ArticleLiterature Review

Eicosanoids in Inflammation: Biosynthesis, Pharmacology, and Therapeutic Frontiers

Authors:
  • Bikam Pharmaceuticals
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Abstract

In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX-2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.

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... Eicosanoids are a family of fatty acid metabolites generated from 20-carbon polyunsaturated fatty acids (PUFAs) synthesized by enzymatic oxygenation pathways involving a distinct family of enzymes, the oxygenases (Khanapure et al., 2007). Eicosanoids are not stored, but promptly synthesized de novo after cell activation (Bozza et al., 2011) through a highly regulated event, primarily involving three oxygenases: cyclooxygenases (COXs), P450 cytochrome epoxygenases (CYP450), and lipoxygenases (LOXs) (Alvarez and Lorenzetti, 2021). ...
... PGE 2 has vasodilation effects and increases the permeability of postcapillary venules, early events in the inflammatory response (Funk, 2001) (Figure 3). Furthermore, PGs may synergize in the blood vessel with other pro-inflammatory mediators, such as histamine or bradykinin, to increase vascular permeability and promote edema (Funk, 2001;Khanapure et al., 2007). ...
Article
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Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids in cells. PUFAs regulate cellular function through the formation of derived lipid mediators termed eicosanoids. The oxygenation of 20-carbon PUFAs via the oxygenases cyclooxygenases, lipoxygenases, or cytochrome P450, generates a class of classical eicosanoids including prostaglandins, thromboxanes and leukotrienes, and also the more recently identified hydroxy-, hydroperoxy-, epoxy- and oxo-eicosanoids, and the specialized pro-resolving (lipid) mediators. These eicosanoids play a critical role in the regulation of inflammation in the blood and the vessel. While arachidonic acid-derived eicosanoids are extensively studied due to their pro-inflammatory effects and therefore involvement in the pathogenesis of inflammatory diseases such as atherosclerosis, diabetes mellitus, hypertension, and the coronavirus disease 2019; in recent years, several eicosanoids have been reported to attenuate exacerbated inflammatory responses and participate in the resolution of inflammation. This review focused on elucidating the biosynthesis and the mechanistic signaling of eicosanoids in inflammation, as well as the pro-inflammatory and anti-inflammatory effects of these eicosanoids in the blood and the vascular wall.
... In our previously published work [7], the fatty acids and fatty acid conjugates family was the most highly significantly expressed for both polar and nonpolar metabolites in plasma from obese mice [7]. Eicosanoids are highly bioactive fatty acid metabolites, and a subset of essential polyunsaturated fatty acids (PUFAs) provides the substrates for their synthesis [17,18]. Using the METLIN-annotated metabolic features shown in Supplemental Tables S3 and S4, the entire linoleic acid elongation and desaturation pathway was downregulated in NGOB vs. WT plasma: in most cases, with statistical significance ( Figure 7A, left, gray vs. black bars). ...
... In our previously published work [7], the fatty acids and fatty acid conjugates family was the most highly significantly expressed for both polar and nonpolar metabolites in plasma from obese mice [7]. Eicosanoids are highly bioactive fatty acid metabolites, and a subset of essential polyunsaturated fatty acids (PUFAs) provides the substrates for their synthesis [17,18]. Using the METLIN-annotated metabolic features shown in Supplemental Tables S3 and S4, the entire linoleic acid elongation and desaturation pathway was downregulated in NGOB vs. WT plasma: in most cases, with statistical significance (Fig-Figure 6. Volcano plots used to determine significantly differentially expressed annotated metabolic features (left) and heat maps created by unsupervised hierarchical clustering using the top 25 most highly differentially expressed of these (right) in pairwise comparisons of (A) NGOB vs. WT plasma samples and (B) T2D vs. NGOB plasma samples. ...
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The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation-a strong genetic model of T2D-were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.
... Arachidonic acid (AA) is found in membrane phospholipids and can be released from the membrane phospholipids (particularly from phospholipase A 2 , PLA 2 ) upon activation to produce interesting classes of inflammation mediators, prostaglandins (PGs) and leukotrienes. Cyclooxygenases (COX-1 and COX-2) in mast cells, macrophages, and endothelial cells produce PGs to trigger vascular and systemic signs and symptoms of inflammation (63). PGE 2 and PGD 2 (mast cells) trigger vasodilation and increases permeability of postcapillary venules to allow for edema formation, whereas PGF 2a stimulates uterine, bronchial, and small arteriole smooth muscle contraction. ...
... Corticosteroids are an essential class of drugs that can prevent the initial release of AA by phospholipase activity in addition to a series of other proposed mechanisms of action. Non-steroidal anti-inflammatory drugs (NSAIDs) like naproxen and ibuprofen are common over the counter and prescription medication that serve as COX inhibitors to limit inflammation, while lipoxygenase inhibitors and leukotriene receptor antagonists serve as therapeutic strategies in asthma management due to their specific induction of bronchial smooth muscle contraction (63). ...
Article
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Inflammation is an essential component of a wide variety of disease processes and oftentimes can increase the deleterious effects of a disease. Finding ways to modulate this essential immune process is the basis for many therapeutics under development and is a burgeoning area of research for both basic and translational immunology. In addition to developing therapeutics for cellular and molecular targets, the use of biomaterials to modify innate and adaptive immune responses is an area that has recently sparked significant interest. In particular, immunomodulatory activity can be engineered into biomaterials to elicit heightened or dampened immune responses for use in vaccines, immune tolerance, or anti-inflammatory applications. Importantly, the inherent physicochemical properties of the biomaterials play a significant role in determining the observed effects. Properties including composition, molecular weight, size, surface charge, and others affect interactions with immune cells (i.e., nano-bio interactions) and allow for differential biological responses such as activation or inhibition of inflammatory signaling pathways, surface molecule expression, and antigen presentation to be encoded. Numerous opportunities to open new avenues of research to understand the ways in which immune cells interact with and integrate information from their environment may provide critical solutions needed to treat a variety of disorders and diseases where immune dysregulation is a key inciting event. However, to elicit predictable immune responses there is a great need for a thorough understanding of how the biomaterial properties can be tuned to harness a designed immunological outcome. This review aims to systematically describe the biological effects of nanoparticle properties—separate from additional small molecule or biologic delivery—on modulating innate immune cell responses in the context of severe inflammation and sepsis. We propose that nanoparticles represent a potential polypharmacological strategy to simultaneously modify multiple aspects of dysregulated immune responses where single target therapies have fallen short for these applications. This review intends to serve as a resource for immunology labs and other associated fields that would like to apply the growing field of rationally designed biomaterials into their work.
... Whereas, Arachidonic acid which can be produced from Linoleic acid, is considered as conditionally essential fatty acid. Thus, suitable amounts of these FAs in diet is necessary, while high levels are involved in inflammatory eicosanoid synthesis [16]. ...
... Furthermore, stratification of cases into two groups on the basis of PC incidence time (less than 3 years for early incidence, n ¼ 13) and (more than 3 years for late incidence, n ¼ 37); demonstrated that high plasma levels of total omega-6 fatty acids in case group with early incidence of PC, was significantly associated with the increased risk of pancreatic cancer 1.2 times more than the group with late incidence [OR ¼ 1.22(1.03e1.45) vs. OR ¼ 1.07(0.99e1. 16)]. Also, the association between plasma levels of total trans and pancreatic cancer risk in cases with early incidence is twice as strong as cases with late incidence [OR ¼ 3.97(1.24e12.67) ...
Article
Background & aims: Pancreatic cancer (PC) with a dismal prognosis is considered as a fatal malignancy, attracting the scientists' attention to study its causes and pathogenesis pathways. Given the lack of enough evidence and conflicting findings about the association of PC risk with plasma fatty acids, we aimed to explore the associations of circulating plasma fatty acids with the risk of PC in a cohort study. Methods: From about 50,000 subjects participated in this cohort study in 2004-2008, fifty incident cases of PC were recruited and 150 controls matched by age, sex and residence place (urban/rural) were randomly selected. The plasma fatty acids composition was measured by gas chromatography with Flame Ionization Detector (GC-FID) in plasma samples collected at the baseline of cohort study. Multivariable conditional logistic regression was used to estimate OR (with 95% CI) of PC risk associated with plasma levels of fatty acids considering known potential risk factors for PC. Results: Our findings showed that total saturated fatty acids and total industrial trans fats were not associated with the risk of PC; whereas, statistically significant inverse associations were found between high plasma levels of total mono-unsaturated fatty acids (MUFAs), omega-3 and ruminant trans fatty acids with the risk of PC [ORQ1-Q4 = 0.31 (0.11-0.89), OR Q2-Q1 = 0.30 (0.10-0.91) and ORQ2-Q1 = 0.15 (0.04-0.49), respectively]. Omega-6 fatty acids especially high plasma levels of Arachidonic acid was positively associated with the risk of PC [ORQ1-Q3 = 11.07 (3.50-35.02)]. Conclusion: Except for the plasma circulating whole fats, the levels of different classes of fats may significantly change pancreatic cancer susceptibility. Unsaturated fatty acids including omega-3-PUFA and MUFA are considered as protective biomarkers in PC prevention. On the contrary, omega-6-fatty acids are positively associated with the risk of PC.
... Eicosanoids have significant activities in the regulation of normal physiological processes and disease pathogenesis in the human body 16,17 . Eicosanoids have pleiotropic roles in inflammation and immunity 18,19 . Many studies have focused on strategies for inhibiting the formation of inflammatory mediators that may contribute to risk of AF 20 . ...
Article
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Chronic inflammation is a continuous low-grade activation of the systemic immune response. Whereas downstream inflammatory markers are associated with atrial fibrillation (AF), upstream inflammatory effectors including eicosanoids are less studied. To examine the association between eicosanoids and incident AF. We used a liquid chromatography-mass spectrometry for the non-targeted measurement of 161 eicosanoids and eicosanoid-related metabolites in the Framingham Heart Study. The association of each eicosanoid and incident AF was assessed using Cox proportional hazards models and adjusted for AF risk factors, including age, sex, height, weight, systolic/diastolic blood pressure, current smoking, antihypertensive medication, diabetes, history of myocardial infarction and heart failure. False discovery rate (FDR) was used to adjust for multiple testing. Eicosanoids with FDR < 0.05 were considered significant. In total, 2676 AF-free individuals (mean age 66 ± 9 years, 56% females) were followed for mean 10.8 ± 3.4 years; 351 participants developed incident AF. Six eicosanoids were associated with incident AF after adjusting for multiple testing (FDR < 0.05). A joint score was built from the top eicosanoids weighted by their effect sizes, which was associated with incident AF (HR = 2.72, CI = 1.71–4.31, P = 2.1 × 10–5). In conclusion, six eicosanoids were associated with incident AF after adjusting for clinical risk factors for AF.
... Eicosanoids which include prostaglandins, thromboxanes, and leukotrienes are released within minutes from MC after activation through FcεRI and play an essential role in the pro-inflammatory response. Eicosanoids are produced in reactions catalyzed by cyclooxygenase and lipoxygenase from n-3 (EPA and DHA) and n-6 (AA and dihomo-γlinolenic acid) PUFA, which are freed from the plasma and nuclear membrane by cytoplasmic phospholipase A 2 after cell activation (55). It is important to note that n-3 and n-6 PUFA are precursors to different classes of eicosanoids, and that eicosanoids synthesized from n-3 PUFA have less proinflammatory potentials than those (such as CysLT) from n-6 PUFA (50). ...
