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Shigeyuki Terada - One of the best experts on this subject based on the ideXlab platform.
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Small Serum protein-1 changes the susceptibility of an apoptosis-inducing metalloproteinase HV1 to a metalloproteinase inhibitor in habu snake (Trimeresurus flavoviridis)
2020Co-Authors: Shigeyuki Terada, Eiki Ogawa, Yuki Mizukami, Shuhei Abe, Rieko Hayashi, Narumi ShioiAbstract:Viperidae snakes containing various venomous proteins also have several anti-toxic proteins in their sera. However, the physiological function of Serum protein has been elucidated incompletely. Small Serum protein (SSP)-1 is a major component of the SSPs isolated from the Serum of a Japanese viper, the habu snake (Trimeresurus flavoviridis). It exists in the blood as a binary complex with habu Serum Factor (HSF), a snake venom metalloproteinase inhibitor. Affinity chromatography of the venom on an SSP-1-immobilized column identified HV1, an apoptosis-inducing metalloproteinase, as the target protein of SSP-1. Biacore measurements revealed that SSP-1 was bound to HV1 with a dissociation constant of 8.2 Â 10 À8 M. However, SSP-1 did not inhibit the peptidase activity of HV1. Although HSF alone showed no inhibitory activity or binding affinity to HV1, the SSP-1HSF binary complex bound to HV1 formed a ternary complex that non-competitively inhibited the peptidase activity of HV1 with a inhibition constant of 5.1 AE 1.3 Â 10 À9 M. The SSP-1HSF complex also effectively suppressed the apoptosis of vascular endothelial cells and caspase 3 activation induced by HV1. Thus, SSP-1 is a unique protein that non-covalently attaches to HV1 and changes its susceptibility to HSF. Keywords: apoptosis/proteinase inhibitor/small Serum protein/snake Serum/snake venom metalloproteinase. Abbreviations: ADAM, a disintegrin and metalloproteinase; ADAMTS, ADAM with thrombospondin type-1 motif; CRISP-3, cysteine-rich secretory protein-3; Dnp, dinitrophenyl; HSF, habu Serum Factor; HVR, hypervariable region; K i , inhibition constant; Mca, (7-methoxycoumarin-4-yl)-acetyl; MDC, metalloproteinase/disintegrin/ cysteine-rich; MMP, matrix metalloproteinase; PSP94, prostatic secretory protein of 94 amino acids; SSP, small Serum protein; SVMP, snake venom metalloproteinase; VEC, vascular endothelial cell
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small Serum protein 1 changes the susceptibility of an apoptosis inducing metalloproteinase hv1 to a metalloproteinase inhibitor in habu snake trimeresurus flavoviridis
Journal of Biochemistry, 2013Co-Authors: Narumi Shioi, Eiki Ogawa, Yuki Mizukami, Rieko Hayashi, Shigeyuki TeradaAbstract:The venom of snakes belonging to the Viperidae family contains metalloproteinases, many of which cause hemorrhage (1). Although snakebites are serious problems for humans and other animals, snakes themselves exhibit a remarkable resistance to their own venom (2, 3). As naturally occurring Factors that neutralize hemorrhagins, three anti-hemorrhagic proteins have been purified from the sera of venomous snakes: habu Serum Factor (HSF) from the Serum of Trimeresurus flavoviridis (4), BJ46a from Bothrops jararaca (5) and mamushi Serum Factor from Gloydius blomhoffi brevicaudus (6). These compounds are acidic glycoproteins with no proteolytic activity. Based on their primary structures, they have been classified as members of the fetuin family that display a double-headed cystatin-like domain and an extra domain. HSF inhibits the protease activity of several snake venom metalloproteinases (SVMPs) (7). It is also resistant to heating and stable in solutions with extreme pH. Small Serum proteins (SSPs) are low-molecular-mass proteins isolated from T. flavoviridis Serum (8). At present, five homologues—namely SSP-1 through SSP-5—have been isolated (9). Structural analysis has