Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Communications  

Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.

DOI： 10.1038/s41467-024-46386-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Pharmaceutical Society of Japan  

<p>Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid β-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.</p>

DOI： 10.1248/bpb.b23-00849

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Pharmaceutical Society of Japan  

<p>White matter lesions induced by chronic cerebral hypoperfusion can cause vascular dementia; however, no appropriate treatments are currently available for these diseases. In this study, we investigated lipid peroxidation, which has recently been pointed out to be associated with cerebrovascular disease and vascular dementia, as a therapeutic target for chronic cerebral hypoperfusion. We used ethoxyquin, a lipid-soluble antioxidant, in a neuronal cell line and mouse model of the disease. The cytoprotective effect of ethoxyquin on glutamate-stimulated HT-22 cells, a mouse hippocampal cell line, was comparable to that of a ferroptosis inhibitor. In addition, the administration of ethoxyquin to bilateral common carotid artery stenosis model mice suppressed white matter lesions, blood–brain barrier disruption, and glial cell activation. Taken together, we propose that the inhibition of lipid peroxidation may be a useful therapeutic approach for chronic cerebrovascular disease and the resulting white matter lesions.</p>

DOI： 10.1248/bpb.b23-00538

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Bioscientifica  

Graphical Abstract

Abstract

Objective

Nonalcoholic steatohepatitis is a chronic liver disease caused by the progression of hepatocellular death and inflammation from simple steatosis. However, the pathogenesis of this disease remains unclear. Lipid peroxidation is one of the most critical factors in the development of nonalcoholic steatohepatitis; however, oxidised lipids – the products of lipid peroxidation – are insufficiently analysed. Here, we comprehensively analysed oxidised lipids in the liver during nonalcoholic steatohepatitis development in a choline-deficient, l-amino acid-defined, high-fat diet-fed mouse model.

Methods

Liver from C57BL/6J mice, fed a standard diet or a choline-deficient l-amino acid-defined high-fat diet for 1, 3, or 6 weeks, were collected to evaluate fibrosis, steatosis, inflammation, liver injury, and oxidised lipid production and to observe the suppression of these parameters upon vitamin E administration. In addition, organellar localisation of lipid peroxidation was assessed using fluorescence imaging. Finally, a mitochondria-targeted antioxidant was administered to model mice to investigate the mechanism underlying lipid peroxidation.

Results

We found an accumulation of oxidised triglycerides in the early stages of nonalcoholic steatohepatitis. Furthermore, our data indicate that oxidised triglycerides are generated by lipid peroxidation in lipid droplets due to mitochondria-derived reactive oxygen species.

Conclusion

These results suggest the importance of lipid droplet peroxidation in the progression of nonalcoholic steatohepatitis and may contribute to the development of therapeutic methods for nonalcoholic steatohepatitis in the future.

Significance statement

We demonstrate the specific and early occurrence of lipid peroxidation in nonalcoholic steatohepatitis pathogenesis and propose a previously unknown mechanism of disease progression.

DOI： 10.1530/rem-22-0024

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Other Link： https://rem.bioscientifica.com/downloadpdf/journals/rem/2023/1/REM-22-0024.xml

Language：English   Publishing type：Research paper (scientific journal)  

Prostaglandin E receptor EP4, a class A G protein-coupled receptor (GPCR), is a common drug target in various disorders, such as acute decompensated heart failure and ulcerative colitis. Here, we report the cryoelectron microscopy (cryo-EM) structure of the EP4-heterotrimeric G protein (Gs) complex with the endogenous ligand at a global resolution of 3.3 Å. In this structure, compared with that in the inactive EP4 structure, the sixth transmembrane domain is shifted outward on the intracellular side, although the shift is smaller than that in other class A GPCRs bound to Gs. Instead, the C-terminal helix of Gs is inserted toward TM2 of EP4, and the conserved C-terminal hook structure formsthe extended state. These structural features are formed by the conserved residues in prostanoid receptors (Phe542.39 and Trp3277.51). These findings may be important for the thorough understanding of the G protein-binding mechanism of EP4 and other prostanoid receptors.

