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  1. Article ; Online: Administration of a Bacterial Lysate to the Airway Compartment Is Sufficient to Inhibit Allergen-Induced Lung Eosinophilia in Germ-free Mice.

    Michael, Ashley N / Pivniouk, Oksana / Ezeh, Peace C / Banskar, Sunil / Hahn, Seongmin / DeVries, Avery / O'Connell, Kathryn / Pivniouk, Vadim / Vercelli, Donata

    Journal of leukocyte biology

    2024  

    Abstract: The nexus between eosinophils and microbes is attracting increasing attention. We previously showed that airway administration of sterile microbial products contained in dust collected from traditional dairy farms virtually abrogated broncho-alveolar ... ...

    Abstract The nexus between eosinophils and microbes is attracting increasing attention. We previously showed that airway administration of sterile microbial products contained in dust collected from traditional dairy farms virtually abrogated broncho-alveolar lavage (BAL) eosinophilia and other cardinal asthma phenotypes in allergen-sensitized specific pathogen-free (SPF) mice. Interestingly, comparable inhibition of allergen-induced BAL eosinophilia and promotion of airway barrier integrity were found upon administration of a sterile, pharmacological grade bacterial lysate, OM-85, to the airway compartment of allergen-sensitized SPF mice. Here we asked whether intrinsic properties of airway-delivered microbial products were sufficient to inhibit allergic lung inflammation or whether these effects were mediated by reprogramming of the host microbiota. We compared germ-free (GF) mice and offspring of GF mice associated with healthy mouse gut microbiota and maintained under SPF conditions for multiple generations (Ex-GF mice). These mice were treated intra-nasally with OM-85 and evaluated in the OVA and Alternaria models of allergic asthma focusing primarily on BAL eosinophilia. Levels of allergen-induced BAL eosinophilia were comparable in GF and conventionalized Ex-GF mice. Airway administration of the OM-85 bacterial lysate was sufficient to inhibit allergen-induced lung eosinophilia in both Ex-GF and GF mice, suggesting that host microbiota are not required for the protective effects of bacterial products in these models and local airway exposure to microbial products is an effective source of protection. OM-85-dependent inhibition of BAL eosinophilia in GF mice was accompanied by suppression of lung type-2 cytokines and eosinophil-attracting chemokines, suggesting that OM-85 may work at least by decreasing eosinophil lung recruitment.
    Language English
    Publishing date 2024-03-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1093/jleuko/qiae047
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis

    Kato, Kosuke / Papageorgiou, Ioannis / Shin, Yoon-Joo / Kleinhenz, Jennifer M. / Palumbo, Sunny / Hahn, Seongmin / Irish, Joseph D. / Rounseville, Skye P. / Knox, Kenneth S. / Hecker, Louise

    Antioxidants. 2022 Feb. 28, v. 11, no. 3

    2022  

    Abstract: Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated ... ...

    Abstract Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-β-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3–6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis.
    Keywords active pharmaceutical ingredients ; animal models ; antioxidants ; dimethyl fumarate ; drugs ; fibroblasts ; fibrosis ; lungs ; oxidative stress ; pulmonary fibrosis ; sclerosis
    Language English
    Dates of publication 2022-0228
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox11030492
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Lung-Targeted Delivery of Dimethyl Fumarate Promotes the Reversal of Age-Dependent Established Lung Fibrosis.

    Kato, Kosuke / Papageorgiou, Ioannis / Shin, Yoon-Joo / Kleinhenz, Jennifer M / Palumbo, Sunny / Hahn, Seongmin / Irish, Joseph D / Rounseville, Skye P / Knox, Kenneth S / Hecker, Louise

    Antioxidants (Basel, Switzerland)

    2022  Volume 11, Issue 3

    Abstract: Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated ... ...

    Abstract Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-β-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3-6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis.
    Language English
    Publishing date 2022-02-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox11030492
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Leveraging ageing models of pulmonary fibrosis: the efficacy of nintedanib in ageing.

