Kyoto Pharmaceutical University

MassBank is the first public repository of mass spectra of small chemical compounds for life sciences (<3000 Da). The database contains 605 electron-ionization mass spectrometry (EI-MS), 137 fast atom bombardment MS and 9276 electrospray ionization (ESI)-MS(n) data of 2337 authentic compounds of metabolites, 11 545 EI-MS and 834 other-MS data of 10,286 volatile natural and synthetic compounds, and 3045 ESI-MS(2) data of 679 synthetic drugs contributed by 16 research groups (January 2010). ESI-MS(2) data were analyzed under nonstandardized, independent experimental conditions. MassBank is a distributed database. Each research group provides data from its own MassBank data servers distributed on the Internet. MassBank users can access either all of the MassBank data or a subset of the data by specifying one or more experimental conditions. In a spectral search to retrieve mass spectra similar to a query mass spectrum, the similarity score is calculated by a weighted cosine correlation in which weighting exponents on peak intensity and the mass-to-charge ratio are optimized to the ESI-MS(2) data. MassBank also provides a merged spectrum for each compound prepared by merging the analyzed ESI-MS(2) data on an identical compound under different collision-induced dissociation conditions. Data merging has significantly improved the precision of the identification of a chemical compound by 21-23% at a similarity score of 0.6. Thus, MassBank is useful for the identification of chemical compounds and the publication of experimental data.

Prostanoids are the cyclooxygenase metabolites of arachidonic acid and include prostaglandin (PG) D(2), PGE(2), PGF(2alpha), PGI(2), and thromboxne A(2). They are synthesized and released upon cell stimulation and act on cells in the vicinity of their synthesis to exert their actions. Receptors mediating the actions of prostanoids were recently identified and cloned. They are G protein-coupled receptors with seven transmembrane domains. There are eight types and subtypes of prostanoid receptors that are encoded by different genes but as a whole constitute a subfamily in the superfamily of the rhodopsin-type receptors. Each of the receptors was expressed in cultured cells, and its ligand-binding properties and signal transduction pathways were characterized. Moreover, domains and amino acid residues conferring the specificities of ligand binding and signal transduction are being clarified. Information also is accumulating as to the distribution of these receptors in the body. It is also becoming clear for some types of receptors how expression of their genes is regulated. Furthermore, the gene for each of the eight types of prostanoid receptor has been disrupted, and mice deficient in each type of receptor are being examined to identify and assess the roles played by each receptor under various physiological and pathophysiological conditions. In this article, we summarize these findings and attempt to give an overview of the current status of research on the prostanoid receptors.

The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. For further resources related to this article, please visit the WIREs website.

The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis. The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs), which can influence the development of obesity. Here Kimura et al.show that SCFAs act via the receptor GPR43, which acts as a sensor for excessive dietary energy and controls body energy utilization as well as metabolic homoeostasis.

