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Lipid mediators are critical in resolving inflammation: a review of the emerging roles of eicosanoids in diabetes mellitus.

Tessaro FH, Ayala TS, Martins JO - Biomed Res Int (2015)

Bottom Line: The biosynthesis pathway of eicosanoids derived from arachidonic acid, such as prostaglandins and leukotrienes, relates to the pathophysiology of diabetes mellitus (DM).A better understanding of how lipid mediators modulate the inflammatory process may help recognize key factors underlying the progression of diabetes complications.Our review presents recent knowledge about eicosanoid synthesis and signaling in DM-related complications, and discusses eicosanoid-related target therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 580, Bloco 17, 05508-000 São Paulo, SP, Brazil.

ABSTRACT
The biosynthesis pathway of eicosanoids derived from arachidonic acid, such as prostaglandins and leukotrienes, relates to the pathophysiology of diabetes mellitus (DM). A better understanding of how lipid mediators modulate the inflammatory process may help recognize key factors underlying the progression of diabetes complications. Our review presents recent knowledge about eicosanoid synthesis and signaling in DM-related complications, and discusses eicosanoid-related target therapeutics.

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Related in: MedlinePlus

Eicosanoid synthesis pathways. After cell stimulation, arachidonic acid (AA) can be metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP 450). COX catalyzes AA in (prostaglandin) PGG2 and PGH2, and these are converted into PGD2, PGE2, PGF2α, PG12, TXA1, and TXA2. The LOX pathway catalyzes AA into hydroxyeicosatetraenoic acids (HETEs) and diverse hydroperoxyeicosatetraenoic acids (HPETEs). This pathway involves four enzymes: 5-LOX, 8-LOX, 12-LOX, and 15-LOX. 5-LOX interacts with a 5-LOX-activating protein (FLAP), enhancing the interaction of 5-LOX to AA. LTA4 hydrolases convert LTA4 into LTB4, and LTC4 synthase can convert LTA4 to LTC4, whereupon it is then metabolized to LTD4 and LTE4. 5-LOX synthetizes LXA4 and LXB4 using 15-HETE. The pathway of CYP-450 leads to the conversion of HETEs, including 16-, 17-, 18-, 19-, and 20-HETE and epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EET.
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fig1: Eicosanoid synthesis pathways. After cell stimulation, arachidonic acid (AA) can be metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP 450). COX catalyzes AA in (prostaglandin) PGG2 and PGH2, and these are converted into PGD2, PGE2, PGF2α, PG12, TXA1, and TXA2. The LOX pathway catalyzes AA into hydroxyeicosatetraenoic acids (HETEs) and diverse hydroperoxyeicosatetraenoic acids (HPETEs). This pathway involves four enzymes: 5-LOX, 8-LOX, 12-LOX, and 15-LOX. 5-LOX interacts with a 5-LOX-activating protein (FLAP), enhancing the interaction of 5-LOX to AA. LTA4 hydrolases convert LTA4 into LTB4, and LTC4 synthase can convert LTA4 to LTC4, whereupon it is then metabolized to LTD4 and LTE4. 5-LOX synthetizes LXA4 and LXB4 using 15-HETE. The pathway of CYP-450 leads to the conversion of HETEs, including 16-, 17-, 18-, 19-, and 20-HETE and epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EET.

Mentions: Eicosanoids are biologically active lipid mediators that regulate inflammation [1] and that include prostaglandins (PGs), prostacyclins, thromboxanes (TX), leukotrienes (LT), and lipoxins (LX) (Figure 1) [2–4]. They may amplify or reduce inflammation, which coordinates cytokine production, antibody formation, cell proliferation and migration, and antigen presentation [2, 5, 6]. To prevent great tissue damage, eicosanoids also control the inflammatory resolution and tissue repair process [7, 8]. Imbalances in eicosanoid synthesis have been reported to drive chronic inflammation [1, 9], which deregulates signaling pathways and/or cellular events leading to abnormal immune functions [6, 10]. In particular, circulating and local mediators, such as eicosanoids, interleukin- (IL-) 1β, tumor necrosis factor- (TNF-) α, IL-6, IL-8, macrophage migration inhibitory factor (MIF), and free radicals, create a state of low-chronic inflammation in diabetic patients [5, 10, 11]. Inflammation may lead to diabetes progression, including damage to the kidneys (diabetic nephropathy), eyes (diabetic retinopathy), nerves (diabetic neuropathy), and cardiovascular system [12] (Figure 2).


