Effect of endothelin-1(1-31)on extracellular signal-regulated kinase and proliferation of human coronary artery smooth muscle cells.


Human chymase, an enzyme forming novel bioactive 31-amino acid length endothelins.


Inhibition of Tryptase TL2 from Human T4+lymphocytes and Inhibition of HIV-1 Replication in H9 Cells by Recombinant Aprotinin and Bikunin Homologues

The serine esterase TL2 from human T4+ lymphocytes is a binding component to HIV-1 glycoprotein gp120 and seems to play a role in the HIV-1 infection mechanism. Recombinant variants of the Kunitz-type serine proteinase inhibitor aprotinin were investigated for their ability to inhibit tryptase TL2 and the binding of gp120 to this enzyme. Furthermore, the viral replication of HIV-1 was investigated H9 cell cultures under the influence of recombinant aprotinin and bikunin variants. In contrast to native aprotinin, the recombinant variant [Arg15, Phe17, Glu52] aprotinin with a reactive-site sequence homologous to the V3 loop of HIV-1 gp120 showed a specific inhibition of tryptase TL2 (> 80%). However, the [Leu15, Phe17, Glu52] aprotinin variant with hydrophobic subsites was the most potent inhibitor of the binding of gp120 to tryptase TL2 (68%). Our results show that the enzyme activity of purified tryptase TL2 is inhibited not only by variants with basic amino acids, but also those with hydrophobic residues in the reactive-site region. Therefore, tryptase TL2 is not a typical trypsin-like or chymotrypsin-like protease. Investigations on inhibition of HIV-1 replication in H9 cell cultures showed that tryptase TL2 is involved in the mechanism of virus internalization into human lymphocytes. The [Leu15, Phe17, Glu52] aprotinin showed a significant retardation of syncytium formation over a period of 5 days in a 1 micro M concentration. Similar investigations were performed with recombinant variants of bikunin, the light chain of human inter-alpha-trypsin inhibitor. Only the single-headed variant [Arg94] delta 2 bikunin inhibited slightly the syncytium formation over a period of 2 days in a 2.2 micro M concentration. Wild-type bikunin and all full-length variants showed no effect, possibly due to steric hindrance by the second domain of the double-headed inhibitor.


Intrinsic Nucleoside Diphosphate Kinase-like Activity as a Novel Function of 14-3-3 Proteins


Human Mucus Protease Inhibitor and its Mutants Prevent Infection by Influenza A and Sendai Viruses

Medical Aspects of Proteases and Protease Inhibitors


Selective Conversion of Big Endothelins to Tracheal Smooth Muscle-Constricting 31-Amino Acid Length Endothelins by Chymase from Human Mast Cells

Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products. Chymases from other species, such as the enzymes from rat connective tissue and mucosal mast cells, and the other chymotrypsin-like proteases examined degraded big ETs. ETs(1-31) exhibited various contractile potencies as to the rat trachea in comparison with 21-amino acid-length endothelins, ETs(1-21), and big ETs: ET-1(1-21) > ET-1(1-31) > big ET-1; ET-2(1-31) > ET-2(1-21) > or = big ET-2; ET-3(1-21) > or = ET-3(1-31) > or = big ET-3. Among the ETs(1-31), ET-2(1-31) was the most potent constrictor, its potency being similar to that of ET-1(1-21) and stronger than that of ET-2(1-21). The contractile activity of ETs(1-31) may not be the consequence of conversion to the corresponding ETs(1-21) by phosphoramidon-sensitive ET-converting enzymes or other chymotrypsin-type proteases and metalloendopeptidases, because the contractile activity was not inhibited significantly on treatment with inhibitors of these proteases before the addition of ET-1(1-31). Inhibitors of chymotrypsin-type serine proteases, on the contrary, significantly enhanced the contractile activity exhibited by ET-1(1-31) and big ET-1, but not that by ET-1(1-21). These results suggest that protease(s) on the surface of the rat trachea tends to degrade ETs(1-31) and big ETs, and thereby reduces their contractile activity. Taken together, the results suggest that trachea-constricting ETs(1-31) generated by human chymase may play a role in the hyper-responsive airway in allergic inflammation.


Structure Studies on the Carbohydrate Moiety of RatLliver Cathepsin L


Protease Inhibitors and a Pulmonary Surfactant in Airway Fluid are Potential Defensive


ウイルス感染を制御する細胞性プロテアーゼとプロテアーゼインヒビター(インフルエンザとエイズウイルスを中心として)


Molecular Basis of Proteolytic Activation of Sendai Virus Infection and the Defensive


HIV-1 の標的細胞認識と感染機序

HIV-1 の標的細胞認識と感染機序

HIV-1 感染による神経障害の診療マニュアル

HIV-1 感染による神経障害の診療マニュアル


Human Mucus Protease Inhibitor in Airway Fluids Is a Potential Defensive Compound against Infection with Influenza A and Sendai Viruses

Tryptase Clara, a trypsin-like protease localized exclusively in and secreted from Clara cells to the bronchial epithelium of rat, proteolytically activates the infectivity of influenza A virus [H. Kido, Y. Yokogoshi, K. Sakai, M. Tashiro, Y. Kishino, A. Fukutomi, and N. Katunuma (1992) J. Biol. Chem. 267, 13573-13579]. We report here that human mucus protease inhibitor (MPI), a major inhibitor of granulocyte elastase in the lining fluids of the human respiratory tract, significantly inhibited proteolytic activation of the infectivity of influenza A and Sendai viruses by tryptase Clara in vitro and multi-cycles of mouse-adapted influenza A virus replication in rat lungs in vitro. Recombinant MPI and the C- but not the N-terminal domain of the MPI inhibited both the proteolytic activity of tryptase Clara and the activation of virus infection. The 50% inhibitory concentrations of recombinant MPI and the C-terminal domain for tryptase Clara with Sendai virus envelope glycoprotein as substrate were 7.4 and 61.6 nM, respectively. These results indicate that MPI is a defensive compound against virus infection. Since there is evidence suggesting that concentrations of MPI in respiratory fluids are insufficient for prevention of virus infection, administration of MPI in the airway may be useful for treatment of these virus infections.


