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tisdag 19 mars 2019

Pyriofosfaatti PPi

uutiset Tiede

Harvinainen parantumaton sairaus tukki Markku Laitisen valtimot ja vei näön – lääkärin nerokkaan oivalluksen ansiosta tautiin kehitetään nyt lääkettä

Markku Laitisen sairastama PXE-sairaus on diagnosoitu Suomessa vain 28 ihmisellä. Tähän ihoon, silmiin ja verisuoniin vaikuttavaan salakavalasti etenevään sairauteen ei ole olemassa hoitoa. Kunnes Tampereella Taysissa työskentelevä lääkäri Pasi Nevalainen keksi, että sairautta voidaan hoitaa elintarvikkeissa lisäaineena käytettävällä pyrofosfaatilla.

 http://www.socialstyrelsen.se/rarediseases/pseudoxanthomaelasticum#anchor_3

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022264/

Tässä on tärkeä karta PXE asiasta. 

Muistiin 19.3. 2019 

söndag 24 februari 2019

PI(4)P-5-kinaasi tuottaa PI(4,5)P2 lipidiä antiangiogeenisessa signalointitiessä

http://www.jbc.org/content/286/39/34335.short?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Journal_of_Biological_Chemistry_TrendMD_0

Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein*

     Current Issue Papers in Press Editors' Picks JBC
    Reviews Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein*
    Atsuko Sakurai‡,1, Xiaoying Jian§, Charity J. Lee‡, Yosif Manavski¶, Emmanouil Chavakis¶‖,2, Julie Donaldson**, Paul A. Randazzo§ and J. Silvio Gutkind‡,3 From the ‡Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, ¶Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany, ‖III. Department of Internal Medicine, Cardiology, Goethe University Frankfurt, Germany, and the **Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892 ↵3 To whom correspondence should be addressed: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Dr., Rm. 211, Bethesda, MD 20892. Tel.: 301-496-3695; Fax: 301-402-0823; E-mail: sg39v{at}nih.gov.

     Abstract The semaphorins are a family of secreted or membrane-bound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells.

    Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADP-ribosylation factor 6), which regulates intracellular trafficking of β1 integrin.

    However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells.

    We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrin-mediated focal adhesions and endothelial cell collapse.

     Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix (ECM) and migration.



    3-luokan semaforiinit
     http://www.jbc.org/content/289/26/17971.long?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Journal_of_Biological_Chemistry_TrendMD_0

    Background: Class 3 semaphorins are guidance molecules for endothelial cells.
    Results: In multiple endothelial cell assays, semaphorin 3d requires neuropilin 1 or PI3K/Akt but not plexin D1, whereas semaphorin 3e requires plexin D1 but not neuropilin 1 or PI3K/Akt.
    Conclusion: Semaphorin 3d and 3e utilize different pathways to mediate similar effects in endothelial cells.
    Significance: Related guidance molecules utilize distinct mechanisms to repel endothelial cells.

    fredag 11 januari 2019

    Mikä geenitausta on hyperfosfatemisen tumoraalin kalsinoosin takana?

    1.  hakusana Hyperphosphataemic tumoral calcinosis
    2. Ilmenee geeni GLNT3 mutaatioita   Katon lopuksi GALNT3 geenin ihmisellä

    2007

    2006 Nov;91(11):4472-5. Epub 2006 Aug 29.
    Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene.

    2009

    2009 Jun;150(6):2543-50. doi: 10.1210/en.2008-0877. Epub 2009 Feb 12.
    Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression.

     2011

    https://www.ncbi.nlm.nih.gov/pubmed/22009723/
    2011 Dec;152(12):4504-13. doi: 10.1210/en.2011-1137. Epub 2011 Oct 18.
    Dietary phosphate restriction normalizes biochemical and skeletal abnormalities in a murine model of tumoral calcinosis.
     
    2014 
     

    2014 Sep 24;15:98. doi: 10.1186/s12863-014-0098-3.
    Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature.
     
     2015 

    2015 Apr;13(2):78-87. doi: 10.1007/s11914-015-0254-3.
    Hyperphosphatemic familial tumoral calcinosis: genetic models of deficient FGF23 action.
     
     2016

     https://www.ncbi.nlm.nih.gov/pubmed/27164190
    2016 Oct;31(10):1845-1854. doi: 10.1002/jbmr.2870. Epub 2016 Sep 20.
    Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome.
     
     

    Oxfordilainen dieettiohje fosfaattia (Pi) rajoittavasta dieetissä

    https://www.ouh.nhs.uk/oku/patient-advice/documents/phosphate-diet.pdf
    Tämä oxfordilainen  artikkeli pyrkii  epäorgaanisen fosfaatin alentamiseen eikä  hienosäätele  erikseen insoitolifosfaatin suhteen, ainoastaan  suosittelee  siihen suuntaan  viitaten  kasviperäiseen  ravintoa, jossa inositolifosfaattia voi onnistua saamaan.

     https://www.ouh.nhs.uk/oku/patient-advice/documents/phosphate-diet.pdf
    On itseasiassa  paradigman muutosta jos  inositolifosfaatti (IP6 ja IP3)  aletaan ottaa  fosfaattiaineenvaihdunnan terapiassa huomioon. 

