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Mecanisme celulare ligand – receptor AGE-RAGE

Mecanisme celulare ligand – receptor AGE-RAGE. Motanuincaltat. AGE (Advanced glycation end products) sunt un grup de macromolecule formate prin glicarea non-enzimatica a proteinelor , lipidelor si acizilor nucleici. . Surse Exogene . Alimente procesate la temperaturi inalte .

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Mecanisme celulare ligand – receptor AGE-RAGE

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  1. Mecanisme celulare ligand – receptor AGE-RAGE Motanuincaltat

  2. AGE (Advanced glycation end products) sunt un grup de macromolecule formate prin glicarea non-enzimatica a proteinelor , lipidelor si acizilor nucleici. Surse Exogene Alimente procesate la temperaturi inalte Surse Endogene Apar mai ales in defecte ale metabolismului glucozei Glucoza reactioneaza cu grupari de AA din proteine, lipide si acizi nucleici AGEs Baze Schiff Produsi Amadori Reactia Maillard

  3. Zahar reducator Arabinose Glyoxal Proteina –NH2 AGE’s Baza Schiff Glyoxal metilglyoxal Rearanjari Amadori Deoxyzomi,Produsi de fragmentatie Ketoamina Reactii non-enzimatice ale gruparilor carbonil ale zaharurilor reducatoare + capetele amino ale proteinelor produc Baze Schiff. Care prin rearanjari Amadori duc la formarea de cetoamine. Alte glicozilari si autooxidari duc la formarea de compusi carbonil foarte reactivi care reactionand cu gruparile amino ale proteinelor duc la formarea de AGEs.

  4. Hydroimidazolone Glucosepane Tipuri majore de AGEs Pentozidina N epsilon-carboxymethyl-lysine (CML) ¬20 compusi au fost descoperiti CML Cel mai raspandit “in vivo” Ligand producator de semnale pentru RAGE Glucosepane Cel mai important AGE cross-linkat la oameni ¬ 10 % din AGEs provenit din dieta este absorbit la oameni

  5. Pana in prezent nu se cunoscbeneficii legate de AGEs StudiulInCHIANTI Curbe de supravietuireindependente de cauze in adulti > 65 ani. Nivelridicat de CML plasmatic factor de riscpentrumortalitate.

  6. Zaharuri Proteine AGEs AGEs crosslinkati Receptori AGE multispecifici Activare cai metabolice si inflamatoare Cytokines (TNF, IL-1, IL-6) RAGE Activare cai metabolice (PKC) AGER 1 AGER 2 Factori crestere (TGF, CTGF, PDGF, VEGF, IGF-1) AGER 3 (Galectin 3) Stres Oxidativ (NADPH Oxidaza) MSRA Molecule adeziune (VCAM-1, ICAM)

  7. RAGE ( Receptor for Advanced Glycation End Products) Receptor “Pattern Recognition” Face parte din superfamilia imunoglobulinelor Receptor transmembranar Coada citoplasmatica Esentiala pentru semnalizarea intracel. Domeniu transmembranar Doua domenii tip C (Constant) Un domeniu tip V Variabil) 2 domenii N-glicozidice Responsabil de cele mai multe legaturi R-L

  8. RAGE Foartebineconservatintrespecii 45 Kda 403 AA (soareci,sobolani,om) Tesut muscular Exprimatintr-o mare varietate de tesuturi Tesut cardiac Tesutpulmonar Tesut neuronal Spredeosebire de altireceptori RAGE LDLR Low Density Lipoprotein Receptor “UP Regulated” de numarul de liganzi “Down Regulated” de numarul de liganzi

  9. Full length RAGE (flRAGE) RAGE Legat de membrana Cotinedomeniultransmembranar + citosolic Membrane Bound RAGE(mRAGE) RAGE solubil (sRAGE) Lipsit de domeniultransmembranar +citosolic ClivajProteolitic Splicing alternativ de ARNm esRAGE ( Endogenous Secretory) ~20 izoformecunoscute ADAM10 Metaloproteinaza Domeniu C terminal ramas Modalitate de a reglaactivitatea flRAGE RICD (RAGE intercelular domain) Gamma-secretaza Igg-RAGE Implicatasi in patogenezaAmyloid Beta

