P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy
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{"title"=>"P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy", "type"=>"journal", "authors"=>[{"first_name"=>"Anthony", "last_name"=>"Sinadinos", "scopus_author_id"=>"55902538700"}, {"first_name"=>"Christopher N.J.", "last_name"=>"Young", "scopus_author_id"=>"54926994700"}, {"first_name"=>"Rasha", "last_name"=>"Al-Khalidi", "scopus_author_id"=>"56940744900"}, {"first_name"=>"Anna", "last_name"=>"Teti", "scopus_author_id"=>"7005130690"}, {"first_name"=>"Paweł", "last_name"=>"Kalinski", "scopus_author_id"=>"7004043968"}, {"first_name"=>"Shafini", "last_name"=>"Mohamad", "scopus_author_id"=>"56940248700"}, {"first_name"=>"Léonore", "last_name"=>"Floriot", "scopus_author_id"=>"56095033500"}, {"first_name"=>"Tiphaine", "last_name"=>"Henry", "scopus_author_id"=>"56095375600"}, {"first_name"=>"Gianluca", "last_name"=>"Tozzi", "scopus_author_id"=>"35756997900"}, {"first_name"=>"Taiwen", "last_name"=>"Jiang", "scopus_author_id"=>"36488037900"}, {"first_name"=>"Olivier", "last_name"=>"Wurtz", "scopus_author_id"=>"6506682396"}, {"first_name"=>"Alexis", "last_name"=>"Lefebvre", "scopus_author_id"=>"56526353700"}, {"first_name"=>"Mikhail", "last_name"=>"Shugay", "scopus_author_id"=>"50861832900"}, {"first_name"=>"Jie", "last_name"=>"Tong", "scopus_author_id"=>"7202724363"}, {"first_name"=>"David", "last_name"=>"Vaudry", "scopus_author_id"=>"6603869843"}, {"first_name"=>"Stephen", "last_name"=>"Arkle", "scopus_author_id"=>"6602924881"}, {"first_name"=>"Jean Claude", "last_name"=>"doRego", "scopus_author_id"=>"56940918900"}, {"first_name"=>"Dariusz C.", "last_name"=>"Górecki", "scopus_author_id"=>"19635041600"}], "year"=>2015, "source"=>"PLoS Medicine", "identifiers"=>{"sgr"=>"84946022511", "doi"=>"10.1371/journal.pmed.1001888", "pui"=>"606752727", "pmid"=>"26461208", "scopus"=>"2-s2.0-84946022511", "issn"=>"15491676", "isbn"=>"1549-1277"}, "id"=>"32d8a531-dddc-31a1-931b-b3b4dd60ebfc", "abstract"=>"BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP-P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target.\\n\\nMETHODS AND FINDINGS: Using a combination of molecular, histological, and biochemical methods and behavioral analyses in vivo we demonstrate, to our knowledge for the first time, that genetic ablation of P2RX7 in the DMD model mouse produces a widespread functional attenuation of both muscle and non-muscle symptoms. In dystrophic muscles at 4 wk there was an evident recovery in key functional and molecular parameters such as improved muscle structure (minimum Feret diameter, p < 0.001), increased muscle strength in vitro (p < 0.001) and in vivo (p = 0.012), and pro-fibrotic molecular signatures. Serum creatine kinase (CK) levels were lower (p = 0.025), and reduced cognitive impairment (p = 0.006) and bone structure alterations (p < 0.001) were also apparent. Reduction of inflammation and fibrosis persisted at 20 mo in leg (p = 0.038), diaphragm (p = 0.042), and heart muscles (p < 0.001). We show that the amelioration of symptoms was proportional to the extent of receptor depletion and that improvements were observed following administration of two P2RX7 antagonists (CK, p = 0.030 and p = 0.050) without any detectable side effects. However, approaches successful in animal models still need to be proved effective in clinical practice.\\n\\nCONCLUSIONS: These results are, to our knowledge, the first to establish that a single treatment can improve muscle function both short and long term and also correct cognitive impairment and bone loss in DMD model mice. The wide-ranging improvements reflect the convergence of P2RX7 ablation on multiple disease mechanisms affecting skeletal and cardiac muscles, inflammatory cells, brain, and bone. Given the impact of P2RX7 blockade in the DMD mouse model, this receptor is an attractive target for translational research: existing drugs with established safety records could potentially be repurposed for treatment of this lethal disease.", "link"=>"http://www.mendeley.com/research/p2rx7-purinoceptor-therapeutic-target-ameliorating-symptoms-duchenne-muscular-dystrophy", "reader_count"=>48, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>8, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>2, "Other"=>1, "Student > Master"=>4, "Student > Bachelor"=>13, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>8, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>2, "Other"=>1, "Student > Master"=>4, "Student > Bachelor"=>13, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>8, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>9, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Physics and Astronomy"=>1, "Chemistry"=>2, "Psychology"=>2, "Social Sciences"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"France"=>1, "Germany"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2357401"], "description"=>"<p>Forelimb grip strength (A) and voluntary wheel run distance (B) were significantly greater in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> mice (grip strength ANOVA, <i>F</i> = 22.99, df = 2, <i>n</i> = 9, 9, 10, <i>p <</i> 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.0118; run distance ANOVA, <i>F</i> = 12.73, df = 2, <i>n</i> = 9, 9, 10, <i>p <</i> 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.016). The rotarod test (C) showed no difference for total average run time and average speed (run time ANOVA, <i>F</i> = 1.23, df = 2, <i>n</i> = 9, 9, 10, <i>p</i> = 0.310; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.300; speed ANOVA, <i>F</i> = 2.23, df = 2, <i>n</i> = 9, 9, 10, <i>p</i> = 0.129; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.109), and the parallel rod floor test (D) showed no significant differences in the average number of activations over several run time-spans between WT, <i>mdx</i>, and Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice (ANOVA, <i>F</i> = 2.6, 0.62, 1.34; df = 2; <i>n</i> = 9, 9, 10; <i>p</i> = 0.094, 0.545, 0.212; at 0–5, 5–10, and 0–10 min, respectively). In the object recognition test (E) there was no significant difference between genotypes at 10-min retention delay, but at 24 h and 48 h, both duration and contact discrimination were significantly different from the 50% chance level for the Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice, but not for <i>mdx</i> mice. Memory retention in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice was equal to that in WT mice, while <i>mdx</i> mice performed at a lower level than WT (contact discrimination 10 min, 24 h, 48 h ANOVA; <i>F</i> = 0.08, 7.37, 6.83; df = 2; <i>n</i> = 10, 9, 10; <i>p</i> = 0.922, 0.003, 0.004; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.984, 0.004, 0.006; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus WT, <i>p</i> = 0.970, 0.908, 0.890; <i>mdx</i> versus WT, <i>p</i> = 0.916, 0.012, 0.017; duration discrimination 10 min, 24 h, 48 h ANOVA; <i>F</i> = 0.09, 16.17, 5.1; df = 2; <i>n</i> = 10, 9, 10; <i>p</i> = 0.913, < 0.001, = 0.013; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.905, < 0.001, = 0.031; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus WT, <i>p</i> = 0.969, 0.994, 0.985; <i>mdx</i> versus WT, <i>p</i> = 0.980, < 0.001, = 0.021,). (F) In the elevated zero maze anxiety test, both the duration and the distance travelled by Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice within the open arm of the maze were greater than those of <i>mdx</i> mice, and <i>mdx</i> mice performed at a lower level than WT (distance and duration ANOVA, <i>F</i> = 10.51, 11.76; df = 2; <i>n</i> = 10, 9, 10; <i>p <</i> 0.001, < 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.045, 0.047; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus WT, <i>p</i> = 0.109, 0.060; <i>mdx</i> versus WT, <i>p</i> < 0.001, < 0.001). In the closed arm (F, bottom), there was no difference in distance travelled, but Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice spent less time in this arm than <i>mdx</i> mice, and <i>mdx</i> mice more time than WT (distance and duration ANOVA, <i>F</i> = 1.42, 11.76; df = 2; <i>n</i> = 10, 9, 10; <i>p</i> = 0.259, < 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.687, 0.047; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus WT, <i>p</i> = 0.659, 0.060; <i>mdx</i> versus WT, <i>p</i> = 0.230, < 0.001). *<i>p <</i> 0.05, **<i>p <</i> 0.005, ***<i>p <</i> 0.001.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573549, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g010", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_improves_mdx_muscle_strength_and_endurance_and_object_recognition_memory_and_decreases_anxiety_in_vivo_/1573549", "title"=>"<i>P2RX7</i> ablation improves <i>mdx</i> muscle strength and endurance and object recognition memory and decreases anxiety in vivo.