4 research outputs found
The level of expression of miR-196a in patients with chronic viral hepatitis C with the first genotype of HCV according to previous experience of antiviral therapy.
The authors present the study of the level of expression of miR-196a in 74 patients with chronic viral hepatitis C with the 1st genotype of HCV, based on previous experience in patients with antiviral therapy regimens containing interferon. The patients were divided into two groups, depending on the previous experience of antiviral therapy with circuits containing interferon – 21 patients who failed after antiviral therapy regimens containing interferon (group 1) and the comparison group (group 2) – 53 naive patients. To study the level of expression of miR-196a (miR-196a), a two-stage study according to the manufacturer's protocol was used. First, total RNA was isolated from the plasma by the method of phenol-chloroform extraction. Futher reverse transcription was performed using a kit for reverse transcription of miR TaqMan® (Applied Biosystems, USA), specific loop primers to achieve mature miRNA, snRNA U6 (as an endogenous control gene), and 10 ng of total RNA. Real-time quantitative PCR was performed using TaqMan® miRNA analysis. In order to optimize the prediction of response to antiviral therapy and the use of optimal treatment regimens for problem patients with treatment failure regimens containing interferon, analysis using ROC curves was used. The average level of expression of miR-196a in patients with chronic hepatitis C was evaluated. In the 1st group of patients it was 0.011 (IQR: 0.002; 0.310) and in the comparison group – 0.346 (IQR: 0.054; 1.239) at p=0.012 by U criterion. The conducted ROC analysis showed that the studied miR-196a could differentiate patients with chronic viral hepatitis C with HCV genotype 1, depending on previous experience of antiviral therapy, namely, patients with treatment failure regimens containing interferons and naive. AUC=0.688 (95% CI 0.570-0.791; p=0.017), J=0.40, Se=57.14%, Sp=83.02%. It gives additional opportunities for correction of therapeutic tactics. Therefore, the level of expression of miR-196a (<-1,75) may be an additional biomarker in the pathogenesis of HCV-infection, which can then be used in the monitoring and treatment of patients. Low expression of miR-196a may be the basis for prescribing more effective direct-acting antiviral therapy to patients and will allow personalizing therapeutic tactics in patients with chronic viral hepatitis C
Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans.
The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing.
In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels.
Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI