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  • 1
    Online Resource
    Online Resource
    KRAB-Induced Heterochromatin Effectively Silences PLOD2 Gene Expression in Somatic Cells and Is Resilient to TGFβ1 Activation
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 10 ( 2020-05-21), p. 3634-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 10 ( 2020-05-21), p. 3634-
    Abstract: Epigenetic editing, an emerging technique used for the modulation of gene expression in mammalian cells, is a promising strategy to correct disease-related gene expression. Although epigenetic reprogramming results in sustained transcriptional modulation in several in vivo models, further studies are needed to develop this approach into a straightforward technology for effective and specific interventions. Important goals of current research efforts are understanding the context-dependency of successful epigenetic editing and finding the most effective epigenetic effector(s) for specific tasks. Here we tested whether the fibrosis- and cancer-associated PLOD2 gene can be repressed by the DNA methyltransferase M.SssI, or by the non-catalytic Krüppel associated box (KRAB) repressor directed to the PLOD2 promoter via zinc finger- or CRISPR-dCas9-mediated targeting. M.SssI fusions induced de novo DNA methylation, changed histone modifications in a context-dependent manner, and led to 50%–70% reduction in PLOD2 expression in fibrotic fibroblasts and in MDA-MB-231 cancer cells. Targeting KRAB to PLOD2 resulted in the deposition of repressive histone modifications without DNA methylation and in almost complete PLOD2 silencing. Interestingly, both long-term TGFβ1-induced, as well as unstimulated PLOD2 expression, was completely repressed by KRAB, while M.SssI only prevented the TGFβ1-induced PLOD2 expression. Targeting transiently expressed dCas9-KRAB resulted in sustained PLOD2 repression in HEK293T and MCF-7 cells. Together, these findings point to KRAB outperforming DNA methylation as a small potent targeting epigenetic effector for silencing TGFβ1-induced and uninduced PLOD2 expression.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21103634
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
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    Functional Validation of the Putative Oncogenic Activity of PLAU
    MDPI AG ; 2022
    In:  Biomedicines Vol. 11, No. 1 ( 2022-12-30), p. 102-
    Details
    In: Biomedicines, MDPI AG, Vol. 11, No. 1 ( 2022-12-30), p. 102-
    Abstract: Plasminogen activator, urokinase (PLAU) is involved in cell migration, proliferation and tissue remodeling. PLAU upregulation is associated with an increase in aggressiveness, metastasis, and invasion of several cancer types, including breast cancer. In patients, this translates into decreased sensitivity to hormonal treatment, and poor prognosis. These clinical findings have led to the examination of PLAU as a biomarker for predicting breast cancer prognosis and therapy responses. In this study, we investigated the functional ability of PLAU to act as an oncogene in breast cancers by modulating its expression using CRISPR-deactivated Cas9 (CRISPR-dCas9) tools. Different effector domains (e.g., transcription modulators (VP64, KRAB)) alone or in combination with epigenetic writers (DNMT3A/3L, MSssI) were fused to dCas9 and targeted to the PLAU promoter. In MDA-MB-231 cells characterized by high PLAU expression downregulation of PLAU expression by CRISPR-dCas9-DNMT3A/3L-KRAB, resulted in decreased cell proliferation. Conversely, CRISPR-dCas9-VP64 induced PLAU upregulation in low PLAU expressing MCF-7 cells and significantly increased aggressiveness and invasion. In conclusion, modulation of PLAU expression affected metastatic related properties of breast cancer cells, thus further validating its oncogenic activity in breast cancer cells.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines11010102
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720867-9
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  • 3
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    Challenges and Outcomes of a Randomized Study of Early Nutrition Support during Autologous Stem-Cell Transplantation
    MDPI AG ; 2014
    In:  Current Oncology Vol. 21, No. 2 ( 2014-04-01), p. 334-339
    Details
    In: Current Oncology, MDPI AG, Vol. 21, No. 2 ( 2014-04-01), p. 334-339