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357394"], "description"=>"<p>(A) Representative Western blots (left) confirming P2RX7 protein expression in 20-mo-old TA and illustrating decreased autophagy (LC3I to LC3II shift), with the results in the graph showing lower levels of LC3II relative to GAPDH in TA from 20-mo-old Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> mice (<i>t</i>-test, <i>t</i> = 3.74, df = 10, <i>p</i> = 0.004). Total protein staining is shown to illustrate the equal protein loading. (B) Representative ImageJ output masks from morphometric analyses of TA fibers (left) and graphs showing representative results (right and bottom). While no differences were found in the proportion of C/N fibers or the average minimum Feret diameter of total or C/N fibers (<i>t</i>-test, <i>t</i> = 0.57, df = 8, <i>p</i> = 0.586; <i>t</i> = 2.04, df = 8, <i>p</i> = 0.076; <i>t</i> = 1.25, df = 8, <i>p</i> = 0.248, respectively), there was a significant increase in the minimum Feret diameter of non-C/N fibers in <i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> muscles (<i>t</i>-test, <i>t</i> = 2.58, df = 8, <i>p</i> = 0.032). *<i>p <</i> 0.05, **<i>p <</i> 0.005.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573543, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g008", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_reduces_the_pathology_in_20_mo_old_tibialis_anterior_muscles_/1573543", "title"=>"<i>P2RX7</i> ablation reduces the pathology in 20-mo-old tibialis anterior muscles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357393"], "description"=>"<p>(A) Representative immunofluorescence micrographs (left) and enumeration of CD11b-expressing cells in 20-mo-old TA showing no significant difference in the numbers of infiltrating leukocytes in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> muscles (<i>t</i>-test, <i>t</i> = 1.82, df = 8, <i>p</i> = 0.107). (B) qPCR gene expression analyses: relative expression levels (2<sup>−ΔΔCT</sup>) in muscle-derived mRNAs from <i>mdx</i> and <i>mdx</i>/P2X7<sup>−/−</sup> TA demonstrate significant decreases in P2RX4 (<i>t</i>-test, <i>t</i> = 4.04, df = 17, <i>p</i> = 0.001) and TNFα (<i>t</i>-test, <i>t</i> = 3.07, df = 18, <i>p</i> = 0.006), with concomitant increases in expression levels of IL12α (<i>t</i>-test, <i>t</i> = 2.56, df = 18, <i>p</i> = 0.020) and Foxp3 (<i>t</i>-test, <i>t</i> = 6.8, df = 17, <i>p <</i> 0.001) in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> muscles. (C) Representative images of trichrome staining (left) and trichrome average intensities in 20-mo-old TA muscles demonstrating a significant decrease in fibrosis in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> mice (ANOVA, <i>F</i> = 6.18, df = 2, <i>n</i> = 3, 5, 4, <i>p</i> = 0.020; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.038). *<i>p <</i> 0.05, **<i>p <</i> 0.005, ***<i>p <</i> 0.001.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573542, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g007", "stats"=>{"downloads"=>4, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_reduces_inflammation_and_fibrosis_in_20_mo_old_tibialis_anterior_muscles_/1573542", "title"=>"<i>P2RX7</i> ablation reduces inflammation and fibrosis in 20-mo-old tibialis anterior muscles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357415"], "description"=>"<p>Absence of dystrophin and resulting loss of the DAP complex lead to myofiber damage. Degenerating/dying muscle releases large quantities of DAMPs, including ATP, which trigger chronic inflammation. P2RX7 activation on dystrophic myofibers exacerbates injury by promoting intracellular Ca<sup>2+</sup> build-up and autophagic cell death. Infiltrating macrophages (Mφ), T-cells, and granulocytes (GrC) cause further myofiber damage, while chronically elevated levels of inflammatory mediators disturb normal brain and bone functions. Chronic inflammation also reduces repair by altering satellite cell (SC) activation and muscle precursor cell differentiation, while high eATP levels combined with P2RX7 overexpression contribute to their death and thus reduce muscle regeneration further still.