Does carbon monoxide inhibit cytochrome oxidase in vivo?

1997 ◽  
Vol 25 (3) ◽  
pp. 406S-406S
Author(s):  
NATHAN A. DAVIES ◽  
CHRISTOS TRIKKAS ◽  
CHRIS E. COOPER
Keyword(s):  
Carbon Monoxide ◽  
Cytochrome Oxidase

scholarly journals Adapting decarbonylation chemistry for the development of prodrugs capable of in-vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules

2021 ◽  
Author(s):  
Ladie Kimberly De La Cruz ◽  
Xiaoxiao Yang ◽  
Anna Menshikh ◽  
Maya Brewer ◽  
Wen Lu ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Animal Models ◽  
Therapeutic Agent ◽  
Organ Injury ◽  
Signaling Molecule ◽  
In Vivo Delivery ◽  
Co Gas

Carbon monoxide as an endogenous signaling molecule exhibits pharmacological efficacy in various animal models of organ injury. To address the difficulty in using CO gas as a therapeutic agent for...

scholarly journals Differential Expression of the CO2 Fixation Operons of Rhodobacter sphaeroides by the Prr/Reg Two-Component System during Chemoautotrophic Growth

2002 ◽  
Vol 184 (23) ◽  
pp. 6654-6664 ◽  
Author(s):  
Janet L. Gibson ◽  
James M. Dubbs ◽  
F. Robert Tabita
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Cytochrome Oxidase ◽  
Rhodobacter Sphaeroides ◽  
Rhodobacter Capsulatus ◽  
Response Regulator ◽  
Signal Transduction Pathway ◽  
Pentose Phosphate ◽  
Bisphosphate Carboxylase

ABSTRACT In Rhodobacter sphaeroides, the two cbb operons encoding duplicated Calvin-Benson Bassham (CBB) CO2 fixation reductive pentose phosphate cycle structural genes are differentially controlled. In attempts to define the molecular basis for the differential regulation, the effects of mutations in genes encoding a subunit of Cbb3 cytochrome oxidase, ccoP, and a global response regulator, prrA (regA), were characterized with respect to CO2 fixation (cbb) gene expression by using translational lac fusions to the R. sphaeroides cbb I and cbbII promoters. Inactivation of the ccoP gene resulted in derepression of both promoters during chemoheterotophic growth, where cbb expression is normally repressed; expression was also enhanced over normal levels during phototrophic growth. The prrA mutation effected reduced expression of cbbI and cbbII promoters during chemoheterotrophic growth, whereas intermediate levels of expression were observed in a double ccoP prrA mutant. PrrA and ccoP1 prrA strains cannot grow phototrophically, so it is impossible to examine cbb expression in these backgrounds under this growth mode. In this study, however, we found that PrrA mutants of R. sphaeroides were capable of chemoautotrophic growth, allowing, for the first time, an opportunity to directly examine the requirement of PrrA for cbb gene expression in vivo under growth conditions where the CBB cycle and CO2 fixation are required. Expression from the cbbII promoter was severely reduced in the PrrA mutants during chemoautotrophic growth, whereas cbbI expression was either unaffected or enhanced. Mutations in ccoQ had no effect on expression from either promoter. These observations suggest that the Prr signal transduction pathway is not always directly linked to Cbb3 cytochrome oxidase activity, at least with respect to cbb gene expression. In addition, lac fusions containing various lengths of the cbbI promoter demonstrated distinct sequences involved in positive regulation during photoautotrophic versus chemoautotrophic growth, suggesting that different regulatory proteins may be involved. In Rhodobacter capsulatus, ribulose 1,5-bisphosphate carboxylase-oxygenase (RubisCO) expression was not affected by cco mutations during photoheterotrophic growth, suggesting that differences exist in signal transduction pathways regulating cbb genes in the related organisms.

Protection against cisplatin-induced nephrotoxicity by a carbon monoxide-releasing molecule

2006 ◽  
Vol 290 (4) ◽  
pp. F789-F794 ◽  
Author(s):  
Yasin Tayem ◽  
Tony R. Johnson ◽  
Brian E. Mann ◽  
Colin J. Green ◽  
Roberto Motterlini
Keyword(s):  
Carbon Monoxide ◽  
Caspase 3 ◽  
Morphological Changes ◽  
Antineoplastic Agent ◽  
Negative Control ◽  
Water Soluble ◽  
Plasma Urea ◽  
Therapeutic Benefits ◽  
Corticomedullary Junction

