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Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 21687

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Dr. Dong Soon Im

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Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
Interests: intercellular lipid mediator; G protein-coupled receptor; immunometabolism; sphingosine 1-phosphate; lysophosphatidic acid; omega-3 polyunsaturated fatty acid; DHA; EPA; inflammation; resolution

Special Issue Information

Dear Colleagues,

Several groups of lipids are now recognized as intercellular signaling molecules. Traditionally, not only arachidonic acid derivatives such as prostaglandins and leukotrienes but also cholesterol derivatives such as estrogen and cortisol have been studied in pharmacology at the molecular level. In the post-genome era, many lipid molecules have been suggested as intercellular signaling lipid molecules. For example, short-, medium-, and long-chain fatty acids, polyunsaturated fatty acids, oxidized fatty acids, and fatty acid derivatives are recognized as pathophysiological regulators. The Special Issue “Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives” aims to stimulate the lipid research field with updated information. This Special Issue will accept articles not only on the pharmacology of fatty acids and fatty acid derivatives but also on their nutrition, biochemistry, pathophysiology, medicinal chemistry, analytical chemistry, bioinformatics, etc.

An aim of this Special Issue is to focus on both basic science and translational research along with clinical implications in order to have a better understanding of the intercellular signaling lipid molecules.

Dr. Dong Soon Im
Guest Editor

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Keywords

free fatty acid
fatty acid derivative
FFAR1
FFAR2
FFAR3
FFAR4
GPR84
lysophosphatidic acid
sphingosine 1-phosphate

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Published Papers (7 papers)

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Research

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11 pages, 3685 KiB

Open AccessArticle

Efficacy Comparison of LPA₂ Antagonist H2L5186303 and Agonist GRI977143 on Ovalbumin-Induced Allergic Asthma in BALB/c Mice

by Ye-Ji Lee and Dong-Soon Im

Int. J. Mol. Sci. 2022, 23(17), 9745; https://doi.org/10.3390/ijms23179745 - 28 Aug 2022

Cited by 13 | Viewed by 1723

Abstract

Lysophosphatidic acid (LPA), an intercellular lipid mediator, is increased in the bronchoalveolar fluids of patients with asthma after allergen exposure. LPA administration exaggerates allergic responses, and the type 2 LPA receptor (LPA₂) has been reported as a therapeutic target for asthma. However, results with LPA₂ agonist and antagonist along with LPA₂ gene deficient mice have been controversial and contradictory. We compared the effects of LPA₂ antagonist (H2L5186303) and agonist (GRI977143) in a single experimental protocol of ovalbumin (OVA)-induced allergic asthma by treating drugs before antigen sensitization or challenge. H2L5186303 showed strong suppressive efficacy when administered before OVA sensitization and challenge, such as suppression of airway hyper responsiveness, inflammatory cytokine levels, mucin production, and eosinophil numbers. However, GRI977143 showed significant suppression when administered before an OVA challenge. Increases in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid, Th2 cytokine levels, inflammatory scores, and mucin production were differentially ameliorated by the two drugs. The results demonstrate the multiple roles of LPA₂ in asthmatic responses. We suggest that the development of LPA₂ antagonists would achieve better therapeutic efficacy against asthma than agonists. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives)

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15 pages, 4076 KiB

Open AccessArticle

Activation of Free Fatty Acid Receptor 4 (FFA4) Ameliorates Ovalbumin-Induced Allergic Asthma by Suppressing Activation of Dendritic and Mast Cells in Mice

by So-Eun Son, Jung-Min Koh and Dong-Soon Im

Int. J. Mol. Sci. 2022, 23(9), 5270; https://doi.org/10.3390/ijms23095270 - 9 May 2022