    Kato, Kosuke / Shin, Yoon-Joo / Palumbo, Sunny / Papageorgiou, Ioannis / Hahn, Seongmin / Irish, Joseph D / Rounseville, Skye P / Krafty, Robert T / Wollin, Lutz / Sauler, Maor / Hecker, Louise

    The European respiratory journal

    2021  Volume 58, Issue 5

    MeSH term(s) Aging ; Humans ; Idiopathic Pulmonary Fibrosis/drug therapy ; Indoles/therapeutic use ; Protein Kinase Inhibitors
    Chemical Substances Indoles ; Protein Kinase Inhibitors ; nintedanib (G6HRD2P839)
    Language English
    Publishing date 2021-11-25
    Publishing country England
    Document type Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 639359-7
    ISSN 1399-3003 ; 0903-1936
    ISSN (online) 1399-3003
    ISSN 0903-1936
    DOI 10.1183/13993003.00759-2021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The OM-85 bacterial lysate inhibits SARS-CoV-2 infection of epithelial cells by downregulating SARS-CoV-2 receptor expression.

    Pivniouk, Vadim / Pivniouk, Oksana / DeVries, Avery / Uhrlaub, Jennifer L / Michael, Ashley / Pivniouk, Denis / VanLinden, Sydney R / Conway, Michelle Y / Hahn, Seongmin / Malone, Sean P / Ezeh, Peace / Churko, Jared M / Anderson, Dayna / Kraft, Monica / Nikolich-Zugich, Janko / Vercelli, Donata

    The Journal of allergy and clinical immunology

    2021  Volume 149, Issue 3, Page(s) 923–933.e6

    Abstract: Background: Treatments for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are urgently needed but remain limited. SARS-CoV-2 infects cells through interactions of its spike (S) protein with ... ...

    Abstract Background: Treatments for coronavirus disease 2019, which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are urgently needed but remain limited. SARS-CoV-2 infects cells through interactions of its spike (S) protein with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) on host cells. Multiple cells and organs are targeted, particularly airway epithelial cells. OM-85, a standardized lysate of human airway bacteria with strong immunomodulating properties and an impeccable safety profile, is widely used to prevent recurrent respiratory infections. We found that airway OM-85 administration inhibits Ace2 and Tmprss2 transcription in the mouse lung, suggesting that OM-85 might hinder SARS-CoV-2/host cell interactions.
    Objectives: We sought to investigate whether and how OM-85 treatment protects nonhuman primate and human epithelial cells against SARS-CoV-2.
    Methods: ACE2 and TMPRSS2 mRNA and protein expression, cell binding of SARS-CoV-2 S1 protein, cell entry of SARS-CoV-2 S protein-pseudotyped lentiviral particles, and SARS-CoV-2 cell infection were measured in kidney, lung, and intestinal epithelial cell lines, primary human bronchial epithelial cells, and ACE2-transfected HEK293T cells treated with OM-85 in vitro.
    Results: OM-85 significantly downregulated ACE2 and TMPRSS2 transcription and surface ACE2 protein expression in epithelial cell lines and primary bronchial epithelial cells. OM-85 also strongly inhibited SARS-CoV-2 S1 protein binding to, SARS-CoV-2 S protein-pseudotyped lentivirus entry into, and SARS-CoV-2 infection of epithelial cells. These effects of OM-85 appeared to depend on SARS-CoV-2 receptor downregulation.
    Conclusions: OM-85 inhibits SARS-CoV-2 epithelial cell infection in vitro by downregulating SARS-CoV-2 receptor expression. Further studies are warranted to assess whether OM-85 may prevent and/or reduce the severity of coronavirus disease 2019.
    MeSH term(s) Adjuvants, Immunologic/administration & dosage ; Angiotensin-Converting Enzyme 2/antagonists & inhibitors ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/immunology ; Animals ; COVID-19/immunology ; COVID-19/prevention & control ; COVID-19/virology ; Caco-2 Cells ; Cell Extracts/administration & dosage ; Cell Extracts/immunology ; Cells, Cultured ; Chlorocebus aethiops ; Down-Regulation/drug effects ; Epithelial Cells/drug effects ; Epithelial Cells/immunology ; Epithelial Cells/virology ; HEK293 Cells ; Host Microbial Interactions/drug effects ; Host Microbial Interactions/immunology ; Humans ; In Vitro Techniques ; Lung/drug effects ; Lung/immunology ; Lung/virology ; Mice ; Mice, Inbred BALB C ; Receptors, Virus/antagonists & inhibitors ; Receptors, Virus/immunology ; SARS-CoV-2/immunology ; Serine Endopeptidases/drug effects ; Serine Endopeptidases/genetics ; Serine Endopeptidases/immunology ; Transcription, Genetic/drug effects ; Transcription, Genetic/immunology ; Vero Cells
    Chemical Substances Adjuvants, Immunologic ; Broncho-Vaxom ; Cell Extracts ; Receptors, Virus ; Ace2 protein, mouse (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, mouse (EC 3.4.21.-)
    Language English
    Publishing date 2021-12-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2021.11.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Airway administration of OM-85, a bacterial lysate, blocks experimental asthma by targeting dendritic cells and the epithelium/IL-33/ILC2 axis.