Proteolytic Activation of the Precursor of Membrane Type 1 Matrix Metalloproteinase by Human Plasmin


Inhibitory Effect of Pulmonary Surfactant on Sendai Virus Infection in Rat Lungs


Cellular Proteases Involved in The Pathogenicity of Enveloped Animal Virus, Human Immunodeficiency Virus, Influenza Virus A and Sendai Virus

In enveloped viruses, post-translational proteolytic activation is a critical step for the fusion activity and thus for the infectivity of the virus. In addition to the membrane receptors for the viruses, proteolytic activation is indispensable for effective virus spread in the infected host and it is a prime determinant for pathogenicity. Here we described the host cellular processing proteases, tryptase Clara and tryptase TL2, which proteolytically activate the infectivity of influenza A and Sendai viruses in the respiratory tract and HIV-1 in human CD4+ T cells, respectively. A novel trypsin-like protease, designated tryptase Clara, was purified from rat lung. The enzyme is localized in Clara cells of the bronchial epithelium and is secreted into the airway lumen. The enzyme specifically recognizes the consensus cleavage motif Gln(Glu)-X-Arg of influenza A and Sendai viruses and proteolytically activates the envelope fusion glycoproteins of the progeny viruses extracellularly in the airway lumen. Human mucus protease inhibitor and pulmonary surfactant in airway fluid inhibited the proteolytic activation of these viruses and also suppressed multiple cycles of viral replication in vitro. These results suggest that an imbalance between the amount of tryptase Clara and that of endogenous inhibitors in airway fluid is a prime determinant for pneumopathogenicity of the viruses. Therefore supplementing an endogenous inhibitor at therapeutic doses may protect against virus infection. In HIV-1 infection, binding of the gp120 envelope glycoprotein to the CD4 receptor is not sufficient in itself to allow virus entry, and an additional component(s) in the membrane is required for cell infection as a cofactor. We isolated a serine protease named tryptase TL2, in the membrane of CD4+ lymphocytes, which specifically binds to the V3 loop of HIV-1 gp120 as a cofactor. After binding, tryptase TL2 proteolytically processed gp120 into two protein species of 70 and 50 kDa and the cleavage was suppressed by a neutralizing antibody against the V3 loop. The amino acids that constitute the cleavage sites in the V3 loop of almost all HIV isolates are variable, but they are restricted to those which are susceptible to chymotryptic and/or tryptic enzyme. The multi-substrate specificity of tryptase TL2, which has tryptic and chymotryptic specificities, may correspond tot he variability of the V3 loop. The selective cleavage of the V3 loop by tryptase TL2 may lead to a conformational change of gp120, resulting in the dissociation of gp120 from gp41, exposing the fusogenic domain of the transmembrane protein gp41 following virus-host cell fusion.


呼吸器感染症と肺サーファクタント サーファクタントの基礎的作用と臨床への応用

呼吸器感染症と肺サーファクタント サーファクタントの基礎的作用と臨床への応用


Purification and Characterization of a Novel Isoform of Mast Cell Tryptase from Rat Tongue

Rat mast cell tryptase was purified to homogeneity from rat tongue by a series of standard chromatographic procedures. Since the enzyme gave band corresponding to molecular mass of 32-35 kDa on sodium dodecyl sulfate polyacrylamide gel electrophoresis and exhibited a molecular mass of 135 kDa on gel filtration, it was presumed to be a noncovalently associated tetramer. The N-terminal amino acid sequence of 50 residues of the enzyme showed the highest degree of homology with the same region in mouse mast cell protease 7 (92%), and less homology to those of tryptases from man and dog, and peritoneal cells of rats and Mongolian gerbils. The inhibitor specificity of rat tongue tryptase was similar to that of rat peritoneal mast cell tryptase free from trypstatin: it was inhibited by alpha 1-antitrypsin, Kunitz-type soybean trypsin inhibitor and Bowman-Birk soybean trypsin inhibitor, but these inhibitors do not inhibit the tryptases from rat skin, human lung, and dog mast cells. Judging from these results, together with other enzymatic properties, the enzyme may be a novel isoform of tryptase in rat tongue. Analysis by differential staining with peroxidase-labeled lectins of the enzyme suggested that it has tri- and/or tetraantennary complex-type oligosaccharides containing a relatively high amount of sialic acid. The immunohistochemical distribution of this enzyme indicated that the reactive antigen was specific in connective tissue but not in mucosal mast cells.


プロテアーゼ阻害薬と感染症

プロテアーゼ阻害薬と感染症


T Cell Membrane Associated Serine Protease, Tryptase TL2, Binds Human Immunodeficiency Virus Type 1 gp120 and Cleaves The Third-Variable-Domain Loop of gp120. Neutralizing Antibodies of Human Immunodeficiency Virus Type I Inhibits Cleavage of gp120


AIDS ウイルスの感染性と複製に関与するT 細胞プロテアーゼ群

AIDS ウイルスの感染性と複製に関与するT 細胞プロテアーゼ群

Journal of Clinical and Experimental Medicine


Cellular Proteases Involved in the Pathogenicity of Human Immunodeficiency and Influenza Virus

Advances in Experimental Medicine and Biology


Cloning of a cDNA encoding a 190-kDa insulin receptor substrate-1-like protein of simian COS cells.

Biochemical and Biophysical Research Communications


Cloning of a cDNA Encoding a 190-kDa Insulin Receptor Substrate-1-like Protein of Simian CO5 Cells

Major insulin signals such as stimulation of glucose uptake and DNA synthesis and modification of hexose metabolism are mediated by the tyrosine-phosphorylated insulin receptor substrate-1 (IRS-1; pp180) in many species of cells. We cloned cDNA encoding a 190-kDa IRS-1-like protein (pp190) in simian COS cells and which is slightly larger than IRS-1 (pp180) of human, rat, and mouse cells. The deduced amino acid sequence of COS pp190 consisted of 1251 amino acids and was 96.4%, 87.9% and 88.7% identical to human, mouse and rat IRS-1. The COS pp190 bound to SH2 (src-homology 2) domains of p85, Grb2/Ash, and SH-PTP2, as did IRS-1. In IRS-1-knockout mice, insulin signals are thought to be mediated by IRS-2 (pp190), which is an alternative signaling molecule and is slightly larger than IRS-1. However, the COS pp190 may be a simian homologue of IRS-1, but not of IRS-2. The results of Southern blotting suggested the possibility that Chinese hamster ovary (CHO) cells have not only the IRS-1 gene but also a gene related to the COS pp190.


