Release of Neuronal HMGB1 by Ethanol through Decreased HDAC Activity Activates Brain Neuroimmune Signaling
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{"title"=>"Release of neuronal HMGB1 by ethanol through decreased HDAC activity activates brain neuroimmune signaling", "type"=>"journal", "authors"=>[{"first_name"=>"Jian Y.", "last_name"=>"Zou", "scopus_author_id"=>"55452766300"}, {"first_name"=>"Fulton T.", "last_name"=>"Crews", "scopus_author_id"=>"11240386800"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"372565647", "pmid"=>"24551070", "doi"=>"10.1371/journal.pone.0087915", "issn"=>"19326203", "scopus"=>"2-s2.0-84895894114", "sgr"=>"84895894114", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"c126514c-22bd-31d9-9a54-09b86d3e7a6f", "abstract"=>"Neuroimmune gene induction is involved in many brain pathologies including addiction. Although increased expression of proinflammatory cytokines has been found in ethanol-treated mouse brain and rat brain slice cultures as well as in post-mortem human alcoholic brain, the mechanisms remain elusive. High-mobility group box 1 (HMGB1) protein is a nuclear protein that has endogenous cytokine-like activity. We previously found increased HMGB1 in post-mortem alcoholic human brain as well as in ethanol treated mice and rat brain slice cultures. The present study investigated the mechanisms for ethanol-induced release of HMGB1 and neuroimmune activation in a model of rat hippocampal-entorhinal cortex (HEC) brain slice cultures. Ethanol exposure triggered dose-dependent HMGB1 release, predominantly from neuronal cells. Inhibitors of histone deacetylases (HDACs) promoted nucleocytoplasmic mobilization of HDAC1/4 and HMGB1 resulting in increased total HMGB1 and acetylated HMGB1 release. Similarly, ethanol treatment was found to induce the translocation of HDAC1/4 and HMGB1 proteins from nuclear to cytosolic fractions. Furthermore, ethanol treatment reduced HDAC1/4 mRNA and increased acetylated HMGB1 release into the media. These results suggest decreased HDAC activity may be critical in regulating acetylated HMGB1 release from neurons in response to ethanol. Ethanol and HMGB1 treatment increased mRNA expression of proinflammatory cytokines TNFalpha and IL-1beta as well as toll-like receptor 4 (TLR4). Targeting HMGB1 or microglial TLR4 by using siRNAs to HMGB1 and TLR4, HMGB1 neutralizing antibody, HMGB1 inhibitor glycyrrhizin and TLR4 antagonist as well as inhibitor of microglial activation all blocked ethanol-induced expression of proinflammatory cytokines TNFalpha and IL-1beta. These results support the hypothesis that ethanol alters HDACs that regulate HMGB1 release and that danger signal HMGB1 as endogenous ligand for TLR4 mediates ethanol-induced brain neuroimmune signaling through activation of microglial TLR4. These findings provide new therapeutic targets for brain neuroimmune activation and alcoholism.", "link"=>"http://www.mendeley.com/research/release-neuronal-hmgb1-ethanol-through-decreased-hdac-activity-activates-brain-neuroimmune-signaling", "reader_count"=>54, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Researcher"=>11, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>16, "Student > Postgraduate"=>5, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>9}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>4, "Researcher"=>11, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>16, "Student > Postgraduate"=>5, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>9}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Biochemistry, Genetics and Molecular Biology"=>9, "Medicine and Dentistry"=>12, "Agricultural and Biological Sciences"=>17, "Neuroscience"=>4, "Arts and Humanities"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Psychology"=>3, "Social Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>12}, "Neuroscience"=>{"Neuroscience"=>4}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>17}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>9}, "Unspecified"=>{"Unspecified"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Poland"=>1, "United Kingdom"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1387205"], "description"=>"<p>A: HEC slices were exposed to ethanol (100 mM) for 4 days in the absence or presence of anti-HMGB1 neutralizing antibody. Chicken IgY (10 µg/ml) was used as control antibody for HMGB1 neutralization. Shown are mean ± SEM of proinflammatory cytokine TNFα and IL-1β mRNA levels, relative to chicken IgY-treated control. Ethanol induction of TNFα and IL-1β mRNA is blocked by HMGB1 neutralizing antibody (*<i>p</i><0.01 compared to Control; #<i>p</i><0.05 compared with EtOH; n = 3). B: HMGB1 inhibitor glycyrrhizin (Glyc) was applied to the cultures during ethanol (100 mM) treatment for 4 days. Shown are mean ± SEM of proinflammatory cytokine TNFα and IL-1β mRNA levels from a representative experiment. Ethanol induction of TNFα and IL-1β mRNA is completely blocked by glycyrrhizin (*<i>p</i><0.001 compared to Control; #<i>p</i><0.0001 compared with EtOH; n = 3). The experiments were repeated at least once with the similar design and results.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "ethanol", "neuroimmune"], "article_id"=>935597, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g009", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HMGB1_mediated_ethanol_neuroimmune_activation_/935597", "title"=>"HMGB1-mediated ethanol neuroimmune activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387187"], "description"=>"<p>A: Shown are mean ± SEM of media HMGB1 levels from a representative dose dependent study indicating broad HDAC inhibitor TSA and selective HDAC1 inhibitor MS-275 trigger active release of neuronal HMGB1 into medium (*p<0.01 compared with control; n = 3). C: ELISA measurements of media HMGB1 from cultures treated with various HDAC inhibitors alone or co-presence of ethanol. Treatments of HEC slices for 4 days with ethanol in the absence or presence of inhibitors including TSA (1 µM), MS-275 (5 µM), sodium butylate (SB, 100 µM) and vaproic acid (VPA, 100 µM) increase media HMGB1 level but only TSA and MS-275 appears to potentiate ethanol action (*p<0.01 compared with Control; #p<0.001 compared with EtOH. n = 3).</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "inhibitors", "hmgb1"], "article_id"=>935582, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g003", "stats"=>{"downloads"=>4, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HDAC_inhibitors_increase_HMGB1_release_/935582", "title"=>"HDAC inhibitors increase HMGB1 release.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387200"], "description"=>"<p>HEC slices were treated with HMGB1 (500 ng/ml) for 96 hrs. and then harvested for detection of proinflammatory cytokine gene expression. Shown are mean ± SEM of cytokines TNFα and IL-β mRNA levels from a representative experiment. Treatment of HEC slices with exogenous HMGB1 induced significant increase in cytokine gene expression. Proinflammatory activity of HMGB1 is abolished by blockade of TLR4 with antagonists Lps-Rs and naltrexone or by knocking down TLR4 with specific siRNA (*p<0.01 compared with Control; #p<0.05 compared with HMGB1 group, n = 3).</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "hmgb1", "proinflammatory"], "article_id"=>935592, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g008", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Exogenous_HMGB1_induces_expression_of_proinflammatory_genes_/935592", "title"=>"Exogenous HMGB1 induces expression of proinflammatory genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387198"], "description"=>"<p>A: Western blot analysis of HEC slice cytosolic protein extracts for HDAC1, HDAC4 and HMGB1 from a representative ethanol time course experiment. B: Western blot analysis of HEC slice nuclear protein extracts for HDAC1, HDAC4 and HMGB1 from the same experiments shown in A. C: Co-immunoprecipitation analysis of culture medium for acetylated HMGB1 level. Anti-rabbit IgG was used as a negative control.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "blot", "hdac1", "hdac4", "acetylated"], "article_id"=>935590, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g007", "stats"=>{"downloads"=>9, "page_views"=>150, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Western_blot_analysis_of_HDAC1_and_HDAC4_as_well_as_acetylated_HMGB1_/935590", "title"=>"Western blot analysis of HDAC1 and HDAC4 as well as acetylated HMGB1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387208"], "description"=>"<p>A: Ethanol (100 mM, 4 days) induction of proinflammatory signaling molecules were significantly blocked by TLR4 antagonist naltrexone (minor form, 250 fM). Shown are mean ± SEM of mRNA levels relative to control (*p<0.001 compared with Control; #p<0.01 compared with Ethanol; n = 3). B: Ethanol induction of TNFα and IL-1β mRNA is completely blocked by naltrexone (plus form, 250 pM) (*<i>p</i><0.001 compared to Control; #<i>p</i><0.0001 compared with EtOH; n = 3).</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "antagonist", "naltrexone", "blocks", "ethanol", "neuroimmune"], "article_id"=>935600, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g011", "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TLR4_antagonist_naltrexone_blocks_ethanol_neuroimmune_activation_/935600", "title"=>"TLR4 antagonist naltrexone blocks ethanol neuroimmune activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387186"], "description"=>"<p>Representative confocal merger images showing A: double immunofluorescent staining with anti-HMGB1 (red) and anti-NeuN (green), a marker for mature neurons. Majority of NeuN+ neurons coexpressing HMGB1 (yellow); B: double immunofluorescent staining with anti-HMGB1 (red) and anti-doubleCortin (DCX, green), a marker for immature neurons. HMGB1 is located in the nuclear of majority DCX+ neurons. Mobilization and translocation of nuclear HMGB1 in HEC slices was further depicted from treatment of Control (C), ethanol (D), TSA (E), Scriptaid (F), LPS (G) and NMDA (H). Nuclear mobilization and/or cytoplasm translocation in neurons were indicated by arrows (original magnification 80x in A–B: 320x in C–H).</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol"], "article_id"=>935581, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Neuronal_expression_of_HMGB1_/935581", "title"=>"Neuronal expression of HMGB1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387206"], "description"=>"<p>A: Minocycline, known to inhibit microglial activation, was applied to HEC slices at different concentrations during ethanol exposure (100 mM, 4 days). Shown are mean ± SEM of proinflammatory cytokine TNFα and IL-1β mRNA levels. Blocking microglial activation by minocycline blunt ethanol induction of cytokine TNFα and IL-1β mRNA (*p<0.01 compared with Control; #p<0.01 comparing to EtOH; n = 3). The experiments were repeated twice with similar design and results. B: Knocking down microglial TLR4 or neuronal HMGB1 with specific siRNA abolished ethanol neuroimmune activation. Shown are mean ± SEM of proinflammatory cytokine TNFα and IL-1β mRNA levels relative to control group treated with negative control siRNA (*p<0.001 compared with Control; #p<0.0001 compared with EtOH; n = 3). The experiments were repeated with similar designs and results.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "tlr4", "hmgb1-mediated", "ethanol", "neuroimmune"], "article_id"=>935598, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g010", "stats"=>{"downloads"=>4, "page_views"=>54, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Microglial_TLR4_plays_a_critical_role_in_HMGB1_mediated_ethanol_neuroimmune_activation_/935598", "title"=>"Microglial TLR4 plays a critical role in HMGB1-mediated ethanol neuroimmune activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387182"], "description"=>"<p>A: ELISA measurements indicate ethanol dose-dependently increase HMGB1 release into culture medium compared with Control (*p<0.05; n = 3); B: Western blotting of the whole cell lysate show HMGB1 protein level was increased progressively over time period in response to ethanol; C: RT-PCR analysis show ethanol-induced mRNA expression and HMGB1 as well as TLR4 and TLR2 (*p<0.05 compared with Control; n = 3).</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "hmgb1"], "article_id"=>935577, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ethanol_increases_HMGB1_expression_and_release_/935577", "title"=>"Ethanol increases HMGB1 expression and release.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387197"], "description"=>"<p>A: Shown are mean ± SEM of HDAC1 and HDAC4 mRNA levels from a representative time course study. Ethanol exposure inhibits both HDAC1 and HDAC4 mRNA expression (*p<0.05 compared with control; n = 3). B: HDAC immunoreactivity (IR) was examined. Shown in bar graph (left) indicate both ethanol and TSA reduce HDAC4 IR in hippocampus (*p<0.05 compared with Control, n = 6). Representative images of HDAC4 IR were depicted from both control (a–b) and ethanol-treated (c–d) slices as indicated at 20x and 40x magnification. C: Representative confocal images of double immunofluorescent staining with HDAC4 (red) and neuronal marker NeuN (green) (a–b) and HMGB1 (c) indicating nuclear localization of HDAC4 in neuronal cells from control slices (a from dentate gyrus; b from hippocampal CA field; c from dentate gyrus). Original magnification 80x.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "ethanol", "hdac", "mrna"], "article_id"=>935589, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g006", "stats"=>{"downloads"=>2, "page_views"=>43, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_ethanol_on_HDAC_mRNA_and_protein_expression_/935589", "title"=>"Effects of ethanol on HDAC mRNA and protein expression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387211"], "description"=>"<p>Primer sequences for quantitative PCR analysis.