Prostaglandin (PG) E2 exerts its actions by acting on a group of G-protein-coupled receptors (GPCRs). There are four GPCRs responding to PGE2 designated subtypes EP1, EP2, EP3, and EP4 and multiple splicing isoforms of the subtype EP3. The EP subtypes exhibit differences in signal transduction, tissue localization, and regulation of expression. This molecular and biochemical heterogeneity of PGE receptors leads to PGE2 being the most versatile prostanoid. Studies on knock-out mice deficient in each EP subtype have defined PGE2 actions mediated by each subtype and identified the role each EP subtype plays in various physiological and pathophysiological responses. Here we review recent advances in PGE receptor research. Prostaglandin (PG) E2 exerts its actions by acting on a group of G-protein-coupled receptors (GPCRs). There are four GPCRs responding to PGE2 designated subtypes EP1, EP2, EP3, and EP4 and multiple splicing isoforms of the subtype EP3. The EP subtypes exhibit differences in signal transduction, tissue localization, and regulation of expression. This molecular and biochemical heterogeneity of PGE receptors leads to PGE2 being the most versatile prostanoid. Studies on knock-out mice deficient in each EP subtype have defined PGE2 actions mediated by each subtype and identified the role each EP subtype plays in various physiological and pathophysiological responses. Here we review recent advances in PGE receptor research. Prostanoids including various prostaglandins (PGs) 2The abbreviations used are: PG, prostaglandin; CNS, central nervous system; COX, cyclooxygenase; GPCR, G-protein-coupled receptor; LPS, lipopolysaccharide; NSAID, non-steroidal anti-inflammatory drug; TX, thromboxane. and thromboxanes (TXs) are cyclooxygenase (COX) metabolites of C20-unsaturated fatty acids such as arachidonic acid. These substances are synthesized in response to various stimuli in a variety of cells, released immediately after synthesis, and act in the vicinity of their synthesis to maintain local homeostasis (1Smith W.L. Langenbach R. J. Clin. Invest. 2001; 107: 1491-1495Crossref PubMed Scopus (533) Google Scholar). Among prostanoids, the E type PGs, particularly PGE2 derived from arachidonic acid, is most widely produced in the body, most widely found in animal species, and exhibits the most versatile actions. Receptors mediating prostanoid actions were characterized first by pharmacological analysis, which indicated the presence of one receptor each, named DP, FP, IP, and TP, for PGs of the D, F, and I types and TXA, respectively, and four different receptors designated EP1, EP2, EP3, and EP4 for the E type PGs (reviewed in Refs. 2Coleman R.A. Smith W.L. Narumiya S. Pharmacol. Rev. 1994; 46: 205-229PubMed Google Scholar and 3Narumiya S. Sugimoto Y. Ushikubi F. Physiol. Rev. 1999; 79: 1193-1226Crossref PubMed Scopus (0) Google Scholar). Molecular identification of these receptors was achieved by their cDNA cloning, which revealed that the prostanoid receptors are G-protein-coupled receptors (GPCRs) and that there is indeed a family of eight GPCRs that correspond to the pharmacologically defined receptors. In addition, a recent study revealed the presence of the ninth prostanoid receptor that belongs not to the prostanoid receptor family described above but to the chemoattractant receptor family (4Hirai H. Tanaka K. Yoshie O. Ogawa K. Kenmotsu K. Takamori Y. Ichimasa M. Sugamura K. Nakamura M. Takano S. Nagata K. J. Exp. Med. 2001; 193: 255-261Crossref PubMed Scopus (967) Google Scholar). This receptor called CRTH2 or DP2 is expressed in Th2 cells and eosinophils and mediates some of the PGD2 actions on these cells such as chemotaxis. cDNA cloning also revealed the presence of several splicing variants for EP3. Thus, there are four GPCRs designated subtypes EP1, EP2, EP3, and EP4 and EP3 variants mediating PGE2 actions. Subsequent analysis has revealed distinct biochemical properties and tissue and cellular localization of each EP subtype. The cloned EP subtypes have also been used in the development of compounds specific to each subtype. Molecular Structures—Fig. 1 shows an alignment of the primary amino acid sequences of the mouse EP1, EP2, and EP4 and three isoforms of mouse EP3 receptors. The mouse EP1, EP2, EP3 (EP3α), and EP4 receptors consist of 405, 362, 366, and 513 amino acids, respectively. EP4 has the longest intracellular C terminus and a relatively long intracellular third loop. The EP1 receptor also has a long third loop, whereas the EP2 and EP3 receptors have a more compact structure. A remarkable feature distinguishing the EP3 receptor from the other EP receptors is the existence of multiple variants generated by alternative splicing of the C-terminal tail. In mouse, alternative splicing creates three EP3 splice isoforms, α, β, and γ, containing C-terminal tails of 30, 26, and 29 amino acids that do not share any structural motifs or hydrophobic features (5Sugimoto Y. Negishi M. Hayashi Y. Namba T. Honda A. Watabe A. Hirata M. Narumiya S. Ichikawa A. J. Biol. Chem. 1993; 268: 2712-2718Abstract Full Text PDF PubMed Google Scholar, 6Irie A. Sugimoto Y. Namba A. Harazono A. Honda A. Watabe A. Negishi M. Narumiya S. Ichikawa A. Eur. J. Biochem. 1993; 217: 313-318Crossref PubMed Scopus (164) Google Scholar). These isoforms show similar ligand binding properties but have different signal transduction properties as described below. Multiple splice isoforms for EP3 also exist in other species including rat, rabbit, bovine, and human (3Narumiya S. Sugimoto Y. Ushikubi F. Physiol. Rev. 1999; 79: 1193-1226Crossref PubMed Scopus (0) Google Scholar). Although all of the four EP subtypes respond to PGE2, the amino acid identity among the EPs is limited; the identity of EP1 to EP2, EP3, and EP4 is 30, 33, and 28%, respectively. The amino acid identity is only 31% even between the two EPs (EP2 and EP4) that couple to the activation of adenylate cyclase. The EP2 receptor is more homologous to IP (40%) and DP (44%), the other two adenylate cyclase-stimulatory prostanoid receptors, than any other EPs, and the EP1 receptor is more homologous to FP (35%) and TP (34%) than other EPs. This limited homology among EPs probably reflects the phylogenetic relationship among the prostanoid receptors (7Toh H. Ichikawa A. Narumiya S. FEBS Lett. 1995; 361: 17-21Crossref PubMed Scopus (129) Google Scholar). Ligand Binding Properties—The EP subtypes bind most potently to PGE2 with Kd values in the range of 1–40 nm. Iloprost, an IP agonist, also binds to EP1 and EP3 with Ki values of about 20 nm. The PGE analogs that have been used in conventional studies are not specific for any given EP subtype except butaprost, which is specific for EP2. Several compounds highly selective for each EP subtype have been developed using cultured cell lines stably expressing each subtype. Examples are shown in Fig. 2 (8Kiriyama M. Ushikubi F. Kobayashi T. Hirata M. Sugimoto Y. Narumiya S. Br. J. Pharmacol. 1997; 122: 217-224Crossref PubMed Scopus (458) Google Scholar, 9Suzawa T. Miyaura C. Inada M. Maruyama T. Sugimoto Y. Ushikubi F. Ichikawa A. Narumiya S. Suda T. Endocrinology. 2000; 141: 1554-1559Crossref PubMed Scopus (318) Google Scholar, 10Kabashima K. Saji T. Murata T. Nagamachi M. Matsuoka T. Segi E. Tsuboi K. Sugimoto Y. Kobayashi T. Miyachi Y. Ichikawa A. Narumiya S. J. Clin. Invest. 