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Infertility is a global problem being associated with emotional and financial burden. Recent studies have shown contribution of a group of non-coding RNAs, namely circular RNAs (circRNAs) to the etiology of some infertility conditions. CircRNA are transcribed from exons and form a circular RNA molecule, being abundant in eukaryotes. Traditionally classified as non-coding RNA, these transcripts are endogenously produced through either non-canonical back-splicing or linear splicing, typically produced from precursor messenger ribonucleic acid (pre-mRNA). While during the canonical splicing process the 3' end of the exon is joined to the 5' end of the succeeding exon to form linear mRNA, during backsplicing, the 3' end to the 5' end of the same exon is joined to make a circular molecule. circRNAs are involved in the regulation of several aspects of spermatogenesis. They appear to influence how stem germ cells grow and divide during the sperm production process. Malfunctions in circRNA activity could contribute to male infertility issues stemming from abnormalities in spermatogenesis. In the current review, we highlight the exciting potential of circRNAs as key players in the male fertility. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC), characterized by high invasiveness, is associated with poor prognosis and elevated mortality rates. Despite the development of effective therapeutic targets for TNBC, systemic chemotherapy and radiotherapy (RdT) remain prevalent treatment modalities. One notable challenge of RdT is the acquisition of radioresistance, which poses a significant obstacle in achieving optimal treatment response. Compelling evidence implicates non-coding RNAs (ncRNAs), gene expression regulators, in the development of radioresistance. This systematic review focuses on describing the role, association, and/or involvement of ncRNAs in modulating radioresponse in TNBC. In adhrence to the PRISMA guidelines, an extensive and comprehensive search was conducted across four databases using carefully selected entry terms. Following the evaluation of the studies based on predefined inclusion and exclusion criteria, a refined selection of 37 original research articles published up to October 2023 was obtained. In total, 33 different ncRNAs, including lncRNAs, miRNAs, and circRNAs, were identified to be associated with radiation response impacting diverse molecular mechanisms, primarily the regulation of cell death and DNA damage repair. The findings highlighted in this review demonstrate the critical roles and the intricate network of ncRNAs that significantly modulates TNBC's responsiveness to radiation. The understanding of these underlying mechanisms offers potential for the early identification of non-responders and patients prone to radioresistance during RdT, ultimately improving TNBC survival outcomes. [ABSTRACT FROM AUTHOR]

Non-coding RNAs (ncRNAs), including circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs), are unique RNA molecules widely identified in the eukaryotic genome. Their dysregulation has been discovered and played key roles in the pathogenesis of numerous diseases, including various cancers. Previously considered devoid of protein-coding ability, recent research has revealed that a small number of open reading frames (ORFs) within these ncRNAs endow them with the potential for protein coding. These ncRNAs-derived peptides or proteins have been proven to regulate various physiological and pathological processes through diverse mechanisms. Their emerging roles in disease diagnosis and targeted therapy underscore their potential utility in clinical settings. This comprehensive review aims to provide a systematic overview of proteins or peptides encoded by lncRNAs and circRNAs, elucidate their production and functional mechanisms, and explore their promising applications in cancer diagnosis, disease prediction, and targeted therapy. [ABSTRACT FROM AUTHOR]

Ferroptosis, a unique type of regulated cell death plays a vital role in inhibiting tumour malignancy and has presented new opportunities for treatment of therapy in hepatocellular carcinoma. Accumulating studies indicate that epigenetic modifications by non-coding RNAs, including microRNAs, long noncoding RNAs, and circular RNAs, can determine cancer cell vulnerability to ferroptosis in HCC. The present review first summarize the updated core molecular mechanisms of ferroptosis. We then provide a concised overview of epigenetic modification of ferroptosis in HCC. Finally, we review the recent progress in understanding of the ncRNA-mediated regulated mechanisms on ferroptosis in HCC. The review will promote our understanding of the ncRNA-mediated epigenetic regulatory mechanisms modulating ferroptosis in malignancy of HCC, highlighting a novel strategies for treatment of HCC through targeting ncRNA-ferroptosis axis. [ABSTRACT FROM AUTHOR]

Background: The yield of major crops is generally limited by sink capacity and source strength. Cucumber is a typical raffinose family oligosaccharides (RFOs)–transporting crop. Non-coding RNAs and alternative polyadenylation (APA) play important roles in the regulation of growth process in plants. However, their roles on the sink‒source regulation have not been demonstrated in RFOs–translocating species. Results: Here, whole–transcriptome sequencing was applied to compare the leaves of cucumber under different sink strength, that is, no fruit-carrying leaves (NFNLs) and fruit-carrying leaves (FNLs) at 12th node from the bottom. The results show that 1101 differentially expressed (DE) mRNAs, 79 DE long non–coding RNAs (lncRNAs) and 23 DE miRNAs were identified, which were enriched in photosynthesis, energy production and conversion, plant hormone signal transduction, starch and carbohydrate metabolism and protein synthesis pathways. Potential co–expression networks like, DE lncRNAs–DE mRNAs/ DE miRNAs–DE mRNAs, and competing endogenous RNA (ceRNA) regulation models (DE lncRNAs–DE miRNAs–DE mRNAs) associated with sink‒source allocation, were constructed. Furthermore, 37 and 48 DE genes, which enriched in MAPK signaling and plant hormone signal transduction pathway, exist differentially APA, and SPS (CsaV3_2G033300), GBSS1 (CsaV3_5G001560), ERS1 (CsaV3_7G029600), PNO1 (CsaV3_3G003950) and Myb (CsaV3_3G022290) may be regulated by both ncRNAs and APA between FNLs and NFNLs, speculating that ncRNAs and APA are involved in the regulation of gene expression of cucumber sink‒source carbon partitioning. Conclusions: These results reveal a comprehensive network among mRNAs, ncRNAs, and APA in cucumber sink–source relationships. Our findings also provide valuable information for further research on the molecular mechanism of ncRNA and APA to enhance cucumber yield. [ABSTRACT FROM AUTHOR]

The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, a unique type of regulated cell death, plays a pivotal role in inhibiting tumour growth, presenting new opportunities in treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine cancer cell vulnerability to ferroptosis. In this review, we first summarize the role of chemotherapeutic resistance in cancer growth/development. Then, we summarize the core molecular mechanisms of ferroptosis, its upstream epigenetic regulation, and its downstream effects on chemotherapeutic resistance. Finally, we review recent advances in understanding how ncRNAs regulate ferroptosis and from such modulate chemotherapeutic resistance. This review aims to enhance general understanding of the ncRNA-mediated epigenetic regulatory mechanisms which modulate ferroptosis, highlighting the ncRNA-ferroptosis axis as a key druggable target in overcoming chemotherapeutic resistance. [ABSTRACT FROM AUTHOR]

Exosomes mediate cell-to-cell crosstalk involving a variety of biomolecules through an intricate signaling network. In recent years, the pivotal role of exosomes and their non-coding RNAs cargo in the development and progression of several cancer types clearly emerged. In particular, tumor bulk and its microenvironment co-evolve through cellular communications where these nanosized extracellular vesicles are among the most relevant actors. Knowledge about the cellular, and molecular mechanisms involved in these communications will pave the way for novel exosome-based delivery of therapeutic RNAs as well as innovative prognostic/diagnostic tools. Despite the valuable therapeutic potential and clinical relevance of exosomes, their role on sarcoma has been vaguely reported because the rarity and high heterogeneity of this type of cancer. Here, we dissected the scientific literature to unravel the multifaceted role of exosomal non-coding RNAs as mediator of cell-to-cell communications in the sarcoma subtypes. [ABSTRACT FROM AUTHOR]