Article
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n-3 polyunsaturated fatty acids (PUFA) influences a variety of disease conditions, such as hypertension, heart disease, diabetes, cancer and allergic diseases, by modulating membrane constitution, inhibiting production of proinflammatory eicosanoids and cytokines, and binding to cell surface and nuclear receptors. We have previously shown that n-3 PUFA inhibit mast cell functions by disrupting high affinity IgE receptor (FcεRI) lipid raft partitioning and subsequent suppression of FcεRI signaling in mouse bone marrow-derived mast cells. However, it is still largely unknown how n-3 PUFA modulate human mast cell function, which could be attributed to multiple mechanisms. Using a human mast cell line (LAD2), we have shown similar modulating effects of n-3 PUFA on FcεRI lipid raft shuttling, FcεRI signaling, and mediator release after cell activation through FcεRI. We have further shown that these effects are at least partially associated with ligation of G protein-coupled receptor 120 expressed on LAD2 cells. This observation has advanced our mechanistic knowledge of n-3 PUFA's effect on mast cells and demonstrated the interplay between n-3 PUFA, lipid rafts, FcεRI, and G protein-coupled receptor 120. Future research in this direction may present new targets for nutritional intervention and therapeutic agents.
... Its activation leads to the hydrolysis of the sn-2 fatty acid substituent from membrane glycerophospholipids [11][12][13][14][15][16] to yield a free fatty acid (e.g., arachidonic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)) and a 2-lysophospholipid [17]. Subsequent metabolism of arachidonic acid by cyclooxygenases (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways leads to the generation of bioactive oxidized eicosanoids, several of which are proinflammatory [18] and recognized contributors to inflammatory diseases [19][20][21][22][23][24][25][26][27]. Some of the most potent inflammatory eicosanoids [21] are prostaglandin E 2 (PGE 2 ), leukotrienes (LTs), hydroxyeicosatetraenoic acids (HETEs), and dihydroxyeicosatetraenoic acids (DHETEs), and they contribute to inflammation and autoimmune diseases [22]. ...
Article
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The Ca2+-independent phospholipase A2β (iPLA2β) is a member of the PLA2 family that has been proposed to have roles in multiple biological processes including membrane remodeling, cell proliferation, bone formation, male fertility, cell death, and signaling. Such involvement has led to the identification of iPLA2β activation in several diseases such as cancer, cardiovascular abnormalities, glaucoma, periodontitis, neurological disorders, diabetes, and other metabolic disorders. More recently, there has been heightened interest in the role that iPLA2β plays in promoting inflammation. Recognizing the potential contribution of iPLA2β in the development of autoimmune diseases, we review this issue in the context of an iPLA2β link with macrophages and T-cells.
... COX-2 is an inducible enzyme, which is either absent or expressed slightly in most cells [11]. However, when cells are stimulated by pro-inflammatory cytokines or cancer-promoting factors, COX-2 shows upregulation and participates in inflammation as well as the formation and development of tumors [12,13]. Studies have shown that COX-2 is involved in CP [14,15], and inhibition of COX-2 suppresses the proliferation of prostatic epithelial cells in CNP [16]. ...
Article
Background: Chronic non-bacterial prostatitis (CNP) is a widespread disease of the male reproductive system. MiR-181c can be expressed in prostate tissue, but it has not been reported in CNP. This study aims to investigate the role of miR-181c in CNP and its mechanism of action on CNP, providing new ideas for the treatment and diagnosis of CNP. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were applied to determine miR-181c expression in clinical CP patients, CNP rats, and LPS-induced human prostaglandin epithelial cell RWPE-1. Then, luciferase reporter assay was performed to verify the targeting relation between miR-181c and COX-2. Through cell transfection experiments, the effect of mi-181c on the expression of COX2 and PGE2 was studied, and the effect of miR-181c/COX-2 on the proliferation of prostate epithelial cells was also explored. Results: qRT-PCR and Western blotting analysis revealed that miR-181c was low expressed in prostate tissue of CP patients and CNP rats and human prostaglandin epithelial cell RWPE-1. The luciferase reporter assay confirmed the targeting relation between miR-181c and COX-2. And miR-181c overexpression reduced the expression of COX-2 and PGE2 and suppressed the proliferation of prostate epithelial cells. COX-2 up-regulation reversed these effects caused by overexpression of miR-181c. Conclusions: miR-181c inhibited the proliferation of prostate epithelial cells through negatively regulating COX-2 to alleviate chronic non-bacterial prostatitis. Keywords: Chronic non-bacterial prostatitis, miR-181c, COX-2, prostatic epithelial cell, proliferation
... [66,70] Fever can be mediated by TNFα and Il-1 and pain by tryptase and PGE2. 26,32 Cecum stool stasis due to local adynamic ileus is another neuroimmunoendocrine manifestation that reinforces this appendicopathy [3,14,16,49,50]. The increased expressions of neuroendocrine and immune mediators indicate that appendicopathy currently called neurocrine, neuroendocrine and neruoimmunoendocrine is real. ...
Article
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Background About 15%–25% of appendices removed to treat acute appendicitis present normal macro- and macroscopic morphology. The objective of this study was to verify an association of proinflammatory, neuroendocrine and immune mediators with morphologically normal appendices removed from patients with clinical laboratorial and imaging characteristics of acute appendicitis. Materials and methods Appendices removed from 121 adult patients of both genders were distributed into three groups according to their following characteristics: group 1: 53 macro- and microscopically normal appendices from patients with clinical, laboratorial and imaging diagnosis of acute appendicitis; group 2: 24 inflamed appendices from patients with clinical, laboratorial, imaging and histopathological diagnosis of acute appendicitis; group 3: 44 normal appendices from patients submitted to right colectomy to treat localized ascending colon adenocarcinoma. All appendices were immunohistochemically studied for gastrin inhibitor peptide, mast cell tryptase, vascular endothelial growth factor; intestinal vasoactive peptide, tumor necrosis factor alpha, interleukin 1, prostaglandin E2, gene-protein product 9.5, CD8 T lymphocytes, synaptophysine, enolase, and S100 protein. Results The group 1 revealed increased levels of synaptophysine, enolase, mast cell tryptase and PGP-9.5 comparing with the other two groups. The group 2 presented increased levels of interleukin 1, CD8 T lymphocytes and prostaglandin E2 comparing with the other two groups. The group 3 confirmed the normal levels of all these neuroendocrine, immune and proinflammatory mediators. Conclusions Morphologically normal appendices removed from patients with clinical and complementary exams indicating acute appendicitis have appendicular neuroimmunoendocrine disorder associated with the mediators synaptophysin, enolase, mast cell-related tryptase and gene-protein product 9.5.
... Os anti-inflamatórios não hormonais (AINE's) são de natureza química muito variada, porém todos atuam praticamente pelo mesmo mecanismo de ação, inibindo a síntese do ácido araquidônico, impedindo a formação de prostaglandinas e outros mediadores químicos do processo inflamatório (KHANAPURE et al., 2007;BARRETO;PEREIRA, 2008). ...
... Os anti-inflamatórios não hormonais (AINE's) são de natureza química muito variada, porém todos atuam praticamente pelo mesmo mecanismo de ação, inibindo a síntese do ácido araquidônico, impedindo a formação de prostaglandinas e outros mediadores químicos do processo inflamatório (KHANAPURE et al., 2007;BARRETO;PEREIRA, 2008). ...
... Eicosanoid levels are known to increase in response to inflammatory stimuli in the lungs [119], and PMN infiltration into the pulmonary space is a hallmark feature of pneumococcal pneumonia. While PMN activity is imperative to innate immunity, uncontrolled inflammation can result in tissue destruction and lung disease. ...
Article
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Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells—a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role.
... The studies of the role of HETEs in cancer focus on 20-HETE. 20-HETE formed by CYP4 enzymes exhibits the proinflammatory function (Khanapure et al., 2007). In recent years, more attention has been paid to the promoting role of 20-HETE in cancer progression (Panigrahy et al., 2010;Alexanian and Sorokin, 2013). ...
Article
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Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosanoids, such as epoxyeicosatrienoic acids (EETs), epoxyoctadecenoic acids (EpOMEs), epoxyeicosatetraenoic acids (EpETEs), and epoxydocosapentaenoic acids (EDPs), as well as hydroxyeicosatetraenoic acids (HETEs), in tumorigenesis and cancer progression have not been fully elucidated yet. Here we summarized the association of polymorphisms of CYP monooxygenases with cancers and the pleiotropic functions of CYP monooxygenase-mediated eicosanoids (EETs, EpOMEs, EpETE, EDPs, and 20-HETE) in the tumorigenesis and metastasis of multiple cancers, including but not limited to colon, liver, kidney, breast and prostate cancers, which hopefully provides valuable insights into cancer therapeutics. We believe that manipulation of CYPs with or without supplement of ω-3 PUFAs to regulate eicosanoid profile is a promising strategy to prevent and/or treat cancers.
... The upstream initiation of inflammatory activity in humans is governed mainly by substrates and products of polyunsaturated ω-3 and ω-6 20-carbon fatty acids. 7,33 The small-molecule derivatives of arachidonic acid and other polyunsaturated fatty acids, termed eicosanoids, serve as both activators and suppressors of systemic inflammatory activity. 34,35 Most research on systemic inflammation in humans has focused on downstream markers of inflammatory activity, such as cytokines and short-term phase reactants. ...
Article
Background Epidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid–derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin‐angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti‐inflammatory eicosanoids are linked with BP. Methods and Results We studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography–mass spectrometry, we profiled 545 distinct high‐quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP ( P <Bonferroni‐corrected threshold of 0.05/545). We used forward selection linear regression modeling in FINRISK to define a general formula for individual eicosanoid risk score. Individuals of the top risk score quartile in FINRISK had a 9.0 (95% CI, 8.0–10.1) mm Hg higher systolic BP compared with individuals in the lowest quartile in fully adjusted models. Observed metabolite associations were consistent across FINRISK and FHS. Conclusions Plasma eicosanoids demonstrate strong associations with BP in the general population. As eicosanoid compounds affect numerous physiological processes that are central to BP regulation, they may offer new insights about the pathogenesis of hypertension, as well as serve as potential targets for therapeutic intervention.
... Mgll is an important lipase that breaks down the endocannabinoid 2-AG to produce ARA, a major precursor for the inflammatory eicosanoids [46][47][48]. Given its involvement in the regulation of these critical lipid signaling pathways with diverse physiological functions, Mgll has been considered a therapeutic target for neuroinflammatory and neurodegenerative disorders [9,49,50]. ...
Article
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Rationale: Monoacylglycerol lipase (Mgll), a hydrolase that breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is a potential target for neurodegenerative diseases, such as Alzheimer's disease (AD). Increasing evidence shows that impairment of adult neurogenesis by perturbed lipid metabolism predisposes patients to AD. However, it remains unknown what causes aberrant expression of Mgll in AD and how Mgll-regulated lipid metabolism impacts adult neurogenesis, thus predisposing to AD during aging. Here, we identify Mgll as an aging-induced factor that impairs adult neurogenesis and spatial memory in AD, and show that metformin, an FDA-approved anti-diabetic drug, can reduce the expression of Mgll to reverse impaired adult neurogenesis, prevent spatial memory decline and reduce β-amyloid accumulation. Methods: Mgll expression was assessed in both human AD patient post-mortem hippocampal tissues and 3xTg-AD mouse model. In addition, we used both the 3xTg-AD animal model and the CbpS436A genetic knock-in mouse model to identify that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway, involving atypical protein kinase C (aPKC)-stimulated Ser436 phosphorylation of histone acetyltransferase CBP through biochemical methods. Furthermore, we performed in vivo adult neurogenesis assay with BrdU/EdU labelling and Morris water maze task in both animal models following pharmacological treatments to show the key role of Mgll in metformin-corrected neurogenesis and spatial memory deficits of AD through reactivating the aPKC-CBP pathway. Finally, we performed in vitro adult neurosphere assays using both animal models to study the role of the aPKC-CBP mediated Mgll repression in determining adult neural stem/progenitor cell (NPC) fate. Results: Here, we demonstrate that aging-dependent induction of Mgll is observed in the 3xTg-AD model and human AD patient post-mortem hippocampal tissues. Importantly, we discover that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway. The accumulation of Mgll in the 3xTg-AD mice reduces the genesis of newborn neurons and perturbs spatial memory. However, we find that metformin-stimulated aPKC-CBP pathway decreases Mgll expression to recover these deficits in 3xTg-AD. In addition, we reveal that elevated Mgll levels in cultured adult NPCs from both 3xTg-AD and CbpS436A animal models are responsible for their NPC neuronal differentiation deficits. Conclusion: Our findings set the stage for development of a clinical protocol where Mgll would serve as a biomarker in early stages of AD to identify potential metformin-responsive AD patients to restore their neurogenesis and spatial memory.
