve injury model in adult mice, we demonstrate that PAE prolongs the chronicity of ongoing allodynia in both sexes, with a more pronounced effect observed in male mice. Our study shows that PAE amplifies proinflammatory responses at the injury site and the spinal cord, driving morphine-prolonged allodynia through NLRP3 inflammasome activation. Furthermore, high mobility group box 1 (HMGB1), a well-established pain-promoting TLR4 agonist, is elevated in allodynic PAE mice. NLRP3 inhibitor, MCC950, effectively reverses morphine-induced allodynia and reduces Caspase-1 activity, IL-1β, and related proinflammatory factors. Although few sex-specific effects were observed, our data convincingly support that PAE and morphine interactions ultimately converge on NLRP3-driven mechanisms in both sexes. Together, this study suggests that PAE modulates later-life neuroimmune function and provides critical insights into immune regulators underlying PAE-induced biological vulnerability to pathological pain processing and adverse effects of opioids.

Heme oxygenase-1 counteracts proinflammatory activation of microglial cells by acting on IRF5

2025-05-30

Patrizia Mancini , Anna Lisa Furfaro , Stefania Vernazza +3 more | Free Radical Biology and Medicine

Acquisition mechanism of heme oxygenase-1 induction by heat shock in human monocytic cell line THP-1 after differentiation to macrophage-like cells

2025-05-30

Daisuke Tsuji , Nobuhiro Ishida , Takafumi Miyamoto +2 more | The Journal of Biochemistry

Abstract Heme oxygenase-1 (HO-1) is unique to be directly regulated by diverse stress-responsible transcription factors, however, the cross-talk between oxidative stress and heat shock stress has not been completely elucidated. … Abstract Heme oxygenase-1 (HO-1) is unique to be directly regulated by diverse stress-responsible transcription factors, however, the cross-talk between oxidative stress and heat shock stress has not been completely elucidated. It is widely accepted that HO activity is not induced by heat shock in cultured cells derived from humans and mice but from rats. Previously, we reported that the discrepancies in heat shock-induced HO-1 expression in different animal species were caused by the access of heat shock factor 1 (HSF1) to heat shock element (HSE) in the different region of the HO-1 gene. Recently, we found that the human monocyte-derived cell line THP-1, which has been extensively used to study monocyte/macrophage functions, represents the heat shock induction of HO-1 after differentiation to macrophage-like cells, although not responsible before differentiation. In this study, we demonstrated that heat shock loading to macrophage-like cells derived from THP-1 specifically activated HSF1 to bind to HSE in the promotor region in the HO-1 gene, resulting in the induction of HO-1. Our finding is significant in understanding the regulation system by macrophages for inflammation caused by oxidative insults and associated with hyperthermia in vivo.

Mechanisms of heme transport in the mitochondria

2025-05-29

Syed Azmal Ali , Ann L. White , Amy E. Medlock +1 more | Biochemical Society Transactions

Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential … Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential for normal cellular metabolism, growth, and development. Despite the vital importance of heme transport within the cell, data are lacking about how newly synthesized heme is shuttled within the mitochondrion or exported from the organelle. Here, we briefly summarize current knowledge about the process of mitochondrial heme distribution and discuss the current unresolved questions pertinent to this process.

Diffusing capacity for carbon monoxide (DLCO) change and outcome in advanced non-small cell lung cancer (aNSCLC) treated with immune checkpoint inhibitors (ICIs).

