33 results on '"Cabrera-Fuentes, H A"'
Search Results
2. Binase penetration into alveolar epithelial cells does not induce cell death
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Cabrera-Fuentes, H. A., Kalacheva, N. V., Mukhametshina, R. T., Zelenikhin, P. V., Kolpakov, A. I., Barreto, G., Preissner, K. T., and Ilinskaya, O. N.
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- 2012
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3. P735Regulation of macrophage polarization by extracellular RNA: The role of sialoadhesin-1
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Cabrera-Fuentes, H A, Galuska, S, Meiler, S, Baumer, Y, Mccurdy, S, Fischer, S, Preissner, KT, and Boisvert, W
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- 2014
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4. P166Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
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- 2014
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5. Chronic inflammatory diseases, myocardial function and cardioprotection
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Lazou, A. Ikonomidis, I. Bartekova, M. Benedek, T. Makavos, G. Palioura, D. Cabrera Fuentes, H. Andreadou, I.
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The association between chronic inflammatory diseases (CIDs) and increased cardiovascular (CV) risk is well documented and can be a most threatening complication in these patients. However, the pathogenetic mechanisms underlying increased CV risk remain elusive, especially in their cellular and biochemical pathways. Using animal models to understand mechanisms underlying cardiac involvement are limited. Additionally, treatments may influence cardiovascular events through different outcomes. Some drugs used to treat CIDs can negatively affect cardiac function by a direct toxicity, whereas others may protect the myocardium. In the present article, we focus on the cardiac manifestations and risk factors, the pathogenetic mechanisms, and the effect of treatments on myocardial function and cardioprotection for five common worldwide CIDs (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, psoriasis and inflammatory bowel disease). We also give recommendations in order to evaluate common targets between CID and CV disease (CVD) and to design therapies to alleviate CID-related CVD. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc. © 2020 The British Pharmacological Society
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- 2020
6. Antitumor macrophage response to bacillus pumilus ribonuclease (Binase)
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Makeeva A., Rodriguez-Montesinos J., Zelenikhin P., Nesmelov A., Preissner K., Cabrera-Fuentes H., and Ilinskaya O.
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© Copyright 2017 Anna Makeeva et al. Extracellular bacterial ribonucleases such as binase from Bacillus pumilus possess cytotoxic activity against tumor cells with a potential for clinical application. Moreover, they may induce activation of tumor-derived macrophages either into the M1-phenotype with well-documented functions in the regulation of the antitumor immune response or into M2-macrophages that may stimulate tumor growth, metastasis, and angiogenesis. In this study, binase or endogenous RNase1 (but not RNA or short oligonucleotides) stimulated the expression of activated NF-κB p65 subunit in macrophages. Since no changes in MyD88 and TRIF adaptor protein expression were observed, toll-like receptors may not be involved in RNase-related NF-κB pathway activation. In addition, short exposure (0.5 hr) to binase induced the release of cytokines such as IL-6, MCP-1, or TNF-α (but not IL-4 and IL-10), indicative for the polarization into antitumor M1-macrophages. Thus, we revealed increased expression of activated NF-κB p65 subunit in macrophages upon stimulation by binase and RNase1, but not RNA or short oligonucleotides.
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- 2017
7. Mortality and cancer after 12 versus 30 months dual antiplatelet therapy: The Korean outcomes registry evaluating antithrombotics (Korea)
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Serebruany V., Kim M., Cabrera-Fuentes H., Lee K., Cho Y., Park K., Park T., Kim Y., and Yoon S.
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Registry ,Aspirin ,Korean ,Mortality ,Cancer ,Clopidogrel - Abstract
© Schattauer 2017.The optimal duration and cancer risks of antiplatelet therapy following percutaneous coronary intervention (PCI) are unclear. We compared cancer and all-cause mortality after dual antiplatelet therapy (DAPT) for the combination of clopidogrel and aspirin (ASA) versus ASA alone over 18 months follow-up in event-free patients at 12 months DAPT from the Health Insurance Review and Assessment (HIRA) dataset via the Korean Outcomes Registry Evaluating Antithrombotics (KOREA). We selected PCI patients who were event free for 12 months and maintained a consistent antiplatelet regimen for 18 more months. The primary endpoints were any cancer and all-cause mortality at 30 months follow-up after PCI. From 320,351 screened post-PCI patient HIRA records, we excluded 294,413 and qualified 25,938, constituting DAPT (n=10,992) and ASA (n=14,946) groups. The Propensity Score Matching (PSM), and Inverse Probability of Treatment Weighting (IPTW) revealed no significant differences in background demographics and clinical characteristics for DAPT versus ASA patients. At 30-months post-PCI, after massive (>91 %) exclusions, cancer risk was higher for continuous DAPT [455 (4.15 %) vs 606 (4.04 %); HR=1.221; 95 %CI: 1.061-1.405; p=0.005], which remained significant by PSM (p=0.006) or IPTW (p=0.007), while all-cause mortality was similar [136 (1.24 %) vs 192 (1.28 %) HR=0.999; 95 %CI: 0.736-1.135; p=0.993]. This analysis suggests a potential mild excess cancer risk, but no mortality benefit in Korean post-PCI patients treated with DAPT for an additional 18 months beyond conventional 12 months DAPT. These data are not supporting continuing DAPT for more than one year in East Asians. Analysing cancer types and assessing potential cancer association with bleeding are warranted.
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- 2017
8. MicroRNA-142 is a multifaceted regulator in organogenesis, homeostasis, and disease
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Shrestha A., Mukhametshina R., Taghizadeh S., Vásquez-Pacheco E., Cabrera-Fuentes H., Rizvanov A., Mari B., Carraro G., and Bellusci S.
