Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, eS−), oxidized (Cys106, eSO2 −), and over-oxidized (Cys106, eSO3 −) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease

A myocardialis necrosis mértékének vizsgálata eltérő supraventricularis szívritmuszavarok rádiófrekvenciás katéterablatiós kezelését követően = Assessment of the extent of myocardial necrosis following radiofrequency catheter ablation of different supraventricular arrhythmias

Absztrakt: Bevezetés: Ismert, hogy katéteres ablatio által okozott szívizom-károsodás következtében megnő a szívizom-specifikus nekroenzimek koncentrációja. Célkitűzés: A magas érzékenységű troponin T (hsTnT) és a szívizom-specifikus kreatin-kináz (CKMB) szintje középtávú változásának elemzése pitvarfibrilláció (PF), pitvari flutter (PFlu), AV-csomó reentry tachycardia (AVNRT) rádiófrekvenciás katéteres ablatióját követően, illetve elektrofiziológiai vizsgálat után. Módszer: Rádiófrekvenciás ablatión, illetve elektrofiziológiai vizsgálaton átesett betegeket vontunk be konszekutívan prospektív vizsgálatunkba. Sorozatvérmintákból meghatároztuk a hsTnT- és a CKMB-szinteket a procedúra előtt és után közvetlenül, majd 4 és 20 órával és 3 hónappal később. Eredmények: Negyvenhét, 55 ± 13 év átlagéletkorú beteget (10 elektrofiziológiai vizsgálat, 12 AVNRT, 13 PFlu és 12 PF) vontunk be vizsgálatunkba. A hsTnT-szintek minden csoportban szignifikánsan megemelkedtek a beavatkozást követően, a CKMB csak a PF-csoportban változott. A hsTnT-szint négy órával a beavatkozást követően az összes ablatión átesett betegnél és az elektrofiziológiai vizsgálaton átesett betegek 80%-ánál meghaladta a referenciatartományt. A legmagasabb átlagos hsTnT-koncentrációk EFV, AVNRT, PFlu esetén 24 ± 11, 260 ± 218 és 541 ± 233 ng/l-nek bizonyultak. A legmagasabb hsTnT-szint a PF-ablatiós csoportban volt kimutatható 20 órával az ablatio után (799 ± 433 ng/l). Pozitív korrelációt találtunk a rádiófrekvenciás ablatiót követő hsTnT-szint és az ablatio ideje között. Következtetések: A hsTnT alkalmas a rádiófrekvenciás ablatio és az elektrofiziológiai vizsgálat utáni myocardialis necrosis vizsgálatára, az ablatión átesett betegek mindegyikénél; elektrofiziológiai vizsgálat után 80%-ban pozitív a hsTnT. A necrosis mértéke jelentősen függ a beavatkozás típusától, és korrelál az ablatio kiterjedtségével. A fentiekben leírt megfigyelések iránymutatásként szolgálnak a rádiófrekvenciás ablatio utáni hsTnT-szint megfelelő értelmezéséhez. Orv Hetil. 2019; 160(14): 540–548. | Abstract: Introduction: Levels of cardiac necroenzymes, high-sensitive troponin (hsTnT) and creatine kinase muscle-brain (CKMB) increase as a result of a myocardial damage following catheter ablation. Aim: To analyze the mid-term alteration of hsTnT and CKMB levels following radiofrequency ablation (RFCA) for atrial fibrillation (AF), atrial flutter (AFlu), AV-nodal reentry tachycardia (AVNRT) and electrophysiological studies (EPS) without ablation. Method: Patients undergoing RFCA for various indications and EPS were consecutively enrolled in our prospective study. Concentrations of hsTnT and CKMB were measured from serial blood samples directly before and after the procedure, 4 and 20 hours later and at 3 months follow-up. Results: Forty-seven patients (10 EPS, 12 AVNRT, 13 AFlu, 12 AF) with mean age of 55 ± 13 were included. hsTnT levels increased significantly in all groups after the procedures, while CKMB changed only in the AF group. hsTnT exceeded the reference value in all patients with ablation and in 80% of patients with EPS 4 hours post-ablation. Peak average hsTnT levels for EPS, AVNRT, AFlu were 24 ± 11, 260 ± 218 and 541 ± 233 ng/L, respectively. The highest hsTnT level was measured in the AF group (799 ± 433 ng/L). We found a positive correlation between hsTnT levels and ablation time after RFCA. Conclusions: The hsTnT levels significantly change after EPS and RFCA, in all patients who underwent ablation, and in 80% of those with EPS had hsTnT positivity in the early post-procedural phase. hsTnT levels depended significantly on the type of the subgroups and correlated with the ablation time. Awareness of those observations is essential to correctly interpret elevated hsTnT levels following RFCA. Orv Hetil. 2019; 160(14): 540–548

Impact of CT-apelin and NT-proBNP on identifying non-responders to cardiac resynchronization therapy

CONTEXT: Assessment of response to cardiac resynchronization therapy (CRT) is essential. OBJECTIVE: To assess the predictive value of CT-apelin together with NT-proBNP in patients undergoing CRT. METHODS: Serum CT-apelin and NT-proBNP were measured by ELISA before, and 6-month after CRT. Primary endpoint was non-response (<4% increase in LVEF) after 6-month. RESULTS: From 81 patients, 15 proved to be non-responders. Six-month CT-apelin was superior compared to NT-proBNP in identifying non-responders by multivariate ROC (CT-apelin:p = 0.01, NT-proBNP:p = 0.13) and by logistic regression (CT-apelin:p = 0.01, NT-proBNP:p = 0.41) analyzes. CONCLUSION: Six-month CT-apelin might be valuable novel biomarker in identifying non-responders to CRT that was superior to NT-proBNP

DJ-1 can form β-sheet structured aggregates that co-localize with pathological amyloid deposits.

The loss of native function of the DJ-1 protein has been linked to the development of Parkinson's (PD) and other neurodegenerative diseases. Here we show that DJ-1 aggregates into β-sheet structured soluble and fibrillar aggregates in vitro under physiological conditions and that this process is promoted by the oxidation of its catalytic Cys106 residue. This aggregation resulted in the loss of its native biochemical glyoxalase function and in addition oxidized DJ-1 aggregates were observed to localize within Lewy bodies, neurofibrillary tangles and amyloid plaques in human PD and Alzheimer's (AD) patients' post-mortem brain tissue. These findings suggest that the aggregation of DJ-1 may be a critical player in the development of the pathology of PD and AD and demonstrate that loss of DJ-1 function can happen through DJ-1 aggregation. This could then contribute to AD and PD disease onset and progression.G.T. thanks the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002) for funding and the NIHR Cambridge Biomedical Research Centre and Unit in Dementia (UK) for salary support for Y. Z. R.A.B. and C.H.W.G. are supported by the NIHR Cambridge Biomedical Research Centre. R. A. B. is supported by the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute and is an NIHR Senior Investigator