Pro- and anti-inflammatory factors, vascular stiffness and outcomes in chronic hemodialysis patients

In this observational study we addressed accelerated arteriosclerosis (AS) in patients with chronic renal failure (CRF) on hemodialysis (HD) by measuring vascular stiffness (VS) parameters and attempted to relate them to pro-inflammatory and protective factors.96 consecutive patients receiving regular HD were included. 20 adult patients without major renal, cardiovascular or metabolic morbidities served as controls.AS parameters (carotid-femoral pulse wave velocity - PWV, aortic augmentation index - Aix) were measured by using applanation tonometry (SphygmoCor, AtCor Medical, Sidney). In addition to routine laboratory tests 25(OH) vitamin D3 (vitamin D3) and high-sensitivity C-reactive protein (hsCRP) were quantified by immunometric assay; whereas fetuin-A, α-Klotho, tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) were determined by ELISA.Pro-inflammatory biomarkers (hsCRP, TNF-α and TGF-β1) were markedly elevated (P < 0.01), while anti-inflammatory factors (fetuin-A: P < 0.05, α-Klotho: P < 0.01, vitamin D3: P < 0.01) significantly depressed in HD patients when compared to controls. PWV was significantly affected only by total cholesterol, fetuin-A and dialysis time. Multiple linear regression analyses revealed that several clinical and laboratory parameters were associated with pro- and anti-inflammatory biomarkers rather than VS. The impact of baseline clinical and biochemical variables on outcome measures were also analyzed after three-year follow-up, and it was demonstrated that low levels of vitamin D, α-Klotho protein and fetuin-A were related to adverse cardiovascular outcomes, whereas all-cause mortality was associated with elevated hsCRP and depressed vitamin D.Our results provide additional information on the pathomechanism of accelerated AS in patients with CRF, and documented direct influence of pro- and anti-inflammatory biomarkers on major outcome measures

Fehérjék konformációs dinamikája mint a biomolekuláris felismerés és jelátvitel meghatározó eleme = Protein conformational dynamics as a key determinant in biomolecular recognition and signal transmission

A térszerkezet alapján, a konformációs dinamika figyelembevételével kíséreltük meg az intramolekuláris és molekulák közötti jelátvitel megértését atomi felbontással. Kísérleti objektumok: a komplement rendszer, azon belül is a nemrég felfedezett lektin út fehérjekomplexei, a flagelláris exportrendszer valamint moduláris monomer, dimer és oligomer felépítésű enzimek álltak. Megállapítottuk, hogy FliI ATPáz, amely képes az exportálandó fehérjéje kitekerésére, a FliJ, FliH és FliS komponensekkel együtt képez olyan szupramolekuláris komplexet, amely képes az export szubsztrátumok felismerésére. Leírtuk a foszfoglicerát kináz enzim alloszterikus működési mechanizmusát, atomi felbontással. Feltártuk az izopropilmalát dehidrogenáz molekuláris csuklóinak működését és szerepét az alegységek kölcsönhatásaiban. Szelektív inhibitorokkal a tankönyvi tézissel ellentétes felismerésre jutottunk, miszerint a komplement rendszer lektin útjának meghatározó aktivátora a MASP-1 szerin proteáz. Így a komplement aktiválással összefüggő betegségek új gyógyszercélpont molekuláját azonosítottuk. Felfedeztük, hogy a MASP-1 képes a kininogén hasítása útján, bradikinint felszabadítva, komplement függő gyulladást keltésére. Felfedeztük, hogy a trombinhoz hasonlóan a MASP-1, PAR-4 receptoron keresztül endotél sejteket aktivál. Bizonyítékot találtunk arra, hogy a fehérjék konformációs dinamikája meghatározza a szerkezet evolúciójának lehetséges irányait, több milliárd éves időskálán is. | The CUB2 domain of C1r without calcium has disordered structure. This flexibility, necessary for autocativation of C1r inside the C1 complex, is regulated by calcium. Using MASP-selective inhibitors we proved that, in contrast to the previous textbook picture, MASP-1 is the exclusive activator of MASP-2. Blocking the proteolytic activity of MASP-1 prevents activation of the lectin pathway, therefore MASP-1 is a new target in treating complement related diseases. We solved the structure of the catalytic region of MASP-1. The structure explains the special enzymatic characteristics of this complement protease. We discovered a new, inflammation related function of the complement system: MASP-1 is able to directly activate endothelial cells through cleaving protease activated receptor-4. We discovered that MASP-1 is able to cleave kininogen and liberates bradykinin. In this way MASP-1 can contribute to the local inflammatory reaction triggered by complement activation. The allosteric mechanismnof human PGK has been explored at atomic details. In the dimeric enzyme IPMDH structural and site-directed mutagenesis studies revealed the operation of the two main molecular hinges and their relationship with the subunit interactions. We have shown that conformational motions are linked to protein evolution by producing structural variants that can be evolutionarily stabilized. This process is exemplified by segment-swapped proteins, a new group of proteins discovered by us

Accuracy in Diagnosis of Celiac Disease Without Biopsies in Clinical Practice

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Mână de mână cu Boala Celiacă (BC)

Proiectul CD SKILLS PP13 a Universității de Stat de Medicină și Farmacie “Nicolae Testemițanu” din Republica Moldova și permisă spre traducere din limba engleză cu suportul tehnic al echipei de implementare: Tatiana Raba, Olesea Nicu, Anton Pivtora