    Abstract: Patients undergoing myeloablative conditioning regimens and autologous stem-cell transplantation (ASCT) are at high risk of malnutrition. This randomized study aimed to determine if early nutrition support (commenced when oral intake is less than 80% of estimated requirements) compared with usual care (commenced when oral intake is less than 50% of estimated requirements) reduces weight loss in wellnourished patients undergoing high-nutritional-risk conditioning chemotherapy and ASCT. In the 50 well-nourished patients who were randomized, the outcomes evaluated included changes in weight and lean body mass (mid-upper arm circumference), length of stay, time to hemopoietic engraftment, and quality of life (Memorial Symptom Assessment Scale – Short Form). On secondary analysis, after exclusion of a single extreme outlier, both groups demonstrated significant weight loss over time (p = 0.0005). Weight loss was less in the early nutrition support group at time of discharge (mean: –0.4% ± 2.9% vs. –3.4% ± 2.6% in the usual care group, p = 0.001). This difference in weight was no longer observed at 6 months after discharge (mean: –1.0% ± 6.8% vs. 1.4% ± 6.1%, p = 0.29). In practice, an early start to nutrition support proved difficult because of patient resistance and physician preference, with 8 patients (33%) in the control group and 4 (15%) in the intervention group not commencing nutrition support when stipulated by the study protocol. No significant differences between the groups were found for other outcomes. In wellnourished patients receiving ASCT, early nutrition support maintained weight during admission, but did not affect other outcomes. Interpretation of results should take into consideration the difficulties encountered with intervention implementation.
    Type of Medium: Online Resource
    ISSN: 1718-7729
    URL: Article
    DOI: 10.3747/co.21.1820
    Language: English
    Publisher: MDPI AG
    Publication Date: 2014
    detail.hit.zdb_id: 2270777-3
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  • 4
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    Neutrophil-to-Lymphocyte Ratio Is an Independent Risk Factor for Coronary Artery Disease in Central Obesity
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 8 ( 2023-04-17), p. 7397-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 8 ( 2023-04-17), p. 7397-
    Abstract: Several inflammatory biomarkers were found to be associated with an increased risk of cardiovascular disease. Neutrophil-to-lymphocyte ratio (NLR) is a marker of subclinical inflammation that increases with the stress response. Visceral adiposity index (VAI) calculated as a combination of anthropometric and metabolic parameters reflects both the extent and function of visceral adipose tissue. Given the association of subclinical inflammation with both obesity and cardiovascular diseases, it is plausible that the inflammation–CVD association is modulated by the amount and function of adipose tissue. Thus, our aim was to examine the association between NLR and coronary artery calcium score (CACS), an intermediate marker of coronary artery disease in asymptomatic patients across VAI tertiles. Methods: Data from 280 asymptomatic participants of a cardiovascular screening program were analysed. In addition to the collection of lifestyle and medical history, a non-contrast cardiac CT scan and laboratory tests were performed on all participants. Multivariate logistic regression was conducted with CACS 〉 100 as the outcome and with conventional cardiovascular risk factors and NLR, VAI, and NLR by VAI tertile as predictors. Results: We found an interaction between VAI tertiles and NLR; NLR values were similar in the lower VAI tertiles, while they were higher in the CACS 〉 100 in the 3rd VAI tertile (CACS ≤ 100: 1.94 ± 0.58 vs. CACS 〉 100: 2.48 ± 1.1, p = 0.008). According to multivariable logistic regression, the interaction between NLR and VAI tertiles remained: NLR was associated with CACS 〉 100 in the 3rd VAI tertile (OR = 1.67, 95% CI 1.06–2.62, p = 0.03) but not in the lower tertiles even after adjustment for age, sex, smoking, history of hypertension, hyperlipidaemia, and diabetes mellitus, as well as high-sensitivity C-reactive protein. Our findings draw attention to the independent association between subclinical, chronic, systemic inflammation and subclinical coronary disease in obesity.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24087397
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 5
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    Allele-Specific Dual PCRs to Identify Members of the 27a Cluster of PPV
    MDPI AG ; 2022
    In:  Viruses Vol. 14, No. 7 ( 2022-07-08), p. 1500-
    Details
    In: Viruses, MDPI AG, Vol. 14, No. 7 ( 2022-07-08), p. 1500-
