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Background: Sepsis can lead to myocardial depression, playing a significant role in sepsis pathophysiology, clinical care, and outcome. To gain more insight into the pathophysiology of the myocardial response in sepsis, we investigated the expression of microRNA in myocardial autopsy specimens in critically ill deceased with sepsis and non-septic controls., Materials and Methods: In this retrospective observational study, we obtained myocardial tissue samples collected during autopsy from adult patients deceased with sepsis (n = 15) for routine histological examination. We obtained control myocardial tissue specimens (n = 15) from medicolegal autopsies of cadavers whose cause of death was injury or who were found dead at home and the cause of death was coronary artery disease with sudden cardiac arrest. RNA was isolated from formalin-fixed paraffin- embedded (FFPE) cardiac samples using the RecoverAll Total Nucleic Acid Isolation Kit for FFPE (Invitrogen). Differentially expressed miRNAs were identified using edgeR v3.32. MicroRNA was considered up- or down-regulated if the false discovery rate was < 0.05 and logarithmic fold change (log2FC) ≥ 1 for up-regulated or log2FC ≤ -1 for down-regulated miRNAs. The mean difference and 95% confidence interval (CI) were calculated for normalized read counts. Predicted miRNA targets were retrieved using Ingenuity Pathway Analysis (IPA) software, and pathway enrichment and classification were performed using PantherDB. For miRNA - mRNA interaction analysis, differentially expressed genes were analyzed by 3`mRNA sequencing., Results: Differential expression analysis identified a total of 32 miRNAs in the myocardial specimens. Eight miRNAs had a significant change in the mean difference based on the 95% CI, with the largest increase in mean counts in septic samples with hsa-miR-12136 and the highest fold change with hsa-miR-146b-5p. The threshold for down-regulated miRNAs in sepsis compared to controls was obtained with hsa-miR-144-5p and hsa-miR-451a, with the latter having the largest decrease in mean counts and fold decrease. The miRNA - mRNA interaction analysis identified eight miRNAs with target genes also differentially expressed in septic hearts. The highest number of potential targets were identified for hsa-miR-363-3p., Conclusions: Several regulatory miRNAs were up-or down-regulated in the myocardial tissue of patients deceased with sepsis compared to non-septic subjects. The predicted target genes of miRNAs and miRNA-mRNA interaction analysis are associated with biological functions related to cardiovascular functions, cell viability, cell adhesion, and regulation of inflammatory and immune response., Competing Interests: Declarations. Ethics approval: The study protocol was approved by the hospital administration and ethics committee of Oulu University Hospital and the Northern Ostrobothnia Hospital District (72/2021; 33/2021). All research was performed in accordance with relevant guidelines and regulations in accordance with the Declaration of Helsinki. The specimens were collected during autopsy for routine histological examination and preserved in the Biobank Borealis of Northern Finland. The use of myocardial tissue obtained from the medicolegal autopsies as case control samples was approved by the Finnish Institute for Health and Welfare (THL/873/5.05.00/2023; THL/697/5.05.00/2017). Consent from next of kin or from the donor was waived by the Ethics Committee since according to the Finnish law, during post-mortem examinations, samples removed can also be used for medical research other than that related to investigation of the cause of death. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis., Methods and Results: Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-β1 and collagen I., Conclusions: Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The prognostic significance of the major redox regulator nuclear factor erythroid-2-related factor (NRF2) is recognized in many cancers, but the role of NRF1 is not generally well understood in cancer. Our aim was to investigate these redox transcription factors in conjunction with redox-related microRNAs in naevi and melanoma. We characterized the immunohistochemical expression of NRF1 and NRF2 in 99 naevi, 88 primary skin melanomas, and 67 lymph node metastases. In addition, NRF1 and NRF2 mRNA and miR-23B, miR-93, miR-144, miR-212, miR-340, miR-383, and miR-510 levels were analysed with real-time qPCR from 54 paraffin-embedded naevi and melanoma samples. The immunohistochemical expression of nuclear NRF1 decreased from benign to dysplastic naevi ( p < 0.001) and to primary melanoma ( p < 0.001) and from primary melanoma to metastatic lesions ( p = 0.012). Also, NRF1 mRNA levels decreased from benign naevi to dysplastic naevi ( p = 0.034). Similarly, immunopositivity of NRF2 decreased from benign to dysplastic naevi ( p = 0.02) and to primary lesions ( p = 0.018). NRF2 mRNA decreased from benign to dysplastic naevi and primary melanomas ( p = 0.012). Analysis from the Gene Expression Omnibus datasets supported the mRNA findings. High nuclear immunohistochemical NRF1 expression in pigment cells associated with a worse survival ( p = 0.048) in patients with N0 disease at the time of diagnosis, and high nuclear NRF2 expression in pigment cells associated with a worse survival ( p = 0.033) in patients with M0 disease at the time of diagnosis. In multivariate analysis, neither of these variables exceeded the prognostic power of Breslow. The levels of miR-144 and miR-212 associated positively with ulceration ( p = 0.012 and p = 0.027, respectively) while miR-510 levels associated positively with lymph node metastases at the time of diagnosis ( p = 0.004). Furthermore, the miRNAs correlated negatively with the immunohistochemical expression of NRF1 and NRF2 but positively with their respective mRNA. Together, this data sheds new light about NFE2L family factors in pigment tumors and suggests that these factors are worth for further explorations., Competing Interests: All authors declare that there are none., (Copyright © 2019 Mari Hämäläinen et al.)