Hayashi Y

References (22)

Title : Peptide mixed phosphonates for covalent complex formation with thioesterases in nonribosomal peptide synthetases - Konno_2023_J.Pept.Sci__e3532
Author(s) : Konno S , Tanaka M , Mizuguchi T , Toyokai H , Taguchi A , Taniguchi A , Hayashi Y
Ref : J Pept Sci , :e3532 , 2023
Abstract : Natural macrocyclic peptides derived from microorganisms are medicinal resources that are important for the development of new therapeutic agents. Most of these molecules are biosynthesized by a nonribosomal peptide synthetase (NRPS). The thioesterase (TE) domain in NRPS is responsible for the macrocyclization of mature linear peptide thioesters in a final biosynthetic step. NRPS-TEs can cyclize synthetic linear peptide analogs and can be utilized as biocatalysts for the preparation of natural product derivatives. Although the structures and enzymatic activities of TEs have been investigated, the substrate recognition and substrate-TE interaction during the macrocyclization step are still unknown. To understand the TE-mediated macrocyclization, here we report the development of a substrate-based analog with mixed phosphonate warheads, which can react irreversibly with the Ser residue at the active site of TE. We have demonstrated that the tyrocidine A linear peptide (TLP) with a p-nitrophenyl phosphonate (PNP) enables efficient complex formation with tyrocidine synthetase C (TycC)-TE containing tyrocidine synthetase.
ESTHER : Konno_2023_J.Pept.Sci__e3532
PubMedSearch : Konno_2023_J.Pept.Sci__e3532
PubMedID: 37423887

Title : Regulation of Presynaptic Release Machinery by Cell Adhesion Molecules - Uchigashima_2023_Adv.Neurobiol_33_333
Author(s) : Uchigashima M , Hayashi Y , Futai K
Ref : Adv Neurobiol , 33 :333 , 2023
Abstract : The synapse is a highly specialized asymmetric structure that transmits and stores information in the brain. The size of pre- and postsynaptic structures and function is well coordinated at the individual synapse level. For example, large postsynaptic dendritic spines have a larger postsynaptic density with higher alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) number on their surface, while juxtaposing presynaptic terminals have a larger active zone and higher release probability. This indicates that pre- and postsynaptic domains bidirectionally communicate to coordinate assembly of specific molecules on both sides of the synaptic cleft. Cell adhesion molecules (CAMs) that localize at synapses form transsynaptic protein interactions across the synaptic cleft and play important roles in synapse formation and regulation. The extracellular domain of CAMs is essential for specific synapse formation and function. In contrast, the intracellular domain is necessary for binding with synaptic molecules and signal transduction. Therefore, CAMs play an essential role on synapse function and structure. In fact, ample evidence indicates that transsynaptic CAMs instruct and modulate functions at presynaptic sites. This chapter focuses on transsynaptic protein interactions that regulate presynaptic functions emphasizing the role of neuronal CAMs and the intracellular mechanism of their regulation.
ESTHER : Uchigashima_2023_Adv.Neurobiol_33_333
PubMedSearch : Uchigashima_2023_Adv.Neurobiol_33_333
PubMedID: 37615873

Title : CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation - Hosokawa_2021_Nat.Neurosci__
Author(s) : Hosokawa T , Liu PW , Cai Q , Ferreira JS , Levet F , Butler C , Sibarita JB , Choquet D , Groc L , Hosy E , Zhang M , Hayashi Y
Ref : Nat Neurosci , : , 2021
Abstract : Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid-liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca(2+) is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca(2+)-induced liquid-liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity.
ESTHER : Hosokawa_2021_Nat.Neurosci__
PubMedSearch : Hosokawa_2021_Nat.Neurosci__
PubMedID: 33927400