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573556, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g013", "stats"=>{"downloads"=>2, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2X7_purinoceptor_involvement_in_the_dystrophic_pathology_/1573556", "title"=>"P2X7 purinoceptor involvement in the dystrophic pathology.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357404"], "description"=>"<p>(A) Representative μ-CT images of distal femurs from 6-mo-old mice. (B) μ-CT morphometry in 4-wk-old proximal tibiae and 6-mo-old femurs. As early as age 4 wk, the BV/TV ratio in <i>mdx</i> mice was reduced, and it remained altered at 6 mo. But P2RX7 ablation significantly improved BV/TV and Tb.Sp parameters in older <i>mdx</i>/P2X7<sup>−/−</sup> mice compared to older <i>mdx</i> mice (4-wk BV/TV ANOVA, <i>F</i> = 4.29, df = 2, <i>n</i> = 6, <i>p</i> = 0.034; Tukey’s test, <i>mdx</i> versus WT, <i>p</i> = 0.029; 6-mo BV/TV ANOVA, <i>F</i> = 7.29, df = 2, <i>n</i> = 4, <i>p</i> = 0.013; Tukey’s test, <i>mdx</i> versus WT, <i>p</i> = 0.014; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.046; 6-mo Tb.Sp ANOVA, <i>F</i> = 48.69, df = 2, <i>n</i> = 4, <i>p <</i> 0.001; Tukey’s test, <i>mdx</i> versus WT, <i>p</i> = 0.008; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p <</i> 0.001.). *<i>p <</i> 0.05, ***<i>p <</i> 0.001.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573553, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g011", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_reduces_mdx_bone_loss_/1573553", "title"=>"<i>P2RX7</i> ablation reduces <i>mdx</i> bone loss.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357384"], "description"=>"<p>(A) Immunofluorescence co-localization of CD68 macrophage marker with P2RX7. To confirm spatial co-localization, side and bottom panels show overlapping <i>z</i>-plane images. (B) M2 macrophage marker (CD163) co-localization with a subset of CD68-positive cells within the inflammatory infiltrate regions in <i>mdx</i> muscle. Blue signal identifies cell nuclei. (C) F4/80 macrophage marker levels shown as normalized average Western blot values (left) and F4/80 relative to CD163 (right). Significantly less F4/80 was found in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> and G-<i>mdx</i>/P2X7<sup>−/−</sup> muscles compared to <i>mdx</i> muscles (Kruskal-Wallis H test, <i>H</i> = 7.73, df = 2, <i>n</i> = 4, <i>p</i> = 0.021; Mann-Whitney U test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>W</i> = 26.0, <i>n</i> = 4, <i>p</i> = 0.030; G-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>W</i> = 26.0, <i>n</i> = 4, <i>p</i> = 0.030), while the ratio of F4/80 level to CD163 level, denoting M1/M2 macrophage ratio, was significantly reduced in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> muscles (Kruskal-Wallis H test, <i>H</i> = 8.77, df = 2, <i>n</i> = 4, <i>p</i> = 0.012; Mann-Whitney U test, <i>W</i> = 26.0, <i>n</i> = 4, <i>p</i> = 0.030). (D) A representative Western blot (top) illustrating decreased P2RX4 protein levels, and corresponding qPCR data (bottom) showing decreased expression of P2RX4 mRNA in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> gastrocnemius compared to <i>mdx</i> gastrocnemius (ANOVA, <i>F</i> = 25.96, df = 2, <i>n</i> = 5, <i>p <</i> 0.001; Tukey’s test, <i>mdx</i> versus C57, <i>p <</i> 0.001; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.017; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus WT, <i>p</i> = 0.005). *<i>p <</i> 0.05, ***<i>p <</i> 0.001. Use of separate Western blots is indicated by solid black lines.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573533, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g004", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_in_mdx_mice_reduces_macrophage_infiltration_/1573533", "title"=>"<i>P2RX7</i> ablation in <i>mdx</i> mice reduces macrophage infiltration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357398"], "description"=>"<p>(A) Representative immunofluorescence micrographs (left) and enumeration of CD11b- and CD68-expressing cells in 20-mo-old diaphragms showing reduced numbers of infiltrating leukocytes (CD11b <i>t-</i>test, <i>t</i> = 3.68, df = 6, <i>p</i> = 0.015) and macrophages (CD68<sup>+</sup><i>t</i>-test, <i>t</i> = 4.73, df = 4, <i>p</i> = 0.009) in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> diaphragms. (B) Trichrome staining (left) and its average intensity in 20-mo-old diaphragms demonstrating no increase in fibrosis in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> over <i>mdx</i> mice (ANOVA, <i>F</i> = 60.32, df = 2, <i>n</i> = 5, 5, 3, <i>p <</i> 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.095; permutation analysis, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>F</i> = 4.47, <i>p</i> = 0.095). (C) Representative ImageJ output masks from morphometric analyses of diaphragm fibers (left) demonstrating the increased average minimum Feret diameter in <i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> diaphragms (ANOVA, <i>F</i> = 75.17, df = 2, <i>n</i> = 3, <i>p <</i> 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.006; permutation analysis, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>F</i> = 20.01, <i>p</i> = 0.099). (D) Graphs showing a lower total number of diaphragm fibers per unit area in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i> mice (left; ANOVA, <i>F</i> = 52.77, df = 2, <i>n</i> = 3, <i>p <</i> 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.001; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus WT, <i>p</i> = 0.051) and the increased proportion of C/N fibers (right; <i>t-</i>test, <i>t</i> = 5, df = 4, <i>p</i> = 0.008). (E) Dystrophin immunofluorescence in representative transverse sections of 20-mo-old diaphragms showing the typical staining (green signal) in dystrophin-positive muscles and clusters of revertant dystrophin-positive fibers in dystrophic samples. The data show significantly fewer revertant fibers in 20-mo-old Pf-<i>mdx</i>/P2X7<sup>−/−</sup> than in <i>mdx</i> diaphragms (<i>t-</i>test, <i>t</i> = 5.12, df = 4, <i>p</i> = 0.007). (F) Representative trichrome staining (left) of whole hearts from 20-mo-old mice showing a significant decrease in cardiac muscle damage (histological lesions) and average area of fibrosis (blue signal in trichrome staining) in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i> mice (ANOVA, <i>F</i> = 166.29, df = 2, <i>n</i> = 4, 3, 3, <i>p <</i> 0.001; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p <</i> 0.001). (G) Representative examples of CD11b<sup>+</sup> leukocyte marker staining (left; red immunofluorescence) and infiltrating cell counts demonstrating fewer infiltrations in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> hearts (ANOVA, <i>F</i> = 19.65, df = 2, <i>n</i> = 3, <i>p</i> = 0.002; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.005). *<i>p <</i> 0.05, **<i>p <</i> 0.005, ***<i>p <</i> 0.001.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573547, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g009", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_continues_to_reduce_dystrophic_pathology_in_20_mo_old_diaphragm_and_heart_/1573547", "title"=>"<i>P2RX7</i> ablation continues to reduce dystrophic pathology in 20-mo-old diaphragm and heart.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357378"], "description"=>"<p>(A) Autophagy induction (LC3I to LC3II shift in representative Western blots) found in <i>mdx</i> muscles is blocked in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> muscles, with average values shown in (B) (ANOVA, <i>F</i> = 11.57, df = 2, <i>n</i> = 4, <i>p</i> = 0.003; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.008). Note: use of separate Western blots is indicated by solid black lines. (C) Greater average diaphragm isometric tetanic forces at 4 mo in both Pf-<i>mdx</i>/P2X7<sup>−/−</sup> and G-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> mice (ANOVA, <i>F</i> = 37.97, df = 2, <i>n</i> = 4, 4, 5, <i>p <</i> 0.001; Tukey’s test, G-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.010; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p <</i> 0.001). *<i>p <</i> 0.05, ***<i>p <</i> 0.001.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573527, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_improves_mdx_mouse_muscles_/1573527", "title"=>"<i>P2RX7</i> ablation improves <i>mdx</i> mouse muscles.