Corm Research Articles

Cell viability and collagen metabolism of MCF-7 breast cancer cells are affected by carbon monoxide released from CORM-2.

Carbon monoxide (CO), despite its reputation as a deadly poison, is being recognized as a powerful physiological regulatory agent with potential anti-cancer properties. To harness the potential of CO towards a safe therapy, CO-Releasing Molecules (CO-RMs) have been developed. In the present study, the effects of tricarbonyldichlororuthenium(II) dimer (CORM-2) on MCF-7 breast cancer cell cultures were evaluated, with particular regard to mechanisms affecting collagen biosynthesis. In our model, CORM-2 exerted dose-dependent cytotoxic and antiproliferative effects, i.e., attenuated cell viability, induced apoptosis and reduced autophagy. Collagen biosynthesis was significantly reduced, with signs of the involvement of nuclear factor kappa B, integrin β1, insulin-like growth factor 1 and proline metabolism as the probable underlying mechanism. No effects of CO-depleted CORM-2 were found, thereby demonstrating that CORM-2 activity is associated with carbon monoxide. Additionally, it was found that CORM-2 had no influence on control fibroblasts cultures. Our results confirm both the cytotoxic and collagen-related properties of CO-releasing molecule in a breast cancer cell culture, and therefore serve to encourage further research in a pre-clinical setting. To the best of our knowledge, this study is the first to attempt to relate the effects of CORM-2 on cell viability and collagen metabolism in a cancer cell culture.

Quest of new molecular frameworks for photoinduced carbon monoxide-releasing molecules: a computational prospective

Quest of new molecular frameworks for photoinduced carbon monoxide-releasing molecules: a computational prospective

Partially Reduced MIL-100(Fe) as a CO Carrier for Sustained CO Release and Regulation of Macrophage Phenotypic Polarization.

Carbon monoxide (CO) is a bioactive molecule with high potential as it shows promising efficacy for regulating inflammation. Materials capable of storing and delivering CO are of great potential therapeutic value. Although CO-releasing molecules (CORMs) have been developed to deliver CO, the short CO duration of minutes to 2 h confines their practical use. In this study, partially reduced MIL-100(Fe) as a new CO-releasing nanoMOF was developed and used for sustained CO release and macrophage (MA) phenotypic polarization regulation. MIL-100(Fe) was synthesized and mildly annealed in vacuum for partial reduction. When the annealing temperature was lower than 250 °C, less Fe(II) present in MIL-100(Fe) and the subsequent CO adsorption and desorption profiles displayed typical features of physisorption. While it was annealed at 250 °C, it showed about 20% of Fe(III) was reduced, which resulted in chemisorption of CO due to the high coordination affinity of Fe(II) to CO. The loading amount of CO was increased, and the CO release was prolonged for about 24 h. Furthermore, the CO release from this nanoMOF could alter the lipopolysaccharide (LPS)-induced macrophage from M1 to the alternative M2 phenotype and promoted the growth of endothelial cells (ECs) by paracrine regulation of MA. It can be envisioned as a promising CO-releasing solid for biomedical application.

Enhanced thermal and photo-stability of a para-substituted dicumyl ketone intercalated in a layered double hydroxide.

A ketodiacid, 4,4′-dicarboxylate-dicumyl ketone (3), has been intercalated into a Zn, Al layered double hydroxide (LDH) by a coprecipitation synthesis strategy. The structure and chemical composition of the resultant hybrid material (LDH-KDA3) were characterized by powder X-ray diffraction (PXRD), FT-IR, FT-Raman and solid-state 13C{1H} NMR spectroscopies, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), and elemental analysis (CHN). PXRD showed that the dicarboxylate guest molecules assembled into a monolayer to give a basal spacing of 18.0 Å. TGA revealed that the organic guest starts to decompose at a significantly higher temperature (ca. 330°C) than that determined for the free ketodiacid (ca. 230°C). Photochemical experiments were performed to probe the photoreactivity of the ketoacid in the crystalline state, in solution, and as a guest embedded within the photochemically-inert LDH host. Irradiation of the bulk crystalline ketoacid results in photodecarbonylation and the exclusive formation of the radical-radical combination product. Solution studies employing the standard myoglobin (Mb) assay for quantification of released CO showed that the ketoacid behaved as a photoactivatable CO-releasing molecule for transfer of CO to heme proteins, although the photoreactivity was low. No photoinduced release of CO was found for the LDH system, indicating that molecular confinement enhanced the photo-stability of the hexasubstituted ketone. To better understand the behavior of 3 under irradiation, a more comprehensive study, involving excitation of this compound in DMSO-d6 followed by 1H NMR, UV-Vis and fluorescence spectroscopy, was undertaken and further rationalized with the help of time-dependent density functional theory (TDDFT) electronic quantum calculations. The photophysical study showed the formation of a less emissive compound (or compounds). New signals in the 1H NMR spectra were attributed to photoproducts obtained via Norrish type I α-cleavage decarbonylation and Norrish type II (followed by CH3 migration) pathways. TDDFT calculations predicted that the formation of a keto-enol system (via a CH3 migration step in the type II pathway) was highly favorable and consistent with the observed spectral data.

