Publications by authors named "Roberta Foresti"

67 Publications

Sensitive quantification of carbon monoxide in vivo reveals a protective role of circulating hemoglobin in CO intoxication.

Commun Biol 2021 Mar 29;4(1):425. Epub 2021 Mar 29.

Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto, Japan.

Carbon monoxide (CO) is a gaseous molecule known as the silent killer. It is widely believed that an increase in blood carboxyhemoglobin (CO-Hb) is the best biomarker to define CO intoxication, while the fact that CO accumulation in tissues is the most likely direct cause of mortality is less investigated. There is no reliable method other than gas chromatography to accurately determine CO content in tissues. Here we report the properties and usage of hemoCD1, a synthetic supramolecular compound composed of an iron(II)porphyrin and a cyclodextrin dimer, as an accessible reagent for a simple colorimetric assay to quantify CO in biological samples. The assay was validated in various organ tissues collected from rats under normal conditions and after exposure to CO. The kinetic profile of CO in blood and tissues after CO treatment suggested that CO accumulation in tissues is prevented by circulating Hb, revealing a protective role of Hb in CO intoxication. Furthermore, hemoCD1 was used in vivo as a CO removal agent, showing that it acts as an effective adjuvant to O ventilation to eliminate residual CO accumulated in organs, including the brain. These findings open new therapeutic perspectives to counteract the toxicity associated with CO poisoning.
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http://dx.doi.org/10.1038/s42003-021-01880-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007703PMC
March 2021

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson's Disease.

Antioxidants (Basel) 2021 Jan 15;10(1). Epub 2021 Jan 15.

Laboratory of Pharmacology, Department of Health Sciences, University of Milan, Via Antonio di Rudinì 8, 20142 Milano, Italy.

Existing therapies for Parkinson's disease (PD) are only symptomatic. As erythropoietin (EPO) is emerging for its benefits in neurodegenerative diseases, here, we test the protective effect driven by EPO in in vitro (SH-SY5Y cells challenged by MPP) and in vivo (C57BL/6J mice administered with MPTP) PD models. EPO restores cell viability in both protective and restorative layouts, enhancing the dopaminergic recovery. Specifically, EPO rescues the PD-induced damage to mitochondria, as shown by transmission electron microscopy, Mitotracker assay and PINK1 expression. Moreover, EPO promotes a rescue of mitochondrial respiration while markedly enhancing the glycolytic rate, as shown by the augmented extracellular acidification rate, contributing to elevated ATP levels in MPP-challenged cells. In PD mice, EPO intrastriatal infusion markedly improves the outcome of behavioral tests. This is associated with the rescue of dopaminergic markers and decreased neuroinflammation. This study demonstrates cellular and functional recovery following EPO treatment, likely mediated by the 37 Kda isoform of the EPO-receptor. We report for the first time, that EPO-neuroprotection is exerted through restoring ATP levels by accelerating the glycolytic rate. In conclusion, the redox imbalance and neuroinflammation associated with PD may be successfully treated by EPO.
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http://dx.doi.org/10.3390/antiox10010121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830512PMC
January 2021

Increased Sirt1 secreted from visceral white adipose tissue is associated with improved glucose tolerance in obese Nrf2-deficient mice.

Redox Biol 2021 01 24;38:101805. Epub 2020 Nov 24.

University Paris-Est Créteil, INSERM, IMRB, F-94010, Créteil, France. Electronic address:

Obesity is associated with metabolic dysregulation characterized by insulin resistance and glucose intolerance. Nuclear factor E2-related factor (Nrf2) is a critical regulator of the stress response and Nrf2-deficient mice (Nrf2) are protected against high fat diet (HFD)-induced metabolic derangement. We searched for factors that could underline this favorable phenotype and found that Nrf2 mice exhibit higher circulating levels of sirtuin 1 (Sirt1), a key player in cellular homeostasis and energy metabolism, compared to wild-type mice. Increased Sirt1 levels in Nrf2 mice were found not only in animals under standard diet but also following HFD. Interestingly, we report here that the visceral adipose tissue (eWAT) is the sole source of increased Sirt1 protein in plasma. eWAT and other fat depots displayed enhanced adipocytes lipolysis, increased fatty acid oxidation and glycolysis, suggesting autocrine and endocrine actions of Sirt1 in this model. We further demonstrate that removal of eWAT completely abolishes the increase in circulating Sirt1 and that this procedure suppresses the beneficial effect of Nrf2 deficiency on glucose tolerance, but not insulin sensitivity, following a HFD regime. Thus, in contrast to many other stressful conditions where Nrf2 deficiency exacerbates damage, our study indicates that up-regulation of Sirt1 levels specifically in the visceral adipose tissue of Nrf2 mice is a key adaptive mechanism that mitigates glucose intolerance induced by nutritional stress.
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http://dx.doi.org/10.1016/j.redox.2020.101805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721645PMC
January 2021

Therapeutic effects of CO-releaser/Nrf2 activator hybrids (HYCOs) in the treatment of skin wound, psoriasis and multiple sclerosis.

Redox Biol 2020 07 1;34:101521. Epub 2020 Apr 1.