Background: The prevalence of infertility among couples is estimated to range from 8 to 12%. A paradigm shift has occurred in understanding of infertility, challenging the notion that it predominantly affects women. It is now acknowledged that a significant proportion, if not the majority, of infertility cases can be attributed to male-related factors. Various elements contribute to male reproductive impairments, including aberrant sperm production caused by pituitary malfunction, testicular malignancies, aplastic germ cells, varicocele, and environmental factors. Main body: The epigenetic profile of mammalian sperm is distinctive and specialized. Various epigenetic factors regulate genes across different levels in sperm, thereby affecting its function. Changes in sperm epigenetics, potentially influenced by factors such as environmental exposures, could contribute to the development of male infertility. Conclusion: In conclusion, this review investigates the latest studies pertaining to the mechanisms of epigenetic changes that occur in sperm cells and their association with male reproductive issues. [ABSTRACT FROM AUTHOR]

Background: Unlike Transposable Elements (TEs) and gene/genome duplication, the role of the so-called nuclear plastid DNA sequences (NUPTs) in shaping the evolution of genome architecture and function remains poorly studied. We investigate here the functional and evolutionary fate of NUPTs in the orphan crop Moringa oleifera (moringa), featured by the highest fraction of plastid DNA found so far in any plant genome, focusing on (i) any potential biases in their distribution in relation to specific nuclear genomic features, (ii) their contribution to the emergence of new genes and gene regions, and (iii) their impact on the expression of target nuclear genes. Results: In agreement with their potential mutagenic effect, NUPTs are underrepresented among structural genes, although their overall transcription levels and broadness were only lower when involved exonic regions; the occurrence of plastid DNA generally did not result in a broader expression, except among those affected in introns by older NUPTs. In contrast, we found a strong enrichment of NUPTs among specific superfamilies of retrotransposons and several classes of RNA genes, including those participating in the protein biosynthetic machinery (i.e., rRNA and tRNA genes) and a specific class of regulatory RNAs. A significant fraction of NUPT RNA genes was found to be functionally expressed, thus potentially contributing to the nuclear pool. Conclusions: Our results complete our view of the molecular factors driving the evolution of nuclear genome architecture and function, and support plastid DNA in moringa as a major source of (i) genome complexity and (ii) the nuclear pool of RNA genes. [ABSTRACT FROM AUTHOR]

Cancer-related cachexia is a metabolic syndrome characterized by weight loss, adipose tissue decomposition, and progressive skeletal muscle atrophy. It is a major complication of many advanced cancers and seriously affects the quality of life and survival of cancer patients. However, the specific molecules that mediate cancer-related cachexia remain elusive, and the fundamental cellular and molecular mechanisms associated with muscle atrophy and lipidolysis in cancer patients still need to be investigated. Exosomes, a newly discovered class of small extracellular vesicles that facilitate intercellular communication, have a significant role in the onset and development of various cancers. Studies have shown that exosomes play a role in the onset and progression of cancer-related cachexia by transporting active molecules such as nucleic acids and proteins. This review aimed to provide an overview of exosome developments in cancer-induced skeletal muscle atrophy and adipose tissue degradation. More importantly, exosomes were shown to have potential as diagnostic markers or therapeutic strategies for cachexia and were prospected, providing novel strategies for the diagnosis and treatment of cancer-related cachexia. [ABSTRACT FROM AUTHOR]

Breast cancer is significantly influenced by endoplasmic reticulum (ER) stress, impacting both its initiation and progression. When cells experience an accumulation of misfolded or unfolded proteins, they activate the unfolded protein response (UPR) to restore cellular balance. In breast cancer, the UPR is frequently triggered due to challenging conditions within tumors. The UPR has a dual impact on breast cancer. On one hand, it can contribute to tumor growth by enhancing cell survival and resistance to programmed cell death in unfavorable environments. On the other hand, prolonged and severe ER stress can trigger cell death mechanisms, limiting tumor progression. Furthermore, ER stress has been linked to the regulation of non-coding RNAs (ncRNAs) in breast cancer cells. These ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play essential roles in cancer development by influencing gene expression and cellular processes. An improved understanding of how ER stress and ncRNAs interact in breast cancer can potentially lead to new treatment approaches. Modifying specific ncRNAs involved in the ER stress response might interfere with cancer cell survival and induce cell death. Additionally, focusing on UPR-associated proteins that interact with ncRNAs could offer novel therapeutic possibilities. Therefore, this review provides a concise overview of the interconnection between ER stress and ncRNAs in breast cancer, elucidating the nuanced effects of the UPR on cell fate and emphasizing the regulatory roles of ncRNAs in breast cancer progression. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is an end-stage of many cardiac diseases and one of the main causes of death worldwide. The current management of this disease remains suboptimal. The adult mammalian heart was considered a post-mitotic organ. However, several reports suggest that it may possess modest regenerative potential. Adult cardiac progenitor cells (CPCs), the main players in the cardiac regeneration, constitute, as it may seem, a heterogenous group of cells, which remain quiescent in physiological conditions and become activated after an injury, contributing to cardiomyocytes renewal. They can mediate their beneficial effects through direct differentiation into cardiac cells and activation of resident stem cells but majorly do so through paracrine release of factors. CPCs can secrete cytokines, chemokines, and growth factors as well as exosomes, rich in proteins, lipids and non-coding RNAs, such as miRNAs and YRNAs, which contribute to reparation of myocardium by promoting angiogenesis, cardioprotection, cardiomyogenesis, anti-fibrotic activity, and by immune modulation. Preclinical studies assessing cardiac progenitor cells and cardiac progenitor cells-derived exosomes on damaged myocardium show that administration of cardiac progenitor cells-derived exosomes can mimic effects of cell transplantation. Exosomes may become new promising therapeutic strategy for heart regeneration nevertheless there are still several limitations as to their use in the clinic. Key questions regarding their dosage, safety, specificity, pharmacokinetics, pharmacodynamics and route of administration remain outstanding. There are still gaps in the knowledge on basic biology of exosomes and filling them will bring as closer to translation into clinic. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common malignancies that pose a serious threat to women's health. Reprogramming of energy metabolism is a major feature of the malignant transformation of breast cancer. Compared to normal cells, tumor cells reprogram metabolic processes more efficiently, converting nutrient supplies into glucose, amino acid and lipid required for malignant proliferation and progression. Non-coding RNAs(ncRNAs) are a class of functional RNA molecules that are not translated into proteins but regulate the expression of target genes. NcRNAs have been demonstrated to be involved in various aspects of energy metabolism, including glycolysis, glutaminolysis, and fatty acid synthesis. This review focuses on the metabolic regulatory mechanisms and clinical applications of metabolism-regulating ncRNAs involved in breast cancer. We summarize the vital roles played by metabolism-regulating ncRNAs for endocrine therapy, targeted therapy, chemotherapy, immunotherapy, and radiotherapy resistance in breast cancer, as well as their potential as therapeutic targets and biomarkers. Difficulties and perspectives of current targeted metabolism and non-coding RNA therapeutic strategies are discussed. [ABSTRACT FROM AUTHOR]