2002; 109: 883-893Crossref PubMed Scopus (411) Google Scholar, 11Amano H. Hayashi I. Endo H. Kitasato H. Yamashina S. Maruyama T. Kobayashi M. Satoh K. Narita M. Sugimoto Y. Murata T. Yoshimura H. Narumiya S. Majima M. J. Exp. Med. 2003; 197: 221-232Crossref PubMed Scopus (283) Google Scholar). Signal Transduction Properties—Signal transduction pathways of EP subtypes have been studied by examining agonist-induced changes in second messengers such as cAMP, Ca2+, and inositol phosphates and agonist-induced changes in activities of downstream kinases. The EP1 receptor mediates a PGE2-induced elevation of the free Ca2+ concentration in Chinese hamster ovary cells. This increase is dependent on extracellular Ca2+ and occurs without a detectable phosphatidylinositide response (12Katoh H. Watabe A. Sugimoto Y. Ichikawa A. Negishi M. Biochim. Biophys. Acta. 1995; 1244: 41-48Crossref PubMed Scopus (73) Google Scholar), suggesting that EP1 regulates Ca2+ channel gating via an unidentified G protein. It was reported that EP1 expressed in Xenopus oocytes can couple to TRP5, a candidate for the receptor-activated Ca2+ channel, and this coupling is inhibited by an antisense oligonucleotide for Gq/G11 but not by one for Gi1 (13Tabata H. Tanaka S. Sugimoto Y. Kanki H. Kaneko S. Ichikawa A. Biochem. Biophys. Res. Commun. 2002; 298: 398-402Crossref PubMed Scopus (29) Google Scholar). The EP2 and EP4 receptors couple to Gs and mediate increases in cAMP concentrations. The major signaling pathway of the EP3 receptor is inhibition of adenylate cyclase via Gi. It should be noted, however, that the EP receptors do not couple exclusively to the pathways described but often to more than one G protein and signal transduction pathway (Table 1). Of interest in this respect is the presence of two EPs, EP2 and EP4, that are coupled to increases in cAMP. They apparently function redundantly in some processes. For example, both EP2 and EP4 mediate induction of RANKL through cAMP by PGE2 in osteoclastogenesis, although the extent of the contribution by each receptor may be different (14Li X. Okada Y. Pilbeam C.C. Lorenzo J.A. Kennedy C.R. Breyer R.M. Raisz L.G. Endocrinology. 2000; 141: 2054-2061Crossref PubMed Scopus (132) Google Scholar, 15Ono K. Akatsu T. Kugai N. Pilbeam C.C. Raisz L.G. Bone. 2003; 33: 798-804Crossref PubMed Scopus (23) Google Scholar). On the other hand, there are processes in which EP2 and EP4 play distinct roles. Some of these may be because of selective expression of either of them in relevant cells such as the action of EP2 during cumulus expansion in ovulation and fertilization (16Hizaki H. Segi E. Sugimoto Y. Hirose M. Saji T. Ushikubi F. Matsuoka T. Noda Y. Tanaka T. Yoshida N. Narumiya S. Ichikawa A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10501-10506Crossref PubMed Scopus (407) Google Scholar) and that of EP4 in closure of the ductus arteriosus (17Segi E. Sugimoto Y. Yamasaki A. Aze Y. Oida H. Nishimura T. Murata T. Matsuoka T. Ushikubi F. Hirose M. Tanaka T. Yoshida N. Narumiya S. Ichikawa A. Biochem. Biophys. Res. Commun. 1998; 246: 7-12Crossref PubMed Scopus (275) Google Scholar). However, only EP4 regulates migration of dendritic cells in the mouse although both EP2 and EP4 are expressed in these cells (18Kabashima K. Sakata D. Nagamachi M. Miyachi Y. Inaba K. Narumiya S. Nat. Med. 2003; 9: 744-749Crossref PubMed Scopus (259) Google Scholar). This EP4-selective action may be related to the fact that EP4 but not EP2 couples to phosphatidylinositol 3-kinase, probably via Gi, in addition to activation of adenylate cyclase (19Fujino H. Xu W. Regan J.W. J. Biol. Chem. 2003; 278: 12151-12156Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 20Fujino H. Regan J.W. Mol. Pharmacol. 2006; 69: 5-10Crossref PubMed Scopus (49) Google Scholar). It is interesting in this respect that EP4 is also implicated in cell migration during tumor invasion (21Timoshenko A.V. Xu G. Chakrabarti S. Lala P.K. Chakraborty C. Exp. Cell Res. 2003; 289: 265-274Crossref PubMed Scopus (133) Google Scholar) for ductus arteriosus closure (22Yokoyama U. Minamisawa S. Hong Q. Ghatak S. Akaike T. Segi-Nishida E. Iwasaki S. Iwamoto M. Misra S. Tamura K. Hori H. Yokota S. Toole B.P. Sugimoto Y. Ishikawa Y. J. Clin. Invest. 2006; 116: 3026-3034Crossref PubMed Scopus (123) Google Scholar) and for zebrafish gastrulation (23Cha D. 2006; PubMed Scopus Google Scholar). the EP3 receptor of multiple isoforms generated by alternative splicing of the C-terminal tail. differences among these splice variants have been including coupling to different signal transduction pathways (Table T. Sugimoto Y. Negishi M. A. Ushikubi F. A. S. Ichikawa A. Narumiya S. 1993; PubMed Scopus Google Scholar), different to agonist-induced M. Sugimoto Y. A. Narumiya S. Ichikawa A. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar), different of H. Negishi M. Ichikawa A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), different intracellular H. H. Y. Nakamura K. S. Negishi M. FEBS Lett. 2000; PubMed Scopus Google Scholar), and different agonist-induced FEBS Lett. PubMed Scopus Google transduction properties of EP receptor subtypes and EP3 cAMP in a and analysis and in have about EP receptor and have shown that each receptor is in the and that the expression are among The tissue of the mouse EP subtypes by is in Fig. Y. Namba T. Honda A. Hayashi Y. Negishi M. Ichikawa A. Narumiya S. J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. Sugimoto Y. Namba T. Watabe A. A. Negishi M. Narumiya S. Ichikawa A. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar, A. Sugimoto Y. Honda A. A. Namba T. Negishi M. S. Narumiya S. Ichikawa A. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar, M. N. Sugimoto Y. K. Negishi M. Narumiya S. Ichikawa A. FEBS Lett. 1995; PubMed Scopus Google Scholar). Among the four EPs, EP3 and EP4 receptors are the most widely with their being expressed in all mouse In the of EP1 is to several such as the and and EP2 is the of the EP receptors. each EP subtype shows a distinct cellular For example, in the EP3 is expressed in the the and the in the EP1 in the and EP4 in the Y. Namba T. R. Negishi M. Ichikawa A. Narumiya S. J. Physiol. 1994; Google Scholar) This to with the regulation of and respectively. A similar of EPs in the has been reported in the and human Breyer R.M. 1993; Full Text PDF PubMed Scopus Google Scholar, Breyer R.M. J. Physiol. Google Scholar). These not for EP2 in the of of EP is by various physiological and pathophysiological In R. Sugimoto Y. Segi E. M. H. F. Maruyama T. H. S. Ichikawa A. J. 2001; PubMed Scopus Google Scholar) and a cell M. R. H. F. Sugimoto Y. Ichikawa A. Biochem. Biophys. Res. Commun. 1998; PubMed Scopus Google Scholar), EP4 is expressed The addition of EP2 expression in both types of cells but the EP4 expression only in cells and the expression of EP4 in the R. Sugimoto Y. Segi E. M. H. F. Maruyama T. H. S. Ichikawa A. J. 2001; PubMed Scopus Google Scholar). a of PGE2 in response to LPS, and of the EP4 expression in the was by with and was by the addition of cAMP or PGE2 but not butaprost, suggesting that EP4 expression is through a loop. The presence of EP2 and EP4 and of their expression by were also in the cell T. O. Smith W.