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Carbon monoxide (CO) is a colorless, odorless, and tasteless flammable gas that is slightly less dense than air. It is toxic to animals that use hemoglobin as an oxygen carrier when encountered in concentrations above about 35 ppm, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal biological functions. In the atmosphere, it is spatially variable and short-lived, having a role in the formation of ground-level ozone.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are members of a drug class that reduces pain, decreases fever, prevents blood clots, and in higher doses, decreases inflammation. Side effects depend on the specific drug but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.
Hydrogen sulfide is the chemical compound with the formula H
2S. It is a colorless chalcogen hydride gas with the characteristic foul odor of rotten eggs. It is very poisonous, corrosive, and flammable.
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Eicosanoids may also act as endocrine agents to control the function of distant cells.
Carboxyhemoglobin or carboxyhaemoglobin (symbol COHb or HbCO) is a stable complex of carbon monoxide and hemoglobin (Hb) that forms in red blood cells upon contact with carbon monoxide (CO). Carboxyhemoglobin is often mistaken for the compound formed by the combination of carbon dioxide and hemoglobin, which is actually carbaminohemoglobin. Exposure to small concentrations of CO hinder the ability of Hb to deliver oxygen to the body, because carboxyhemoglobin forms more readily than does oxyhemoglobin (HbO2). CO is produced in normal metabolism and is also a common chemical. Tobacco smoking (through carbon monoxide inhalation) raises the blood levels of COHb by a factor of several times from its normal concentrations.
A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signalling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the mu opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.
Carbonyl sulfide is the chemical compound with the linear formula OCS. Normally written as COS as a chemical formula that does not imply its structure, it is a colourless flammable gas with an unpleasant odor. It is a linear molecule consisting of a carbonyl group double bonded to a sulfur atom. Carbonyl sulfide can be considered to be intermediate between carbon dioxide and carbon disulfide, both of which are valence isoelectronic with it.
Heme oxygenase or haem oxygenase (HO) is an enzyme that catalyzes the degradation of heme. This produces biliverdin, ferrous iron, and carbon monoxide. HO was first described in the late 1960's when Raimo Tenhunen demonstrated an enzymatic reaction for heme catabolism. HO is the premier source for endogenous carbon monoxide (CO) production. Indeed, monitored small doses of CO are being studied for therapeutic benefits.
The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, Soluble epoxide hydrolase (sEH), also termed Epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them or of nearby cells. The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as heart attacks and brain strokes not only by their anti-hypertension action but possibly also by their anti-inflammatory effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.
Cyclopentenone prostaglandins are a subset of prostaglandins (PGs) or prostanoids that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated cyclopentenone structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.
Hydroxycarboxylic acid receptor 2 (HCA2), also known as niacin receptor 1 (NIACR1) and GPR109A, is a protein which in humans is encoded by the HCAR2 gene. HCA2, like the other hydroxycarboxylic acid receptors HCA1 and HCA3, is a Gi/o-coupled G protein-coupled receptor (GPCR). The primary endogenous agonists of HCA2 are D-β-hydroxybutyric acid and butyric acid (and their conjugate bases, β-hydroxybutyrate and butyrate). HCA2 is also a high-affinity biomolecular target for niacin (aka nicotinic acid).
N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50nM which makes it the putative endogenous TRPV1 agonist.
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists. PEA has been studied in in vitro and in vivo systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor, through which it exerts a variety of biological effects, some related to chronic inflammation and pain.
John L. Wallace is a medical scientist and was the founder of the Inflammation Research Network at The University of Calgary and inaugural director of the Farncombe Institute at McMaster University. In November 2013, he became the tenth recipient of the Heymans Foundation Memorial Medal. Since its inauguration in 1972, the Medal had been awarded ten times; six of the previous recipients were Nobel Laureates. Wallace is also the 2009 recipient of the Premier's Summit Award in Innovation, Canada's largest value research award aimed at supporting the work of an individual scientist.
Antibe Therapeutics is a Toronto-based pharmaceutical company that develops pain and inflammation-reducing drugs based on gaseous mediator technology. Antibe was founded by John L. Wallace, also a co-founder of NicOx, the first company to develop drugs utilizing gaseous mediators. In 2015, Antibe acquired Citagenix, a developer and distributor involved in regenerative medicine. The Company is in the final stage of its Phase 2 trials for its first drug.
Diallyl trisulfide (DATS), also known as Allitridin, is an organosulfur compound with the formula S(SCH2CH=CH2)2. It is one of several produced by the hydrolysis of allicin, including diallyl disulfide and diallyl tetrasulfide, DATS is one of the most potent.
Carbon monoxide-releasing molecules (CORMs) are chemical compounds designed to release controlled amounts of carbon monoxide (CO). CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcoming limitations of CO gas inhalation protocols.
Gaseous signaling molecules are gaseous molecules that are either synthesised internally (endogenously) in the organism, tissue or cell or are received by the organism, tissue or cell from outside and that are used to transmit chemical signals which induce certain physiological or biochemical changes in the organism, tissue or cell. The term is applied to, for example, oxygen, carbon dioxide, nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide, nitrous oxide, hydrogen cyanide, ammonia, methane, hydrogen, ethylene, etc.
Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.
References
- ↑ Leffler, C. W.; Parfenova, H; Jaggar, J. H.; Wang, R (March 2006). "Carbon monoxide and hydrogen sulfide: gaseous messengers in cerebrovascular circulation". J. Appl. Physiol. 100 (3): 1065–76. doi:10.1152/japplphysiol.00793.2005. PMC 1363746 . PMID 16467393.
- ↑ Rodrigues, L.; Ekundi-Valentim, E.; Florenzano, J.; Cerqueira, A. R. A.; Soares, A. G.; Schmidt, T. P.; Santos, K. T.; Teixeira, S. A.; Ribela, M. T. C. P.; Rodrigues, S. F.; de Carvalho, M. H. (2017-01-01). "Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice". Pharmacological Research. 115: 255–266. doi:10.1016/j.phrs.2016.11.006. hdl: 10871/24576 . ISSN 1043-6618.
- ↑ Sulaieva, Oksana; Wallace, John L (2015-12-01). "Gaseous mediator-based anti-inflammatory drugs". Current Opinion in Pharmacology. Gastrointestinal • Endocrine and metabolic diseases. 25: 1–6. doi:10.1016/j.coph.2015.08.005. ISSN 1471-4892.
- ↑ Sulaieva, O. N.; Wallace, J. L. (2016). "New strategy for gastrointestinal protection based on gaseous mediators application". Russian Journal of Gastroenterology, Hepatology, Coloproctology. Retrieved 2020-04-27.
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