Venous thromboembolism, which includes deep venous thrombosis (DVT) and pulmonary embolism, is the third most common vascular disease in the world and seriously threatens the lives of patients. Currently, the effect of conventional treatments on DVT is limited. Endothelial progenitor cells (EPCs) play an important role in the resolution and recanalization of DVT, but an unfavorable microenvironment reduces EPC function. Non-coding RNAs, especially long non-coding RNAs and microRNAs, play a crucial role in improving the biological function of EPCs. Non-coding RNAs have become clinical biomarkers of diseases and are expected to serve as new targets for disease intervention. A theoretical and experimental basis for the development of new methods for preventing and treating DVT in the clinic will be provided by studies on the role and molecular mechanism of non-coding RNAs regulating EPC function in the occurrence and development of DVT. To summarize, the characteristics of venous thrombosis, the regulatory role of EPCs in venous thrombosis, and the effect of non-coding RNAs regulating EPCs on venous thrombosis are reviewed. This summary serves as a useful reference and theoretical basis for research into the diagnosis, prevention, treatment, and prognosis of venous thrombosis. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC), characterized by high invasiveness, is associated with poor prognosis and elevated mortality rates. Despite the development of effective therapeutic targets for TNBC, systemic chemotherapy and radiotherapy (RdT) remain prevalent treatment modalities. One notable challenge of RdT is the acquisition of radioresistance, which poses a significant obstacle in achieving optimal treatment response. Compelling evidence implicates non-coding RNAs (ncRNAs), gene expression regulators, in the development of radioresistance. This systematic review focuses on describing the role, association, and/or involvement of ncRNAs in modulating radioresponse in TNBC. In adhrence to the PRISMA guidelines, an extensive and comprehensive search was conducted across four databases using carefully selected entry terms. Following the evaluation of the studies based on predefined inclusion and exclusion criteria, a refined selection of 37 original research articles published up to October 2023 was obtained. In total, 33 different ncRNAs, including lncRNAs, miRNAs, and circRNAs, were identified to be associated with radiation response impacting diverse molecular mechanisms, primarily the regulation of cell death and DNA damage repair. The findings highlighted in this review demonstrate the critical roles and the intricate network of ncRNAs that significantly modulates TNBC's responsiveness to radiation. The understanding of these underlying mechanisms offers potential for the early identification of non-responders and patients prone to radioresistance during RdT, ultimately improving TNBC survival outcomes. [ABSTRACT FROM AUTHOR]

Across the world, oral cancer is a prevalent tumor. Over the years, both its mortality and incidence have grown. Oral cancer metastasis is a complex process involving cell invasion, migration, proliferation, and egress from cancer tissue either by lymphatic vessels or blood vessels. MicroRNAs (miRNAs) are essential short non-coding RNAs, which can act either as tumor suppressors or as oncogenes to control cancer development. Cancer metastasis is a multi-step process, in which miRNAs can inhibit or stimulate metastasis at all stages, including epithelial-mesenchymal transition, migration, invasion, and colonization, by targeting critical genes in these pathways. On the other hand, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), two different types of non-coding RNAs, can regulate cancer metastasis by affecting gene expression through cross-talk with miRNAs. We reviewed the scientific literature (Google Scholar, Scopus, and PubMed) for the period 2000–2023 to find reports concerning miRNAs and lncRNA/circRNA-miRNA-mRNA networks, which control the spread of oral cancer cells by affecting invasion, migration, and metastasis. According to these reports, miRNAs are involved in the regulation of metastasis pathways either by directly or indirectly targeting genes associated with metastasis. Moreover, circRNAs and lncRNAs can induce or suppress oral cancer metastasis by acting as competing endogenous RNAs to inhibit the effect of miRNA suppression on specific mRNAs. Overall, non-coding RNAs (especially miRNAs) could help to create innovative therapeutic methods for the control of oral cancer metastases. [ABSTRACT FROM AUTHOR]

Neurological disorders such as stroke, multiple sclerosis, as well as the neurodegenerative diseases Parkinson's or Alzheimer's disease are accompanied or even powered by danger associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue. Besides protein-related DAMPs or "alarmins", numerous nucleic acid DAMPs exist in body fluids, such as cell-free nuclear and mitochondrial DNA as well as different species of extracellular RNA, collectively termed as self-extracellular nucleic acids (SENAs). Among these, microRNA, long non-coding RNAs, circular RNAs and extracellular ribosomal RNA constitute the majority of RNA-based DAMPs. Upon tissue injury, necrosis or apoptosis, such SENAs are released from neuronal, immune and other cells predominantly in association with extracellular vesicles and may be translocated to target cells where they can induce intracellular regulatory pathways in gene transcription and translation. The majority of SENA-induced signaling reactions in the brain appear to be related to neuroinflammatory processes, often causally associated with the onset or progression of the respective disease. In this review, the impact of the diverse types of SENAs on neuroinflammatory and neurodegenerative diseases will be discussed. Based on the accumulating knowledge in this field, several specific antagonistic approaches are presented that could serve as therapeutic interventions to lower the pathological outcome of the indicated brain disorders. [ABSTRACT FROM AUTHOR]

Background: The interaction networks between coding and non-coding RNAs (ncRNAs) including long non-coding RNA (lncRNA), covalently closed circular RNA (circRNA) and miRNA are significant to elucidate molecular processes of biological activities and interactions between host and pathogen. Congenital infection caused by vertical transmission of microsporidia N. bombycis can result in severe economic losses in the silkworm-feeding industry. However, little is known about ncRNAs that take place in the microsporidia congenital infection. Here we conducted whole-transcriptome RNA-Seq analyses to identify ncRNAs and regulatory networks for both N. bombycis and host including silkworm embryos and larvae during the microsporidia congenital infection. Results: A total of 4,171 mRNAs, 403 lncRNA, 62 circRNAs, and 284 miRNAs encoded by N. bombycis were identified, among which some differentially expressed genes formed cross-talk and are involved in N. bombycis proliferation and infection. For instance, a lncRNA/circRNA competing endogenous RNA (ceRNA) network including 18 lncRNAs, one circRNA, and 20 miRNAs was constructed to describe 14 key parasites genes regulation, such as polar tube protein 3 (PTP3), ricin-B-lectin, spore wall protein 4 (SWP4), and heat shock protein 90 (HSP90). Regarding host silkworm upon N. bombycis congenital infection, a total of 14,889 mRNAs, 3,038 lncRNAs, 19,039 circRNAs, and 3,413 miRNAs were predicted based on silkworm genome with many differentially expressed coding and non-coding genes during distinct developmental stages. Different species of RNAs form interacting network to modulate silkworm biological processes, such as growth, metamorphosis and immune responses. Furthermore, a lncRNA/circRNA ceRNA network consisting of 140 lncRNAs, five circRNA, and seven miRNAs are constructed hypothetically to describe eight key host genes regulation, such as Toll-6, Serpin-6, inducible nitric oxide synthase (iNOS) and Caspase-8. Notably, cross-species analyses indicate that parasite and host miRNAs play a vital role in pathogen-host interaction in the microsporidia congenital infection. Conclusion: This is the first comprehensive pan-transcriptome study inclusive of both N. bombycis and its host silkworm with a specific focus on the microsporidia congenital infection, and show that ncRNA-mediated regulation plays a vital role in the microsporidia congenital infection, which provides a new insight into understanding the basic biology of microsporidia and pathogen-host interaction. [ABSTRACT FROM AUTHOR]

Reproductive traits play a vital role in determining the production efficiency of sheep. Maximizing the production is of paramount importance for breeders worldwide due to the growing population. Circular RNAs (circRNAs) act as miRNA sponges by absorbing miRNA activity through miRNA response elements (MREs) and participate in ceRNA regulatory networks (ceRNETs) to regulate mRNA expression. Despite of extensive research on role of circRNAs as miRNA sponges in various species, their specific regulatory roles and mechanism in sheep ovarian tissue are still not well understood. In this study, we performed whole genome sequencing of circRNAs, miRNA and mRNA employing bioinformatic techniques on ovine tissues of two contrasting sheep breeds "Small tail Han (X_LC) and Dolang sheep (D_LC)", which results into identification of 9,878 circRNAs with a total length of 23,522,667 nt and an average length of 2,381.32 nt. Among them, 44 differentially expressed circRNAs (DECs) were identified. Moreover, correlation between miRNA-mRNA and lncRNA-miRNA provided us with to prediction of miRNA binding sites on nine differentially expressed circRNAs and 165 differentially expressed mRNAs using miRanda. miRNA-mRNA and lncRNA-miRNA pairs with negative correlation were selected to determine the ceRNA score along with positively correlated pairs from lncRNA and mRNA network. Integration of ceRNA score and positively correlated pairs exhibit a significant ternary relationship among circRNAs-miRNA-mRNA demonestrated by ceRNA, comprising of 50 regulatory pairs sharring common nodes and predicted potential differentially expressed circRNAs-miRNAs-mRNAs regulatory axis. Based on functional enrichment analysis shortlisted key ceRNA regulatory pairs associated with reproduction including circRNA_3257-novel579_mature-EPHA3, circRNA_8396-novel130_mature-LOC101102473, circRNA_4140- novel34_mature > novel661_mature-KCNK9, and circRNA_8312-novel339_mature-LOC101110545. Furthermore, expression profiling, functional enrichments and qRT-PCR analysis of key target genes infer their implication in reproduction and metabolism. ceRNA target mRNAs evolutionary trajectories, expression profiling, functional enrichments, subcellular localizations following genomic organizations will provide new insights underlying molecular mechanisms of reproduction, and establish a solid foundation for future research. Graphical abstract summarizing the scheme of study [ABSTRACT FROM AUTHOR]