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disease ,ERK ,miR-142 ,stem cells ,WNT signaling ,development - Abstract
© 2016 Wiley Periodicals, Inc.Over the past decade, microRNA-142 (miR-142) is emerging as a major regulator of cell fate decision in the hematopoietic system. However, miR-142 is expressed in many other tissues, and recent evidence suggests that it may play a more pleiotropic role during embryonic development. In addition, miR-142 has been shown to play important functions in disease. miR-142 displays a functional role in cancer, virus infection, inflammation, and immune tolerance. Both a guide strand (miR-142-3p) and passenger strand (miR-142-5p) are generated from the miR-142 hairpin. miR-142-3p and -5p display overlapping but also independent target genes. Loss of function mouse models (genetrap, global knock out [KO], and conditional KO) have been reported and support the important role of miR-142 in different biological processes. This review will summarize the abundant literature already available for miR-142 and will lay the foundation for future works on this important microRNA. Developmental Dynamics 246:285–290, 2017. © 2016 Wiley Periodicals, Inc.
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- 2017
9. Circadian variation in acute myocardial infarct size assessed by cardiovascular magnetic resonance in reperfused STEMI patients
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Bulluck, Heerajnarain, Nicholas, Jennifer, Crimi, Gabriele, White, Steven K., Ludman, Andrew J., Pica, Silvia, Raineri, Claudia, Cabrera-Fuentes, H. A, Yellon, Derek, Rodriguez-Palomares, Jose, García-Dorado, David, Hausenloy, Derek J., and Universitat Autònoma de Barcelona
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ST-segment elevation myocardial infarction ,Myocardial infarct size ,Circadian rhythm ,Cardiovascular magnetic resonance ,cardiovascular diseases - Abstract
Clinical studies using serum cardiac biomarkers to investigate a circadian variation in acute myocardial infarct (MI) size in ST-segment elevation myocardial infarction (STEMI) patients reperfused by primary percutaneous coronary intervention (PPCI) have produced mixed results. We aimed to investigate this phenomenon using acute MI size measured by cardiovascular magnetic resonance (CMR). Patient-level data was obtained from 4 randomized controlled trials investigating the MI-limiting effects of cardioprotective therapies in this pooled analysis. The primary analysis was performed in those patients with no pre-infarct angina; duration of ischemia > 60 min and < 360 min; Thrombolysis In Myocardial Infarction (TIMI) flow pre-PPCI ≤ 1; TIMI flow post-PPCI 3; and no collateral flow. 169 out of 376 patients with CMR data met the inclusion criteria for the primary analysis. A 24-hour circadian variation in acute MI size as a % of the area-at-risk (%AAR), after adjusting for confounders, was observed with a peak and nadir MI size in patients with symptom onset between 00:00 and 01:00 and between 12:00 and 13:00 respectively (difference from the average MI size 5.2%, 95%CI 1.1-9.4%; p = 0.013). This was associated with a non-significant circadian variation in left ventricular ejection fraction (LVEF) (difference from the average LVEF 5.9%, 95%CI − 0.6-2.2%, p = 0.073). There was no circadian variation in MI size or LVEF in the whole cohort. We report a circadian variation in acute MI size assessed by CMR in a subset of STEMI patients treated by PPCI, with the largest and smallest MI size occurring in patients with symptom onset between 00:00 and 01:00 and between 12:00 and 13:00 respectively.
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- 2017
10. Full left ventricular coverage is essential for the accurate quantification of the area-at-risk by T1 and T2 mapping
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Bulluck H., Bryant J., Lim M., Tan X., Ramlall M., Francis R., Kotecha T., Cabrera-Fuentes H., Knight D., Fontana M., Moon J., and Hausenloy D.
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© 2017 The Author(s). T2-weighted cardiovascular magnetic resonance (CMR) using a 3-slice approach has been shown to accurately quantify the edema-based area-at-risk (AAR) in ST-segment elevation myocardial infarction (STEMI). We aimed to compare the performance of a 3-slice approach to full left ventricular (LV) coverage for the AAR by T1 and T2 mapping and MI size. Forty-eight STEMI patients were prospectively recruited and underwent a CMR at 4 ± 2 days. There was no difference between the AAR full LV and AAR 3-slices by T1 (P = 0.054) and T2-mapping (P = 0.092), with good correlations but small biases and wide limits of agreements (T1-mapping: N = 30, R 2 = 0.85, bias = 1.7 ± 9.4% LV; T2-mapping: N = 48, R 2 = 0.75, bias = 1.7 ± 12.9% LV). There was also no significant difference between MI size 3-slices and MI size full LV (P = 0.93) with an excellent correlation between the two (R 2 0.92) but a small bias of 0.5% and a wide limit of agreement of ±7.7%. Although MSI was similar between the 2 approaches, MSI 3-slices performed poorly when MSI was < 0.50. Furthermore, using AAR 3-slices and MI size full LV resulted in 'negative' MSI in 7/48 patients. Full LV coverage T1 and T2 mapping are more accurate than a 3-slice approach for delineating the AAR, especially in those with MSI < 0.50 and we would advocate full LV coverage in future studies.
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- 2017
11. From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on 'New frontiers in cardiovascular research'
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Cabrera-Fuentes H., Aragones J., Bernhagen J., Boening A., Boisvert W., Bøtker H., Bulluck H., Cook S., Di Lisa F., Engel F., Engelmann B., Ferrazzi F., Ferdinandy P., Fong A., Fleming I., Gnaiger E., Hernández-Reséndiz S., Kalkhoran S., Kim M., Lecour S., Liehn E., Marber M., Mayr M., Miura T., Ong S., Peter K., Sedding D., Singh M., Suleiman M., Schnittler H., Schulz R., Shim W., Tello D., Vogel C., Walker M., Li Q., Yellon D., Hausenloy D., and Preissner K.