    Abstract: Porcine Parvovirus (PPV) is one of the most important infectious agents causing severe reproductive failure in pigs. In the last two decades a particular, a novel genotype emerged in Europe and PPV-27a was named as the prototype of this genetic cluster. It was suggested that members of the PPV-27a cluster may adversely influence effective vaccination against PPV. For a reliable updated 27a definition, we aligned 93 databank-deposited partial or full nucleotide and protein sequences of the VP2 of different PPV isolates. We confirmed that the 27a cluster could indeed be distinguished from other members of the species, however, some divergences were identified compared to earlier defined genetic markers. Based on genetic differences, we developed a dual allele-specific polymerase chain reaction for the easy and quick discrimination of members of the 27a cluster from other PPV strains. The detection limit of dual PCR was found 〈 1.66 × 104 copies/reaction. To sensitize and make it more user friendly, the method was further developed for qPCR application with fluorescent probes. Regarding the detection limit of the two PCRs ( 〈 1.66 × 104 copies/reaction of the dual PCR versus 〈 2.40 × 102 copy/reaction of the dual qPCR), approximately two log improvement was achieved in the sensitivity of the method.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v14071500
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2516098-9
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  • 6
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    Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo
    MDPI AG ; 2022
    In:  Pharmaceuticals Vol. 15, No. 9 ( 2022-08-26), p. 1055-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 15, No. 9 ( 2022-08-26), p. 1055-
    Abstract: Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post-marketing studies. Therefore, we aimed to investigate the hidden cardiotoxicity of rosiglitazone in ischemia/reperfusion (I/R) injury models. Rats were treated orally with either 0.8 mg/kg/day rosiglitazone or vehicle for 28 days and subjected to I/R with or without cardioprotective ischemic preconditioning (IPC). Rosiglitazone did not affect mortality, arrhythmia score, or infarct size during I/R. However, rosiglitazone abolished the antiarrhythmic effects of IPC. To investigate the direct effect of rosiglitazone on cardiomyocytes, we utilized adult rat cardiomyocytes (ARCMs), AC16, and differentiated AC16 (diffAC16) human cardiac cell lines. These were subjected to simulated I/R in the presence of rosiglitazone. Rosiglitazone improved cell survival of ARCMs at 0.3 μM. At 0.1 and 0.3 μM, rosiglitazone improved cell survival of AC16s but not that of diffAC16s. This is the first demonstration that chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models. However, the inhibition of the antiarrhythmic effects of IPC may have some clinical relevance that needs to be further explored.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph15091055
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2193542-7
    SSG: 15,3
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  • 7
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    Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs
    MDPI AG ; 2019
    In:  International Journal of Molecular Sciences Vol. 20, No. 4 ( 2019-02-25), p. 991-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 4 ( 2019-02-25), p. 991-
    Abstract: Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms20040991
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 8
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    Hidden Cardiotoxicity of Rofecoxib Can be Revealed in Experimental Models of Ischemia/Reperfusion
    MDPI AG ; 2020
    In:  Cells Vol. 9, No. 3 ( 2020-02-26), p. 551-
    Details
    In: Cells, MDPI AG, Vol. 9, No. 3 ( 2020-02-26), p. 551-
    Abstract: Cardiac adverse effects are among the leading causes of the discontinuation of clinical trials and the withdrawal of drugs from the market. The novel concept of ‘hidden cardiotoxicity’ is defined as cardiotoxicity of a drug that manifests in the diseased (e.g., ischemic/reperfused), but not in the healthy heart or as a drug-induced deterioration of cardiac stress adaptation (e.g., ischemic conditioning). Here, we aimed to test if the cardiotoxicity of a selective COX-2 inhibitor rofecoxib that was revealed during its clinical use, i.e., increased occurrence of proarrhythmic and thrombotic events, could have been revealed in early phases of drug development by using preclinical models of ischemia/reperfusion (I/R) injury. Rats that were treated with rofecoxib or vehicle for four weeks were subjected to 30 min. coronary artery occlusion and 120 min. reperfusion with or without cardioprotection that is induced by ischemic preconditioning (IPC). Rofecoxib increased overall the arrhythmias including ventricular fibrillation (VF) during I/R. The proarrhythmic effect of rofecoxib during I/R was not observed in the IPC group. Rofecoxib prolonged the action potential