Controlled therapeutic delivery of CO from carbon monoxide-releasing molecules (CORMs).

Carbon monoxide (CO) has been regarded as a "silent killer" for its toxicity toward biological systems. However, a low concentration of endogenously produced CO has shown a number of therapeutic benefits such as anti-inflammatory, anti-proliferative, anti-apoptosis, and cytoprotective activities. Carbon monoxide-releasing molecules (CORMs) have been developed as alternatives to direct CO inhalation, which requires a specialized setting for strict dose control. CORMs are efficient CO donors, with central transition metals (such as ruthenium, iron, cobalt, and manganese) surrounded by CO as a ligand. CORMs can stably store and subsequently release their CO payload in the presence of certain triggers including solvent, light, temperature, and ligand substitution. However, CORMs require appropriate delivery strategies to improve short CO release half-life and target specificity. Herein, we highlighted the therapeutic potential of inhalation and CORMs-delivered CO. The applications of conjugate and nanocarrier systems for controlling CO release and improving therapeutic efficacy of CORMs are also described in detail. The review concludes with some of the hurdles that limit clinical translation of CORMs. Keeping in mind the tremendous potential and growing interest in CORMs, this review would be helpful for designing controlled CO release systems for clinical applications.

Carbon Monoxide-Releasing Molecule-3 Suppresses the Malignant Biological Behavior of Tongue Squamous Cell Carcinoma via Regulating Keap1/Nrf2/HO-1 Signaling Pathway.

Carbon monoxide-releasing molecule-3 (CORM-3) is a water-soluble complex which has the ability to release carbon monoxide (CO). The study is aimed at investigating the epidemiological characters and effects of CORM-3 on tongue squamous cell carcinoma (TSCC) cells and the mechanisms involved. Firstly, CAL27 and SCC4 were treated with CORM-3 or iCORM-3. The proliferation, migration, and invasion of cells were separately evaluated by CCK-8, scratch assay, and transwell assay. We found that the optimal concentration of CORM-3 on the proliferation of CAL27 and SCC4 cells was 400 μM, and CORM-3 was significantly inhibited the proliferation, migration, and invasion of TSCC cells. Meanwhile, CORM-3 increased the protein expression of HO-1 detected by western blot. Short-hairpin RNAs (shRNAs) were constructed to manipulate the expression of HO-1 in CAL27 and SCC4 cells. Then, rescue assays were conducted to explore the reversion effect of shHO-1 on the CORM-3 function. Mechanistically, CORM-3 decreased the protein of Keap1 expression as well as increased Nrf2 expression. Upregulation of E-cadherin was observed, as well as the downregulation of N-cadherin expression significantly. The antitumor effect of CORM-3 was used to xenograft tumor in nude mice for further investigation in vivo, and the result showed that CORM-3 significantly suppressed tumor growth in xenograft nude mice. These data suggest that CORM-3 acts as a tumor suppressor by regulating the Keap1/Nrf2/HO-1 signaling pathway in TSCC, which provides a potential chemotherapeutic strategy for TSCC.

Multicomponent Self-Assembly of Diaminobenzoquinonato-Bridged Manganese(I) Metallosupramolecular Rectangles: Host-Guest Interactions, Anticancer Activity, and Visible-Light-Induced CO Releasing Studies.