Inserm U955, Equipe 12, Créteil, 94010, France; University Paris Est, Faculty of Medicine, Créteil, 94010, France. Electronic address:

Carbon monoxide (CO) produced by heme oxygenase-1 (HO-1) or delivered by CO-releasing molecules (CO-RMs) exerts anti-inflammatory action, a feature also exhibited by the nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the stress response. We have recently developed new hybrid molecules (HYCOs) consisting of CO-RMs conjugated to fumaric esters known to activate Nrf2/HO-1. Here we evaluated the biological activities of manganese (Mn) and ruthenium (Ru)-based HYCOs in human monocytes and keratinocytes in vitro as well as in vivo models of inflammation. The effects of HYCOs were compared to: a) dimethyl fumarate (DMF), a known fumaric ester used in the clinic; b) a CO-RM alone; or c) the combination of the two compounds. Mn-HYCOs donated CO and up-regulated Nrf2/HO-1 in vitro more efficiently than Ru-HYCOs. However, irrespective of the metal, a strong reduction in anti-inflammatory markers in monocytes stimulated by LPS was observed with specific HYCOs. This effect was not observed with DMF, CO-RM alone or the combination of the two, indicating the enhanced potency of HYCOs compared to the separate entities. Selected HYCOs given orally to mice accelerated skin wound closure, reduced psoriasis-mediated inflammation and disease symptoms equalling or surpassing the effect of DMF, and ameliorated motor dysfunction in a mouse model of multiple sclerosis. Thus, HYCOs have potent anti-inflammatory activities that are recapitulated in disease models in which inflammation is a prominent component. Prolonged daily administration of HYCOs (up to 40 days) is well tolerated in animals. Our results clearly confirm that HYCOs possess a dual mode of action highlighting the notion that simultaneous Nrf2 targeting and CO delivery could be a clinically relevant application to combat inflammation.
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http://dx.doi.org/10.1016/j.redox.2020.101521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184182PMC
July 2020

Design and Biological Evaluation of Manganese- and Ruthenium-Based Hybrid CO-RMs (HYCOs).

ChemMedChem 2019 09 23;14(18):1684-1691. Epub 2019 Aug 23.

Université Paris Est, ICMPE (UMR 7182), CNRS, UPEC, 94320, Thiais, France.

Interest in the therapeutic effects of carbon monoxide (CO), a product of heme degradation catalyzed by the enzyme heme oxygenase-1 (HO-1), has led to the development of CO-releasing molecules (CO-RMs) for the controlled delivery of this gas in vivo. We recently proposed conjugating a cobalt-based CO-RM with various activators of nuclear factor erythroid 2-related factor 2 (Nrf2), the transcription factor that regulates HO-1 expression, in order to exploit the beneficial effects of exogenous and endogenous CO. In this study, we describe the preparation of hybrid molecules (termed HYCOs) conjugating a fumaric acid derivative as an Nrf2 activator to a Mn- or a Ru-based CO-RM known to be pharmacologically active. With the exception of an acyl-manganese complex, these hybrids were obtained by associating the two bioactive entities by means of a linker of variable structure. X-ray diffraction analyses and preliminary biological investigations are also presented.
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http://dx.doi.org/10.1002/cmdc.201900426DOI Listing
September 2019

TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages.

Free Radic Biol Med 2019 06 24;137:131-142. Epub 2019 Apr 24.

Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. Electronic address:

Heme oxygenase (HO)-1, a stress-inducible enzyme that converts heme into carbon monoxide (CO), iron and biliverdin, exerts important anti-inflammatory effects in activated macrophages. HO-1 expression is mainly governed by a mutual interplay between the transcriptional factor NRF2 and the nuclear repressor BTB and CNC homology 1 (BACH1), a heme sensor protein. In the current study we hypothesized that alterations in the levels of intracellular labile heme in macrophages stimulated by lipopolysaccharide (LPS), a prototypical pro-inflammatory Toll-like receptor (TLR)4 agonist, are responsible for BACH1-dependent HO-1 expression. To this end, labile heme was determined in both mouse bone marrow-derived macrophages (mBMDMs) and human monocyte-derived macrophages (hMDMs) using an apo-horseradish peroxidase-based assay. We found that LPS raised the levels of labile heme, depressed BACH1 protein and up-regulated HO-1 in mBMDMs. In contrast, in hMDMs LPS decreased labile heme levels while increasing BACH1 expression and down-regulating HO-1. These effects were abolished by the TLR4 antagonist TAK-242, suggesting that TLR4 activation triggers the signaling cascade leading to changes in the labile heme pool. Studies using mBMDMs from BACH1-/- and NRF2-/- mice revealed that regulation of HO-1 and levels of labile heme after LPS stimulation are strictly dependent on BACH1, but not NRF2. A strong interplay between BACH1-mediated HO-1 expression and intracellular levels of labile heme was also confirmed in hMDMs with siRNA knockdown studies and following inhibition of de novo heme synthesis with succinylacetone. Finally, CORM-401, a compound that liberates CO, counteracted LPS-dependent down-regulation of HO-1 and restored levels of labile heme in hMDMs. In conclusion, alterations of labile heme levels in macrophages following TLR4 stimulation play a crucial role in BACH1-mediated regulation of HO-1 expression.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.04.024DOI Listing
June 2019

Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis.

Redox Biol 2019 04 20;22:101147. Epub 2019 Feb 20.