Nephrotoxicity is one of the main side effects caused by cisplatin (CP), a widely used antineoplastic agent. Here, we examined the effect of a novel water-soluble carbon monoxide-releasing molecule (CORM-3) on CP-mediated cytotoxicity in renal epithelial cells and explored the potential therapeutic benefits of carbon monoxide in CP-induced nephrotoxicity in vivo. Exposure of LLC-PK1 cells to CP (50 μM) caused significant apoptosis as evidenced by caspase-3 activation and an increased number of floating cells. Treatment with CORM-3 (1–50 μM) resulted in a remarkable and concentration-dependent decrease in CP-induced caspase-3 activity and cell detachment. This effect involved activation of the cGMP pathway as 1H-oxadiazole [4, 3-a] quinoxaline-1-ore (ODQ), a guanylate cyclase inhibitor, completely abolished the protection elicited by CORM-3. Using a rat model of CP-induced renal failure, we found that treatment with CP (7.5 mg/kg) caused a significant elevation in plasma urea (6.6-fold) and creatinine (3.1-fold) levels, which was accompanied by severe morphological changes and marked apoptosis in tubules at the corticomedullary junction. A daily administration of CORM-3 (10 mg/kg ip), starting 1 day before CP treatment and continuing for 3 days thereafter, resulted in amelioration of renal function as shown by reduction of urea and creatinine levels to basal values, a decreased number of apoptotic tubular cells, and an improved histological profile. A negative control (iCORM-3) that is incapable of liberating CO failed to prevent renal dysfunction mediated by CP, indicating that CO is directly involved in renoprotection. Our data demonstrate that CORM-3 can be used as an effective therapeutic adjuvant in the treatment of CP-induced nephrotoxicity.

scholarly journals Carbon Monoxide Inhibits Tenascin-C Mediated Inflammation via IL-10 Expression in a Septic Mouse Model

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Md. Jamal Uddin ◽  
Chun-shi Li ◽  
Yeonsoo Joe ◽  
Yingqing Chen ◽  
Qinggao Zhang ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Proinflammatory Cytokines ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Septic Mouse ◽  
Induced Expression ◽  
Tenascin C ◽  
Co Gas

Tenascin-C (TN-C), an extracellular matrix (ECM) glycoprotein, is specifically induced upon tissue injury and infection and during septic conditions. Carbon monoxide (CO) gas is known to exert various anti-inflammatory effects in various inflammatory diseases. However, the mechanisms underlying the effect of CO on TN-C-mediated inflammation are unknown. In the present study, we found that treatment with LPS significantly enhanced TN-C expression in macrophages. CO gas, or treatment with the CO-donor compound, CORM-2, dramatically reduced LPS-induced expression of TN-C and proinflammatory cytokines while significantly increased the expression of IL-10. Treatment with TN-C siRNA significantly suppressed the effects of LPS on proinflammatory cytokines production. TN-C siRNA did not affect the CORM-2-dependent increase of IL-10 expression. In cells transfected with IL-10 siRNA, CORM-2 had no effect on the LPS-induced expression of TN-C and its downstream cytokines. These data suggest that IL-10 mediates the inhibitory effect of CO on TN-C and the downstream production of proinflammatory cytokines. Additionally, administration of CORM-2 dramatically reduced LPS-induced TN-C and proinflammatory cytokines production while expression of IL-10 was significantly increased. In conclusion, CO regulated IL-10 expression and thus inhibited TN-C-mediated inflammationin vitroandin vivo.

Bioconversion of Carbon Monoxide to Formate Using Artificially Designed Carbon Monoxide:Formate Oxidoreductase in Hyperthermophilic Archaea

2021 ◽  
Author(s):  
Jae Kyu Lim ◽  
Ji-In Yang ◽  
Yun Jae Kim ◽  
Yeong-Jun Park ◽  
Yong Hwan Kim
Keyword(s):  
Carbon Monoxide ◽  
Electron Transfer ◽  
Fusion Protein ◽  
Direct Electron Transfer ◽  
Co2 Reduction ◽  
Hyperthermophilic Archaea ◽  
Production Activity ◽  
Formate Production

Abstract Ferredoxin-dependent metabolic engineering of electron transfer circuits has been developed to enhance redox efficiency in the field of synthetic biology, e.g., for hydrogen production and for reduction of flavoproteins or NAD(P)+. Here, we present the bioconversion of carbon monoxide (CO) gas to formate via a synthetic CO:formate oxidoreductase (CFOR), designed as an enzyme complex for direct electron transfer between noninteracting CO dehydrogenase and formate dehydrogenase using an electron-transferring Fe-S fusion protein. The CFOR-introduced Thermococcus onnurineus mutant strains showed CO-dependent formate production in vivo and in vitro. The formate production rate from purified CFOR complex and specific formate productivity from the bioreactor were 348 ± 34 μmol/mg/min and 90.2 ± 20.4 mmol/g-cells/h, respectively. The CO-dependent CO2 reduction/formate production activity of synthetic CFOR was confirmed, indicating that direct electron transfer between two unrelated dehydrogenases was feasible via mediation of the FeS-FeS fusion protein.