Simple Preparation of Rat Brain Lysosomes and Their Proteolytic Properties


Control of Tryptase and Chymase Activity by Protease Inhibitors

Mast Cell Proteases in Immunology and Biology


Calcium Requirement and Inhibitor Spectrum for Intracellular HIV Type 1 gp160 Processing in Cultured HeLa Cells and CD4+ Lymphocytes: Similarity to Those of Viral Envelope Glycoprotein Maturase


トリプターゼクララとインフルエンザウイルス感染

トリプターゼクララとインフルエンザウイルス感染


Detection of Tryptase TL2 and CD26 Antigen in Brain-Derived Cells Non-Permissive to T-Cell-Line-Tropic Human Immunodeficiency Virus Type 1


Purification of Meprin from Human Kidney and its Role in Parathyroid Hormone Degradation


Inhibition of Tryptase TL2 from Human T4+ lymphocytes and In Vitro Inhibition of HIV-1 Replication in H9 Cells by Recombinant Aprotinin and Bikunin Variants


Involvement of a Cystatin-a-Sensitive Cysteine Proteinase in the Degradation of Native L-lactate Dehydrogenase and Serum Albumin by Rat Liver or Kidney Lysosomes


Close Co-localization of CD4 and a Serine Esterase Tryptase TL2 on the Cell-surface of Human Monocytoid and CD4+ lymphoid Cells

Tryptase TL2, a serine esterase in the membrane of human monocytoid and CD4+ lymphoid cells, specifically binds to the V3 domain of HIV-1 gp120. Here we report that monoclonal antibodies against CD4 that recognize the epitope interacting with gp120 specifically blocked the immunostaining of cell-surface tryptase TL2, although the antibody does not cross-react with tryptase TL2. Down-regulation of cell-surface CD4 induced by HIV-1 Nef prevented this blocking effect. These data suggest that CD4 is closely co-localized with tryptase TL2 on the cell surface and that regulation of the expression of tryptase TL2 is not associated with that of CD4.


Meprin is Predominantly Involved in Parathyroid Hormone Degradation by the Microvillar Membranes of Rat Kidney


Inhibitors of Chymotrypsin-like Proteases Inhibit Eosinophil Peroxidase Release from Activated Human Eosinophils


Assignment of Disulfide Bridges in the Fusion Glycoprotein of Sendai Virus

The mature fusion (F) glycoprotein of the paramyxovirus family consists of two disulfide-linked subunits, the N-terminal F2 and the C-terminal F1 subunits, and contains 10 cysteine residues which are highly conserved at specific positions. The high level of conservation strongly suggests that they are indeed disulfide linked and play important roles in the folding and functioning of the molecule. However, it has not even been clarified which cysteine residues link the F2 and F1 subunits. This report describes our assignment of the disulfide bridges in purified Sendai virus F glycoprotein by fragmentation of the polypeptide and isolation of cystine-containing peptides and determination of their N-terminal sequences. The data demonstrate that all of the 10 cysteine residues participate in disulfide bridges and that Cys-70, the only cysteine in F2, and Cys-199, the most upstream cysteine in F1, form the interchain bond. Of the remaining eight cysteine residues clustered near the transmembrane domain of F1, the specific bridges identified are Cys-338 to Cys-347 and Cys-362 to Cys-370. Although no exact pairings between the subsequent four residues were defined, it seems likely that the most downstream, Cys-424, is linked to Cys-394, Cys-399, or Cys-401. Thus, we conclude that the cysteine-rich domain indeed contributes to the formation of a bunched structure containing at least two tandem cystine loops.


インフルエンザの感染機序:気管支粘膜上皮細胞のプロテアーゼと制御因子

インフルエンザの感染機序:気管支粘膜上皮細胞のプロテアーゼと制御因子


Sendai Virus Infection Changes the Subcellular Localization of Tryptase Clara in Rat Bronchiolar Epithelial Cells


HIV の外膜蛋白質 gp120 のV3領域と特異的に結合するトリプターゼ TL2


Chromaffin Cells Express Alzheimer Amyloid Precursor Protien in the Same Manner as Brain Cells


ウイルス感染と細胞内プロテアーゼ ーインフルエンザウイルス,エイズウイルスを中心としてー


Interaction of Hepatitis B Virus X Protein with a Serine Protease, Tryptase TL2, as an Inhibitor

X protein of hepatitis B virus (HBV) transactivates transcription of various viral and cellular genes. It has been suggested that X protein plays a major role in hepatocarcinogenesis by HBV. The protein possesses amino acid sequence homology to the functionally essential domain of Kunitz-type serine protease inhibitors. This Kunitz domain-like sequence in X protein is indispensable for the transactivation function. To clarify whether X protein has a serine protease inhibitor activity, a search was made for serine proteases which interact with, but not degrade X protein. Tryptase TL2, one of serine proteases in hepatic cells, was found to directly interact with X protein without degradation. Moreover, the activities of tryptase TL2 and an analogous protease were substantially inhibited by X protein. These results suggest that transactivation function of X protein is exerted by modulation of the hepatic serine protease activity, giving rise to quantitative or qualitative change of cellular transcription factor(s) through protection from proteolytic degradation and/or suppression of processing.


A Processing Protease for gp160 HIV-1 Envelope Glycoprotein Precursor in Human T4+ lymphocytes

Biological Functions of Proteases and Inhibitors


Cellular processing proteases for the envelope glycoprotein precursors of human immunodeficiency virus-1 and of influenza and parainfluenza viruses


Participation of cathepsin B in Processing of antigen Presentation to MHC-Class II


Purification and Molecular Cloning of Chymase from Human Tonsils


生物化学実験法:蛋白質分解酵素I

生物化学実験法:蛋白質分解酵素I


Antibody Against the Carboxyl Terminus of the F2 Subunit of Sendai Virus Fusion Glycoprotein Inhibits Proteolytic Activation


肥満細胞とプロテアーゼの多様性およびその生理的意義,肥満細胞の新しい側面とアレルギー性疾患治療


Pulmonary Surfactant is A Potential Endogenous Inhibitor of Proteolytic Activation of Sendai Virus and Influenza A Virus


活性化好酸球からの Eosinoophil Peroxidase 放出におけるキモトリプシン型プロテアーゼの関与


Processing Protease for gp160 Human Immunodeficiency Virus Type I Envelope Glycoprotein Precursor in Human T4+ lymphocytes: Purification and Characterization

A processing protease for the human immunodeficiency virus type I (HIV-I) envelope glycoprotein gp160 precursor has been purified to homogeneity from the post-nuclear membrane fraction of a human T4+ lymphocyte clone. Most of the processing activity was found to be present in the fractions of endoplasmic reticulum and Golgi apparatus of the cells. The purified enzyme has a monomeric structure with a molecular mass of 26 +/- 3 kDa, as judged by gel-permeation liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing and nonreducing conditions. The purified enzyme converted gp160 to gp120 and gp41, showing a pH optimum of 6.5-7.0. Direct amino acid sequencing of the amino terminus of the product gp41 revealed that the cleavage site of gp160 was between Arg511 and Ala512. The enzyme activity was inhibited by trypsin-type protease inhibitors, but was not affected by CaCl2, MgCl2 or chelating agents. The properties of the purified enzyme are clearly distinct from those of processing proteases reported previously. Although the significance of the enzyme in vivo is not currently certain, judging from its cleavage specificity and subcellular localization, this endopeptidase appears to be a processing enzyme for the human immunodeficiency virus type I gp160 precursor protein in human T cells.