Diabetes mellitus, a group of metabolic disorders characterized by high levels of blood glucose caused by insulin defect or impairment, is a major risk factor for cardiovascular diseases and related mortality. Patients with diabetes experience a state of chronic or intermittent hyperglycemia resulting in damage to the vasculature, leading to micro- and macro-vascular diseases. These conditions are associated with low-grade chronic inflammation and accelerated atherosclerosis. Several classes of leukocytes have been implicated in diabetic cardiovascular impairment. Although the molecular pathways through which diabetes elicits an inflammatory response have attracted significant attention, how they contribute to altering cardiovascular homeostasis is still incompletely understood. In this respect, non-coding RNAs (ncRNAs) are a still largely under-investigated class of transcripts that may play a fundamental role. This review article gathers the current knowledge on the function of ncRNAs in the crosstalk between immune and cardiovascular cells in the context of diabetic complications, highlighting the influence of biological sex in such mechanisms and exploring the potential role of ncRNAs as biomarkers and targets for treatments. The discussion closes by offering an overview of the ncRNAs involved in the increased cardiovascular risk suffered by patients with diabetes facing Sars-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Background: Despite significant advancements in multiple myeloma (MM) therapy, the highly heterogenous treatment response hinders reliable prognosis and tailored therapeutics. Herein, we have studied the clinical utility of miRNAs in ameliorating patients' management. Methods: miRNA-seq was performed in bone marrow CD138+ plasma cells (PCs) of 24 MM and smoldering MM (sMM) patients to analyze miRNAs profile. CD138+ and circulating miR-25 levels were quantified using in house RT-qPCR assays in our screening MM/sMM cohort (CD138+ plasma cells n = 167; subcohort of MM peripheral plasma samples n = 69). Two external datasets (Kryukov et al. cohort n = 149; MMRF CoMMpass study n = 760) served as institutional-independent validation cohorts. Patients' mortality and disease progression were assessed as clinical endpoints. Internal validation was performed by bootstrap analysis. Clinical benefit was estimated by decision curve analysis. Results: miRNA-seq highlighted miR-25 of CD138+ plasma cells to be upregulated in MM vs. sMM, R-ISS II/III vs. R-ISS I, and in progressed compared to progression-free patients. The analysis of our screening cohort highlighted that CD138+ miR-25 levels were correlated with short-term progression (HR = 2.729; p = 0.009) and poor survival (HR = 4.581; p = 0.004) of the patients; which was confirmed by Kryukov et al. cohort (HR = 1.878; p = 0.005) and MMRF CoMMpass study (HR = 1.414; p = 0.039) validation cohorts. Moreover, multivariate miR-25-fitted models contributed to superior risk-stratification and clinical benefit in MM prognostication. Finally, elevated miR-25 circulating levels were correlated with poor survival of MM patients (HR = 5.435; p = 0.021), serving as a potent non-invasive molecular prognostic tool. Conclusions: Our study identified miR-25 overexpression as a powerful independent predictor of poor treatment outcome and post-treatment progression, aiding towards modern non-invasive disease prognosis and personalized treatment decisions. [ABSTRACT FROM AUTHOR]

PIWI-interacting RNA (piRNA) is a class of recently discovered small non-coding RNA molecules with a length of 18–33 nt that interacts with the PIWI protein to form the piRNA/PIWI complex. The PIWI family is a subfamily of Argonaute (AGO) proteins that also contain the AGO family which bind to microRNA (miRNA). Recently studies indicate that piRNAs are not specific to in the mammalian germline, they are also expressed in a tissue-specific manner in a variety of human tissues and participated in various of diseases, such as cardiovascular, neurological, and urinary tract diseases, and are especially prevalent in malignant tumors in these systems. However, the functions and abnormal expression of piRNAs in respiratory tract diseases and their underlying mechanisms remain incompletely understood. In this review, we discuss current studies summarizing the biogenetic processes, functions, and emerging roles of piRNAs in respiratory tract diseases, providing a reference value for future piRNA research. [ABSTRACT FROM AUTHOR]

Background: The vast and promising class of long non-coding RNAs (lncRNAs) has been under investigation for distinct therapeutic applications. Nevertheless, their role as molecular drivers of bone regeneration remains poorly studied. The lncRNA H19 mediates osteogenic differentiation of Mesenchymal Stem/Stromal Cells (MSCs) through the control of intracellular pathways. However, the effect of H19 on the extracellular matrix (ECM) components is still largely unknown. This research study was designed to decode the H19-mediated ECM regulatory network, and to reveal how the decellularized siH19-engineered matrices influence MSC proliferation and fate. This is particularly relevant for diseases in which the ECM regulation and remodeling processes are disrupted, such as osteoporosis. Methods: Mass spectrometry-based quantitative proteomics analysis was used to identify ECM components, after oligonucleotides delivery to osteoporosis-derived hMSCs. Moreover, qRT-PCR, immunofluorescence and proliferation, differentiation and apoptosis assays were performed. Engineered matrices were decellularized, characterized by atomic force microscopy and repopulated with hMSC and pre-adipocytes. Clinical bone samples were characterized by histomorphometry analysis. Results: Our study provides an in-depth proteome-wide and matrisome-specific analysis of the ECM proteins controlled by the lncRNA H19. Using bone marrow-isolated MSC from patients with osteoporosis, we identified fibrillin-1 (FBN1), vitronectin (VTN) and collagen triple helix repeat containing 1 (CTHRC1), among others, as having different pattern levels following H19 silencing. Decellularized siH19-engineered matrices are less dense and have a decreased collagen content compared with control matrices. Repopulation with naïve MSCs promotes a shift towards the adipogenic lineage in detriment of the osteogenic lineage and inhibits proliferation. In pre-adipocytes, these siH19-matrices enhance lipid droplets formation. Mechanistically, H19 is targeted by miR-29c, whose expression is decreased in osteoporotic bone clinical samples. Accordingly, miR-29c impacts MSC proliferation and collagen production, but does not influence ALP staining or mineralization, revealing that H19 silencing and miR-29c mimics have complementary but not overlapping functions. Conclusion: Our data suggest H19 as a therapeutic target to engineer the bone ECM and to control cell behavior. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common tumors worldwide and the leading cause of tumor-related mortality. Endoscopy and serological tumor marker testing are currently the main methods of GC screening, and treatment relies on surgical resection or chemotherapy. However, traditional examination and treatment methods are more harmful to patients and less sensitive and accurate. A minimally invasive method to respond to GC early screening, prognosis monitoring, treatment efficacy, and drug resistance situations is urgently needed. As a result, liquid biopsy techniques have received much attention in the clinical application of GC. The non-invasive liquid biopsy technique requires fewer samples, is reproducible, and can guide individualized patient treatment by monitoring patients' molecular-level changes in real-time. In this review, we introduced the clinical applications of circulating tumor cells, circulating free DNA, circulating tumor DNA, non-coding RNAs, exosomes, and proteins, which are the primary markers in liquid biopsy technology in GC. We also discuss the current limitations and future trends of liquid biopsy technology as applied to early clinical biopsy technology. [ABSTRACT FROM AUTHOR]

