MicroRNA in Fibrotic Disorders: A Potential Target for Future Therapeutics.

Fibrotic disorders are defined by accumulating excessive extracellular matrix (ECM) components, especially collagens, in various organs, leading to tissue scarring and organ dysfunction. These conditions are associated with significant challenges in the healthcare system because of their progressive nature and limited treatment options. MicroRNAs (miRNAs) are small non-coding RNA molecules (approximately 22 nucleotides) that modulate gene expression by selectively targeting mRNAs for degradation or translational repression. MiRNAs have recently been identified as potential targets for therapeutic developments in fibrotic disorders. They play vital roles in inducing fibrotic phenotype by regulating fibroblast activation and ECM remodeling. Multiple strategies for targeting specific miRNAs in fibrotic disorders have been explored, including antisense oligonucleotides, small molecule modulators, and natural compounds. This review discussed the role of miRNAs in different fibrotic disorders, including cardiac fibrosis, liver fibrosis, kidney fibrosis, lung fibrosis, dermal fibrosis, and primary myelofibrosis, with recent advances in developing miRNA-based therapeutics.

A Data-Mining Approach to Identify NF-kB-Responsive microRNAs in Tissues Involved in Inflammatory Processes: Potential Relevance in Age-Related Diseases.

The nuclear factor NF-kB is the master transcription factor in the inflammatory process by modulating the expression of pro-inflammatory genes. However, an additional level of complexity is the ability to promote the transcriptional activation of post-transcriptional modulators of gene expression as non-coding RNA (i.e., miRNAs). While NF-kB's role in inflammation-associated gene expression has been extensively investigated, the interplay between NF-kB and genes coding for miRNAs still deserves investigation. To identify miRNAs with potential NF-kB binding sites in their transcription start site, we predicted miRNA promoters by an in silico analysis using the PROmiRNA software, which allowed us to score the genomic region's propensity to be miRNA cis-regulatory elements. A list of 722 human miRNAs was generated, of which 399 were expressed in at least one tissue involved in the inflammatory processes. The selection of "high-confidence" hairpins in miRbase identified 68 mature miRNAs, most of them previously identified as inflammamiRs. The identification of targeted pathways/diseases highlighted their involvement in the most common age-related diseases. Overall, our results reinforce the hypothesis that persistent activation of NF-kB could unbalance the transcription of specific inflammamiRNAs. The identification of such miRNAs could be of diagnostic/prognostic/therapeutic relevance for the most common inflammatory-related and age-related diseases.

Corrigendum to "Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells?"

[This corrects the article DOI: 10.1155/2017/2309034.].

A Practical Guide to miRNA Target Prediction.

MicroRNAs (miRNAs) are small endogenous noncoding RNA molecules that posttranscriptionally regulate gene expression. Since their discovery, a huge number of miRNAs have been identified in a wide range of species. Through binding to the 3' UTR of mRNA, miRNA can block translation or stimulate degradation of the targeted mRNA, thus affecting nearly all biological processes. Prediction and identification of miRNA target genes is crucial toward understanding the biology of miRNAs. Currently, a number of sophisticated bioinformatics approaches are available to perform effective prediction of miRNA target sites. In this chapter, we present the major features that most algorithms take into account to efficiently predict miRNA target: seed match, free energy, conservation, target site accessibility, and contribution of multiple binding sites. We also give an overview of the frequently used bioinformatics tools for miRNA target prediction. Understanding the basis of these prediction methodologies may help users to better select the appropriate tools and analyze their output.

Exosome-based immunomodulation during aging: A nano-perspective on inflamm-aging.

Exosomes are nanovesicles formed by inward budding of endosomal membranes. They exert complex immunomodulatory effects on target cells, acting both as antigen-presenting vesicles and as shuttles for packets of information such as proteins, coding and non-coding RNA, and nuclear and mitochondrial DNA fragments. Albeit different, all such functions seem to be encompassed in the adaptive mechanism mediating the complex interactions of the organism with a variety of stressors, providing both for defense and for the evolution of symbiotic relationships with others organisms (gut microbiota, bacteria, and viruses). Intriguingly, the newly deciphered human virome and exosome biogenesis seem to share some physical-chemical characteristics and molecular mechanisms. Exosomes are involved in immune system recognition of self from non-self throughout life: they are therefore ideal candidate to modulate inflamm-aging, the chronic, systemic, age-related pro-inflammatory status, which influence the development/progression of the most common age-related diseases (ARDs). Not surprisingly, recent evidence has documented exosomal alteration during aging and in association with ARDs, even though data in this field are still limited. Here, we review current knowledge on exosome-based trafficking between immune cells and self/non-self cells (i.e. the virome), sketching a nano-perspective on inflamm-aging and on the mechanisms involved in health maintenance throughout life.