Institute of Transfusion Medicine, Hannover Medical School, Hannover, 30625, Germany. Electronic address:

Macrophages adopt different phenotypes in response to microenvironmental changes, which can be principally classified into inflammatory and anti-inflammatory states. Inflammatory activation of macrophages has been linked with metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis. In contrast to mouse macrophages, little information is available on the link between metabolism and inflammation in human macrophages. In the current report it is demonstrated that lipopolysaccharide (LPS)-activated human peripheral blood monocyte-derived macrophages (hMDMs) fail to undergo metabolic reprogramming towards glycolysis, but rely on oxidative phosphorylation for the generation of ATP. By contrast, activation by LPS led to an increased extracellular acidification rate (glycolysis) and decreased oxygen consumption rate (oxidative phosphorylation) in mouse bone marrow-derived macrophages (mBMDMs). Mitochondrial bioenergetics after LPS stimulation in human macrophages was unchanged, but was markedly impaired in mouse macrophages. Furthermore, treatment with 2-deoxyglucose, an inhibitor of glycolysis, led to cell death in mouse, but not in human macrophages. Finally, glycolysis appeared to be critical for LPS-mediated induction of the anti-inflammatory cytokine interleukin-10 in both human and mouse macrophages. In summary, these findings indicate that LPS-induced immunometabolism in human macrophages is different to that observed in mouse macrophages.
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http://dx.doi.org/10.1016/j.redox.2019.101147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396203PMC
April 2019

Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice.

JCI Insight 2018 11 15;3(22). Epub 2018 Nov 15.

Inserm U955, Team 12, Créteil, France.

Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide-releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents.
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http://dx.doi.org/10.1172/jci.insight.123485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302946PMC
November 2018

Effects of 3-Bromo-4,5-dihydroisoxazole Derivatives on Nrf2 Activation and Heme Oxygenase-1 Expression.

ChemistryOpen 2018 Nov 12;7(11):858-864. Epub 2018 Oct 12.

Department of Pharmaceutical Sciences University of Milan viaMangiagalli 25 20133 Milan Italy.

Natural and synthetic electrophilic compounds have been shown to activate the antioxidant protective Nrf2 (nuclear factor erythroid 2-related factor 2)/heme oxygenase-1 (HO-1) axis in cells and tissues. Here, we tested the ability of different isoxazoline-based electrophiles to up-regulate Nrf2/HO-1. The potency of activation is dependent on the leaving group at the 3-position of the isoxazoline nucleus, and an additional ring on the molecule limits the Nrf2/HO-1 activating properties. Among the synthetized compounds, we identified 3-bromo-5-phenyl-4,5-dihydroisoxazole as the derivative with best activating properties in THP-1 human monocytic cells. We have confirmed that the target of our compounds is the Cys151 of the BTB domain of Keap1 by using mass spectrometry analyses and X-ray crystallography. Our findings demonstrate that these compounds affect the Nrf2/HO-1 axis and highlight a positive activity that can be of relevance from a therapeutic perspective in inflammation and infection.
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http://dx.doi.org/10.1002/open.201800185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207109PMC
November 2018

HYCO-3, a dual CO-releaser/Nrf2 activator, reduces tissue inflammation in mice challenged with lipopolysaccharide.

Redox Biol 2019 01 26;20:334-348. Epub 2018 Oct 26.

Inserm U955, Equipe 12, Créteil 94000, France; University Paris-Est, Faculty of Medicine, Créteil 94000, France. Electronic address:

Oxidative stress and inflammation are predominant features of several chronic diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a major arbiter in counteracting these insults via up-regulation of several defensive proteins, including heme oxygenase-1 (HO-1). HO-1-derived carbon monoxide (CO) exhibits anti-inflammatory actions and can be delivered to tissues by CO-releasing agents. In this study we assessed the pharmacological and anti-inflammatory properties of HYCO-3, a dual activity compound obtained by conjugating analogues of the CO-releasing molecule CORM-401 and dimethyl fumarate (DMF), an immunomodulatory drug known to activate Nrf2. HYCO-3 induced Nrf2-dependent genes and delivered CO to cells in vitro and tissues in vivo, confirming that the two expected pharmacological properties of this agent are achieved. In mice challenged with lipopolysaccharide, orally administered HYCO-3 reduced the mRNA levels of pro-inflammatory markers (TNF-α, IL-1β and IL-6) while increasing the expression of the anti-inflammatory genes ARG1 and IL-10 in brain, liver, lung and heart. In contrast, DMF or CORM-401 alone or their combination decreased the expression of pro-inflammatory genes but had limited influence on anti-inflammatory markers. Furthermore, HYCO-3 diminished TNF-α and IL-1β in brain and liver but not in lung and heart of Nrf2 mice, indicating that the CO-releasing part of this hybrid contributes to reduction of pro-inflammation and that this effect is organ-specific. These data demonstrate that the dual activity of HYCO-3 results in enhanced efficacy compared to the parent compounds indicating the potential exploitation of hybrid compounds in the development of effective anti-inflammatory therapies.
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http://dx.doi.org/10.1016/j.redox.2018.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223233PMC
January 2019

Heme oxygenase-1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction.

Aging Cell 2018 Dec 19;17(6):e12837. Epub 2018 Oct 19.

Inserm U955, Equipe 04, Créteil, France.

Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by an irreversible proliferation arrest associated with secretion of inflammatory mediators. ROS production, known to induce senescence, is increased in COPD fibroblasts and mitochondria dysfunction participates in this process. Among the battery of cellular responses against oxidative stress damage, heme oxygenase (HO)-1 plays a critical role in defending the lung against oxidative stress and inflammation. Therefore, we investigated whether pharmacological induction of HO-1 by chronic hemin treatment attenuates senescence and improves dysfunctional mitochondria in COPD fibroblasts. Fibroblasts from smoker controls (S-C) and COPD patients were isolated from lung biopsies. Fibroblasts were long-term cultured in the presence or absence of hemin, and/or ZnPP or QC-15 (HO-1 inhibitors). Lung fibroblasts from smokers and COPD patients displayed in long-term culture a senescent phenotype, characterized by a reduced replicative capacity, an increased senescence and inflammatory profile. These parameters were significantly higher in senescent COPD fibroblasts which also exhibited decreased mitochondrial activity (respiration, glycolysis, and ATP levels) which led to an increased production of ROS, and mitochondria biogenesis and impaired mitophagy process. Exposure to hemin increased the gene and protein expression level of HO-1 in fibroblasts and diminished ROS levels, senescence, the inflammatory profile and simultaneously rescued mitochondria dysfunction by restoring mitophagy in COPD cells. The effects of hemin were abolished by a cotreatment with ZnPP or QC-15. We conclude that HO-1 attenuates senescence in COPD fibroblasts by protecting, at least in part, against mitochondria dysfunction and restoring mitophagy.
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http://dx.doi.org/10.1111/acel.12837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260925PMC
December 2018

Effects of Novel Nitric Oxide-Releasing Molecules against Oxidative Stress on Retinal Pigmented Epithelial Cells.

