The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform
Junken Aoki - One of the best experts on this subject based on the ideXlab platform.
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Elevated phosphatidylserine-specific phospholipase A1 level in hyperthyroidism
Clinica chimica acta; international journal of clinical chemistry, 2020Co-Authors: Kazuki Nakawatari, Junken Aoki, Makoto Kurano, Osamu Araki, Masako Nishikawa, Satoshi Shimamoto, Koji Igarashi, Masami Murakami, Yutaka YatomiAbstract:Abstract Objectives Although a single nucleotide polymorphism in a specific receptor for Lysophosphatidylserine, a lysophospholipid mediator involved in the immune system, is reportedly associated with Graves’ disease, the association between Lysophosphatidylserine and thyroid disorders remains to be elucidated. Therefore, we aimed to investigate the association between the level of phosphatidylserine-specific phospholipase A1 (PS-PLA1), which produces Lysophosphatidylserine, and thyroid disorders. Methods We measured serum PS-PLA1 levels in the patients with various thyroid disorders (n = 120) and normal subjects (n = 58). Results We observed that the serum PS-PLA1 levels were higher in the subjects with Graves’ disease, subacute thyroiditis, or silent thyroiditis, while they were not modulated in the patients with hypothyroidism. The serum PS-PLA1 levels were strongly correlated with the levels of thyroid hormones, especially in the subjects with Graves’ disease. Moreover, we found that the serum PS-PLA1 levels were lowered by treatment with anti-thyroid reagents in subjects with Graves’ disease and that the changes in PS-PLA1 were strongly correlated with those in thyroid hormones. Conclusion These results suggest that PS-PLA1 might be a novel target in the treatment of hyperthyroidism, especially Graves’ disease, and that its measurement might be useful as a supplementary diagnostic test for thyroid function.
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Regulation of plasma glycero-lysophospholipid levels by lipoprotein metabolism.
The Biochemical journal, 2019Co-Authors: Makoto Kurano, Junken Aoki, Kuniyuki Kano, Masumi Hara, Kazuhisa Tsukamoto, Yutaka YatomiAbstract:Glycero-lysophospholipids, such as lysophosphatidic acids and Lysophosphatidylserine, are gathering attention, since specific receptors have been identified. Most of these compounds have been proposed to be bound to albumin, while their associations with lipoproteins have not been fully elucidated. Therefore, in this study, we aimed to investigate the contents of glycero-lysophospholipids (lysophosphatidic acids, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, and Lysophosphatidylserine) on lipoproteins and the modulation of their metabolism by lipoprotein metabolism. We observed that moderate amounts of glycero-lysophospholipids, with the exception of Lysophosphatidylserine, were distributed on the LDL and HDL fractions, and glycero-lysophospholipids that had bound to albumin were observed in lipoprotein fractions when they were co-incubated. The overexpression of cholesteryl ester transfer protein decreased the plasma levels of lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, and lysophosphatidylinositol and it increased their contents in apoB-containing lipoproteins, while it decreased their contents in HDL and lipoprotein-depleted fractions in mice. The overexpression of the LDL receptor (LDLr) decreased the plasma levels of lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, and lysophosphatidylinositol and decreased the contents of these compounds in the LDL, HDL, and lipoprotein-depleted fractions, while the knockdown of the LDLr increased them. These results suggest the potential importance of glycero-lysophospholipids in the pleiotropic effects of lipoproteins as well as the importance of lipoprotein metabolism in the regulation of glycero-lysophospholipids.