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). analysis indicated a increase in EP4 after In with expression of both EP2 and EP4 and in a S. K. C. Breyer R.M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In such as the ovary and expression of the EP subtypes in specific cell In the the EP4 expression is found in oocytes in this expression and EP4 is expressed first in both cells and cumulus cells and only in cells in EP2 expression is found in both cells and cumulus cells in This expression increases and to the cumulus cells expression changes in a similar to EP2 in cumulus and cells E. K. Sugimoto Y. M. H. S. Tsuboi K. Tanaka S. Ichikawa A. Biol. 2003; PubMed Scopus Google Scholar). In the mice are with and EP2 is expressed on in cells. EP4 expression is limited to cells on increases on and is found in cells as as EP3 expression is found in this expression and EP3 is expressed in with a increase on and M. Sugimoto Y. K. K. M. Negishi M. Ichikawa A. Endocrinology. 1997; PubMed Scopus Google Scholar). analysis has been for EP2 and Several sequences relevant to stimuli such as for and are and several to have been characterized in the of the EP2 S. Tanaka S. Sugimoto Y. M. R. Ichikawa A. 2003; PubMed Scopus Google Scholar). The of the EP4 several such as for and as as a response analysis an between and T. O. Smith W.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). deficient in each EP subtype have been and studies using these knock-out mice and EP have identified EP subtypes mediating various PGE2 actions (Table EP subtypes mediate processes to be inhibited by non-steroidal anti-inflammatory For example, the EP3 receptor mediates of F. Segi E. Sugimoto Y. Murata T. Matsuoka T. Kobayashi T. H. K. M. Ichikawa A. Tanaka T. Yoshida N. Narumiya S. 1998; PubMed Scopus Google Scholar), and EP1 and EP3 the of the and mediate response by of Y. T. H. Ushikubi F. Tanaka Y. Kobayashi T. S. Satoh N. T. M. A. H. Y. K. Narumiya S. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). EP2 ovulation and fertilization by expansion of the the for the of on ovulation (16Hizaki H. Segi E. Sugimoto Y. Hirose M. Saji T. Ushikubi F. Matsuoka T. Noda Y. Tanaka T. Yoshida N. Narumiya S. Ichikawa A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 10501-10506Crossref PubMed Scopus (407) Google Scholar). studies have revealed that different EP subtypes as as the IP receptor function in both the and in the For example, the acid revealed the of both IP and EP3 in A. H. H. Y. Ushikubi F. Matsuoka T. Narumiya S. Sugimoto Y. Ichikawa A. S. Biochem. Pharmacol. 2001; PubMed Scopus Google Scholar, T. Ushikubi F. Matsuoka T. Hirata M. Yamasaki A. Sugimoto Y. Ichikawa A. Aze Y. Tanaka T. Yoshida N. A. S. Narumiya S. 1997; PubMed Scopus Google Scholar). that is by and and mediated by the receptor is by PGE2 and acting on EP1 and IP, T. T. K. T. Segi E. Sugimoto Y. T. Narumiya S. M. Mol. PubMed Scopus Google Scholar). in the PGE2 acting on EP2 in the inhibition of in the and the of through the to of the H. S. C. M. A. K. Narumiya S. U. J. Clin. Invest. PubMed Scopus (164) Google function of EP receptor and Y. T. H. Ushikubi F. 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D. Tanaka S. H. Y. K. S. G. Ichikawa A. J. PubMed Scopus Google in X. Q. T. Breyer R.M. K. J. PubMed Scopus Google Y. Breyer R.M. T. Res. PubMed Scopus Google F. Segi E. Sugimoto Y. Murata T. Matsuoka T. Kobayashi T. H. K. M. Ichikawa A. Tanaka T. Yoshida N. Narumiya S. 1998; PubMed Scopus Google type I T. H. Segi E. Matsuoka T. Sugimoto Y. Tanaka S. Tanaka H. H. Ichikawa A. Narumiya S. Nat. PubMed Scopus Google with tumor and H. Hayashi I. Endo H. Kitasato H. Yamashina S. Maruyama T. Kobayashi M. Satoh K. Narita M. Sugimoto Y. Murata T. Yoshimura H. Narumiya S. Majima M. J. Exp. Med. 2003; 197: 221-232Crossref PubMed Scopus (283) Google K. H. S. O. H. Sugimoto Y. Ichikawa A. Ushikubi F. Narumiya S. 1999; Full Text Full Text PDF PubMed Scopus Google A. H. H. Y. Ushikubi F. Matsuoka T. Narumiya S. Sugimoto Y. Ichikawa A. S. Biochem. Pharmacol. 2001; PubMed Scopus Google with T. S. T. Kobayashi T. Sugimoto Y. Ushikubi F. Ichikawa A. Narumiya S. S. 2003; PubMed Scopus Google Scholar, I. H. K. Sugimoto Y. Ichikawa A. Ushikubi F. Narumiya S. Y. PubMed Scopus Google closure of ductus E. Sugimoto Y. Yamasaki A. Aze Y. Oida H. Nishimura T. Murata T. Matsuoka T. Ushikubi F. Hirose M. Tanaka T. Yoshida N. Narumiya S. Ichikawa A. Biochem. Biophys. Res. Commun. 1998; 246: 7-12Crossref PubMed Scopus (275) Google Scholar, U. Minamisawa S. Hong Q. Ghatak S. Akaike T. Segi-Nishida E. Iwasaki S. Iwamoto M. Misra S. Tamura K. Hori H. Yokota S. Toole B.P. Sugimoto Y. Ishikawa Y. J. Clin. Invest. 2006; 116: 3026-3034Crossref PubMed Scopus (123) Google K. Oida H. Kobayashi T. Maruyama T. Tanaka M. T. K. Segi E. T. M. K. Y. Sugimoto Y. Ushikubi F. S. K. Nakamura T. Narumiya S. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google K. Saji T. Murata T. Nagamachi M. Matsuoka T. Segi E. Tsuboi K. Sugimoto Y. Kobayashi T. Miyachi Y. Ichikawa A. Narumiya S. J. Clin. Invest. 2002; 109: 883-893Crossref PubMed Scopus (411) Google cell migration and K. Sakata D. Nagamachi M. Miyachi Y. Inaba K. Narumiya S. Nat. Med. 2003; 9: 744-749Crossref PubMed Scopus (259) Google in T. Segi-Nishida E. Miyachi Y. Narumiya S. J. Exp. Med. 2006; PubMed Scopus Google Scholar in a particularly PGE2, have been to play a major role in by acting on the and and of the from the knock-out mouse however, is that including PGE2 both and anti-inflammatory and these actions are often produced through regulation of expression in relevant For example, with the anti-inflammatory and of EP2 and EP4 redundantly mediate development of T. Segi-Nishida E. Miyachi Y. Narumiya S. J. Exp. Med. 2006; PubMed Scopus Google Scholar). however, the actions of these prostanoid receptors are by induction of in the for studies using the revealed of IP T. Ushikubi F. Matsuoka T. Hirata M. Yamasaki A. Sugimoto Y. Ichikawa A. Aze Y. Tanaka T. Yoshida N. A. S. Narumiya S. 1997; PubMed Scopus Google Scholar), and using revealed of EP2, EP3, and IP in K. A. H. F. Ushikubi F. Narumiya S. S. J. Pharmacol. Exp. PubMed Scopus Google Scholar). actions of are in or and are by actions of other This may are without on and responses. Examples are the between the T. Hirata M. Tanaka H. Y. Murata T. K. Sugimoto Y. Kobayashi T. Ushikubi F. Aze Y. N. Y. Yoshida N. K. A. Honda Y. H. Narumiya S. 2000; PubMed Scopus Google Scholar) and the T. H. Segi E. Matsuoka T. Sugimoto Y. Tanaka S. Tanaka H. H. Ichikawa A. Narumiya S. Nat. PubMed Scopus Google Scholar) pathways in of DP and EP3 are both in the and activation of the expression of a of and of mice studies have also revealed that multiple in responses. most of these actions are found in the and not in the The pathway M. E. R. C. Narumiya S. A. Y. M. G. F. Eur. J. 2003; 33: PubMed Scopus Google Scholar) and the pathway (18Kabashima K. Sakata D. Nagamachi M. Miyachi Y. Inaba K. Narumiya S. Nat. Med. 2003; 9: 744-749Crossref PubMed Scopus (259) Google Scholar) and of cells in the and the pathway between cells and and K. Murata T. Tanaka H. Matsuoka T. Sakata D. Yoshida N. K. T. Tanaka T. M. H. Ushikubi F. Narumiya S. Nat. 2003; PubMed Scopus Google Scholar). PGE2 with other can various of in a and the in both and anti-inflammatory The PGE2 exerts its a in have been through the biochemical identification and cDNA cloning of the four EP subtype receptors. development of highly selective and to each EP subtype and by studies on mice deficient in each EP receptor to to various processes. all of and all on prostanoid receptors.

During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48-60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.

The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, formerly AERS) is a database that contains information on adverse event and medication error reports submitted to the FDA. Besides those from manufacturers, reports can be submitted from health care professionals and the public. The original system was started in 1969, but since the last major revision in 1997, reporting has markedly increased. Data mining algorithms have been developed for the quantitative detection of signals from such a large database, where a signal means a statistical association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the information component (IC), and the empirical Bayes geometric mean (EBGM). A survey of our previous reports suggested that the ROR provided the highest number of signals, and the EBGM the lowest. Additionally, an analysis of warfarin-, aspirin- and clopidogrel-associated adverse events suggested that all EBGM-based signals were included in the PRR-based signals, and also in the IC- or ROR-based ones, and that the PRR- and IC-based signals were in the ROR-based ones. In this article, the latest information on this area is summarized for future pharmacoepidemiological studies and/or pharmacovigilance analyses.

The ProteomeXchange (PX) Consortium of proteomics resources (http://www.proteomexchange.org) was formally started in 2011 to standardize data submission and dissemination of mass spectrometry proteomics data worldwide. We give an overview of the current consortium activities and describe the advances of the past few years. Augmenting the PX founding members (PRIDE and PeptideAtlas, including the PASSEL resource), two new members have joined the consortium: MassIVE and jPOST. ProteomeCentral remains as the common data access portal, providing the ability to search for data sets in all participating PX resources, now with enhanced data visualization components.We describe the updated submission guidelines, now expanded to include four members instead of two. As demonstrated by data submission statistics, PX is supporting a change in culture of the proteomics field: public data sharing is now an accepted standard, supported by requirements for journal submissions resulting in public data release becoming the norm. More than 4500 data sets have been submitted to the various PX resources since 2012. Human is the most represented species with approximately half of the data sets, followed by some of the main model organisms and a growing list of more than 900 diverse species. Data reprocessing activities are becoming more prominent, with both MassIVE and PeptideAtlas releasing the results of reprocessed data sets. Finally, we outline the upcoming advances for ProteomeXchange.