DOI： 10.1016/j.str.2020.11.007

Language：English   Publishing type：Research paper (scientific journal)  

G protein-coupled receptors (GPCRs), which are indispensable to life and also implicated in a number of diseases, construct important drug targets. For the efficient structure-guided drug design, however, their structural stabilities must be enhanced. An amino-acid mutation is known to possibly lead to the enhancement, but currently available experimental and theoretical methods for identifying stabilizing mutations suffer such drawbacks as the incapability of exploring the whole mutational space with minor effort and the unambiguous physical origin of the enhanced or lowered stability. In general, after the identification is successfully made for a GPCR, the whole procedure must be followed all over again for the identification for another GPCR. Here we report a theoretical strategy by which many different GPCRs can be considered at the same time. The strategy is illustrated for three GPCRs of Class A in the inactive state. We argue that a mutation of the residue at a position of N-BW = 3.39 (N-BW is the Ballesteros-Weinstein number), a hot-spot residue, leads to substantially higher stability for significantly many GPCRs Of Class A in the inactive state. The most stabilizing mutations of the residues with N-BW = 3.39 are then identified for two of the three GPCRs, using the improved version of our free-energy function, These identifications are experimentally corroborated, which is followed:by the determination of,new three-dimensional (3D) structures for the two GPCRs. We expect that on the basis of the strategy, the 3D structures of many GPCRs of Class A can be solved for the first time in succession.

DOI： 10.1021/acs.jpcb.7b02997

Language：English   Publishing type：Research paper (scientific journal)  

Prostanoids comprising prostaglandins (PGs) and thromboxanes (TXs) have been shown to play physiological and pathological roles in zebrafish. However, the molecular basis of zebrafish prostanoid receptors has not been established. Here, we demonstrate that there exist at least five 'contractile' (Ca2+-mobilizing) and one 'inhibitory' (G(i)-coupled) prostanoid receptors in zebrafish; five 'contractile' receptors consisting of two PGE(2) receptors (EP1a and EP1b), two PGF(2 alpha) receptors (FP1 and FP2), and one TXA(2) receptor TP, and one 'inhibitory' receptor, the PGE2 receptor EP3. [H-3]PGE(2) specifically bound to the membranes of cells expressing zebrafish EP1a, EP1b and EP3 with a Kd of 4.8, 1.8 and 13.6 nM, respectively, and [H-3]PGF(2 alpha), specifically bound to the membranes of cells expressing zebrafish FP1 and FP2, with a Kd of 6.5 and 1.6 nM, respectively. U-46619, a stable agonist for human and mouse TP receptors, significantly increased the specific binding of [S-35]GTP gamma S to membranes expressing the zebrafish TP receptor. Upon agonist stimulation, all six receptors showed an increase in intracellular Ca2+ levels, although the increase was very weak in EP1b, and pertussis toxin abolished only the EP3-mediated response. Zebrafish EP3 receptor also suppressed forskolin-induced cAMP formation in a pertussis toxin-sensitive manner. In association with the low structural conservation with mammalian receptors, most agonists and antagonists specific for mammalian EP1, EP3 and TP failed to work on each corresponding zebrafish receptor. This work provides further insights into the diverse prostanoid actions mediated by their receptors in zebrafish. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2013.07.075

Language：English   Publishing type：Research paper (scientific journal)  