Title : Effects of neural stem cell transplantation in Alzheimer's disease models - Hayashi_2020_J.Biomed.Sci_27_29
Author(s) : Hayashi Y , Lin HT , Lee CC , Tsai KJ
Ref : J Biomed Sci , 27 :29 , 2020
Abstract : Currently there are no therapies for treating Alzheimer's disease (AD) that can effectively halt disease progression. Existing drugs such as acetylcholinesterase inhibitors or NMDA receptor antagonists offers only symptomatic benefit. More recently, transplantation of neural stem cells (NSCs) to treat neurodegenerative diseases, including AD, has been investigated as a new therapeutic approach. Transplanted cells have the potential to replace damaged neural circuitry and secrete neurotrophic factors to counter symptomatic deterioration or to alter lesion protein levels. However, since there are animal models that can recapitulate AD in its entirety, it is challenging to precisely characterize the positive effects of transplanting NSCs. In the present review, we discuss the types of mouse modeling system that are available and the effect in each model after human-derived NSC (hNSC) or murine-derived NSC (mNSC) transplantation. Taken together, results from studies involving NSC transplantation in AD models indicate that this strategy could serve as a new therapeutic approach.
ESTHER : Hayashi_2020_J.Biomed.Sci_27_29
PubMedSearch : Hayashi_2020_J.Biomed.Sci_27_29
PubMedID: 31987051

Title : A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons - Hayashi_2016_Sci.Rep_6_23969
Author(s) : Hayashi Y , Nishimune H , Hozumi K , Saga Y , Harada A , Yuzaki M , Iwatsubo T , Kopan R , Tomita T
Ref : Sci Rep , 6 :23969 , 2016
Abstract : Notch signaling plays crucial roles for cellular differentiation during development through gamma-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Although recent studies implicate that Notch regulates synaptic plasticity or cognitive performance, the molecular mechanism how Notch works in mature neurons remains uncertain. Here we demonstrate that a novel Notch signaling is involved in expression of synaptic proteins in postmitotic neurons. Levels of several synaptic vesicle proteins including synaptophysin 1 and VGLUT1 were increased when neurons were cocultured with Notch ligands-expressing NIH3T3 cells. Neuron-specific deletion of Notch genes decreased these proteins, suggesting that Notch signaling maintains the expression of synaptic vesicle proteins in a cell-autonomous manner. Unexpectedly, cGMP-dependent protein kinase (PKG) inhibitor, but not gamma-secretase inhibitor, abolished the elevation of synaptic vesicle proteins, suggesting that generation of Notch intracellular domain is dispensable for this function. These data uncover a ligand-dependent, but gamma-secretase-independent, non-canonical Notch signaling involved in presynaptic protein expression in postmitotic neurons.
ESTHER : Hayashi_2016_Sci.Rep_6_23969
PubMedSearch : Hayashi_2016_Sci.Rep_6_23969
PubMedID: 27040987

Title : Species and inter-individual differences in metabolic capacity of di(2-ethylhexyl)phthalate (DEHP) between human and mouse livers - Ito_2014_Environ.Health.Prev.Med_19_117
Author(s) : Ito Y , Kamijima M , Hasegawa C , Tagawa M , Kawai T , Miyake M , Hayashi Y , Naito H , Nakajima T
Ref : Environ Health Prev Med , 19 :117 , 2014
Abstract : OBJECTIVES: This study was conducted to assess inter-species and inter-individual differences in the metabolism of di(2-ethylhexyl)phthalate (DEHP) in humans and mice. METHODS: The activities of four DEHP-metabolizing enzymes [lipase, UDP-glucuronocyltransferase (UGT), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH)] were measured in the livers of 38 human subjects of various ages and in eight 129/Sv male mice. RESULTS: Microsomal lipase activity was significantly lower in humans than in mice. The V max/K m value in humans was one-seventh of that in mice, microsomal UGT activity in humans was a sixth of that in mice, and cytosolic ALDH activity for 2-ethylhexanal in humans was one-half of that in mice. In contrast, ADH activity for 2-ethylhexanol was twofold higher in humans than in mice. The total amount of DEHP urinary metabolites and the concentration of mono(2-ethylhexyl)phthalate (MEHP) were much higher in intact mice than in the U.S. general population based on data reported elsewhere, regardless of the similar estimated DEHP intake between these mice and the human reference population. However, mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) and mono(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) levels were higher in the latter than in the former. Of note, inter-subject variability in the activities of all enzymes measured was 10-26-fold. CONCLUSION: The inter-individual variation in the metabolism of DEHP in humans may be greater than the difference between mice and humans (inter-species variation), and both may affects the risk assessment of DEHP.
ESTHER : Ito_2014_Environ.Health.Prev.Med_19_117
PubMedSearch : Ito_2014_Environ.Health.Prev.Med_19_117
PubMedID: 24078404