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "sequences", "quantitative", "pcr"], "article_id"=>935603, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.t001", "stats"=>{"downloads"=>16, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primer_sequences_for_quantitative_PCR_analysis_/935603", "title"=>"Primer sequences for quantitative PCR analysis.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387190"], "description"=>"<p>A: Western blot analysis of HEC slice cytosolic protein extracts for HDAC1 and HMGB1 from a representative experiment with ethanol (100 mM) and MS-275 (5 µM). B: Western blot analysis of HEC slice nuclear protein extracts for HDAC1, HDAC4 and HMGB1 from the same experiments shown in A. C: Co-immunoprecipitation analysis of culture medium for acetylated HMGB1 level. Anti-rabbit IgG was used as a negative control.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "hdac1", "ms-275", "causing", "cytoplasmic", "mobilization"], "article_id"=>935585, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g005", "stats"=>{"downloads"=>12, "page_views"=>35, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_HDAC1_by_MS_275_causing_cytoplasmic_mobilization_of_HDAC1_and_HMGB1_/935585", "title"=>"Inhibition of HDAC1 by MS-275 causing cytoplasmic mobilization of HDAC1 and HMGB1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387210"], "description"=>"<p>Ethanol exposure decreases neuronal HDACs activity causing increased acetylation of HMGB1. Acetylated HMGB1 is mobilized into cytosolic compartment and subsequently secreted into extracellular space. Extracellular HMGB1 activates TLR4 in microglia to initiate neuron-glia neuroimmune communication by producing a wide array of proinflammatory cytokines or mediators such as TNFα, IL-1β, iNOs and MCP-1. Activated microglia may also induce expression and release of HMGB1 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087915#pone.0087915-LoCoco1\" target=\"_blank\">[56]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087915#pone.0087915-Murakami1\" target=\"_blank\">[57]</a>. Proinflammatory cytokines and extracellular HMGB1 create a positive feedback loop that amplifies neuroimmune responses with engagements of other TLRs and RAGE as well as individual cytokine receptors across cell types. In addition, extracellular HMGB1 can exert potent proinflammatory activity by forming complexes with proinflammatory cytokines TNFα and IL-1β (unpublished data). Targeting multiple sites involving in HMGB1-TLR4 signaling may prove to be effective therapeutic approaches for combating brain neuroimmune activation associated with alcoholism and drug addiction <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087915#pone.0087915-Crews1\" target=\"_blank\">[1]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087915#pone.0087915-Crews4\" target=\"_blank\">[47]</a>.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "ethanol-induced", "neuronal", "hmgb1", "activating", "microglial", "tlr4", "creating", "amplifies", "innate"], "article_id"=>935602, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g012", "stats"=>{"downloads"=>5, "page_views"=>348, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_of_ethanol_induced_release_of_neuronal_HMGB1_activating_microglial_TLR4_and_creating_a_positive_feedback_loop_that_amplifies_innate_immune_cascades_/935602", "title"=>"Schematic of ethanol-induced release of neuronal HMGB1 activating microglial TLR4 and creating a positive feedback loop that amplifies innate immune cascades.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1387188"], "description"=>"<p>A: Western blot analysis of HEC slice cytosolic protein extracts for HDAC1, HDAC4 and HMGB1 from a representative experiment with ethanol (100 mM) and TSA (1 µM). B: Western blot analysis of HEC slice nuclear protein extracts for HDAC1, HDAC4 and HMGB1 from the same experiments shown in A. C: Co-immunoprecipitation analysis of culture medium for acetylated HMGB1 level. Anti-rabbit IgG was used as a negative control.</p>", "links"=>[], "tags"=>["genetics", "epigenetics", "Histone modification", "immunology", "Immune system", "cytokines", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "neuroscience", "Molecular neuroscience", "toxicology", "Public health", "alcohol", "cytoplasmic", "mobilization", "hdac1"], "article_id"=>935583, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Jian Y. Zou", "Fulton T. Crews"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087915.g004", "stats"=>{"downloads"=>3, "page_views"=>48, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TSA_induced_cytoplasmic_mobilization_of_HDAC1_and_4_as_well_as_HMGB1_/935583", "title"=>"TSA-induced cytoplasmic mobilization of HDAC1 and 4 as well as HMGB1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-02-14 02:43:09"}

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