2025-05-28

Ángela Guirao Montes , Alfredo Sánchez , M. Arnal Rondan +7 more | Journal of Clinical Oncology

e20602 Background: Despite recent therapeutic advances, identifying effective prognostic markers in aNSCLC remains an unmet need. DLC) has shown prognostic value in non-oncological pulmonary conditions but is underexplored in predicting … e20602 Background: Despite recent therapeutic advances, identifying effective prognostic markers in aNSCLC remains an unmet need. DLC) has shown prognostic value in non-oncological pulmonary conditions but is underexplored in predicting outcomes in aNSCLC. We aimed to evaluate the prognostic value of DLCO changes following treatment with ICIs. Methods: The NEUMOTOX study, a prospective observational study, enrolled aNSCLC patients undergoing treatment with ICI, with or without chemotherapy, from August 2022 to April 2024. DLCO was measured at baseline and at 3-6, 9, and 12 weeks. Using Cox proportional hazards models, the analysis specifically focused on the 6-week data to evaluate the relationship between early DLCO changes and OS and PFS, adjusting for ECOG, LIPI score, and PDL1 expression. Results: 47 patients had evaluable baseline and 6-week post-baseline DLCO measurements. The median baseline DLCO was 59%. 15 (32%) patients experienced a ≥15% reduction in DLCO at 6 weeks. Patients with DLCO decrease experienced lower OS (NR vs 12.5m; 1yr-OS 78.6% vs 53.8%; HR 3.7; p=0.011) and rPFS (7.7 vs 4m; HR 3.8; p=0.003) rates, in unadjusted and adjusted cox-regression models (Table 1 ). Conclusions: Significant reductions in DLCO early during ICI therapy are associated with poorer outcomes in aNSCLC patients. Monitoring DLCO changes could serve as an effective prognostic tool. Further research is needed to validate DLCO as a prognostic biomarker in clinical practice. Multivariable OS and rPFS model. Overall Survival rPFS Variable HR (95%CI); p-value HR (95%CI); p-value Baseline DLCO 1.04 (0.99-1.1);p=0.1 1.04 (1.01-1.08); p=0.011 DLCO ≥15% decrease 7.5 (1.7-33);p=0.009 7.6 (1.8-31.6); p=0.006 PLD1 (0, 1-50%, ≥50%) 0.17 (0.05-0.55); p=0.003 0.93 (0.47-1.86); p=0.8 ECOG 13.2 (1.9-50); p=0.01 1.35 (0.44-4.2); p=0.06 LIPI score 26 (4-55); p<0.001 1.6 (0.65-3.95); p=0.3

Bilirubin metabolism in the liver orchestrates antiviral innate immunity in the body

2025-05-28

Qian Du , Wei He , Xiangjie Chen +7 more | Cell Reports

Antiviral effects of heme oxygenase-1 against canine coronavirus and canine influenza virus in vitro

2025-05-27

Jae‐Hyeong Kim , Dong‐Hwi Kim , Kyu‐Beom Lim +7 more

Thioredoxin-Interacting Protein (TXNIP) in Gestational Diabetes Mellitus

2025-05-26

Ioanna Kokkinopoulou , Anna Papadopoulou

Background: Thioredoxin-interacting protein (TXNIP) is a major inhibitor of the thioredoxin (TRX) antioxidant system and an important player in the development and aggravation of intracellular oxidative stress. Although first recognized … Background: Thioredoxin-interacting protein (TXNIP) is a major inhibitor of the thioredoxin (TRX) antioxidant system and an important player in the development and aggravation of intracellular oxidative stress. Although first recognized as a metabolic regulator, recent studies have identified the multifaceted role of this protein in other molecular pathways involving inflammation, apoptosis, and glucose metabolism. Methods: This review aims to highlight the importance of TXNIP in diabetes-related pathophysiology and explore the existing evidence regarding TXNIP’s role in GDM-associated pathogenetic mechanisms, revealing common regulatory pathways. Results: Among other complex diseases, TXNIP has been found upregulated in diabetic pancreatic beta cells, thus contributing to diabetes pathogenesis and its related complications. In addition, depletion of TXNIP has been shown to decrease the negative consequences of excessive stress in various cellular systems and diseases, pointing towards a potential therapeutic target. In line with these findings, TXNIP has been investigated in the pathogenesis of Gestational Diabetes Mellitus (GDM), a common pregnancy complication affecting the mother and the neonate. Overexpression of TXNIP has been found in GDM placentas or trophoblast cell lines mimicking GDM conditions and has been associated with key dysregulated mechanisms of GDM pathophysiology, like oxidative stress, inflammation, apoptosis, impaired autophagy, altered trophoblast behavior, and placental morphology. Interestingly, TXNIP has been found upregulated in GDM maternal serum and downregulated in umbilical cord blood, indicating potential compensatory protective mechanisms to GDM-related oxidative stress. Conclusions: Due to its contribution to the regulation of critical cellular processes such as inflammation, metabolism, and apoptosis, TXNIP finds its place in the pathophysiology of gestational diabetes through a currently limited number of scientific reports.