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Association between serum autotaxin or phosphatidylserine‐specific phospholipase A1 levels and melanoma
The Journal of dermatology, 2018Co-Authors: Makoto Kurano, Junken Aoki, Satoshi Shimamoto, Koji Igarashi, Tomomitsu Miyagaki, Takuya Miyagawa, Hitoshi Ikeda, Shinichi Sato, Yutaka YatomiAbstract:Autotaxin (ATX), a producing enzyme for lysophosphatidic acids, was first identified from the medium of a melanoma cell line and has been considered to be one of the candidate targets to treat melanoma; however, the association between serum ATX and melanoma in human subjects has not been elucidated. Along with ATX, phosphatidylserine-specific phospholipase A1 (PS-PLA1 ) is a producing enzyme for Lysophosphatidylserine, a similar glycero-lysophospholipid mediator to lysophosphatidic acids. In the present study, we aimed to investigate the association between serum ATX or PS-PLA1 levels and melanoma. We measured the serum levels of ATX, ATX isoforms and PS-PLA1 in subjects with melanoma (n = 57) and healthy subjects (n = 58). We further investigated the existence of trends according to the clinical stages of melanoma. We observed that serum total ATX and classical ATX levels were significant higher and serum novel ATX levels tended to be higher in male subjects with melanoma, while no significant difference was observed between the two groups in female subjects. The trend test revealed that the serum total ATX and ATX isoforms were significantly associated with the clinical stages of female subjects with melanoma. Regarding PS-PLA1 , serum PS-PLA1 levels were significantly higher in the melanoma subjects and associated with the clinical stages. The present study is the first study which revealed the association between ATX or PS-PLA1 and melanoma, suggesting the possible involvement of ATX/lysophosphatidic acids or PS-PLA1 /Lysophosphatidylserine axis in the pathogenesis of melanoma.
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Lysophosphatidylserine suppresses il 2 production in cd4 t cells through lps3 gpr174
Biochemical and Biophysical Research Communications, 2017Co-Authors: Yuji Shinjo, Kumiko Makide, Junken Aoki, Asuka Inoue, Yuko Otani, Tomohiko Ohwada, Kuniyuki Kano, Keita Satoh, Fumiya FukamiAbstract:Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS1/GPR34, LPS2/P2Y10, and LPS3/GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS3 is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS3-deficient mice. In LPS3-deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS3 axis in T cells.
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Lysophosphatidylserine suppresses IL-2 production in CD4 T cells through LPS3/GPR174.
Biochemical and biophysical research communications, 2017Co-Authors: Yuji Shinjo, Kumiko Makide, Asuka Inoue, Yuko Otani, Tomohiko Ohwada, Kuniyuki Kano, Keita Satoh, Fumiya Fukami, Junken AokiAbstract:Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS1/GPR34, LPS2/P2Y10, and LPS3/GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS3 is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS3-deficient mice. In LPS3-deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS3 axis in T cells.
Kumiko Makide - One of the best experts on this subject based on the ideXlab platform.
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Lysophosphatidylserine suppresses il 2 production in cd4 t cells through lps3 gpr174
Biochemical and Biophysical Research Communications, 2017Co-Authors: Yuji Shinjo, Kumiko Makide, Junken Aoki, Asuka Inoue, Yuko Otani, Tomohiko Ohwada, Kuniyuki Kano, Keita Satoh, Fumiya FukamiAbstract:Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS1/GPR34, LPS2/P2Y10, and LPS3/GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS3 is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS3-deficient mice. In LPS3-deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS3 axis in T cells.
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Lysophosphatidylserine suppresses IL-2 production in CD4 T cells through LPS3/GPR174.
Biochemical and biophysical research communications, 2017Co-Authors: Yuji Shinjo, Kumiko Makide, Asuka Inoue, Yuko Otani, Tomohiko Ohwada, Kuniyuki Kano, Keita Satoh, Fumiya Fukami, Junken AokiAbstract:Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS1/GPR34, LPS2/P2Y10, and LPS3/GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS3 is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS3-deficient mice. In LPS3-deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS3 axis in T cells.
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Lysophosphatidylserine as an Inflammatory Mediator
Chronic Inflammation, 2016Co-Authors: Kumiko Makide, Asuka Inoue, Junken AokiAbstract:Lysophosphatidylserine (LysoPS), a deacylated form of phosphatidylserine (PS), has been assumed to serve as a bioactive lysophospholipid mediator. However, LysoPS has received little attention because its mode of actions as well as its synthetic pathways have been obscure. Recently G protein-coupled receptors (GPCRs) specific for LysoPS, and enzymes responsible for the generation of LysoPS have been identified. These LysoPS-related molecules are mainly expressed on immune cells, which led us to assume that LysoPS may have some roles in inflammation. Here we summarised the newly discovered LysoPS receptors and enzymes including our recent works.
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Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity.