... Dentre estes mediadores inflamatórios estão os eicosanóides, os quais são sintetizados a partir da metabolização do ácido araquidônico, produzido pela ação das enzimas fosfolipases nos fosfolipídeos presentes na membrana celular. Por meio da ação das enzimas ciclo-oxigenases ou lipoxigenases ocorrerão modificações estruturais na cadeia do ácido araquidônico levando a síntese de prostaglandinas e tromboxanos ou leucotrienos e lipoxinas, respectivamente (Williams e Higgs, 1988;Cotran et al., 2000;Bozza et al., 2007;Khanapure et al., 2007;Harizi et al., 2008;Haeggstoom et al., 2010;Hirata e Narumiya, 2012;Le Bel et al., 2014;Capra et al., 2015). ...
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A lesão periapical é uma resposta inflamatória que resulta na reabsorção do tecido ósseo ao redor dos dentes. Essa reação é controlada por mediadores inflamatórios e osteoclastogênicos, que atuam no recrutamento de células de defesa, proliferação de células precursoras de osteoclastos, diferenciação e maturação celular, resultando na degradação das matrizes do tecido ósseo. Assim, a identificação de moléculas que participam deste processo se torna oportuna com o objetivo de determinar possíveis alvos‐terapêuticos. Portanto, a proposta deste trabalho foi investigar potenciais reguladores da inflamação, osteoclastogênese e reabsorção óssea periapical após indução de lesão periapical experimental em camundongos (Mus musculus). Suscintamente, demonstramos que a contaminação dos canais radiculares de dentes molares de camundongos C57Bl6 por micro‐ organismos advindos da cavidade bucal ou pelo lipopolissacarídeo bacteriano (LPS) de E. coli (0,1 μg / μL) induziram o desenvolvimento da lesão periapical experimental com características distintas. Porém, ambas foram caracterizadas por um aumento local na síntese de RNAm para as enzimas 5‐lipoxigenase (5‐LO) e ciclo‐oxigenase‐2 do metabolismo do ácido araquidônico bem como de receptores de superfície (EP1‐EP4 e BLT1‐BLT2) e nucleares (PPAR) que medeiam os efeitos biológicos dos mediadores lipídicos prostaglandina E2 e leucotrieno B4 (LTB4). Tendo em vista que a contaminação microbiana dos canais radiculares induziu a inflamação periapical e a reabsorção óssea diferentemente do LPS, que induziu somente a inflamação periapical nas condições aqui apresentadas, aprofundamos nossa investigação para identificar outros mediadores inflamatórios envolvidos no processo. Interessantemente, a contaminação dos canais radiculares induziu a síntese de RNAm para citocinas, quimiocinas e seus receptores e, na ausência da via 5‐LO, conseguida por meio da utilização de animais knockout para o gene Alox5 (129‐Alox5tm1Fun), a produção gênica de diversos mediadores foi inibida. Diferentemente, os reguladores da osteoclastogênese (RANK, RANKL e OPG) e a ativação de osteoclastos in vivo foram maiores nos animais deficientes de 5‐LO, ainda que esse possível papel protetor não tenha impedido a reabsorção óssea periapical que foi semelhante à observada nos animais selvagens (129). Quando investigado in vitro, utilizando uma cultura de células da linhagem monocítica (J774A.1), o leucotrieno B4, um dos produtos do metabolismo do ácido araquidônico pela via 5‐LO, inibiu a transcrição de genes condizentes com um fenótipo osteoclástico e ativação das células, mensurada por meio da atividade da enzima fosfatase ácida resistente ao tartarato. Em conjunto, estes resultados mostram que a via 5‐LO e o mediador lipídico LTB4 apresentam um papel importante na regulação da síntese de mediadores inflamatórios na lesão periapical e um papel protetor na sinalização osteoclastogênica, prevenindo a formação e ativação de osteoclastos. Não obstante, essa paradoxal relação inflamação‐sinalização osteoclastogênica, não impediu a reabsorção óssea durante o desenvolvimento da lesão periapical. Palavras‐chave: Lesão periapical, Inflamação, Osteoclastogênese, Reabsorção óssea, Mediadores lipídicos, Mediadores inflamatórios, Enzima 5‐lipoxigenase, Leucotrieno B4. ABSTRACT Silva FWGP. Investigation of potential regulators of inflammation, osteoclastogenesis and periapical bone resorption [thesis]. Ribeirão Preto: Faculdade de Odontologia de Ribeirão Preto da Universidade de São Paulo; 2016. Apical periodontitis is an inflammatory response that results in resorption of bone tissue surrounding the teeth. This reaction is orchestrated by inflammatory and osteoclastogenic mediators, involved in the recruitment of defense cells, proliferation of osteoclast precursor cells followed by cellular differentiation and maturation, that finally results in degradation of the bone tissue matrix. The identification of molecules that regulate this process becomes appropriate in order to shed light on novel potential therapeutical targets. Therefore, the purpose of this research was to investigate potential regulators of inflammation, osteoclastogenesis and periapical bone resorption after induction of experimental apical periodontitis in mice (Mus musculus). Briefly, we demonstrated that contamination of molar root canals of C56Bl6 mice by microorganisms from the oral cavity or inoculation of bacterial lipopolysaccharide (LPS) of E. coli (0.1 μg / μL) into the root canals induced the development of apical periodontits with distinct characteristics, even though both were characterized by a local increase in mRNA synthesis to enzymes of arachidonic acid metabolism 5‐lipoxygenase (5‐LO) and cyclooxygenase‐2 as well as surface (EP1‐EP4 and BLT1‐BLT2) and nuclear (PPAR) receptors that mediate the biological effects of the lipid mediators prostaglandin E2 and leukotriene B4 (LTB4). Considering that microbial contamination of the root canals induced periapical inflammation and bone resorption unlike LPS that induced only periapical inflammation under the conditions presented here, we carried out the investigation to identify a wide variety of inflammatory mediators involved in the process. Interestingly, contamination of the root canals induced the synthesis of mRNAs for cytokines, chemokines and their receptors and, in the absence of the 5‐LO pathway, by means of using Alox5 knockout mice (129‐Alox5tm1Fun), gene expression of several mediators was inhibited. In contrast, the regulators of osteoclastogenesis (RANK, RANKL and OPG) and the in vivo activation of osteoclasts were higher in animals deficient for 5‐LO, although this protective role did not prevent periapical bone resorption, which was similar to that found in wild type mice (129). In vitro investigation, by means of culturing monocytic lineage cells (J774A.1), LTB4, one of the products of arachidonic acid metabolism by 5‐LO, inhibited the transcription of genes that are consistent with an osteoclastic phenotype and cell activation, measured by means of the activity of the enzyme tartrate resistant acid phosphatase. Taken together, these results show that the 5‐LO pathway and the lipid mediator LTB4 have an important role in regulating the synthesis of inflammatory mediators in apical periodontitis and present a protective role in osteoclastogenic signaling, preventing the formation and activation of osteoclasts. Nevertheless, this paradoxical inflammatory‐osteoclastogenic signaling did not prevent the periapical bone resorption during development of apical periodontitis.
... At the first stage of the study the combinatorial library was created and analyzed using molecular docking [21,22]. That was done, considering the important role of eicosanoids as mediators of inflammation. ...
Article
Background Computer aided drug design is among the most effective methods of medicinal chemistry. Abovementioned approaches were used for purposeful search of antiinflammatory agents among quinazoline condensed derivatives. Objective Purposeful synthesis of novel 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2- a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)carboxylic acids and their salts as promising antiinflammatory agents, evaluation of their structure by physicochemical methods and establishing of their anti-inflammatory activity. Methods The structures of target compounds were proposed due to their structure similarity to existing drugs and experimental agents with anti-inflammatory activity. The features of the synthesized compounds structures were evaluated by IR-, NMR spectroscopy and chromatographymass spectrometry and were discussed in detail. Probable molecular mechanisms of activity were predicted by molecular docking. The anti-inflammatory activity was determined by their ability to reduce the formalin- and carrageenan-induced paw edema in rats. Results It was found, that condensation of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)ones with 2- oxoglutaric acid yielded 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3- c]quinazoline-5a(6H)carboxylic acids which may be considered as a promising anti-inflammatory agents. In silico study showed, that obtained compounds revealed affinity to the molecular targets and corresponded to the «drug-like» criteria. Additionally docking study allowed to estimate the nature of interactions between synthesized compounds and molecular targets. The in vivo experiments showed that obtained compounds demonstrated the significant anti-inflammatory activity comparable or higher than activity of the reference drug «Diclofenac». Conclusion The developed and implemented search strategy of the anti-inflammatory agents was justified. 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline5a(6H)carboxylic acids possessed the mentioned activity and additional introduction of fluorine atoms in position 11 or 12 of the heterocyclic system led to amplification of anti-inflammatory activity.
... Higher levels of LTB4 and PGs have been reported in the joints of the patients with OA and LTB4 is thought to mediate the cartilage damage. 6,7 Enzymes like cyclooxygenase (COX) and lipoxygenase (LOX), with cytochrome P450 (CYP) pathways, are associated with the arachidonic acid (ARA) pathway. [8][9][10][11] The higher levels of leukotrineB4 (LTB4) and prostaglandins (PGs) have been reported in the joints of the patients with OA wherein LTB4 is thought to mediate the cartilage damage. ...
Article
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Osteoarthritis is a progressive joint disease associated with aging in elderly is, characterized by pain, inflammation, and difficulty in movement. The pathways involved in the progression of this disease remain unclear. The mediators, eicosanoids and leukotrienes are produced by COX-1/COX-2 or 5-LOX. Physicians have always used nonsteroidal anti-inflammatory drugs to treat the pain associated with osteoarthritis. A competitive inhibitor of LOX-5 and COX-2 that has both analgesic and anti-inflammatory activity is licofelone; one of the most promising candidates for the treatment of osteoarthritis is under clinical trial in treatment. A significant reduction in cartilage volume was displayed. A significant improvement over baseline on the WOMAC index and GI tolerance was also observed. Improving the symptoms related pain sensation with a happier life. With new strategies in OA, new methods to target pain, inflammation and movement restrictions would be the ultimate goal in patient satisfaction for the future. Licofelone was found to be effective compared to NSAIDs or coxibs in the treatment of OA. Does this mean this could be the answer?
... In addition, when released from membrane phospholipids, derivatives oxidized by enzymes can participate in cell signaling. LA can also be metabolized via multiple pathways to form several proinflammatory eicosanoids, such as prostaglandins, thromboxane, and leukotrienes (15)(16)(17). The number of sperm is the main indicator of fertility. ...
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Background: This study was conducted to identify potential seminal plasma metabolic markers associated with disease activity in Kallmann syndrome (KS). Methods: We collected medical records and seminal plasma samples from 17 KS patients and 20 age-matched healthy controls (HC) and performed metabolomics analysis using the UPLC-QTOF-MS method. Results: Partial least squares discriminant analysis (PLS-DA) showed that the metabolomics profile of KS patients was clearly separated from HC. Statistical analysis of the data indicates that there are differential metabolites between KS patients and HC. The main metabolic pathways focus on linoleic acid (LA) metabolism, Glycerophospholipid metabolism. Conclusions: The seminal plasma metabolomics profile of KS patients has changed. Glycerophospholipids and LA are promising biomarkers for KS diagnosis.