Prostanoids comprising prostaglandins (PGs) and thromboxanes have been shown to play physiological and pathological roles in zebrafish. However, the molecular basis of zebrafish prostanoid receptors has not been characterized to date. Here, we demonstrate that there exist at least six 'relaxant' (Gs-coupled) prostanoid receptors in zebrafish; one PGI(2) receptor IP and five PGE(2) receptors comprising two EP2 (EP2a and EP2b), and three EP4 receptors (EP4a, EP4b and EP4c). In contrast, we failed to find a zebrafish PGD(2) receptor with any structure and/or character similarities to the mammalian DP1 receptor. [H-3]iloprost, a stable IP radioligand, specifically bound to the membrane of cells expressing zebrafish IP with a Kd of 42 nM, and [H-3]PGE(2) specifically bound to the membranes of cells expressing zebrafish EP2a, EP2b, EP4a, EP4b and EP4c with a Kd of 6.9, 6.0, 1.4, 3.3 and 1.2 nM, respectively. Upon agonist stimulation, the 'relaxant' prostanoid receptors showed intracellular cAMP accumulation. The responsiveness of these zebrafish receptors to subtype-specific agonists correlated with their structural conservation to the corresponding receptor in mammals. RT-PCR analysis revealed that the six zebrafish prostanoid receptors show unique tissue distribution patterns; each receptor gene may hence be under unique transcriptional regulation. This work provides further insights into the diverse functions of prostanoids in zebrafish. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2013.06.017

Language：English   Publishing type：Research paper (scientific journal)  

Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A(2), regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD(2) synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell-deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS-ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3-L-PGDS-DP1 loop that drives mast cell maturation.

DOI： 10.1038/ni.2586

Language：Japanese  

Functions of Prostaglandin Receptors in Contact Dermatitis and Application to Drug Discovery
Contact dermatitis is an inflammatory skin disease caused by toxic factors that activate the skin innate immunity (irritant contact dermatitis) or by a T cell-mediated hypersensitivity reaction (allergic contact dermatitis). These inflammatory kin diseases are sometimes still not easy to control. Therefore, the development of new effective drugs with fewer side elects is anticipated. In the skin under pathophysiological conditions, multiple prostaglandins are produced and their receptors are expressed in time- and/or cell-dependent manners. However, the precise role of prostaglandins and their receptors in contact dermatitis has not been fully understood. Recently, studies using mice with a disruption of each prostaglandin receptor gene, as well as receptor-selective compounds revealed that prostaglandin receptors have manifold functions, sometimes resulting in opposite outcomes. Here, we review new advances in the roles of prostaglandin receptors in contact hypersensitivity as a cutaneous immune response model, and also discuss the clinical potentials of receptor-selective drugs.

DOI： 10.1248/yakushi.12-00232-2

Language：English   Publishing type：Research paper (scientific journal)  

Prostaglandin E-2-EP4 signaling suppresses adipocyte differentiation in mouse embryonic fibroblasts via an autocrine mechanism
The prostaglandin (PG) receptors EP4 and FP have the potential to exert negative effects on adipogenesis, but the exact contribution of endogenous PG-driven receptor signaling to this process is not fully understood. In this study, we employed an adipocyte differentiation system from mouse embryonic fibroblasts (MEF) and compared the effects of each PG receptor-deficiency on adipocyte differentiation. In wild-type (WT) MEF cells, inhibition of endogenous PG synthesis by indomethacin augmented the differentiation, whereas exogenous PGE(2), as well as an FP agonist, reversed the effect of indomethacin. In EP4-deficient cells, basal differentiation was upregulated to the levels in indomethacin-treated WT cells, and indomethacin did not further enhance differentiation. Differentiation in FP-deficient cells was equivalent to WT and was still sensitive to indomethacin. PGE(2) or indomethacin treatment of WT MEF cells for the first two days was enough to suppress or enhance transcription of the Pparg2 gene as well as the subsequent differentiation, respectively. Differentiation stimuli induced COX-2 gene and protein expression, as well as PGE(2) production, in WT MEF cells. These results suggest that PGE(2)-EP4 signaling suppresses adipocyte differentiation by affecting Pparg2 expression in an autocrine manner and that FP-mediated inhibition is not directly involved in adipocyte differentiation in the MEF system.-Inazumi, T., N. Shirata, K. Morimoto, H. Takano, E. Segi-Nishida, and Y. Sugimoto. Prostaglandin E-2-EP4 signaling suppresses adipocyte differentiation in mouse embryonic fibroblasts via an autocrine mechanism. J. Lipid Res. 2011. 52: 1500-1508.