Positive Association Between Total Bilirubin and Early-Stage Parkinson's Disease

2025-05-23

Wen Zhou , Qingqing Xia , Duan Liu +2 more

The correlation between total bilirubin and Parkinson's disease (PD) remains unclear currently. This study aimed to assess the association between total bilirubin and early-stage PD. The ultimate goal is to … The correlation between total bilirubin and Parkinson's disease (PD) remains unclear currently. This study aimed to assess the association between total bilirubin and early-stage PD. The ultimate goal is to gain a deeper understanding of the implications of this relationship between total bilirubin and early-stage PD. We conducted a retrospective cross-sectional study involving 1631 participants which collected from 2010 to 11 December 2024 in PPMI cohort. Logistic regression, smooth curve fitting, subgroup analysis, and sensitivity analyses were employed to validate the research objectives. The overall prevalence of PD was 81.5 % (1329/1631). Specifically, the prevalence was 78.0 % (294/377) for total bilirubin tertile 1 (T1, 3-7 μmol/L), 80.8 % (498/616) for tertile 2 (T2, 7-10 μmol/L), and 84.2 % (537/638) for tertile 3 (T3, 10-48 μmol/L), respectively (P = 0.043). Multivariate odds ratio regression adjusted for risk factors demonstrates a 5-unit increment in the total bilirubin raises the risk of early-stage PD by 1.16 times, respectively. Smooth splines analysis suggested a linear association between levels of total bilirubin and risk of early-stage PD (P nonlinearity = 0.968). Further exploratory subgroup analysis within the age, sex, BMI, and MCI groups showed that there were no significant interactions between the subgroups (all P values for interaction were >0.05). Additional sensitivity analyses supported the primary findings and indicated the conclusions are robust. The observed association between elevated total bilirubin levels and early-stage PD risk suggests that bilirubin may serve as a potential biomarker for early diagnosis and disease monitoring.

One-for-All Photoactivatable Manganese-Based Carbon Monoxide-Releasing Molecules (CORMs) for Synergistic Therapy of Mycobacterial Infection

2025-05-22

Yanxian Lai , Liu Wang , Haitao Ma +7 more

Tuberculosis presents a severe threat to human health. It is of crucial importance to develop novel and effective treatments to combat mycobacterial infections, especially those caused by drug-resistant bacteria. In … Tuberculosis presents a severe threat to human health. It is of crucial importance to develop novel and effective treatments to combat mycobacterial infections, especially those caused by drug-resistant bacteria. In this study, a tricarbonyl manganese(I) complex (Mn-PTP) was synthesized for the purpose of conducting synergistic therapy against mycobacterial infection. When subjected to white light irradiation, Mn-PTP generated multiple reactive species, including type I/II combined reactive oxygen species (ROS), carbon monoxide (CO), the toxic ligand PTP, and manganese oxides (MnOX) with catalase-like ability. The antibacterial experiment demonstrated that irradiated Mn-PTP exhibited specific antibacterial effects on Mycobacterium smegmatis (M. smegmatis). It was found to cause damage to the bacterial membrane and effectively eradicate biofilms. Moreover, the in vivo experiment revealed that the photoactive Mn-PTP could promote the healing process of M. smegmatis-infected skin wounds. This study pioneers innovative frameworks for developing one-for-all small-molecule pharmaceuticals capable of enabling synergistic therapeutic strategies against mycobacterial infections.