During feeding, the gut microbiota contributes to the host energy acquisition and metabolic regulation thereby influencing the development of metabolic disorders such as obesity and diabetes. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues. In this review, we summarize the roles of gut microbial SCFAs in the host energy regulation and present an overview of the current understanding of its physiological functions.

Mass spectrometry (MS) is by far the most used experimental approach in high-throughput proteomics. The ProteomeXchange (PX) consortium of proteomics resources (http://www.proteomexchange.org) was originally set up to standardize data submission and dissemination of public MS proteomics data. It is now 10 years since the initial data workflow was implemented. In this manuscript, we describe the main developments in PX since the previous update manuscript in Nucleic Acids Research was published in 2020. The six members of the Consortium are PRIDE, PeptideAtlas (including PASSEL), MassIVE, jPOST, iProX and Panorama Public. We report the current data submission statistics, showcasing that the number of datasets submitted to PX resources has continued to increase every year. As of June 2022, more than 34 233 datasets had been submitted to PX resources, and from those, 20 062 (58.6%) just in the last three years. We also report the development of the Universal Spectrum Identifiers and the improvements in capturing the experimental metadata annotations. In parallel, we highlight that data re-use activities of public datasets continue to increase, enabling connections between PX resources and other popular bioinformatics resources, novel research and also new data resources. Finally, we summarise the current state-of-the-art in data management practices for sensitive human (clinical) proteomics data.

