Therapeutic Inhibition of Pro-Inflammatory Signaling and Toxicity to Staphylococcal Enterotoxin B by a Synthetic Dimeric BB-Loop Mimetic of MyD88
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{"title"=>"Therapeutic inhibition of pro-inflammatory signaling and toxicity to staphylococcal enterotoxin B by a synthetic dimeric BB-loop mimetic of MyD88", "type"=>"journal", "authors"=>[{"first_name"=>"Teri L.", "last_name"=>"Kissner", "scopus_author_id"=>"6603253051"}, {"first_name"=>"Gordon", "last_name"=>"Ruthel", "scopus_author_id"=>"6602507350"}, {"first_name"=>"Shahabuddin", "last_name"=>"Alam", "scopus_author_id"=>"7202098885"}, {"first_name"=>"Enrique", "last_name"=>"Mann", "scopus_author_id"=>"7102262863"}, {"first_name"=>"Dariush", "last_name"=>"Ajami", "scopus_author_id"=>"6603812675"}, {"first_name"=>"Mitra", "last_name"=>"Rebek", "scopus_author_id"=>"12751919500"}, {"first_name"=>"Eileen", "last_name"=>"Larkin", "scopus_author_id"=>"35741196300"}, {"first_name"=>"Stefan", "last_name"=>"Fernandez", "scopus_author_id"=>"7202872616"}, {"first_name"=>"Robert G.", "last_name"=>"Ulrich", "scopus_author_id"=>"7201561808"}, {"first_name"=>"Sun", "last_name"=>"Ping", "scopus_author_id"=>"55324380200"}, {"first_name"=>"David S.", "last_name"=>"Waugh", "scopus_author_id"=>"7102167761"}, {"first_name"=>"Julius", "last_name"=>"Rebek", "scopus_author_id"=>"7103282536"}, {"first_name"=>"Kamal U.", "last_name"=>"Saikh", "scopus_author_id"=>"6602811285"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"365338879", "doi"=>"10.1371/journal.pone.0040773", "sgr"=>"84864408767", "scopus"=>"2-s2.0-84864408767", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"22848400"}, "id"=>"70a68c16-ac86-311c-9cff-a6e08efabb3b", "abstract"=>"Staphylococcal enterotoxin B (SEB) exposure triggers an exaggerated pro-inflammatory cytokine response that often leads to toxic shock syndrome (TSS) associated with organ failure and death. MyD88 mediates pro-inflammatory cytokine signaling induced by SEB exposure and MyD88(-/-) mice are resistant to SEB intoxication, suggesting that MyD88 may be a potential target for therapeutic intervention. We targeted the BB loop region of the Toll/IL-1 receptor (TIR) domain of MyD88 to develop small-molecule therapeutics. Here, we report that a synthetic compound (EM-163), mimic to dimeric form of BB-loop of MyD88 attenuated tumor necrosis factor (TNF)- α, interferon (IFN)-γ, interleukin (IL)-1β, IL-2 and IL-6 production in human primary cells, whether administered pre- or post-SEB exposure. Results from a direct binding assay, and from MyD88 co-transfection/co-immunoprecipitation experiments, suggest that EM-163 inhibits TIR-TIR domain interaction. Additional results indicate that EM-163 prevents MyD88 from mediating downstream signaling. In an NF-kB-driven reporter assay of lipopolysaccharide-stimulated MyD88 signaling, EM-163 demonstrated a dose-dependent inhibition of reporter activity as well as TNF-α and IL-1β production. Importantly, administration of EM-163 pre- or post exposure to a lethal dose of SEB abrogated pro-inflammatory cytokine responses and protected mice from toxic shock-induced death. Taken together, our results suggest that EM-163 exhibits a potential for therapeutic use against SEB intoxication.", "link"=>"http://www.mendeley.com/research/therapeutic-inhibition-proinflammatory-signaling-toxicity-staphylococcal-enterotoxin-b-synthetic-dim", "reader_count"=>13, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>2, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>2, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>4, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Sports and Recreations"=>1, "Chemistry"=>2, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>2}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Brazil"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