The alpha-Type 85-kDa subunit of Phosphatidylinositol 3-Kinase is Phosphorylatedat Tyrosines 368, 580, and 607 by the Insulin Receptor


ウイルス感染とプロテアーゼ ーエイズウイルス,インフルエンザウイルスの感染と増殖に関与するプロテアーゼー


Purification of a Trypsin-Type Protease from Human Umbilical Vein Endothelial Cells, That is Highly Sensitive to The Kunitz Inhibitor Domain Peptide of Alzheimer's Disease Amyloid Protein Precursor


アレルギー性炎症とプロテアーゼ

アレルギー性炎症とプロテアーゼ


A Membrane-Bound Metallo-Endopeptidase from Rat Kidney: Its Immunological Characterization,

The structure and location of a membrane-bound metallo-endopeptidase, previously purified from rat kidney [Yamaguchi et al. (1991) Eur. J. Biochem. 200, 563-571], were examined by immunochemical and immunohistochemical methods with a rabbit polyclonal antibody against the purified enzyme. On treatment with endoglycosidase F, the subunit of the purified enzyme (molecular mass = 88 kDa) was converted to a smaller form (78.5 kDa), indicating that the enzyme contained at least 11% N-linked carbohydrate. Treatment of kidney membranes with papain resulted in release of the enzyme, as shown by Western blotting analysis of the solubilized fraction. Immunoassays of rat tissues showed that only the kidney, and small and large intestine expressed significant amounts of the antigen. Moreover, immunohistochemical studies showed that the antigen was confined to the luminal surfaces of the proximal renal tubules and the intestinal villi. Thus, like another kidney membrane metallo-endopeptidase, meprin [Kounnas et al. (1991) J. Biol. Chem. 266, 17350-17357], the purified enzyme is shown to be a glycoprotein that is probably anchored in the plasma membrane, and located in the luminal surface of microvillar membranes of the kidney and intestine. These results indicate that our enzyme and meprin have clear structural and topological similarities.


Tーリンパ球膜局在新プロテアーゼの発見とそのAIDS ウイルス受容体としての作用機序の解明


The a-Type 85-kDa Subunit of Phosphatidylinositol 3-Kinase is Phosphorylated at Tyrosine 368, 580, and 607 by The Insulin Receptor

We have shown previously that insulin stimulated the tyrosine phosphorylation of the alpha-type 85-kDa subunit (p85) of phosphatidylinositol (PI) 3-kinase in vitro and in vivo. In the present work, we identified the major tyrosine phosphorylation sites of the alpha-type p85 by the insulin receptor. [32P]Phosphopeptides obtained from lysylendopeptidase digestion of phosphorylated alpha-type p85 in intact cells after insulin treatment were analyzed using reverse-phase high performance liquid chromatography and thin layer electrophoresis. The tyrosine phosphorylation sites of alpha-type p85 in vivo were assigned to three major phosphopeptides, designated p1, p2, and p3. Highly purified insulin receptor also phosphorylated the purified p85 of PI 3-kinase from the bovine thymus at p1. The purified glutathione S-transferase (GST)-p85 (alpha-type) fusion protein and its truncated proteins from Escherichia coli were also phosphorylated by the purified insulin receptor at p1, p2, and p3 in vitro. Analysis of [32P]phosphopeptide of the truncated GST-p85 (alpha-type) fusion proteins and radiosequence analysis revealed that the p1, p2, and p3 phosphopeptides were phosphorylated at tyrosines 607, 580, and 368, respectively. In addition, phenylalanine substitutions at tyrosine 607 and 580 reduced the p1 and p2 phosphopeptides in vivo, respectively. We conclude that the alpha-type p85 of PI 3-kinase was phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor in vivo.


プロテアーゼインヒビター

プロテアーゼインヒビター


Electron Immunohistochemical Localization in Rat Bronchiolar Epithelial Cells of Tryptase Clara which Determines The Pneumotropism and Pathogenicity of Sendai Virus and Influenza Virus

The intracellular localization in rat bronchiolar epithelial cells of a novel trypsin-like protease named tryptase Clara, a possible activator of inactive viral fusion glycoprotein of influenza A and wild-type Sendai virus in the respiratory tract, was examined by electron microscopy. In thin sections embedded in LR White, gold particles indicating immunoreactivity of tryptase Clara were detected specifically in secretory granules of Clara cells. No immunoreactivity was detected in bronchiolar ciliated cells, alveolar cells including epithelial Type I and II cells, or alveolar macrophages. Some granules enveloped in a thin membrane and labeled intensely with immunogold particles were seen protruding from peripheral and submembrane regions and a few were observed free in the airway lumen. Scanning electron microscopy also revealed smooth droplets along the main body of Clara cells. These data suggest that tryptase Clara is secreted into the bronchiolar lumen. These findings are the first to show the subcellular localization of tryptase Clara in rat bronchioles and suggest the site of proteolytic activation of the progeny of enveloped pneumotropic viruses, such as Sendai virus and influenza virus.