The NOX2-ROS-NLRP3 inflammasome axis in traumatic brain injury

2025-05-21

Janeen Laabei , Gloria Vegliante , Nathan Ryzewski Strogulski +7 more

Background: Phagocyte NADPH oxidase 2 (NOX2) is an enzyme complex responsible for reactive oxygen species (ROS) production. Chronic NOX2 activity sustains oxidative stress/damage and drives neuroinflammation following traumatic brain injury … Background: Phagocyte NADPH oxidase 2 (NOX2) is an enzyme complex responsible for reactive oxygen species (ROS) production. Chronic NOX2 activity sustains oxidative stress/damage and drives neuroinflammation following traumatic brain injury (TBI). NOX2 acts as a priming signal for NLRP3 inflammasome activation, which also plays a role in secondary injury after TBI. GSK2795039 is a small molecule brain penetrable drug that inhibits NOX2 in a NADPH competitive manner. Here, we investigated whether pharmacological inhibition of NOX2 using GSK2795039 can reduce secondary neuroinflammation after TBI, specifically via inhibition of downstream NLRP3 inflammasome activation, in both resident microglia and infiltrating myeloid cells in the injured brain. Methods: Immortalised microglial (IMG) cells or primary microglia were pre-treated with GSK2795039 (NOX2 inhibitor) or MCC950 (NLRP3 inhibitor) and stimulated with lipopolysaccharide and nigericin to induce NOX2/ROS and NLRP3 inflammasome activation. The controlled cortical impact model, pharmacokinetic analyses, multi-dimensional flow cytometry, histology and neurobehavioral assessments were used to translate in vitro findings to an experimental TBI model in adult male C57BL6/J mice. Results: The small molecule NOX2 inhibitor, GSK2795039, attenuated microglial NOX2 activity, thereby reducing ROS, nitrite and cytokine levels, as well as NLRP3 inflammasome components in pro-inflammatory microglia. TBI recruited NOX2/ROS/IL-1β+ neutrophils and inflammatory monocytes into injured brain parenchyma with peak monocytic NOX2/ROS/IL-1β production at 3 days post-injury (DPI), coincident with peak NOX2/ROS/IL-1β expression in microglia. Systemic administration of GSK2795039 (100mg/kg; I.P.) starting 2 hours post-injury attenuated NOX2/IL-1β+ microglial and infiltrating myeloid cell activation at 3 DPI. In addition, NOX2 inhibition reduced numbers of IL-1R+ T cells in the brain of TBI mice, indicating that myeloid-T cell crosstalk was altered by GSK2795039 treatment. Innate and adaptive neuroimmune changes were associated with improvements in motor function post-TBI. In the chronic phase through 28 DPI, pharmacological inhibition of NOX2 by GSK2795039 treatment resulted in modest improvements in neurobehavioral deficits and TBI neuropathology. Conclusions: These preclinical studies identify the NOX2-ROS-NLRP3 inflammasome axis along with myeloid-T cell crosstalk as effective targets for TBI neuroinflammation. Our translational studies indicate that NOX2 may be a promising therapeutic target for mitigating neuroinflammation in microglia, and peripheral immune cells, following experimental TBI in mice.

CORM-3 mitigates hypoxia/reoxygenation-induced injury in neonatal rat cardiomyocytes by regulating complex IV activity and modulating the production of reactive oxygen species.