Title : Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-y lcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes - Yoshida_2012_Bioorg.Med.Chem_20_5705
Author(s) : Yoshida T , Akahoshi F , Sakashita H , Kitajima H , Nakamura M , Sonda S , Takeuchi M , Tanaka Y , Ueda N , Sekiguchi S , Ishige T , Shima K , Nabeno M , Abe Y , Anabuki J , Soejima A , Yoshida K , Takashina Y , Ishii S , Kiuchi S , Fukuda S , Tsutsumiuchi R , Kosaka K , Murozono T , Nakamaru Y , Utsumi H , Masutomi N , Kishida H , Miyaguchi I , Hayashi Y
Ref : Bioorganic & Medicinal Chemistry , 20 :5705 , 2012
Abstract : Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the gamma-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl carbonyl]thiazolidine (8 g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8 g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8 g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8 g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.
ESTHER : Yoshida_2012_Bioorg.Med.Chem_20_5705
PubMedSearch : Yoshida_2012_Bioorg.Med.Chem_20_5705
PubMedID: 22959556
Gene_locus related to this paper: human-DPP4

Title : Fused bicyclic heteroarylpiperazine-substituted L-prolylthiazolidines as highly potent DPP-4 inhibitors lacking the electrophilic nitrile group - Yoshida_2012_Bioorg.Med.Chem_20_5033
Author(s) : Yoshida T , Akahoshi F , Sakashita H , Sonda S , Takeuchi M , Tanaka Y , Nabeno M , Kishida H , Miyaguchi I , Hayashi Y
Ref : Bioorganic & Medicinal Chemistry , 20 :5033 , 2012
Abstract : Hypoglycemic agents with a mechanism of depeptidyl peptidase IV (DPP-4) inhibition are suitable for once daily oral dosing. It is difficult to strike a balance between inhibitory activity and duration of action in plasma for inhibitors bearing an electrophilic nitrile group. We explored fused bicyclic heteroarylpiperazine substituted at the gamma-position of the proline structure in the investigation of L-prolylthiazolidines lacking the electrophilic nitrile. Among them, 2-trifluoroquinolyl compound 8g is the most potent, long-lasting DPP-4 inhibitor (IC(50) = 0.37 nmol/L) with high selectivity against other related peptidases. X-ray crystal structure determination of 8g indicates that CH-pi interactions generated between the quinolyl ring and the guanidinyl group of Arg358 enhances the DPP-4 inhibitory activity and selectivity.
ESTHER : Yoshida_2012_Bioorg.Med.Chem_20_5033
PubMedSearch : Yoshida_2012_Bioorg.Med.Chem_20_5033
PubMedID: 22824762
Gene_locus related to this paper: human-DPP4

Title : Activity-dependent proteolytic cleavage of neuroligin-1 - Suzuki_2012_Neuron_76_410
Author(s) : Suzuki K , Hayashi Y , Nakahara S , Kumazaki H , Prox J , Horiuchi K , Zeng M , Tanimura S , Nishiyama Y , Osawa S , Sehara-Fujisawa A , Saftig P , Yokoshima S , Fukuyama T , Matsuki N , Koyama R , Tomita T , Iwatsubo T
Ref : Neuron , 76 :410 , 2012
Abstract : Neuroligin NLG a postsynaptic adhesion molecule is involved in the formation of synapses by binding to a cognate presynaptic ligand neurexin Here we report that neuroligin-1 NLG1 undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment CTF in adult rat brains in vivo as well as in neuronal cultures Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands NLG1-CTF was subsequently cleaved by presenilin/gamma-secretase Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures Collectively neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.
ESTHER : Suzuki_2012_Neuron_76_410
PubMedSearch : Suzuki_2012_Neuron_76_410
PubMedID: 23083742