    Hyperfosfateminen tumoröösi kalsinoosi (Lancet uutinen)

     Lancet  Numero 10167, Vol 393. Jan 12, 2019 
    Lehti kuvaa  havinaisen potilastapauksen.
    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)33045-9/fulltext?rss=yes
    18-vuotiaalla nuorella miehellä 1 vuoden kestäneiden vasemman  lonkan alueen vaivan selvittelyssä  lopulta  hyperfosfateminen tuumorin muodostanut  kalsinoosi. 
    Mitään traumaa ei ollut anamneesissa ei myöskään mitään autoimmuunisiin häiriöihin viitaavaa.  Tuumorimassa isontrokanterin seudussa oli lisäksi paloiden aristavaa ja rajoitti nivelen liikuntaa, lonkan  rotaatiota ja abduktiota.  Aiemmassa omassa ja perheanamneesissa ei ollut  syitä selvittävää.  Tgasoröntgentutkimus ja tietokonetomografia selvittivä  molemmin puolisen, bilateraalisen, vierasvarjon, joka oli  periartikulaarinen, lohkoinen, kalkkiutunut pehmytosamassa - vasemmalla  tämä röäntgenologinen löytö oli selvempi kuin oikella. 
    Nyt selvitettiin seerumia:  S-urfea, kreatiniini, virtsahappo, kokonaiskalsium, alkaalinen fosfaatti ja PTH( paratyreoideahormoni) - nämä kaikki olvat normaaleita.
     Sensijaan  seeurin epäorgaaninen fosfaatti (Pi) oli koholla: 2- 19 mmol/L. ( Normaalialue on 0.81- 1.45 mmol/l).
     Munuaisen tubulaarinen  maksimaalinen  fosfaatin reabsorptiotahti korjattuna glomerulaarisen  filtraation suhteen  oli myös koholla  2-16 mmol/L ( normaalialue on 1.07- 1.89 mmol/L)  ja tämä  viittasi munuaisen kohonneeseen tubulaariseen fosfaatin takaisin absorptioon
    Ottaen huomioon potilaan iän ja  lonkkaseudun bilateraaliset , periartikulaarisessa pehmeässä  kudoksessa sijaitsevat, kalkkiutuneet massat , fosfaatin reabsorptioon liittyneen hyperfosfatemian  ja sekundäärisistä  tai muista syistä   ektooppisiin kalkkiutumiin johtavien seikkojen puuttumisen potilaan diagnoosiksi asetettiin  hyperfosfateminen tumoraali kalsinoosi. 
    Tehtiin oireenmukainen  vasemman puolisen massan kirurginen  poisto. Operaaation aikana havaittiin  kystistä massaa, jonka sisällä oli liituista  valkoista materiaalia . Histologinen tutkimus osoitti amorfista kalkkiutunutta jyväistä materiaalia, jota ympäröi histiosyytti- ja jättisolureaktio, mikä vahvisti diagnoosin. 
    Operaation jälkeen  tehtiin yrityksiä alentaa veren fosfaattipitoisuutta käyttäen kombinoidusti  fosfaattiredusoitua dieettiä  ja  alle 800 mg tablettia   kalsiumitonta   fosfaatin sitojaa  sevelamerihydrokloridia, joka sitää suolistossa fosfaattia, sekä  p.o. asetatsolamidia , joka indusoi fosfaturiaa.

    • Postoperatively, attempts were made to lower the patient's blood phosphate concentration using a combination of a phosphate-restricted diet with less than 800 mg/day tablets of the non-calcium-based phosphate binder, sevelamer hydrochloride—which binds phosphate in the intestine, and oral acetazolamide to induce phosphaturia.

    • An 18-year-old man presented to our department with a 1-year history of pain in the region of his left hip and difficulty in squatting. He reported no history of any local trauma. There was no history suggestive of an autoimmune disorder. Clinical examination found a tender, hard mass in the left greater trochanteric region with painful, restricted rotation and abduction movements of the hip. Both his medical history and family history were unremarkable. Plain x-ray and CT scans of the pelvis ( figure) showed bilateral—left greater than the right—and periarticular, lobulated, calcific, soft tissue masses. Serum urea, creatinine, uric acid, total calcium, alkaline phosphate, and parathyroid hormone concentrations were normal. However, serum inorganic phosphorus was elevated at 2·10 mmol/L (normal range 0·81–1·45 mmol/L). The ratio of the renal tubular maximum reabsorption rate of phosphate to corrected glomerular filtration rate was also elevated at 2·16 mmol/L (normal range 1·07–1·89 mmol/L), suggestive of increased renal tubular phosphate reabsorption.
    •  Considering the patient's age, presence of bilateral, and periarticular soft tissue, calcific masses about the hip, hyperphosphataemia with increased tubular phosphate reabsorption, and the absence of indications that the ectopic calcification was secondary to any other causes, the patient was diagnosed with hyperphosphataemic tumoral calcinosis. 
    • The symptomatic, left-sided mass was surgically excised: during the operation it appeared as a cystic mass containing chalky white material. Histological examination showed amorphous and granular calcified material surrounded by histiocytic and giant cell reaction—confirming the diagnosis. Postoperatively, attempts were made to lower the patient's blood phosphate concentration using a combination of a phosphate-restricted diet with less than 800 mg/day tablets of the non-calcium-based phosphate binder, sevelamer hydrochloride—which binds phosphate in the intestine, and oral acetazolamide to induce phosphaturia.

    fredag 30 november 2018

    Human NUDIX genes

    https://www.ncbi.nlm.nih.gov/pubmed/29142246

    Abstract

    The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.
    PMID:
    29142246
    PMCID:
    PMC5688067
    DOI:
    10.1038/s41467-017-01642-w