Hospitalized patients in internal medicine have an increased risk of low physical reserve which further declines during the hospital stay. The diagnosis requires bed-side testing of functional domains or more complex investigations of the muscle mass. Clinically useful biomarkers of functional status are needed, thus we aimed to explore the potential of microRNAs. Among hospitalized patients, we recorded the basic demographics, anthropometrics, nutritional status, and physical function domains: hand-grip strength (HGS, abnormal values M<30 kg, W<20 kg), balance (<30 s), chair-stands speed (CHSS<0.5/s) and gait speed (GS<0.8 m/s). A panel of five micro-RNAs (miRNA 1, miRNA 133a, miRNA 133b, miRNA 29a, miRNA 29b) and basic blood biochemistry and vitamin D values were recorded. We enrolled 80 patients (M40, W40), with a mean age of 68.8± 8.4 years. Obesity was observed in 27.5 % and 30 %, low HGS and low CHSS in 65.0, 77.5 %, and 80, 90 % of men and women respectively. The median hospital stay was 6.5 days. MiRNA29a and miRNA29b have the strongest correlation with the triceps skinfold (miRNA 29b, r=0.377, p=0.0006) and CHSS (miRNA 29a, r=0.262, p=0.02). MiRNA 29a, miRNA 29b and 133a levels were significantly higher in patients with CHSS<0.5/s. Other anthropometric parameters, mobility domains, or vitamin D did not correlate. All miRNAs except of miRNA 1, could predict low CHSS (miRNA29b, AUROC=0.736 CI 0.56-0.91, p=0.01), particularly in patients with low HGS (miRNA 29b, AUROC=0.928 CI 0.83-0.98). Among hospitalized patients in internal medicine, low functional status was frequent. MicroRNAs were fair biomarkers of the antigravity domain, but not other domains. Larger studies with clinical endpoints are needed., Petra Vrbová, Simona Valášková, Andrea Gažová, Juraj Smaha, Martin Kužma, Ján Kyselovič, Juraj Payer, Tomáš Koller., and Obsahuje bibliografii
The aim of this study was to measure expression levels of microRNAs (miRNAs) (miRNA-1, -15b and -21) in the rat myocardium after a single dose of ionizing radiation (6-7 Gy/min, total 25 Gy). The rats were treated with selected drugs (Atorvastatin, acetylsalicylic acid (ASA), Tadalafil, Enbrel) for six weeks after irradiation. MiRNAs levels were measured by RT-qPCR. Irradiation down-regulated miRNA-1 in irradiated hearts. In Tadalafil- and Atorvastatin-treated groups, miRNA-1 expression levels were further decreased compared with irradiated controls. However, Enbrel increased miRNA-1 level in irradiated hearts similarly to that in non-irradiated untreated group. Increase of miRNA-15b is pro-apoptotic in relationship with ischemia. Irradiation caused down-regulation of miRNA-15b. Administration of ASA in the irradiated group resulted in the increase of miRNA-15b expression compared to non-treated controls without irradiation. After Enbrel administration, miRNA-15b levels were overexpressed compared to non-treated normal group. MiRNA-21 belongs to the most markedly up-regulated miRNAs in response to cardiogenic stress. MiRNA-21 was increased nearly 2-fold compared to non-treated hearts whereas Tadalafil reduced miRNA-21 levels (about 40 %). Our study suggests that Enbrel and Tadalafil changed miRNAs expression values of the irradiated rats to the values of nonirradiated controls, thus they might be helpful in mitigation of radiation-induced toxicity., B. Kura, C. Yin, K. Frimmel, J. Krizak, L. Okruhlicova, R. C. Kukreja, J. Slezak., and Obsahuje bibliografii
Sinonasal carcinomas are head and neck tumours arising from the nasal cavity and paranasal sinuses characterized by unfavourable outcome, difficult treatment, diagnosis and prognosis. MicroRNAs are key molecules in the regulation of development and progression of cancer and their expression profiles could be used as prognostic biomarkers, to predict the patients’ survival and response to treatment. In this study, we used quantitative real-time PCR with TaqMan® Advanced miRNA Assays to investigate the relative expression values of selected micro-RNAs in a unique set of formalin-fixed paraffin-embedded tissue samples obtained from 46 patients with sinonasal squamous cell carcinoma. Our results showed statistically significant up-regulation of three mature microRNAs: miR-9-5p (fold change: 6.80), miR-9-3p (fold change: 3.07) and let-7d (fold change: 3.93) in sinonasal carcinoma patients. Kaplan-Meier survival analysis and logrank test identified association between higher expression of