Title : Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methyl pyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor - Kato_2011_Bioorg.Med.Chem_19_7221
Author(s) : Kato N , Oka M , Murase T , Yoshida M , Sakairi M , Yamashita S , Yasuda Y , Yoshikawa A , Hayashi Y , Makino M , Takeda M , Mirensha Y , Kakigami T
Ref : Bioorganic & Medicinal Chemistry , 19 :7221 , 2011
Abstract : In the course of our program for discovery of novel DPP-IV inhibitors, a series of pyrazolo[1,5-a]pyrimidines were found to be novel DPP-IV inhibitors. We identified N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methyl pyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (4a) and described its pharmacological profiles.
ESTHER : Kato_2011_Bioorg.Med.Chem_19_7221
PubMedSearch : Kato_2011_Bioorg.Med.Chem_19_7221
PubMedID: 22019046

Title : Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors - Kato_2011_Org.Med.Chem.Lett_1_7
Author(s) : Kato N , Oka M , Murase T , Yoshida M , Sakairi M , Yakufu M , Yamashita S , Yasuda Y , Yoshikawa A , Hayashi Y , Shirai M , Mizuno Y , Takeuchi M , Makino M , Takeda M , Kakigami T
Ref : Org Med Chem Lett , 1 :7 , 2011
Abstract : Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity.
ESTHER : Kato_2011_Org.Med.Chem.Lett_1_7
PubMedSearch : Kato_2011_Org.Med.Chem.Lett_1_7
PubMedID: 22373386

Title : One-pot high-yielding synthesis of the DPP4-selective inhibitor ABT-341 by a four-component coupling mediated by a diphenylprolinol silyl ether -
Author(s) : Ishikawa H , Honma M , Hayashi Y
Ref : Angew Chem Int Ed Engl , 50 :2824 , 2011
PubMedID: 21387497

Title : Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin - Futai_2007_Nat.Neurosci_10_186
Author(s) : Futai K , Kim MJ , Hashikawa T , Scheiffele P , Sheng M , Hayashi Y
Ref : Nat Neurosci , 10 :186 , 2007
Abstract : The structure and function of presynaptic and postsynaptic components of the synapse are highly coordinated. How such coordination is achieved and the molecules involved in this process have not been clarified. Several lines of evidence suggest that presynaptic functionalities are regulated by retrograde mechanisms from the postsynaptic side. We therefore sought postsynaptic mechanisms responsible for trans-synaptic regulation of presynaptic function at excitatory synapses in rat hippocampal CA1 pyramidal neurons. We show here that the postsynaptic complex of scaffolding protein PSD-95 and neuroligin can modulate the release probability of transmitter vesicles at synapse in a retrograde way, resulting in altered presynaptic short-term plasticity. Presynaptic beta-neurexin serves as a likely presynaptic mediator of this effect. Our results indicate that trans-synaptic protein-protein interactions can link postsynaptic and presynaptic function.
ESTHER : Futai_2007_Nat.Neurosci_10_186
PubMedSearch : Futai_2007_Nat.Neurosci_10_186
PubMedID: 17237775