The Journal of Histochemistry and Cytochemistry


プロテアーゼとそのインヒビター ---生理的意義および病態との関連

プロテアーゼとそのインヒビター ---生理的意義および病態との関連


エイズウイルス感染と細胞内プロテアーゼ

エイズウイルス感染と細胞内プロテアーゼ


Tryptase Clara, An Activating Protease for Sendai Virus in Rat Lungs, is Involved in Pneumopathogenicity

Tryptase Clara is an arginine-specific serine protease localized exclusively in and secreted from Clara cells of the bronchial epithelium of rats (H. Kido, Y. Yokogoshi, K. Sakai, M. Tashiro, Y. Kishino, A. Fukutomi, and N. Katunuma, J. Biol. Chem. 267:13573-13579, 1992). The purified protease was shown in vitro to behave similarly to trypsin, cleaving the precursor glycoprotein F of Sendai virus at residue Arg-116 and activating viral infectivity in a dose-dependent manner. Anti-tryptase Clara antibody inhibited viral activation by the protease in vitro in lung block cultures and in vivo in infected rats. When the enzyme-specific antibody was administered intranasally to rats that were also infected intranasally with Sendai virus, activation of progeny virus in the lungs was significantly inhibited. Thus, multiple cycles of viral replication were suppressed, resulting in a reduction in lung lesions and in the mortality rate. These findings indicate that tryptase Clara is an activating protease for Sendai virus in rat lungs and is therefore involved in pulmonary pathogenicity of the virus in rats.


HIV (侵入に関与する細胞因子)

HIV (侵入に関与する細胞因子)


Isolation and Characterization of A Novel Trypsin-like Protease Found in Rat Bronchiolar Epithelial Clara Cells: A Possible Activator of The Viral Fusion Glycoprotein

A novel trypsin-like protease associated with rat bronchiolar epithelial Clara cells, named Tryptase Clara, was purified to homogeneity from rat lung by a series of standard chromatographic procedures. The enzyme has apparent molecular masses of 180 +/- 16 kDa on gel filtration and 30 +/- 1.5 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. Its isoelectric point is pH 4.75. Studies with model peptide substrates showed that the enzyme preferentially recognizes a single arginine cleavage site, cleaving Boc-Gln-Ala-Arg-4-methylcoumaryl-7-amide most efficiently and having a pH optimum of 7.5 with this substrate. The enzyme is strongly inhibited by aprotinin, diisopropylfluorophosphate, antipain, leupeptin, and Kunitz-type soybean trypsin inhibitor, but inhibited only slightly by Bowman-Birk soybean trypsin inhibitor, benzamidine, and alpha 1-antitrypsin. Immunohistochemical studies indicated that the enzyme is located exclusively in the bronchiolar epithelial Clara cells and colocalized with surfactant. An immunoreactive protein with a molecular mass of 28.5 kDa was also detected in airway secretions by Western blotting analyses, suggesting that the 30-kDa protease in Clara cells is processed before or after its secretion. Proteolytic cleavage of the hemagglutinin of influenza virus is a prerequisite for the virus to become infectious. Tryptase Clara was shown to cleave the hemagglutinin and activate infectivity of influenza A virus in a dose-dependent way. These results suggest that the enzyme is a possible activator of inactive viral fusion glycoprotein in the respiratory tract and thus responsible for pneumopathogenicity of the virus.


AIDSウイルス感染に関与する新しい細胞膜局在セリンプロテアーゼ -AIDSウイルスの新しいレセプターの可能性-

Journal of Clinical and Experimental Medicine


Biomodulators of Glucocorticoid: Amplifiers and Suppressors of Glucocorticoid Action

Proceedings of The 1st International Congress on "Vitamins and Biofactors in Life Science"


エイズウイルス感染におけるヒトTリンパ球のプロテアーゼ群の役割

エイズウイルス感染におけるヒトTリンパ球のプロテアーゼ群の役割


A Membrane-bound Metallo-endopeptidase from Rat Kidney:Characteristics of Its Hydrolysis of Peptide Hormones and Neuropeptides


A Novel Membrane-bound Serine Esterase in Human T4+ lymphocytes is A Binding Protein of Envelope Glycoprotein gp120 of HIV-1

A novel membrane-bound serine esterase, named tryptase TL2, which is immunologically reactive with the antibody inhibiting induction of syncytia by human immunodeficiency virus-1 (HIV-1) (HATTORI, T., KOITO, A., TAKATSUKI, K., KIDO, H., and KATUNUMA, N., 1989, FEBS Lett., 248, 48-52), has been purified from a human T4+ lymphocyte clone. The enzyme has a molecular mass of 198 +/- 15 kDa, and is composed of two subunits of 32 kDa and four subunits of 28 kDa. The enzyme was strongly inhibited by the envelope glycoprotein gp120 of HIV-1, by synthetic peptides of V3 domains of gp120 s with the sequence GPGR in their center, which correspond to the principal neutralizing epitopes of the gp120s of various HIV-1 strains, by Kunitz-type inhibitors with the sequence GPCR in their active site, such as trypstatin, H130, and [Arg15, Glu52] aprotinin and by the microbial inhibitors leupeptin and antipain. This enzyme was specifically bound to the inhibitor V3 domain of gp120 of HIV-1, and this binding was blocked by the inhibitors of tryptase TL2, with a central motif GPCR or GPGR sequence in their center, but not by leupeptin and antipain without the motif. These findings suggest that tryptase TL2 is important in target site recognition and binding of HIV-1 in co-operation with CD4 receptor in the initial process of HIV-1 infection.


ウイルス感染における宿主細胞プロテアーゼの役割

ウイルス感染における宿主細胞プロテアーゼの役割


H-7 Reduces The Nuclear Binding of [3H]Dexamethasone in Rat Liver Slice But Does Not Affect The Phosphorylation of Glucocorticoid Receptor


A Membrane-bound Metallo-endopeptidase from Rat Kidney Hydrolyzing Parathyroid Hormone: Purification and Characterization


Tリンパ球膜の新セリンプロテアーゼ

Tリンパ球膜の新セリンプロテアーゼ


Tryptase TL2 in The Membrane of Human T4+ lymphocytes is A Novel Binding Protein of The V3 Domain of HIV-1 Envelope Glycoprotein gp120


Recent Advances in Research on Tryptases and Endogenous Tryptase Inhibitors

Monogr. Allergy: Neutral Proteases of Mast Cells


新しいbioreactant としての細胞性セリンプロテアーゼと内在性インヒビター


Protease-specificity of Kunitz Inhibitor Domain of Alzheimer's Disease Amyloid Protein Precursor

The putative inhibitor domain of Alzheimer's disease amyloid protein precursor was purified from E. coli containing a synthetic gene encoding the Kunitz domain. The purified protein (A4 inhibitor) inhibited the activity of trypsin, forming a 1:1 molar complex with the enzyme. It also strongly inhibited plasmin (Ki = 7.5 x 10(-11) M) from human serum and tryptase (Ki = 2.2 x 10(-10) M) from rat mast cells (tryptase M). In addition, it inhibited rat pancreatic trypsin, alpha-chymotrypsin and kallikrein and human serum kallikrein, but did not inhibit rat chymase, pancreatic elastase, alpha-thrombin, urokinase, papain or cathepsin B.