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Drug targeting ,Ischemia–reperfusion injury ,Remote ischemic conditioning ,Cardioprotection ,Cardiovascular disease ,Cardiomyocyte signaling pathways ,Mitochondria ,Induced pluripotent stem cells ,Lipid metabolism ,Extracellular RNA (eRNA) ,Endothelial permeability ,Co-morbidities ,Heart regeneration ,MicroRNAs (miRNAs) - Abstract
© 2016, The Author(s).In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.
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- 2016
12. Necrotic Arachnidism by Zorocrates guerrerensis First Case Reported in Mexico
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Cabrera-Fuentes H, Sánchez-Vega Jt, Cruz-García Jq, César G. Durán-Barrón, and Olguín-Pérez L
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Arachnid ,Veterinary medicine ,biology ,business.industry ,Necrotic Arachnidism ,General Engineering ,Zoology ,biology.organism_classification ,Genus ,Mexico city ,Medicine ,Arthropod ,Species richness ,business ,Endemism ,Medical attention - Abstract
Necrotic Arachnidism by Zorocrates guerrerensis First Case Reported in Mexico The spiders (filo Arthropoda) occupy seventh place in global species richness. The genus Zorocrates Simon, consists of endemic species in Mexico. This arthropod used for feeding or defense, glandular secretions to manipulate their prey (including human), affecting their state of health or causing the death, by what are considered species of medical importance. We present the case clinical female 19 years old, resident of the Mexico City, who came to the Parasitology Laboratory, National Autonomous University of Mexico (UNAM), commenting that three days before, sitting on his bed, felt pain in the left external tibial region at the level of the third half, discovering a large insect, repelling it immediately; minutes later, there are burning, and erythema in the area of reference, which evolves with formation of vials, which spontaneously bursts. Then presented erythematous, itchy, painful plaques, reason for the requested medical attention. The ulcerative lesion studied with slow progress until the cicatricial process. Responsible arachnid is presented to the laboratory until the end of the treatment, which is identified as Zorocrates guerrerensis, species located in areas of the Mexico City (bedrooms, bathrooms, patios, zotehuelas, cisterns and gardens). There are no cases reported in Mexico and the world, about accidents caused by this species. It is suggested that the injury is due to the mechanics of the bite and not by the toxic effects of its secretion, which has not yet been characterized and that cannot be ruled out, along with other components, as head of the pathophysiological manifestations.
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- 2016
13. Influence of extracellular rnas, released by rheumatoid arthritis synovial fibroblasts, on their adhesive and invasive properties
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Zimmermann-Geller B., Köppert S., Fischer S., Cabrera-Fuentes H., Lefèvre S., Rickert M., Steinmeyer J., Rehart S., Umscheid T., Schönburg M., Muller-Ladner U., Preissner K., Frommer K., and Neumann E.
- Abstract
© 2016 by The American Association of Immunologists, Inc.Extracellular RNA (exRNA) has been characterized as a molecular alarm signal upon cellular stress or tissue injury and to exert biological functions as a proinflammatory, prothrombotic, and vessel permeability-regulating factor. In this study, we investigated the contribution of exRNA and its antagonist RNase1 in a chronic inflammatory joint disease, rheumatoid arthritis (RA). Upon immunohistochemical inspection of RA, osteoarthritis (OA), and psoriatic arthritis synovium, exRNA was detectable only in the RA synovial lining layer, whereas extracellular DNAwas detectable in various areas of synovial tissue. In vitro, exRNA (150-5000 nt) was released by RA synovial fibroblasts (RASF) under hypoxic conditions but not under normoxia or TNF-A treatment. RNase activity was increased in synovial fluid from RA and OA patients compared with psoriatic arthritis patients, whereas RNase activity of RASF and OASF cultures was not altered by hypoxia. Reduction of exRNA by RNase1 treatment decreased adhesion of RASF to cartilage, but it had no influence on their cell proliferation or adhesion to endothelial cells. In vivo, treatment with RNase1 reduced RASF invasion into coimplanted cartilage in the SCID mouse model of RA. We also analyzed the expression of neuropilins in synovial tissue and SF, as they may interact with vascular endothelial growth factor signaling and exRNA. The data support the concepts that the exRNA/RNase1 system participates in RA pathophysiology and that RASF are influenced by exRNA in a prodestructive manner. The Journal of Immunology, 2016, 197: 2589-2597.
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- 2016
14. Role of the MPTP in conditioning the heart - Translatability and mechanism
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Ong S., Dongworth R., Cabrera-Fuentes H., and Hausenloy D.
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nervous system ,animal diseases ,cardiovascular system ,cardiovascular diseases ,nervous system diseases - Abstract
© 2014 The Authors. British Journal of Pharmacology published by John Wiley Sons Ltd on behalf of The British Pharmacological Society. Mitochondria have long been known to be the gatekeepers of cell fate. This is particularly so in the response to acute ischaemia-reperfusion injury (IRI). Following an acute episode of sustained myocardial ischaemia, the opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion, mediates cell death. Preventing MPTP opening at the onset of reperfusion using either pharmacological inhibitors [such as cyclosporin A (CsA) ] or genetic ablation has been reported to reduce myocardial infarct (MI) size in animal models of acute IRI. Interestingly, the endogenous cardioprotective intervention of ischaemic conditioning, in which the heart is protected against MI by applying cycles of brief ischaemia and reperfusion to either the heart itself or a remote organ or tissue, appears to be mediated through the inhibition of MPTP opening at reperfusion. Small proof-of-concept clinical studies have demonstrated the translatability of this therapeutic approach to target MPTP opening using CsA in clinical settings of acute myocardial IRI. However, given that CsA is a not a specific MPTP inhibitor, more novel and specific inhibitors of the MPTP need to be discovered - the molecular identification of the MPTP should facilitate this. In this paper, we review the role of the MPTP as a target for cardioprotection, the potential mechanisms underlying MPTP inhibition in the setting of ischaemic conditioning, and the translatability of MPTP inhibition as a therapeutic approach in the clinical setting.
