Berberine Inhibits HIV Protease Inhibitor-Induced Inflammatory Response by Modulating ER Stress Signaling Pathways in Murine Macrophages
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{"title"=>"Berberine inhibits HIV protease inhibitor-induced inflammatory response by modulating ER stress signaling pathways in murine macrophages", "type"=>"journal", "authors"=>[{"first_name"=>"Weibin", "last_name"=>"Zha", "scopus_author_id"=>"35265595800"}, {"first_name"=>"Guang", "last_name"=>"Liang", "scopus_author_id"=>"55728604600"}, {"first_name"=>"Jian", "last_name"=>"Xiao", "scopus_author_id"=>"56973066400"}, {"first_name"=>"Elaine J.", "last_name"=>"Studer", "scopus_author_id"=>"7007139798"}, {"first_name"=>"Phillip B.", "last_name"=>"Hylemon", "scopus_author_id"=>"7005846301"}, {"first_name"=>"William M.", "last_name"=>"Pandak", "scopus_author_id"=>"7003541039"}, {"first_name"=>"Guangji", "last_name"=>"Wang", "scopus_author_id"=>"10639401500"}, {"first_name"=>"Xiaokun", "last_name"=>"Li", "scopus_author_id"=>"37761910800"}, {"first_name"=>"Huiping", "last_name"=>"Zhou", "scopus_author_id"=>"7404742223"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"358448333", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0009069", "scopus"=>"2-s2.0-77949366398", "pmid"=>"20161729", "sgr"=>"77949366398"}, "id"=>"bea9e57d-faca-3b7a-b393-9f3a7fe7ef9c", "abstract"=>"BACKGROUND: HIV protease inhibitor (PI)-induced inflammatory response plays an important role in HIV PI-associated dyslipidemia and cardiovascular complications. This study examined the effect of berberine, a traditional herb medicine, on HIV PI-induced inflammatory response and further investigated the underlying cellular/molecular mechanisms in macrophages. METHODOLOGY AND PRINCIPAL FINDINGS: Cultured mouse J774A.1 macrophages and primary mouse macrophages were used in this study. The expression of TNF-alpha and IL-6 were detected by real-time RT-PCR and ELISA. Activations of ER stress and ERK signaling pathways were determined by Western blot analysis. Immunofluorescent staining was used to determine the intracellular localization of RNA binding protein HuR. RNA-pull down assay was used to determine the association of HuR with endogenous TNF-alpha and IL-6. Berberine significantly inhibited HIV PI-induced TNF-alpha and IL-6 expression by modulating ER stress signaling pathways and subsequent ERK activation, in turn preventing the accumulation of the RNA binding protein HuR in cytosol and inhibiting the binding of HuR to the 3'-UTRs of TNF-alpha and IL-6 in macrophages. CONCLUSIONS AND SIGNIFICANCE: Inhibition of ER stress represents a key mechanism by which berberine prevents HIV PI-induced inflammatory response. Our findings provide a new insight into the molecular mechanisms of berberine and show the potential application of berberine as a complimentary therapeutic agent for HIV infection.", "link"=>"http://www.mendeley.com/research/berberine-inhibits-hiv-protease-inhibitorinduced-inflammatory-response-modulating-er-stress-signalin", "reader_count"=>26, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>6, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>13, "Medicine and Dentistry"=>6, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>13}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Lebanon"=>1, "Canada"=>1, "India"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/864605"], "description"=>"<p>Primary mouse macrophages were pretreated with berberine (BBR, 2.0 µg/ml) for 2 h, then treated with lopinavir/ritonavir (LOPV/RITV = 4∶1, 15 µM) for 24 h. At the end of treatment, cell culture medium was collected. (A). The protein levels of TNF-α and IL-6 were determined by ELISA as described in “<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009069#s4\" target=\"_blank\">Methods</a>”. Values are mean ± SD of 3 independent experiments. *<i>p</i><0.05, statistical significance relative to vehicle control, DMSO. <sup>#</sup><i>p</i><0.05, statistical significance between LOPV/RITV and LOPV/RITV+BBR group. (B). Representative immunoblots for CHOP, ATF-4, XBP-1 and lamin B from nuclear extracts of primary mouse macrophages pre-treated with various amounts of berberine (BBR, 2.0 µg/ml) for 2 h, then treated with lopinavir/ritonavir (LOPV/RITV = 4∶1, 15 µM) for 24 h. Lamin B was used as loading control.</p>", "links"=>[], "tags"=>["berberine", "hiv", "pi-induced", "il-6", "upr", "activation"], "article_id"=>535053, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_berberine_on_HIV_PI_induced_TNF_945_and_IL_6_expression_and_UPR_activation_in_primary_mouse_macrophages_/535053", "title"=>"Effect of berberine on HIV PI-induced TNF-α and IL-6 expression and UPR activation in primary mouse macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-02-09 01:24:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/864876"], "description"=>"<p>Mouse J774A.1 cells were pretreated with various amounts of berberine (BBR, 0, 0.5, 1, 2 µg/ml) for 2 h and then treated with atazanavir (ATZV, 15 µM) or lopinavir (LOPV, 15 µM) for 24 h. The nuclear proteins and cytoplasmic proteins were isolated as described in “<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009069#s4\" target=\"_blank\">Methods</a>”. Three independent experiments were performed. Representative immunoblots against HuR from (A) nuclear proteins; (B) cytoplasmic