The Experts below are selected from a list of 123 Experts worldwide ranked by ideXlab platform

Li Sun - One of the best experts on this subject based on the ideXlab platform.

  • a teleost cd46 is involved in the regulation of complement activation and pathogen infection
    Scientific Reports, 2017
    Co-Authors: Zhihai Sui, Li Sun
    Abstract:

    In mammals, CD46 is involved in the inactivation of complement by factor I (FI). In teleost, Study on the function of CD46 is very limited. In this Study, we examined the immunological property of a CD46 molecule (CsCD46) from tongue sole, a teleost species with important economic value. We found that recombinant CsCD46 (rCsCD46) interacted with FI and inhibited complement activation in an FI-dependent manner. rCsCD46 also interacted with bacterial pathogens via a different mechanism to that responsible for the FI interaction, involving different rCsCD46 sites. Cellular Study showed that CsCD46 was expressed on peripheral blood leukocytes (PBL) and protected the cells against the killing effect of complement. When the CsCD46 on PBL was blocked by antibody before incubation of the cells with bacterial pathogens, Cellular infection was significantly reduced. Consistently, when tongue sole were infected with bacterial pathogens in the presence of rCsCD46, tissue dissemination and survival of the pathogens were significantly inhibited. These results provide the first evidence to indicate that CD46 in teleosts negatively regulates complement activation via FI and protects host cells from complement-induced damage, and that CD46 is required for optimal bacterial infection probably by serving as a receptor for the bacteria.

  • Poly(I:C) Induces Antiviral Immune Responses in Japanese Flounder (Paralichthys olivaceus) That Require TLR3 and MDA5 and Is Negatively Regulated by Myd88
    2016
    Co-Authors: Zhi-xia Zhou, Bao-cun Zhang, Li Sun
    Abstract:

    Polyinosinic:polycytidylic acid (poly(I:C)) is a ligand of toll-like receptor (TLR) 3 that has been used as an immunostimulant in humans and mice against viral diseases based on its ability to enhance innate and adapt immunity. Antiviral effect of poly(I:C) has also been observed in teleost, however, the underling mechanism is not clear. In this Study, we investigated the potential and signaling mechanism of poly(I:C) as an antiviral agent in a model of Japanese flounder (Paralichthys olivaceus) infected with megalocytivirus. We found that poly(I:C) exhibited strong antiviral activity and enhanced activation of head kidney macrophages and peripheral blood leukocytes. In vivo studies showed that (i) TLR3 as well as MDA5 knockdown reduced poly(I:C)-mediated immune response and antiviral activity to significant extents; (ii) when Myd88 was overexpressed in flounder, poly(I:C)-mediated antiviral activity was significantly decreased; (iii) when Myd88 was inactivated, the antiviral effect of poly(I:C) was significantly increased. Cellular Study showed that (i) the NF-kB activity induced by poly(I:C) was upregulated in Myd88-overexpressing cells and unaffected in Myd88-inactivated cells; (ii) Myd88 overexpression inhibited and upregulated the expression of poly(I:C)-induced antiviral genes and inflammatory genes respectively; (iii) Myd88 inactivation enhanced the expression of the antiviral genes induced by poly(I:C). Taken together, these results indicate that poly(I:C) is an immunostimulant with antiviral potential, and that the immune response of poly(I:C) requires TLR3 and MDA5 and is negatively regulated by Myd88 in a manner not involving NK-kB. These result

  • immune effects of r848 evidences that suggest an essential role of tlr7 8 induced myd88 and nf κb dependent signaling in the antiviral immunity of japanese flounder paralichthys olivaceus
    Developmental and Comparative Immunology, 2015
    Co-Authors: Zhi-xia Zhou, Li Sun
    Abstract:

    The imidazoquinoline compound R848 is a specific agonist of toll-like receptor (TLR) 7/TLR8 that has been used as an immunostimulant in humans against viral diseases. Although R848-induced immune response has been reported in teleost fish, the relevant mechanism is not clear. In this Study, we investigated the antiviral potential and the signaling pathway of R848 in a model of Japanese flounder (Paralichthys olivaceus). We found that R848 was able to inhibit the replication of megalocytivirus, stimulated the proliferation of peripheral blood leukocytes (PBL), enhanced the expression of immune genes, and reduced apoptosis of PBL. When endosomal acidification was blocked by chloroquine (CQ), R848-mediated antiviral activity and immune response were significantly reduced. Likewise, inhibition of Myd88 activation markedly impaired the pro-proliferation and anti-apoptosis effect of R848. Cellular Study showed that cultured founder cells treated with R848 exhibited augmented NF-κB activity, which, however, was dramatically reduced in the presence of CQ and Myd88 inhibitor. Furthermore, when NF-κB was inactivated, the effect of R848 on cell proliferation and apoptosis was significantly decreased. Taken together, these results indicate that R848 is an immunostimulant with antiviral property in a teleost species, and that the immune response of R848 is mediated by, most likely, TLR7/TLR8 signaling pathway, in which Myd88 and NK-κB play an essential role.

  • poly i c induces antiviral immune responses in japanese flounder paralichthys olivaceus that require tlr3 and mda5 and is negatively regulated by myd88
    PLOS ONE, 2014
    Co-Authors: Zhi-xia Zhou, Bao-cun Zhang, Li Sun
    Abstract:

    Polyinosinic:polycytidylic acid (poly(I:C)) is a ligand of toll-like receptor (TLR) 3 that has been used as an immunostimulant in humans and mice against viral diseases based on its ability to enhance innate and adapt immunity. Antiviral effect of poly(I:C) has also been observed in teleost, however, the underling mechanism is not clear. In this Study, we investigated the potential and signaling mechanism of poly(I:C) as an antiviral agent in a model of Japanese flounder (Paralichthys olivaceus) infected with megalocytivirus. We found that poly(I:C) exhibited strong antiviral activity and enhanced activation of head kidney macrophages and peripheral blood leukocytes. In vivo studies showed that (i) TLR3 as well as MDA5 knockdown reduced poly(I:C)-mediated immune response and antiviral activity to significant extents; (ii) when Myd88 was overexpressed in flounder, poly(I:C)-mediated antiviral activity was significantly decreased; (iii) when Myd88 was inactivated, the antiviral effect of poly(I:C) was significantly increased. Cellular Study showed that (i) the NF-κB activity induced by poly(I:C) was upregulated in Myd88-overexpressing cells and unaffected in Myd88-inactivated cells; (ii) Myd88 overexpression inhibited and upregulated the expression of poly(I:C)-induced antiviral genes and inflammatory genes respectively; (iii) Myd88 inactivation enhanced the expression of the antiviral genes induced by poly(I:C). Taken together, these results indicate that poly(I:C) is an immunostimulant with antiviral potential, and that the immune response of poly(I:C) requires TLR3 and MDA5 and is negatively regulated by Myd88 in a manner not involving NK-κB. These results provide insights to the working mechanism of poly(I:C), TLR3, and Myd88 in fish.

  • Junctional adhesion molecule A of red drum (Sciaenops ocellatus): a possible immunomodulator and a target for bacterial immune evasion.
    Veterinary immunology and immunopathology, 2014
    Co-Authors: Jian Zhang, Min Zhang, Li Sun
    Abstract:

    Junctional adhesion molecules (JAMs) are a family of type I cell surface receptors with two immunoglobulin (Ig) domains in the extraCellular region. The family contains three classical members, i.e., JAM-A, -B, and -C. To date very little is known about the function of JAMs in teleost. In this work, we identified a JAM-A homologue (named SoJAMa) from red drum (Sciaenops ocellatus) and examined its expression and biological property. SoJAMa is composed of 347 amino acid residues and was predicted to be a transmembrane protein with a large extraCellular region that contains two Ig domains. SoJAMa expression occurred in multiple tissues, in particular immune relevant organs. SoJAMa expression was downregulated by experimental challenge with an extraCellular pathogen but upregulated by challenge with an intraCellular pathogen that is known to be capable of immune evasion. Likewise, Cellular Study showed that infection of peripheral blood leukocytes (PBL) with intraCellular pathogen induced significantly higher expression of SoJAMa. Immunofluorescence microscopy showed that SoJAMa was localized on the surface of PBL and recognized by antibodies against recombinant SoJAMa. Blockage of the SoJAMa on PBL with antibodies resulted in augmented respiratory burst activity. Consistently, antibody-treated PBL exhibited enhanced resistance against bacterial infection. Taken together, these results suggest for the first time that a teleost JAM-A likely possesses immunoregulatory property in a negative manner, and that this property may be taken advantage of by intraCellular pathogens as an invasion strategy.