scholarly journals Ruthenium, Not Carbon Monoxide, Inhibits the Procoagulant Activity of Atheris, Echis, and Pseudonaja Venoms

2020 ◽  
Vol 21 (8) ◽  
pp. 2970 ◽  
Author(s):  
Vance G. Nielsen
Keyword(s):  
Carbon Monoxide ◽  
Phospholipase A2 ◽  
Procoagulant Activity ◽  
Inhibitory Effects ◽  
Snake Venoms ◽  
Radical Intermediate ◽  
Experimental Systems ◽  
Phospholipase A2 Activity

The demonstration that carbon monoxide releasing molecules (CORMs) affect experimental systems by the release of carbon monoxide, and not via the interaction of the inactivated CORM, has been an accepted paradigm for decades. However, it has recently been documented that a radical intermediate formed during carbon monoxide release from ruthenium (Ru)-based CORM (CORM-2) interacts with histidine and can inactivate bee phospholipase A2 activity. Using a thrombelastographic based paradigm to assess procoagulant activity in human plasma, this study tested the hypothesis that a Ru-based radical and not carbon monoxide was responsible for CORM-2 mediated inhibition of Atheris, Echis, and Pseudonaja species snake venoms. Assessment of the inhibitory effects of ruthenium chloride (RuCl3) on snake venom activity was also determined. CORM-2 mediated inhibition of the three venoms was found to be independent of carbon monoxide release, as the presence of histidine-rich albumin abrogated CORM-2 inhibition. Exposure to RuCl3 had little effect on Atheris venom activity, but Echis and Pseudonaja venom had procoagulant activity significantly reduced. In conclusion, a Ru-based radical and ion inhibited procoagulant snake venoms, not carbon monoxide. These data continue to add to our mechanistic understanding of how Ru-based molecules can modulate hemotoxic venoms, and these results can serve as a rationale to focus on perhaps other, complementary compounds containing Ru as antivenom agents in vitro and, ultimately, in vivo.

scholarly journals A Novel Carbon Monoxide-Releasing Molecule Fully Protects Mice from Severe Malaria

2011 ◽  
Vol 56 (3) ◽  
pp. 1281-1290 ◽  
Author(s):  
Ana C. Pena ◽  
Nuno Penacho ◽  
Liliana Mancio-Silva ◽  
Rita Neres ◽  
João D. Seixas ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Severe Malaria ◽  
Adjuvant Treatment ◽  
Malaria Infection ◽  
Severe Disease ◽  
Inhalation Therapy ◽  
Heme Oxygenase 1 ◽  
Primary Therapy ◽  
Content Type

ABSTRACTSevere forms of malaria infection, such as cerebral malaria (CM) and acute lung injury (ALI), are mainly caused by the apicomplexan parasitePlasmodium falciparum. Primary therapy with quinine or artemisinin derivatives is generally effective in controllingP. falciparumparasitemia, but mortality from CM and other forms of severe malaria remains unacceptably high. Herein, we report the design and synthesis of a novel carbon monoxide-releasing molecule (CO-RM; ALF492) that fully protects mice against experimental CM (ECM) and ALI. ALF492 enables controlled CO deliveryin vivowithout affecting oxygen transport by hemoglobin, the major limitation in CO inhalation therapy. The protective effect is CO dependent and induces the expression of heme oxygenase-1, which contributes to the observed protection. Importantly, when used in combination with the antimalarial drug artesunate, ALF492 is an effective adjunctive and adjuvant treatment for ECM, conferring protection after the onset of severe disease. This study paves the way for the potential use of CO-RMs, such as ALF492, as adjunctive/adjuvant treatment in severe forms of malaria infection.

scholarly journals A neuroglobin-based high-affinity ligand trap reverses carbon monoxide–induced mitochondrial poisoning

2020 ◽  
Vol 295 (19) ◽  
pp. 6357-6371 ◽  
Author(s):  
Jason J. Rose ◽  
Kaitlin A. Bocian ◽  
Qinzi Xu ◽  
Ling Wang ◽  
Anthony W. DeMartino ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Mitochondrial Respiration ◽  
Oxygen Delivery ◽  
Oxygen Electrode ◽  
Heart Tissue ◽  
Tissue Respiration ◽  
Co Poisoning ◽  
Affinity Ligand

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.

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