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- 2015
15. Mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease
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Ong S., Kalkhoran S., Cabrera-Fuentes H., and Hausenloy D.
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MFN2 ,MFN1 ,Mitochondrial fission ,Mitochondrial fusion ,Drp1 ,OPA1 - Abstract
© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license. The past decade has witnessed a number of exciting developments in the field of mitochondrial dynamics - a phenomenon in which changes in mitochondrial shape and movement impact on cellular physiology and pathology. By undergoing fusion and fission, mitochondria are able to change their morphology between elongated interconnected networks and discrete fragmented structures, respectively. The cardiac mitochondria, in particular, have garnered much interest due to their unique spatial arrangement in the adult cardiomyocyte, and the multiple roles they play in cell death and survival. In this article, we review the role of the mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease.
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- 2015
16. Regulation of monocyte/macrophage polarisation by extracellular RNA
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Cabrera-Fuentes H., Lopez M., McCurdy S., Fischer S., Meiler S., Baumer Y., Galuska S., Preissner K., and Boisvert W.
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Inflammation ,Monocyte/macrophage polarization ,Extracellular RNA ,Gene expression ,Microarray technology - Abstract
© Schattauer 2015. Monocytes/macrophages respond to external stimuli with rapid changes in the expression of numerous inflammation-related genes to undergo polarisation towards the M1 (pro-inflammatory) or M2 (antiinflammatory) phenotype. We have previously shown that, independently of Toll-like receptor activation, extracellular RNA (eRNA) could exert pro-thrombotic and pro-inflammatory properties in the cardiovascular system to provoke cytokine mobilisation. Here, mouse bone marrow-derived-macrophages (BMDM) differentiated with mouse macrophage-colony-stimulating factor (M-CSF) were found to be skewed towards the M1 phenotype when exposed to eRNA. This resulted in up-regulated expression of inflammatory markers such as Tnf-α and Il-6, together with Il-12 and iNOS, whereas anti-inflammatory genes such as chitinase-like proteins (Ym1/2) and macrophage mannose receptor-2 (Cd206) were significantly down-regulated. Human peripheral blood monocytes were treated with eRNA and analysed by micro-array analysis of the whole human genome, revealing an up-regulation of 79 genes by at least four-fold; 27 of which are related to signal transduction and 15 genes associated with inflammatory response. In accordance with the proposed actions of eRNA as a pro-inflammatory “alarm signal”, these data shed light on the role of eRNA in the context of chronic inflammatory diseases such as atherosclerosis.
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- 2015
17. RNase1 as a potential mediator of remote ischaemic preconditioning for cardioprotection
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Cabrera-Fuentes H., Niemann B., Grieshaber P., Wollbrueck M., Gehron J., Preissner K., and Böning A.
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Ribonuclease-1 (RNase1) ,Tumour necrosis factor-α (TNF-α) ,Extracellular RNA (eRNA) ,Ischaemia-reperfusion ,Cardiac surgery ,Acute inflammation ,Remote ischaemic preconditioning - Abstract
© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. OBJECTIVES: Remote ischaemic preconditioning (RIPC) is a non-invasive and virtually cost-free strategy for protecting the heart against acute ischaemia-reperfusion injury (IRI). We have recently shown that the inhibition of extracellular RNA (eRNA) using non-toxic RNase1 protected the heart against acute IRI, reduced myocardial infarct (MI) size and preserved left ventricular systolic function in rodent animal MI models. Based on this previous work in animals, the role of the eRNA/RNase1 system in cardiac RIPC in humans should be defined. METHODS: Fourteen patients underwent cardiac surgery without RIPC; from each patient, six separate 5 ml blood specimens from radial artery and two blood specimens from coronary sinus at different time points during heart surgery were taken. Six healthy donors received RIPC (4 × 5 min upper limb ischaemia); blood parameters were quantified before and after RIPC. Twelve patients underwent cardiac surgery of which 6 received RIPC, whereas the remaining 6 were exposed to sham procedure. Circulating eRNA was quantified in plasma from arterial and coronary sinus blood obtained from patients undergoing cardiac by standard procedures. Tumour necrosis factor-α (TNF-α) production by heart tissue was assessed by enzyme-linked immuno-sorbent assay; RNase activity was quantified by an enzymatic assay. RESULTS: Before surgery, eRNA levels were similar in both groups (14 ± 6 vs 13 ± 5 ng/ml; P = 0.9967). In patients without RIPC, arterial eRNA levels rose during surgery (87 ± 12 ng/ml) and peaked after (127 ± 11 ng/ml) aortic declamping; accordingly, eRNA levels in coronary sinus blood were significantly higher (206 ± 32 ng/ml; P = 0.0129) than that in radial artery. Moreover, significant elevation of TNF-α (36 ± 6 ng/ml; P = 0.0059) particularly in coronary sinus blood after opening of the aortic clamping was observed. Interestingly, applying a RIPC protocol significantly increased levels of plasma endogenous vascular RNase1 by >7-fold, and the levels of arterial (31 ± 7 ng/ml; P = 0.0024) and coronary sinus (37 ± 9 ng/ml; P < 0.0001) circulating eRNA, as well as circulating TNF-α (20 ± 4 ng/ml; P = 0.0050) levels were significantly reduced. CONCLUSIONS: Upon RIPC, the level of cardioprotective RNase1 increased, while the concentration of damaging eRNA and TNF-α decreased. The present findings imply a significant contribution of the RIPC-dependent (endothelial) RNase1 for improving the outcome of cardiac surgery. However, the exact mechanism of RNase1-induced cardioprotection still remains to be explored.