The ProteomeXchange (PX) consortium of proteomics resources (http://www.proteomexchange.org) has standardized data submission and dissemination of mass spectrometry proteomics data worldwide since 2012. In this paper, we describe the main developments since the previous update manuscript was published in Nucleic Acids Research in 2017. Since then, in addition to the four PX existing members at the time (PRIDE, PeptideAtlas including the PASSEL resource, MassIVE and jPOST), two new resources have joined PX: iProX (China) and Panorama Public (USA). We first describe the updated submission guidelines, now expanded to include six members. Next, with current data submission statistics, we demonstrate that the proteomics field is now actively embracing public open data policies. At the end of June 2019, more than 14 100 datasets had been submitted to PX resources since 2012, and from those, more than 9 500 in just the last three years. In parallel, an unprecedented increase of data re-use activities in the field, including 'big data' approaches, is enabling novel research and new data resources. At last, we also outline some of our future plans for the coming years.

Abstract The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern 1 . In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell–cell fusion 2,3 , the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity.

Allergic asthma is caused by the aberrant expansion in the lung of T helper cells that produce type 2 (TH2) cytokines and is characterized by infiltration of eosinophils and bronchial hyperreactivity. This disease is often triggered by mast cells activated by immunoglobulin E (IgE)-mediated allergic challenge. Activated mast cells release various chemical mediators, including prostaglandin D2 (PGD2), whose role in allergic asthma has now been investigated by the generation of mice deficient in the PGD receptor (DP). Sensitization and aerosol challenge of the homozygous mutant (DP-/-) mice with ovalbumin (OVA) induced increases in the serum concentration of IgE similar to those in wild-type mice subjected to this model of asthma. However, the concentrations of TH2 cytokines and the extent of lymphocyte accumulation in the lung of OVA-challenged DP-/- mice were greatly reduced compared with those in wild-type animals. Moreover, DP-/- mice showed only marginal infiltration of eosinophils and failed to develop airway hyperreactivity. Thus, PGD2 functions as a mast cell-derived mediator to trigger asthmatic responses.

Major advancements have recently been made in mass spectrometry-based proteomics, yielding an increasing number of datasets from various proteomics projects worldwide. In order to facilitate the sharing and reuse of promising datasets, it is important to construct appropriate, high-quality public data repositories. jPOSTrepo (https://repository.jpostdb.org/) has successfully implemented several unique features, including high-speed file uploading, flexible file management and easy-to-use interfaces. This repository has been launched as a public repository containing various proteomic datasets and is available for researchers worldwide. In addition, our repository has joined the ProteomeXchange consortium, which includes the most popular public repositories such as PRIDE in Europe for MS/MS datasets and PASSEL for SRM datasets in the USA. Later MassIVE was introduced in the USA and accepted into the ProteomeXchange, as was our repository in July 2016, providing important datasets from Asia/Oceania. Accordingly, this repository thus contributes to a global alliance to share and store all datasets from a wide variety of proteomics experiments. Thus, the repository is expected to become a major repository, particularly for data collected in the Asia/Oceania region.

The effect of an antimicrobial peptide, magainin 2, on the flip-flop rates of phospholipids was investigated by use of fluorescent lipids, i.e., anionic N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)dipalmitoyl-L-alpha- phosphatidylethanolamine (NBD-PE), 1-oleoyl-2-[12-((7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)- dodecanoyl]-L-alpha-phosphatidic acid (C12-NBD-PA), 1-oleoyl-2-[12- ((7-nitrobenz-2-oxa-1,3-diazol-4-yl)- amino)dodecanoyl]-L-alpha-phosphatidyl-L-serine (C12-NBD-PS), and zwitterionic 1-palmitoyl-2-[6-((7- nitrobenz-2-oxa-1,3-diazol-4-yl)amino)caproyl]-L-alpha-phosphatidy lcholine (C6-NBD-PC). Their intrinsic flip-flop half-lives at 30 degrees C in the absence of the peptide were 1.1 h, ca. 7 h, ca. 8 days, and > 2 days, respectively. The peptide accelerated the flip-flop half-lives of the fluorescent lipids to an order of minutes. Furthermore, the flip-flop was coupled with the membrane permeabilization and the peptide translocation [Matsuzaki, K., Murase, O., Fujii, N., & Miyajima, K. (1995) Biochemistry 34, 6521-6526], suggesting pore-mediated flip-flop. The flip-flop rate was independent of the initial labeling conditions (outer leaflet label or inner leaflet label). From these results, a model was proposed, in which the lipids translocate across the membrane by lateral diffusion along the wall of the pores composed of the peptides and the lipids. A simple theoretical calculation could explain the coupling of the flip-flop with the permeabilization.