indicated that they belong to the prostatic secretory protein of 94 amino acids (PSP94) family, which is characterized by a low molecular mass of ∼10 kDa and 10 conserved cysteine residues (10, 11). Although SSP-1, SSP-2 and SSP-5 are composed of ∼90 amino acids, SSP-3 and SSP-4 have only 60, as they lack the 30 C-terminal residues. All the SSPs exist in high-molecular-mass forms in Serum (12), and because they do not self-associate in physiological buffers, they may be present in protein complexes. Similar to the SSPs in vipers, human PSP94 exists in complex with a specific protein (PSP94-binding protein) in the blood and with cysteine-rich secretory protein-3 (CRISP-3) in prostate fluid (13). In a search for SSP-binding proteins in T. flavoviridis Serum, we isolated a novel protein called serotriflin that shows significant sequence similarity to triflin, a CRISP family protein in T. flavoviridis venom (14). Although serotriflin was isolated as a binding protein candidate for SSPs, it showed affinity only to SSP-2 and SSP-5 (12). Recently, we have reported that HSF is the carrier protein for all SSPs (15). We know little about the physiological functions of SSPs. SSP-2 and SSP-5 bind triflin and serotriflin (12). Although SSP-1 and SSP-3 suppress the proteolytic activity of brevilysin H6 (16), an SVMP isolated from the venom of Chinese viper (G. blomhoffi brevicaudus), the inhibition is weak compared with that by HSF (8). As SSPs and brevilysin H6 are present in different animals, H6 cannot be a physiological target of SSP. Furthermore, we have found no other SVMPs that are sensitive to SSP-1 in the venom of T. flavoviridis. In this study, we determined the target molecules of SSP-1 using affinity chromatography on an SSP-1-immobilized column. We found that HV1 in T. flavoviridis venom is the binding protein of SSP-1. HV1 is a homodimeric protein with a molecular mass of 110 kDa that induces apoptosis in vascular endothelial cells (VECs) (17). Although HV1 is a typical P-III class dimeric SVMP composed of metalloproteinase/disintegrin/cysteine-rich (MDC) domains (18), its biochemical properties have yet to be reported. We also examined the interaction of SSP-1 and HV1 and the effects of SSP-1 on the proteolytic and apoptosis-inducing activity of HV1.
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properties and cdna cloning of antihemorrhagic Factors in sera of chinese and japanese mamushi gloydius blomhoffi
Toxicon, 2008Co-Authors: Narumi Aoki, Masanobu Deshimaru, Kadzuyo Tsutsumi, Shigeyuki TeradaAbstract:Abstract An antihemorrhagic protein has been isolated from the Serum of Chinese mamushi ( Gloydius blomhoffi brevicaudus ) by using a combination of ethanol precipitation and a reverse-phase high-performance liquid chromatography (HPLC) on a C8 column. This protein—designated Chinese mamushi Serum Factor (cMSF)—suppressed mamushi venom-induced hemorrhage in a dose-dependent manner. It had no effect on trypsin, chymotrypsin, thermolysin, and papain but inhibited the proteinase activities of several snake venom metalloproteinases (SVMPs) including hemorrhagic enzymes isolated from the venoms of mamushi and habu ( Trimeresurus flavoviridis ). A similar protein (Japanese MSF, jMSF) with antihemorrhagic activity has also been purified from the sera of Japanese mamushi ( G. blomhoffi ). The N-terminal 70 and 51 residues of the intact cMSF and jMSF were directly analyzed; a similarity between the sequences of two MSFs to that of antihemorrhagic protein (HSF) from habu Serum was noticed. To obtain the complete amino acid sequences of MSFs, cDNAs encoding these proteins were cloned from the liver mRNA of Chinese and Japanese vipers based on their N-terminal amino acid sequences. The mature forms of both MSFs consisted of 305 amino acids with a 19-residue signal sequence, and a unique 17-residue deletion was detected in their His-rich domains.