duration (APD) in isolated papillary muscles, which was not seen in the simulated IPC group. Interestingly, while showing hidden cardiotoxicity manifested as a proarrhythmic effect during I/R, rofecoxib decreased the infarct size and increased the survival of adult rat cardiac myocytes that were subjected to simulated I/R injury. This is the first demonstration that rofecoxib increased acute mortality due to its proarrhythmic effect via increased APD during I/R. Rofecoxib did not interfere with the cardiprotective effect of IPC; moreover, IPC was able to protect against rofecoxib-induced hidden cardiotoxicity. These results show that cardiac safety testing with simple preclinical models of I/R injury uncovers hidden cardiotoxicity of rofecoxib and might reveal the hidden cardiotoxicity of other drugs.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells9030551
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2661518-6
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  • 9
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    Maternally Derived Antibody Levels Influence on Vaccine Protection against PCV2d Challenge
    MDPI AG ; 2021
    In:  Animals Vol. 11, No. 8 ( 2021-07-29), p. 2231-
    Details
    In: Animals, MDPI AG, Vol. 11, No. 8 ( 2021-07-29), p. 2231-
    Abstract: Piglets from a porcine circovirus type 2 (PCV2) stable farm of low and high levels of maternally derived antibodies (MDA) against PCV2 were vaccinated either with a whole virus type or a PCV2 ORF2 antigen-based commercial subunit vaccine at three weeks of age. Two non-vaccinated groups served as low and high MDA positive controls. At four weeks post vaccination, all piglets were challenged with a PCV2d-2 type virus strain and were checked for parameters related to vaccine protection over a four-week observation period. MDA levels evidently impacted the outcome of the PCV2d-2 challenge in non-vaccinated animals, while it did not have a significant effect on vaccine-induced protection levels. The humoral immune response developed faster in the whole virus vaccinates than in the subunit vaccinated pigs in the low MDA groups. Further, high MDA levels elicited a stronger negative effect on the vaccine-induced humoral immune response for the subunit vaccine than for the whole virus vaccine. The group-based oral fluid samples and the group mean viraemia and faecal shedding data correlated well, enabling this simple, and animal welfare-friendly sampling method for the evaluation of the PCV2 viral load status of these nursery piglets.
    Type of Medium: Online Resource
    ISSN: 2076-2615
    URL: Article
    DOI: 10.3390/ani11082231
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2606558-7
    SSG: 23
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  • 10
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    A Case of Infectious Laryngotracheitis in an Organic Broiler Chicken Farm in Greece
    MDPI AG ; 2021
    In:  Veterinary Sciences Vol. 8, No. 4 ( 2021-04-16), p. 64-
    Details
    In: Veterinary Sciences, MDPI AG, Vol. 8, No. 4 ( 2021-04-16), p. 64-
    Abstract: Infectious laryngotracheitis is an economically significant viral disease of chickens, that mainly affects the upper respiratory tract, and is present worldwide. This case reports the first outbreak of infectious laryngotracheitis in a four-week-old organic broiler farm and surrounding flocks in Greece, with typical clinical symptoms and lesions, allegedly provoked by a wild strain of infectious laryngotracheitis virus. Our findings contradict the general perception indicating that the disease appears mainly in older birds and that vaccine strains are the primary cause of infectious laryngotracheitis outbreaks in most continents. A recombinant vectored vaccine was administered, supplementary to biosecurity measures, containing the viral spread. The responsible strain was potentially circulating in the area; therefore, an industry-wide holistic approach was applied, including the vaccination of neighboring broilers and breeders with the same vaccine, the rapid molecular diagnosis of the disease, and strict biosecurity protocols. The results of this holistic effort were effective because, following the application of vaccine and management protocols, manifestations of the disease in regional flocks dropped significantly, and there was no recurrence to date. These findings suggest that vaccination protocols should be modified, especially for organic broilers, to include vaccination against infectious laryngotracheitis.
    Type of Medium: Online Resource
    ISSN: 2306-7381
    URL: Article
    DOI: 10.3390/vetsci8040064
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2768971-2
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