TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor
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{"title"=>"TMPyP4, a stabilizer of nucleic acid secondary structure, is a novel acetylcholinesterase inhibitor", "type"=>"journal", "authors"=>[{"first_name"=>"Nana", "last_name"=>"Fujiwara", "scopus_author_id"=>"56526235200"}, {"first_name"=>"Michael", "last_name"=>"Mazzola", "scopus_author_id"=>"56957899600"}, {"first_name"=>"Elizabeth", "last_name"=>"Cai", "scopus_author_id"=>"56526692500"}, {"first_name"=>"Meng", "last_name"=>"Wang", "scopus_author_id"=>"56109243900"}, {"first_name"=>"John W.", "last_name"=>"Cave", "scopus_author_id"=>"7005691924"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"606828454", "doi"=>"10.1371/journal.pone.0139167", "isbn"=>"1932-6203", "pmid"=>"26402367", "issn"=>"19326203", "scopus"=>"2-s2.0-84946949688", "sgr"=>"84946949688"}, "id"=>"7a065116-b8a9-3aa5-bced-be85651d75b2", "abstract"=>"The porphyrin compound, TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine), is widely used as a photosensitizer and a modulator of nucleic acid secondary structure stability. Our group recently showed in cultured cells and forebrain slice cultures that this compound can also down regulate expression of Tyrosine hydroxylase (Th), which encodes the rate-limiting enzyme in catecholamine biosynthesis, by stabilizing DNA secondary structures in the Th proximal promoter. The current study sought to establish whether treatment with TMPyP4 could modify mouse Th expression levels in vivo. Intraperitoneal administration of low TMPyP4 doses (10mg/kg), similar to those used for photosensitization, did not significantly reduce Th transcript levels in several catecholaminergic regions. Administration of a high dose (40 mg/kg), similar to those used for tumor xenograph reduction, unexpectedly induced flaccid paralysis in an age and sex-dependent manner. In vitro analyses revealed that TMPyP4, but not putative metabolites, inhibited Acetylcholinesterase activity and pre-treatment of TMPyP4 with Hemeoxygenase-2 (HO-2) rescued Acetylcholinesterase function. Age-dependent differences in HO-2 expression levels may account for some of the variable in vivo effects of high TMPyP4 doses. Together, these studies indicate that only low doses of TMPyP4, such as those typically used for photosensitization, are well tolerated in vivo. Thus, despite its widespread use in vitro, TMPyP4 is not ideal for modifying neuronal gene expression in vivo by manipulating nucleic acid secondary structure stability, which highlights the need to identify more clinically suitable compounds that can modulate nucleic acid secondary structure and gene expression.", "link"=>"http://www.mendeley.com/research/tmpyp4-stabilizer-nucleic-acid-secondary-structure-novel-acetylcholinesterase-inhibitor", "reader_count"=>7, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Student > Master"=>2}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>1, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Student > Master"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>2, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2287160"], "description"=>"<p>Molecular structures of TMPyP4 and TMPyP2.</p>", "links"=>[], "tags"=>["Novel Acetylcholinesterase Inhibitor", "gene expression", "forebrain slice cultures", "tumor xenograph reduction", "dna", "vivo", "Th transcript levels", "TMPyP 4 doses", "mouse Th expression levels", "ho", "TMPyP 4", "structure stability"], "article_id"=>1555191, "categories"=>["Uncategorised"], "users"=>["Nana Fujiwara", "Michael Mazzola", "Elizabeth Cai", "Meng Wang", "John W. Cave"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139167.g001", "stats"=>{"downloads"=>6, "page_views"=>107, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Molecular_structures_of_TMPyP4_and_TMPyP2_/1555191", "title"=>"Molecular structures of TMPyP4 and TMPyP2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-24 03:00:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2287161"], "description"=>"<p><b>A</b>, transcription assays with SH-SY5Y cells transfected with a reporter under the control of the rat 4.5kb <i>Th</i> promoter that are also treated with either saline, TMPyP2 or TMPyP4. Mean relative promoter activities are shown with error bars representing the standard deviation. ** indicates p<0.001, * indicates p = 0.02 and n.s. indicates not significant. <b>B</b>, <i>Th</i> transcript levels, as measured by quantitative RT-PCR, in the adrenal glands, olfactory bulb and midbrain of adult mice administered either saline, TMPyP2 or TMPyP4 (n = 8 for both male and female). Mean relative transcript levels are shown with error bars representing the standard error of the mean. ** indicates p<0.01, * indicates p = 0.03 and n.s. indicates not significant.</p>", "links"=>[], "tags"=>["Novel Acetylcholinesterase Inhibitor", "gene expression", "forebrain slice cultures", "tumor xenograph reduction", "dna", "vivo", "Th transcript levels", "TMPyP 4 doses", "mouse Th expression levels", "ho", "TMPyP 4", "structure stability"], "article_id"=>1555192, "categories"=>["Uncategorised"], "users"=>["Nana Fujiwara", "Michael Mazzola", "Elizabeth Cai", "Meng Wang", "John W. Cave"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139167.g002", "stats"=>{"downloads"=>3, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vitro_vs_in_vivo_modulation_of_Th_expression_by_TMPyP4_/1555192", "title"=>"<i>In vitro vs</i>. <i>in vivo</i> modulation of <i>Th</i> expression by TMPyP4.