  10. Promotorul RAGE S-au identificat mai multe situsuri Nf-kappaB Activarea Nf-kB Expresie marita RAGE Expresie prelungita Nf-kB Expresie sustinuta RAGE Celule in proximitatea ligandului Celule musculare netede Endotelium Celule mononucleate Activarea cronica a inflamatiei

  11. Mai multe familii de liganzi actioneaza asupra RAGE HGMB1/amphoterin Proteinele High Mobility Proteine cromozomiale S100A12/EN-RAGE Grupul Proteinelor S100/calgranulin S100B S100A6 Colagen IV Proteine matriceale Colagen I Amyloid Beta Asociata cu Maladia Alzheimer + degenerare neuronala

  12. Recunoaasterea antigen fara a fi mediat de anticorp Receptor complement Mac-1 Macrophage-1 antigen AGEs CML Moleculele AGE -prevalente in conditii patologice Stres Oxidativ Nu toti membrii unei anumite familii se leaga la RAGE Hiperglicemie

  13. Cea mai importanta consecinta patologica Ligand-RAGE Sistem NAD(P) H oxidaza Cel putin in parte Activarea celulara ROS Cale Ras-MAP kinazica Regulator a multe gene “response- to- injury” Nf-kB Activarea multor gene de relevantadeosebitapentruinflamatie, imunitatesiaterosleroza.

  14. AGEs, Amphoterine, Calgranuline, AB, altiliganzi Liganzi Domeniu V RAGE Domenii C NAD(P)H oxidaza ROS P21RAS MAP Kinaze Nf-kB RAGE ActivareLeucocite IL-6, TNF- alpha, Molecule Adeziune

  15. IL-6 esRAGE Mac 1 MMP/ADAM10 Rage activatisiregleazapropriul receptor prinNf-Kb Nf-kB ICAM VCAM Inflamatie, proliferare, afectareatesuturilorsustinute

  16. RAGE aflatipesuprafatacelulei Nu prezinta o conditiesuficientapentrugenerarea ROS siactivarecelulara Coadacarboxi-terminalacitosolica a RAGE Situsurifosforilare Criticapentruactivareacelulara RAGE dependenta Domeniikinazice Altesitusuriactivare Formele truncate de RAGE (faracoadacarboxiterminala Retincapacitatea de legare a liganduluidar nu mediazasemnalecelulare

  17. RAGE solubil (sRAGE) “Receptorimomeala” extracelulari esRAGE ( Endogenous Secretory) Tot o forma solubila (nelegata de membrana) Inhibarecrutarealeucocitelor AntagonizeazaflRAGE Se leaga de liganzi (Ex DAMPs) esRAGEsisRAGEactioneaza ca liganzimomeala pentruHMGB1 sRAGE Efect pro-inflamator via interactia cu Mac1 IL-6 Mediata de Nf-kB Tnf-alpha

  18. RAGE si liganzii sai Neurobiologie Cancer AGE’s Inflamare Numeroase alte conditii Crosslinkare RAGE-AGE Declin multi-sistemic Rol determinant Diabet Degenerarea Neuronala Osteoporoza Ateroscleroza Imbatranire

  19. Posibile interventii terapeutice In multe patologii activitatea RAGE-AGE este marita (Ex Diabet) Interferenta in cercul vicios AGE-RAGE Stare prelungita de activare celulara sRAGE RAGE-IGG Compusi asemanatori Prevenirea formarii de AGE’s Aminoguanidina AGE-Crosslinkati AGE Breakers (agenti clivare) ALT - 711 Alagebrium

  20. Totusi Nu s-a identificat cu claritate sursa de AGE’s descrisa in organele umane odata cu inaintarea in varsta Creste absorbtia si sinteza endogena de AGE’s odata cu varsta sau AGE’s cauzeaza in parte aceste patologii? AGE’s fac parte din cauza cauza sau din efect? Stres oxidativ si peroxidarea lipidelor pot induce sinteza de AGE’s Markeri ai stresului oxidativ si al inflamatiei sau factor cauzal? Expunerea populatiei vestice la AGE este mare. -> dieta vestica este bogata in AGE’s Daca AGE’s exogen are efecte nocive sau nu ramane un aspect controversat.

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