Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells - Possible Relevance to Autism Spectrum Disorders
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{"title"=>"Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB-dependent catecholaminergic neurotransmission, in PC12 cells - Possible relevance to autism spectrum disorders", "type"=>"journal", "authors"=>[{"first_name"=>"Bistra B.", "last_name"=>"Nankova", "scopus_author_id"=>"6603805908"}, {"first_name"=>"Raj", "last_name"=>"Agarwal", "scopus_author_id"=>"56648855500"}, {"first_name"=>"Derrick F.", "last_name"=>"MacFabe", "scopus_author_id"=>"15136490500"}, {"first_name"=>"Edmund F.", "last_name"=>"La Gamma", "scopus_author_id"=>"7003893810"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"373867592", "sgr"=>"84908185298", "issn"=>"19326203", "pmid"=>"25170769", "scopus"=>"2-s2.0-84908185298", "doi"=>"10.1371/journal.pone.0103740", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)"}, "id"=>"cba091be-0de9-309c-8a38-1d0e2769ee09", "abstract"=>"Alterations in gut microbiome composition have an emerging role in health and disease including brain function and behavior. Short chain fatty acids (SCFA) like propionic (PPA), and butyric acid (BA), which are present in diet and are fermentation products of many gastrointestinal bacteria, are showing increasing importance in host health, but also may be environmental contributors in neurodevelopmental disorders including autism spectrum disorders (ASD). Further to this we have shown SCFA administration to rodents over a variety of routes (intracerebroventricular, subcutaneous, intraperitoneal) or developmental time periods can elicit behavioral, electrophysiological, neuropathological and biochemical effects consistent with findings in ASD patients. SCFA are capable of altering host gene expression, partly due to their histone deacetylase inhibitor activity. We have previously shown BA can regulate tyrosine hydroxylase (TH) mRNA levels in a PC12 cell model. Since monoamine concentration is known to be elevated in the brain and blood of ASD patients and in many ASD animal models, we hypothesized that SCFA may directly influence brain monoaminergic pathways. When PC12 cells were transiently transfected with plasmids having a luciferase reporter gene under the control of the TH promoter, PPA was found to induce reporter gene activity over a wide concentration range. CREB transcription factor(s) was necessary for the transcriptional activation of TH gene by PPA. At lower concentrations PPA also caused accumulation of TH mRNA and protein, indicative of increased cell capacity to produce catecholamines. PPA and BA induced broad alterations in gene expression including neurotransmitter systems, neuronal cell adhesion molecules, inflammation, oxidative stress, lipid metabolism and mitochondrial function, all of which have been implicated in ASD. In conclusion, our data are consistent with a molecular mechanism through which gut related environmental signals such as increased levels of SCFA's can epigenetically modulate cell function further supporting their role as environmental contributors to ASD.", "link"=>"http://www.mendeley.com/research/enteric-bacterial-metabolites-propionic-butyric-acid-modulate-gene-expression-including-crebdependen", "reader_count"=>85, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Librarian"=>1, "Student > Doctoral Student"=>3, "Researcher"=>9, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>6, "Student > Master"=>12, "Other"=>6, "Student > Bachelor"=>15, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>1, "Librarian"=>1, "Student > Doctoral Student"=>3, "Researcher"=>9, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>6, "Student > Master"=>12, "Other"=>6, "Student > Bachelor"=>15, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>6}, "reader_count_by_subject_area"=>{"Unspecified"=>7, "Agricultural and Biological Sciences"=>28, "Philosophy"=>1, "Chemical Engineering"=>2, "Chemistry"=>3, "Computer Science"=>2, "Energy"=>1, "Biochemistry, Genetics and Molecular Biology"=>10, "Nursing and Health Professions"=>2, "Medicine and Dentistry"=>18, "Neuroscience"=>5, "Psychology"=>3, "Social Sciences"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>18}, "Social Sciences"=>{"Social Sciences"=>2}, "Psychology"=>{"Psychology"=>3}, "Unspecified"=>{"Unspecified"=>7}, "Chemical Engineering"=>{"Chemical Engineering"=>2}, "Chemistry"=>{"Chemistry"=>3}, "Neuroscience"=>{"Neuroscience"=>5}, "Energy"=>{"Energy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>28}, "Computer Science"=>{"Computer Science"=>2}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}, "Philosophy"=>{"Philosophy"=>1}}, "reader_count_by_country"=>{"Korea (South)"=>1, "Denmark"=>1, "Spain"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1655561"], "description"=>"<p>The symbols ↑ and ↓ indicate up- and down-regulated genes, respectively. Numbers following the ↑ or ↓ symbols represent the fold-change for the gene expression level. Sorting was done according to the magnitude of the signal (fold change) in BA group. The top 10 for each, upregulated and down regulated genes are shown. For more details, see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103740#pone.0103740.s003\" target=\"_blank\">Table S3</a>.