proteins; (C) total cellular proteins. Lamin B and β-actin were used as loading controls for nuclear proteins and cytosolic/total cellular proteins. The density of the immunoreactive bands was analyzed using Image J software and normalized to lamin B or β-actin control. D. Immunofluorescent staining of cellular distribution of HuR. Cells were pretreated with berberine (BBR, 0.5 µg/ml) for 2 h and then treated with vehicle control DMSO, atazanavir (ATZV, 15 µM) or lopinavir (LOPV, 15 µM) for 24 h. Expression of HuR was detected with mouse monoclonal antibody against HuR and donkey anti-mouse IgG conjugated with Alex Fluor-594. Nuclei were stained with DAPI. HuR expression was visualized under a confocal fluorescence microscope with a 40× objective using a dual filter set for DAPI and rhodamine. Three experiments were performed that showed similar results.</p>", "links"=>[], "tags"=>["berberine", "hiv", "pi-induced", "cytoplasmic", "translocation", "rna", "binding", "hur"], "article_id"=>535323, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069.g006", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_berberine_on_HIV_PI_induced_cytoplasmic_translocation_of_RNA_binding_protein_HuR_in_mouse_macrophages_/535323", "title"=>"Effect of berberine on HIV PI-induced cytoplasmic translocation of RNA binding protein HuR in mouse macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-02-09 01:28:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/864688"], "description"=>"<p>Representative immunoblots from three independent experiments for phospho(p)-ERK and total (T)-ERK from the total cell lysates of mouse J774A.1 cells treated with berberine (BBR, 0.5 µg/ml) and individual HIV PIs (15 µM) for 4 h. ATZV: atazanavir; LOPV: lopinavir; RITV: ritonavir. <b>B: Time course of berberine uptake.</b> Mouse J774A.1 cells were treated with berberine (BBR, 5 µM) for various time periods (0 to 24 h), the concentration of BBR in culture medium and total intracellular amount were determined by HPLC as described in “<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009069#s4\" target=\"_blank\">Methods</a>”. <b>C: Dose-dependence of berberine uptake in macrophages.</b> Cells were treated with various amounts of berberine (BBR, 0.5 to 15 µM) for 1, 8, or 24 h. The intracellular concentrations of BBR were determined as described above and expressed as pmol/mg protein. <b>D. Effect of lopinavir on berberine uptake in macrophages</b>. Mouse J774A.1 cells were treated with berberine (BBR, 5 µM) in the presence or absence of lopinavir (LOPV, 15 µM) for various time periods (0 to 24 h), the concentration of BBR in culture medium and total intracellular amount were determined by HPLC as described above.</p>", "links"=>[], "tags"=>["berberine", "hiv", "pi-induced", "erk", "activation"], "article_id"=>535130, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_Effect_of_berberine_on_HIV_PI_induced_ERK_activation_in_macrophages_/535130", "title"=>"A. Effect of berberine on HIV PI-induced ERK activation in macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-02-09 01:25:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/864966"], "description"=>"<p>Mouse J774A.1 cells were pretreated with berberine (BBR, 0.5 µg/ml) for 2 h and then treated with lopinavir (LOPV, 15 µM) for 24 h. Total cell lysates were subjected to immunoprecipitation (IP) using either a HuR Ab or an isotype-matched control IgG1. mRNA levels in IP materials were detected by real-time RT-PCR using gene-specific primers as described in “<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009069#s4\" target=\"_blank\">Methods</a>” and expressed as fold enrichment of mRNA in HuR IP over control IgG1 IP. Values are mean ± SD of three independent experiments. Statistical significance relative to vehicle control, *p<0.05. Statistical significance of the same HIV PI treatment between control group and BBR group, <sup>#</sup><i>p</i><0.05.</p>", "links"=>[], "tags"=>["berberine", "endogenous", "hur", "il-6", "hiv", "pi-treated"], "article_id"=>535413, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069.g007", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_berberine_on_association_of_endogenous_HuR_with_TNF_945_and_IL_6_in_HIV_PI_treated_macrophages_/535413", "title"=>"Effect of berberine on association of endogenous HuR with TNF-α and IL-6 in HIV PI-treated macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-02-09 01:30:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/864787"], "description"=>"<p>Mouse J774A.1 cells were pretreated with berberine (BBR, 0.5 µg/ml) for 1 h, then treated with lopinavir (LOPV, 15 µM) or vehicle control (DMSO) for 4 h before addition of actinomycin D (5.0 µg/ml)(time 0). Total cellular RNA was extracted at 0, 0.5, 1, 2, and 4 h after actinomycin D addition. TNF-α (A) and IL-6 (B) mRNA levels were determined by real-time RT-PCR as described in “<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009069#s4\" target=\"_blank\">Methods</a>”. Values are mean ± SD of three independent experiments.