miR-9-5p and longer survival of the patients (P = 0.0264). Lower expression of let-7d was detected in the patients with impaired survival, and higher expression of miR-137 was linked to shorter survival of the patients., We alsoidentified several correlations between expression of the studied microRNAs and recorded clinico-pathological data. Higher expression of miR-137 and lower expression of let-7d correlated with local recurrence (P = 0.045 and P = 0.025); lower expression of miR-9-5p and higher expression of miR-155-5p correlated with regional recurrence (P = 0.045 and P = 0.036). Higher expression of miR-9-3p correlated with occupational risk (P = 0.031), presence of vascular invasion (P = 0.013) and perineural invasion (P = 0.031). Higher expression of miR-155-5p was present in the samples originating from maxillary sinus (P = 0.011), cN1-3 classified tumours (P = 0.009) and G2-3 classified tumours (P = 0.017). In conclusion, our study supports the hypothesis of future prospect to use expression of miRNAs as prognostic biomarkers of squamous cell sinonasal carcinoma. In particular, miR-9-5p and miR-9-3p seem to be important members of the sinonasal cancer pathogenesis., and Corresponding author: Helena Kovaříková
MicroRNAs are emerging as important regulators of cardiac function. This study investigated the role of microRNA-24 (miR-24) in ischemic cardiomyocytes, based on the observation that miR-24 expression was significantly enhanced in the ischemic myocardium of rats. Using primary cultured rat cardiomyocytes, cell injury was induced by ischemic conditions, and the cells were evaluated for changes in lactate dehydrogenase (LDH) release, cell viability, apoptosis and necrosis. The results showed that miR-24 was increased in myocytes exposed to ischemia. When miR-24 was further overexpressed in ischemic myocytes using the mimic RNA sequence, LDH release was reduced, cell viability was enhanced, and apoptosis and necrosis rates were both decreased. By contrast, a deficiency in miR-24 resulted in the largest LDH release, lowest cell viability and highest apoptosis and necrosis rates in normal and ischemic myocytes, with significant changes compared to that of non-transfected myocytes. Additionally, the mRNA and protein levels of the pro-apoptotic gene, BCL2L11, were down-regulated by miR-24 overexpression and up-regulated by miR-24 deficiency. The luciferase reporter assay confirmed BCL2L11 to be a target of miR-24. Overall, this study showed a protective role for miR-24 against myocardial ischemia by inhibiting BCL2L11, and may represent a potential novel treatment for ischemic heart disease., D.-F. Li ... [et al.]., and Obsahuje seznam literatury
Autologous stem cell therapy is the most promising alternative treatment in patients with chronic ischemic diseases, including ischemic heart disease and critical limb ischemia, which are characterized by poor prognosis related to serious impair of quality of life, high risk of cardiovascular events and mortality rates. However, one of the most serious shortcomings of stem cell transplantation are low survival after transplantation to the site of injury, as large number of stem cells are lost within 24 hours after delivery. Multiple studies suggest that combination of lipid-lowering drugs, statins, and stem cell transplantation might improve therapeutic efficacy in regenerative medicine. Statins are inhibitors of HMG-CoA reductase and belong to recommended therapy in all patients suffering from critical limb ischemia. Statins possess non-lipid effects which involve improvement of endothelial function, decrease of vascular inflammation and oxidative stress, anti-cancer and stem cell modulation capacities. These non-lipid effects are explained by inhibition of mevalonate synthesis via blocking isoprenoid intermediates synthesis, such as farnesylpyrophospate and geranylgeranylpyrophospate and result in modulation of the PI3K/Akt pathway. Moreover, statin-mediated microRNA regulation may contribute to the pleiotropic functions. MicroRNA interplay in gene regulatory network of IGF/Akt pathway may be of special significance for the treatment of critical limb ischemia. We assume further studies are needed for detailed analysis of statin interactions with microRNA at the molecular level and their link to PI3K/Akt and IGF/Akt pathway in stem cells, which are currently the most promising treatment strategy used in chronic ischemic diseases.