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- 2015
18. Hmga2 is required for canonical WNT signaling during lung development
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Singh I., Mehta A., Contreras A., Boettger T., Carraro G., Wheeler M., Cabrera-Fuentes H., Bellusci S., Seeger W., Braun T., and Barreto G.
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HMGA2 ,GATA6 ,WNT signaling ,Branching morphogenesis ,Lung development - Abstract
Background: The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here we deciphered the role of the high-mobility-group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2-deficient mice (Hmga2-/-).Results: We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2-/- mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA-binding protein 6 and frizzled homolog 2. Analysis of siRNA-mediated loss-of-function experiments in embryonic lung explant culture confirmed the role of Hmga2 as a key regulator of distal lung epithelium differentiation and supported the causal involvement of enhanced canonical WNT signaling in mediating the effect of Hmga2-loss-of-fuction. Finally, we found that HMGA2 directly regulates Gata6 and thereby modulates Fzd2 expression.Conclusions: Our results support that Hmga2 regulates canonical WNT signaling at different points of the pathway. Increased expression of the secreted WNT glycoproteins might explain a paracrine effect by which Hmga2-knockout enhanced cell proliferation in the mesenchyme of the developing lung. In addition, HMGA2-mediated direct regulation of Gata6 is crucial for fine-tuning the activity of WNT signaling in the airway epithelium. Our results are the starting point for future studies investigating the relevance of Hmga2-mediated regulation of WNT signaling in the adult lung within the context of proper balance between differentiation and self-renewal of lung stem/progenitor cells during lung regeneration in both homeostatic turnover and repair after injury. © 2014 Singh et al.; licensee BioMed Central Ltd.
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- 2014
19. Thrombin selectively induces transcription of genes in human monocytes involved in inflammation and wound healing
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Lopéz M., Bruges G., Crespo G., Salazar V., Deglesne P., Schneider H., Cabrera-Fuentes H., Lienhard Schmitz M., and Preissner K.
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Inflammation ,Protease-activated receptor ,Thrombin ,Gene expression ,Mitogen-activated protein kinases ,Microarray technology ,Tissue factor - Abstract
© Schattauer 2014. Thrombin is essential for blood coagulation but functions also as a mediator of cellular signalling. Gene expression microarray experiments in human monocytes revealed thrombin-induced upregulation of a limited subset of genes, which are almost exclusively involved in inflammation and wound healing. Among these, the expression of F3 gene encoding for tissue factor (TF) was enhanced indicating that this physiological initiator of coagulation cascade may create a feed-forward loop to enhance blood coagulation. Activation of protease-activated receptor type 1 (PAR1) was shown to play a main role in promoting TF expression. Moreover, thrombin induced phosphorylation of ERK1/2, an event that is required for expression of thrombin-regulated genes. Thrombin also increased the expression of TF at the protein level in monocytes as evidenced by Western blot and immunostaining. Furthermore, FXa generation induced by thrombin-stimulated monocytes was abolished by a TF blocking antibody and therefore it is entirely attributable to the expression of tissue factor. This cellular activity of thrombin provides a new molecular link between coagulation, inflammation and wound healing.
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- 2014
20. Role of extracellular rna in atherosclerotic plaque formation in mice
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Simsekyilmaz S., Cabrera-Fuentes H., Meiler S., Kostin S., Baumer Y., Liehn E., Weber C., Boisvert W., Preissner K., and Zernecke A.
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nucleic acids ,inflammation ,vascular diseases ,atherosclerosis - Abstract
BACKGROUND -: Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage and to act as a proinflammatory mediator. Here, we addressed the role of eRNA in high-fat diet-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice. METHODS AND RESULTS -: The presence of eRNA was revealed in atherosclerotic lesions from high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44±9 versus 70±7 mU/mg protein; P=0.0012), followed by a decrease to levels below baseline after 4 weeks of high-fat diet (44±9 versus 12±2 mU/mg protein; P
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- 2014
21. Case report: Cyclospora cayetanensis: This emerging protozoan pathogen in Mexico
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Śanchez-Vega J., Cabrera-Fuentes H., Romero-Olmedo A., Ortiz-Fŕias J., Sokolina F., and Barreto G.
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A Mexican airline pilot had clinical manifestations of illness after a five-day stay in Lima, Peru. Six months later in Mexico, he was given a diagnosis of infection with Cyclospora cayetanensis by using coproparasitoscopic serial tests. He was treated twice with nitazoxadine successfully. Copyright © 2014 by The American Society of Tropical Medicine and Hygiene.
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- 2014
22. Bacillus intermedius ribonuclease (BINASE) induces apoptosis in human ovarian cancer cells
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Garipov A., Nesmelov A., Cabrera-Fuentes H., and Ilinskaya O.