    Pivniouk, Vadim / Gimenes-Junior, Joao A / Ezeh, Peace / Michael, Ashley / Pivniouk, Oksana / Hahn, Seongmin / VanLinden, Sydney R / Malone, Sean P / Abidov, Amir / Anderson, Dayna / Gozdz, Justyna / DeVries, Avery / Martinez, Fernando D / Pasquali, Christian / Vercelli, Donata

    The Journal of allergy and clinical immunology

    2021  Volume 149, Issue 3, Page(s) 943–956

    Abstract: Background: Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is ... ...

    Abstract Background: Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is widely used empirically to prevent respiratory infections and a clinical trial is testing its ability to prevent asthma in high-risk children. We previously showed that intranasal administration of microbial products from farm environments abrogates experimental allergic asthma.
    Objectives: We sought to investigate whether direct administration of OM-85 to the airway compartment protects against experimental allergic asthma; and to identify protective cellular and molecular mechanisms activated through this natural route.
    Methods: Different strains of mice sensitized and challenged with ovalbumin or Alternaria received OM-85 intranasally, and cardinal cellular and molecular asthma phenotypes were measured. Airway transfer experiments assessed whether OM-85-treated dendritic cells protect allergen-sensitized, OM-85-naive mice against asthma.
    Results: Airway OM-85 administration suppressed allergic asthma in all models acting on multiple innate and adaptive immune targets: the airway epithelium/IL-33/ILC2 axis, lung allergen-induced type 2 responses, and dendritic cells whose Myd88/Trif-dependent tolerogenic reprogramming was sufficient to transfer OM-85-induced asthma protection.
    Conclusions: We provide the first demonstration that administering a standardized bacterial lysate to the airway compartment protects from experimental allergic asthma by engaging multiple immune pathways. Because protection required a cumulative dose 27- to 46-fold lower than the one reportedly active through the oral route, the efficacy of intranasal OM-85 administration may reflect its direct access to the airway mucosal networks controlling the initiation and development of allergic asthma.
    MeSH term(s) Allergens ; Animals ; Asthma ; Cell Extracts ; Dendritic Cells ; Disease Models, Animal ; Epithelium ; Humans ; Immunity, Innate ; Interleukin-33 ; Lung ; Lymphocytes ; Mice ; Mice, Inbred BALB C ; Ovalbumin
    Chemical Substances Allergens ; Broncho-Vaxom ; Cell Extracts ; Interleukin-33 ; Ovalbumin (9006-59-1)
    Language English
    Publishing date 2021-09-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2021.09.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Pak2 regulates myeloid-derived suppressor cell development in mice.

    Zeng, Yi / Hahn, Seongmin / Stokes, Jessica / Hoffman, Emely A / Schmelz, Monika / Proytcheva, Maria / Chernoff, Jonathan / Katsanis, Emmanuel

    Blood advances

    2017  Volume 1, Issue 22, Page(s) 1923–1933

    Abstract: Myeloid-derived suppressor cells (MDSCs) are ... ...