The one-pot self-assembly of Mn2(CO)10, a bis-chelated diaminobenzoquinonato (ON∩ON) bridge (L), and a linear ditopic linker (N∩N) (L') has resulted into the formation of M4L2L2'-type manganese(I)-based tetranuclear metallorectangles of the general formula [{(CO)3Mn(μ-η4-L)Mn(CO)3}2(μ-(N-N)2)] (1-8), wherein L is 2,5-bis(n-butylamine)-1,4-benzoquinone (bbbq) and/or 2,5-bis(phenethylamino)-1,4-benzoquinone (bpbq) and N-N is 4,4'-bipyridine (bpy), trans-1,2-bis(4-pyridyl) ethylene (bpe), phenyl-1,4-bis(isonicotinate) (pbin), and N,N'-bis(4-pyridylformamide)-1,4-benzene (bpfb). Metallorectangles 1-8 were characterized by infrared, ultraviolet-visible (UV-vis) absorption, and 1H nuclear magnetic resonance spectroscopies, elemental analysis, and electrospray ionization-mass spectrometry. The molecular and crystal structures of 1•n(CHCl3) and coronene⊂3•coronene were determined by the single-crystal X-ray diffraction method. Host-guest binding abilities of 1, 3, and 7 with coronene, pyrene, and 4,4'-dihydroxybiphenyl were investigated using UV-vis absorption and emission spectroscopic techniques. Formation of host-guest complexes was further confirmed by the single-crystal X-ray structural analysis. Absorption of spectra of these metallorectangles showed high-intensity metal-ligand charge transfer as a broad band in the visible region. In vitro cytotoxicity assays were performed on 1, 3, 5, and 7 against lung, colon, and cervical cancer cells as well as normal cells. Compounds 5 and 7 were identified as visible-light-induced CO-releasing molecules from the myoglobin assay.

Carbon monoxide-releasing molecule-401, a water-soluble manganese-based metal carbonyl, suppresses Prevotella intermedia lipopolysaccharide-induced production of nitric oxide in murine macrophages

Context Many reports in the literature have suggested the therapeutic value of carbon monoxide-releasing molecules (CORMs) against various diseases. However, to date, little is known about their possible influence on periodontal disease. Objective This study was performed to investigate the influence of CORM-401 on the generation of nitric oxide (NO) in murine macrophage cells activated with lipopolysaccharide (LPS) derived from Prevotella intermedia, a pathogen associated with periodontal disease. Materials and methods LPS was isolated by the hot phenol-water method. Culture supernatants were analyzed for NO. Real-time PCR and immunoblotting were conducted to quantify mRNA and protein expression, respectively. NF-κB-dependent SEAP levels were estimated by reporter assay. DNA-binding of NF-κB was also analyzed. Results CORM-401 caused an apparent suppression of NO production through inhibition of iNOS at both the mRNA and protein levels in RAW264.7 cells stimulated with P. intermedia LPS. CORM-401 upregulated the expression of both the HO-1 gene and its protein in LPS-activated cells, and treatment with the HO-1 inhibitor significantly reversed the attenuating influence of CORM-401 against LPS-induced generation of NO. CORM-401 caused an apparent attenuation of NF-κB-dependent SEAP release induced by LPS. IκB-α degradation and nuclear translocation of NF-κB p50 subunit induced by LPS were significantly reduced by CORM-401. Additionally, CORM-401 significantly attenuated DNA-binding of p65 and p50 induced by LPS. CORM-401 attenuated NO generation induced by P. intermedia LPS independently of PPAR-γ, JNK, p38 and STAT1/3. Conclusion The modulation of host inflammatory response by CORM-401 might be of help in the therapy of periodontal disease.

Activation of Carbon Dioxide by 9-Carbene-9-borafluorene Monoanion: Carbon Monoxide Releasing Transformation of Trioxaborinanone to Luminescent Dioxaborinanone.

The first structurally characterized example of a trioxaborinanone (2) is produced by the reaction of a 9-carbene-9-borafluorene monoanion and carbon dioxide. When compound 2 is heated or irradiated with UV light, carbon monoxide (CO) is released, and a luminescent dioxaborinanone (3) is formed. Notably, carbon monoxide releasing molecules (CORMs) are of interest for their ability to deliver a specific amount of CO. Due to the turn-on fluorescence observed as a result of the conversion to 3, CORM 2 serves as a means to optically observe CO loss "by eye" under thermal or photochemical conditions.