Title : Lead optimization of [(S)-gamma-(arylamino)prolyl]thiazolidine focused on gamma-substituent: Indoline compounds as potent DPP-IV inhibitors - Sakashita_2007_Bioorg.Med.Chem_15_641
Author(s) : Sakashita H , Akahoshi F , Yoshida T , Kitajima H , Hayashi Y , Ishii S , Takashina Y , Tsutsumiuchi R , Ono S
Ref : Bioorganic & Medicinal Chemistry , 15 :641 , 2007
Abstract : Dipeptidyl peptidase IV (DPP-IV) inhibitors are looked to as a potential new antidiabetic agent class. A series of [(S)-gamma-(arylamino)prolyl]thiazolidine compounds in which the electrophilic nitrile is removed are chemically stable DPP-IV inhibitors. To discover a structure for the gamma-substituent of the proline moiety more suitable for interacting with the S(2) pocket of DPP-IV, optimization focused on the gamma-substituent was carried out. The indoline compound 22e showed a DPP-IV-inhibitory activity 100-fold more potent than that of the prolylthiazolidine 10 and comparable to that of NVP-DPP728. It also displayed improved inhibitory selectivity for DPP-IV over DPP8 and DPP9 compared to compound 10. Indoline compounds such as 22e have a rigid conformation with double restriction of the aromatic moiety by proline and indoline structures to promote interaction with the binding site in the S(2) pocket of DPP-IV. The double restriction effect provides a potent inhibitory activity which compensates for the decrease in activity caused by removing the electrophilic nitrile.
ESTHER : Sakashita_2007_Bioorg.Med.Chem_15_641
PubMedSearch : Sakashita_2007_Bioorg.Med.Chem_15_641
PubMedID: 17113301

Title : [(S)-gamma-(4-Aryl-1-piperazinyl)-l-prolyl]thiazolidines as a novel series of highly potent and long-lasting DPP-IV inhibitors - Yoshida_2007_Bioorg.Med.Chem.Lett_17_2618
Author(s) : Yoshida T , Sakashita H , Akahoshi F , Hayashi Y
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :2618 , 2007
Abstract : In the search for an inhibitor of dipeptidyl peptidase IV (DPP-IV) highly potent both in vitro and in vivo, we synthesized a series of L-prolylthiazolidine-based DPP-IV inhibitors having 4-arylpiperazine or 4-arylpiperidine at the gamma-position of the proline structure. Of these compounds, the 4-(5-nitro-2-pyridyl)piperazine analog 21e showed a sub-nanomolar (IC(50)=0.92 nmol/L) DPP-IV inhibitory activity and a long-lasting in vivo DPP-IV inhibition profile.
ESTHER : Yoshida_2007_Bioorg.Med.Chem.Lett_17_2618
PubMedSearch : Yoshida_2007_Bioorg.Med.Chem.Lett_17_2618
PubMedID: 17317162
Gene_locus related to this paper: human-DPP4

Title : Serum-free culture conditions for serial subculture of undifferentiated PC12 cells - Ohnuma_2006_J.Neurosci.Methods_151_250
Author(s) : Ohnuma K , Hayashi Y , Furue M , Kaneko K , Asashima M
Ref : Journal of Neuroscience Methodsods , 151 :250 , 2006
Abstract : PC12 cells, a widely used model neuronal cell line, are usually cultured in serum-supplemented medium. This report describes a serum-free medium for the culture of PC12 cells. PC12 cells grown in the two media types had similar growth rates and released dopamine in response to high potassium-induced calcium elevation. However, the levels of dopamine and of dopamine release in cells cultured in the serum-free medium were less than 10% of that in cells cultured in serum-supplemented medium. Dopamine levels recovered within 10 days if cells were returned to serum-supplemented medium, but dopamine release could not be recovered. Nerve growth factor (NGF) induced similar responses in PC12 cells cultured in both media, including phosphorylation of extracellular signal-regulated protein kinases and neurite extension. Transferrin was necessary for survival of neurite-bearing PC12 cells subcultured in serum-free medium and insulin promoted the cells proliferation. Ten days culture with NGF produced a similar increase in neurofilament expression and acetylcholinesterase activity in both media. These results suggest that PC12 in the hormonally defined serum-free media are qualitatively the same as those cultured in serum-supplemented media, and therefore this new culture protocol should enable more precise studies of PC12 cells culture in the absence of confounding unknown factors.
ESTHER : Ohnuma_2006_J.Neurosci.Methods_151_250
PubMedSearch : Ohnuma_2006_J.Neurosci.Methods_151_250
PubMedID: 16169086