... COX activity is the rate-limiting step for the conversion of arachidonic acid (AA) to prostaglandins (PGs) and other metabolites that act as key regulators of airway cellular physiology (Laporte et al., 1999). COX-1 is expressed constitutively, whereas COX-2 is inducible and becomes elevated in several inflammatory conditions, including chronic airway diseases such as asthma (Khanapure et al., 2007;Pang et al., 1998;Torres et al., 2008;Wenzel, 1997). Furthermore, the prostanoid metabolism pathway is very complex and involves the release of a variety of mediators, which induce different signaling in various effector cells, thereby regulating pathophysiological outcomes in diseases. ...
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Diacylglycerol kinase (DGK), a lipid kinase, catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid, thereby terminating DAG-mediated signaling by Gq-coupled receptors that regulate contraction of airway smooth muscle (ASM). A previous study from our laboratory demonstrated that DGK inhibition or genetic ablation leads to reduced ASM contraction and provides protection for allergen-induced airway hyperresponsiveness. However, the mechanism by which DGK regulates contractile signaling in ASM is not well established. Herein, we investigated the role of prorelaxant cAMP-protein kinase A (PKA) signaling in DGK-mediated regulation of ASM contraction. Pretreatment of human ASM cells with DGK inhibitor I activated PKA as demonstrated by the phosphorylation of PKA substrates, VASP, Hsp20, and CREB, which was abrogated when PKA was inhibited pharmacologically or molecularly using overexpression of the PKA inhibitor peptide, PKI. Furthermore, inhibition of DGK resulted in induction of cyclooxygenase (COX) and generation of prostaglandin E2 (PGE2) with concomitant activation of Gs-cAMP-PKA signaling in ASM cells in an autocrine/paracrine fashion. Inhibition of protein kinase C (PKC) or extracellular-signal-regulated kinase (ERK) attenuated DGK-mediated production of PGE2 and activation of cAMP-PKA signaling in human ASM cells, suggesting that inhibition of DGK activates the COX-PGE2 pathway in a PKC-ERK-dependent manner. Finally, DGK inhibition-mediated attenuation of contractile agonist-induced phosphorylation of myosin light chain 20 (MLC-20), a marker of ASM contraction, involves COX-mediated cAMP production and PKA activation in ASM cells. Collectively these findings establish a novel mechanism by which DGK regulates ASM contraction and further advances DGK as a potential therapeutic target to provide effective bronchoprotection in asthma.
... AA is primarily metabolized through three major pathways, mediated by the activity of cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes ( Figure 1). All three pathways generate eicosanoids (20 carbon fatty acids), which play a role in many biological processes including inflammation [11], immune function [12,13], vascular function [14], and pain perception [15]. This review will focus on the enzymes that metabolize AA in each of these pathways as well as the metabolites generated and their effects on beta-cell mass and function. ...
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Arachidonic acid (AA) is a polyunsaturated 20-carbon fatty acid present in phospholipids in the plasma membrane. The three primary pathways by which AA is metabolized are mediated by cyclooxygenase (COX) enzymes, lipoxygenase (LOX) enzymes, and cytochrome P450 (CYP) enzymes. These three pathways produce eicosanoids, lipid signaling molecules that play roles in biological processes such as inflammation, pain, and immune function. Eicosanoids have been demonstrated to play a role in inflammatory, renal, and cardiovascular diseases as well type 1 and type 2 diabetes. Alterations in AA release or AA concentrations have been shown to affect insulin secretion from the pancreatic beta cell, leading to interest in the role of AA and its metabolites in the regulation of beta-cell function and maintenance of beta-cell mass. In this review, we discuss the metabolism of AA by COX, LOX, and CYP, the roles of these enzymes and their metabolites in beta-cell mass and function, and the possibility of targeting these pathways as novel therapies for treating diabetes.
... Arachidonic acid gives origin to PGs, thromboxanes, and leukotrienes, through the action of the enzymes COX and LOX, and these potent molecules will exert their effect by binding to specific membrane and nuclear receptors. 16 Therefore these enzymatic systems are also seen as important targets for the development of antiinflammatory agents. ...
Chapter
Cyanobacteria depend on solar radiation for photosynthesis and have, since ancient times, developed different strategies to cope with the damaging radiation in the UV range. Among these, the production of small molecules that act as UV filters has been thoroughly investigated for these organisms. Two major families of UV filters are produced by cyanobacteria—scytonemins and mycosporine-like amino acids. Here, we present an overview of the diversity, distribution, structural features, and UV protective properties of these metabolites. We also provide an account of their associated biological activities and biotechnological potential. Finally, we look into how these valuable small molecules can be accessed, namely, their biological sources, their biosynthesis and heterologous expression, as well as synthetic routes that have been developed to access these scaffolds. Finally, we briefly cover additional cyanobacterial compounds that have unique UV-radiation absorbing chromophores. Keywords: UV-A; UV-B; scytonemin; MAAs; biosynthesis; sunscreens
... In mammals eicosanoid biosynthesis is believed to be promoted by the activity of phospholipase A2 (PLA2), which cleaves fatty acids to release arachidonic acid (AA). The released AA is used to synthesize eicosanoids via three pathways: the cyclooxygenase (COXs) pathway, which generate prostaglandins (PGs) and thromboxanes (TXs); the lipoxygenase (LOX) pathway, which enables the production of leukotrienes (LTs), lipoxins (LXs) and hydroxyeicosatetraenoic acids (HETEs) and hydroperoxyeicosatetraenoic acids (HPETEs); as well as the cytochrome P450 pathway, which enables the generation of PGs, TXs, HETEs, HPETEs and epoxyeicosatrienoic acids (EETEs) (Khanapure et al., 2007;Haeggstrom and Funk, 2011). ...
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Apoptosis and autophagy, the mechanisms of programmed cell death, play critical roles in physiological and pathological processes in both vertebrates and invertebrates. Apoptosis is also known to play an important role in the immune response, particularly in the context of entomopathogenic infection. Of the factors influencing the apoptotic process during infection, two of the lesser known groups are caspases and eicosanoids. The aim of this study was to determine whether infection by the entomopathogenic soil fungus Conidiobolus coronatus is associated with apoptosis and changes in caspase activity in the hemocytes of Galleria mellonella larvae, and to confirm whether fungal infection may affect eicosanoid levels in the host. Larvae were exposed for 24 h to fully grown and sporulating fungus. Hemolymph was collected either immediately after termination of exposure (F24 group) or 24 h later (F48 group). Apoptosis/necrosis tests were performed in hemocytes using fluorescence microscopy and flow cytometry, while ELISA tests were used to measure eicosanoid levels. Apoptosis and necrosis occurred to the same degree in F24, but necrosis predominated in F48. Fungal infection resulted in caspase activation, increased PGE1, PGE2, PGA1, PGF2α, and 8-iso-PGF2α levels and decreased TXB2 levels, but had no effect on TXA2 or 11-dehydro-TXB2 concentrations. In addition, infected larvae demonstrated significantly increased PLA2 activity, known to be involved in eicosanoid biosynthesis. Our findings indicate that fungal infection simultaneously induces apoptosis in insects and stimulates general caspase activity, and this may be correlated with changes in the concentrations of eicosanoids.
... In addition to metalloproteinases, tetracyclines also inhibit enzymes from the hydrolase group alpha-amylases and phospholipases. Phospholipase A2 is a key enzyme in the biosynthesis of inflammatory mediators such as prostaglandins [24]. ...
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Tetracyclines are a group of antibiotics whose first representative was discovered over 70 years ago. Since then, they have been of great interest in dermatology. In addition to their antibacterial activity, they are able to inhibit metalloproteinases and exhibit anti-inflammatory, anti-apoptotic and antioxidant effects. The side effects have been thoroughly studied over the years, the most characteristic and important ones in daily dermatological practice being: phototoxicity, hyperpigmentation, onycholysis, photoonycholysis, induced lupus erythematosus, and idiopathic intracranial hypertension. In this article, we summarize the use of tetracyclines in infectious diseases and inflammatory dermatoses, and further discuss the instances where the efficacy and safety of tetracyclines have been highlighted over the past few years.
... In addition to metalloproteinases, they also inhibit enzymes from the hydrolase group -alpha-amylases and phospholipases. Phospholipase A2 is a key enzyme in the biosynthesis of inflammatory mediators such as prostaglandins [24]. ...
Preprint
Tetracyclines are a group of antibiotics whose first representative was discovered over 70 years ago. Since then, they have been of great interest in dermatology. In addition to their antibacterial activity, they are able to inhibit metalloproteinases and exhibit anti-inflammatory, anti-apoptotic and antioxidant effects. The side effects have been thoroughly studied over the years. The most characteristic and important in daily dermatolgical practice are: phototoxicity, hyperpigmentation, onycholysis, photoonycholysis, induced lupus erythematosus, idiopathic intracranial hypertension. In this article, we summarize the use of tetracyclines in infectious diseases and inflammatory dermatoses, and further discuss indications where the efficacy and safety of tetracyclines have been highlighted over the past few years.
... The understanding of SASP regulation in senescent cells is incomplete; however, 5lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2) are upregulated in senescent cells [15][16][17] and are known to regulate inflammatory cytokines through eicosanoid synthesis [18,19]. Leukotrienes (LT) and prostaglandins (PG) are two classes of eicosanoids generated by the metabolism of arachidonic acid via the 5-LO and COX-2 pathways, respectively [20,21]. ...
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Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.
... Increased levels of eicosanoid 12 (S) HETE were observed in the lungs in response to inflammatory triggers [34], and the leakage of neutrophils into the pulmonary space is a defining characteristic of lung damage. One explanation for the link between 12 (S) HETE and lung injury is that in a mouse model of acute lung injury (ALI), CLP-induced sepsis caused inflammation, increased vascular permeability, and upregulation of lipoxygenases. ...
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One of the most complex clinical challenges facing medical practice is sepsis-induced lung dysfunction resulting from polymicrobial sepsis. Although many therapeutic approaches have been used in such clinical challenges, there is still further need for a new effective therapeutic approach. The objective of this study was to investigate if Montelukast could protect the lungs during polymicrobial sepsis by regulating inflammatory markers and the oxidative stress pathways. Twenty-four mature male Swiss-albino mice aged 8-12 weeks, with a weight of 20-30 g, were randomized into 4 equal groups (n=6), sham (laparotomy without cecal ligation and puncture (CLP)), CLP (laparotomy with CLP), vehicle 1 (equivalent volume of DMSO 1 hour prior to CLP), Montelukast (10 mg/kg IP 1 hour prior to CLP). Lung tissue pro-inflammatory mediators IL-6, IL-1β, IL-17, LTB-4 12(S) HETE, and oxidative stress were assessed using ELISA. The levels of F2 isoprostane were considerably greater in the sepsis group (p<0.05) as compared to the sham group, while Montelukast was significantly lower (p<0.05) in these inflammatory mediators and oxidative stress as compared to the sepsis group. Histologically, the lung tissue damage was significant (p<0.05) in all mice in the sepsis group, while Montelukast significantly reduced lung tissue injury (p<0.05). The current findings indicated that Montelukast could attenuate lung dysfunction during CLP-induced polymicrobial sepsis in male mice through their modulating effects on pro-inflammatory and oxidative stress downstream signalling pathways and subsequently decrease lung tissue cytokine concentrations (IL-1β, IL-6, IL-17, LTB-4, and 12(S)HETE).
... Thus, a set of Lipid mediators acts as pro-inflammatory mediators that turn on inflammation, while some lipid mediators act as endogenous agonists to activate termination of inflammation by stimulating resolution. 11,12 ...
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Severe Corona Virus Disease is characterized by angiocentric inflammation of lungs and cytokine storm leading to potentially fatal multiple organ failure. Several studies have shown the high levels of pro-inflammatory cytokines, indicative of a poor prognosis in COVID-19. Eicosanoids play an important role in the induction of inflammation and cytokine production, while anti-inflammatory and pro-resolving properties of some eicosanoic acid derivatives enable inflamed tissues to return to homeostasis through the resolution of inflammation by aiding the clearance of cell debris and downregulation of pro-inflammatory stimulants. This review attempts to provide an overall insight on the eicosanoids synthesis and their role in the resolution of inflammation in the context of Corona Virus infection.