Progress of research on microRNAs with diagnostic value in asbestos exposure: A call for method standardization.

Malignant mesothelioma (MM) is an insidious, lethal asbestos-related cancer that is poorly responsive to current treatments. Specific and sensitive biomarkers providing early MM diagnosis in exposed subjects, who are at high-risk of developing it, are sorely needed. MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs with a well-established diagnostic role in cancer and pollution exposure. In a recent systematic review and qualitative meta-analysis followed by a functional investigation, we examined all the available data on the miRNA biomarkers involved in asbestos exposure and MM pathways. This invited commentary aims to provide an insightful critique into the state of the art of the research into clinically relevant miRNA biomarkers, highlighting the strengths and weaknesses of current research efforts in this field. It also reviews the suggestions advanced to improve biomarker development productivity and the translation of research results into clinical practice, stressing that multicenter multidisciplinary studies adopting standardized methods and protocol sharing are the key to move from the workbench to the clinic.

Bioactive Nutrients and Nutrigenomics in Age-Related Diseases.

The increased life expectancy and the expansion of the elderly population are stimulating research into aging. Aging may be viewed as a multifactorial process that results from the interaction of genetic and environmental factors, which include lifestyle. Human molecular processes are influenced by physiological pathways as well as exogenous factors, which include the diet. Dietary components have substantive effects on metabolic health; for instance, bioactive molecules capable of selectively modulating specific metabolic pathways affect the development/progression of cardiovascular and neoplastic disease. As bioactive nutrients are increasingly identified, their clinical and molecular chemopreventive effects are being characterized and systematic analyses encompassing the "omics" technologies (transcriptomics, proteomics and metabolomics) are being conducted to explore their action. The evolving field of molecular pathological epidemiology has unique strength to investigate the effects of dietary and lifestyle exposure on clinical outcomes. The mounting body of knowledge regarding diet-related health status and disease risk is expected to lead in the near future to the development of improved diagnostic procedures and therapeutic strategies targeting processes relevant to nutrition. The state of the art of aging and nutrigenomics research and the molecular mechanisms underlying the beneficial effects of bioactive nutrients on the main aging-related disorders are reviewed herein.

Mitochondrial (Dys) Function in Inflammaging: Do MitomiRs Influence the Energetic, Oxidative, and Inflammatory Status of Senescent Cells?

A relevant feature of aging is chronic low-grade inflammation, termed inflammaging, a key process promoting the development of all major age-related diseases. Senescent cells can acquire the senescence-associated (SA) secretory phenotype (SASP), characterized by the secretion of proinflammatory factors fuelling inflammaging. Cellular senescence is also accompanied by a deep reshaping of microRNA expression and by the modulation of mitochondria activity, both master regulators of the SASP. Here, we synthesize novel findings regarding the role of mitochondria in the SASP and in the inflammaging process and propose a network linking nuclear-encoded SA-miRNAs to mitochondrial gene regulation and function in aging cells. In this conceptual structure, SA-miRNAs can translocate to mitochondria (SA-mitomiRs) and may affect the energetic, oxidative, and inflammatory status of senescent cells. We discuss the potential role of several of SA-mitomiRs (i.e., let-7b, miR-1, miR-130a-3p, miR-133a, miR-146a-5p, miR-181c-5p, and miR-378-5p), using miR-146a as a proof-of-principle model. Finally, we propose a comprehensive, metabolic, and epigenetic view of the senescence process, in order to amplify the range of possible approaches to target inflammaging, with the ultimate goal of decelerating the aging rate, postponing or blunting the development of age-related diseases.

Leukocyte telomere length and mortality risk in patients with type 2 diabetes.

Leukocyte telomere length (LTL) shortening is found in a number of age-related diseases, including type 2 diabetes (T2DM). In this study its possible association with mortality was analyzed in a sample of 568 T2DM patients (mean age 65.9 ± 9 years), who were followed for a median of 10.2 years (interquartile range 2.2). A number of demographic, laboratory and clinical parameters determined at baseline were evaluated as mortality risk factors. LTL was measured by quantitative real-time PCR and reported as T/S (telomere-to-single copy gene ratio). Age, gender, creatinine, diabetes duration at baseline, and LTL were significantly different between T2DM patients who were dead and alive at follow-up. In the Cox regression analysis adjusted for the confounding variables, shorter LTL, older age, and longer disease duration significantly increased the risk of all-cause mortality (HR = 3.45, 95%CI 1.02-12.5, p = 0.004). Kaplan-Maier analysis also found a different cumulative mortality risk for patients having an LTL shorter than the median (T/S ≤0.04) and disease duration longer than the median (>10 years) (log-rank = 11.02, p = 0.011). Time-dependent mortality risk stratification showed that T2DM duration and LTL combined was a fairly good predictor of mortality over the first 76 months of follow-up.In conclusion, LTL combined with clinical parameters can provide additive prognostic information on mortality risk in T2DM patients.