Title : [(S)-gamma-(Arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors - Sakashita_2006_Bioorg.Med.Chem_14_3662
Author(s) : Sakashita H , Akahoshi F , Kitajima H , Tsutsumiuchi R , Hayashi Y
Ref : Bioorganic & Medicinal Chemistry , 14 :3662 , 2006
Abstract : Dipeptidyl peptidase-IV (DPP-IV) inhibitors, or glucagon-like peptide-1 (GLP-1) enhancers, are looked to as a potential new class of antidiabetic agents. In particular, potent and long-acting inhibitors might offer advantages in exploiting DPP-IV inhibition. The series of [(S)-gamma-(arylamino)prolyl]-(S)-2-cyanopyrrolidine compounds on which we reported previously has a highly potent inhibitory activity but seemed to be unstable in neutral aqueous solution. Here, we describe [(S)-gamma-(arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors. They are the thiazolidine analogs of [(S)-gamma-(arylamino)prolyl]-(S)-2-cyanopyrrolidine but with the electrophilic nitrile removed to improve chemical stability in aqueous solution. Of the compounds investigated in the present study, the [((S)-gamma-3,4-dicyanophenylamino)prolyl]thiazolidine 12 m was the most potent. The structure-activity relationship (SAR) of the gamma-substituent in the proline moiety of the thiazolidide was similar to that obtained with the (S)-2-cyanopyrrolidide. The gamma-substituent in the proline moiety of both the (S)-2-cyanopyrrolidide and the thiazolidide may engage with the S(2) binding pocket of DPP-IV and thereby achieve hydrophobic interaction in the same manner. Based on pharmacokinetic experiments in rats, the representative compound 11, which displayed high oral bioavailability (BA=83.9%) and long half-life in plasma (t(1/2)=5.27 h), was found to have an excellent pharmacokinetic profile.
ESTHER : Sakashita_2006_Bioorg.Med.Chem_14_3662
PubMedSearch : Sakashita_2006_Bioorg.Med.Chem_14_3662
PubMedID: 16460948
Gene_locus related to this paper: human-DPP4

Title : Species and tissue differences in the expression of DPPY splicing variants - Takimoto_2006_Biochem.Biophys.Res.Commun_348_1094
Author(s) : Takimoto K , Hayashi Y , Ren X , Yoshimura N
Ref : Biochemical & Biophysical Research Communications , 348 :1094 , 2006
Abstract : The non-functional dipeptidyl peptidase, DPPY (DPP10), regulates the expression and gating of K+ channels in Kv4 family by tightly binding to these pore-forming subunits. Neural tissue-specific expression of this and the related DPPX (DPP6) is thought to confer rapid inactivation and other unique properties of neuronal Kv4 channels. Here we report that DPPY mRNA is abundant in human adrenal gland, but very low in the corresponding rat tissue. Furthermore, multiple DPPY splicing variants with alternative first exons are significant in the brain, whereas the expression of DPPY gene in the adrenal gland and pancreas is predominantly initiated at the two latter sites. These splicing variants, as well as an N-terminal peptide-deleted DPPY, produce similar changes in Kv4.3 gating. Thus, transcription of DPPY gene is species- and tissue-specifically controlled.
ESTHER : Takimoto_2006_Biochem.Biophys.Res.Commun_348_1094
PubMedSearch : Takimoto_2006_Biochem.Biophys.Res.Commun_348_1094
PubMedID: 16899223
Gene_locus related to this paper: human-DPP10 , ratno-q6q629

Title : Transmembrane interaction mediates complex formation between peptidase homologues and Kv4 channels - Ren_2005_Mol.Cell.Neurosci_29_320
Author(s) : Ren X , Hayashi Y , Yoshimura N , Takimoto K
Ref : Molecular & Cellular Neurosciences , 29 :320 , 2005
Abstract : An asthma-related peptidase homologue (DPP10) may act as an auxiliary subunit of Kv4 channels, similar to DPPX. Here we show that DPP10 preferentially binds to Kv4 channel proteins to increase current density and alter channel gating. DPP10 also forms complexes by themselves and with DPPX in the absence of Kv4 channels. DPP10 mRNA is abundantly expressed in nodose and dorsal root ganglia, suggesting that DPP10 participates in controlling airway reactivity and mechanosensation. The region from the N-terminus to the end of the transmembrane of DPP10 mediates its association with the channel, whereas the S1-S2 portion of the channel is sufficient for complex formation. This N-terminal portion of DPP10 also confers all the gating effects produced by the peptidase homologue. Thus, interaction between transmembranes of DPP10/DPPX and Kv4 channel mediates functional complex formation. We call this protein DPPY, instead of DPP10, because of its revealed role as a Kv4 channel regulator.
ESTHER : Ren_2005_Mol.Cell.Neurosci_29_320
PubMedSearch : Ren_2005_Mol.Cell.Neurosci_29_320
PubMedID: 15911355