... In this study, EcN treatment increased leukotriene (a metabolite of arachidonic acid) intensity relative to untreated Def pig (indicating an impaired immune response) in PM analysis suggesting that such treatment reduced HRV disease and the inflammatory environment in malnourished hosts. Moreover, arachidonic acid is involved in the immune function of several organs and systems either directly or via conversion to eicosanoids (84,85). Eiconoids exhibit a role in inflammation, protection of mucosal integrity of the gastrointestinal tract, and regulation of aggregation of platelets. ...
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Human rotavirus (HRV) is the most common cause of viral gastroenteritis in children, especially in developing countries, where the efficacy of oral HRV vaccines is reduced. Escherichia coli Nissle 1917 (EcN) is used to treat enteric infections and ulcerative colitis while tryptophan (TRP) is a biomarker of malnutrition, and its supplementation can alleviate intestinal inflammation and normalize intestinal microbiota in malnourished hosts. Supplementation of EcN + TRP to malnourished humanized gnotobiotic piglets enhanced immune responses and resulted in greater protection against HRV infection and diarrhea.
... Combining proteomic with metabolomic profiling is especially attractive, since it may support a functional interpretation of the involved pathways. In addition, signaling lipids are key players during inflamation and act in a concerted fashion with proteins [36,37]. Thus, we have applied an in-depth proteome, metabolome and eicosanoid profiling of the endometriotic epithelial cell line 12-Z to investigate and characterize their responsiveness towards inflammatory signals. ...
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Endometriosis is a benign disease affecting one in ten women of reproductive age worldwide. Although the pain level is not correlated to the extent of the disease, it is still one of the cardinal symptoms strongly affecting the patients’ quality of life. Yet, a molecular mechanism of this pathology, including the formation of pain, remains to be defined. Recent studies have indicated a close interaction between newly generated nerve cells and macrophages, leading to neurogenic inflammation in the pelvic area. In this context, the responsiveness of an endometriotic cell culture model was characterized upon inflammatory stimulation by employing a multi-omics approach, including proteomics, metabolomics and eicosanoid analysis. Differential proteomic profiling of the 12-Z endometriotic cell line treated with TNFα and IL1β unexpectedly showed that the inflammatory stimulation was able to induce a protein signature associated with neuroangiogenesis, specifically including neuropilins (NRP1/2). Untargeted metabolomic profiling in the same setup further revealed that the endometriotic cells were capable of the autonomous production of 7,8-dihydrobiopterin (BH2), 7,8-dihydroneopterin, normetanephrine and epinephrine. These metabolites are related to the development of neuropathic pain and the former three were found up-regulated upon inflammatory stimulation. Additionally, 12-Z cells were found to secrete the mono-oxygenated oxylipin 16-HETE, a known inhibitor of neutrophil aggregation and adhesion. Thus, inflammatory stimulation of endometriotic 12-Z cells led to specific protein and metabolite expression changes suggesting a direct involvement of these epithelial-like cells in endometriosis pain development.
Article
The membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene codes for an enzyme involved in regulating arachidonic acid incorporation in lysophosphatidylinositol. Patients with homozygous nonsense mutations in MBOAT7 have intellectual disability (ID) accompanied with seizure and autism. Accumulating evidences obtained from human genetic studies have shown that MBOAT7 is also involved in fatty liver disease. Here we identified two novel homozygous variants in MBOAT7, NM_024298.5: c.1062C>A; p.(Tyr354*) and NM_024298.5: c.1135del; p.(Leu379Trpfs*9), in two unrelated Iranian families by means of whole exome sequencing. Sanger sequencing performed to confirm the identified variants and also investigate whether they co-segregate with the patients' phenotypes. To understand the functional consequences of these changes, we overexpressed recombinant wild type MBOAT7 and mutants in vitro and showed these mutations resulted in abolished protein synthesis and expression, indicating a complete loss of function. Albeit, we did not trace any liver diseases in our patients, but presence of globus pallidus signal changes in Magnetic Resonance Images might be indicative of metabolic changes as a result of loss of MBOAT7 expression in hepatic cells. These signal changes could also help as an important marker of MBOAT7 deficiency while analyzing the genomic data of patients with similar phenotypes.
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Polyunsaturated fatty acids (ω-3 acids, PUFAs) are essential components of cell membranes in all mammals. A multifactorial beneficial influence of ω-3 fatty acids on the health of humans and other mammals has been observed for many years. Therefore, ω-3 fatty acids and their function in the prophylaxis and treatment of various pathologies have been subjected to numerous studies. Regarding the documented therapeutic influence of ω-3 fatty acids on the nervous and immune systems, the aim of this paper is to present the current state of knowledge and the critical assessment of the role of ω-3 fatty acids in the prophylaxis and treatment of spinal cord injury (SCI) in rodent models. The prophylactic properties (pre-SCI) include the stabilization of neuron cell membranes, the reduction of the expression of inflammatory cytokines (IL-1β, TNF-α, IL-6, and KC/GRO/CINC), the improvement of local blood flow, reduced eicosanoid production, activation of protective intracellular transcription pathways (dependent on RXR, PPAR-α, Akt, and CREB), and increased concentration of lipids, glycogen, and oligosaccharides by neurons. On the other hand, the therapeutic properties (post-SCI) include the increased production of endogenous antioxidants such as carnosine and homocarnosine, the maintenance of elevated GSH concentrations at the site of injury, reduced concentrations of oxidative stress marker (MDA), autophagy improvement (via increasing the expression of LC3-II), and p38 MAPK expression reduction in the superficial dorsal horns (limiting the sensation of neuropathic pain). Paradoxically, despite the well-documented protective activity of ω-3 acids in rodents with SCI, the research does not offer an answer to the principal question of the optimal dose and treatment duration. Therefore, it is worth emphasizing the role of multicenter rodent studies with the implementation of standards which initially may even be based on arbitrary criteria. Additionally, basing on available research data, the authors of this paper make a careful attempt at referring some of the conclusions to the human population. 1. Introduction Polyunsaturated fatty acids (ω-3 acids, PUFAs) are essential components of cell membranes in all mammals [1]. They facilitate normal functioning of the body, but many mammals are unable to synthesize them which necessitates their dietary supply. The group of ω-3 includes alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) [1, 2]. A multifactorial beneficial influence of ω-3 fatty acids on the health of humans and other mammals has been observed for many years. Therefore, ω-3 fatty acids and their function in the prophylaxis and treatment of various pathologies have been subjected to numerous studies. The research includes mainly cardiovascular, immune, and nervous system diseases [3–5]. The treatment of patients after spinal cord injury (SCI) constitutes a particular challenge for contemporary medicine, as those injuries primarily contribute to disorders of the nerve tissue and the immune system during inflammation. Complexity of the natural course of SCI-related pathophysiological events occurs as a result of two subsequent phases such as primary and secondary (delayed) injuries where all parts and compartments of the spinal cord are vulnerable and could be affected [6]. Occurring primary injury is associated with application of external physical force whose character determines the severity of the initial injury [7]. Therefore, primary injury in the case of SCI could in this case result from an external mechanical force (direct/indirect) as well as rapid acceleration/deceleration, ballistic penetration, and less blast exposure arising from shock wave [7]. The macrostructural changes after primary injury in the spinal cord cover damage, laceration, and swelling of the neural tissue as well as various types of structural damage of meninges, ligaments, and bone structures [8]. These events are also connected to the observed changes associated with alternations in circulation of the cerebrospinal fluid (CSF) including an increase of intraspinal pressure (ISP) resulting in subsequent reduction of spinal cord perfusion pressure (SCPP) [9]. The main effects of primary injury cover immediate death of various cell populations associated with rapid reflux of neurotransmitters, dysregulation of transmembrane permeability, and dysfunction of neurovascular units forming blood-spinal cord barrier [10]. Secondary damage includes nonlinear phenomena, including several self-propagating immunology, neurometabolic, and neurochemical events resulting in progressive neurodegeneration [11]. The main mechanisms involved in secondary injury cover local and systemic immunoactivation that involves a multitude of inflammatory mediators and cells, cell death via necrosis or apoptosis, glutamate excitotoxicity, induction of oxidative stress and free-radical generation, altered energy metabolism due to mitochondria dysfunction, and impairment of adenosine-5-triphosphate (ATP) production and calcium- (Ca²⁺-) mediated neurotoxicity associated with abnormal cell membrane permeability [12]. Both, primary and secondary injury-associated events in all neurostructural levels finally lead to progressive neuronal loss, demyelination, lesion expansion, and glial scar formation which results in neurodegeneration of affected parts of the spinal cord manifesting themselves as neurological deficits due to interruption of axonal connections [13, 14]. SCI should be treated not only as local damage but also as systemic pathology, which is manifested in an immune response involving changes in the transcriptome set, proteome set, immune cell recruitment, and the production of inflammatory mediators [15]. One of the main events in SCI is the activation and proliferation of microglial cells (Iba-1⁺) and astrocytes (GFAP⁺) which together with immune cells participate in the creation of a tightly regulated inflammatory microenvironment [16]. In this case, activated microglia cells and astrocytes serve as one of the main sources of cytokines, proteinases, extracellular matrix molecules (ECMs), and growth factors at the epicenter of lesions [17]. Of all secreted cytokines, both in experimental and clinical conditions, tumor necrosis factor alpha (TNF-α) together with interleukin 1 beta (IL-1β) and interleukin 6 (IL-6) dominate in the pathogenesis of SCI and other neurological diseases [18]. It is estimated that approximately 6 million patients are affected by SCI worldwide. Those patients suffer from impaired mobility manifesting as paraplegia or tetraplegia [19]. SCI is associated with the occurrence of numerous complications with the most common ones being the infections of the urinary or respiratory system, development of pressure ulcers, cardiovascular disorders, sleep disturbance, depression, muscle atrophy, and osteoporosis [20]. Circumstances in which SCIs occur in people are commonly heterogenous, sudden, and difficult to predict (e.g., traffic accidents and falls from a height) which makes it hard to formulate reliable conclusions from the implemented treatment. It is much easier to introduce reliable conditions of research on SCI on the animal model during controlled laboratory trials. Rodents, such as mice and rats, belong to the group of animals whose physiology of life processes presents numerous similarities to that of humans. Therefore, this kind of research is currently the most preferred. Regarding the documented therapeutic influence of ω-3 fatty acids on the nervous and immune systems [21, 22], the aim of this paper is to present the current state of knowledge and the critical assessment of the role of ω-3 fatty acids in the prophylaxis and treatment of SCI in rodent models. Basing on available research data in this area, the authors of this paper make a careful attempt at referring some of the conclusions to the human population. 2. The Structure of ω-3 Fatty Acids Fatty acids are characterized by the presence of the carbon chain with a methyl group (-CH3) at one end and a carboxyl group (–COOH) at the other [23]. Unsaturated fatty acids are characterized by the carbon chain which includes at least one double bond. Compounds including one double bond are called monounsaturated fatty acids (MUFAs), while those with two or more double bonds, PUFAs [24]. Another criterion of fatty acid classification is the number of carbon atoms in the carbon chain. Short-chain fatty acids contain up to 13 carbon atoms; long-chain ones, between 14 and 19; and very long-chain fatty acids, over 20 carbon atoms. Notably, fatty acids which occur in humans are mainly characterized by the even number of carbon atoms in the carbon chain. ω-3 fatty acids are a group of chemical compounds with the common feature—the presence of the last double bond in the carbon chain three carbon atoms away from the -CH3 group. They include polyunsaturated fatty acids such as ALA (the carbon chain consists of 18 carbon atoms), EPA (20 carbon atoms in the carbon chain), and DHA (22 carbon atoms in the carbon chain) [23, 24]. Their structure and more, including the location of the double bonds, are presented in Figure 1.