Biochemical and Biophysical Research Communications


腸内最近由来物質のグルココルチコイド修飾作用

腸内最近由来物質のグルココルチコイド修飾作用

腸内フローラと生体ホメオスタシス(光岡知足 編)

腸内フローラと生体ホメオスタシス(光岡知足 編)


セリンプロテアーゼとアレルギー炎症の成立機序

セリンプロテアーゼとアレルギー炎症の成立機序

肥満細胞·生理と病理(黒沢元博 編)

肥満細胞·生理と病理(黒沢元博 編)


酵素に特異的なセリンプロテアーゼインヒビター —特異的基質のホウ酸誘導体—

酵素に特異的なセリンプロテアーゼインヒビター —特異的基質のホウ酸誘導体—


Biological Functions of Chymase and Tryptase and their Inhibitors in Rat Mast Cells

Intracellular Proteolysis: Mechanisms and Regulations


バイオモジュレーターとしての細胞内Kunitz 型インヒビター —トリプスタチンを中心としてー


肥満細胞セリン·プロテアーゼとアレルギー炎症の成立機序

肥満細胞セリン·プロテアーゼとアレルギー炎症の成立機序


アレルギーとプロテアーゼ,プロテアーゼインヒビター

アレルギーとプロテアーゼ,プロテアーゼインヒビター


Diacylglycerols Enhance the Anti-tumor Effect of Glucocorticoid on L5178Y Lymphoblasts in Vivo

1,2-Dioleoyl-rac-glycerol, a potent activator of protein kinase C, was found to enhance the growth-inhibitory effect of triamcinolone acetonide on L5178Y lymphoblasts in adrenalectomized, male DBA/2 mice. On the other hand, in mice without adrenalectomy, it markedly inhibited tumor growth without increasing the plasma level of corticosterone or adrenocorticotropic hormone or reducing the body weight. These results suggest that diacylglycerol enhances the action of endogenous glucocorticoid to a sufficient level to inhibit the growth of lymphoblasts. Of various diacylglycerols with different carbon chain lengths tested, 1,2-dioleoyl-rac-glycerol was the most potent growth inhibitor and was maximally effective at a dose of above 30 micrograms/100 g body weight. This finding suggests that diacylglycerols may be useful for enhancing the antitumor effect of a low dose of glucocorticoid or endogenous glucocorticoid on lymphoblasts without any significant side effect.


Involvement of Tryptase-related Cellular Protease(s) in Human Immunodeficiency Virus Type 1 Infection


Biological Functions of Serine Proteases in Mast Cells in Allergic Inflammation

Serine proteases in mast cell granules, such as chymase, atypical chymase, and tryptase, which are major proteins in the granules, may play important roles in the process of immunoglobulin E (IgE)-mediated degranulation and in pathobiological alterations in tissues. Indeed, inhibitors of chymase, substrate analogs, and antichymase F(ab')2, but not inhibitors of tryptase, markedly inhibited histamine release induced by IgE-receptor bridging but not that induced by Ca ionophore. In contrast, inhibitors of metalloprotease inhibited histamine release induced not only by IgE-receptor bridging but also by Ca ionophore. These results suggest that chymase and metalloprotease are involved at different steps in the process of degranulation. The extents of inhibition of histamine release were closely correlated with the amounts of the inhibitors of chymase accumulated in the granules. After degranulation, the released proteases may in part contribute to pathobiological alterations in allergic disorders through generations of C3a anaphylatoxin and thrombin by human and rat tryptase, respectively, and those of angiotensin II and a chemotactic factor of neutrophils by human and rat chymase, respectively. Moreover, chymase and atypical chymase from rat were shown to destroy type IV collagen, and human tryptase was found to hydrolyze various plasma proteins, such as fibrinogen and high-molecular-weight kininogen. The biological activities of tryptase and chymase from rat may be regulated by their dissociation from and association with trypstatin, an endogenous inhibitor of these proteases.


Kunitz-type Protease Inhibitor Found in Rat Mast Cell: Purification, Properties and Amino Acid Sequence

A low molecular weight serine protease inhibitor, named trypstatin, was purified from rat peritoneal mast cells. It is a single polypeptide with 61 amino acid residues and an Mr of 6610. Trypstatin markedly inhibits blood coagulation factor Xa (Ki = 1.2 x 10(-10) M) and tryptase (Ki = 3.6 x 10(-10) M) from rat mast cells, which have activities that convert prothrombin to thrombin. It also inhibits porcine pancreatic trypsin (Ki = 1.4 x 10(-8) M) and chymase (Ki = 2.4 x 10(-8) M) from rat mast cells, but not papain, alpha-thrombin, or porcine pancreatic elastase. Trypstatin forms a complex in a molar ratio of 1:1 with trypsin and one subunit of tryptase. The complete amino acid sequence of this inhibitor was determined and compared with those of Kunitz-type inhibitors. Trypstatin has a high degree of sequence homology with human and bovine inter-alpha-trypsin inhibitors, A4(751) Alzheimer's disease amyloid protein precursor, and basic pancreatic trypsin inhibitor. However, unlike other known Kunitz-type protease inhibitors, it inhibits factor Xa most strongly.


Studies on Biomodulators of Glucocorticoid Action: Amplifiers and Suppressors of Glucocorticoid Action


Peptide Boronic Acids, Substrate Analogs, Inhibit Chymase, and Histamine Release from Rat Mast Cells

Peptide boronic acids, such as methoxysuccinyl-Ala-Ala-Pro-(L)boro-Phe-OH, its pinacol ester, and t-butyloxycarbonyl-Phe-Pro-(L)boro-Phe-pinacol, inhibited the activity of chymase from connective tissue mast cells approximately 40- to 80-fold more than atypical chymase from mucosal mast cells, and did not inhibit trypsin. Only peptide boronic acids containing "L" forms of boronic acids were inhibitory. The Ki values of these peptide boronic acids for chymase were in the 60-170 nM concentration range, like those of the natural inhibitors tested, but all the natural inhibitors tested except Eglin C and chymostatin inhibited both chymase and trypsin. Thus these peptide boronic acids should be useful for selective inhibition of chymase with less inhibitory activity for atypical chymase and without inhibition of trypsin. These peptide boronic acids markedly inhibited histamine release induced by anti-rat immunoglobulin E, suggesting that chymase in connective tissue mast cells plays some role in the process of histamine release. These peptides are assumed to be therapeutically useful for treatment of allergic inflammations catalyzed by chymase.