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  • {"files"=>["https://ndownloader.figshare.com/files/600185"], "description"=>"<p>EM-163 was synthesized from compound EM-110 as described in Materials and Methods.</p>", "links"=>[], "tags"=>["immunology", "Infectious diseases", "Biochemistry"], "article_id"=>270661, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synthesize_of_compound_EM_163_/270661", "title"=>"Synthesize of compound EM-163.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:11:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/600358"], "description"=>"<p>Structure of monomeric (Compound1) and dimeric (EM-163) mimetics of the BB-loop in the TIR domain of MyD88.</p>", "links"=>[], "tags"=>["monomeric", "dimeric", "mimetics", "bb-loop", "tir"], "article_id"=>270836, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structure_of_monomeric_Compound1_and_dimeric_EM_163_mimetics_of_the_BB_loop_in_the_TIR_domain_of_MyD88_/270836", "title"=>"Structure of monomeric (Compound1) and dimeric (EM-163) mimetics of the BB-loop in the TIR domain of MyD88.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:13:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/600508"], "description"=>"<p>A microarray-based binding assay was optimized to measure compound EM-163 binding to MyD88. Nitrocellulose coated slides were spotted in quadruplicate with anti-MyD88 antibody and MyD88 TIR domain monomer proteins using the ArrayJet Marathon printer. Biotinlyated MyD88 (25 µg/ml) was pre-incubated with compound (100 µg/ml and 50 µg/ml), dimethylsulfoxide as control, or left without pre-incubation. Streptavidin- labeled with alexa fluor 647, was added for 1 h at room temperture to detect MyD88 binding interaction. Slides analyzed using the Genepix 4000B. Data represent four similar experiments.</p>", "links"=>[], "tags"=>["inhibits", "tir-tir"], "article_id"=>270987, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EM_163_inhibits_TIR_TIR_interaction_/270987", "title"=>"EM-163 inhibits TIR-TIR interaction.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:16:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/600682"], "description"=>"<p>Increased accumulation of MyD88 in CD14<sup>+</sup> monocytes treated with SEB in the presence of EM-163 at 1 h and 4 h. Confocal images show expression of nuclei (blue) and intracellular MyD88 (red) proteins in CD14<sup>+</sup> monocytes. Monocytes were untreated or treated with SEB, EM-163 or SEB plus EM-163 (250 µM). Cell nuclei were labeled with DAPI (blue). Scale bar  = 10 µm. Data reperesent three similar experiments with different donors.</p>", "links"=>[], "tags"=>["stimulation", "monocytes", "em-163", "leads", "intracellular", "accumulation"], "article_id"=>271153, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SEB_stimulation_of_human_monocytes_in_the_presence_of_EM_163_leads_to_intracellular_accumulation_of_MyD88_/271153", "title"=>"SEB stimulation of human monocytes in the presence of EM-163 leads to intracellular accumulation of MyD88.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:19:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/600826"], "description"=>"<p>HEK 293T cells were co-transfected with plasmids MyD88- Flag or pCMV-HA-MyD88. Seven hours after transfection, cells were incubated for 13 h with or without −163 (500 µM to 5 µM). (<b>A</b>), Cell extracts were immunoprecipitated (IP) with anti-Flag antibody, and immune-precipitated proteins were analyzed in Western blot with anti-HA. (<b>B</b>) Densitometry analysis of the results shown in (<b>A</b>). The results are representative of three independent experiments.</p>", "links"=>[], "tags"=>["targets", "myd88", "stabilizes"], "article_id"=>271312, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EM_163_targets_newly_expressed_MyD88_and_stabilizes_the_MyD88_complex_/271312", "title"=>"EM-163 targets newly expressed MyD88 and stabilizes the MyD88 complex.