CORM-3 Attenuates Oxidative Stress-Induced Bone Loss via the Nrf2/HO-1 Pathway.

Bone metabolism occurs in the entire life of an individual and is required for maintaining skeletal homeostasis. The imbalance between osteogenesis and osteoclastogenesis eventually leads to osteoporosis. Oxidative stress is considered a major cause of bone homeostasis disorder, and relieving excessive oxidative stress in bone mesenchymal stem cells (BMSCs) is a potential treatment strategy for osteoporosis. Carbon monoxide releasing molecule-3 (CORM-3), the classical donor of carbon monoxide (CO), possesses antioxidation, antiapoptosis, and anti-inflammatory properties. In our study, we found that CORM-3 could reduce reactive oxygen species (ROS) accumulation and prevent mitochondrial dysfunction thereby restoring the osteogenic potential of the BMSCs disrupted by hydrogen peroxide (H2O2) exposure. The action of CORM-3 was preliminarily considered the consequence of Nrf2/HO-1 axis activation. In addition, CORM-3 inhibited osteoclast formation in mouse primary bone marrow monocytes (BMMs) by inhibiting H2O2-induced polarization of M1 macrophages and endowing macrophages with M2 polarizating ability. Rat models further demonstrated that CORM-3 treatment could restore bone mass and enhance the expression of Nrf2 and osteogenic markers in the distal femurs. In summary, CORM-3 is a potential therapeutic agent for the treatment of osteoporosis.

Effects of treatment with a carbon monoxide donor and an activator of heme oxygenase 1 on the nociceptive, apoptotic and/or oxidative alterations induced by persistent inflammatory pain in the central nervous system of mice

The activation of heme oxygenase 1 (HO-1)/carbon monoxide (CO) inhibits chronic inflammatory pain, but its role in the central nervous system (CNS) is not entirely known. We evaluated whether the treatment with an HO-1 inducer, cobalt protoporphyrin IX (CoPP), or a CO-releasing molecule, tricarbonyldichlororuthenium(II)dimer (CORM-2), modulates the nociceptive, apoptotic and/or oxidative responses provoked by persistent inflammatory pain in the CNS. In C57BL/6 male mice with peripheral inflammation caused by complete Freund’s adjuvant (CFA), we assessed the effects of CORM-2 and CoPP on the expression of protein kinase B (Akt), the apoptotic protein BAX, and the antioxidant enzymes HO-1 and NADPH quinone oxidoreductase 1 (NQO1) in the periaqueductal gray matter (PAG), amygdala (AMG), ventral hippocampus (VHPC) and medial septal area (MSA). Our results showed that the increased expression of p-Akt caused by peripheral inflammation in the four analyzed brain areas was reversed by CORM-2 and CoPP therapies. Both treatments also normalized the upregulation of BAX induced by CFA on the VHPC and MSA. Oxidative stress, demonstrated with the decreased expression of HO-1 on the PAG and AMG, was normalized in CORM-2 and CoPP treated animals. CoPP also increased the expression of HO-1 on VHPC, and both treatments up-regulated the NQO1 levels on the PAG of CFA-injected animals. In conclusion, both CORM-2 and CoPP treatments inhibited the nociceptive and apoptotic responses generated by peripheral inflammation and/or potentiated the antioxidant responses in several brain areas revealing the new modulatory effects of these treatments in the CNS of animals with chronic inflammatory pain.

Strategy for Detecting Carbon Monoxide: Cu2+-Assisted Fluorescent Probe and Its Applications in Biological Imaging.

Herein, a novel strategy was proposed for identifying carbon monoxide (CO), which plays a crucial part in living systems. For the first time, we have managed to design, synthesize, and characterize successfully this new Cu2+-assisted fluorescent probe (DPHP) in detecting CO. Compared with the commonly adopted Pd0-mediated Tsuji-Trost reaction recognition method, such a new strategy did not engage costly palladium (II) salt and generated no leaving group, indicating a satisfactory anti-interference ability. The recognition mechanism was confirmed by IR, 1H NMR titration, HR-MS, cyclic voltammetry, X-ray photoelectron spectroscopy, electron paramagnetic resonance, and optical properties. Surprisingly, it was found that the new method achieved high selectivity and rapid identification of CO with a lower limit of detection (1.7 × 10-8 M). More intriguingly, it could recognize endogenous and exogenous CO in HeLa cells. The cytotoxicity of this new method was so low that it allowed the detection of CO in mice and zebrafish. Basically, our results trigger a novel viewpoint of rationally designing and synthesizing advanced materials for CO detection with unique features, impelling new research in detection chemistry.