Title : The transcriptional landscape of the mammalian genome - Carninci_2005_Science_309_1559
Author(s) : Carninci P , Kasukawa T , Katayama S , Gough J , Frith MC , Maeda N , Oyama R , Ravasi T , Lenhard B , Wells C , Kodzius R , Shimokawa K , Bajic VB , Brenner SE , Batalov S , Forrest AR , Zavolan M , Davis MJ , Wilming LG , Aidinis V , Allen JE , Ambesi-Impiombato A , Apweiler R , Aturaliya RN , Bailey TL , Bansal M , Baxter L , Beisel KW , Bersano T , Bono H , Chalk AM , Chiu KP , Choudhary V , Christoffels A , Clutterbuck DR , Crowe ML , Dalla E , Dalrymple BP , de Bono B , Della Gatta G , di Bernardo D , Down T , Engstrom P , Fagiolini M , Faulkner G , Fletcher CF , Fukushima T , Furuno M , Futaki S , Gariboldi M , Georgii-Hemming P , Gingeras TR , Gojobori T , Green RE , Gustincich S , Harbers M , Hayashi Y , Hensch TK , Hirokawa N , Hill D , Huminiecki L , Iacono M , Ikeo K , Iwama A , Ishikawa T , Jakt M , Kanapin A , Katoh M , Kawasawa Y , Kelso J , Kitamura H , Kitano H , Kollias G , Krishnan SP , Kruger A , Kummerfeld SK , Kurochkin IV , Lareau LF , Lazarevic D , Lipovich L , Liu J , Liuni S , McWilliam S , Madan Babu M , Madera M , Marchionni L , Matsuda H , Matsuzawa S , Miki H , Mignone F , Miyake S , Morris K , Mottagui-Tabar S , Mulder N , Nakano N , Nakauchi H , Ng P , Nilsson R , Nishiguchi S , Nishikawa S , Nori F , Ohara O , Okazaki Y , Orlando V , Pang KC , Pavan WJ , Pavesi G , Pesole G , Petrovsky N , Piazza S , Reed J , Reid JF , Ring BZ , Ringwald M , Rost B , Ruan Y , Salzberg SL , Sandelin A , Schneider C , Schonbach C , Sekiguchi K , Semple CA , Seno S , Sessa L , Sheng Y , Shibata Y , Shimada H , Shimada K , Silva D , Sinclair B , Sperling S , Stupka E , Sugiura K , Sultana R , Takenaka Y , Taki K , Tammoja K , Tan SL , Tang S , Taylor MS , Tegner J , Teichmann SA , Ueda HR , van Nimwegen E , Verardo R , Wei CL , Yagi K , Yamanishi H , Zabarovsky E , Zhu S , Zimmer A , Hide W , Bult C , Grimmond SM , Teasdale RD , Liu ET , Brusic V , Quackenbush J , Wahlestedt C , Mattick JS , Hume DA , Kai C , Sasaki D , Tomaru Y , Fukuda S , Kanamori-Katayama M , Suzuki M , Aoki J , Arakawa T , Iida J , Imamura K , Itoh M , Kato T , Kawaji H , Kawagashira N , Kawashima T , Kojima M , Kondo S , Konno H , Nakano K , Ninomiya N , Nishio T , Okada M , Plessy C , Shibata K , Shiraki T , Suzuki S , Tagami M , Waki K , Watahiki A , Okamura-Oho Y , Suzuki H , Kawai J , Hayashizaki Y
Ref : Science , 309 :1559 , 2005
Abstract : This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
ESTHER : Carninci_2005_Science_309_1559
PubMedSearch : Carninci_2005_Science_309_1559
PubMedID: 16141072
Gene_locus related to this paper: mouse-abhd1 , mouse-abhd3 , mouse-abhd4 , mouse-acot4 , mouse-adcl4 , mouse-DGLB , mouse-ephx3 , mouse-Kansl3 , mouse-lipli , mouse-LIPN , mouse-Ppgb , mouse-q3uuq7 , mouse-srac1 , mouse-Tex30 , mouse-tmco4 , mouse-tmm53 , mouse-f172a

