Modulation Of miRNAs Research Articles

MicroRNA expression profile in retina and choroid in oxygen-induced retinopathy model.

BackgroundIschemic retinopathies (IRs) are leading causes of visual impairment. They are characterized by an initial phase of microvascular degeneration and a second phase of aberrant pre-retinal neovascularization (NV). microRNAs (miRNAs) regulate gene expression, and a number play a role in normal and pathological NV. But, post-transcriptional modulation of miRNAs in the eye during the development of IRs has not been systematically evaluated.Aims & methodsUsing Next Generation Sequencing (NGS) we profiled miRNA expression in the retina and choroid during vasodegenerative and NV phases of oxygen-induced retinopathy (OIR).ResultsApproximately 20% of total miRNAs exhibited altered expression (up- or down-regulation); 6% of miRNA were found highly expressed in retina and choroid of rats subjected to OIR. During OIR-induced vessel degeneration phase, miR-199a-3p, -199a-5p, -1b, -126a-3p displayed a robust decreased expression (> 85%) in the retina. While in the choroid, miR-152-3p, -142-3p, -148a-3p, -532-3p were upregulated (>200%) and miR-96-5p, -124-3p, -9a-3p, -190b-5p, -181a-1-3p, -9a-5p, -183-5p were downregulated (>70%) compared to controls. During peak pathological NV, miR-30a-5p, -30e-5p and 190b-5p were markedly reduced (>70%), and miR-30e-3p, miR-335, -30b-5p strongly augmented (by up to 300%) in the retina. Whereas in choroid, miR-let-7f-5p, miR-126a-5p and miR-101a-3p were downregulated by (>81%), and miR-125a-5p, let-7e-5p and let-7g-5p were upregulated by (>570%) during NV. Changes in miRNA observed using NGS were validated using qRT-PCR for the 24 most modulated miRNAs. In silico approach to predict miRNA target genes (using algorithms of miRSystem database) identified potential new target genes with pro-inflammatory, apoptotic and angiogenic properties.ConclusionThe present study is the first comprehensive description of retinal/choroidal miRNAs profiling in OIR (using NGS technology). Our results provide a valuable framework for the characterization and possible therapeutic potential of specific miRNAs involved in ocular IR-triggered inflammation, angiogenesis and degeneration.

MiRNA Modulation of Insect Virus Replication

The outcome of virus infection in insects is impacted by regulation of both host and virus gene expression. A class of small RNAs called microRNAs (miRNA) have emerged as important regulators of gene expression that can influence the outcome of virus infection. miRNA regulation occurs at a comparatively late stage of gene expression, allowing for rapid control and fine-tuning of gene expression levels. Here we discuss the biogenesis of miRNAs from both host and virus genomes, the interactions that lead to regulation of gene expression, and the miRNA-mRNA interactions that lead to either antivirus or provirus consequences in the course of virus infection in insects.

Resveratrol chemosensitizes adriamycin-resistant breast cancer cells by modulating miR-122-5p.

Breast cancer is one of the major malignancies threatening women's health worldwide, and chemotherapy tolerance has become a severe limitation of clinical treatment. Recent findings have revealed that resveratrol, as a dietary agent with antitumour activity, could prevent cancer progression by regulating microRNAs (miRNAs). Additionally, dysregulated miRNAs have been found to contribute significantly to chemoresistance by an increasing number of studies. In this study, experiments were designed to study the functional role of resveratrol in MCF-7 cells (low-invasive breast cancer) in chemosensitivity to adriamycin and to determine the targeted miRNAs of resveratrol and their key target proteins linked to cell activity. We demonstrated that in resveratrol-induced chemosensitivity, cell cycle and apoptosis were arrested in adriamycin-resistant breast cancer cells after modulation of the critical suppresser, miR-122-5p. Further miRNA modulation with miR-122-5p mimics or miR-122-5p inhibitors indicated a major effect of miR-122-5p on the regulation of key antiapoptotic proteins (B-cell lymphoma 2 [Bcl-2]) and cyclin-dependent kinases (CDK2, CDK4, and CDK6) in drug-resistant breast cancer cells in response to resveratrol. In conclusion, our results indicate that resveratrol acts as a potential inducer to enhance the chemosensitivity of breast cancer and also suggest that miR-122-5p is involved in the pathway of cell-cycle arrest by targeting Bcl-2 and CDKs.

MiR-22-5p and miR-29a-5p Are Reliable Reference Genes for Analyzing Extracellular Vesicle-Associated miRNAs in Adipose-Derived Mesenchymal Stem Cells and Are Stable under Inflammatory Priming Mimicking Osteoarthritis Condition.