</p><p>Comparison analysis of differentially expressed genes triggered by PPA and BA in PC12 cells: Top 10 most affected common genes.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156032, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t002", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_analysis_of_differentially_expressed_genes_triggered_by_PPA_and_BA_in_PC12_cells_Top_10_most_affected_common_genes_/1156032", "title"=>"Comparison analysis of differentially expressed genes triggered by PPA and BA in PC12 cells: Top 10 most affected common genes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655609", "https://ndownloader.figshare.com/files/1655610", "https://ndownloader.figshare.com/files/1655611"], "description"=>"<div><p>Alterations in gut microbiome composition have an emerging role in health and disease including brain function and behavior. Short chain fatty acids (SCFA) like propionic (PPA), and butyric acid (BA), which are present in diet and are fermentation products of many gastrointestinal bacteria, are showing increasing importance in host health, but also may be environmental contributors in neurodevelopmental disorders including autism spectrum disorders (ASD). Further to this we have shown SCFA administration to rodents over a variety of routes (intracerebroventricular, subcutaneous, intraperitoneal) or developmental time periods can elicit behavioral, electrophysiological, neuropathological and biochemical effects consistent with findings in ASD patients. SCFA are capable of altering host gene expression, partly due to their histone deacetylase inhibitor activity. We have previously shown BA can regulate tyrosine hydroxylase (TH) mRNA levels in a PC12 cell model. Since monoamine concentration is known to be elevated in the brain and blood of ASD patients and in many ASD animal models, we hypothesized that SCFA may directly influence brain monoaminergic pathways. When PC12 cells were transiently transfected with plasmids having a luciferase reporter gene under the control of the TH promoter, PPA was found to induce reporter gene activity over a wide concentration range. CREB transcription factor(s) was necessary for the transcriptional activation of TH gene by PPA. At lower concentrations PPA also caused accumulation of TH mRNA and protein, indicative of increased cell capacity to produce catecholamines. PPA and BA induced broad alterations in gene expression including neurotransmitter systems, neuronal cell adhesion molecules, inflammation, oxidative stress, lipid metabolism and mitochondrial function, all of which have been implicated in ASD. In conclusion, our data are consistent with a molecular mechanism through which gut related environmental signals such as increased levels of SCFA's can epigenetically modulate cell function further supporting their role as environmental contributors to ASD.</p></div>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156077, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0103740.s001", "https://dx.doi.org/10.1371/journal.pone.0103740.s002", "https://dx.doi.org/10.1371/journal.pone.0103740.s003"], "stats"=>{"downloads"=>0, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Enteric_Bacterial_Metabolites_Propionic_and_Butyric_Acid_Modulate_Gene_Expression_Including_CREB_Dependent_Catecholaminergic_Neurotransmission_in_PC12_Cells_Possible_Relevance_to_Autism_Spectrum_Disorders_/1156077", "title"=>"Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells - Possible Relevance to Autism Spectrum Disorders", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655554"], "description"=>"<p>Differentially expressed genes in BA and PPA groups (t-test compared to control group p<0.01) were subjected to enrichment analysis (which consists of matching gene IDs for the common, similar and unique sets of the uploaded files with gene IDs in functional ontologies in MetaCore). The figure illustrates the distribution by GO processes. The gene content is aligned between all uploaded files. The set of common gene IDs is marked as blue and white stripes. The unique genes for the files are marked as colored bars (BA - orange; PPA- blue). The sorting was done by common gene IDs; p-value was set for 0.05; both signals (induced and repressed) were included. The data shown are for sorting method “similarity by”. The degree of “relevance” to different categories for the uploaded datasets is defined by p values, so that the lower p-value gets higher priority. The top 10 processes are listed based on their −log (p-value).</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156026, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Enrichment_analysis_of_differentially_expressed_genes_distribution_by_gene_ontology_GO_processes_/1156026", "title"=>"Enrichment analysis of differentially expressed genes: distribution by gene ontology (GO) processes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655570"], "description"=>"<p>Total gene IDs in the ontology – 85, matches for PPA – 13, for BA -15.</p><p>Gene ontology annotation analysis: Dopamine & serotonin pathways.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156040, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t006", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_ontology_annotation_analysis_Dopamine_amp_serotonin_pathways_/1156040", "title"=>"Gene ontology annotation analysis: Dopamine & serotonin pathways.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655564"], "description"=>"<p>Sorting was done by the magnitude of the signal in BA group for both, upregulated (↑) and down regulated (↓) genes.</p><p>Common genes oppositionally affected by PPA and BA.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156035, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t004", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Common_genes_oppositionally_affected_by_PPA_and_BA_/1156035", "title"=>"Common genes oppositionally affected by PPA and BA.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655563"], "description"=>"<p>Sorting was done according the magnitude of the signal (most affected, fold change) in PPA group for both upregulated (↑) and down regulated genes (↓).</p><p>Examples of common genes which were affected more by PPA.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156034, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t003", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Examples_of_common_genes_which_were_affected_more_by_PPA_/1156034", "title"=>"Examples of common genes which were affected more by PPA.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655577"], "description"=>"<p>Total gene IDs in the ontology - 101, matches for PPA - 6, for BA- 12.</p><p>Gene ontology annotation analysis: GAP junction proteins.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156047, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t008", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_ontology_annotation_analysis_GAP_junction_proteins_/1156047", "title"=>"Gene ontology annotation analysis: GAP junction proteins.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655578"], "description"=>"<p>The list of biological networks was generated using the Analyze Networks (AN) algorithm with default settings (MetaCore), based on relative enrichment with the uploaded data and the relative saturation of networks with canonical pathways.</p><p><u>P-value</u>: represents the probability for a particular mapping of an experiment to a map (or network, or process) to arise by chance considering the number of genes in the experiment versus the number of genes in the map within the “full set” of all genes on maps. <u>Z-score</u> ranks the sub-networks of the AN algorithm with regard to their saturation with genes from the experiment.</p><p>Most relevant biological networks identified for common genes.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156048, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t009", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Most_relevant_biological_networks_identified_for_common_genes_/1156048", "title"=>"Most relevant biological networks identified for common genes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655573"], "description"=>"<p>Total gene IDs in the ontology - 90, matches for PPA – 8, for BA – 18.</p><p>Gene ontology annotation analysis: Fatty acid metabolism.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156043, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t007", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_ontology_annotation_analysis_Fatty_acid_metabolism_/1156043", "title"=>"Gene ontology annotation analysis: Fatty acid metabolism.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655558"], "description"=>"<p>PC12 cells were treated with 1 mM PPA, 10 mM PPA, 1 mM BA, 6 mM BA or vehicle for 48 hrs. Total RNA samples were isolated from individual petri dishes (n>6 per experimental group). Northern blot analysis was performed as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103740#s2\" target=\"_blank\">Methods</a> section, using probes specific for rat genes, encoding tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), neuropeptide Y (NPY), Chromogranin A (ChrA), pre-proenkephalin (PENK) and GTP cyclohydrolase (GTPCH). The results are presented as mean ± SEM value relative to the mRNA levels in control, vehicle treated cells. 18S rRNA was used as a house keeping gene for normalization of data.</p><p>Effect of PPA and BA on neurotransmitter related gene expression in PC12 cells.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156028, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_PPA_and_BA_on_neurotransmitter_related_gene_expression_in_PC12_cells_/1156028", "title"=>"Effect of PPA and BA on neurotransmitter related gene expression in PC12 cells.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655534"], "description"=>"<p>PC12 cells were treated with SCFA: propionic acid (PPA, 1 mM), butyric acid (BA, 1 mM) or valproic acid (VPA, 0.1 mM). At indicated times (48 hrs) total RNA or total cell lysates (0, 24, 48 and 72 hrs) were prepared and subjected to Northern (A) or Western blot analyses (B, PPA and BA). The data on <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103740#pone-0103740-g002\" target=\"_blank\">Fig. 2A</a> are presented as mean ± SEM value relative to the mRNA levels in control, vehicle treated cells. 