Cited by 12 | Viewed by 2940

Abstract

Epidemiological and clinical studies have suggested that intake of n-3 polyunsaturated fatty acids (PUFA) reduces the incidence of allergic airway diseases and improves pulmonary function in patients with allergic asthma. However, the pharmacological targets of PUFA have not been elucidated upon. We investigated whether free fatty acid receptor 4 (FFA4, also known as GPR120) is a molecular target for beneficial PUFA in asthma therapy. In an ovalbumin (OVA)-induced allergic asthma model, compound A (a selective agonist of FFA4) was administrated before OVA sensitization or OVA challenge in FFA4 wild-type (WT) and knock-out (KO) mice. Compound A treatment of RBL-2H3 cells suppressed mast cell degranulation in vitro in a concentration-dependent manner. Administration of compound A suppressed in vivo allergic characteristics in bronchoalveolar lavage fluid (BALF) and lungs, such as inflammatory cytokine levels and eosinophil accumulation in BALF, inflammation and mucin secretion in the lungs. Compound A-induced suppression was not only observed in mice treated with compound A before OVA challenge, but in mice treated before OVA sensitization as well, implying that compound A acts on mast cells as well as dendritic cells. Furthermore, this suppression by compound A was only observed in FFA4-WT mice and was absent in FFA4-KO mice, implying that compound A action is mediated through FFA4. Activation of FFA4 may be a therapeutic target of PUFA in allergic asthma by suppressing the activation of dendritic cells and mast cells, suggesting that highly potent specific agonists of FFA4 could be a novel therapy for allergic asthma. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives)

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14 pages, 3501 KiB

Open AccessArticle

Free Fatty Acid Receptor 4 (FFA4) Activation Ameliorates Imiquimod-Induced Psoriasis in Mice

by So-Eun Son, Jung-Min Koh and Dong-Soon Im

Int. J. Mol. Sci. 2022, 23(9), 4482; https://doi.org/10.3390/ijms23094482 - 19 Apr 2022

Cited by 5 | Viewed by 2520

Abstract

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been used as an adjunct therapy for psoriasis due to its anti-inflammatory properties. Free fatty acid receptor 4 (FFA4 or GPR120) is a receptor-sensing n-3 PUFA. In the present study, we examined whether FFA4 acted as a therapeutic target for n-3 PUFA in psoriasis therapy. Experimentally, psoriasis-like skin lesions were induced by treatment with imiquimod for 6 consecutive days. A selective FFA4 agonist, Compound A (30 mg/kg), was used in FFA4 WT and FFA4 KO mice. Imiquimod-induced psoriasis-like skin lesions, which present as erythematous papules and plaques with silver scaling, as well as markedly elevated IL-17/IL-23 cytokine levels in skin tissues, were significantly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Enlarged lymph nodes and spleens, as well as imiquimod-induced, elevated IL-17/IL-23 cytokine levels, were also strongly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Imiquimod-induced increases in the CD4⁺IL-17A⁺ T cell population in lymph nodes and spleens were suppressed by Compound A treatment in FFA4 WT mice; however, this was not seen in FFA4 KO mice. Furthermore, compound A suppressed the differentiation of CD4⁺ naïve T cells from splenocytes into T_H17 cells in an FFA4-dependent manner. In conclusion, we demonstrated that the activation of FFA4 ameliorates imiquimod-induced psoriasis, and the suppression of the differentiation of T_H17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives)

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16 pages, 3514 KiB

Open AccessArticle

GPR55 Antagonist CID16020046 Protects against Atherosclerosis Development in Mice by Inhibiting Monocyte Adhesion and Mac-1 Expression

by Seung-Jin Lee and Dong-Soon Im

Int. J. Mol. Sci. 2021, 22(23), 13084; https://doi.org/10.3390/ijms222313084 - 3 Dec 2021

Cited by 7 | Viewed by 2560

Abstract

GPR55 recognizes several lipid molecules such as lysophosphatidylinositol. GPR55 expression was reported in human monocytes. However, its role in monocyte adhesion and atherosclerosis development has not been studied. The role of GPR55 in monocyte adhesion and atherosclerosis development was investigated in human THP-1 monocytes and ApoE^−/− mice using O-1602 (a potent agonist of GPR55) and CID16020046 (a specific GPR55 antagonist). O-1602 treatment significantly increased monocyte adhesion to human umbilical vein endothelial cells, and the O-1602-induced adhesion was inhibited by treatment with CID16020046. O-1602 induced the expression of Mac-1 adhesion molecules, whereas CID16020046 inhibited this induction. Analysis of the promoter region of Mac-1 elucidated the binding sites of AP-1 and NF-κB between nucleotides −750 and −503 as GPR55 responsive elements. O-1602 induction of Mac-1 was found to be dependent on the signaling components of GPR55, that is, Gq protein, Ca²⁺, CaMKK, and PI3K. In Apo^−/⁻ mice, administration of CID16020046 ameliorated high-fat diet-induced atherosclerosis development. These results suggest that high-fat diet-induced GPR55 activation leads to the adhesion of monocytes to endothelial cells via induction of Mac-1, and CID16020046 blockage of GPR55 could suppress monocyte adhesion to vascular endothelial cells through suppression of Mac-1 expression, leading to protection against the development of atherosclerosis. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives)