2025-05-20

Fang Du , Qingsheng Niu , Xiaojuan Yang +2 more | PubMed

Myocardial ischemia-reperfusion injury (MIRI) is a major contributor to myocardial infarction and leads to significant myocardial dysfunction. Mitochondria, crucial for cellular energy production, are particularly susceptible to damage during ischemia/reperfusion … Myocardial ischemia-reperfusion injury (MIRI) is a major contributor to myocardial infarction and leads to significant myocardial dysfunction. Mitochondria, crucial for cellular energy production, are particularly susceptible to damage during ischemia/reperfusion (I/R) events. Carbon monoxide-releasing molecule-3 (CORM-3), a water-soluble compound that releases carbon monoxide (CO), has demonstrated multiple protective effects against I/R injury. Mitochondria are recognized as selective targets for CO's protective actions in cells. This study aimed to explore whether CORM-3 mitigates cardiomyocyte injury during hypoxia/reoxygenation (H/R) by regulating the mitochondrial-mediated apoptosis pathway and mitochondrial respiration. Neonatal rat cardiomyocytes were cultured and randomly assigned into four groups: control group, H/R group (hypoxia for three hours followed by reoxygenation for six hours), CORM-3 group, and inactivated CORM-3 (iCORM-3) group. CORM-3 and iCORM-3 (12.5 µmol/L) were administered at the onset of hypoxia. Mitochondrial ultrastructure was assessed using transmission electron microscopy. The protein levels of caspase-3, caspase-9, mitochondrial cytochrome c, and cytosolic cytochrome c were analyzed via western blot. Mitochondrial membrane potential and intracellular reactive oxygen species (ROS) were measured by flow cytometry. ATP levels were quantified using an ATP Assay Kit, and mitochondrial respiratory chain complex IV activity was determined using a cytochrome oxidase activity colorimetric assay kit. CORM-3 effectively reduced myocardial mitochondrial structural damage induced by H/R and downregulated the expression of caspase-3, caspase-9, and cytosolic cytochrome c. Moreover, CORM-3 inhibited cytochrome c release from mitochondria and enhanced mitochondrial membrane potential. Additionally, CORM-3 diminished ROS production and increased the activity of mitochondrial respiratory complex IV in cardiomyocytes. CORM-3 also alleviated the decline in ATP levels following H/R. The protective effects were lost when using inactivated CORM-3 (iCORM-3), suggesting that CO is the active mediator. The results indicate that CORM-3 effectively alleviates myocardial injury during H/R by inhibiting mitochondria-mediated apoptosis and enhancing mitochondrial respiratory function.

