The Story of Eicosanoid Inhibitionreturn to itm online. REDUCING INFLAMMATION WITH DIET AND SUPPLEMENTS: The Story of Eicosanoid Inhibitiongeneral review by Subhuti Dharmananda, Ph. D., Director, Institute for Traditional Medicine, Portland, Oregon. Several important diseases are mediated by production of molecules known as eicosanoids, so named because they are derivatives of the 2. These diseases include heart attack, asthma, arthritis, ulcerative colitis, asthma, dysmenorrhea, and recurrent headaches. Although there are some caveats to this statement, the general view is that inhibiting COX- 2 reduces inflammation, while inhibiting COX- 1, which can also inhibit inflammation, produces many of the undesired side effects of the drugs (by blocking production of desirable prostaglandins, thus causing gastric damage and, with prolonged use of high doses, renal toxicity). Most recently, much interest has focused on LOX (lipoxygenase) inhibitors that mainly block leukotriene synthesis. ![]() There are three main LOX enzymes that are known to be involved in the leukotriene pathway, 5- LOX, 1. LOX, and 1. 5- LOX. Figure 4: Steps in the biosynthesis of eicosanoids where different drugs have their effects (the usual NSAIDs are COX inhibitors; LOX inhibitors are NSIADS of a new type). TABLE 1. Properties of Significant Eicosanoids. LTs also promote bronchoconstriction and vasoconstriction; they decrease myocardial contractility and coronary blood flow. DIET, EICOSANOIDS, AND INFLAMMATIONEven if drug therapy successfully blocks the COX and LOX enzyme systems, arachidonic acid can still be converted into other damaging molecules, such as epoxy derivatives. ![]() ![]() Right: enzyme action on dietary oils: production of arachidonic acid from omega- 6 fatty acids; omega- 3 fatty acids yield, instead, eicosapentaenoic acid (EPA), which is further metabolized to form docosahexaenoic acid (DHA). Fatty Acids of Food Oils in Descending Rank by Short Chain Omega- 3/Omega- 6 Ratio. The oils have been subdivided by categories, but the list order for all oils is by omega- 3/omega- 6 rank, not just by category. ![]() Examples of Fish with High Levels of Fats and Omega- 3 Fatty Acids. Sample Plant Constituents with Cox- 2 Inhibitor Activity. The substances listed here have been subjected to in vitro testing with effective concentrations determined. Sample Plant Constituents with Lox- Inhibitor Activity. Constituent. Sample Plant Source. Inhibitor Activity Measure. Allicin. garlic (dasuan). D = 2. 5 ug/ml. Berbamine. IC5. 0 = 4. 0 u. MBerberine. IC5. 0 = 1. 18 u. MBoswellic acid. frankincense (ruxiang). IC5. 0 = 1. 5 u. MCaffeic acid. Discover the health benefits of conjugated linoleic acid also known as CLA. Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) play a critical role in normal skin function and appearance. IC5. 0 = 6. 2- 1. MEpicatechin. IC5. MEpicatechin- gallate. Eicosanoid Targeted receptors Functions regulated Clinical relevancy; PGE2: PTGER1, PTGER2, PTGER3, PTGER4: inflammation; fever; pain perception; allodynia; Partuition. Colitis refers to inflammation of the inner lining of the colon. Symptoms of the inflammation of the colon lining include diarrhea, pain, and blood in the stool. This article examines the potent extract of green tea, & its medical applications. Ronald Hoffman's informative article to improve you health now! Background Statins lower the levels of low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP). Whether this latter property affects clinical outcomes. IC5. 0 = 1. 8 u. MEpigallocatechin. IC5. 0 = 2. 1 u. MFisetin. IC5. 0 = 1. 1 u. MFlavone. IC5. 0 = 3. 2 u. MGalangin. IC5. 0 = 2. 0 u. MMorin. IC5. 0 = 1. 60 u. MQuercetin. IC5. 0 = 0. MTheaflavin digallate. IC5. 0 = 0. 2. 5 u. MUrsolic acid. ligustrum (nuzhenzi). IC5. 0 = 1. 80 u. MSUMMARY AND SUGGESTIONSThere is no doubt that inhibiting eicosanoid synthesis by modern drugs therapies is effective for many people in reducing the inflammation and the accompanying pain of many diseases, particularly arthritis. Particularly promising are branched chain fatty acids, mainly 1. MTA and 1. 3- MTA (methyltetradecanoic acid); these are potent inhibitors of the 5- LOX enzyme. There is growing evidence that dietary factors can influence diseases, particularly in terms of lowering risk over an extended period of time. Pentacyclic Triterpenes (PCTs) as Inhibitors of Inflammation. Pentacyclic triterpenes (PCTs) are a subdivision of an important group of botanical active constituents known as triterpenoids; when complexed with sugar molecules PCTs are called triterpene glycosides, or saponins. Isolated oleanolic acid has already been used in China as a treatment for hepatitis for many years. Ursolic acid was named after the herb Uva Ursi (bearberry; urs is the root term for bear). Ursolic acid is one of the main waxy components on apples that contributes to the smooth, shiny appearance (not to be confused with waxes sometimes added to aid storage of fruits). Acharan Narula describes use of 3. Olenoate, a product of oleanolic acid in capsules of 1. Macrophage Polarization in Inflammatory Diseases Int J Biol Sci. Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 3. P. R. China; 2. Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 1. P. R. China; 3. State Key Laboratory of Kidney Disease, the Chinese PLA General Hospital, Beijing 1. P. R. China.* contributed equally to the study. How. to cite this article. Liu YC, Zou XB, Chai YF, Yao YM. Macrophage Polarization in Inflammatory Diseases. Int J Biol Sci 2. Available from. http: //www. Abstract. Diversity and plasticity are two hallmarks of macrophages. M1 macrophages (classically activated macrophages) are pro- inflammatory and have a central role in host defense against infection, while M2 macrophages (alternatively activated macrophages) are associated with responses to anti- inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. Here we reviewed the characters and functions of macrophage polarization in infection, atherosclerosis, obesity, tumor, asthma, and sepsis, and proposed that targeting macrophage polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of inflammatory diseases. Keywords: macrophage polarization, alternatively activated macrophage, signal pathways, inflammatory diseases, immune regulation. Introduction. Macrophages were first identified by Elie Metchnikoff as phagocytic cells which helped to eliminate pathogens in both invertebrates and vertebrates. In 1. 90. 5, his research findings suggested that macrophages from infected animals had elevated ability of killing bacteria, thereby proposing the basis of the concept of macrophage activation . After six decades of efforts, the mechanisms with regard to killing bacteria of macrophages were gradually elucidated, but there were still no definite answers about how macrophages became more efficient bacterial killers. In 1. 97. 3, North and his colleagues found that independent cellular factors could also promote resistance of infection without involvement of pathogens . Almost at the same time, David indicated that lymphocytes were the major antigen- specific cells responsible for microbicidal activation of macrophages . Soon after that, interferon (IFN)- . It transforms resting macrophages into active ones which have stronger antigen presenting capacity and complement mediated phagocytosis, and secrete more pro- inflammatory cytokines as well as toxic mediators. As the first type of antimicrobial macrophage activation was recognized, it became known as classically activated macrophages (CAM, also known as M1). In 1. 98. 9, when the heterogeneity in the helper T- cell compartment was subsequently reported, Mosrnann and Coffman reviewed the different functions and lymphokines secretion between two types of cloned helper T cells (Th), and proposed the concept of Th. Th. 2 . One year later, Abramson and his colleagues recognized that interleukin (IL)- 4, which was mainly produced by Th. IFN- . With the discovery of up- regulation of macrophage mannose receptor (MRC1) as a specific marker of IL- 4/IL- 1. MHC- II, the concept of alternatively activated macrophages (AAM, also known as M2) was first proposed . In the following years, when the plasticity of macrophages in response to different environment was gradually studied, Mosser and Edwards reviewed the full spectrum of macrophage activation and pointed out that M1 and M2 were two terminals of the spectrum . In addition to IL- 4/IL- 1. LPS) or IL- 1, transforming growth factor- . As they shared properties with IL- 4/IL- 1. M2- like phenotype . M1 and M2 phenotype macrophages can be converted into each other in their specific microenvironment, and they are quite different with Th. Th. 2 . Many key transcription factors are involved in macrophage polarization. Here we briefly review the polarization of macrophages and their functions in some typical inflammatory diseases. Figure 1. Timeline: advance in research of macrophage polarization. The figure illustrates several mechanisms underlying macrophage polarization and shows the feedback regulation between M1 and M2 signal pathways. Those include the activation of STAT1 mediated by IFN- . The feedback regulation between M1 and M2 are implemented by STAT1- STAT6, IRF5- IRF4, NF- . Generally, macrophages are deliberated to be polarized toward an M1 phenotype in the early stage of bacterial infection. When the pathogen associated molecular patterns (PAMPs) presented in bacteria are recognized by pathogen recognition receptors (such as Toll- like receptors, TLRs), macrophages are activated and produce a large amount of pro- inflammatory mediators including TNF- . This mechanism has been considered to be involved in infection with Salmonella typhi, Salmonella typhimurium, Listeria monocytogenes . If macrophage- mediated inflammatory response cannot be quickly controlled, a cytokine storm is formed, thereby contributing to the pathogenesis of severe sepsis . For example, microarray analysis and transcriptional profiling of peripheral blood cells showed that typical M1 genes and M1- related genes were replaced by M2 signature during treatment or convalescence in patients with typhoid fever . LPS, large molecules in the outer membrane of gram- negative bacteria, play a critical pro- inflammatory role in acute infections. As the infection persists, host may present a LPS- tolerant state, and macrophages are polarized to M2 phenotype. A recent study has confirmed that the p. NF- . As the excessive injury is reduced, however, M2 phenotype macrophages also induce an immunosuppressive state, resulting in a more susceptible situation to re- infection, thus relapse may occur or a carrier state may be found. Virus. Macrophage polarization is also involved in virus infection, and M2 phenotype macrophages can suppress inflammation and promote tissue healing. Influenza virus augments the phagocytic function of human macrophages, which is a major feature of M2 phenotype, to clear the apoptotic cells and accelerate the resolution of inflammation . In severe acute respiratory syndrome (SARS)- Cov infection, M2 phenotype macrophages are critical to regulate immune response and protect host from the long term progression to fibrotic lung disease by a STAT dependent pathway . In addition, severe respiratory syncytial virus (RSV) induced bronchiolitis is closely associated with mixed M1 and M2 macrophages . IL- 4- STAT6 dependent M2 macrophage polarization can attenuate inflammation and epithelial damage, and cyclooxygenase- 2 inhibitor, which increases expression of lung M2 macrophages, is proposed as a treatment strategy . However, the tissue- resident macrophage plays a completely different role in the virus infection. For instance, Kupffer cells (KCs) limit the severity of the virally infected liver through removing apoptotic hepatocytes in a manner dependent on scavenger receptors and thus play a major pathological role in chronic virus associated diseases . In addition, as the major target of HIV- 1 infection, resident macrophage acts as viral reservoir which protects HIV- 1 from hostile elements and induces HIV- 1 associated neurological damage . In general, macrophages undergo a dynamic switch toward M2 phenotype. For instance, during the early stage of Taenia crassiceps infestation, it is characterized by responses of Th. M1 phenotype macrophages, however, as infection goes to a late stage, Th. IL- 4- mediated M2 phenotype would become dominant with a decreased parasite burden . In addition, different subtypes of parasite show different macrophage phenotypes during infection. Toxoplasma gondii has been shown to have three distinct clonal lineages, type I, type II, and type III, and they differ in virulence. Type I and III infected macrophages are alternatively activated through activation of STAT6 by Toxoplasma rhoptry kinase ROP1. II infected macrophages are classically activated through activation of NF- . Moreover, it is not a terminal differentiation for M2 phenotype in parasite infestation. In a recent study, utilizing a murine model of filarial infection demonstrated that macrophages which are exposed to Th. LPS or IFN- . Some important molecules are involved in this process. For example, in Leishmania infantum infection, Dectin- 1 and mannose receptor, two kinds of C- type lectin receptors (CLRs) expressed on macrophages, respectively activate Sykp. NADPH oxidase signaling pathways, and they are crucial for reactive oxygen species (ROS) production and also trigger Syk- coupled signaling for caspase- 1 induced IL- 1. In contrast, specific intercellular adhesion molecule- 3- grabbing nonintegrin receptor 3 (SIGNR3), another kind of CLRs, helps parasite resilience through inhibition of the leukotriene (LTB) 4- IL- 1. Therefore, CLRs are key modulators for macrophage polarization, and are served as potential targets for prevention as well as treatment of Leishmania infantum infection . Arg. 1 is not only an important marker of M2 phenotype macrophages but also a regulator of the immune response in parasite infestation. A study using myeloid cell restricted Arg. Schistosoma mansoni infection model suggested that Arg. Th. 2- mediated fibrotic pathology and intestinal damage associated with increased Th. Th. 17 cytokines, nitric oxide synthase (NOS) 2 levels, and endotoxemia. However, it is not a generalized effect in the pathogenesis of parasite infestation. Arg. 1 blockade or deficiency in hematopoietic and endothelial cell lineages had little effect on response to acute orchronic infection by Trichuris muris. It underlies the leading cause of death in developed countries and is likely soon to attain this status worldwide . An error occurred while setting your user cookie. Please set your. browser to accept cookies to continue. This cookie stores just a. ID; no other information is captured. Accepting the NEJM cookie is.
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