DOI： 10.1194/jlr.M013615

Language：English   Publishing type：Research paper (scientific journal)  

To understand the role of prostaglandin (PG) receptor EP2 (Ptger2) signaling in ovulation and fertilization, we investigated time-dependent expression profiles in wild-type (WT) and Ptger2(-/-) cumuli before and after ovulation by using microarrays. We prepared cumulus cells from mice just before and 3, 9 and 14 h after human chorionic gonadotropin injection. Key genes including cAMP-related and epidermal growth factor (EGF) genes, as well as extracellular matrix-(ECM-) related and chemokine genes were up-regulated in WT cumuli at 3 h and 14 h, respectively. Ptger2 deficiency differently affected the expression of many of the key genes at 3 h and 14 h. These results indicate that the gene expression profile of cumulus cells greatly differs before and after ovulation, and in each situation, PGE(2)-EP2 signaling plays a critical role in cAMP-regulated gene expression in the cumulus cells under physiological conditions. (C) 2010 Published by Elsevier Masson SAS.

DOI： 10.1016/j.biochi.2010.04.006

Language：English   Publishing type：Research paper (scientific journal)  

We previously demonstrated that prostaglandin EP3 receptor augments EP2-elicited cAMP formation in COS-7 cells in a G(i/o)-insensitive manner. The purpose of our current study was to identify the signaling pathways involved in EP3-induced augmentation of receptor-stimulated cAMP formation. The enhancing effect of EP3 receptor was irrespective of the C-terminal structure of the EP3 isoform. This EP3 action was abolished by treatment with inhibitors for phospholipase C and intracellular Ca2+-related signaling molecules such as U73122, staurosporine, 2-APB and SK&F 96365. Indeed, an EP3 agonist stimulated IP3 formation and intracellular Ca2+ mobilization, which was blocked by U73122, but not by pertussis toxin. The enhancing effect by EP3 on cAMP formation was mimicked by both a Ca2+ ionophore and the activation of a typical G(q)-coupled receptor. Moreover, EP3 was exclusively localized to the raft fraction in COS-7 cells and EP3-elicited augmentation of cAMP formation was abolished by cholesterol depletion and introduction of a dominant negative caveolin-1 mutant. These results Suggest that EP3 elicits adenylyl cyclase superactivation via G(q)/phospholipase C activation and intracellular Ca2+ mobilization in a lipid raft microdomain-dependent manner. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.09.064

Language：English   Publishing type：Research paper (scientific journal)  

Cumulus cells surround the oocyte and regulate the production and assembly of the extracellular matrix (ECM) around the cumulus-oocyte complex for its timely interaction with sperm in the oviduct. We recently found that C-C chemokines such as CCL2, CCL7, and CCL9 are produced and stimulate integrin-mediated ECM assembly in the postovulatory cumulus to protect eggs and that prostaglandin E(2)-EP2 signaling in the cumulus cells facilitates fertilization by suppressing this chemokine signaling, which otherwise results in fertilization failure by preventing sperm penetration through the cumulus ECM. However, it remains unknown as to what mechanisms underlie chemokine-induced cumulus ECM assembly. Here we report that inhibition of EP2 signaling or addition of CCL7 augments RhoA activation and induces the surface accumulation of integrin and the contraction of cumulus cells. Enhanced surface accumulation of integrin then stimulates the formation and assembly of fibronectin fibrils as well as induces cumulus ECM resistance to hyaluronidase and sperm penetration. These changes in the cumulus ECM as well as cell contraction are relieved by the addition of Y27632 or blebbistatin. These results suggest that chemokines induce integrin engagement to the ECM and consequent ECM remodeling through the RhoA/Rho kinase/actomyosin pathway, making the cumulus ECM barrier resistant to sperm penetration. Based on these results, we propose that prostaglandin E(2)-EP2 signaling negatively regulates chemokine-induced Rho/ROCK signaling in cumulus cells for successful fertilization. (Endocrinology 150: 3345-3352, 2009)