In this review the authors outline traditional antiresorptive pharmaceuticals, such as bisphosphonates, monoclonal antibodies against RANKL, SERMs, as well as a drug with an anabolic effect on the skeleton, parathormone. However, there is also a focus on non-traditional strategies used in therapy for osteolytic diseases. The newest antiosteoporotic pharmaceuticals increase osteoblast differentiation via BMP signaling (harmine), or stimulate osteogenic differentiation of mesenchymal stem cells through Wnt/β-catenin (icarrin, isoflavonoid caviunin, or sulfasalazine). A certain promise in the treatment of osteoporosis is shown by molecules targeting non-coding microRNAs (which are critical for osteoclastogenesis) or those stimulating osteoblast activity via epigenetic mechanisms. Vitamin D metabolites have specific antiosteoporotic potencies, modulating the skeleton not only via mineralization, but markedly also through the direct effects on the bone microstructure., I. Zofkova, J. Blahos., and Obsahuje bibliografii
The goal of this study is to evaluate if promotion of angiogenesis by systemic treatment with an antagomir against miR-92a, a well established inhibitor of angiogenesis, will maximize the benefits of exercise on bone. Ten week old female C57BL6/J mice were subjected to two weeks of external load by four point bending. During the first week of mechanical loading (ML), mice were injected (2.7 mg/kg of bodyweight) with antagomir against miR-92 or control antagomir (3 alternate days via retro-orbital). No difference in tissues weights (heart, kidney, liver) were found in mice treated with miR-92 vs. control antagomir suggesting no side effects. Two weeks of ML increased tibia TV, BV/TV and density by 6-15 %, as expected, in the control antagomir treated mice. Similar increases in the above parameters (7-16 %) were also seen in mice treated miR-92 antagomir. Administration of miR-92 antagomir was effective in reducing levels of mir-92 in heart, liver and skeletal muscle and in contrast, expression levels of two other microRNA’s miR-93 and miR-20a remain constant, thus suggesting specificity of the antagomir used. Surprisingly, we failed to detect significant changes in the expression levels of vascular genes (VEGF, CD31 and Tie2) in heart, liver or skeletal muscle. Based on these findings, we conclude that systemic administration of antagomir against miR-92 while reduced expression levels of miR-92 in the tissues; it did not significantly alter either angiogenic or osteogenic response, thus suggesting possible redundancy in miR-92 regulation of angiogenesis., A. Sengul, ... [et al.]., and Obsahuje seznam literatury
Wnt/β-catenin signaling is involved in virtually every aspect of embryonic development and also controls homeostatic selfrenewal in a number of adult tissues. Recently, emerging evidence from researches of organ fibrosis suggest that sustained Wnt/β-catenin pathway reactivation is linked to the pathogenesis of fibrotic disorders. Here we focus on Wnt/β-catenin-related pathogenic effects in different organs, such as lung fibrosis, liver fibrosis, skin fibrosis and renal fibrosis. Additionally, Wnt/β- catenin signaling works in a combinatorial manner with TGF-β signaling in the process of fibrosis, and TGF-β signaling can induce expression of Wnt/β-catenin superfamily members and vice versa. Moreover, network analysis, based on pathway databases, revealed that key factors in the Wnt pathway were targeted by some differentially expressed microRNAs detected in fibrosis diseases. These findings demonstrated the crosstalks between Wnt/β-catenin pathway and TGF-β signalings, and microRNAs, highlighting the role of Wnts in organ fibrogenesis. Most importantly, nowadays there is a variety of Wnt pathway inhibitors which give us the potential therapeutic feasibility, modulation of the Wnt pathway may, therefore, present as a suitable and promising therapeutic strategy in the future., Y. Guo ... [et al.]., and Obsahuje seznam literatury