Lipid mediators are critical in resolving inflammation: a review of the emerging roles of eicosanoids in diabetes mellitus.

Tessaro FH, Ayala TS, Martins JO - Biomed Res Int (2015)

Eicosanoid synthesis pathways. After cell stimulation, arachidonic acid (AA) can be metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP 450). COX catalyzes AA in (prostaglandin) PGG2 and PGH2, and these are converted into PGD2, PGE2, PGF2α, PG12, TXA1, and TXA2. The LOX pathway catalyzes AA into hydroxyeicosatetraenoic acids (HETEs) and diverse hydroperoxyeicosatetraenoic acids (HPETEs). This pathway involves four enzymes: 5-LOX, 8-LOX, 12-LOX, and 15-LOX. 5-LOX interacts with a 5-LOX-activating protein (FLAP), enhancing the interaction of 5-LOX to AA. LTA4 hydrolases convert LTA4 into LTB4, and LTC4 synthase can convert LTA4 to LTC4, whereupon it is then metabolized to LTD4 and LTE4. 5-LOX synthetizes LXA4 and LXB4 using 15-HETE. The pathway of CYP-450 leads to the conversion of HETEs, including 16-, 17-, 18-, 19-, and 20-HETE and epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EET.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4383369&req=5

fig1: Eicosanoid synthesis pathways. After cell stimulation, arachidonic acid (AA) can be metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP 450). COX catalyzes AA in (prostaglandin) PGG2 and PGH2, and these are converted into PGD2, PGE2, PGF2α, PG12, TXA1, and TXA2. The LOX pathway catalyzes AA into hydroxyeicosatetraenoic acids (HETEs) and diverse hydroperoxyeicosatetraenoic acids (HPETEs). This pathway involves four enzymes: 5-LOX, 8-LOX, 12-LOX, and 15-LOX. 5-LOX interacts with a 5-LOX-activating protein (FLAP), enhancing the interaction of 5-LOX to AA. LTA4 hydrolases convert LTA4 into LTB4, and LTC4 synthase can convert LTA4 to LTC4, whereupon it is then metabolized to LTD4 and LTE4. 5-LOX synthetizes LXA4 and LXB4 using 15-HETE. The pathway of CYP-450 leads to the conversion of HETEs, including 16-, 17-, 18-, 19-, and 20-HETE and epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EET.
Mentions: Eicosanoids are biologically active lipid mediators that regulate inflammation [1] and that include prostaglandins (PGs), prostacyclins, thromboxanes (TX), leukotrienes (LT), and lipoxins (LX) (Figure 1) [2–4]. They may amplify or reduce inflammation, which coordinates cytokine production, antibody formation, cell proliferation and migration, and antigen presentation [2, 5, 6]. To prevent great tissue damage, eicosanoids also control the inflammatory resolution and tissue repair process [7, 8]. Imbalances in eicosanoid synthesis have been reported to drive chronic inflammation [1, 9], which deregulates signaling pathways and/or cellular events leading to abnormal immune functions [6, 10]. In particular, circulating and local mediators, such as eicosanoids, interleukin- (IL-) 1β, tumor necrosis factor- (TNF-) α, IL-6, IL-8, macrophage migration inhibitory factor (MIF), and free radicals, create a state of low-chronic inflammation in diabetic patients [5, 10, 11]. Inflammation may lead to diabetes progression, including damage to the kidneys (diabetic nephropathy), eyes (diabetic retinopathy), nerves (diabetic neuropathy), and cardiovascular system [12] (Figure 2).

Bottom Line: The biosynthesis pathway of eicosanoids derived from arachidonic acid, such as prostaglandins and leukotrienes, relates to the pathophysiology of diabetes mellitus (DM).A better understanding of how lipid mediators modulate the inflammatory process may help recognize key factors underlying the progression of diabetes complications.Our review presents recent knowledge about eicosanoid synthesis and signaling in DM-related complications, and discusses eicosanoid-related target therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 580, Bloco 17, 05508-000 São Paulo, SP, Brazil.

ABSTRACT
The biosynthesis pathway of eicosanoids derived from arachidonic acid, such as prostaglandins and leukotrienes, relates to the pathophysiology of diabetes mellitus (DM). A better understanding of how lipid mediators modulate the inflammatory process may help recognize key factors underlying the progression of diabetes complications. Our review presents recent knowledge about eicosanoid synthesis and signaling in DM-related complications, and discusses eicosanoid-related target therapeutics.

Show MeSH
Related in: MedlinePlus