DOI： 10.1210/en.2008-1449

Language：English   Publishing type：Research paper (scientific journal)  

By using the recently established culture system that reproduces the terminal differentiation process of connective tissue-type mast cells, we found significant transcriptional induction of CD44. As CD44 is a primary receptor for hyaluronan (HA), which is one of the major extracellular matrix components, we investigated the role of CD44 in cutaneous mast cells. When co-cultured with fibroblasts, mouse bone marrow-derived cultured mast cells (BMMCs) were found to form clusters in an HA-dependent manner. As compared with BMMCs derived from the wild-type mice, those from the CD44(-/-) mice exhibited impaired growth during the co-cultured period. Furthermore, in the peritoneal cavities and ear tissues, mature mast cells were fewer in number in the CD44(-/-) mice than in the wild-type mice. We investigated roles of CD44 in mast cell proliferation by reconstituting BMMCs into the tissues of mast cell-deficient, Kit(W)/Kit(W-v) mice, and found that the number of metachromatic cells upon acidic toluidine blue staining in the tissues transplanted with CD44(-/-) BMMCs was not significantly changed for 10 weeks, whereas that in the tissues transplanted with the CD44(+/+) BMMCs was significantly increased. These results suggest that CD44 plays a crucial role in the regulation of the cutaneous mast cell number.

DOI： 10.1038/labinvest.2008.159

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：北海道   Country：Japan  

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Event date： 2022.12

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Venue：熊本   Country：Japan  

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Event date： 2022.11

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Event date： 2022.11

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Venue：名古屋   Country：Japan  

Event date： 2022.11

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Venue：名古屋   Country：Japan  

Event date： 2022.3

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Venue：オンライン   Country：Japan  

Event date： 2021.11

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Event date： 2021.11

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Event date： 2021.11

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Event date： 2021.10

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Event date： 2021.10

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Event date： 2021.6

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Venue：オンライン開催   Country：Japan  

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Country：Japan  

プロスタグランジンI₂によるマスト細胞応答の制御

Language：Others  

Country：United States  

Towards structure determination of the human prostanoid receptor bound to the antibody

Language：Japanese  

Country：Japan  

プロスタサイクリンIP受容体がマスト細胞炎症性応答に与える影響

Language：Japanese  

Country：Japan  

マスト細胞炎症性応答に対するプロスタサイクリンIP受容体の役割

Language：Japanese  

Country：Japan  

マスト細胞炎症性応答におけるプロスタサイクリンIP受容体の役割

Language：Japanese  

Country：Japan  

シリルアリールトリフラート型のチエノベンザイン前駆体の合成と多置換ベンゾチオフェン合成への応用

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Country：United States  

Theoretical Identification of Hot-Spot Residues to be Mutated Common in G Protein-Coupled Receptors of Class A

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Country：Japan  

Identification of thermostabilizing mutations for G-protein coupled receptors: Rapid method based on statistical thermodynamics

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Country：Japan  

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Lysosomal lipid peroxidation promotes ferroptosis induction

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Country：Japan  

Structural analysis of prostaglandin receptors to elucidate the signaling mechanism

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Country：Japan  

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Determination of the responsible gene for oxidized phosphatidylcholine translocation in apoptosis

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Country：Japan  

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Country：Japan  

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Country：Japan  

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プロスタグランジン研究の新展開―エイコサノイド周辺脂質を含めた研究動向 4.抗原非依存性急性炎症におけるプロスタグランジンの役割

Language：Japanese  

サイトカインの種類 4.ケモカイン 23)CCL7