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357377"], "description"=>"<p>The color-coding legend applies to all graphs in the figure. (A) Collagen type-IV (green) and nuclei (blue) immunofluorescence with an accompanying frequency histogram (B) of the minimum Feret diameter of C/N fibers from 4-wk-old <i>mdx</i> and Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice showing the right shift in TA muscle fiber size corresponding with the greater average Feret diameter of Pf-<i>mdx</i>/P2X7<sup>−/−</sup> fibers (<i>t</i>-test, <i>t</i> = 6.99, df = 6, <i>p</i> < 0.001). (C) Elevated myogenin levels (average Western blot values) in both Pf-<i>mdx</i>/P2X7<sup>−/−</sup> and G-<i>mdx</i>/P2X7<sup>−/−</sup> muscle (ANOVA, <i>F</i> = 33.38, df = 2, <i>n</i> = 4, 3, 4, <i>p <</i> 0.001; Tukey’s test, G-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> < 0.001; G-<i>mdx</i>/P2X7<sup>−/−</sup> versus Pf-<i>mdx</i>/P2X7<sup>−/−</sup>, <i>p</i> = 0.516; Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> < 0.001) and (D) significantly lower average serum CK levels in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> muscle (Mann-Whitney U test, <i>W</i> = 388, <i>n</i> = 18, 16, <i>p</i> = 0.012; permutation analysis, <i>F</i> = 7.07, <i>p</i> = 0.013; log<sub>10</sub> serum CK ANOVA, <i>F</i> = 3.76, df = 2, <i>n</i> = 19, 18, 16, <i>p</i> = 0.030; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.025). (E) Example immunofluorescence micrographs of IgG penetration into muscle fibers and (F) chart showing reduced average IgG influx into Pf-<i>mdx</i>/P2X7<sup>−/−</sup> muscle (ANOVA, <i>F</i> = 5.52, df = 2, <i>n</i> = 3, 5, 3, <i>p</i> = 0.031; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.032). *<i>p <</i> 0.05, ***<i>p <</i> 0.001.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573526, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_reduces_mdx_mouse_muscle_pathology_/1573526", "title"=>"P2RX7 ablation reduces <i>mdx</i> mouse muscle pathology.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357374"], "description"=>"<p>(A) Schematics of mouse breeding. (B) Representative Western blots showing increased expression of P2RX7 in 4-wk-old <i>mdx</i> compared to wild-type (WT) gastrocnemius and its absence in <i>mdx</i>/P2X7<sup>−/−</sup>. Use of separate Western blots is indicated by solid black lines. (C) Micrographs of P2RX7 immunofluorescence localization (green signal) in 4-wk-old tibialis anterior (TA) muscle from WT, <i>mdx</i>, and Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice showing expression in areas rich with infiltrating cells, and negative control using no primary antibody and with a blue signal denoting nuclear counterstaining.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573523, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g001", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_and_characterization_of_mdx_P2X7_8722_8722_mice_/1573523", "title"=>"Generation and characterization of <i>mdx</i>/P2X7<sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357392"], "description"=>"<p>Fragments per kilobase per million fragments mapped (FPKM) values for each sample were obtained using Cuffnorm (Tuxedo suite), log-transformed, and normalized to zero mean and unit standard deviation (rows with missing expression values were removed). Hierarchical clustering was performed using the Ward’s method [<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001888#pmed.1001888.ref042\" target=\"_blank\">42</a>]. KO, knockout.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573540, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g006", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_genes_associated_with_fibrosis_as_measured_by_RNA_Seq_/1573540", "title"=>"Expression of genes associated with fibrosis as measured by RNA-Seq.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357417", "https://ndownloader.figshare.com/files/2357418", "https://ndownloader.figshare.com/files/2357419", "https://ndownloader.figshare.com/files/2357420", "https://ndownloader.figshare.com/files/2357421", "https://ndownloader.figshare.com/files/2357422", "https://ndownloader.figshare.com/files/2357423", "https://ndownloader.figshare.com/files/2357424", "https://ndownloader.figshare.com/files/2357425", "https://ndownloader.figshare.com/files/2357426", "https://ndownloader.figshare.com/files/2357427", "https://ndownloader.figshare.com/files/2357428", "https://ndownloader.figshare.com/files/2357429"], "description"=>"<div><p>Background</p><p>Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density.