Carbon Monoxide in Medicine: Emerging Therapeutic Perspectives

2025-05-16

Dominika Krzysztofik , Monika Marcinkowska , Marcin Kołaczkowski

Przedmiot badań. Praca poświęcona jest analizie literatury dotyczącej terapeutycznych zastosowań tlenku węgla. Tlenek węgla (CO), niegdyś uważany wyłącznie za toksyczny gaz, obecnie jest postrzegany jako cząsteczka o istotnym potencjale terapeutycznym. … Przedmiot badań. Praca poświęcona jest analizie literatury dotyczącej terapeutycznych zastosowań tlenku węgla. Tlenek węgla (CO), niegdyś uważany wyłącznie za toksyczny gaz, obecnie jest postrzegany jako cząsteczka o istotnym potencjale terapeutycznym. Endogenna produkcja CO w organizmie podkreśla jego naturalną rolę w procesach fizjologicznych i sygnalizacyjnych. Zróżnicowane właściwości biologiczne tlenku węgla stanowiły impuls do przeprowadzenia pierwszych badań mających na celu weryfikację jego potencjału terapeutycznego oraz zastosowanie tej cząsteczki w leczeniu różnorodnych schorzeń. Cel badań. Celem pracy jest przedstawienie aktualnego stanu wiedzy dotyczącego potencjalnych zastosowań terapeutycznych tlenku węgla, zarówno w postaci inhalacji, jak i przeglądowi nowoczesnych związków chemicznych, tzw. donorów CO. Materiał i metody. Analiza literatury opierała się na pracach naukowych z lat 2015–2025, dostępnych m.in. w bazach PubMed, PubChem, Google Scholar, Wiley Online Library oraz Web of Science. Zastosowane słowa kluczowe to: „tlenek węgla” (carbon monoxide), „cząsteczki uwalniające tlenek węgla” (carbon monoxide releasing molecules, CORMs), „donory CO” (CO donors), „terapeutyczne zastosowanie tlenku węgla” (therapeutic use of carbon monoxide), „organiczne CORMs” (organic CORMs), „wolne od metali CORMS” (metal-free CORMs). Wyniki. Dane przedstawione w publikacjach wskazują, że tlenek węgla charakteryzuje się zróżnicowanym zakresem właściwości terapeutycznych, w tym działaniem przeciwzapalnym, cytoprotekcyjnym, immunomodulacyjnym oraz antyproliferacyjnym. Pierwsze próby klinicznego zastosowania terapeutycznego tlenku węgla opierały się na kontrolowanych inhalacjach CO. Jednakże metoda ta stanowi istotne wyzwanie w praktyce klinicznej, szczególnie pod względem doboru odpowiedniej dawki oraz braku korelacji między stężeniem karboksyhemoglobiny (COHb) we krwi a efektem terapeutycznym. Dodatkowo, badania przeprowadzone na modelach zwierzęcych sugerują, że skuteczność terapeutyczna tlenku węgla może być bardziej związana z jego miejscowym stężeniem w tkankach docelowych niż ze stężeniem COHb w krążeniu systemowym. Alternatywnym podejściem do podawania tlenku węgla metodą wziewną jest zastosowanie tzw. donorów CO, czyli proleków uwalniających tlenek węgla pod wpływem różnych czynników, takich jak wartość pH, temperatura, enzymy lub światło. W pracach eksperymentalnych dowiedziono, że to podejście cechuje się wysoką skutecznością farmakologiczną i wyższym profilem bezpieczeństwa. Szczególnie obiecujące wyniki uzyskano w przypadku podawania donorów tlenku węgla drogą doustną w zwierzęcych modelach schorzeń gastroenterologicznych, gdzie donory CO potwierdziły właściwości cytoprotekcyjne oraz przeciwzapalne. Wnioski. Pomimo obiecujących wyników w pracach eksperymentalnych, konieczne są dalsze badania nad optymalizacją właściwości lekopodobnych oraz parametrów farmakokinetycznych donorów tlenku węgla, aby w pełni wykorzystać potencjał terapeutyczny CO. Umożliwi to przeprowadzenie badań przedklinicznych i stworzy potencjalne możliwości zastosowania klinicznego. W szczególności dalsze badania nad doustnymi donorami CO mogą stanowić istotny krok w kierunku opracowania skutecznych i bezpiecznych terapii.

Human Sputum Microbiome Composition and Sputum Inflammatory Cell Profiles Are Altered with Controlled Wood Smoke Exposure as a Model for Wildfire Smoke.

2025-05-16

Catalina Cobos-Uribe , Radhika Dhingra , Martha Almond +4 more

Wood smoke exposure is increasing worldwide due to the rise in wildfire events. Various studies have associated exposure to wildfire-derived smoke with adverse respiratory conditions. However, the mechanism by which … Wood smoke exposure is increasing worldwide due to the rise in wildfire events. Various studies have associated exposure to wildfire-derived smoke with adverse respiratory conditions. However, the mechanism by which this occurs is unknown. Previous studies using wood smoke as a model of wildfire smoke have focused on the respiratory immune response and have reported increased neutrophil percentage and cytokine production in airway samples. The effect of wood smoke on the respiratory microbiome, however, has not been examined. Healthy volunteers (N=54) were subjected to controlled wood smoke exposure (500 µg/m3) for two hours, and induced sputum samples were collected and processed for microbiome analysis, immune mediators, and cell differentials at baseline, six- and 24-hours post-exposure. A negative binomial mixed model analysis examined associations between microbiome components and inflammatory cells in sputum. Following wood smoke exposure, while sputum microbiome diversity remained unchanged, the microbiome composition was altered, particularly the abundance of several low-abundance bacteria, including Fretibacterium and Selenomonas, indicating that this inhalational exposure can alter the composition of the sputum microbiome. Additionally, a significant decrease in macrophage cells was observed at 24 hours without a significant change in neutrophils. We further found small but significant associations between different taxa and macrophages (per mg of sputum), including a negative association with Fretibacterium. Together, these findings demonstrate that inhalational wood smoke exposure can modify several low-abundance bacteria within the respiratory microbiome and that these changes are associated with sputum inflammatory cell alterations, providing insights for future studies to focus on respiratory innate immune host-microbiome crosstalk in the context of environmental exposures.