Oxid Med Cell Longev 2017 12;2017:1420892. Epub 2017 Oct 12.

Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Catania, Italy.

Oxidative stress is a hallmark of retinal degenerations such as age-related macular degeneration and diabetic retinopathy. Enhancement of heme oxygenase-1 (HO-1) activity in the retina would exert beneficial effects by protecting cells from oxidative stress, therefore promoting cell survival. Because a crosstalk exists between nitric oxide (NO) and HO-1 in promotion of cell survival under oxidative stress, we designed novel NO-releasing molecules also capable to induce HO-1. Starting from curcumin and caffeic acid phenethyl ester (CAPE), two known HO-1 inducers, the molecules were chemically modified by acylation with 4-bromo-butanoyl chloride and 2-chloro-propanoyl chloride, respectively, and then treated in the dark with AgNO to obtain the nitrate derivatives VP10/12 and VP10/39. Human retinal pigment epithelial cells (ARPE-19) subjected to HO-mediated oxidative stress were treated with the described NO-releasing compounds. VP10/39 showed significant ( < 0.05) antioxidant and protecting activity against oxidative damage, in comparison to VP10/12, which in turn showed at 100 M concentration a slight but significant cell toxicity. Only VP10/39 significantly ( < 0.05) induced HO-1 in ARPE-19, most likely through covalent bond formation at Cys151 of the Keap1-BTB domain, as revealed from molecular docking analysis. In conclusion, the present data indicate VP10/39 as a promising candidate to protect ARPE-19 cells against oxidative stress.
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http://dx.doi.org/10.1155/2017/1420892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660806PMC
July 2018

Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties.

Cell Death Differ 2017 07 19;24(7):1224-1238. Epub 2017 May 19.

Université Paris-Est, UMR-S955, UPEC, Créteil, Paris, France.

Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms - activation of autophagy, HO-1 and mitochondrial biogenesis - occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.
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http://dx.doi.org/10.1038/cdd.2017.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520168PMC
July 2017

Detection and Removal of Endogenous Carbon Monoxide by Selective and Cell-Permeable Hemoprotein Model Complexes.

J Am Chem Soc 2017 04 17;139(16):5984-5991. Epub 2017 Apr 17.

Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University , Kyotanabe, Kyoto 610-0321, Japan.

Carbon monoxide (CO) is produced in mammalian cells during heme metabolism and serves as an important signaling messenger. Here we report the bioactive properties of selective CO scavengers, hemoCD1 and its derivative R8-hemoCD1, which have the ability to detect and remove endogenous CO in cells. HemoCD1 is a supramolecular hemoprotein-model complex composed of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphinatoiron(II) and a per-O-methylated β-cyclodextrin dimer having an pyridine linker. We demonstrate that hemoCD1 can be used effectively to quantify endogenous CO in cell lysates by a simple spectrophotometric method. The hemoCD1 assay detected ca. 260 pmol of CO in 10 hepatocytes, which was well-correlated with the amount of intracellular bilirubin, the final breakdown product of heme metabolism. We then covalently attached an octaarginine peptide to a maleimide-appended hemoCD1 to synthesize R8-hemoCD1, a cell-permeable CO scavenger. Indeed, R8-hemoCD1 was taken up by intact cells and captured intracellular CO with high efficiency. Moreover, we revealed that removal of endogenous CO by R8-hemoCD1 in cultured macrophages led to a significant increase (ca. 2.5-fold) in reactive oxygen species production and exacerbation of inflammation after challenge with lipopolysaccharide. Thus, R8-hemoCD1 represents a powerful expedient for exploring specific and still unidentified biological functions of CO in cells.
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http://dx.doi.org/10.1021/jacs.7b02229DOI Listing
April 2017

Carbon monoxide reverses the metabolic adaptation of microglia cells to an inflammatory stimulus.

Free Radic Biol Med 2017 03 18;104:311-323. Epub 2017 Jan 18.

Inserm U955, Equipe 12, Créteil 94000, France; University Paris-Est, Faculty of Medicine, Créteil 94000, France. Electronic address:

Microglia fulfill important immunological functions in the brain by responding to pathological stresses and modulating their activities according to pro- or anti-inflammatory stimuli. Recent evidence indicates that changes in metabolism accompany the switch in microglia activation state, favoring glycolysis over oxidative phosphorylation when cells exhibit a pro-inflammatory phenotype. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory action and affects mitochondrial function in cells and tissues. In the present study, we analyzed the metabolic profile of BV2 and primary mouse microglia exposed to the CO-releasing molecules CORM-401 and CORM-A1 and investigated whether CO affects the metabolic adaptation of cells to the inflammatory stimulus lipopolysaccharide (LPS). Microglia respiration and glycolysis were measured using an Extracellular Flux Analyzer to provide a real-time bioenergetic assessment, and biochemical parameters were evaluated to define the metabolic status of the cells under normal or inflammatory conditions. We show that CO prevents LPS-induced depression of microglia respiration and reduction in ATP levels while altering the early expression of inflammatory markers, suggesting the metabolic changes induced by CO are associated with control of inflammation. CO alone affects microglia respiration depending on the concentration, as low levels increase oxygen consumption while higher amounts inhibit respiration. Increased oxygen consumption was attributed to an uncoupling activity observed in cells, at the molecular level (respiratory complex activities) and during challenge with LPS. Thus, application of CO is a potential countermeasure to reverse the metabolic changes that occur during microglia inflammation and in turn modulate their inflammatory profile.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.01.022DOI Listing
March 2017

Biological signaling by carbon monoxide and carbon monoxide-releasing molecules.

Am J Physiol Cell Physiol 2017 Mar 11;312(3):C302-C313. Epub 2017 Jan 11.

Inserm U955, Team 12, Créteil, France; and Faculty of Medicine, Université Paris Est, Créteil, France

Carbon monoxide (CO) is continuously produced in mammalian cells during the degradation of heme. It is a stable gaseous molecule that reacts selectively with transition metals in a specific redox state, and these characteristics restrict the interaction of CO with defined biological targets that transduce its signaling activity. Because of the high affinity of CO for ferrous heme, these targets can be grouped into heme-containing proteins, representing a large variety of sensors and enzymes with a series of diverse function in the cell and the organism. Despite this notion, progress in identifying which of these targets are selective for CO has been slow and even the significance of elevated carbonmonoxy hemoglobin, a classical marker used to diagnose CO poisoning, is not well understood. This is also due to the lack of technologies capable of assessing in a comprehensive fashion the distribution and local levels of CO between the blood circulation, the tissue, and the mitochondria, one of the cellular compartments where CO exerts its signaling or detrimental effects. Nevertheless, the use of CO gas and CO-releasing molecules as pharmacological approaches in models of disease has provided new important information about the signaling properties of CO. In this review we will analyze the most salient effects of CO in biology and discuss how the binding of CO with key ferrous hemoproteins serves as a posttranslational modification that regulates important processes as diverse as aerobic metabolism, oxidative stress, and mitochondrial bioenergetics.
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http://dx.doi.org/10.1152/ajpcell.00360.2016DOI Listing
March 2017

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival.

Circ Res 2016 06;118(12):1940-1959

Inserm, U955, Equipe 12, Créteil, 94000, France.

Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. Although the antioxidant and heat-shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin, and iron. The remarkable cardioprotective effects ascribed to heme oxygenase-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling, and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of heme oxygenase-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.306588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905590PMC
June 2016

Diverse Nrf2 Activators Coordinated to Cobalt Carbonyls Induce Heme Oxygenase-1 and Release Carbon Monoxide in Vitro and in Vivo.

J Med Chem 2016 Jan 15;59(2):756-62. Epub 2016 Jan 15.

Equipe 12, Inserm U955 , 8 Rue du Général Sarrail, Créteil, 94000, France.

The Nrf2/heme oxygenase-1 (HO-1) axis affords significant protection against oxidative stress and cellular damage. We synthesized a series of cobalt-based hybrid molecules (HYCOs) that combine an Nrf2 inducer with a releaser of carbon monoxide (CO), an anti-inflammatory product of HO-1. Two HYCOs markedly increased Nrf2/HO-1 expression, liberated CO and exerted anti-inflammatory activity in vitro. HYCOs also up-regulated tissue HO-1 and delivered CO in blood after administration in vivo, supporting their potential use against inflammatory conditions.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01509DOI Listing
January 2016

Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule.

Biochem Pharmacol 2016 Feb 22;102:64-77. Epub 2015 Dec 22.

Université Paris-Est, Faculté de Medicine, Créteil 94000, France; INSERM, U955, Equipe 12, Créteil 94000, France. Electronic address:

Carbon monoxide (CO) is generated by heme oxygenase-1 (HO-1) and displays important signaling, anti-apoptotic and anti-inflammatory activities, indicating that pharmacological agents mimicking its action may have therapeutic benefit. This study examined the biochemical and pharmacological properties of CORM-401, a recently described CO-releasing molecule containing manganese as a metal center. We used in vitro approaches, ex-vivo rat aortic rings and the EA.hy926 endothelial cell line in culture to address how CORM-401 releases CO and whether the compound modulates vascular tone and pro-angiogenic activities, respectively. We found that CORM-401 released up to three CO/mole of compound depending on the concentration of the acceptor myoglobin. Oxidants such as H2O2, tert-butyl hydroperoxide or hypochlorous acid increased the CO liberated by CORM-401. CORM-401 also relaxed pre-contracted aortic rings and vasorelaxation was enhanced in combination with H2O2. Consistent with the release of multiple CO molecules, CORM-401-induced vasodilation was three times higher than that elicited by CORM-A1, which exhibits a similar half-life to CORM-401 but liberates only one CO/mole of compound. Furthermore, endothelial cells exposed to CORM-401 accumulated CO intracellularly, accelerated migration in vitro and increased VEGF and IL-8 levels. Studies using pharmacological inhibitors revealed HO-1 and p38 MAP kinase as two independent and parallel mechanisms involved in stimulating migration. We conclude that the ability of CORM-401 to release multiple CO, its sensitivity to oxidants which increase CO release, and its vascular and pro-angiogenic properties highlight new advances in the design of CO-releasing molecules that can be tailored for the treatment of inflammatory and oxidative stress-mediated pathologies.
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http://dx.doi.org/10.1016/j.bcp.2015.12.014DOI Listing
February 2016

Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions.