Journal of medicinal chemistry, 2016Co-Authors: Sejin Jung, Asuka Inoue, Masaya Ikubo, Sho Nakamura, Yuko Otani, Kuniyuki Kano, Akiharu Uwamizu, Takayuki Kishi, Misa Sayama, Kumiko MakideAbstract:Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator that specifically activates membrane proteins of the P2Y and its related families of G protein-coupled receptors (GPCR), GPR34 (LPS1), P2Y10 (LPS2), and GPR174 (LPS3). Here, in order to increase potency and receptor selectivity, we designed and synthesized LysoPS analogues containing the conformational constraints of the glycerol moiety. These reduced structural flexibility by fixation of the glycerol framework of LysoPS using a 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton, and related structures identified compounds which exhibited high potency and selectivity for activation of GPR34 or P2Y10. Morphing of the structural shape of the 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton into a planar benzene ring enhanced the P2Y10 activation potentcy rather than the GPR34 activation.
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Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity
2016Co-Authors: Sejin Jung, Asuka Inoue, Masaya Ikubo, Sho Nakamura, Yuko Otani, Kuniyuki Kano, Akiharu Uwamizu, Takayuki Kishi, Misa Sayama, Kumiko MakideAbstract:Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator that specifically activates membrane proteins of the P2Y and its related families of G protein-coupled receptors (GPCR), GPR34 (LPS1), P2Y10 (LPS2), and GPR174 (LPS3). Here, in order to increase potency and receptor selectivity, we designed and synthesized LysoPS analogues containing the conformational constraints of the glycerol moiety. These reduced structural flexibility by fixation of the glycerol framework of LysoPS using a 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton, and related structures identified compounds which exhibited high potency and selectivity for activation of GPR34 or P2Y10. Morphing of the structural shape of the 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton into a planar benzene ring enhanced the P2Y10 activation potentcy rather than the GPR34 activation
Asuka Inoue - One of the best experts on this subject based on the ideXlab platform.
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Lysophosphatidylserine suppresses il 2 production in cd4 t cells through lps3 gpr174
Biochemical and Biophysical Research Communications, 2017Co-Authors: Yuji Shinjo, Kumiko Makide, Junken Aoki, Asuka Inoue, Yuko Otani, Tomohiko Ohwada, Kuniyuki Kano, Keita Satoh, Fumiya FukamiAbstract:Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS1/GPR34, LPS2/P2Y10, and LPS3/GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS3 is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS3-deficient mice. In LPS3-deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS3 axis in T cells.
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Lysophosphatidylserine suppresses IL-2 production in CD4 T cells through LPS3/GPR174.
Biochemical and biophysical research communications, 2017Co-Authors: Yuji Shinjo, Kumiko Makide, Asuka Inoue, Yuko Otani, Tomohiko Ohwada, Kuniyuki Kano, Keita Satoh, Fumiya Fukami, Junken AokiAbstract:Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS1/GPR34, LPS2/P2Y10, and LPS3/GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS3 is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS3-deficient mice. In LPS3-deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS3 axis in T cells.
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Lysophosphatidylserine as an Inflammatory Mediator
Chronic Inflammation, 2016Co-Authors: Kumiko Makide, Asuka Inoue, Junken AokiAbstract:Lysophosphatidylserine (LysoPS), a deacylated form of phosphatidylserine (PS), has been assumed to serve as a bioactive lysophospholipid mediator. However, LysoPS has received little attention because its mode of actions as well as its synthetic pathways have been obscure. Recently G protein-coupled receptors (GPCRs) specific for LysoPS, and enzymes responsible for the generation of LysoPS have been identified. These LysoPS-related molecules are mainly expressed on immune cells, which led us to assume that LysoPS may have some roles in inflammation. Here we summarised the newly discovered LysoPS receptors and enzymes including our recent works.
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Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity.