    Abstract Myeloid-derived suppressor cells (MDSCs) are CD11b
    Language English
    Publishing date 2017-10-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2876449-3
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2017007435
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma.

    Havas, Aaron P / Rodrigues, Kameron B / Bhakta, Anvi / Demirjian, Joseph A / Hahn, Seongmin / Tran, Jack / Scavello, Margarethakay / Tula-Sanchez, Ana A / Zeng, Yi / Schmelz, Monika / Smith, Catharine L

    Cancer biology & therapy

    2016  Volume 17, Issue 12, Page(s) 1240–1252

    Abstract: Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in ... ...

    Abstract Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, cell-type specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.
    MeSH term(s) Apoptosis/drug effects ; Cell Line, Tumor ; Cytotoxins/pharmacology ; Drug Evaluation, Preclinical ; Drug Synergism ; G2 Phase Cell Cycle Checkpoints/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Hydroxamic Acids/pharmacology ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Mitosis/drug effects ; Models, Biological ; Paclitaxel/pharmacology ; Polyploidy ; Sulfonamides/pharmacology ; Tubulin Modulators/pharmacology ; Up-Regulation ; Vincristine/pharmacology
    Chemical Substances Cytotoxins ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Sulfonamides ; Tubulin Modulators ; Vincristine (5J49Q6B70F) ; belinostat (F4H96P17NZ) ; Paclitaxel (P88XT4IS4D)
    Language English
    Publishing date 2016-10-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2146305-0
    ISSN 1555-8576 ; 1538-4047
    ISSN (online) 1555-8576
    ISSN 1538-4047
    DOI 10.1080/15384047.2016.1250046
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Anticancer activity and cellular repression of c-MYC by the G-quadruplex-stabilizing 11-piperazinylquindoline is not dependent on direct targeting of the G-quadruplex in the c-MYC promoter.

    Boddupally, Peda V L / Hahn, Seongmin / Beman, Cristina / De, Biswanath / Brooks, Tracy A / Gokhale, Vijay / Hurley, Laurence H

    Journal of medicinal chemistry

    2012  Volume 55, Issue 13, Page(s) 6076–6086

    Abstract: This G-rich region of the c-MYC promoter has been shown to form a G-quadruplex structure that acts as a silencer element for c-MYC transcriptional control. In the present work, we have synthesized a series of 11-substituted quindoline analogues as c-MYC ... ...

    Abstract This G-rich region of the c-MYC promoter has been shown to form a G-quadruplex structure that acts as a silencer element for c-MYC transcriptional control. In the present work, we have synthesized a series of 11-substituted quindoline analogues as c-MYC G-quadruplex-stabilizing compounds, and the cell-free and in vitro activity of these compounds were evaluated. Two lead compounds (4 and 12) demonstrated good cell-free profiles, and compound 4 (2-(4-(10H-indolo[3,2-b]quinolin-11-yl)piperazin-1-yl)-N,N-dimethylethanamine) significantly down-regulated c-MYC expression. However, despite the good cell-free activity and the effect of these compounds on c-MYC gene expression, we have demonstrated, using a cellular assay in a Burkitt's lymphoma cell line (CA46-specific), that these effects were not mediated through targeting of the c-MYC G-quadruplex. Thus, caution should be used in assigning the effects of G-quadruplex-interactive compounds that lower c-MYC to direct targeting of these promoter elements unless this assay, or similar ones, demonstrates direct targeting of the G-quadruplex in cells.
    MeSH term(s) Alkaloids/chemistry ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; G-Quadruplexes/drug effects ; Gene Expression Regulation/drug effects ; HCT116 Cells ; Humans ; Indoles/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacology ; Inhibitory Concentration 50 ; Neoplasms/metabolism ; Promoter Regions, Genetic/drug effects ; Proto-Oncogene Proteins c-myc/antagonists & inhibitors ; Proto-Oncogene Proteins c-myc/genetics ; Quinolines/chemical synthesis ; Quinolines/chemistry ; Quinolines/pharmacology ; Silencer Elements, Transcriptional
    Chemical Substances Alkaloids ; Antineoplastic Agents ; Indoles ; Proto-Oncogene Proteins c-myc ; Quinolines ; quindoline (243-58-3)
    Language English
    Publishing date 2012-06-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm300282c
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  10. Article ; Online: Pak2 regulates hematopoietic progenitor cell proliferation, survival, and differentiation.