Chapter
Ximenynic acid is a natural conjugated acetylenic fatty acid and primarily exists in the Santalales order. This unusual fatty acid has shown its beneficial effects based on in vitro and in vivo studies. Here, we summarized the research findings of ximenynic acid concerning its anti-inflammation, anticancer, antimicrobial, and larvicidal activities. Ximenynic acid may present an exciting opportunity for the treatment of inflammatory diseases in clinics. Moreover, it involves long-chain fatty acid metabolism, which may regulate insulin secretion and improve insulin resistance. Ximenynic acid also has a vast potential market, because it is widely used in the cosmetics industry. With the discovery of its various biological activities, the demand for ximenynic acid is dramatically increasing. Therefore, it is essential to know how to obtain high-purity ximenynic acid. Natural ximenynic acid is primarily found in the seed oils of three families of Santalales, the Opiliaceae, Olacaceae, and Santalaceae, with total fatty acid content ranging from 1% to 95%. There are a variety of ways to separate and purify ximenynic acid from plant oil. The common ways are recrystallization and chromatography. Besides, ximenynic acid can also be acquired by employing synthesis technology, such as the well-studied chemical synthesis method. Ximenynic acid can be chemically synthesized using coaster oil as the precursor or from propargyl bromide and heptaldehyde, and might be biosynthesized from oleic acid during seed development by dehydrogenation of delta 9, 11 positions. Therefore, biosynthesis of ximenynic acid might be a promising way to obtain ximenynic acid in the future. But so far, the available information about ximenynic acid research is still limited. Further studies, especially on its activities, applications, and advanced preparation methods, are needed.
Article
Zusammenfassung Unsere Lebenserwartung ist zu ca. 30 % genetisch determiniert, die restlichen 70 % bestimmen Ernährung, körperliche Aktivität und soziale Kontakte. Wesentliche Faktoren des Alterungsprozesses sind Immunoseneszenz und Inflammaging, die mit zunehmendem Mobilitäts- und Funktionsverlust assoziiert sind. Die ausreichende Zufuhr von Mikro- und Makronährstoffen spielt bei der Modulation des Immunsystems und der Verringerung des Inflammaging eine wichtige Rolle. Neben einer erhöhten Proteinzufuhr zum Erhalt der Muskelmasse spielen im Alter v. a. die ω-3-Fettsäuren Eicosapentaensäure (EPA) und Docosahexaensäure (DHA) eine wichtige Rolle. Diese maritimen Fettsäuren wirken durch verschiedene Mechanismen antientzündlich und können so dazu beitragen, das Altern zu verlangsamen und der Entstehung von Alterskrankheiten vorzubeugen.
Article
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Inflammation is an immune response of the human body but excessive inflammation is taken as a major factor in the development of many diseases including autoimmune disorders, cancer and nerve disorders etc. In this regards the need is to suppress the inflammatory response. Suppression of extra or imperfect inflammatory response is not a big deal provided there is an exact knowledge of particular target in the body. Recent advancements in Pharmacological aspect made the therapy with improved outcomes in number of patients. Anticytokine therapy might be one of the important and novel approaches for inflammation and Arthritis. This can be achieved only when we go through the pathophysiology of expression and identification of mediators. Let's take an example of cytokine like interleukins (IL), chemokines, interferons (INF), tumor necrosis factors (TNF-α), growth factors, and colony stimulating factors) release pathway which is a major signalling protein in inflammatory response. In the present study we have reviewed the recent pharmacological therapeutic advancement, inflammatory mediators, receptors, and major signalling pathways. Such information will not only provide the idea about the mechanism of action of Pharmaceuticals and molecular targets but also it provides a new aspect for drug designing and new corrective approaches in existing clinical medicines. This study will be a source of good information for the researchers working in the area of drug designing and molecular Pharmacology especially in anti-inflammatory and anti arthritic medicines for target based therapy.
Book
PREFACE Cyanobacteria are among the most successful and ancient forms of life ever known. These photosynthetic autotrophs have been studied for decades as model organisms in various aspects, from photosynthesis to biotechnological applications and, more recently, for their pharmacological potential in umpteen fields. In fact, cyanobacteria are now recognized as top metabolic producers of a huge number of bioactive compounds with medical interest and that can revolutionize drug discovery and development. Allied to their metabolic capabilities, cyanobacteria benefit from a cost-effective energy-capturing ability, and high cultivation yields with minimum nutritional requirements, being extremely attractive in terms of industrial-scale production processes. This book was designed to bring together fields in which cyanobacteria derived compounds most stood out, with a special focus on those related to therapeutics, cosmetics, and nutrition, emphasizing unique molecules not found in higher organisms. Of the most promising compounds isolated so far, those acting as anti-inflammatories, anti-carcinogens, antimicrobials, and UV protectors fill a prominent place within drug discovery programs. The metabolic richness of cyanobacteria has also been upholding their key role in the field of cosmetics and nutraceuticals, with the last occupying a prominent place in a rapidly expanding market. Apart from the pharmacological and biotechnological approach, this book does not set aside the well-known cyanobacterial toxins, warning to their substantial economic and social impacts, and drawing attention to the urgency of fully addressing algal blooms and their systematic monitoring. Additionally, and given its extreme importance, this book provides a distinctive approach to cyanobacteria systematics, by exploring general aspects and biodiversity of these organisms to discuss trends in cyanobacterial taxonomy. Overall, The Pharmacological Potential of Cyanobacteria is intended to be a useful resource for students, researchers, and professionals working in the field of cyanobacteria, serving as a guide in the discovery, research, and application of these unique microorganisms. Graciliana Lopes, Marisa Silva and Vitor Vasconcelos
Book
Cyanobacteria are among the most successful and ancient forms of life ever known. These photosynthetic autotrophs have been studied for decades as model organisms in various aspects, from photosynthesis to biotechnological applications and, more recently, for their pharmacological potential in umpteen fields. In fact, cyanobacteria are now recognized as top metabolic producers of a huge number of bioactive compounds with medical interest and that can revolutionize drug discovery and development. Allied to their metabolic capabilities, cyanobacteria benefit from a cost-effective energy-capturing ability, and high cultivation yields with minimum nutritional requirements, being extremely attractive in terms of industrial-scale production processes. This book was designed to bring together fields in which cyanobacteria derived compounds most stood out, with a special focus on those related to therapeutics, cosmetics, and nutrition, emphasizing unique molecules not found in higher organisms. Of the most promising compounds isolated so far, those acting as anti-inflammatories, anti-carcinogens, antimicrobials, and UV protectors fill a prominent place within drug discovery programs. The metabolic richness of cyanobacteria has also been upholding their key role in the field of cosmetics and nutraceuticals, with the last occupying a prominent place in a rapidly expanding market. Apart from the pharmacological and biotechnological approach, this book does not set aside the well-known cyanobacterial toxins, warning to their substantial economic and social impacts, and drawing attention to the urgency of fully addressing algal blooms and their systematic monitoring. Additionally, and given its extreme importance, this book provides a distinctive approach to cyanobacteria systematics, by exploring general aspects and biodiversity of these organisms to discuss trends in cyanobacterial taxonomy. Overall, The Pharmacological Potential of Cyanobacteria is intended to be a useful resource for students, researchers, and professionals working in the field of cyanobacteria, serving as a guide in the discovery, research, and application of these unique microorganisms. Graciliana Lopes, Marisa Silva and Vitor Vasconcelos
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The cytochrome P450 enzyme superfamily (CYP), E.C. 1.14.-.-, are haem-containing monooxygenases with a vast range of both endogenous and exogenous substrates. These include sterols, fatty acids, eicosanoids, fat-soluble vitamins, hormones, pesticides and carcinogens as well as drugs. Listed below are the human enzymes, their relationship with rodent CYP enzyme activities is obscure in that the species orthologue may not metabolise the same substrates. Some of the CYP enzymes located in the liver are particularly important for drug metabolism, both hepatic and extrahepatic CYP enzymes also contribute to patho/physiological processes. Genetic variation of CYP isoforms is widespread and likely underlies a proportion of individual variation in drug disposition. The superfamily has the root symbol CYP, followed by a number to indicate the family, a capital letter for the subfamily with a numeral for the individual enzyme. Some CYP are able to metabolise multiple substrates, others are oligo- or mono- specific.
Article
Cytochrome P450 4F (CYP4F) enzymes are responsible for the metabolism of eicosanoids, which play important roles in inflammation. Nuclear receptor liver X receptor alpha (LXRα) is a critical signal node connecting inflammation and lipid metabolism. Studies revealed that the release of cytokines and nuclear factor-κB (NF-κB) can change the CYP4F11 expression in HepG2 cells. However, the effect of LXRα on the CYP4F family and the underlying mechanism remain unclear. This study found that CYP4F11 is a target gene of LXRα. Luciferase assays and siRNA transfection showed that LXRα increased the transcription of CYP4F11 and LXRα agonist GW3965 could induce the expression of CYP4F11 by activating the LXRα-CYP4F11 pathway. Besides, overexpression of CYP4F11 could decrease TNF-α and IL-1β in lipopolysaccharide (LPS)-induced THP-1 cells. The finding of the regulation of CYP4F11 may contribute to the anti-inflammatory activity of LXRα agonists.
Chapter
Eine hohe psychische und physische Leistungsfähigkeit bis ins fortgeschrittene Alter steht bei den meisten Menschen ganz oben auf der persönlichen Wunschliste, um möglichst lange selbstständig in der gewohnten Umgebung zu leben. In den letzten 100 Jahren hat sich die mittlere Lebenserwartung der Europäer durch die moderne medizinische Versorgung und Verbesserung der Lebensbedingungen nahezu verdoppelt. Während in Deutschland zu Beginn des letzten Jahrhunderts der Anteil der über 60-Jährigen noch 5 % betrug, sind es gegenwärtig bereits nach Angaben des Statistischen Bundesamtes 26 %, und für das Jahr 2030 wird mit bis zu 36 % der Bevölkerung gerechnet, die das 60. Lebensjahr überschritten haben. Während früher über zwei Drittel der Menschen an Infektionen starben, sterben heute etwa 70 % an Alterskrankheiten (Ben-Haim et al. 2018).
Chapter
Fighting against free radicals has become an important strategy in the prevention of oxidative stress-related diseases including cancer. Antioxidants are complex compounds found in vegetables and in our diet that act as a protective shield for our body against such disastrous diseases. In fact, antioxidants are able to interact with free radicals such as hydroxyl, peroxyl, and superoxide groups, preventing them from binding with biological macromolecules (proteins, lipids, and DNA) in healthy human cells. Therefore, lipid peroxidation, oxidative DNA, and protein damage that may result from this interaction will be reduced considerably leading to a significant reduction in genetic events that favor cancer progression. Medicinal plants are known to contain diverse secondary metabolites that are used in the prevention and treatment of diseases or in the promotion of well-being. For this reason, they are potential sources of free radical scavengers, warranting their investigation as antiradical and anticancer agents.
Chapter
Except for an essential step for the pathology of multiple diseases including atherosclerosis and rheumatoid arthritis, inflammation is an imperative therapeutic target for developing novel approaches for pharmacological interventions. Thus, a molecular understanding of inflammation not only provides a venue for knowledge that reveals the mechanisms of drug action and their biological targets, but also has spawned innovative maneuvers to influence multifaceted biological systems from different levels, providing new prospects for drug design and suggesting important new implications for existing clinical medicine. Meanwhile, the modulation of inflammation with the use of medicinal plants proposes an alternate to conventional therapeutic strategies for numerous ailments, particularly when suppression of inflammation is expected. Given that the mechanisms of insult in these disorders are facilitated by manipulating immune responses, it is factual to assume that the natural sources used for such illnesses may alleviate the immune signals and the subsequent inflammation. In the modern literature, several species of medicinal plants have been shown to have substantial antiinflammatory and immunomodulatory actions, including inhibitory effects on the suppression of cellular and humoral immunity, lymphocyte activation, and propagation of apoptosis. Herein, we review the molecular pharmacology and signaling pathways of inflammation, the chemical components and biological activities of medicinal plants, and their mechanism of action during inflammation at the molecular level. An extensive review of the literature and electronic databases was conducted, encompassing PubMed, Google Scholar, and ScienceDirect to assemble the information.