</p><p>Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the <i>mdx</i> mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP–P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of <i>P2RX7</i> attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target.</p><p>Methods and Findings</p><p>Using a combination of molecular, histological, and biochemical methods and behavioral analyses in vivo we demonstrate, to our knowledge for the first time, that genetic ablation of <i>P2RX7</i> in the DMD model mouse produces a widespread functional attenuation of both muscle and non-muscle symptoms. In dystrophic muscles at 4 wk there was an evident recovery in key functional and molecular parameters such as improved muscle structure (minimum Feret diameter, <i>p <</i> 0.001), increased muscle strength in vitro (<i>p</i> < 0.001) and in vivo (<i>p</i> = 0.012), and pro-fibrotic molecular signatures. Serum creatine kinase (CK) levels were lower (<i>p</i> = 0.025), and reduced cognitive impairment (<i>p</i> = 0.006) and bone structure alterations (<i>p <</i> 0.001) were also apparent. Reduction of inflammation and fibrosis persisted at 20 mo in leg (<i>p</i> = 0.038), diaphragm (<i>p</i> = 0.042), and heart muscles (<i>p <</i> 0.001). We show that the amelioration of symptoms was proportional to the extent of receptor depletion and that improvements were observed following administration of two P2RX7 antagonists (CK, <i>p</i> = 0.030 and <i>p</i> = 0.050) without any detectable side effects. However, approaches successful in animal models still need to be proved effective in clinical practice.</p><p>Conclusions</p><p>These results are, to our knowledge, the first to establish that a single treatment can improve muscle function both short and long term and also correct cognitive impairment and bone loss in DMD model mice. The wide-ranging improvements reflect the convergence of P2RX7 ablation on multiple disease mechanisms affecting skeletal and cardiac muscles, inflammatory cells, brain, and bone. Given the impact of P2RX7 blockade in the DMD mouse model, this receptor is an attractive target for translational research: existing drugs with established safety records could potentially be repurposed for treatment of this lethal disease.</p></div>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573558, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>["https://dx.doi.org/10.1371/journal.pmed.1001888.s001", "https://dx.doi.org/10.1371/journal.pmed.1001888.s002", "https://dx.doi.org/10.1371/journal.pmed.1001888.s003", "https://dx.doi.org/10.1371/journal.pmed.1001888.s004", "https://dx.doi.org/10.1371/journal.pmed.1001888.s005", "https://dx.doi.org/10.1371/journal.pmed.1001888.s006", "https://dx.doi.org/10.1371/journal.pmed.1001888.s007", "https://dx.doi.org/10.1371/journal.pmed.1001888.s008", "https://dx.doi.org/10.1371/journal.pmed.1001888.s009", "https://dx.doi.org/10.1371/journal.pmed.1001888.s010", "https://dx.doi.org/10.1371/journal.pmed.1001888.s011", "https://dx.doi.org/10.1371/journal.pmed.1001888.s012", "https://dx.doi.org/10.1371/journal.pmed.1001888.s013"], "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_Purinoceptor_A_Therapeutic_Target_for_Ameliorating_the_Symptoms_of_Duchenne_Muscular_Dystrophy_/1573558", "title"=>"P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357405"], "description"=>"<p>(A) Comparison of serum CK levels in <i>mdx</i> mice (control) and <i>mdx</i> mice injected with the P2RX7 antagonist CBB. Note the high variability of CK levels in the dystrophic sera. Daily administration of CBB over the 4-wk period reduced CK levels (<i>t-</i>test, <i>t</i> = 2.3, df = 26, <i>p</i> = 0.030), in line with the effects of P2RX7 ablation in 4-wk-old Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice. (B) Representative Western blots (left) and average value plots (right) demonstrating significantly decreased levels of the CD11b leukocyte marker in gastrocnemius muscles of <i>mdx</i> mice injected with ox-ATP compared to <i>mdx</i> saline-injected controls (<i>t-</i>test, <i>t</i> = 2.84, df = 4, <i>p</i> = 0.047). Use of separate Western blots is indicated by solid black lines. (C) Comparisons of serum CK levels (left) and F4/80<sup>+</sup> macrophage loads in <i>mdx</i> mice showing significant decreases (CK <i>t-</i>test, <i>t</i> = 2.26, df = 9, <i>p</i> = 0.050; F4/80 <i>t-</i>test, <i>t</i> = 4.34, df = 4, <i>n</i> = 3, <i>p</i> = 0.012) following 14 daily administrations of the competitive P2RX7 antagonist A-438079. *<i>p <</i> 0.05.