Title : Clinical significance of 99mTc-DTPA-galactosyl human serum albumin liver scintigraphy in follow-up patients with biliary atresia - Ishii_2003_J.Pediatr.Surg_38_1486
Author(s) : Ishii T , Nio M , Shimaoka S , Sano N , Sasaki H , Kimura D , Hayashi Y , Ohi R
Ref : J Pediatr Surg , 38 :1486 , 2003
Abstract : PURPOSE: Technetium 99m DTPA-galactosyl human serum albumin (GSA) liver scintigraphy was performed in follow-up patients with biliary atresia, and its clinical significance was investigated.
METHODS: Between 1994 and 2001, GSA liver scintigraphy was performed 153 times in 57 follow-up patients. HH15, LHL15, and H/L15 (HH15/LHL15) were obtained. Patients were divided into 3 groups according to the clinical status (good, n = 17; fair, n = 24; poor, n = 16). The correlation between these parameters and liver function tests was examined. Twenty-six patients of the 57 underwent 3 serial GSA scintigraphies and also were divided into 3 groups (good, n = 13; fair, n = 8; poor, n = 5). (3rd/1st)H/L15 (3rd H/L15/1st H/L15) was obtained and compared.
RESULTS: H/L15 had a correlation with serum albumin and serum cholinesterase. H/L15 was statistically different among 3 groups (good, 0.97 +/- 0.15; fair, 0.94 +/- 0.09; poor, 1.12 +/- 0.21; P <.05). Although most patients in the good (10 patients; 76.9%) and fair (7 patients; 87.5%) groups showed (3rd/1st)H/L15 of less than 1.1, 3 patients (60%) in the poor group showed (3rd/1st)H/L15 of more than 1.1. (3rd/1st)H/L15 in the poor group was significantly higher than those in good and fair groups (P <.05).
CONCLUSIONS: Technetium 99m-GSA liver scintigraphy is useful to assess the functional hepatic reserve in follow-up patients with biliary atresia. Serial assessment with GSA scintigraphy can provide the trend of the patient's liver condition and can estimate the prognosis of the liver.
ESTHER : Ishii_2003_J.Pediatr.Surg_38_1486
PubMedSearch : Ishii_2003_J.Pediatr.Surg_38_1486
PubMedID: 14577072

Title : Molecular cloning and sequence analysis of human dipeptidyl peptidase IV, a serine proteinase on the cell surface - Misumi_1992_Biochim.Biophys.Acta_1131_333
Author(s) : Misumi Y , Hayashi Y , Arakawa F , Ikehara Y
Ref : Biochimica & Biophysica Acta , 1131 :333 , 1992
Abstract : The cDNA coding for the human dipeptidyl peptidase IV (DPPIV) has been isolated and sequenced. The nucleotide sequence (3465 bp) of the cDNA contains an open reading frame encoding a polypeptide comprising 766 amino acids, one residue less than those of rat DPPIV. The predicted amino acid sequence exhibits 84.9% identity to that of the rat enzyme, and contains nine potential N-linked glycosylation sites, one site more than those in the rat enzyme. A putative catalytic triad for serine proteinases, serine, aspartic acid and histidine, are found in a completely conserved COOH-terminal region (positions 625-752).
ESTHER : Misumi_1992_Biochim.Biophys.Acta_1131_333
PubMedSearch : Misumi_1992_Biochim.Biophys.Acta_1131_333
PubMedID: 1352704
Gene_locus related to this paper: human-DPP4