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active fragments of the antihemorrhagic protein hsf from Serum of habu trimeresurus flavoviridis
Toxicon, 2007Co-Authors: Narumi Aoki, Masanobu Deshimaru, Shigeyuki TeradaAbstract:Abstract Certain snakes have antihemorrhagic proteins in their sera. Habu Serum Factor (HSF), an antihemorrhagic protein isolated from the Serum of the Japanese habu snake (Trimeresurus flavoviridis) is composed of two cystatin-like domains (D1 and D2) and a His-rich domain, and it inhibits several snake venom metalloproteinases (SVMPs). The activity of HSF can be abolished by trinitrophenylation of Lys residues with 2,4,6-trinitrobenzene sulphonic acid. Upon complex formation of HSF with SVMP, however, the loss of its inhibitory activity by the chemical modification was suppressed, and Lys15, Lys41, and Lys103 residues in HSF were not trinitrophenylated. In order to identify the domain that is critical to the inhibitory activity on SVMPs, native HSF was digested with papain followed by cleavage with cyanogen bromide, yielding a low-molecular mass fragment that was composed of two peptide chains (residues 5–89 and 312–317) linked by a disulfide bond. This fragment inhibited several SVMPs and showed significant antihemorrhagic activity. This indicates that the N-terminal half of D1 is indispensable for the antihemorrhagic activity of HSF. Furthermore, a three-dimensional model of two cystatin-like domains constructed by the homology modeling has indicated that three Lys residues (15, 41, and 103) are exposed to the same surface of HSF molecule.
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properties and cdna cloning of an antihemorrhagic Factor hsf purified from the Serum of trimeresurus flavoviridis
Toxicon, 2005Co-Authors: Masanobu Deshimaru, Narumi Aoki, Shigeyuki Terada, Chie Tanaka, Kazuya Fujino, Shosaku Hattori, Motonori OhnoAbstract:Habu Serum Factor (HSF) is a metalloproteinase inhibitor that is isolated from the Serum of habu snake (Trimeresurus flavoviridis), and it can suppress snake venom-induced hemorrhage. In the present study, the inhibitory property and fundamental structure of HSF were analyzed in detail. HSF inhibited all the hemorrhagic and most of the non-hemorrhagic metalloproteinases tested from the venoms of T. flavoviridis and Gloydius halys brevicaudus. HSF was extremely stable in a broad range of temperature and pH, and the treatments with a temperature of 100 °C or pH ranging from 1 to 13 barely affects its reactivity against G. halys brevicaudus H6 protease. Gel filtration chromatography revealed that HSF binds to the H6 protease with a 1:1 molar ratio. A secondary structure profile of HSF that was monitored by circular dichroism spectrum remained unvaried up to 2 M urea. The activity of HSF was stoichiometrically abolished by chemical modification with 2,4,6-trinitrobenzene sulfonic acid and N-bromosuccinimide; this indicates that Lys and Trp residues in its sequence play a role in the inhibitory mechanism. In this study, the amino acid sequence of HSF that was obtained by cDNA cloning was identical to that reported previously, except for five substitutions. We concluded that these discrepancies reflect a difference in the places of capture of the snake specimens.
Yuehhsiu Chien - One of the best experts on this subject based on the ideXlab platform.
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the split virus influenza vaccine rapidly activates immune cells through fcγ receptors
Vaccine, 2014Co-Authors: William E Ogorman, Huang Huang, Yuling Wei, Kara L Davis, Michael D Leipold, Sean C Bendall, Brian A Kidd, Cornelia L Dekker, Holden T Maecker, Yuehhsiu ChienAbstract:Seasonal influenza vaccination is one of the most common medical procedures and yet the extent to which it activates the immune system beyond inducing antibody production is not well understood. In the United States, the most prevalent formulations of the vaccine consist of degraded or “split” viral particles distributed without any adjuvants. Based on previous reports we sought to determine whether the split influenza vaccine activates innate immune receptors—specifically Toll-like receptors. High-dimensional proteomic profiling of human whole-blood using Cytometry by Time-of-Flight (CyTOF) was used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response ex vivo. This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature quite distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a Serum Factor was necessary for vaccine-dependent immune activation. We found this Serum Factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza virus “splitting” inactivates any potential adjuvants endogenous to influenza, such as RNA, but in previously exposed individuals can elicit a potent immune response by facilitating the rapid formation of immune complexes.