A Red-Light-Driven CO-Releasing Complex: Photoreactivities and Excited-State Dynamics of Highly Distorted Tricarbonyl Rhenium Phthalocyanines.

A complex comprising one [Re(CO)3 ]+ unit and a phthalocyanine (Pc) ligand (Re1 Pc) is shown to function as a photo-induced CO-releasing molecule (photoCORM) in the presence of O2 and a coordinative solvent under irradiation with red light, which can deeply penetrate living tissues. Transient absorption spectroscopic measurements indicate very short excited-state lifetimes and ultrafast intersystem crossing for Re1 Pc and Re2 Pc, which contains two [Re(CO)3 ]+ units. The excited-state properties are ascribed to efficient spin-orbit coupling and large Franck-Condon factors originating from the complexes' distorted structures, that is, unsymmetric coordination of [Re(CO)3 ]+ unit(s), one of which was confirmed by single-crystal X-ray analysis of a symmetrically substituted Pc with two [Re(CO)3 ]+ units. Re1 Pc represents a promising red-light-driven photoCORM that can be applied in biological environments or therapeutic applications.

Synthesis and Biological Evaluation of Water‐Soluble Esterase‐Activated CO‐Releasing Molecules Targeting Mitochondria

Due to the beneficial effects of carbon monoxide as a cell‐protective and anti‐inflammatory agent, CO‐releasing molecules (CORMs) offer some promising potential applications in medicine. In this context, we synthesized a set of acyloxy‐cyclohexadiene‐Fe(CO)3 complexes, all displaying a N‐methyl‐pyridinium triflate moiety in the ester side chain, as mitochondria‐targeting esterase‐triggered CORM prodrugs. Whereas the compounds in which the acyloxy substituent is attached to the 2‐position of the diene‐Fe(CO)3 unit (A series) spontaneously release CO upon dissolution in phosphate buffer, which remarkably is partly suppressed in the presence of porcine liver esterase (PLE), the 1‐substituted isomers (B series) show the expected PLE‐induced release of CO (up to 3 equiv.). The biological activity of Mito‐CORMs 2/3‐B and their isophorone‐derived analogs 2/3‐A’, which also displayed PLE‐induced CO release, was assessed by using human umbilical vein endothelial cells (HUVEC). Whereas Mito‐CORMs 2/3‐B were not cytotoxic up to 500 μM (MTT assay), Mito‐CORMs 2/3‐A’ caused significant toxicity at concentrations above 50 μM. The anti‐inflammatory potential of both Mito‐CORM variants was demonstrated by concentration‐dependent down‐regulation of the pro‐inflammatory markers VCAM‐1, ICAM‐1 and CXCL1 as well as induction of HO‐1 in TNFα‐stimulated human umbilical vein endothelial cells (HUVECs; western blotting and qPCR). Energy phenotyping by seahorse real‐time cell metabolic analysis, revealed opposing shifts of metabolic potentials in cells treated either with Mito‐CORMs 2/3‐B (increased mitochondrial respiration and glycolytic activity) or Mito‐CORMs 2/3‐A’ (suppressed mitochondrial respiration and increased glycolytic activity). Thus, the Mito‐CORMs represent valuable tools for the safe and targeted delivery of CO to mitochondria as a subcellular compartment to induce positive anti‐inflammatory effects with only minor shifts in cellular energy metabolism. Also, due to their water solubility, these compounds provide a promising starting point for further pharmacological studies.

CORM-3 induces DNA damage through Ru(II) binding to DNA.