Antibodies and Inhibitions of Chymase are Incorporated into Mast Cell Granules and Inhibit Histamine Release


Epidermal Growth Factor as a New Regulator of Induction of Tyrosine Aminotransferase and Tryptophan Oxygenase by Glucocorticoid


Tumor-promoting Phorbol Ester Amplifies the Inductions of Tyrosine Aminotransferase and Ornithine Decarboxylase by Glucocorticoid


Inhibition by 1-(5-Isoguinolinesulfonyl)-2-Methyl-piperazine, an Inhibitor of Protein Kinase C, of Enzyme Induction by Glucocorticoid and of Nuclear Translocation of Glucocorticoid-Receptor Complexes


Studies on Biomodulators of Glucocorticoid Actions: The Nature and the Modes of Actions of Glucocorticoid Potency Amplifiers

We have found many compounds that amplify the action of glucocorticoid without themselves having any glucocorticoid-like action and have proposed the concept of 'Glucocorticoid Action Biomodulators'. These biomodulators consist of 'Glucorticoid Sensitivity Amplifiers', which greatly amplify the action of glucocorticoid at doses of glucocorticoid that alone have minimal effects, and 'Glucocorticoid Potency Amplifiers', which markedly enhance the effect of glucocorticoid at doses that have maximal effects. Potent activators of protein kinase C, such as 1,2-racemic dioctanoylglycerol, 12-o-tetradecanoyl-phorbol-13-acetate, and epidermal growth factor (EGF), markedly enhanced the induction of tyrosine aminotransferase and ornithine decarboxylase by dexamethasone in adrenalectomized rats in vivo and in primary cultures of adult rat hepatocytes in vitro. They amplified enzyme induction by even a large amount of dexamethasone that had a maximal effect, but had no effect in the absence of glucocorticoid. These modes of amplification show that these compounds are 'Glucocorticoid Potency Amplifiers'. They amplified not only enzyme induction in liver but also growth inhibition by glucocorticoid of solid tumor L5178Y lymphoblasts. They specifically amplified the actions of glucocorticoids and did not amplify the actions of other steroids, such as 17-beta estradiol, glucagon and insulin. The induction of tyrosine aminotransferase by glucocorticoid and its amplification by EGF were both inhibited by 1-(5-iso-quinoline-sulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, and not by N-[2-(methylamino)-ethyl]-5-isoquinoline-sulfonamide, an inhibitor of cyclic nucleotide dependent protein kinases, suggesting that the induction and the amplification are mediated by protein kinase C.


Kinetic Studies on the Inhibitions of Mast Cell Chymase by Natural Serine Proteae Inhibitors. Indications for Potential Biological Functions of these Inhibitors


IgE-Mast cell 関与のアレルギー炎症成立機序と顆粒局在Serine protease群の役割

財団法人 日本応用酵素協会

財団法人 日本応用酵素協会


Diacylglycerol Amplified the Induction in Vivo of Tyrosine Aminotransferase and Ornithine Decarboxylase by Glucocorticoid

In adrenalectomized rats, diacylglycerol, a potent activator of protein kinase C, specifically enhanced the induction of tyrosine aminotransferase and ornithine decarboxylase by even maximally effective doses of dexamethasone phosphate, but itself had no effect on these enzyme inductions in the absence of glucocorticoid. The amplifications of enzyme induction by diacylglycerol was dose-dependent and the time courses of the amplified inductions were similar to those of the inductions by dexamethasone phosphate alone. Since diacylglycerol did not affect the induction of these enzymes by glucagon and insulin, its amplifying effect seemed to be specific for induction by glucocorticoids.

Biochemical and Biophysical Research Communications


A Chymotrypsin-type Serine Protease in Rat Basophilic Leukemia Cells: Evidence for its Immunological Identity with Atypical Mast Cell Protease

Activity of a chymotrypsin-type serine protease was found in a subline of rat basophilic leukemia (RBL-2H3) cells. The protease was immunologically cross-reactive with anti-atypical mast cell protease immunoglobulin (Ig) G, and its activity was inhibited in a dose-dependent manner by the antibody. The apparent m.w. of the protease that reacted with the antibody was 25,000, which was identical with that of atypical mast cell protease in rat mucosal mast cells. These results show that the chymotrypsin type serine protease in RBL-2H3 cells is immunologically identical with atypical mast cell protease, which was first purified from rat small intestine. Immunohistochemical studies showed that the protease was located not only in intracytoplasmic granules but also in organelles synthesizing protein, such as cisternae of the rough endoplasmic reticulum, perinuclear spaces, and the Golgi apparatus. However, no immunoreactivity was demonstrated in rat basophils. The activity of the protease increased in the exponential phase of growth of RBL-2H3 cells in which some activity was also detected in the medium, and it decreased in the late stationary phase.


Biological Functions of Serine Proteases in the Granules of Rat Mast Cells

The effects of specific low- and high-molecular weight inhibitors of chymase and tryptase and F(ab')2 of antichymase on histamine release from activated mast cells were examined. The release of histamine induced by anti-rat immunoglobulin E was markedly inhibited by F(ab')2 fragments of antichymase and the low-molecular weight inhibitor of chymase chymostatin, whereas release of histamine induced by calcium ionophore A23187 was inhibited only by chymostatin. Neither the inhibitor nor the antibody affected histamine release induced by compound 48/80. These results suggest that two main chymotrypsin-type proteases are involved in process of degranulation: one is chymase, which acts at a step before calcium entry, and the other is an unidentified protease, which acts at a step after calcium entry. These results are summarized in Figure 8. After degranulation, released chymase remains associated with the cell surface while released tryptase was found in the extracellular milieu. Tryptase converted bovine prothrombin to thrombin, as shown by increase in thrombin activity with a synthetic substrate, t-butyloxy-carbonyl-Val-Pro-Arg-4-methyl-coumaryl-7-amide. The apparent Km value toward prothrombin was relatively low (2.3 microM), suggesting that tryptase contributes to blood coagulation or the process of fibrosis in tissues. The proteolytic products of IgG1 produced by chymase had chemotactic activity for neutrophil leukocytes in vitro and in vivo. These findings indicate the possible functions of these proteases after degranulation.