Diagnostic value of microRNAs in asbestos exposure and malignant mesothelioma: systematic review and qualitative meta-analysis.

BACKGROUND: Asbestos is a harmful and exceptionally persistent natural material. Malignant mesothelioma (MM), an asbestos-related disease, is an insidious, lethal cancer that is poorly responsive to current treatments. Minimally invasive, specific, and sensitive biomarkers providing early and effective diagnosis in high-risk patients are urgently needed. MicroRNAs (miRNAs, miRs) are endogenous, non-coding, small RNAs with established diagnostic value in cancer and pollution exposure. A systematic review and a qualitative meta-analysis were conducted to identify high-confidence miRNAs that can serve as biomarkers of asbestos exposure and MM. METHODS: The major biomedical databases were systematically searched for miRNA expression signatures related to asbestos exposure and MM. The qualitative meta-analysis applied a novel vote-counting method that takes into account multiple parameters. The most significant miRNAs thus identified were then subjected to functional and bioinformatic analysis to assess their biomarker potential. RESULTS: A pool of deregulated circulating and tissue miRNAs with biomarker potential for MM was identified and designated as "mesomiRs" (MM-associated miRNAs). Comparison of data from asbestos-exposed and MM subjects found that the most promising candidates for a multimarker signature were circulating miR-126-3p, miR-103a-3p, and miR-625-3p in combination with mesothelin. The most consistently described tissue miRNAs, miR-16-5p, miR-126-3p, miR-143-3p, miR-145-5p, miR-192-5p, miR-193a-3p, miR-200b-3p, miR-203a-3p, and miR-652-3p, were also found to provide a diagnostic signature and should be further investigated as possible therapeutic targets. CONCLUSION: The qualitative meta-analysis and functional investigation confirmed the early diagnostic value of two miRNA signatures for MM. Large-scale, standardized validation studies are needed to assess their clinical relevance, so as to move from the workbench to the clinic.

Bioinformatic tools for microRNA dissection.

Recently, microRNAs (miRNAs) have emerged as important elements of gene regulatory networks. MiRNAs are endogenous single-stranded non-coding RNAs (~22-nt long) that regulate gene expression at the post-transcriptional level. Through pairing with mRNA, miRNAs can down-regulate gene expression by inhibiting translation or stimulating mRNA degradation. In some cases they can also up-regulate the expression of a target gene. MiRNAs influence a variety of cellular pathways that range from development to carcinogenesis. The involvement of miRNAs in several human diseases, particularly cancer, makes them potential diagnostic and prognostic biomarkers. Recent technological advances, especially high-throughput sequencing, have led to an exponential growth in the generation of miRNA-related data. A number of bioinformatic tools and databases have been devised to manage this growing body of data. We analyze 129 miRNA tools that are being used in diverse areas of miRNA research, to assist investigators in choosing the most appropriate tools for their needs.

MiR-21-5p and miR-126a-3p levels in plasma and circulating angiogenic cells: relationship with type 2 diabetes complications.

Innovative biomarkers are required to manage type 2 diabetic patients (T2DM). We focused our study on miR-126-3p and miR-21-5p levels, as biomarkers of endothelial function and inflammation. MiRNAs levels were measured in plasma from 107 healthy subjects (CTR) and 193 diabetic patients (T2DM), 76 without (T2DM NC) and 117 with (T2DM C) complications. When diabetic complication were analysed as a whole, miR-126-3p and miR-21-5p levels declined significantly from CTR to T2DM NC and T2DM C patients. When miRNAs levels were related to specific complications, significantly higher miR-21-5p levels (0.46 ± 0.44 vs. 0.26 ± 0.33, p < 0.001) and significant lower miR-126-3p levels (0.21 ± 0.21 vs. 0.28 ± 0.22, p = 0.032) were found in T2DM with previous major cardiovascular events (MACE) vs. all the others T2DM patients. To confirm these results we focused on circulating angiogenic cells (CACs) from a subgroup of 10 CTR, 15 T2DM NC and 15 T2DM patients with MACE. CACs from T2DM patients expressed higher miR-21-5p and lower miR-126-3p levels than CACs from CTR. Furthermore, CACs from T2DM + MACE showed the highest levels of miR-21-5p. Circulating miR-21-5p and miR-126-3p emerge as dynamic biomarkers of systemic inflammatory/angiogenic status. Their expression levels in CACs from T2DM with MACE suggest a shift from a proangiogenic to a proinflammatory profile.