18S rRNA was used as a house keeping gene for normalization of data. *P<0.05 SCFA vs. vehicle treated. For Western blotting (2B) cells were lysed after indicated incubation times and equal amounts of proteins were subjected to analyses using TH-specific antibody as described in Experimental procedures. Membranes were re-probed with β-actin specific antibody as loading control. The autoradiographs were analyzed by densitometry. Values are presented as the ratio of TH to that of beta-actin as fold difference from control, vehicle- treated cells. N = 6–8 independent samples per group, and the experiment was repeated twice with similar results <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103740#pone.0103740-Parab1\" target=\"_blank\">[63]</a>.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156005, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PPA_induces_accumulation_of_TH_mRNA_and_TH_protein_in_vitro_/1156005", "title"=>"PPA induces accumulation of TH mRNA and TH protein in vitro.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655566"], "description"=>"<p>Total gene IDs in the ontology- 106, matches for PPA – 9, for BA - 12.</p><p>Gene ontology annotation analysis: Oxidative stress.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156037, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t005", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_ontology_annotation_analysis_Oxidative_stress_/1156037", "title"=>"Gene ontology annotation analysis: Oxidative stress.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655540"], "description"=>"<p>Total RNA was isolated from PC12 cells following 48 hrs exposures to BA (6 mM), PPA (10 mM) or vehicle and subjected to microarray analysis. Genes that changed two-fold or greater in SCFA-treated groups (*p<0.05) compared to the control (vehicle treated PC12 cells) group were imported into MetaCore GeneGo for comparison analyses. Differentially expressed unique (1599 for BA and 355 for PPA experimental group) and common for both groups genes (1010) were identified. Fisher's exact test p-value was <2.2e-16.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156011, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_gene_expression_profiles_evoked_by_SCFA_in_PC12_cells_/1156011", "title"=>"Differential gene expression profiles evoked by SCFA in PC12 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655580"], "description"=>"<p>SCFA alter the expression of genes implicated in ASD in human and animal studies.</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1156050, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.t010", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SCFA_alter_the_expression_of_genes_implicated_in_ASD_in_human_and_animal_studies_/1156050", "title"=>"SCFA alter the expression of genes implicated in ASD in human and animal studies.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:05:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655525"], "description"=>"<p>Plasmid constructs with wild type (WT) rat TH promoter (−773/+27 bp) driving the expression of luciferase reporter gene or having a G-to A transition mutation in the CRE promoter element (mCRE) were electroporated in PC12 cells pre-treated for one day with increasing concentrations of PPA (0.1 to 10 mM, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103740#pone-0103740-g001\" target=\"_blank\">Fig. 1A</a>)). The same doses of PPA were given immediately after electroporation for additional 24 hours, when changes in reporter gene activity were determined. In the second set of experiments (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103740#pone-0103740-g001\" target=\"_blank\">Figure 1B</a>), PC12 cells were co-transfected with combination of wt TH promoter construct and plasmids expressing wild type or dominant negative CREB mutants (binding-defective K-CREB or phosphorylation-defective 133CREB). To half of the cultures, 10 mM PPA was given 1 day before and immediately after electroporation for additional 24 h (black bars). Controls received vehicle 24 hrs before and immediately after electroporation (open bars). The values shown are means ± SEM from three experiments. The luciferase activities (RLU/s/µg protein) are expressed as fold stimulation relative to control cells co-transfected with the same plasmids but not treated with PPA. *P<0.05 (PPA vs. vehicle treated; **P<0.002 (wt vs. mutant constructs).</p>", "links"=>[], "tags"=>["ba", "autism spectrum disorders", "brain monoaminergic pathways", "host gene expression", "gut microbiome composition", "PC 12 cells", "reporter gene activity", "ASD animal models", "Modulate Gene Expression", "creb", "cell adhesion molecules", "ASD patients", "luciferase reporter gene", "function", "Autism Spectrum Disorders Alterations", "PC 12 cell model", "concentration", "ppa", "th", "scfa", "histone deacetylase inhibitor activity"], "article_id"=>1155999, "categories"=>["Biological Sciences"], "users"=>["Bistra B. Nankova", "Raj Agarwal", "Derrick F. MacFabe", "Edmund F. La Gamma"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0103740.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PPA_activates_the_transcription_of_TH_gene_in_CREB_dependant_manner_/1155999", "title"=>"PPA activates the transcription of TH gene in CREB-dependant manner.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:05:12"}

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Relative Metric

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