Pharmacol Res 2015 Sep 15;99:296-307. Epub 2015 Jul 15.

Université Paris-Est, Faculty of Medicine, Créteil, 94000, France; Inserm U955, Equipe 12, 94000 Créteil, France. Electronic address:

Retinal pigment epithelial cells exert an important supporting role in the eye and develop adaptive responses to oxidative stress or high glucose levels, as observed during diabetes. Endogenous antioxidant defences are mainly regulated by Nrf2, a transcription factor that is activated by naturally-derived and electrophilic compounds. Here we investigated the effect of the Nrf2 activators dimethylfumarate (DMF) and carnosol on antioxidant pathways, oxygen consumption rate and wound healing in human retinal pigment epithelial cells (ARPE-19) cultured in medium containing normal (NG, 5mM) or high (HG, 25 mM) glucose levels. We also assessed wound healing using an in vivo corneal epithelial injury model. We found that Nrf2 nuclear translocation and heme oxygenase activity increased in ARPE cells treated with 10 μM DMF or carnosol irrespective of glucose culture conditions. However, HG rendered retinal cells more sensitive to regulators of glutathione synthesis or inhibition and caused a decrease of both cellular and mitochondrial reactive oxygen species. Culture in HG also reduced ATP production and mitochondrial function as measured with the Seahorse XF analyzer and electron microscopy analysis revealed morphologically damaged mitochondria. Acute treatment with DMF or carnosol did not restore mitochondrial function in HG cells; conversely, the compounds reduced cellular maximal respiratory and reserve capacity, which were completely prevented by N-acetylcysteine thus suggesting the involvement of thiols in this effect. Interestingly, the scratch assay showed that wound closure was faster in cells cultured in HG than NG and was accelerated by carnosol. This effect was reversed by an inhibitor of heme oxygenase activity. Moreover, topical application of carnosol to the cornea of diabetic rats significantly accelerated wound healing. In summary, these data indicate that culture of retinal epithelial cells in HG does not affect the activation of the Nrf2/heme oxygenase axis but influences other crucial oxidative and mitochondrial-dependent cellular functions. The additional effect on wound closure suggests that results obtained in in vitro experimental settings need to be carefully evaluated in the context of the glucose concentrations used in cell culture.
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http://dx.doi.org/10.1016/j.phrs.2015.07.006DOI Listing
September 2015

Carbon monoxide released by CORM-401 uncouples mitochondrial respiration and inhibits glycolysis in endothelial cells: A role for mitoBKCa channels.

Biochim Biophys Acta 2015 Oct 14;1847(10):1297-309. Epub 2015 Jul 14.

Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow 30-348, Poland. Electronic address:

Carbon monoxide (CO), a product of heme degradation by heme oxygenases, plays an important role in vascular homeostasis. Recent evidence indicates that mitochondria are among a number of molecular targets that mediate the cellular actions of CO. In the present study we characterized the effects of CO released from CORM-401 on mitochondrial respiration and glycolysis in intact human endothelial cells using electron paramagnetic resonance (EPR) oximetry and the Seahorse XF technology. We found that CORM-401 (10-100μM) induced a persistent increase in the oxygen consumption rate (OCR) that was accompanied by inhibition of glycolysis (extracellular acidification rate, ECAR) and a decrease in ATP-turnover. Furthermore, CORM-401 increased proton leak, diminished mitochondrial reserve capacity and enhanced non-mitochondrial respiration. Inactive CORM-401 (iCORM-401) neither induced mitochondrial uncoupling nor inhibited glycolysis, supporting a direct role of CO in the endothelial metabolic response induced by CORM-401. Interestingly, blockade of mitochondrial large-conductance calcium-regulated potassium ion channels (mitoBKCa) with paxilline abolished the increase in OCR promoted by CORM-401 without affecting ECAR; patch-clamp experiments confirmed that CO derived from CORM-401 activated mitoBKCa channels present in mitochondria. Conversely, stabilization of glycolysis by MG132 prevented CORM-401-mediated decrease in ECAR but did not modify the OCR response. In summary, we demonstrated in intact endothelial cells that CO induces a two-component metabolic response: uncoupling of mitochondrial respiration dependent on the activation of mitoBKCa channels and inhibition of glycolysis independent of mitoBKCa channels.
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http://dx.doi.org/10.1016/j.bbabio.2015.07.004DOI Listing
October 2015

Pharmacology of the 'gasotransmitters' NO, CO and H2S: translational opportunities.

Br J Pharmacol 2015 Mar;172(6):1395-6

Faculty of Pharmacy, University of Athens, Athens, Greece; 'George P. Livanos and Marianthi Simou Laboratories', Evangelismos Hospital, 1st Department of Critical Care and Pulmonary Services, University of Athens, Greece.

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http://dx.doi.org/10.1111/bph.13005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369252PMC
March 2015

Regulation of vascular tone in rabbit ophthalmic artery: cross talk of endogenous and exogenous gas mediators.

Biochem Pharmacol 2014 Dec 29;92(4):661-8. Epub 2014 Oct 29.

Department of Clinical and Molecular Biomedicine, Catania University, Catania, Italy.

Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H2S) modulate vascular tone. In view of their therapeutic potential for ocular diseases, we examined the effect of exogenous CO and H2S on tone of isolated rabbit ophthalmic artery and their interaction with endogenous and exogenous NO. Ophthalmic artery segments mounted on a wire myograph were challenged with cumulative concentrations of phenylephrine (PE) in the presence or absence of NG-nitro-L-arginine (LNNA) to inhibit production of NO, the CO-releasing molecules CORMs or the H2S-donor GYY4137. The maximal vasoconstriction elicited by PE reached 20-30% of that induced by KCl but was dramatically increased by incubation with LNNA. GYY4137 significantly raised PE-mediated vasoconstriction, but it did not change the response to PE in the presence of LNNA or the relaxation to sodium nitroprusside (SNP). CORMs concentration-dependently inhibited PE-induced constriction, an effect that was synergistic with endogenous NO (reduced by LNNA), but insensitive to blockade of guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-α]quinoxalin-1-one (ODQ). In vascular tissues cyclic GMP (cGMP) levels seemed reduced by GYY4137 (not significantly), but were not changed by CORM. These data indicate that CO is able per se to relax isolated ophthalmic artery and to synergize with NO, while H2S counteracts the effect of endogenous NO. CO does not stimulate cGMP production in our system, while H2S may reduce cGMP production stimulated by endogenous NO. These findings provide new insights into the complexities of gas interactions in the control of ophthalmic vascular tone, highlighting potential pharmacological targets for ocular diseases.
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http://dx.doi.org/10.1016/j.bcp.2014.10.011DOI Listing
December 2014

Permanent culture of macrophages at physiological oxygen attenuates the antioxidant and immunomodulatory properties of dimethyl fumarate.

J Cell Physiol 2015 May;230(5):1128-38

Université Paris-Est, UMR_S955, UPEC, France; INSERM, U955, Equipe 03, France.

We hypothesized that O2 tension influences the redox state and the immunomodulatory responses of inflammatory cells to dimethyl fumarate (DMF), an activator of the nuclear factor Nrf2 that controls antioxidant genes expression. This concept was investigated in macrophages permanently cultured at either physiological (5% O2) or atmospheric (20% O2) oxygen levels and then treated with DMF or challenged with lipopolysaccharide (LPS) to induce inflammation. RAW 264.7 macrophages cultured at 20% O2 exhibited a pro-oxidant phenotype, reflected by a lower content of reduced glutathione, higher oxidized glutathione and increased production of reactive oxygen species when compared to macrophages continuously grown at 5% O2. At 20% O2, DMF induced a stronger antioxidant response compared to 5% O2 as evidenced by a higher expression of heme oxygenase-1, NAD(P)H:quinone oxydoreductase-1 and superoxide dismutase-2. After challenge of macrophages with LPS, several pro-inflammatory (iNOS, TNF-α, MMP-2, MMP-9), anti-inflammatory (arginase-1, IL-10) and pro-angiogenic (VEGF-A) mediators were evaluated in the presence or absence of DMF. All markers, with few interesting exceptions, were significantly reduced at 5% O2. This study brings new insights on the effects of O2 in the cellular adaptation to oxidative and inflammatory stimuli and highlights the importance of characterizing the effects of chemicals and drugs at physiologically relevant O2 tension. Our results demonstrate that the common practice of culturing cells at atmospheric O2 drives the endogenous cellular environment towards an oxidative stress phenotype, affecting inflammation and the expression of antioxidant pathways by exogenous modulators.
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http://dx.doi.org/10.1002/jcp.24844DOI Listing
May 2015

Design and synthesis of new hybrid molecules that activate the transcription factor Nrf2 and simultaneously release carbon monoxide.

Chemistry 2014 Nov 15;20(45):14698-704. Epub 2014 Sep 15.

Inserm, Unité 955, Equipe 3 and Faculté de Médicine, Université Paris-Est Créteil, 8 Rue du General Sarrail, 94000 Créteil (France).

The transcription factor Nrf2 and its downstream target heme oxygenase-1 (HO-1) are essential protective systems against oxidative stress and inflammation. The products of HO-1 enzymatic activity, biliverdin and carbon monoxide (CO), actively contribute to this protection, suggesting that exploitation of these cellular systems may offer new therapeutic avenues in a variety of diseases. Starting from a CO-releasing compound and a chemical scaffold exhibiting electrophilic characteristics (esters of fumaric acid), we report the synthesis of hybrid molecules that simultaneously activate Nrf2 and liberate CO. These hybrid compounds, which we termed "HYCOs", release CO to myoglobin and activate the CO-sensitive fluorescent probe COP-1, while also potently inducing nuclear accumulation of Nrf2 and HO-1 expression and activity in different cell types. Thus, we provide here the first example of a new class of pharmacologically active molecules that target the HO-1 pathway by combining an Nrf2 activator coordinated to a CO-releasing group.
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http://dx.doi.org/10.1002/chem.201403901DOI Listing
November 2014

Heme oxygenase-1 in diabetic vascular dysfunction.

Vascul Pharmacol 2014 Sep 23;62(3):132-3. Epub 2014 May 23.

INSERM Unit 955, Equipe 3, University Paris-Est, Faculty of Medicine, Créteil 94000 France. Electronic address:

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http://dx.doi.org/10.1016/j.vph.2014.05.006DOI Listing
September 2014

Isothiocyanate-cysteine conjugates protect renal tissue against cisplatin-induced apoptosis via induction of heme oxygenase-1.

Pharmacol Res 2014 Mar 13;81:1-9. Epub 2014 Jan 13.