Journal of medicinal chemistry, 2016Co-Authors: Sejin Jung, Asuka Inoue, Masaya Ikubo, Sho Nakamura, Yuko Otani, Kuniyuki Kano, Akiharu Uwamizu, Takayuki Kishi, Misa Sayama, Kumiko MakideAbstract:Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator that specifically activates membrane proteins of the P2Y and its related families of G protein-coupled receptors (GPCR), GPR34 (LPS1), P2Y10 (LPS2), and GPR174 (LPS3). Here, in order to increase potency and receptor selectivity, we designed and synthesized LysoPS analogues containing the conformational constraints of the glycerol moiety. These reduced structural flexibility by fixation of the glycerol framework of LysoPS using a 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton, and related structures identified compounds which exhibited high potency and selectivity for activation of GPR34 or P2Y10. Morphing of the structural shape of the 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton into a planar benzene ring enhanced the P2Y10 activation potentcy rather than the GPR34 activation.
Akiharu Uwamizu - One of the best experts on this subject based on the ideXlab platform.
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Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity.
Journal of medicinal chemistry, 2016Co-Authors: Sejin Jung, Asuka Inoue, Masaya Ikubo, Sho Nakamura, Yuko Otani, Kuniyuki Kano, Akiharu Uwamizu, Takayuki Kishi, Misa Sayama, Kumiko MakideAbstract:Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator that specifically activates membrane proteins of the P2Y and its related families of G protein-coupled receptors (GPCR), GPR34 (LPS1), P2Y10 (LPS2), and GPR174 (LPS3). Here, in order to increase potency and receptor selectivity, we designed and synthesized LysoPS analogues containing the conformational constraints of the glycerol moiety. These reduced structural flexibility by fixation of the glycerol framework of LysoPS using a 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton, and related structures identified compounds which exhibited high potency and selectivity for activation of GPR34 or P2Y10. Morphing of the structural shape of the 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton into a planar benzene ring enhanced the P2Y10 activation potentcy rather than the GPR34 activation.
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Conformational Constraint of the Glycerol Moiety of Lysophosphatidylserine Affords Compounds with Receptor Subtype Selectivity
2016Co-Authors: Sejin Jung, Asuka Inoue, Masaya Ikubo, Sho Nakamura, Yuko Otani, Kuniyuki Kano, Akiharu Uwamizu, Takayuki Kishi, Misa Sayama, Kumiko MakideAbstract:Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator that specifically activates membrane proteins of the P2Y and its related families of G protein-coupled receptors (GPCR), GPR34 (LPS1), P2Y10 (LPS2), and GPR174 (LPS3). Here, in order to increase potency and receptor selectivity, we designed and synthesized LysoPS analogues containing the conformational constraints of the glycerol moiety. These reduced structural flexibility by fixation of the glycerol framework of LysoPS using a 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton, and related structures identified compounds which exhibited high potency and selectivity for activation of GPR34 or P2Y10. Morphing of the structural shape of the 2-hydroxymethyl-3-hydroxytetrahydropyran skeleton into a planar benzene ring enhanced the P2Y10 activation potentcy rather than the GPR34 activation
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Structure–Activity Relationships of Lysophosphatidylserine Analogs as Agonists of G-Protein-Coupled Receptors GPR34, P2Y10, and GPR174
Journal of medicinal chemistry, 2015Co-Authors: Masaya Ikubo, Asuka Inoue, Sho Nakamura, Yuko Otani, Akiharu Uwamizu, Sejin Jung, Takayuki Kishi, Misa Sayama, Keisuke Suzuki, Akira ShutoAbstract:Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure–activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of p...
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structure activity relationships of Lysophosphatidylserine analogs as agonists of g protein coupled receptors gpr34 p2y10 and gpr174
Journal of Medicinal Chemistry, 2015Co-Authors: Masaya Ikubo, Asuka Inoue, Sho Nakamura, Yuko Otani, Akiharu Uwamizu, Sejin Jung, Takayuki Kishi, Misa Sayama, Keisuke Suzuki, Akira ShutoAbstract:Lysophosphatidylserine (LysoPS) is an endogenous lipid mediator generated by hydrolysis of membrane phospholipid phosphatidylserine. Recent ligand screening of orphan G-protein-coupled receptors (GPCRs) identified two LysoPS-specific human GPCRs, namely, P2Y10 (LPS2) and GPR174 (LPS3), which, together with previously reported GPR34 (LPS1), comprise a LysoPS receptor family. Herein, we examined the structure–activity relationships of a series of synthetic LysoPS analogues toward these recently deorphanized LysoPS receptors, based on the idea that LysoPS can be regarded as consisting of distinct modules (fatty acid, glycerol, and l-serine) connected by phosphodiester and ester linkages. Starting from the endogenous ligand (1-oleoyl-LysoPS, 1), we optimized the structure of each module and the ester linkage. Accordingly, we identified some structural requirements of each module for potency and for receptor subtype selectivity. Further assembly of individually structure-optimized modules yielded a series of p...