    Zeng, Yi / Broxmeyer, Hal E / Staser, Karl / Chitteti, Brahmananda Reddy / Park, Su-Jung / Hahn, Seongmin / Cooper, Scott / Sun, Zejin / Jiang, Li / Yang, XianLin / Yuan, Jin / Kosoff, Rachelle / Sandusky, George / Srour, Edward F / Chernoff, Jonathan / Clapp, D Wade

    Stem cells (Dayton, Ohio)

    2015  Volume 33, Issue 5, Page(s) 1630–1641

    Abstract: p21-Activated kinase 2 (Pak2), a serine/threonine kinase, has been previously shown to be essential for hematopoietic stem cell (HSC) engraftment. However, Pak2 modulation of long-term hematopoiesis and lineage commitment remain unreported. Using a ... ...

    Abstract p21-Activated kinase 2 (Pak2), a serine/threonine kinase, has been previously shown to be essential for hematopoietic stem cell (HSC) engraftment. However, Pak2 modulation of long-term hematopoiesis and lineage commitment remain unreported. Using a conditional Pak2 knockout mouse model, we found that disruption of Pak2 in HSCs induced profound leukopenia and a mild macrocytic anemia. Although loss of Pak2 in HSCs leads to less efficient short- and long-term competitive hematopoiesis than wild-type cells, it does not affect HSC self-renewal per se. Pak2 disruption decreased the survival and proliferation of multicytokine stimulated immature progenitors. Loss of Pak2 skewed lineage differentiation toward granulocytopoiesis and monocytopoiesis in mice as evidenced by (a) a three- to sixfold increase in the percentage of peripheral blood granulocytes and a significant increase in the percentage of granulocyte-monocyte progenitors in mice transplanted with Pak2-disrupted bone marrow (BM); (b)Pak2-disrupted BM and c-kit(+) cells yielded higher numbers of more mature subsets of granulocyte-monocyte colonies and polymorphonuclear neutrophils, respectively, when cultured in the presence of granulocyte-macrophage colony-stimulating factor. Pak2 disruption resulted, respectively, in decreased and increased gene expression of transcription factors JunB and c-Myc, which may suggest underlying mechanisms by which Pak2 regulates granulocyte-monocyte lineage commitment. Furthermore, Pak2 disruption led to (a) higher percentage of CD4(+) CD8(+) double positive T cells and lower percentages of CD4(+) CD8(-) or CD4(-) CD8(+) single positive T cells in thymus and (b) decreased numbers of mature B cells and increased numbers of Pre-Pro B cells in BM, suggesting defects in lymphopoiesis.
    MeSH term(s) Anemia, Macrocytic/pathology ; Animals ; Apoptosis ; Cell Differentiation ; Cell Proliferation ; Cell Survival ; Gene Deletion ; Gene Expression Regulation ; Hematopoiesis ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/enzymology ; Leukopenia/pathology ; Lymphopoiesis ; Mice, Knockout ; Myeloid Cells/pathology ; Phenotype ; Transcription Factors/metabolism ; p21-Activated Kinases/deficiency ; p21-Activated Kinases/metabolism
    Chemical Substances Transcription Factors ; Pak2 protein, mouse (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2015-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1143556-2
    ISSN 1549-4918 ; 1066-5099
    ISSN (online) 1549-4918
    ISSN 1066-5099
    DOI 10.1002/stem.1951
    Database MEDical Literature Analysis and Retrieval System OnLINE

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