Fibroblast growth factors (FGFs) are a family of structurally related polypeptides that are essential for embryonic development and that function postnatally as homoeostatic factors, in the response to injury, in the regulation of electrical excitability of cells and as hormones that regulate metabolism. In humans, FGF signalling is involved in developmental, neoplastic, metabolic and neurological diseases. Fgfs have been identified in metazoans but not in unicellular organisms. In vertebrates, FGFs can be classified as having intracrine, paracrine and endocrine functions. Paracrine and endocrine FGFs act via cell-surface FGF receptors (FGFRs); while, intracrine FGFs act independent of FGFRs. The evolutionary history of the Fgf family indicates that an intracrine Fgf is the likely ancestor of the Fgf family. During metazoan evolution, the Fgf family expanded in two phases, after the separation of protostomes and deuterostomes and in the evolution of early vertebrates. These expansions enabled FGFs to acquire diverse actions and functions.

To find the exact substrate specificities of three species of tripartite efflux systems of Pseudomonas aeruginosa, MexAB-OprM, MexCD-OprJ, and MexXY-OprM, we constructed a series of isogenic mutants, each of which constitutively overproduced one of the three efflux systems and lacked the other two, and their isogenic mutants, which lacked all these systems. Comparison of the susceptibilities of the constructed mutants to 52 antimicrobial agents belonging to various groups suggested the following substrate specificities. All of the efflux systems extrude a wide variety of antimicrobial agent groups, i.e., quinolones, macrolides, tetracyclines, lincomycin, chloramphenicol, most penicillins (all but carbenicillin and sulbenicillin), most cephems (all but cefsulodin and ceftazidime), meropenem, and S-4661, but none of them extrude polymyxin B or imipenem. Extrusion of aminoglycosides is specific to MexXY-OprM, and extrusion of a group of the beta-lactams, i.e., carbenicillin, sulbenicillin, ceftazidime, moxalactam, and aztreonam, is specific to MexAB-OprM. Moreover, MexAB-OprM and MexCD-OprJ extrude novobiocin, cefsulodin, and flomoxef, while MexXY-OprM does not. These substrate specificities are distinct from those reported previously.

MicroRNAs (miRNAs) comprise species of short noncoding RNA that regulate gene expression post-transcriptionally. Recent studies have demonstrated that epigenetic mechanisms, including DNA methylation and histone modification, not only regulate the expression of protein-encoding genes, but also miRNAs, such as let-7a, miR-9, miR-34a, miR-124, miR-137, miR-148 and miR-203. Conversely, another subset of miRNAs controls the expression of important epigenetic regulators, including DNA methyltransferases, histone deacetylases and polycomb group genes. This complicated network of feedback between miRNAs and epigenetic pathways appears to form an epigenetics-miRNA regulatory circuit, and to organize the whole gene expression profile. When this regulatory circuit is disrupted, normal physiological functions are interfered with, contributing to various disease processes. The present minireview details recent discoveries involving the epigenetics-miRNA regulatory circuit, suggesting possible biological insights into gene-regulatory mechanisms that may underlie a variety of diseases.

Previous studies using B16BL6-derived exosomes labelled with gLuc-lactadherin (gLuc-LA), a fusion protein of Gaussia luciferase (a reporter protein) and lactadherin (an exosome-tropic protein), showed that the exosomes quickly disappeared from the systemic circulation after intravenous injection in mice. In the present study, the mechanism of rapid clearance of intravenously injected B16BL6 exosomes was investigated. gLuc-LA-labelled exosomes were obtained from supernatant of B16BL6 cells after transfection with a plasmid DNA encoding gLuc-LA. Labelling was stable when the exosomes were incubated in serum. By using B16BL6 exosomes labelled with PKH26, a lipophilic fluorescent dye, it was demonstrated that PKH26-labelled B16BL6 exosomes were taken up by macrophages in the liver and spleen but not in the lung, while PKH26-labelled exosomes were taken up by the endothelial cells in the lung. Subsequently, gLuc-LA-labelled B16BL6 exosomes were injected into macrophage-depleted mice prepared by injection with clodronate-containing liposomes. The clearance of the intravenously injected B16BL6 exosomes from the blood circulation was much slower in macrophage-depleted mice than that in untreated mice. These results indicate that macrophages play important roles in the clearance of intravenously injected B16BL6 exosomes from the systemic circulation.

We have recently reported that angiotensin II (Ang II)-induced mitogen-activated protein kinase (MAPK) activation is mainly mediated by Ca2+-dependent activation of a protein tyrosine kinase through Gq-coupled Ang II type 1 receptor in cultured rat vascular smooth muscle cells (VSMC). In the present study, we found Ang II rapidly induced the tyrosine phosphorylation of the epidermal growth factor (EGF) receptor and its association with Shc and Grb2. These reactions were inhibited by the EGF receptor kinase inhibitor, AG1478. The Ang II-induced phosphorylation of the EGF receptor was mimicked by a Ca2+ ionophore and completely inhibited by an intracellular Ca2+ chelator. Thus, AG1478 abolished the MAPK activation induced by Ang II, a Ca2+ ionophore as well as EGF but not by a phorbol ester or platelet-derived growth factor-BB in the VSMC. Moreover, Ang II induced association of EGF receptor with catalytically active c-Src. This reaction was not affected by AG1478. These data indicate that Ang II induces Ca2+-dependent transactivation of the EGF receptor which serves as a scaffold for pre-activated c-Src and for downstream adaptors, leading to MAPK activation in VSMC.