Chapter
Inflammation is considered as an adaptive response to stimuli like injury or infection. But prolonged or chronic inflammation is capable of causing damage and is proved to be the trigger behind many diseases. So the mechanisms are extensively studied to get a grip on the control over them. There unveiled the multiverse of mechanisms, which raised the requirement of multitarget drugs, than “one target-one drug” concept. Synthetic drugs are invented to meet the purpose but mostly associated with considerable side effects. So the natural compounds with the multitarget approach have become the needs of the time. The current chapter discusses multiple targets involved in the inflammation events and some significant natural compounds that exhibit multitarget perspective on antiinflammatory activities.
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Scope We investigated the FADS1 rs174550 genotype interaction with dietary intakes of high linoleic acid (LA) and high alpha‐linolenic acid (ALA) on the response of fatty acid composition of plasma phospholipids (PLs), and markers of low‐grade inflammation and glucose‐insulin homeostasis. Methods and Results One‐hundred thirty homozygotes men for FADS1 rs174550 SNP (TT and CC genotypes) were randomized to an 8‐week intervention with either LA‐ or ALA‐enriched diet (13 E% PUFA). The source of LA and ALA were 30–50 ml of sunflower oil (SFO, 62–63 % LA) and Camelina sativa oil (CSO, 30–35 % ALA), respectively. In the SFO arm, there was a significant genotype x diet interaction for the proportion of arachidonic acid in plasma phospholipids (p<0.001), disposition index (DI30) (p = 0.039), and for serum high‐sensitive c‐reactive protein (hs‐CRP, p = 0.029) after excluding the participants with hs‐CRP concentration of >10 mg/l and users of statins or anti‐inflammatory therapy. In the CSO arm, there were significant genotype x diet interactions for n‐3 polyunsaturated fatty acids, but not for the clinical characteristics. Conclusions The FADS1 genotype modifies the response to high PUFA diets, especially to high‐LA diet. These findings suggest that approaches considering FADS variation might be useful in personalized dietary counseling. This article is protected by copyright. All rights reserved
Article
Background and Purpose Oridonin (Ori) has been shown to protect against acute liver injury (ALI) induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Oxylipins are oxidation products of polyunsaturated fatty acids (PUFAs) and are key proinflammatory mediators. This study aimed to investigate the changes in oxylipins in the livers of mice with D-GalN/LPS-induced ALI and the effects of Ori on these changes. Results 54 oxylipins in liver tissues were identified and qualitatively and quantitatively analyzed by ultra-performance liquid chromatography-electrospray ionization triple quadrupole mass spectrometry (UPLC-QTRAP/MS/MS). The levels of 12-HETE, 12-HEPE, 14(S)-HDHA, PGE2, dihomo-γ-linolenic acid and 13-HOTrE in the liver were significantly increased in the D-GalN/LPS-induced ALI group compared with the control group, and the levels of EPA and 7-HDHA were significantly decreased. However, pretreatment with Ori dramatically decreased the levels of 12-HETE, 12-HEPE, 14(S)-HDHA, PGE2 and 13-HOTrE compared with those of the ALI group and induced 7-HDHA and 15-oxoETE. Moreover, Ori reduced the protein levels of COX-1, COX-2, ALOX5, ALOX12 and ALOX15 induced by D-GalN/LPS, indicating that Ori altered oxylipins through the COX and LOX pathways. Conclusions These results suggest that the protective effect of Ori on ALI is partly mediated by affecting the oxylipin pathway.
Book
Inflammation and Natural Products brings together research in the area of the natural products and their anti-inflammatory action in medical, nutraceutical and food products, addressing specific chronic inflammatory diseases like cancer and the mechanistic aspects of the mode of action of some key natural products. Inflammation is a complicated process, driven by infection or injury or genetic changes, which results in triggering signalling cascades, activation of transcription factors, gene expression, increased levels of inflammatory enzymes, and release of various oxidants and pro-inflammatory molecules in inflammatory cells. Excessive oxidants and inflammatory mediators have a harmful effect on normal tissue, including toxicity, loss of barrier function, abnormal cell proliferation, inhibiting normal function of tissues and organs and finally leading to systemic disorders. The emerging development of natural product formulations utilizing the unique anti-inflammatory compounds such as polyphenols, polysaccharides, terpenes, fatty acids, proteins and several other bioactive components has shown notable successes. Inflammation and Natural Products: Recent Development and Current Status provides a comprehensive resource, ranging from detailed explanation on inflammation to molecular docking strategies for naturally occurring compounds with anti-inflammatory activity. It is useful for graduate students, academic and professionals in the fields of pharmaceutical and medical sciences and specialists from natural product-related industries.
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Arachidonic acid is metabolized by cyclooxygenase, lipoxygenase, and cytochrome P450 enzymes to produce prostaglandins, leukotrienes, epoxyeicosatrienoic acids (EETs), and hydroxyeicosatetraenoic acids (HETEs), along with other eicosanoids. Eicosanoids have important physiological and pathological roles in the body, including the cardiovascular system. Evidence from several experimental and clinical studies indicates differences in eicosanoid levels, as well as in the activity or expression levels of their synthesizing and metabolizing enzymes between males and females. In addition, there is a clear state of gender specificity in cardiovascular diseases (CVD), which tend to be more common in men compared to women, and their risk increases significantly in postmenopausal women compared to younger women. This could be largely attributed to sex hormones, as androgens exert detrimental effects on the heart and blood vessels, whereas estrogen exhibits cardioprotective effects. Many of androgen and estrogen effects on the cardiovascular system are mediated by eicosanoids. For example, androgens increase the levels of cardiotoxic eicosanoids like 20-HETE, while estrogens increase the levels of cardioprotective EETs. Thus, sex differences in eicosanoid levels in the cardiovascular system could be an important underlying mechanism for the different effects of sex hormones and the differences in CVD between males and females. Understanding the role of eicosanoids in these differences can help improve the management of CVD.
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Eicosanoids are 20-carbon fatty acids, where the usual focus is the polyunsaturated analogue arachidonic acid and its metabolites. Arachidonic acid is thought primarily to derive from phospholipase A2 action on membrane phosphatidylcholine, and may be re-cycled to form phospholipid through conjugation with coenzyme A and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450-like epoxygenases, particularly CYP2J2. Isoprostanes are structural analogues of the prostanoids (hence the nomenclature D-, E-, F-isoprostanes and isothromboxanes), which are produced in the presence of elevated free radicals in a non-enzymatic manner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined.
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Ischemic heart disease is among the primary causes of cardiovascular-related deaths worldwide. Conventional treatments including surgical interventions and medical therapies aid in preventing further damage to heart muscle but are unable to provide a permanent solution. In recent years, stem cell therapy has emerged as an attractive alternative to restore damaged myocardium after myocardial injury. Allogeneic (donor-derived) mesenchymal stem cells (MSCs) have shown great promise in preclinical and clinical studies, making them the most widely accepted candidates for cardiac cell therapy. MSCs promote cardiac repair by modulating host immune system and secreting various soluble factors, of which prostaglandin E2 (PGE2) is an important one. PGE2 plays a significant role in regulating cardiac remodeling following myocardial injury. In this review, we provide an overview of allogeneic MSCs as candidates for myocardial regeneration with a focus on the role of the PGE2/cyclooxygenase-2 (COX2) pathway in mediating these effects.
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Eicosanoids containing a 12-hydroxyl group preceded by at least two conjugated double bonds are metabolized to 10,11-dihydro and 10,11-dihydro-12-oxo products by porcine polymorphonuclear leukocytes (PMNL) (Wainwright, S. L., Falck, J. R., Yadagiri, P., and Powell, W. S. (1990) Biochemistry 29, 10126-10135). These 10,11-dihydro metabolites could either have been formed by the direct reduction of the 10,11-double bond of the substrate, as previous evidence suggested, or via an initially formed 12-oxo intermediate. To gain some insight into the mechanism for the formation of dihydro products by this pathway, we investigated the metabolism of leukotriene B4 (LTB4), 12(S)-hydroxy-5,8,10,14-eicosatetraenoicacid(12(S)-HETE), and 12(R)-HETE by subcellular fractions from porcine PMNL. In the presence of NAD+ and a microsomal fraction from PMNL, each of the above 12-hydroxyeicosanoids was converted to a single product with a lambda max approximately 40 nm higher than that of the substrate, indicating that the conjugated diene or triene chromophore had been extended by one double bond, presumably by oxidation of the 12-hydroxyl group to an oxo group. In the case of LTB4, this was confirmed by mass spectrometry, which indicated that the product was identical to 12-oxo-LTB4. LTB4 was not converted to any products by a cytosolic fraction from PMNL, but was converted to both 10,11-dihydro-LTB4 and 10,11-dihydro-12-oxo-LTB4 by the 1500 x g supernatant in the presence of NAD+. Negligible amounts of dihydro products were formed in the presence of NADH or NADPH, suggesting that initial oxidation of the 12-hydroxyl group is a requirement for reduction of the 10,11-double bond. Consistent with this hypothesis, 12-oxo-LTB4 was rapidly metabolized to 10,11-dihydro-12-oxo-LTB4 by the cytosolic fraction in the presence of NADH. Only small amounts of this product, along with some LTB4, were formed by the microsomal fraction. These results indicate that the initial step in the formation of 10,11-dihydro products from 12-hydroxyeicosanoids is oxidation of the 12-hydroxyl group by a microsomal 12-hydroxyeicosanoid dehydrogenase in the presence of NAD+, which is followed by reduction of the olefinic double bond by a cytosolic delta 10-reductase in the presence of NADH.
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The ability of leukotrienes derived from eicosapentaenoic acid were compared with counterpart leukotrienes derived from arachidonic acid in terms of their ability to affect susceptibility of the stomach to injury induced by a topical irritant and their ability to alter gastric blood flow. Intra-arterial infusion of leukotriene C4 (LTC4) and LTD4 (0.1-3 micrograms/kg/min for 5 min) produced dose-dependent increases in gastric mucosal damage induced by topically applied 20% ethanol, as assessed macroscopically, by changes in transmucosal potential difference and by measurement of efflux of protein into the gastric lumen. Similar doses of LTC5 or LTD5 did not produce significant changes in any of these three parameters, when compared with control rats receiving the vehicle. With a higher dose of LTC5 or LTD5 (5 micrograms/kg/min), significant damage was observed. LTC4 and LTD4 were also found to be more potent at reducing gastric blood flow than LTC5 and LTD5. These results demonstrate that the peptido-leukotrienes derived from eicosapentaenoic acid (LTC5 and LTD5) are on the order of five times less potent than the leukotrienes derived from arachidonic acid (LTC4 and LTD4), in terms of increasing the susceptibility of the gastric mucosa to damage and reducing gastric blood flow. These results may have important implications in terms of the hypothesis that fish oil diets may be protective or may accelerate healing in ulcerative diseases of the gastrointestinal tract.
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The interest in lipid mediators of inflammation as potential contributors to the pathogenesis of gastric ulcer has increased markedly over the past 20 yr. Although a great deal is known about the actions of mediators such as leukotrienes, thromboxane, and platelet-activating factor in experimental models of ulceration, evidence supporting a role for these mediators in human gastric ulcer is sorely lacking. This review attempts to answer a number of questions regarding the contribution of these mediators to the pathogenesis of gastric ulceration and the possible use of specific inhibitors, antagonists, and dietary manipulation in the treatment of gastric ulcer. Potential directions for future research in this field are suggested as are some of the pitfalls to be avoided in such studies.