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endocrine system diseases ,Caspase-3 ,Ovarian cancer ,Binase ,Apoptosis ,EZH2 ,PARP - Abstract
© 2014 Elsevier B.V. All rights reserved. The cytotoxic effects of Bacillus intermedius RNase (binase) towards ovarian cancer cells (SKOV3 and OVCAR5) were studied in comparison to normal ovarian epithelial cells (HOSE1 and HOSE2). Binase decreased viability and induced the selective apoptosis of ovarian cancer cells. The apoptosis rate was 50% in SKOV3 and 48% in OVCAR5 cells after 24 h of binase treatment (50 μg/ml). Binase-induced apoptosis in these cell lines was accompanied by caspase-3 activation and poly(ADP-ribose) polymerase fragmentation. Normal ovarian epithelial cells were not affected by binase, except for a slight decrease of HOSE2 cell viability and the appearance of traces of activated caspase-3, but not the poly(ADP-ribose) polymerase 85-kDA fragment. Binase did not induce alteration of EZH2 (enhancer of zeste-homolog-2) protein expression neither, in tumor nor in normal cells. In conclusion, selective binase-induced cell death and apoptosis via poly(ADP-ribose) polymerase fragmentation may serve as a new treatment option against ovarian cancer progression.
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- 2014
23. Internalization of Bacillus intermedius ribonuclease (BINASE) induces human alveolar adenocarcinoma cell death
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Cabrera-Fuentes H., Aslam M., Saffarzadeh M., Kolpakov A., Zelenikhin P., Preissner K., and Ilinskaya O.
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Binase ,Human alveolar adenocarcinoma cells ,Apoptosis ,DSB ,Permeability ,Cytotoxic RNase ,Internalization - Abstract
Ribonuclease (RNase) treatment represents a novel mechanism based approach to anticancer therapy as an alternative to the DNA damaging drugs commonly used in clinical practice. Apart from their ribonucleolytic activity, cytotoxic effects have attracted a considerable attention to RNases because of their potential as selective agents for treatment of certain malignancies. Among these enzymes, Binase, an RNase from Bacillus intermedius, has shown promising results. Here, we have found that binase selectively attacked human A549 alveolar adenocarcinoma cells to trigger an apoptotic response, whereas normal lung epithelial cells LEK were not affected by the ribonuclease. The tumor transformation led to the modification of certain cellular characteristics causing cell sensitivity to binase. Although a general mode for RNases cytotoxicity includes their penetration into the cell, translocation to the cytosol and degradation of ribonucleic acid, many aspects of this process have not been fully elucidated. Our data revealed the following time-dependent changes induced by binase in A549 cells: (a) fast permanent internalization of the enzyme during the first hours of treatment; (b) temporary increase in cellular permeability for macromolecules during the 4-6hof treatment; (c) apoptotic alterations in population after 24hand (d) DNA fragmentation and cell death after 72hof treatment with binase. Elucidation of these molecular strategies used by this promising toxin provides us essential information for the development of new anticancer drugs. © 2013 Elsevier Ltd.
- Published
- 2013
24. Influence of chronic food deprivation on structure-function relationship of juvenile rat fast muscles
- Author
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Ruiz-Rosado A., Cabrera-Fuentes H., González-Calixto C., González-López L., Cázares-Raga F., Segura-Alegría B., Lochnit G., De La Cruz Hernández-Hernández F., Preissner K., and Jiménez-Estrada I.
- Subjects
EDL muscle ,Oxidative fibers ,Undernutrition ,Glycolytic fibers ,Muscle fatigue - Abstract
In the present study, we analyze the influence of chronic undernutrition on protein expression, muscle fiber type composition, and fatigue resistance of the fast extensor digitorum longus (EDL) muscle of male juvenile rats (45 ± 3 days of life; n = 25 and 31 rats for control and undernourished groups, respectively). Using 2D gel electrophoresis and mass spectrometry, we identified in undernourished muscles 12 proteins up-regulated (8 proteins of the electron transport chain and the glycolytic pathway, 2 cross-bridge proteins, chaperone and signaling proteins that are related to the stress response). In contrast, one down-regulated protein related to the fast muscle contractile system and two other proteins with no changes in expression were used as charge controls. By means of COX and alkaline ATPase histochemical techniques and low-frequency fatigue protocols we determined that undernourished muscles showed a larger proportion (15 % increase) of Type IIa/IId fibers (oxidative- glycolytic) at the expense of Type IIb (glycolytic) fibers (15.5 % decrease) and increased fatigue resistance (55.3 %). In addition, all fiber types showed a significant reduction in their cross-sectional area (slow: 64.4 %; intermediate: 63.9 % and fast: 61.2 %). These results indicate that undernourished EDL muscles exhibit an increased expression of energy metabolic and myofibrillar proteins which are associated with the predominance of oxidative and Type IIa/IId fibers and to a higher resistance to fatigue. We propose that such alterations may act as protective and/or adaptive mechanisms that counterbalance the effect of chronic undernourishment. © 2013 Springer Science+Business Media Dordrecht.
- Published
- 2013
25. Binase penetration into alveolar epithelial cells does not induce cell death
- Author
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Cabrera Fuentes H., Katacheva N., Mukhametshina R., Zelenikhin P., Kolpakov A., Barreto G., Preissner K., and Ilinskaya O.
- Subjects
Cytotoxicity ,Immunofluorescence ,type II alveolar epithelial cells ,Binase ,MLE-12 ,respiratory system ,ATII ,Alveolar epithelial cells type II ,Internalization - Abstract
Microbial ribonucleases possess a broad spectrum of biological activities, which demonstrate stimulating properties at low concentrations and cytotoxicity and genotoxicity at high concentrations. Mechanisms of their penetration into the cells still remain unclear. In this study penetration of Bacillus intermedius RNase (binase) in alveolar lung epithelial cells, type II (ATII) pneumocytes, has been investigated. Using immunofluorescence analysis we have shown for the first time internalization of binase by primary non-differentiated pneumocytes ATII. The enzyme did not penetrate in MLE-12 (Murine Lung Epithelial-12 cells). However, binase was cytotoxic towards tumor MLE-12 cells, but not ATII cells. These results clearly indicate higher sensitivity of tumor cells to binase compared to normal cells; they also demonstrate that penetration of the enzyme into alveolar epithelial cells is not directly associated with their death. © 2012 Pleiades Publishing, Ltd.