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the split virus influenza vaccine activates fcγ receptors instead of toll like receptors vac2p 930
Journal of Immunology, 2014Co-Authors: William E Ogorman, Huang Huang, Yuling Wei, Kara L Davis, Michael D Leipold, Sean C Bendall, Brian A Kidd, Cornelia L Dekker, Holden T Maecker, Yuehhsiu ChienAbstract:Seasonal influenza vaccination is the most common medical procedure targeting the immune system and yet the extent to which influenza vaccination activates innate immunity in humans is not fully understood. Currently, the most prevalent formulations of the vaccine consist of degraded or “split” viral particles often prepared without any adjuvants. We sought to determine whether the unadjuvanted split influenza vaccine activates innate immune receptors—specifically Toll-like receptors. A mass-cytometry (CyTOF) based proteomic profiling platform was developed and used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response in human whole-blood (ex vivo). This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a Serum Factor was necessary for vaccine-dependent immune activation. We found this Serum Factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza vaccine splitting inactivates any microbial adjuvants endogenous to influenza but potentially elicits a potent immune modulator by facilitating the rapid formation of immune complexes.
William E Ogorman - One of the best experts on this subject based on the ideXlab platform.
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the split virus influenza vaccine rapidly activates immune cells through fcγ receptors
Vaccine, 2014Co-Authors: William E Ogorman, Huang Huang, Yuling Wei, Kara L Davis, Michael D Leipold, Sean C Bendall, Brian A Kidd, Cornelia L Dekker, Holden T Maecker, Yuehhsiu ChienAbstract:Seasonal influenza vaccination is one of the most common medical procedures and yet the extent to which it activates the immune system beyond inducing antibody production is not well understood. In the United States, the most prevalent formulations of the vaccine consist of degraded or “split” viral particles distributed without any adjuvants. Based on previous reports we sought to determine whether the split influenza vaccine activates innate immune receptors—specifically Toll-like receptors. High-dimensional proteomic profiling of human whole-blood using Cytometry by Time-of-Flight (CyTOF) was used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response ex vivo. This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature quite distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a Serum Factor was necessary for vaccine-dependent immune activation. We found this Serum Factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza virus “splitting” inactivates any potential adjuvants endogenous to influenza, such as RNA, but in previously exposed individuals can elicit a potent immune response by facilitating the rapid formation of immune complexes.
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the split virus influenza vaccine activates fcγ receptors instead of toll like receptors vac2p 930
Journal of Immunology, 2014Co-Authors: William E Ogorman, Huang Huang, Yuling Wei, Kara L Davis, Michael D Leipold, Sean C Bendall, Brian A Kidd, Cornelia L Dekker, Holden T Maecker, Yuehhsiu ChienAbstract:Seasonal influenza vaccination is the most common medical procedure targeting the immune system and yet the extent to which influenza vaccination activates innate immunity in humans is not fully understood. Currently, the most prevalent formulations of the vaccine consist of degraded or “split” viral particles often prepared without any adjuvants. We sought to determine whether the unadjuvanted split influenza vaccine activates innate immune receptors—specifically Toll-like receptors. A mass-cytometry (CyTOF) based proteomic profiling platform was developed and used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response in human whole-blood (ex vivo). This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a Serum Factor was necessary for vaccine-dependent immune activation. We found this Serum Factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza vaccine splitting inactivates any microbial adjuvants endogenous to influenza but potentially elicits a potent immune modulator by facilitating the rapid formation of immune complexes.
Paul Warwicker - One of the best experts on this subject based on the ideXlab platform.
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genetic studies into inherited and sporadic hemolytic uremic syndrome
Kidney International, 1998Co-Authors: Paul Warwicker, Timothy H J Goodship, Rosemary L Donne, Yves PirsonAbstract:Genetic studies into inherited and sporadic hemolytic uremic syndrome. Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Although familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that may have relevance to acquired HUS. We have undertaken a genetic linkage study based on a candidate gene approach. A common area bounded by the markers D1S212 and D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max 3.94). We demonstrate that the gene for Factor H lies within the region. Subsequent mutation analysis of the Factor H gene has revealed two mutations in patients with HUS. In an individual with the sporadic/relapsing form of the disease we have found a mutation comprising a deletion, subsequent frame shift and premature stop codon leading to half normal levels of Serum Factor H. In one of the three families there is a point mutation in exon 20 causing an arginine to glycine change, which is likely to alter structure and hence function of the Factor H protein. Factor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of these findings and previous reports of HUS in patients with Factor H deficiency, we postulate that abnormalities of Factor H may be involved in the etiology of HUS.
David T Woodley - One of the best experts on this subject based on the ideXlab platform.
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transforming growth Factor alpha a major human Serum Factor that promotes human keratinocyte migration
Journal of Investigative Dermatology, 2006Co-Authors: Yong Li, Mei Chen, Wei Li, David T WoodleyAbstract:In unwounded skin, human keratinocytes (HKs) are in contact with a plasma filtrate. In an acute wound, HKs come in contact with Serum for the first time. Because human Serum (HS), but not plasma, promotes HK migration, we speculated that a major HK pro-motility Factor in vivo comes from Serum. In this study, we compared all of the published growth Factors (GFs), reported to promote HK migration, with HS. No single GF could duplicate the HK pro-motility activity in HS. Among these GFs, tumor growth Factor (TGF) α showed the highest HK pro-motility activity, reaching ∼80% of the activity in HS. The order of potency was: TGF α >insulin>EGF>heparin binding (HB)-EGF>IGF-1>basic fibroblast growth Factor >IL-8>HGF>IL-1>KGF>TGF β . Interestingly, the combination of TGF α and insulin could duplicate the HK pro-motility activity in HS, although only the TGF α , but not insulin, levels increase in Serum over plasma. Addition of neutralizing antibodies against TGF α to Serum or depletion of TGF α from Serum by immunoprecipitation significantly abolished its HK pro-motility activity. Plasma with added TGF α stimulated HK migration that reached more than 80% of the Serum stimulation. Since insulin levels are identical between plasma and Serum, we propose that TGF α is the physiologic HK pro-motility Factor in HS.
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vitronectin driven human keratinocyte locomotion is mediated by the alpha v beta 5 integrin receptor
Journal of Biological Chemistry, 1994Co-Authors: Janice P Kim, Randall H Kramer, Ken Zhang, J D Chen, David T WoodleyAbstract:Abstract Vitronectin is a soluble Serum Factor that is known to promote epiboly of keratinocytes in explant cultures and enhance cell spreading and attachment to matrix. Recently, vitronectin was demonstrated to promote human keratinocyte locomotion. The mechanism(s) by which vitronectin enhances keratinocyte migration is unknown. In this study, we quantitated the vitronectin-driven migration of human keratinocytes in the presence of antibodies to vitronectin receptors. We found that vitronectin's effect of promoting human keratinocyte migration was inhibited by antibody-directed against the alpha v beta 5 receptor. In addition, we surface-labeled human keratinocytes, chromatographed extracts of the cell membranes on a vitronectin column, and then immunoprecipitated the bound and eluted proteins with antibodies to specific vitronectin receptors. We identified the vitronectin receptors on human keratinocytes as bands of 150,000 and 100,000 daltons without reduction and as 125,000 and 110,000 daltons under reducing conditions. Immunoprecipitation with specific antibodies identified the major receptor to be the alpha v beta 5 integrin. In addition, we quantitated vitronectin-driven migration of human keratinocytes in the presence of Arg-Gly-Asp (RGD) and control peptides. We found that the presence of RGD, but not control peptide, inhibited vitronectin-driven migration of human keratinocytes. These studies demonstrate that human keratinocytes express vitronectin receptors and use the alpha v beta 5 receptor for cellular locomotion.