Background: Prenatal exposure to ethanol can cause fetal alcohol spectrum disorder (FASD), a prevalent, preventable pediatric disorder. Identifying genetic risk alleles for FASD is challenging since time, dose, and frequency of exposure are often unknown, and manifestations of FASD are diverse and evident long after exposure. Drosophila melanogaster is an excellent model to study the genetic basis of the effects of developmental alcohol exposure since many individuals of the same genotype can be reared under controlled environmental conditions. Results: We used 96 sequenced, wild-derived inbred lines from the Drosophila melanogaster Genetic Reference Panel (DGRP) to profile genome-wide transcript abundances in young adult flies that developed on ethanol-supplemented medium or standard culture medium. We found substantial genetic variation in gene expression in response to ethanol with extensive sexual dimorphism. We constructed sex-specific genetic networks associated with alcohol-dependent modulation of gene expression that include protein-coding genes, Novel Transcribed Regions (NTRs, postulated to encode long non-coding RNAs) and female-specific coordinated regulation of snoRNAs that regulate pseudouridylation of ribosomal RNA. We reared DGRP lines which showed extreme upregulation or downregulation of snoRNA expression during developmental alcohol exposure on standard or ethanol supplemented medium and demonstrated that developmental exposure to ethanol has genotype-specific effects on adult locomotor activity and sleep. Conclusions: There is significant and sex-specific natural genetic variation in the transcriptional response to developmental exposure to ethanol in Drosophila that comprises networks of genes affecting nervous system development and ethanol metabolism as well as networks of regulatory non-coding RNAs. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) have become a research hotspot in recent years with their universality, diversity, stability, conservativeness, and spatiotemporal specificity. N6-methyladenosine (m6A), the most abundant modification in the eukaryotic cells, is engaged in the pathophysiological processes of various diseases. An increasing amount of evidence has suggested that m6A modification is common in circRNAs and is associated with their biological functions. This review summarizes the effects of m6A modification on circRNAs and their regulation mechanisms in cancers, providing some suggestions of m6A-modified circRNAs in cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Cryptosporidium species are zoonotic protozoans that are important causes of diarrhoeal disease in both humans and animals. Non-coding RNAs (ncRNAs) play an important role in the innate immune defense against Cryptosporidium infection, but the underlying molecular mechanisms in the interaction between human ileocecal adenocarcinoma (HCT-8) cells and Cryptosporidium species have not been entirely revealed. Methods: The expression profiles of messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) in the early phase of infection of HCT-8 cells with Cryptosporidium parvum and at 3 and 12 h post infection were analyzed using the RNA-sequencing technique. The biological functions of differentially expressed RNAs (dif-RNAs) were discovered through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The targeting relationships between three ncRNAs and mRNAs were analyzed using bioinformatics methods, followed by building a competing endogenous RNA (ceRNA) regulatory network centered on miRNAs. Results: After strictly filtering the raw data, our analysis revealed 393 dif-lncRNAs, 69 dif-miRNAs and 115 dif-mRNAs at 3 hpi, and 450 dif-lncRNAs, 129 dif-miRNAs, 117 dif-mRNAs and one dif-circRNA at 12 hpi. Of these, 94 dif-lncRNAs, 24 dif-miRNAs and 22 dif-mRNAs were detected at both post-infection time points. Eleven dif-lncRNAs, seven dif-miRNAs, eight dif-mRNAs and one circRNA were randomly selected and confirmed using the quantitative real-time PCR. Bioinformatics analyses showed that the dif-mRNAs were significantly enriched in nutritional absorption, metabolic processes and metabolism-related pathways, while the dif-lncRNAs were mainly involved in the pathways related to the infection and pathogenicity of C. parvum (e.g. tight junction protein) and immune-related pathways (e.g. cell adhesion molecules). In contrast, dif-miRNAs and dif-circRNA were significantly enriched in apoptosis and apoptosis-related pathways. Among the downregulated RNAs, the miRNAs has-miR-324-3p and hsa-miR-3127-5p appear to be crucial miRNAs which could negatively regulate circRNA, lncRNA and mRNA. Conclusions: The whole transcriptome profiles of HCT-8 cells infected with C. parvum were obtained in this study. The results of the GO and KEGG pathway analyses suggest significant roles for these dif-RNAs during the course of C. parvum infection. A ceRNA regulation network containing miRNA at its center was constructed for the first time, with hsa-miR-324-3p and hsa-miR-3127-5p being the crucial miRNAs. These findings provide novel insights into the responses of human intestinal epithelial cells to C. parvum infection. [ABSTRACT FROM AUTHOR]

Background: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy that lacks specific biomarkers and drug targets. Competing endogenous RNAs (ceRNAs) play vital roles in oncogenesis and tumor progression by sponging microRNAs (miRNAs). Nevertheless, the regulatory mechanisms of survival-related ceRNA networks in CLL remain to be uncovered. Methods: We included 865 de novo CLL patients to investigate RNA expression profiles and Illumina sequencing was performed on four CLL patients, two CLL cell lines and six healthy donors in our center. According to univariate Cox regression, LASSO regression as well as multivariate Cox regression analyses, we established a novel risk score model in CLL patients. Immune signatures were compared between the low- and high-risk groups with CIBERSORT and ESTIMATE program. Afterwards, we analyzed the relationship between differentially expressed miRNAs (DEmiRNAs) and IGHV mutational status, p53 mutation status and del17p. Based on the survival analyses and differentially expressed RNAs with targeting relationships, the lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed. In addition, the circRNA circ_0002078/miR-185-3p/TCF7L1 axis was verified and their interrelations were delineated by dual-luciferase reporter gene assay. Results: Totally, 57 differentially expressed mRNAs (DEmRNAs) and 335 DEmiRNAs were identified between CLL patient specimens and normal B cells. A novel risk score model consisting of HTN3, IL3RA and NCK1 was established and validated. The concordance indexes of the model were 0.825, 0.719 and 0.773 in the training, test and total sets, respectively. The high-risk group was related to del(13q14) as well as shorter overall survival (OS). Moreover, we identified DEmiRNAs that related to cytogenetic abnormality of CLL patients, which revealed that miR-324-3p was associated with IGHV mutation, p53 mutation and del17p. The survival-related lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed to further facilitate the development of potential predictive biomarkers. Besides, the expression of circ_0002078 and TCF7L1 were significantly elevated and miR-185-3p was obviously decreased in CLL patients. Circ_0002078 regulated TCF7L1 expression by competing with TCF7L1 for miR-185-3p. Conclusions: The comprehensive analyses of RNA expression profiles provide pioneering insights into the molecular mechanisms of CLL. The novel risk score model and survival-related ceRNA networks promote the development of prognostic biomarkers and potential therapeutic vulnerabilities for CLL. [ABSTRACT FROM AUTHOR]

Lung cancer is the second cancer and the leading cause of tumor-related mortality worldwide. Angiogenesis is a crucial hallmark of cancer development and a promising target in lung cancer. However, the anti-angiogenic drugs currently used in the clinic do not achieve long-term efficacy and are accompanied by severe adverse reactions. Therefore, the development of novel anti-angiogenic therapeutic approaches for lung cancer is urgently needed. Non-coding RNAs (ncRNAs) participate in multiple biological processes in cancers, including tumor angiogenesis. Many studies have demonstrated that ncRNAs play crucial roles in tumor angiogenesis. This review discusses the regulatory functions of different ncRNAs in lung cancer angiogenesis, focusing on the downstream targets and signaling pathways regulated by these ncRNAs. Additionally, given the recent trend towards utilizing ncRNAs as cancer therapeutics, we also discuss the tremendous potential applications of ncRNAs as biomarkers or novel anti-angiogenic tools in lung cancer. [ABSTRACT FROM AUTHOR]