- Published
- 2012
26. Antitumor RNase (binase) induces the alteration of cellular permeability
- Author
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Cabrera-Fuentes H., Zelenikhin P., Kolpakov A., and Ilinskaya O.
- Subjects
Ca2+ ,Cytotoxicity ,Binase ,Cellular permeability - Abstract
Some RNases including ones of microbial origin possess antitumor activity, which mechanisms remains unclear. Here we investigated the first step of RNase action towards eukaryotic cells which is connected with increase of cell permeability for ions and macromolecules. Using radiological analysis of 45Ca2+uptake by Candida yeast and fluorescence imaging of human embryo kidney cells HEK stained by Ca2+-specific Fura-2/AM day the level of intracellular Ca2+ under treatment with the RNase of Bacillus intermedius (binase) was studied. Viability of lung carcinoma epithelial cells A549 treated by binase was measured by WST proliferation kit, stability of erythrocytes was tested by lysis assay. We have shown that binase induces the permeability increase of lower and higher eukaryotic cells for Ca2+as well as the increase of protein permeability of A549 cells. Binase treatment protects erythrocytes from osmotic shock. The protective or cytotoxic binase effect followed by increase of cellular permeability is realized depending on the dell type, where the expression of Kca channels and of certain oncogens, particularly of ras family, is crucial. The obtained data supports the significance of the cell permeability increase as a primary step in the mechanisms of binase-induced biological effects.
- Published
- 2012
27. Attenuation of Myocardial Ischemia/Reperfusion Reaction by RNAse1 Treatment
- Author
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Giese, K., primary, Böning, A., additional, Niemann, B., additional, Cabrera-Fuentes, H., additional, Preissner, K., additional, and Heep, M., additional
- Published
- 2015
- Full Text
- View/download PDF
28. 008 * RNASE1 AS A POTENTIAL MEDIATOR OF REMOTE ISCHAEMIC PRECONDITIONING FOR CARDIOPROTECTION
- Author
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Boening, A., primary, Niemann, B., additional, Grieshaber, P., additional, Preissner, K. T., additional, and Cabrera-Fuentes, H., additional
- Published
- 2014
- Full Text
- View/download PDF
29. C0266: Regulation of Macrophage Polarization by Extracellular RNA: The Role of Sialoadhesin-1
- Author
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Alejandro Cabrera-Fuentes, H., primary, Galuska, S., additional, Preissner, K.T., additional, and Boisvert, W.A., additional
- Published
- 2014
- Full Text
- View/download PDF
30. P166 Extracellular RNA in cardiac ischemia/reperfusion injury: prevention of heart failure and cell damage by RNase1.
- Author
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Cabrera-Fuentes, H A, Ruiz-Meana, M, Kostin, S, Lecour, S, Hausenloy, DJ, Garcia-Dorado, DJ, Schluter, KD, and Preissner, KT
- Subjects
- *
RNA , *REPERFUSION injury , *HEART failure , *RIBONUCLEASES , *MORTALITY , *MYOCARDIAL infarction - Abstract
Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant. Extracellular RNA (eRNA), exposed after cell damage, serves as cofactor for coagulation proteases and cytokines thereby promoting their procoagulant and proinflammatory functions in vivo. Following myocardial ischemia/reperfusion (I/R) in mice or I/R induced in the isolated Langendorff heart, increased eRNA levels were found together with cell injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced tumor-necrosis-factor-a (TNF-α) liberation by activation of TNF-α converting enzyme (TACE) and provoked cardiomyocyte death. Conversely, TNF-a promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores (mPTP) as well as oxidative damage in cardiomyocytes. Together, RNase1 as well as inhibition of TACE provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-a interplay and significantly reduce or prevent the pathological outcome of ischemic heart injury. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