</p>", "links"=>[], "tags"=>["berberine", "hiv", "pi-induced", "il-6", "mrna"], "article_id"=>535235, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069.g005", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_berberine_on_HIV_PI_induced_TNF_945_and_IL_6_mRNA_stability_in_macrophages_/535235", "title"=>"Effect of berberine on HIV PI-induced TNF-α and IL-6 mRNA stability in macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-02-09 01:27:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/864396"], "description"=>"<p>Mouse J774A.1 cells were pretreated with berberine (BBR, 0.1 or 1.0 µg/ml) for 2 h, then treated with DMSO, atazanavir (ATZV, 15 µM), lopinavir (LOPV, 15 µM), or ritonavir (RITV, 15 µM) for 24 h. At the end of treatment, cell culture medium was collected. The protein levels of TNF-α and IL-6 were determined by ELISA as described in “<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009069#s4\" target=\"_blank\">Methods</a>”. Values are mean ± SD of 3 independent experiments. *<i>p</i>< 0.05, statistical significance relative to vehicle control, DMSO. <sup>#</sup><i>p</i><0.05, statistical significance of the same HIV PI treatment between control group and BBR group. A. TNF-α; B. IL-6.</p>", "links"=>[], "tags"=>["berberine", "hiv", "pi-induced", "il-6"], "article_id"=>534845, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069.g001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_berberine_on_HIV_PI_induced_TNF_945_and_IL_6_expression_in_J774A_1_macrophages_/534845", "title"=>"Effect of berberine on HIV PI-induced TNF-α and IL-6 expression in J774A.1 macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-02-09 01:20:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/428752"], "description"=>"<div><h3>Background</h3><p>HIV protease inhibitor (PI)-induced inflammatory response plays an important role in HIV PI-associated dyslipidemia and cardiovascular complications. This study examined the effect of berberine, a traditional herb medicine, on HIV PI-induced inflammatory response and further investigated the underlying cellular/molecular mechanisms in macrophages.</p><h3>Methodology and Principal Findings</h3><p>Cultured mouse J774A.1 macrophages and primary mouse macrophages were used in this study. The expression of TNF-α and IL-6 were detected by real-time RT-PCR and ELISA. Activations of ER stress and ERK signaling pathways were determined by Western blot analysis. Immunofluorescent staining was used to determine the intracellular localization of RNA binding protein HuR. RNA-pull down assay was used to determine the association of HuR with endogenous TNF-α and IL-6. Berberine significantly inhibited HIV PI-induced TNF-α and IL-6 expression by modulating ER stress signaling pathways and subsequent ERK activation, in turn preventing the accumulation of the RNA binding protein HuR in cytosol and inhibiting the binding of HuR to the 3′-UTRs of TNF-α and IL-6 in macrophages.</p><h3>Conclusions and Significance</h3><p>Inhibition of ER stress represents a key mechanism by which berberine prevents HIV PI-induced inflammatory response. Our findings provide a new insight into the molecular mechanisms of berberine and show the potential application of berberine as a complimentary therapeutic agent for HIV infection.</p></div>", "links"=>[], "tags"=>["berberine", "inhibits", "hiv", "protease", "inhibitor-induced", "inflammatory", "modulating", "er", "signaling", "pathways", "murine", "macrophages"], "article_id"=>144644, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Berberine_Inhibits_HIV_Protease_Inhibitor_Induced_Inflammatory_Response_by_Modulating_ER_Stress_Signaling_Pathways_in_Murine_Macrophages/144644", "title"=>"Berberine Inhibits HIV Protease Inhibitor-Induced Inflammatory Response by Modulating ER Stress Signaling Pathways in Murine Macrophages", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-02-09 01:17:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/864513"], "description"=>"<p>Representative immunoblots from three independent experiments for CHOP, ATF-4, XBP-1 and lamin B from nuclear extracts of mouse J774A.1 cells pre-treated with various amounts of berberine (BBR, 0, 0.5, 1, 2.0 µg/ml) for 2 h, then treated with (<b>A</b>) atazanavir (ATZV, 15 µM); (<b>B</b>) lopinavir (LOPV, 15 µM) for 4 h. Lamin B was used as loading control.</p>", "links"=>[], "tags"=>["berberine", "hiv", "pi-induced", "upr", "activation"], "article_id"=>534962, "categories"=>["Pharmacology", "Medicine"], "users"=>["Weibin Zha", "Guang Liang", "Jian Xiao", "Elaine J. Studer", "Phillip B. Hylemon", "William M. Pandak, Jr.", "Guangji Wang", "Xiaokun Li", "Huiping Zhou"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0009069.g002", "stats"=>{"downloads"=>2, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_berberine_on_HIV_PI_induced_UPR_activation_in_J774A_1_macrophages_/534962", "title"=>"Effect of berberine on HIV PI-induced UPR activation in J774A.1 macrophages.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-02-09 01:22:42"}

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  • {"unique-ip"=>"28", "full-text"=>"30", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
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  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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  • {"unique-ip"=>"19", "full-text"=>"15", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"23", "full-text"=>"27", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
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Relative Metric

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