As one of the leading causes of death, hematologic malignancies are associated with an ever-increasing incidence, and drug resistance and relapse of patients after treatment represent clinical challenges. Therefore, there are pressing demands to uncover biomarkers to indicate the development, progression, and therapeutic targets for hematologic malignancies. Circular RNAs (circRNAs) are covalently closed circular-single-stranded RNAs whose biosynthesis is regulated by various factors and is widely-expressed and evolutionarily conserved in many organisms and expressed in a tissue−/cell-specific manner. Recent reports have indicated that circRNAs plays an essential role in the progression of hematological malignancies. However, circRNAs are difficult to detect with low abundance using conventional techniques. We need to learn more information about their features to develop new detection methods. Herein, we sought to retrospect the current knowledge about the characteristics of circRNAs and summarized research on circRNAs in hematological malignancies to explore a potential direction. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death. As other heterogeneous solid tumours, HCC results from a unique synergistic combination of genetic alterations mixed with epigenetic modifications. In HCC the patterns and frequencies of somatic variations change depending on the nearby chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutations. Epigenetics refers to heritable states of gene expression without alteration to the DNA sequence itself and, unlike genetic changes, the epigenetic modifications are reversible and affect gene expression more extensively than genetic changes. Thus, studies of epigenetic regulation and the involved molecular machinery are greatly contributing to the understanding of the mechanisms that underline HCC onset and heterogeneity. Moreover, this knowledge may help to identify biomarkers for HCC diagnosis and prognosis, as well as future new targets for more efficacious therapeutic approaches. In this comprehensive review we will discuss the state-of-the-art knowledge about the epigenetic landscape in hepatocarcinogenesis, including evidence on the diagnostic and prognostic role of non-coding RNAs, modifications occurring at the chromatin level, and their role in the era of precision medicine. Apart from other better-known risk factors that predispose to the development of HCC, characterization of the epigenetic remodelling that occurs during hepatocarcinogenesis could open the way to the identification of personalized biomarkers. It may also enable a more accurate diagnosis and stratification of patients, and the discovery of new targets for more efficient therapeutic approaches. [ABSTRACT FROM AUTHOR]

Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a "self-degradation" mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients. Highlights: • Prostate cancer is among the leading causes of death in men where targeting autophagy is of importance in treatment; • Autophagy governs proliferation and metastasis capacity of prostate cancer cells; • Autophagy modulation is of interest in improving the therapeutic response of prostate cancer cells; • Molecular pathways, especially involving non-coding RNAs, regulate autophagy in prostate cancer; • Autophagy possesses both diagnostic and prognostic roles in prostate cancer, with promises for clinical application. [ABSTRACT FROM AUTHOR]

This work presents mSRFR (microalgae SMOTE Random Forest Relief model), a classification tool for noncoding RNAs (ncRNAs) in microalgae, including green algae, diatoms, golden algae, and cyanobacteria. First, the SMOTE technique was applied to address the challenge of imbalanced data due to the different numbers of microalgae ncRNAs from different species in the EBI RNA-central database. Then the top 20 significant features from a total of 106 features, including sequence-based, secondary structure, base-pair, and triplet sequence-structure features, were selected using the Relief feature selection method. Next, ten-fold cross-validation was applied to choose a classifier algorithm with the highest performance among Support Vector Machine, Random Forest, Decision Tree, Naïve Bayes, K-nearest Neighbor, and Neural Network, based on the receiver operating characteristic (ROC) area. The results showed that the Random Forest classifier achieved the highest ROC area of 0.992. Then, the Random Forest algorithm was selected and compared with other tools, including RNAcon, CPC, CPC2, CNCI, and CPPred. Our model achieved a high accuracy of about 97% and a low false-positive rate of about 2% in predicting the test dataset of microalgae. Furthermore, the top features from Relief revealed that the %GA dinucleotide is a signature feature of microalgal ncRNAs when compared to Escherichia coli, Saccharomyces cerevisiae, Arabidopsis thaliana, and Homo sapiens. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of morbidity and mortality worldwide. Significant improvements in the modern era of anticancer therapeutic strategies have increased the survival rate of cancer patients. Unfortunately, cancer survivors have an increased risk of cardiovascular diseases, which is believed to result from anticancer therapies. The emergence of cardiovascular diseases among cancer survivors has served as the basis for establishing a novel field termed cardio-oncology. Cardio-oncology primarily focuses on investigating the underlying molecular mechanisms by which anticancer treatments lead to cardiovascular dysfunction and the development of novel cardioprotective strategies to counteract cardiotoxic effects of cancer therapies. Advances in genome biology have revealed that most of the genome is transcribed into non-coding RNAs (ncRNAs), which are recognized as being instrumental in cancer, cardiovascular health, and disease. Emerging studies have demonstrated that alterations of these ncRNAs have pathophysiological roles in multiple diseases in humans. As it relates to cardio-oncology, though, there is limited knowledge of the role of ncRNAs. In the present review, we summarize the up-to-date knowledge regarding the roles of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in cancer therapy-induced cardiotoxicities. Moreover, we also discuss prospective therapeutic strategies and the translational relevance of these ncRNAs. [ABSTRACT FROM AUTHOR]

Background: Root knot nematodes (RKN) are plant parasitic nematodes causing major yield losses of widely consumed food crops such as rice (Oryza sativa). Because non-coding RNAs, including small interfering RNAs (siRNA), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are key regulators of various plant processes, elucidating their regulation during this interaction may lead to new strategies to improve crop protection. In this study, we aimed to identify and characterize rice siRNAs, miRNAs and lncRNAs responsive to early infection with RKN Meloidogyne graminicola (Mg), based on sequencing of small RNA, degradome and total RNA libraries from rice gall tissues compared with uninfected root tissues. Results: We found 425 lncRNAs, 3739 siRNAs and 16 miRNAs to be differentially expressed between both tissues, of which a subset was independently validated with RT-qPCR. Functional prediction of the lncRNAs indicates that a large part of their potential target genes code for serine/threonine protein kinases and transcription factors. Differentially expressed siRNAs have a predominant size of 24 nts, suggesting a role in DNA methylation. Differentially expressed miRNAs are generally downregulated and target transcription factors, which show reduced degradation according to the degradome data. Conclusions: To our knowledge, this work is the first to focus on small and long non-coding RNAs in the interaction between rice and Mg, and provides an overview of rice non-coding RNAs with the potential to be used as a resource for the development of new crop protection strategies. [ABSTRACT FROM AUTHOR]

In recent years, it has been demonstrated that extracellular vesicles (EVs) can be released by almost all cell types, and detected in most body fluids. In the tumour microenvironment (TME), EVs serve as a transport medium for lipids, proteins, and nucleic acids. EVs participate in various steps involved in the development and progression of malignant tumours by initiating or suppressing various signalling pathways in recipient cells. Although tumour-derived EVs (T-EVs) are known for orchestrating tumour progression via systemic pathways, EVs from non-malignant cells (nmEVs) also contribute substantially to malignant tumour development. Tumour cells and non-malignant cells typically communicate with each other, both determining the progress of the disease. In this review, we summarise the features of both T-EVs and nmEVs, tumour progression, metastasis, and EV-mediated chemoresistance in the TME. The physiological and pathological effects involved include but are not limited to angiogenesis, epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodelling, and immune escape. We discuss potential future directions of the clinical application of EVs, including diagnosis (as non-invasive biomarkers via liquid biopsy) and therapeutic treatment. This may include disrupting EV biogenesis and function, thus utilising the features of EVs to repurpose them as a therapeutic tool in immunotherapy and drug delivery systems. We also discuss the overall findings of current studies, identify some outstanding issues requiring resolution, and propose some potential directions for future research. BhtAgaVHwj7KnN4ehE_Kwa Video abstract [ABSTRACT FROM AUTHOR]