Corynoxeine Supplementation Ameliorates Colistin-Induced Kidney Oxidative Stress and Inflammation in Mice

2025-05-15

Yue Liu , R Zhang , Tony Velkov +3 more

This study investigated the protective effects of corynoxeine, a natural alkaline compound, on colistin-caused nephrotoxicity using a murine model. Forty mice were divided randomly into control, corynoxeine-only (20 mg/kg/day, intraperitoneal … This study investigated the protective effects of corynoxeine, a natural alkaline compound, on colistin-caused nephrotoxicity using a murine model. Forty mice were divided randomly into control, corynoxeine-only (20 mg/kg/day, intraperitoneal injection), colistin-only (20 mg/kg/day, intraperitoneal injection), and colistin (20 mg/kg/day) + corynoxeine (5 and 20 mg/kg/day) groups (8 mice in each group). All treatments were maintained for seven consecutive days. Results showed that colistin treatment at 20 mg/kg/day for seven days significantly increased serum urea nitrogen and creatinine levels and induced the loss and degeneration of renal tubular epithelial cells, which were markedly ameliorated by corynoxeine co-treatment at 5 or 20 mg/kg/day. Corynoxeine supplementation also markedly attenuated colistin-induced increases in malondialdehyde levels and decreases in reduced glutathione levels and superoxide dismutase and catalase activities in the kidneys. Furthermore, corynoxeine supplementation significantly decreased the expression of transforming growth factor β (TGF-β) and nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) proteins and nuclear factor kappa B (NF-κB), interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-α mRNAs, while it significantly increased the expression of erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins in the kidneys. In conclusion, these results reveal that corynoxeine can protect against colistin-induced nephrotoxicity in mice by inhibiting oxidative stress and inflammation, which may partly be attributed to its ability on the activation of the Nrf2/HO-1 pathway and the inhibition of the TGF-β/NOX4 and NF-κB pathways.

Localized Light-Triggered CO Delivery: Comparing the Amount of CO Delivered and Cellular Toxicity

2025-05-14

C. Taylor Dederich , Livia S. Lazarus , Abby D. Benninghoff +1 more

Molecules that enable the controlled delivery of carbon monoxide (CO) in biological environments are of significant current interest to probe the beneficial roles of CO for humans. Assumptions regarding the … Molecules that enable the controlled delivery of carbon monoxide (CO) in biological environments are of significant current interest to probe the beneficial roles of CO for humans. Assumptions regarding the ability of molecules to reliably deliver CO continue to impact the field, including in work involving non-metal CO delivery motifs. Flavonols are drawing increasing interest as light-triggered CO release motifs due to their ease of synthesis, functionalization, and fluorescence trackability. Importantly, the light-driven CO release properties of flavonols depend on their structure and must be fully evaluated under various conditions to understand the relationship between the amount of CO delivered and the induced biological effects. Herein, we use a family of amine-functionalized π-extended flavonols to demonstrate that structural differences result in differing interactions with biomolecules, cellular uptake, and changes in subcellular localization, which can affect the amount of CO delivered intracellularly. This results in differences in the CO-induced cellular toxicity.