When the ‘CO-releasing molecule-3’, CORM-3 (Ru(CO)3Cl(glycinate)), is dissolved in water it forms a range of ruthenium complexes. These are taken up by cells and bind to intracellular ligands, notably thiols such as cysteine and glutathione, where the Ru(II) reaches high intracellular concentrations. Here, we show that the Ru(II) ion also binds to DNA, at exposed guanosine N7 positions. It therefore has a similar cellular target to the anticancer drug cisplatin, but not identical, because Ru(II) shows no evidence of forming intramolecular crossbridges in the DNA. The reaction is slow, and with excess Ru, intermolecular DNA crossbridges are formed. The addition of CORM-3 to human colorectal cancer cells leads to strand breaks in the DNA, as assessed by the alkaline comet assay. DNA damage is inhibited by growth media containing amino acids, which bind to extracellular Ru and prevent its entry into cells. We conclude that the cytotoxicity of Ru(II) is different from that of platinum, making it a promising development target for cancer therapeutics.

Carbon Monoxide-Releasing Molecule-3 Enhances Osteogenic Differentiation of Rat Bone Marrow Mesenchymal Stem Cells via miR-195-5p/Wnt3a Pathway.

PurposeBone marrow-derived mesenchymal stem cells (BMSCs) are hopeful in promoting bone regeneration as their pluripotency in differentiation. Our previous study showed that carbon monoxide-releasing molecule-3 (CORM-3) increased the osteogenic differentiation of rat BMSCs in vitro. However, the mechanism remained unclear. MicroRNAs (miRNAs) play a very important role in modulating the osteogenic differentiation of BMSCs. Therefore, we researched the miRNAs involved in CORM-3-stimulated osteogenic differentiation.MethodsThe CORM-3-stimulated osteogenic differentiation of rat BMSCs was further studied in vivo. Based on the gene sequencing experiment, the rat BMSCs were transfected with miR-195-5p mimics and inhibitor, pcDNA3.1-Wnt3a and Wnt3a siRNA. The osteogenic differentiation of rat BMSCs was measured by quantitative real-time polymerase chain reaction, Western blot and alizarin red staining. Additionally, the targeting relationship between miR-195-5p and Wnt3a was confirmed by the dual-luciferase assay.ResultsMiR-195-5p was down-expressed during the CORM-3-stimulated osteogenic differentiation of rat BMSCs. CORM-3-stimulated osteogenic differentiation of rat BMSCs was inhibited with miR-195-5p overexpression, evidenced by significantly reduced mRNA and protein expressions of runt-related transcription factor 2 and osteopontin, and matrix mineralization demonstrated. On the contrary, the osteogenic differentiation was enhanced with inhibition of miR-195-5p. CORM-3-stimulated osteogenic differentiation of rat BMSCs was increased by overexpression of Wnt3a, while the opposite was observed in the Wnt3a-deficient cells. Moreover, the decreased osteogenic differentiation capacity by increased expression of miR-195-5p was rescued by Wnt3a overexpression, showing miR-195-5p directly targeted Wnt3a.ConclusionThese results demonstrate that CORM-3 promoted osteogenic differentiation of rat BMSCs via miR-195-5p/Wnt3a, which bodes well for the application of CORM-3 in the treatment of periodontal disease and other bone-defect diseases.

Rational design of dual ratiometric photoacoustic and fluorescent probe for reliable imaging and quantitative detection of endogenous CO during drug-induced liver injury and repair

Carbon monoxide (CO) is an essential gaseous signaling molecule and strongly associated with many physiological and pathological processes. The study of CO chemistry in biology remains challenging, primarily due to limitations in available tools for quantitative detection of the CO fluctuations in vivo. Photoacoustic/fluorescent (PA/FL) dual-mode imaging is a vital tool for in vivo study which has complementary advantages from two modalities. To our knowledge, there are currently no PA/FL dual ratiometric probes to visualize CO in live animals. In this work, we reported the first dual ratiometric PA/FL probe DOP-CO for reliable imaging and quantitative detection of CO based on a novel “Atom Surgery” strategy. As expected, probe DOP-CO was successfully applied to ratiometric imaging of exogenous and endogenous CO release behavior in HepG2 cells. Notably, tail vein injection of DOP-CO resulted in liver-enrichment of mice and the endogenous CO fluctuations in the liver triggered by liver injury and liver repair, respectively, was confirmed by PA/FL dual-modality ratiometric imaging. More importantly, the dual ratiometric probe prepared in this study not only contributes to gain insight into the relationship between CO fluctuations and liver injury, but also provides a promising tool to investigate more CO-mediated biological processes.