Objective: Data normalization and clustering are mandatory steps in gene expression and downstream analyses, respectively. However, user-friendly implementations of these methodologies are available exclusively under expensive licensing agreements, or in stand-alone scripts developed, reflecting on a great obstacle for users with less computational skills. Results: We developed an online tool called CORAZON (Correlations Analyses Zipper Online), which implements three unsupervised learning methods to cluster gene expression datasets in a friendly environment. It allows the usage of eight gene expression normalization/transformation methodologies and the attribute's influence. The normalizations requiring the gene length only could be performed to RNA-seq, meanwhile the others can be used with microarray and/or NanoString data. Clustering methodologies performances were evaluated through five models with accuracies between 92 and 100%. We applied our tool to obtain functional insights of non-coding RNAs (ncRNAs) based on Gene Ontology enrichment of clusters in a dataset generated by the ENCODE project. The clusters where the majority of transcripts are coding genes were enriched in Cellular, Metabolic, Transports, and Systems Development categories. Meanwhile, the ncRNAs were enriched in the Detection of Stimulus, Sensory Perception, Immunological System, and Digestion categories. CORAZON source-code is freely available at https://gitlab.com/integrativebioinformatics/corazon and the web-server can be accessed at http://corazon.integrativebioinformatics.me. [ABSTRACT FROM AUTHOR]

The discovery of the role of non-coding RNAs (ncRNAs) in the onset and progression of malignancies is a promising frontier of cancer genetics. It is clear that ncRNAs are candidates for therapeutic intervention, since they may act as biomarkers or key regulators of cancer gene network. Recently, profiling and sequencing of ncRNAs disclosed deep deregulation in human cancers mostly due to aberrant mechanisms of ncRNAs biogenesis, such as amplification, deletion, abnormal epigenetic or transcriptional regulation. Although dysregulated ncRNAs may promote hallmarks of cancer as oncogenes or antagonize them as tumor suppressors, the mechanisms behind these events remain to be clarified. The development of new bioinformatic tools as well as novel molecular technologies is a challenging opportunity to disclose the role of the "dark matter" of the genome. In this review, we focus on currently available platforms, computational analyses and experimental strategies to investigate ncRNAs in cancer. We highlight the differences among experimental approaches aimed to dissect miRNAs and lncRNAs, which are the most studied ncRNAs. These two classes indeed need different investigation taking into account their intrinsic characteristics, such as length, structures and also the interacting molecules. Finally, we discuss the relevance of ncRNAs in clinical practice by considering promises and challenges behind the bench to bedside translation. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis describes the inappropriate proliferation of cardiac fibroblasts (CFs), leading to accumulation of extracellular matrix (ECM) proteins in the cardiac muscle, which is found in many pathophysiological heart conditions. A range of molecular components and cellular pathways, have been implicated in its pathogenesis. In this review, we focus on the TGF-β and WNT signaling pathways, and their mutual interaction, which have emerged as important factors involved in cardiac pathophysiology. The molecular and cellular processes involved in the initiation and progression of cardiac fibrosis are summarized. We focus on TGF-β and WNT signaling in cardiac fibrosis, ECM production, and myofibroblast transformation. Non-coding RNAs (ncRNAs) are one of the main players in the regulation of multiple pathways and cellular processes. MicroRNAs, long non-coding RNAs, and circular long non-coding RNAs can all interact with the TGF-β/WNT signaling axis to affect cardiac fibrosis. A better understanding of these processes may lead to new approaches for diagnosis and treatment of many cardiac conditions. Video Abstract [ABSTRACT FROM AUTHOR]

Background: Given the vast range of molecular mechanisms giving rise to breast cancer, it is unlikely universal cures exist. However, by providing a more precise prognosis for breast cancer patients through integrative models, treatments can become more individualized, resulting in more successful outcomes. Specifically, we combine gene expression, pseudogene expression, miRNA expression, clinical factors, and pseudogene-gene functional networks to generate these models for breast cancer prognostics. Establishing a LASSO-generated molecular gene signature revealed that the increased expression of genes STXBP5, GALP and LOC387646 indicate a poor prognosis for a breast cancer patient. We also found that increased CTSLP8 and RPS10P20 and decreased HLA-K pseudogene expression indicate poor prognosis for a patient. Perhaps most importantly we identified a pseudogene-gene interaction, GPS2-GPS2P1 (improved prognosis) that is prognostic where neither the gene nor pseudogene alone is prognostic of survival. Besides, miR-3923 was predicted to target GPS2 using miRanda, PicTar, and TargetScan, which imply modules of gene-pseudogene-miRNAs that are potentially functionally related to patient survival. Results: In our LASSO-based model, we take into account features including pseudogenes, genes and candidate pseudogene-gene interactions. Key biomarkers were identified from the features. The identification of key biomarkers in combination with significant clinical factors (such as stage and radiation therapy status) should be considered as well, enabling a specific prognostic prediction and future treatment plan for an individual patient. Here we used our PseudoFuN web application to identify the candidate pseudogene-gene interactions as candidate features in our integrative models. We further identified potential miRNAs targeting those features in our models using PseudoFuN as well. From this study, we present an interpretable survival model based on LASSO and decision trees, we also provide a novel feature set which includes pseudogene-gene interaction terms that have been ignored by previous prognostic models. We find that some interaction terms for pseudogenes and genes are significantly prognostic of survival. These interactions are cross-over interactions, where the impact of the gene expression on survival changes with pseudogene expression and vice versa. These may imply more complicated regulation mechanisms than previously understood. Conclusions: We recommend these novel feature sets be considered when training other types of prognostic models as well, which may provide more comprehensive insights into personalized treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a Gram-positive bacterium that colonizes the gastrointestinal and genitourinary tract of humans. This bacterium has also been isolated from various animals, such as fish and cattle. Non-coding RNAs (ncRNAs) can act as regulators of gene expression in bacteria, such as Streptococcus pneumonia e and Streptococcus pyogenes. However, little is known about the genomic distribution of ncRNAs and RNA families in S. agalactiae. Results: Comparative genome analysis of 27 S. agalactiae strains showed more than 5 thousand genomic regions identified and classified as Core, Exclusive, and Shared genome sequences. We identified 27 to 89 RNA families per genome distributed over these regions, from these, 25 were in Core regions while Shared and Exclusive regions showed variations amongst strains. We propose that the amount and type of ncRNA present in each genome can provide a pattern to contribute in the identification of the clonal types. Conclusions: The identification of RNA families provides an insight over ncRNAs, sRNAs and ribozymes function, that can be further explored as targets for antibiotic development or studied in gene regulation of cellular processes. RNA families could be considered as markers to determine infection capabilities of different strains. Lastly, pan-genome analysis of GBS including the full range of functional transcripts provides a broader approach in the understanding of this pathogen. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a crucial role in tumorigenesis. Here, we report a novel lncRNA, RP11-436H11.5, that regulates renal cell carcinoma (RCC) cell proliferation and invasion by sponging miR-335-5p. Methods: Expression of lncRNA RP11-436H11.5 was determined by a qRT-PCR assay in RCC tissues. RCC cell proliferation and invasion were measured by a cell proliferation assay and a transwell invasion assay. Expression of BCL-W was detected by a western blot assay. Interactions between lncRNA RP11-436H11.5 and miR-335-5p were measured by a luciferase reporter assay and a RNA-pull down assay. In vivo experiments were used to detect tumor formation. Results: In this study, the qRT-PCR results illustrated that lncRNA RP11-436H11.5 was more highly expressed in RCC tissues than in adjacent normal renal tissues. The results of survival analysis indicated that patients in the high lncRNA RP11-436H11.5 group presented significantly worse outcomes compared with those in the low lncRNA RP11-436H11.5 group. Downregulation of lncRNA RP11-436H11.5 suppressed RCC cell proliferation and invasion in vitro and in vivo. Luciferase reporter assay results demonstrated that lncRNA RP11-436H11.5 enhanced BCL-W expression by regulating miR-335-5p expression. LncRNA RP11-436H11.5 could function as a miR-335-5p decoy to derepress expression of BCL-W. Conclusions: LncRNA RP11-436H11.5 could function as a competing endogenous RNA to promote RCC cell proliferation and invasion, which might serve as a therapeutic application to suppress RCC progression. [ABSTRACT FROM AUTHOR]