Tetsuo Nagano - One of the best experts on this subject based on the ideXlab platform.

  • rational evolution of a novel type of potent and selective proviral integration site in moloney murine leukemia virus kinase 1 pim1 inhibitor from a screening hit compound
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Hirofumi Nakano, Nae Saito, Lorien J Parker, Yukio Tada, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano
    Abstract:

    Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening Study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a Cellular Study, 14 potently inhibited the growth of human leukemia cell line MV4–11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

Hirofumi Nakano - One of the best experts on this subject based on the ideXlab platform.

  • Rational Evolution of a Novel Type of Potent and Selective Proviral Integration Site in Moloney Murine Leukemia Virus Kinase 1 (PIM1) Inhibitor from a Screening-Hit Compound
    2016
    Co-Authors: Hirofumi Nakano, Nae Saito, Yukio Tada, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Lorien Parker, Masanao Abe, Takayoshi Okabe
    Abstract:

    Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening Study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a Cellular Study, 14 potently inhibited the growth of human leukemia cell line MV4–11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14

  • rational evolution of a novel type of potent and selective proviral integration site in moloney murine leukemia virus kinase 1 pim1 inhibitor from a screening hit compound
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Hirofumi Nakano, Nae Saito, Lorien J Parker, Yukio Tada, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano
    Abstract:

    Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening Study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a Cellular Study, 14 potently inhibited the growth of human leukemia cell line MV4–11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

Takayoshi Okabe - One of the best experts on this subject based on the ideXlab platform.

  • Rational Evolution of a Novel Type of Potent and Selective Proviral Integration Site in Moloney Murine Leukemia Virus Kinase 1 (PIM1) Inhibitor from a Screening-Hit Compound
    2016
    Co-Authors: Hirofumi Nakano, Nae Saito, Yukio Tada, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Lorien Parker, Masanao Abe, Takayoshi Okabe
    Abstract:

    Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening Study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a Cellular Study, 14 potently inhibited the growth of human leukemia cell line MV4–11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14

  • rational evolution of a novel type of potent and selective proviral integration site in moloney murine leukemia virus kinase 1 pim1 inhibitor from a screening hit compound
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Hirofumi Nakano, Nae Saito, Lorien J Parker, Yukio Tada, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano
    Abstract:

    Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening Study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a Cellular Study, 14 potently inhibited the growth of human leukemia cell line MV4–11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.

Nae Saito - One of the best experts on this subject based on the ideXlab platform.

  • Rational Evolution of a Novel Type of Potent and Selective Proviral Integration Site in Moloney Murine Leukemia Virus Kinase 1 (PIM1) Inhibitor from a Screening-Hit Compound
    2016
    Co-Authors: Hirofumi Nakano, Nae Saito, Yukio Tada, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Lorien Parker, Masanao Abe, Takayoshi Okabe
    Abstract:

    Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening Study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a Cellular Study, 14 potently inhibited the growth of human leukemia cell line MV4–11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14

  • rational evolution of a novel type of potent and selective proviral integration site in moloney murine leukemia virus kinase 1 pim1 inhibitor from a screening hit compound
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Hirofumi Nakano, Nae Saito, Lorien J Parker, Yukio Tada, Keiko Tsuganezawa, Shigeyuki Yokoyama, Akiko Tanaka, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano
    Abstract:

    Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening Study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a Cellular Study, 14 potently inhibited the growth of human leukemia cell line MV4–11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.