ThioCORMates: Tunable and Cost-Effective Carbon Monoxide-Releasing Molecules.

Carbon monoxide-releasing molecules (CORMs) can offer a safer alternative to CO delivery than the use of CO gas cylinders. Upon treatment with an amine base, S-aryl thioformates ("thioCORMates") release CO nearly quantitatively at room temperature, a gas which can then be harnessed for carbonylative cross-coupling, biological study, or inorganic synthesis. These bench-stable molecules are easily synthesized from the corresponding thiophenol and can be electronically tuned to release CO at different rates-from less than 1 min to greater than 1 h-offering a practical alternative to existing CORM technology. Finally, isotopically labeled 13 CO can be conveniently generated and used, with the thioCORMate synthesized from 13 C-formic acid.

Continuous Endogenous Exhaled CO Monitoring by Laser Spectrometer in Human EVLP Before Lung Transplantation.

Endogenous production of carbon monoxide (CO) is affected by inflammatory phenomena and ischemia-reperfusion injury. Precise measurement of exhaled endogenous CO (eCO) is possible thanks to a laser spectrometer (ProCeas® from AP2E company). We assessed eCO levels of human lung grafts during the normothermic Ex-Vivo Lung Perfusion (EVLP). ProCeas® was connected in bypass to the ventilation circuit. The surgical team took the decision to transplant the lungs without knowing eCO values. We compared eCO between accepted and rejected grafts. EVLP parameters and recipient outcomes were also compared with eCO values. Over 7 months, eCO was analyzed in 21 consecutive EVLP grafts. Two pairs of lungs were rejected by the surgical team. In these two cases, there was a tendency for higher eCO values (0.358 ± 0.52 ppm) compared to transplanted lungs (0.240 ± 0.76 ppm). During the EVLP procedure, eCO was correlated with glucose consumption and lactate production. However, there was no association of eCO neither with edema formation nor with the PO2/FiO2 ratio per EVLP. Regarding post-operative data, every patient transplanted with grafts exhaling high eCO levels (>0.235 ppm) during EVLP presented a Primary Graft Dysfunction score of 3 within the 72 h post-transplantation. There was also a tendency for a longer stay in ICU for recipients with grafts exhaling high eCO levels during EVLP. eCO can be continuously monitored during EVLP. It could serve as an additional and early marker in the evaluation of the lung grafts providing relevant information for post-operative resuscitation care.

Biological and Pharmacological Properties of Carbon Monoxide: A General Overview

Carbon monoxide (CO) is one of the most common causes of inhalation poisoning worldwide. However, it is also well known that CO is produced endogenously in the heme degradation reaction catalyzed by heme oxygenase (HO) enzymes. HO catalyzes the degradation of heme to equimolar quantities of CO, iron ions (Fe2+), and biliverdin. Three oxygen molecules (O2) and the electrons provided by NADPH-dependent cytochrome P450 reductase are used in the reaction. HO enzymes comprise three distinct isozymes: the inducible form, heme oxygenase-1 (HO-1); the constitutively expressed isozyme, heme oxygenase-2 (HO-2); and heme oxygenase-3 (HO-3), which is ubiquitously expressed but possesses low catalytic activity. According to some authors, HO-3 is rather a pseudogene originating from the HO-2 transcript, and it has only been identified in rats. Therefore, cellular HO activity is provided by two major isoforms—the inducible HO-1 and the constitutively expressed HO-2. For many years, endogenously generated CO was treated as a by-product of metabolism without any serious physiological or biochemical significance, while exogenous CO was considered only as an extremely toxic gas with lethal effects. Research in recent years has proven that endogenous and exogenous CO (which may be surprising, given public perceptions) acts not only as an agent that affects many intracellular pathways, but also as a therapeutic molecule. Hence, the modulation of the HO/CO system may be one option for a potential therapeutic strategy. Another option is the administration of CO by exogenous inhalation. As alternatives to gas administration, compounds known as CO-releasing molecules (CORMs) can be administered, since they can safely release CO in the body. The aim of this article is to provide a brief overview of the physiological and biochemical properties of CO and its therapeutic potential.