Background: Biotrophic fungal plant pathogens cause billions of dollars in losses to North American crops annually. The model for functional investigation of these fungi is Ustilago maydis. Its 20.5 Mb annotated genome sequence has been an excellent resource for investigating biotrophic plant pathogenesis. Expressed-sequence tag libraries and microarray hybridizations have provided insight regarding the type of transcripts produced by U. maydis but these analyses were not comprehensive and there were insufficient data for transcriptome comparison to other smut fungi. To improve transcriptome annotation and enable comparative analyses, comprehensive strand-specific RNA-seq was performed on cell-types of three related smut species: U. maydis (common smut of corn), Ustilago hordei (covered smut of barley), and Sporisorium reilianum (head smut of corn). Results: In total, >1 billion paired-end sequence reads were obtained from haploid cell, dikaryon and teliospore RNA of U. maydis, haploid cell RNA of U. hordei, and haploid and dikaryon cell RNA of S. reilianum.Thesequenceswere assembled into transfrags using Trinity, and updated gene models were created using PASA and categorized with Cufflinks Cuffcompare. Representative genes that were predicted for the first time with these RNA-seq analyses and genes with novel annotation features were independently assessed by reverse transcriptase PCR. The analyses indicate hundreds more predicted proteins, relative to the previous genome annotation, could be produced by U. maydis from altered transcript forms, and that the number of non-coding RNAs produced, including transcribed intergenic sequences and natural antisense transcripts, approximately equals the number of mRNAs. This high representation of non-coding RNAs appears to be a conserved feature of the smut fungi regardless of whether they have RNA interference machinery. Approximately 50% of the identified NATs were conserved among the smut fungi. Conclusions: Overall, these analyses revealed: 1) smut genomes encode a number of transcriptional units that is twice the number of annotated protein-coding genes, 2) a small number of intergenic transcripts may encode proteins with characteristics of fungal effectors, 3) the vast majority of intergenic and antisense transcripts do not contain ORFs, 4) a large proportion of the identified antisense transcripts were detected at orthologous loci among the smut fungi, and 5) there is an enrichment of functional categories among orthologous loci that suggests antisense RNAs could have a genome-wide, non-RNAi-mediated, influence on gene expression in smut fungi. [ABSTRACT FROM AUTHOR]

Background: The genes coding for Y RNAs are evolutionarily conserved in vertebrates. These non-coding RNAs are essential for the initiation of chromosomal DNA replication in vertebrate cells. However thus far, no information is available about Y RNAs in Chinese hamster cells, which have already been used to detect replication origins and alternative DNA structures around these sites. Here, we report the gene sequences and predicted structural characteristics of the Chinese hamster Y RNAs, and analyze their ability to support the initiation of chromosomal DNA replication in vitro. Results: We identified DNA sequences in the Chinese hamster genome of four Y RNAs (chY1, chY3, chY4 and chY5) with upstream promoter sequences, which are homologous to the four main types of vertebrate Y RNAs. The chY1, chY3 and chY5 genes were highly conserved with their vertebrate counterparts, whilst the chY4 gene showed a relatively high degree of diversification from the other vertebrate Y4 genes. Molecular dynamics simulations suggest that chY4 RNA is structurally stable despite its evolutionarily divergent predicted stem structure. Of the four Y RNA genes present in the hamster genome, we found that only the chY1 and chY3 RNA were strongly expressed in the Chinese hamster GMA32 cell line, while expression of the chY4 and chY5 RNA genes was five orders of magnitude lower, suggesting that they may in fact not be expressed. We synthesized all four chY RNAs and showed that any of these four could support the initiation of DNA replication in an established human cell-free system. Conclusions: These data therefore establish that non-coding chY RNAs are stable structures and can substitute for human Y RNAs in a reconstituted cell-free DNA replication initiation system. The pattern of Y RNA expression and functionality is consistent with Y RNAs of other rodents, including mouse and rat. [ABSTRACT FROM AUTHOR]

Background: Nicotiana benthamiana is a widely used model plant species for research on plant-pathogen interactions as well as other areas of plant science. It can be easily transformed or agroinfiltrated, therefore it is commonly used in studies requiring protein localization, interaction, or plant-based systems for protein expression and purification. To discover and characterize the miRNAs and their cleaved target mRNAs in N. benthamiana, we sequenced small RNA transcriptomes and degradomes of two N. benthamiana accessions and validated them by Northern blots. Results: We used a comprehensive molecular approach to detect and to experimentally validate N. benthamiana miRNAs and their target mRNAs from various tissues. We identified 40 conserved miRNA families and 18 novel microRNA candidates and validated their target mRNAs with a genomic scale approach. The accumulation of thirteen novel miRNAs was confirmed by Northern blot analysis. The conserved and novel miRNA targets were found to be involved in various biological processes including transcription, RNA binding, DNA modification, signal transduction, stress response and metabolic process. Among the novel miRNA targets we found the mRNA of REPRESSOR OF SILENCING (ROS1). Regulation of ROS1 by a miRNA provides a new regulatory layer to reinforce transcriptional gene silencing by a post-transcriptional repression of ROS1 activity. Conclusions: The identified conserved and novel miRNAs along with their target mRNAs also provides a tissue specific atlas of known and new miRNA expression and their cleaved target mRNAs of N. benthamiana. Thus this study will serve as a valuable resource to the plant research community that will be beneficial well into the future. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs are small noncoding RNAs that play critical roles in regulation of gene expression in wide array of tissues including the ovary through sequence complementarity at post-transcriptional level. Tight regulation of multitude of genes involved in ovarian development and folliculogenesis could be regulated at transcription level by these miRNAs. Therefore, tissue specific miRNAs identification is considered a key step towards understanding the role of miRNAs in biological processes. Methods: To investigate the role of microRNAs during ovarian development and folliculogenesis we sequenced eight different libraries using Illumina deep sequencing technology. Different developmental stages were selected to explore miRNAs expression pattern at different stages of gonadal maturation with/without treatment of PMSG/hCG for superovulation. Results: From massive sequencing reads, clean reads of 16-26 bp were selected for further analysis of differential expression analysis and novel microRNA annotation. Expression analysis of all miRNAs at different developmental stages showed that some miRNAs were present ubiquitously while others were differentially expressed at different stages. Among differentially expressed miRNAs we reported 61 miRNAs with a fold change of more than 2 at different developmental stages among all libraries. Among the up-regulated miRNAs, mmu-mir-1298 had the highest fold change with 4.025 while mmu-mir-150 was down-regulated more than 3 fold. Furthermore, we found 2659 target genes for 20 differentially expressed microRNAs using seven different target predictions programs (DIANA-mT, miRanda, miRDB, miRWalk, RNAhybrid, PICTAR5, TargetScan). Analysis of the predicted targets showed certain ovary specific genes targeted by single or multiple microRNAs. Furthermore, pathway annotation and Gene ontology showed involvement of these microRNAs in basic cellular process. Conclusions: These results suggest the presence of different miRNAs at different stages of ovarian development and superovulation. Potential role of these microRNAs was elucidated using bioinformatics tools in regulation of different pathways, biological functions and cellular components underlying ovarian development and superovulation. These results provide a framework for extended analysis of miRNAs and their roles during ovarian development and superovulation. Furthermore, this study provides a base for characterization of individual miRNAs to discover their role in ovarian development and female fertility. [ABSTRACT FROM AUTHOR]