Tryptase from Rat Mast Cells Converts Bovine Prothrombin to Thrombin

The effect of tryptase purified from rat peritoneal mast cells on bovine prothrombin was examined. Tryptase activated prothrombin, as evidenced by the increase in thrombin activity with a synthetic substrate, t-butyloxy-carbonyl-Val-Pro-Arg-4-methylcoumaryl-7-amide. The apparent Km value toward bovine prothrombin and the kcat value were 2.3 microM and 46.3 s-1, respectively. Studies on the time course of prothrombin activation by tryptase and by activated factor X (Xa), and analysis of the activation products on sodium dodecyl sulfate gel electrophoresis showed that the process of activation of prothrombin by tryptase was similar to that by Xa except that an intermediate of 67,000 daltons was formed.


Antibody and Inhibitor of Chymase Inhibit Histamine Release in Immunoglobulin E-Activated Mast Cells

The low-molecular-weight inhibitor of chymase, chymostatin, and F(ab')2 fragments of anti-chymase markedly inhibited histamine release induced by anti-rat immunoglobulin E (IgE) but not that induced by compound 48/80. Inhibitors with molecular weights of more than 6,000, such as alpha 1-antichymotrypsin and aprotinin, and non-immunized F(ab')2 had no effect on histamine release. These results suggest that chymase in mast cell granules plays an essential role in the process of IgE-mediated degranulation. After degranulation, released chymase was associated with the cell surface while released tryptase was present in the extracellular milieu as a complex with a protein associated with tryptase (trypstatin).


Chymotrypsin-type and Trypsin-type Serine Protease in Rat Mast Cells: Properties and Functions


Inhibition of Chymase Activity by Phosphoglycerides


Inhibition of Chymase Activity by Long Ghain Fatty Acids


A Simple Method for Purification of Chymase from Rat Tongue and Rat Peritoneal Cells


Purification and Structure of a New Nucleotide from Proteus Mirabilis that Amplifies Induction of Tyrosine Aminotransferase by Glucocorticoid


Amplification of Growth Inhibition by Glucocorticoid on L5178Y and L1210 Lymphoblasts in Vivo


Amplification of the Cytotoxic Action of Glucocorticoid in Cultured L5178Y Lymphoblasts


A New Factor from Enteric Bacteria of Rats Amplifying Induction of Liver Enzyme by Glucocorticoid


Establishment of a Clonal Strain of Hepatoma Cells Derived fromMorris Hepatoma 8999

Gann : Japanese Journal of Cancer Research


Application of moisturizer to neonates prevents development of atopic dermatitis.

Daily application of moisturizer during the first 32 weeks of life reduces the risk of AD/eczema in infants. Allergic sensitization during this time period is associated with the presence of eczematous skin but not with moisturizer use.

The Journal of Allergy and Clinical Immunology


高性能タンパクチップの臨床応用ー減感作療法やアレルギー・アトピーの発症予防への応用ー

日本ラテックスアレルギー研究会会誌

日本ラテックスアレルギー研究会会誌


Extraction and quantification of adenosine triphosphate in mammalian tissues and cells.

Adenosine 5'-triphosphate (ATP) is the "energy currency" of organisms and plays central roles in bioenergetics, whereby its level is used to evaluate cell viability, proliferation, death, and energy transmission. In this chapter, we describe an improved and efficient method for extraction of ATP from tissues and cells using phenol-based reagents. The chaotropic extraction reagents reported so far co-precipitate ATP with insoluble proteins during extraction and with salts during neutralization. In comparison, the phenol-based reagents extract ATP well without the risks of co-precipitation. The extracted ATP can be quantified by the luciferase assay or high-performance liquid chromatography.


Pathogenesis of influenza-associated encephalopathy --- CPT2 SNP as a phathogenetic risk factor

インフルエンザ脳症の発症機序 --- CPT2遺伝子多型が解き明かす発症リスク

インフルエンザ脳症は，インフルエンザ感染による脳の血管内皮細胞膜の透過性亢進による脳浮腫の重篤な病態である．発症機序の解析から，インフルエンザ感染の高熱時に脳の血管内皮細胞膜の透過性が亢進しやすい患者のリスク因子として遺伝子多型が解明された．脳の血管内皮細胞は全身の血管内皮細胞のなかでもとくにエネルギー代謝の活発な細胞で，そのエネルギー源の約70%は脂肪酸代謝に依存している特徴をもつ．そのため重症化患者では，長鎖脂肪酸代謝酵素Calnitine Palmitoyltransferase 2 の熱不安定性遺伝子多型がリスク因子として集中していることが判明した．血管内皮細胞のエネルギークライシスが，脂肪代謝改善薬bezafibrate で改善されることが明らかになった．今後，脳症のリスク回避薬として期待される．

Journal of Clinical and Experimental Medicine


New effective nasal immunization of influenza vaccine by a natural mucosal adjuvant from the lung and its synthetic compound.


Low-affinity allergen-specific IgE in cord blood and affinity maturation after birth.


Antigen-specific T-cell responses in patients with non-IgE-mediated gastrointestinal food allergy are predominantly skewed to T(H)2.


Pathogenesis of influenza-associated encephalopathy: disorder of fatty acid metabolism in mitochondria and increased membrane permeability in endothelial cells

インフルエンザ脳症の発症原因 -ミトコンドリア脂肪酸代謝障害と血管内皮細胞の膜透過性の亢進-


肺サーファクタントを基盤にした経鼻インフルエンザワクチン開発

肺サーファクタントを基盤にした経鼻インフルエンザワクチン開発

Journal of Japanese Medical Society for Lung Surfactant and Biological Interface

日本肺サーファクタント·界面医学会雑誌


SP-BとSP-Cの構造および機能

SP-BとSP-Cの構造および機能

日本肺サーファクタント·界面医学会雑誌


インフルエンザとマクロライド --- 4)マクロライドの宿主粘膜免疫の増強効果とタミフル併用時の免疫増強作用


インフルエンザウイルス感染症に効果的なマクロライドの粘膜粘液

インフルエンザウイルス感染症に効果的なマクロライドの粘膜粘液


アレルゲン同定法の近未来展望

アレルゲン同定法の近未来展望


インフルエンザ重傷化のメカニズム示す(第57回日本化学療法学会)

インフルエンザ重傷化のメカニズム示す(第57回日本化学療法学会)