Université Paris-Est, UMR_S955, UPEC, F-94000 Créteil, France; Inserm U955, Equipe 3, F-94000 Créteil, France. Electronic address:

Heme oxygenase-1 (HO-1) is a redox sensitive inducible enzyme endowed with important antioxidant and cytoprotective activities. Here we report that two water-soluble isothiocyanate-cysteine conjugates, S-[N-benzyl(thiocarbamoyl)]-l-cysteine (BTTC) and S-[N-(3-phenylpropyl)(thiocarbamoyl)]-l-cysteine (PTTC), potently increase HO-1 protein expression and heme oxygenase activity in renal tubular epithelial cells at 5 and 10μM, while higher concentrations are themselves cytotoxic and pro-apoptotic. Inhibitors of the pro-survival pathways ERK, MAPK and PI3K almost completely abolished the increase in HO-1 induction and heme oxygenase activity, while the JNK pathway appeared to be mainly involved in the apoptosis triggered by the isothiocyanates. We also found that renal cells exposed to 50μM cisplatin (CDDP), a chemotherapeutic agent known for its nephrotoxic actions, displayed a marked increase in caspase-3 activity and the number of apoptotic cells. These effects were abolished by pre-incubation of cells with concentrations of BTCC or PTCC that maximize HO-1 induction and were reversed by the inhibitor of heme oxygenase activity tin protoporphyrin IX (SnPPIX). Moreover, in a model of CDDP-induced nephrotoxicity in vivo, pre-treatment of rats with a daily dose of BTCC or PTCC (25mg/kg, i.p.) completely abolished the increase in serum creatinine and urea levels and markedly reduced the severity of renal tissue apoptosis caused by CDDP. The renoprotective effects of BTCC and PTCC in vivo were markedly attenuated by administration of rats with SnPPIX. These findings indicate that water-soluble isothiocyanates counteract renal dysfunction and apoptosis by up-regulating the HO-1 system and could be used as a supplementary treatment to mitigate CDDP-induced nephrotoxic effects.
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http://dx.doi.org/10.1016/j.phrs.2014.01.001DOI Listing
March 2014

Heme oxygenase-1 as a target for drug discovery.

Antioxid Redox Signal 2014 Apr 28;20(11):1810-26. Epub 2014 Feb 28.

1 Université Paris-Est , UMR_S955, F-94000, Créteil, France .

Significance: Heme oxygenase enzymes, which exist as constitutive (HO-2) and inducible (HO-1) isoforms, degrade heme to carbon monoxide (CO) and the bile pigment biliverdin. In the last two decades, substantial scientific evidence has been collected on the function of HO-1 in cell homeostasis, emphasizing these two important features: (i) HO-1 is a fundamental "sensor" of cellular stress and directly contributes toward limiting or preventing tissue damage; (ii) the products of HO-1 activity dynamically participate in cellular adaptation to stress and are inherently involved in the mechanisms of defence.

Recent Advances: On the basis of its promising cytoprotective features, scientists have pursued the targeting of HO-1 as an attractive cellular pathway for drug discovery. Three different pharmacological approaches are currently being investigated in relation to HO-1, namely the use of CO gas, the development of CO-releasing molecules (CO-RMs), and small molecules possessing the ability to up-regulate HO-1 in cells and tissues. CRITICAL ISSUE: Studies on the regulation and amplification of the HO-1/CO pathway by selective pharmacological approaches may lead to the discovery of novel drugs for the treatment of a variety of diseases.

Future Directions: In this review, we will discuss in detail the importance of pharmacologically manipulating the HO-1 pathway and its products for conferring protection against a variety of conditions that are characterized by oxidative stress and inflammation. We will also evaluate each of the strategic approaches being developed by considering their intrinsic advantages and disadvantages, which may have implications for their use as therapeutics in specific pathological conditions.
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http://dx.doi.org/10.1089/ars.2013.5658DOI Listing
April 2014

Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.

Pharmacol Res 2013 Oct 11;76:132-48. Epub 2013 Aug 11.

Université Paris-Est, UMR_S955, UPEC, F-94000 Créteil, France; Inserm U955, Equipe 3, F-94000 Créteil, France. Electronic address:

The nuclear factor erythroid derived 2-related factor 2 (Nrf2) and the antioxidant protein heme oxygenase-1 (HO-1) are crucial components of the cellular stress response. These two systems work together to combat oxidative stress and inflammation and are attractive drug targets for counteracting different pathologies, including neuroinflammation. We aimed to identify the most effective Nrf2/HO-1 activators that modulate the inflammatory response in microglia cells. In the present study, we searched the literature and selected 56 compounds reported to activate Nrf2 or HO-1 and analyzed them for HO-1 induction at 6 and 24h and cytotoxicity in BV2 microglial cells in vitro. Approximately 20 compounds up-regulated HO-1 at the concentrations tested (5-20 μM) with carnosol, supercurcumin, cobalt protoporphyrin-IX and dimethyl fumarate exhibiting the best induction/low cytotoxicity profile. Up-regulation of HO-1 by some compounds resulted in increased cellular bilirubin levels but did not augment the expression of proteins involved in heme synthesis (ALAS 1) or biliverdin reductase. Bilirubin production by HO-1 inducers correlated with their potency in inhibiting nitrite production after challenge with interferon-γ (INF-γ) or lipopolysaccharide (LPS). The compounds down-regulated the inflammatory response (TNF-α, PGE2 and nitrite) more strongly in cells challenged with INF-γ than LPS, and silencing HO-1 or Nrf2 with shRNA differentially affected the levels of inflammatory markers. These findings indicate that some small activators of Nrf2/HO-1 are effective modulators of microglia inflammation and highlight the chemical scaffolds that can serve for the synthesis of potent new derivatives to counteract neuroinflammation and neurodegeneration.
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http://dx.doi.org/10.1016/j.phrs.2013.07.010DOI Listing
October 2013