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Lysophospholipid Mediators: Their Receptors and Synthetic Pathways
Bioactive Lipid Mediators, 2015Co-Authors: Kuniyuki Kano, Kumiko Makide, Jun Ishiguro, Akiharu Uwamizu, Yuji Shinjo, Hiroshi Yukiura, Shizu Aikawa, Kahori Namiki, Hiroki Kawana, Saki NemotoAbstract:It is now widely accepted that lysophospholipids (LPLs), a product of the phospholipase A reaction, function as mediators through G protein-coupled receptors (GPCRs). Notably, recent studies of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) have revealed their essential roles in vivo. In addition, recent studies have identified several GPCRs for other lysophospholipids such as Lysophosphatidylserine (LysoPS) and lysophosphatidylinositol (LPI). In this chapter, we summarize the actions and production of these LPLs as lipid mediators including LysoPS and LPI.
Siddhesh S. Kamat - One of the best experts on this subject based on the ideXlab platform.
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Fatty acid chain length drives Lysophosphatidylserine-dependent immunological outputs.
Cell chemical biology, 2021Co-Authors: Neha Khandelwal, Minhaj Shaikh, Amol Mhetre, Shubham Singh, Theja Sajeevan, Alaumy Joshi, Kithiganahalli Narayanaswamy Balaji, Harinath Chakrapani, Siddhesh S. KamatAbstract:In humans, Lysophosphatidylserines (lyso-PSs) are potent lipid regulators of important immunological processes. Given their structural diversity and commercial paucity, here we report the synthesis of methyl esters of lyso-PS (Me-lyso-PSs) containing medium- to very-long-chain (VLC) lipid tails. We show that Me-lyso-PSs are excellent substrates for the lyso-PS lipase ABHD12, and that these synthetic lipids are acted upon by cellular carboxylesterases to produce lyso-PSs. Next, in macrophages we demonstrate that VLC lyso-PSs orchestrate pro-inflammatory responses and in turn neuroinflammation via a Toll-like receptor 2 (TLR2)-dependent pathway. We also show that long-chain (LC) lyso-PSs robustly induce intracellular cyclic AMP production, cytosolic calcium influx, and phosphorylation of the nodal extracellular signal-regulated kinase to regulate macrophage activation via a TLR2-independent pathway. Finally, we report that LC lyso-PSs potently elicit histamine release during the mast cell degranulation process, and that ABHD12 is the major lyso-PS lipase in these immune cells.
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The Lysophosphatidylserines—An Emerging Class of Signalling Lysophospholipids
The Journal of Membrane Biology, 2020Co-Authors: Karthik Shanbhag, Neha Khandelwal, Amol Mhetre, Siddhesh S. KamatAbstract:Lysophospholipids are potent hormone-like signalling biological lipids that regulate many important biological processes in mammals (including humans). Lysophosphatidic acid and sphingosine-1-phosphate represent the best studied examples for this lipid class, and their metabolic enzymes and/or cognate receptors are currently under clinical investigation for treatment of various neurological and autoimmune diseases in humans. Over the past two decades, the lysophsophatidylserines (lyso-PSs) have emerged as yet another biologically important lysophospholipid, and deregulation in its metabolism has been linked to various human pathophysiological conditions. Despite its recent emergence, an exhaustive review summarizing recent advances on lyso-PSs and the biological pathways that this bioactive lysophospholipid regulates has been lacking. To address this, here, we summarize studies that led to the discovery of lyso-PS as a potent signalling biomolecule, and discuss the structure, its detection in biological systems, and the biodistribution of this lysophospholipid in various mammalian systems. Further, we describe in detail the enzymatic pathways that are involved in the biosynthesis and degradation of this lipid and the putative lyso-PS receptors reported in the literature. Finally, we discuss the various biological pathways directly regulated by lyso-PSs in mammals and prospect new questions for this still emerging biomedically important signalling lysophospholipid. Graphic abstract
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The Lysophosphatidylserines-An Emerging Class of Signalling Lysophospholipids.