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-24 03:00:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2287162"], "description"=>"<p><b>A</b>, oxidation of heme by Hemeoxygenase (HO) enzymes produces biliverdin and carbon monoxide. <b>B</b>, oxidation of TMPyP4 by HO enzymes is expected to generate either 4-formyl-1-methylpyridinium (4F-MP) or 4-carboxy-1-methylpyridinium (4C-MP). Both 4F-MP and 4C-MP have a structural resemblance to acetylcholine. <b>C</b>, fluorometric assay of AChE activity in presence of TMPyP2, TMPyP4, 4F-MP, 4C-MP and an established AChE inhibitor (Donepezil). <b>D</b>, pre-incubation of TMPyP4 with recombinant HO-2 prior rescued AChE activity in a concentration-dependent manner.</p>", "links"=>[], "tags"=>["Novel Acetylcholinesterase Inhibitor", "gene expression", "forebrain slice cultures", "tumor xenograph reduction", "dna", "vivo", "Th transcript levels", "TMPyP 4 doses", "mouse Th expression levels", "ho", "TMPyP 4", "structure stability"], "article_id"=>1555193, "categories"=>["Uncategorised"], "users"=>["Nana Fujiwara", "Michael Mazzola", "Elizabeth Cai", "Meng Wang", "John W. Cave"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139167.g003", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_TMPyP4_inhibits_AChE_activity_/1555193", "title"=>"TMPyP4 inhibits AChE activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-24 03:00:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2287164"], "description"=>"<p><b>A</b>-<b>B</b>, western blots for HO-1/2 and GAPDH in the liver and skeletal muscle, respectively, of young and old adult mice for both sexes. <b>C</b> and <b>E</b>, <b>D</b> and <b>F</b>, average relative western blot band intensities for HO-1/2 in liver and skeletal muscle tissue, respectively. Averages are from 3 independent trials for each age and gender in both liver and muscle tissue.</p>", "links"=>[], "tags"=>["Novel Acetylcholinesterase Inhibitor", "gene expression", "forebrain slice cultures", "tumor xenograph reduction", "dna", "vivo", "Th transcript levels", "TMPyP 4 doses", "mouse Th expression levels", "ho", "TMPyP 4", "structure stability"], "article_id"=>1555195, "categories"=>["Uncategorised"], "users"=>["Nana Fujiwara", "Michael Mazzola", "Elizabeth Cai", "Meng Wang", "John W. Cave"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139167.g004", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Age_and_gender_analysis_of_HO_1_2_expression_levels_in_liver_and_skeletal_muscle_/1555195", "title"=>"Age and gender analysis of HO-1/2 expression levels in liver and skeletal muscle.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-24 03:00:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2287165"], "description"=>"<p><b>A</b> and <b>B</b>, fluorometric AChE activity assays with liver and skeletal muscle tissue lysates, respectively, from young adult mice (aged 1.5–3 months). For both males and females, data points are the combination of four individuals. AChE activities of tissue lysates are reported relative to the activity of an AChE standard supplied with the assay kit.</p>", "links"=>[], "tags"=>["Novel Acetylcholinesterase Inhibitor", "gene expression", "forebrain slice cultures", "tumor xenograph reduction", "dna", "vivo", "Th transcript levels", "TMPyP 4 doses", "mouse Th expression levels", "ho", "TMPyP 4", "structure stability"], "article_id"=>1555196, "categories"=>["Uncategorised"], "users"=>["Nana Fujiwara", "Michael Mazzola", "Elizabeth Cai", "Meng Wang", "John W. Cave"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139167.g005", "stats"=>{"downloads"=>7, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gender_based_analysis_of_AChE_activity_/1555196", "title"=>"Gender-based analysis of AChE activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-09-24 03:00:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/2287166"], "description"=>"<p>Young adult mice were aged between 1.5–3 months, whereas old adults were aged between 6–12 months. Breathing rate, muscle tone, grasping and righting reflexes were qualitatively assessed: ++, normal/unaffected; +, moderately impaired; +/-, severely impaired;-, completely impaired. For each age and gender, n = 5 mice.</p><p>Physiological symptoms observed following a single injection with a high dose (40mg/kg) of either TMPyP2 or TMPyP4.</p>", "links"=>[], "tags"=>["Novel Acetylcholinesterase Inhibitor", "gene expression", "forebrain slice cultures", "tumor xenograph reduction", "dna", "vivo", "Th transcript levels", "TMPyP 4 doses", "mouse Th expression levels", "ho", "TMPyP 4", "structure stability"], "article_id"=>1555197, "categories"=>["Uncategorised"], "users"=>["Nana Fujiwara", "Michael Mazzola", "Elizabeth Cai", "Meng Wang", "John W. Cave"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139167.t001", "stats"=>{"downloads"=>9, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Physiological_symptoms_observed_following_a_single_injection_with_a_high_dose_40mg_kg_of_either_TMPyP2_or_TMPyP4_/1555197", "title"=>"Physiological symptoms observed following a single injection with a high dose (40mg/kg) of either TMPyP2 or TMPyP4.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-09-24 03:00:03"}

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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