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Granulocytes and mononuclear cells were isolated from the blood of asthmatic and healthy children. Stimulation with ionophore A 23187 induced a significantly higher leukotriene C4 (LTC4) generation from granulocytes of asthmatic children than from granulocytes of healthy controls. In contrast, mononuclear cells from patients and controls did not differ in their ability to produce LTC4. Additional analysis showed that the difference in LTC4 generation of granulocytes was due to increased formation but not to decreased oxidative degradation of LTC4. Analysis of LTC4 generation of purified neutrophils and eosinophils revealed that LTC4 was generated almost exclusively by eosinophils and, in particular, the hypodense population. Granulocytes from patients with a history of severe asthma displayed a higher LTC4 formation than granulocytes from patients with less severe disease.
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The stereochemistry and double bond geometry of a novel series of leukocyte-derived arachidonic acid metabolites, the lipoxins, was determined by comparison to pure unambiguous synthetic standards. The lipoxins were found to be a mixture of four lipoxin A isomers and two lipoxin B isomers. In determining the biosynthesis of these compounds, they were shown to be formed via a tetraene epoxide. In addition, it was shown that all of the lipoxin isomers formed by the incubation of 15-hydroperoxyeicosatetraenoic acid with human leukocytes were also formed by nonenzymatic hydrolysis of this tetraene epoxide.
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Aspirin (acetylsalicylic acid) reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one-quarter. The mechanism is believed to be inhibition of thromboxane biosynthesis by inactivation of platelet cyclo-oxygenase-1 enzyme. However, aspirin is not that effective; it still fails to prevent the majority of serious vascular events. Mechanisms that may account for the failure of aspirin to prevent vascular events include non-atherothrombotic causes of vascular disease, non-adherence to aspirin therapy, an inadequate dosage, alternative ‘upstream’ pathways of platelet activation (e.g. via stimulation of the ADP, collagen or thrombin receptors on platelets), aspirin-insensitive thromboxane biosynthesis (e.g. via monocyte cyclo-oxygenase-2), or drugs that interfere with the antiplatelet effects of aspirin. Genetic or acquired factors may further modify the inhibitory effects of aspirin on platelets (e.g. polymorphisms involving platelet-associated proteins, increased platelet turnover states). Identification and treatment of the potential causes of aspirin failure could prevent at least another 20% of serious vascular events (i.e. over and above those that are currently prevented by aspirin). There is currently no role for routine laboratory testing to measure the antiplatelet effects of aspirin. Clinicians should ensure that patients at high risk of atherothrombosis (>3% risk over 5 years) are compliant with aspirin therapy and are taking the correct dosage (75–150 mg/day). Patients who cannot tolerate aspirin, are allergic to aspirin, or have experienced recurrent serious atherothrombotic events whilst taking aspirin, should be treated with clopidogrel, and patients with acute coronary syndromes benefit from the combination of clopidogrel plus aspirin. Future research is required to standardize and validate laboratory testing of the antiplatelet effects of aspirin and to identify treatments that can both improve these laboratory measures and reduce the risk of future atherothrombotic events.
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The first total synthesis of the methyl ester of 20-oxo-LTB426 is described. The key synthon 6 is an advanced new intermediate which has been used in the synthesis of LTB41, 20-oxo-LTB4 methyl ester 26, and 20-hydroxy-LTB42. The synthetic 26 has been used to study the cytosolic aldehyde dehydrogenase-catalyzed oxidation of LTB4 to its ω-carboxy metabolite.
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Background: It is the rare physician who includes diet therapy and nutritional supplements in patient care. Perhaps this is because chiropractic and medical schools devote very few classroom hours to nutrition. It is also possible that physicians are under the misconception that a detailed biochemical understanding of each individual disease is required before nutritional interventions can be used. Objective: The purpose of this article is two-fold: (1) to demonstrate that chronic pain and other degenerative conditions encountered in clinical practice have similar biochemical etiologies, such as a diet-induced proinflammatory state, and (2) to outline a basic nutritional program that can be used by all practitioners. Data Sources: The data were accumulated over a period of years by reviewing contemporary articles and books and subsequently by retrieving relevant articles. Articles were also selected through MEDLINE and manual library searches. Results: The typical American diet is deficient in fruits and vegetables and contains excessive amounts of meat, refined grain products, and dessert foods. Such a diet can have numerous adverse biochemical effects, all of which create a proinflammatory state and predispose the body to degenerative diseases. It appears that an inadequate intake of fruits and vegetables can result in a suboptimal intake of antioxidants and phytochemicals and an imbalanced intake of essential fatty acids. Through different mechanisms, each nutritional alteration can promote inflammation and disease. Conclusion: We can no longer view different diseases as distinct biochemical entities. Nearly all degenerative diseases have the same underlying biochemical etiology, that is, a diet-induced proinflammatory state. Although specific diseases may require specific treatments, such as adjustments for hypomobile joints, β-blockers for hypertension, and chemotherapy for cancer, the treatment program must also include nutritional protocols to reduce the proinflammatory state.
Article
The first total synthesis of 5-oxo-12(S)-hydroxy-6(E),8(Z),10(E), 14(Z)-eicosatetraenoic acid (5-oxo-12-HETE) 6 and its 8-trans-isomer 7 is reported. The synthetic 5-oxo-12-HETE 6 and its 8,9-trans-isomer 7 were used to identify their formation in mixtures of platelets and neutrophils by transcellular metabolism.
Article
The first total synthesis of the 5(S)-hydroxy-10,11-dihydro-12-oxo-6(Z),8(E),14(Z)-eicosatrienoic acid (10,11-dihydro-12-oxo-LTB4) (3) is reported. This compound is a key pivotal intermediate in the biotransformation of LTB4 by the so-called “LTB4 reductase pathway”.
Article
The first total synthesis of an ω-amino 5-HETE derivative 27 has been accomplished by a new counterclockwise strategy, in which C-1 is constructed first and C-20 last. The ω-amino 5-HETE derivative was transformed to an affinity chromatography ligand, the biotinylated 5-HETE 30. This affinity chromatography ligand is aimed at purifying the 5-hydroxyeicosanoid dehydrogenase enzyme, which is responsible for the conversion of 5-HETE to 5-oxo-ETE, a potent eosinophil chemotactic factor.
Article
The first total synthesis of the highly unstable biological mediator 12-etoicosaetranoic acid (12-KETE) and its 8,9-trans -isomer is presented. The strategy focuses on the stable precursor dithiane and its conversion to and . Biochemical experiments show that the two isomers are not interconverted in vivo, raising the possibility that the trans-isomer may be formed by a primary biochemical mechanism.
Article
Background: The cysteinyl leukotrienes (CysLTs) mediate their biological actions through two receptors: CysLT1 receptor and CysLT2 receptor. Objective: This study was undertaken to examine the direct effects of CysLTs on eosinophils, such as chemotaxis and degranulation, focusing on CysLT1. Methods: Eosinophils were isolated from venous blood from normal volunteers who had no history of allergy (purity >99&percnt;). They were subjected to reverse transcription-PCR analysis and flow-cytometric analysis for CysLT1. Binding assays were performed with [3H]LTD4. Purified eosinophils loaded with Fura-2 acetoxymethyl ester were stimulated with CysLTs, and Ca2&plus; influx was measured. Eosinophil migration in response to CysLTs was measured using a 96-well multiwell Boyden chamber. Eosinophils were treated with LTD4 at 10–6M for 60 min followed by incubation for 4 h at 37°C in the presence or absence of IL-5 and eosinophil-derived neurotoxin (EDN) release was evaluated. Results: The expression of the mRNA and protein of CysLT1 on eosinophils and [3H]LTD4-specific binding to eosinophils were observed. Neither Th1 cytokine (IFN-γ) nor Th2 cytokines (IL-4 or IL-5) affected CysLT1 expression in eosinophils. CysLTs induced an increase in intracellular free Ca2&plus; in eosinophils via CysLT1, as suggested by the efficient inhibition by a CysLT1 antagonist, pranlukast, in addition to the rank order of potency being LTD4, LTC4 and LTE4. LTD4 stimulated eosinophils to migrate at 10–6M via CysLT1. LTE4 also induced significant eosinophil migration at 10–6M. LTD4 enhanced EDN release induced by IL-5 via CysLT1. Conclusion: CysLTs induce migration and enhance degranulation in eosinophils via CysLT1. Accordingly, interaction of CysLTs and CysLT1 on eosinophils has the potential to play a prominent role in the pathophysiology of asthma.
Article
In 1975, Hamberg et al. 1 reported evidence for the existence of an unstable platelet-aggregating factor which they named thromboxane A2 (TXA2) and for which they proposed a novel bicyclic oxetane structure (1, below) based on the short half-life of the factor (t 1/2(37°C) = 32 s at pH 7.4) and the isolation of degradation products related to thromboxane (TXB2) (2, below). As natural TXA2 has not yet been isolated and characterized as a pure compound, we have synthesized the proposed structure (1) from TXB2 and compared its biological properties with those of authentic, biologically generated material. Here we present evidence that synthetic material having structure (1) is indistinguishable from platelet-derived TXA2 in various biological assays and that the proposed structure (1) for TXA2 is correct.
Article
The first total synthesis of a potent inflammatory mediator 5-oxo-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid (5-oxo-ETE) 2 and its biotransformation product 6,7-dihydro-5-oxo-ETE 5 is reported. A convergent synthesis for the unstable title compounds is accomplished via two synthons, dithiolane aldehyde 13 and bisdienyl phosphonium bromide 19. The synthetic 5-oxo-ETE 2 and its 8,9-trans isomer 3 were used to unequivocally confirm the structure of the biologically derived mediators. In addition, using synthetic 6,7-dihydro-5-oxo-ETE 5 we have been able to identify in neutrophils the formation of 6,7-dihydro-5-oxo-ETE 5.
Article
The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.
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IntroductionHuman Platelets, Thromboembolic Disorders, and NONitrovasodilators Glyceryl Trinitrate, Nitroglycerin (GTN)Isosorbide Dinitrate (ISDN) and Isosorbide Mononitrate (ISMN)Sodium Nitroprusside (SNP)Oxatriazolium NO Donors SydnoniminesNitrosothiol NO Donors S-Nitroso-glutathione (GSNO)L-Arginine {S(+)-2-Amino-5-[(aminoiminomethyl)amino]pentanoic acid} (L-arg)NCX-4016 [2-Acetoxybenzoate 2-(1-nitroxy-methyl)-phenyl ester]Conclusion and Future Prospects Glyceryl Trinitrate, Nitroglycerin (GTN)Isosorbide Dinitrate (ISDN) and Isosorbide Mononitrate (ISMN)Sodium Nitroprusside (SNP) Sydnonimines S-Nitroso-glutathione (GSNO)
Article
We investigated the effect of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulphinyl)phenyl]pyrazole), a novel and selective cyclo-oxygenase (COX)-2 inhibitor, in rat adjuvant arthritis. The results were compared with that of indomethacin. We tested the inhibitory effects of FR140423 on paw oedema and the formation of the arachidonic acid metabolites prostaglandin (PG) E2 and leukotriene (LT) B4 in inflamed paws immunized with heat-killed and dried Mycobacterium tuberculosis. Oral administration of FR140423 showed a dose-dependent anti-inflammatory effect. This effect was two- to threefold more potent than that of indomethacin. The increase of PGE2 and LTB4 in inflamed paws was associated with the development of paw swelling. FR140423 and indomethacin dose-dependently suppressed the level of PGE2 but not LTB4 in arthritic paws. Unlike indomethacin, FR140423 did not induce gastric lesions even at doses up to 10 mg kg−1 in arthritic rats. FR140423 has a potent anti-inflammatory effect mediated by inhibition of PGE2 produced by COX-2 in inflamed tissues. The safety profile of FR140423 appears to be an improvement on the safety profile of indomethacin.