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16 pages, 6526 KiB

Open AccessArticle

DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy

by Jinglong Chen, Danping Wang, Yibo Zong and Xiaojing Yang

Int. J. Mol. Sci. 2021, 22(11), 5675; https://doi.org/10.3390/ijms22115675 - 26 May 2021

Cited by 29 | Viewed by 3966

Abstract

Oxidative stress occurs in a variety of clinical liver diseases and causes cellular damage and mitochondrial dysfunction. The clearance of damaged mitochondria by mitophagy may facilitate mitochondrial biogenesis and enhance cell survival. Although the supplementation of docosahexaenoic acid (DHA) has been recognized to relieve the symptoms of various liver diseases, the antioxidant effect of DHA in liver disease is still unclear. The purpose of our research was to investigate the antioxidant effect of DHA in the liver and the possible role of mitophagy in this. In vitro, H₂O₂-induced injury was caused in AML12 cells. The results showed that DHA repressed the level of reactive oxygen species (ROS) induced by H₂O₂ and stimulated the cellular antioxidation response. Most notably, DHA restored oxidative stress-impaired autophagic flux and promoted protective autophagy. In addition, PINK/Parkin-mediated mitophagy was activated by DHA in AML12 cells and alleviated mitochondrial dysfunction. The ERK1/2 signaling pathway was inhibited during oxidative stress but reactivated by DHA treatment. It was proven that the expression of ERK1/2 was involved in the regulation of mitophagy by the ERK1/2 inhibitor. We further proved these results in vivo. DHA effectively alleviated the liver oxidative damage caused by CCl₄ and enhanced antioxidation capacity; intriguingly, autophagy was also activated. In summary, our data demonstrated that DHA protected hepatocytes from oxidative damage through GPR120/ERK-mediated mitophagy. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives)

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11 pages, 3353 KiB

Open AccessArticle

2-Arachidonyl-lysophosphatidylethanolamine Induces Anti-Inflammatory Effects on Macrophages and in Carrageenan-Induced Paw Edema

by Soo-Jin Park and Dong-Soon Im

Int. J. Mol. Sci. 2021, 22(9), 4865; https://doi.org/10.3390/ijms22094865 - 4 May 2021

Cited by 18 | Viewed by 3047

Abstract

2-Arachidonyl-lysophosphatidylethanolamine, shortly 2-ARA-LPE, is a polyunsaturated lysophosphatidylethanolamine. 2-ARA-LPE has a very long chain arachidonic acid, formed by an ester bond at the sn-2 position. It has been reported that 2-ARA-LPE has anti-inflammatory effects in a zymosan-induced peritonitis model. However, it’s action mechanisms are poorly investigated. Recently, resolution of inflammation is considered to be an active process driven by M2 polarized macrophages. Therefore, we have investigated whether 2-ARA-LPE acts on macrophages for anti-inflammation, whether 2-ARA-LPE modulates macrophage phenotypes to reduce inflammation, and whether 2-ARA-LPE is anti-inflammatory in a carrageenan-induced paw edema model. In mouse peritoneal macrophages, 2-ARA-LPE was found to inhibit lipopolysaccharide (LPS)-induced M1 macrophage polarization, but not induce M2 polarization. 2-ARA-LPE inhibited the inductions of inducible nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages at the mRNA and protein levels. Furthermore, products of the two genes, nitric oxide and prostaglandin E₂, were also inhibited by 2-ARA-LPE. However, 1-oleoyl-LPE did not show any activity on the macrophage polarization and inflammatory responses. The anti-inflammatory activity of 2-ARA-LPE was also verified in vivo in a carrageenan-induced paw edema model. 2-ARA-LPE inhibits LPS-induced M1 polarization, which contributes to anti-inflammation and suppresses the carrageenan-induced paw edema in vivo. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives)

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Review

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23 pages, 929 KiB

Open AccessReview

Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses

by Bhakta Prasad Gaire and Ji-Woong Choi

Int. J. Mol. Sci. 2021, 22(15), 7864; https://doi.org/10.3390/ijms22157864 - 23 Jul 2021

Cited by 20 | Viewed by 3796

Abstract

Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Fatty Acids and Fatty Acid Derivatives)

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