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:21:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/601022"], "description"=>"<p>EM-163 inhibition was measured by monitoring LPS-induced SEAP activity via a MyD88-mediated NF-kB driven signaling pathway. HEK 293 stable transfected cell line (TLR4-MD2-NF-kB-SEAP) was activated with LPS (TLR-4 ligand) and treated with varying concentrations of EM-163 (1 mM to 50 µM). Culture supernatants were tested for SEAP activity and compared to levels in the absence of EM-163. (<b>A</b>) Inhibition of SEAP reporter activity, (<b>B</b>) inhibition of TNF-α and IL-1β production, <i>(</i><b>C</b>) Inhibition of TNF-α and IL-1β production by EM-163 after SEB stimulation of HEK 293 cells transfected with HLA-DR (α/β) and FLAG-MyD88. Results represent three experiments.</p>", "links"=>[], "tags"=>["inhibits", "myd88-mediated", "signaling", "cytokine"], "article_id"=>271503, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EM_163_inhibits_MyD88_mediated_signaling_and_cytokine_production_/271503", "title"=>"EM-163 inhibits MyD88-mediated signaling and cytokine production.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:25:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/601198"], "description"=>"<p>Human MNCs (5×10<sup>5</sup>/well) were treated with EM-163 for 30 min before (pre-exposure) or 30 min after (post-exposure) being exposed to SEB(200 ng/ml) and varying concentrations of EM-163 (1 mM, 500 µM, 100 µM and 10 µM). Culture supernatants were collected after 16 h and analyzed for cytokine release using a MSD assay. The IC<sub>50</sub> value was calculated as the concentration required for inhibition of cytokine production by 50% relative to the control. Data represent five experiments.</p>", "links"=>[], "tags"=>["em-163", "inhibits", "il-2"], "article_id"=>271676, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pre_or_post_exposure_treatment_of_EM_163_inhibits_TNF_945_IFN_947_IL_2_and_IL_1_946_production_/271676", "title"=>"Pre or post exposure treatment of EM-163 inhibits TNF-α, IFN-γ, IL-2 and IL-1β production.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:27:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/601349"], "description"=>"<p>BALB/c mice (n = 6) were injected (i.p.) with different amounts of EM-163, 30 min later injected with SEB followed by LPS 2 h later. Mice were observed to determine if mice survived, or time to death if they did not. Control mice injected only with 60 µg of LPS or 1 µg of SEB survived. Data represent three separate experiments. Kaplan Meier survival analysis and log-rank tests were performed to compare survival curves with stepdown Bonferroni adjustment for pair wise comparisons between groups. (<b>A)</b>, Pre-treatment of EM-163, 0.42 mg/mouse, or 0.86 mg/mouse protected mice against lethal SEB (0.5 µg/mouse,1 LD<sub>50)</sub> challenge, p = 0.0015; Pre-treatment of EM-163 protected mice challenged with SEB (5 µg/mouse equivalent to10 LD<sub>50),</sub> p≤0.0261<sub>;</sub> (<b>B</b>). Administration of EM-163 in mice inhibited pro-inflammatory cytokine response. Similar to experimental settings as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040773#pone-0040773-g007\" target=\"_blank\">Figure 7A</a><b>,</b> mice (n = 6) were bled at 4 h, serum were pooled from each group [LPS, SEB+LPS, EM-163 (1.7 mg/mouse)] and measured serum cytokines. (<b>C</b>). Post-exposure to SEB (0.5 µg I LD<sub>50</sub>), EM-163 treated mice were protected, p  = 0.0102; Post-exposure to SEB challenge, EM-163 delayed death (5 µg = 10 LD<sub>50</sub>), p≤0.0129.</p>", "links"=>[], "tags"=>["attenuates", "seb", "-induced", "pro-inflammatory", "serum", "cytokines", "lethality"], "article_id"=>271823, "categories"=>["Biochemistry", "Infectious Diseases", "Immunology"], "users"=>["Teri L. Kissner", "Gordon Ruthel", "Shahabuddin Alam", "Enrique Mann", "Dariush Ajami", "Mitra Rebek", "Eileen Larkin", "Stefan Fernandez", "Robert G. Ulrich", "Sun Ping", "David S. Waugh", "Julius Rebek Jr", "Kamal U. Saikh"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040773.g008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EM_163_attenuates_SEB_induced_pro_inflammatory_serum_cytokines_and_lethality_in_mice_/271823", "title"=>"EM-163 attenuates SEB -induced pro-inflammatory serum cytokines and lethality in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-27 00:30:23"}

PMC Usage Stats | Further Information

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