Manganese Porphyrin Treatment Improves Redox Status Caused by Acute Compressive Spinal Cord Trauma

2025-05-14

Raquel Vieira Niella , Janaína Maria Xavier Corrêa , Claire Souza da Costa Marques +7 more

There is increasing interest in identifying drugs that can prevent or delay neurological complications following spinal cord injury, thus expanding the therapeutic window for other potential neuroprotective agents. In this … There is increasing interest in identifying drugs that can prevent or delay neurological complications following spinal cord injury, thus expanding the therapeutic window for other potential neuroprotective agents. In this context, manganese porphyrins (MnPs) have shown high antioxidant and anti-inflammatory potential in various experimental disease models, including stroke, cancer, diabetes, ischemia, and radiotherapy. However, they have been little evaluated in spinal cord injuries. This study aimed to assess the therapeutic potential of the manganese porphyrins [MnTE-2-PyP]5+ (MnPI) and [MnT(5-Br-3-E-Py)P]5+ (MnPII) in acute compressive spinal cord trauma in rats. Twenty-four animals were used (six animals/group). Following general inhalation anesthesia, acute compressive spinal cord trauma was induced in all groups except for the negative control (SHAM). Treatment commenced 60 min post-trauma, with animals receiving treatment for seven days at 24 h intervals. While no improvement in motor capacity was observed, MnPs effectively blocked the increase in oxidative stress and endoplasmic reticulum (ER) stress mediators caused by trauma, maintaining the protein expression levels of Hifα, 8-OHdG and MDA, as well as the expression of the genes Grp78, Chop, Ho1, and Perk, similar to those of the control group. Moreover, there was an increase in protein expression of SOD1, Cat, and GPX1, along with a restoration of SOD and CAT enzymatic activity. Additionally, MnPs improved the expression of IL-6, neurotrophic markers, and apoptotic factors. In conclusion, treatment with MnPs attenuated the oxidative stress and ER stress caused by acute compressive spinal cord trauma and restored spinal expression of neurotrophic mediators.

Autophagy Impairment-Derived SQSTM1 Accumulation Promotes Ferroptosis in Corneal Epithelial Cells Through ACSL4 in Dry Eye

2025-05-13

Runze Zhang , Lihong Liang , Kai Liao +5 more

To reveal the function of autophagy impairment-derived sequestosome 1 (SQSTM1) in inducing ferroptosis in an experimental dry eye model and investigate the underlying mechanism. To induce the dry eye animal … To reveal the function of autophagy impairment-derived sequestosome 1 (SQSTM1) in inducing ferroptosis in an experimental dry eye model and investigate the underlying mechanism. To induce the dry eye animal model, 8-week-old C57BL/6 mice were subcutaneously injected with scopolamine and exposed to a desiccated environment. To build the in vitro dry eye model, human corneal epithelial cells (HCECs) were applied with desiccating stress. Cell viability was examined using a CCK-8 kit. Intracellular reactive oxygen species (ROS), oxidative lipid, and Fe2+ were detected using the H2DCFDA assay kit, C11 BODIPY probe, and FerroOrange probe. Gene expression was screened by RNA sequencing. Protein expression was evaluated by western blot and immunofluorescence staining. Corneal defect area was assessed by fluorescein sodium staining. Conjunctiva goblet cells were counted by periodic acid-Schiff staining. Tear secretion was measured using phenol red cotton thread. Desiccating stress induced ferroptosis and SQSTM1 accumulation in both HCECs and C57BL/6 mice. SQSTM1 knockdown alleviated ferroptosis in HCECs. In contrast, the overexpression of SQSTM1 promoted ferroptotic changes. Additionally, overexpression of SQSTM1 significantly increased acyl-CoA synthetase long chain family member 4 (ACSL4). Also, targeted inhibition of ACSL4 mitigated the dry eye symptoms and ferroptosis caused by both SQSTM1 overexpression and desiccating stress. The accumulation of SQSTM1 triggers corneal epithelial cells ferroptosis through ACSL4 in dry eye disease.

Delayed Postanoxic Encephalopathy Following Acute Carbon Monoxide Poisoning: A Case Report and Literature Review

2025-05-13

Mina Aallam , Nada Nfaoui , Yasmina Zakaria +2 more