The Journal of membrane biology, 2020Co-Authors: Karthik Shanbhag, Neha Khandelwal, Amol Mhetre, Siddhesh S. KamatAbstract:Lysophospholipids are potent hormone-like signalling biological lipids that regulate many important biological processes in mammals (including humans). Lysophosphatidic acid and sphingosine-1-phosphate represent the best studied examples for this lipid class, and their metabolic enzymes and/or cognate receptors are currently under clinical investigation for treatment of various neurological and autoimmune diseases in humans. Over the past two decades, the lysophsophatidylserines (lyso-PSs) have emerged as yet another biologically important lysophospholipid, and deregulation in its metabolism has been linked to various human pathophysiological conditions. Despite its recent emergence, an exhaustive review summarizing recent advances on lyso-PSs and the biological pathways that this bioactive lysophospholipid regulates has been lacking. To address this, here, we summarize studies that led to the discovery of lyso-PS as a potent signalling biomolecule, and discuss the structure, its detection in biological systems, and the biodistribution of this lysophospholipid in various mammalian systems. Further, we describe in detail the enzymatic pathways that are involved in the biosynthesis and degradation of this lipid and the putative lyso-PS receptors reported in the literature. Finally, we discuss the various biological pathways directly regulated by lyso-PSs in mammals and prospect new questions for this still emerging biomedically important signalling lysophospholipid.
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Immunomodulatory Lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay
Nature Chemical Biology, 2015Co-Authors: Siddhesh S. Kamat, Kaddy Camara, William H Parsons, Dong-hui Chen, Melissa M Dix, Thomas D Bird, Amy R Howell, Benjamin F CravattAbstract:ABHD16A is identified as a major enzyme catalyzing production of lyso-PS from phosphatidylserine (PS). A new ABHD16A inhibitor and knockout mice show a dynamic interplay occurring during inflammation between ABHD16A and disease-linked ABHD12, an enzyme that degrades lyso-PS. ABHD16A is identified as a major enzyme catalyzing production of lyso-PS from phosphatidylserine (PS). A new ABHD16A inhibitor and knockout mice show a dynamic interplay occurring during inflammation between ABHD16A and disease-linked ABHD12, an enzyme that degrades lyso-PS. Lysophosphatidylserines (lyso-PSs) are a class of signaling lipids that regulate immunological and neurological processes. The metabolism of lyso-PSs remains poorly understood in vivo . Recently, we determined that ABHD12 is a major brain lyso-PS lipase, implicating lyso-PSs in the neurological disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC), which is caused by null mutations in the ABHD12 gene. Here, we couple activity-based profiling with pharmacological and genetic methods to annotate the poorly characterized enzyme ABHD16A as a phosphatidylserine (PS) lipase that generates lyso-PS in mammalian systems. We describe a small-molecule inhibitor of ABHD16A that depletes lyso-PSs from cells, including lymphoblasts derived from subjects with PHARC. In mouse macrophages, disruption of ABHD12 and ABHD16A respectively increases and decreases both lyso-PSs and lipopolysaccharide-induced cytokine production. Finally, Abhd16a ^−/− mice have decreased brain lyso-PSs, which runs counter to the elevation in lyso-PS in Abhd12 ^−/− mice. Our findings illuminate an ABHD16A-ABHD12 axis that dynamically regulates lyso-PS metabolism in vivo , designating these enzymes as potential targets for treating neuroimmunological disorders.
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Immunomodulatory Lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay
Nature chemical biology, 2015Co-Authors: Siddhesh S. Kamat, Kaddy Camara, William H Parsons, Dong-hui Chen, Melissa M Dix, Thomas D Bird, Amy R Howell, Benjamin F CravattAbstract:ABHD16A is identified as a major enzyme catalyzing production of lyso-PS from phosphatidylserine (PS). A new ABHD16A inhibitor and knockout mice show a dynamic interplay occurring during inflammation between ABHD16A and disease-linked ABHD12, an enzyme that degrades lyso-PS.