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573554, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g012", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Short_term_P2RX7_antagonist_administration_reduces_severity_of_muscle_pathology_/1573554", "title"=>"Short-term P2RX7 antagonist administration reduces severity of muscle pathology.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/2357386"], "description"=>"<p>(A) Enumeration of CD4- and CD8-positive cells in TA muscle from <i>mdx</i> and Pf-<i>mdx</i>/P2X7<sup>−/−</sup> mice showed no statistical difference in these cell numbers between the two genotypes (CD4 <i>t</i>-test, <i>t</i> = 0.97, df = 7, <i>p</i> = 0.366; CD8 <i>t</i>-test, <i>t</i> = 0.95, df = 8, <i>p</i> = 0.372). This finding corresponded with CD4 and CD8 qPCR data (<a href=\"http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001888#pmed.1001888.s012\" target=\"_blank\">S1 Table</a>). (B) Selected results of qPCR gene expression analyses using inflammatory panels: relative expression levels (2<sup>−ΔΔCT</sup>) in muscle-derived mRNAs from <i>mdx</i> and <i>mdx</i>/P2X7<sup>−/−</sup> mice demonstrate significant differences in expression levels of Foxp3 (Kruskal-Wallis H test, <i>H</i> = 10.26, df = 2, <i>n</i> = 5, <i>p</i> = 0.006; Mann-Whitney U test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>W</i> = 16.0, <i>n</i> = 5, <i>p</i> = 0.022), IL12α (Kruskal-Wallis H test, <i>H</i> = 11.08, df = 2, <i>n</i> = 9, 10, 10, <i>p</i> = 0.004; Mann-Whitney U test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>W</i> = 61.0, <i>n</i> = 10, <i>p</i> = 0.001), TNFα (<i>t</i>-test, <i>t</i> = 2.86, df = 6, <i>p</i> = 0.029), and Ly6G (ANOVA, <i>F</i> = 14.68, df = 2, <i>n</i> = 3, 4, 4, <i>p</i> = 0.002; Tukey’s test, Pf-<i>mdx</i>/P2X7<sup>−/−</sup> versus <i>mdx</i>, <i>p</i> = 0.002) transcripts in <i>mdx</i>/P2X7<sup>−/−</sup> mice compared to <i>mdx</i>. Lower expression of <i>Ly6G</i> mRNA corresponded with a lower number of Ly6G immunopositive neutrophils (red signal in Ly6G immunolocalization micrograph) (C) and significantly lower Ly6G protein levels (D) in Pf-<i>mdx</i>/P2X7<sup>−/−</sup> compared to <i>mdx</i> muscles (<i>t</i>-test, <i>t</i> = 4.14, df = 6, <i>p</i> = 0.006). Blue signal—Hoechst nuclear counterstaining. *<i>p <</i> 0.05, **<i>p <</i> 0.005.</p>", "links"=>[], "tags"=>["bone density.Current interventions", "dystrophic muscles", "Serum creatine kinase", "bone loss", "DMD model mouse", "P 2RX ablation", "Animal models", "P 2RX", "DMD model mice", "DMD lymphoblasts", "side effects", "P 2RX antagonists", "DMD mouse model", "Feret diameter", "receptor depletion", "heart muscles", "bone structure alterations", "practice.ConclusionsThese results", "P 2RX attenuates", "receptor suitability", "translational research", "DMD mutations", "DMD model mouse phenotype", "atp", "mdx mouse model", "Duchenne Muscular Dystrophy BackgroundDuchenne", "P 2RX blockade", "DMD product", "striated muscles", "disease mechanisms", "P 2RX Purinoceptor", "safety records", "DMD pathology", "muscle structure", "Therapeutic Target", "ck", "muscle strength", "Pleiotropic Effects", "muscle disease", "4 wk", "20 mo", "Muscle Function"], "article_id"=>1573535, "categories"=>["Uncategorised"], "users"=>["Anthony Sinadinos", "Christopher N. J. Young", "Rasha Al-Khalidi", "Anna Teti", "Paweł Kalinski", "Shafini Mohamad", "Léonore Floriot", "Tiphaine Henry", "Gianluca Tozzi", "Taiwen Jiang", "Olivier Wurtz", "Alexis Lefebvre", "Mikhail Shugay", "Jie Tong", "David Vaudry", "Stephen Arkle", "Jean-Claude doRego", "Dariusz C. Górecki"], "doi"=>"https://dx.doi.org/10.1371/journal.pmed.1001888.g005", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P2RX7_ablation_in_mdx_mice_reduces_the_inflammatory_signature_/1573535", "title"=>"<i>P2RX7</i> ablation in <i>mdx</i> mice reduces the inflammatory signature.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-13 03:08:09"}

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

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