- Full Text
- View/download PDF
31. P735 Regulation of macrophage polarization by extracellular RNA: The role of sialoadhesin-1.
- Author
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Cabrera-Fuentes, H A, Galuska, S, Meiler, S, Baumer, Y, Mccurdy, S, Fischer, S, Preissner, KT, and Boisvert, W
- Subjects
- *
MACROPHAGE activation , *EXTRACELLULAR matrix proteins , *RNA , *CELL adhesion , *TUMOR necrosis factors , *PHENOTYPES , *CYTOKINES - Abstract
Macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. This unique property of macrophages allows these cells to modulate chronic inflammatory processes such as atherogenesis. We have previously shown that extracellular RNA (eRNA) can exert prothrombotic and inflammatory properties in the vasculature as a cofactor in protease auto-activation and cytokine mobilization. Given the association of eRNA with macrophages within atherosclerotic lesions, we assessed whether eRNA generated by the macrophages themselves may induce inflammatory responses within macrophages, independent of Toll-like receptor signaling. Recombinant mouse macrophage CSF-driven bone marrow-derived macrophage (BMDM) differentiation was skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in the overexpression of inflammatory markers such as Tnf-α, Arg2, Il-1β, Il-6, or Ifn-Γ together with Il-12 and iNOS, whereas anti-inflammatory genes such as Il-10 and Il-4 together with Arg1 and macrophage mannose receptor-2 (Cd206) were significantly down-regulated by eRNA. Accordingly, the release of TNF-α and IL-6 proteins into the cell supernatant was significantly elevated by eRNA stimulation. Moreover, the capacity of granulocyte macrophage CSF-driven BMDM differentiation (already representing M1 phenotype) towards further M1 polarization in response to eRNA was moderate. Nevertheless, a significant down-regulation of M2 markers was found. Sialoadhesin-1 (SN-1) is a membrane-anchored basic protein, predominantly expressed on macrophages and involved in cellular interactions via recognition of sialylated glycoconjugates. Interestingly, exposure of SN-1-/- BMDM towards eRNA resulted in prominent down-regulation of pro-inflammatory cytokines together with M1 phenotype markers, while anti-inflammatory cytokines together with M2 phenotype mediators were significantly raised. In accordance with our proposal that eRNA serves as pro-inflammatory "alarm signal" during physiologically distressed conditions, these data may shed light on the role of eRNA and macrophages in chronic inflammatory environment such as atherosclerosis. The self-perpetuating process of atherosclerosis as a largely inflammation-driven pathology may be controlled by SN-1 expression on lesional macrophages as well as the injury-mediated release of eRNA as a master trigger in inflammation. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
- Full Text
- View/download PDF
32. RNase1 prevents the damaging interplay between extracellular RNA and tumour necrosis factor-α in cardiac ischaemia/reperfusion injury.
- Author
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Cabrera-Fuentes HA, Ruiz-Meana M, Simsekyilmaz S, Kostin S, Inserte J, Saffarzadeh M, Galuska SP, Vijayan V, Barba I, Barreto G, Fischer S, Lochnit G, Ilinskaya ON, Baumgart-Vogt E, Böning A, Lecour S, Hausenloy DJ, Liehn EA, Garcia-Dorado D, Schlüter KD, and Preissner KT
- Subjects
- Animals, Antioxidants metabolism, Cell Hypoxia, Cytoprotection, Disease Models, Animal, Mice, Mitochondria, Heart drug effects, Mitochondria, Heart enzymology, Mitochondria, Heart pathology, Myocardial Infarction enzymology, Myocardial Infarction genetics, Myocardial Infarction immunology, Myocardial Infarction pathology, Myocardial Reperfusion Injury enzymology, Myocardial Reperfusion Injury genetics, Myocardial Reperfusion Injury immunology, Myocardial Reperfusion Injury pathology, Myocardium immunology, Myocardium pathology, Myocytes, Cardiac enzymology, Myocytes, Cardiac immunology, Myocytes, Cardiac pathology, RNA genetics, Rats, Reactive Oxygen Species metabolism, Signal Transduction drug effects, Time Factors, Tumor Necrosis Factor-alpha immunology, Autocrine Communication drug effects, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocardium enzymology, Myocytes, Cardiac drug effects, RNA metabolism, Ribonucleases pharmacology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant, and the initial mechanistic trigger of myocardial "ischaemia/reperfusion (I/R) injury" remains greatly unexplained. Here we show that factors released from the damaged cardiac tissue itself, in particular extracellular RNA (eRNA) and tumour-necrosis-factor α (TNF-α), may dictate I/R injury. In an experimental in vivo mouse model of myocardial I/R as well as in the isolated I/R Langendorff-perfused rat heart, cardiomyocyte death was induced by eRNA and TNF-α. Moreover, TNF-α promoted further eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R with the massive production of oxygen radicals, mitochondrial obstruction, decrease in antioxidant enzymes and decline of cardiomyocyte functions. The administration of RNase1 significantly decreased myocardial infarction in both experimental models. This regimen allowed the reduction in cytokine release, normalisation of antioxidant enzymes as well as preservation of cardiac tissue. Thus, RNase1 administration provides a novel therapeutic regimen to interfere with the adverse eRNA-TNF-α interplay and significantly reduces or prevents the pathological outcome of ischaemic heart disease.
- Published
- 2014
- Full Text
- View/download PDF
33. [Binase penetration into alveolar epithelial cells does not induce cell death].
- Author
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Cabrera Fuentes HA, Kalacheva NV, Mukhametshina RT, Zelenichin PV, Kolpakov AI, Barreto G, Praĭssner KT, and Il'inskaia ON
- Subjects
- Alveolar Epithelial Cells cytology, Alveolar Epithelial Cells drug effects, Animals, Antigens, Polyomavirus Transforming genetics, Cell Death drug effects, Cell Differentiation, Endoribonucleases pharmacology, Epithelial Cells cytology, Epithelial Cells drug effects, Lung Neoplasms genetics, Lung Neoplasms pathology, Mice, Pulmonary Alveoli drug effects, Endoribonucleases pharmacokinetics, Lung Neoplasms drug therapy, Pulmonary Alveoli cytology
- Abstract
Microbial ribonucleases possess a broad spectra of biological activities, demonstrating stimulating properties at low concentrations and cytotoxicity and genotoxicity at high concentrations. The mechanisms of their penetration into the cells are not clear so far. This research is aimed to the study of Bacillus intermedius RNase (binase) penetration in alveolar lung epithelial cells--pneumocytes of type II. Using immunofluorescence we have shown for the first time have internalization of binase by primary non-differentiated pneumocytes ATII. The enzyme did not penetrate in pneumocytes MLE-12, which also derived from type II cells. However, binase was cytotoxic towards tumor MLE-12 cells, but not ATII cells. The obtained results testified the higher sensitivity of tumor cells towards binase compared with normal cells, and also showed that penetration of the enzyme into alveolar cells did not directly correlated with the cell death.
- Published
- 2012
- Full Text
- View/download PDF
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