During the last two decades, mesenchymal stem cells (MSCs) gained a place of privilege in the field of regenerative medicine. Recently, extracellular vesicles (EVs) have been identified as major mediators of MSCs immunosuppressive as well as pro-regenerative activities in many disease models, including inflammatory/degenerative conditions as joint diseases and osteoarthritis. In order to shed light on EVs potential, a rigorous profiling of embedded proteins, lipids and nucleic acids (mRNA/miRNA) is mandatory. Nevertheless, reliable strategies to efficiently score miRNA cargo and modulation under diverse experimental conditions or treatments are missing. The aim of this work was to identify reliable reference genes (RGs) to analyze miRNA content in EVs secreted by adipose-derived MSCs (ASCs) and verify their consistency under inflammatory conditions that were proposed to enhance ASC-EVs immunomodulatory and regenerative potential. RefFinder algorithm, that integrates the currently available major computational programs (geNorm, NormFinder, BestKeeper, and Delta Ct method), allowed to identify miR-22-5p and miR-29a-5p as the most stable RGs. Notably, both miRNAs maintained the highest stability when EVs isolated from IFNg-treated ASCs were included in the analysis. In addition, considerable effects of suboptimal RGs choice on the reliable quantification of miRNAs involved at different levels (tissue homeostasis or macrophage polarization) in the osteoarthritis phenotype, and thus considered as promising therapeutic molecule, have clearly been demonstrated. In conclusion, a proper normalization method is not only needed for research purposes but also mandatory to characterize clinical products and predict their therapeutic potential, especially in the emerging field of MSCs derived-EVs as new tools for regenerative medicine.

PB2194 DE‐REGULATION OF MIRNAS DURING TREATMENT OF PATIENTS AFFECTED BY MYELOFIBROSIS WITH RUXOLITINIB

Background:MicroRNAs (miRNAs) are a family of small non coding RNAsthathave been associated with control of cell cycle, signal transduction, and many other cell functions in several hematological diseases. In myelofibrosis (MF), it has been reported that 48 miRNAs were expressed in a different way in respect of healthy donors, with particular relevance attributed to miR‐127, miR‐140 and miR‐345 [Liu Y, 2017]. Moreover, hyper‐expression of miR‐494, silencing SOCS6, might contribute to the megakaryocyte hyperplasia commonly observed in MF, thus sustaining a pathogenetic role for these small RNAs [Rontauroli S, 2017]. Nevertheless, it is not yet clear what kind of modulation of miRNAs can occur during treatment with ruxolitinib.Aims:The aim of the present study was to identify eventual changes of miRNAs expression during ruxolitinib therapy in order to try to better understand the action mechanism of this JAK2 inhibitor.MethodsmiRNAs were extracted from bone marrow and peripheral blood samples harvested in 4 patients with MF before starting ruxolitinib and after 3 months of therapy. As controls, 15 peripheral blood samples from healthy subjects and one sample from a bone marrow donor were employed. The expression of 675 miRNAs was assessed by the TaqMan®Low Density Arrays kit (ThermoFisher) and miRGator software was used to identify the respective target genes.Results:No differences in terms of miRNAs expression levels were observed between bone marrow and peripheral blood of MF cases, nor between patients and controls. After 3 months of ruxolitinib, 9 miRNAs resulted significantly up‐regulated: miR‐25, miR‐145, miR‐186, miR‐142‐3b, let‐7b, miR‐30d, miR‐188, miR‐942, and miR‐378. Interestingly, among targets genes of these miRNAs, there are JAK2, MPL, TET2, ASXL1, CBL, IDH1, IDH2, IKZF1, EZH2, genes that are either responsible for MF pathogenesis or prognostic in terms of long‐term outcome. Interestingly, miRNA‐145 has been previously reported to be up‐regulated in PV, and let‐7b is inversely correlated with JAK2V617F mutation in MPN [Bruchova H, 2008]. In our series of 20 patients treated by ruxolitinib we did not observe a significant modulation of JAK2 mutational load, but the interaction between let‐7b and JAK2 could be an interesting issue. Moreover, miR‐188 has been reported to suppress macrophage oxidation and plasma expression of pro‐inflammatory factors [Zhang XF, 2018], that could explain the anti‐inflammatory action of ruxolitinib observed in vivo, with a significant improvement of quality of life of MF patients during treatment. This anti‐inflammatory effect could be also sustained by the miR‐186, that has been reported to inhibit HIF‐1alpha factor, involved in the inflammatory processes [Gardner PJ, 2017], and by the up‐regulation of miR‐145, that seems to inhibit TGFBR2 and reduce sepsis in a murine model [Ma F, 2019]. Moreover, the over‐expression of miR‐30d has been associated with a reduced proliferation in colon cancer [Muhammad S, 2019], and miR‐142 high levels play an anti‐oncogenic activity in breast cancer [Mansoori B, 2019]. If it would be true also in MF, we could argue that ruxolitinib could also exert an anti‐proliferative effect.Summary/Conclusion:Even if only preliminary and on a very small number of cases, this study supports the possible role of miRNAs in the modulating the expression of genes involved in pathogenesis and progression of MF during treatment with ruxolitinib. This could help to better understand the action mechanisms of this important drug.

Relationship between cellular and exosomal miRNAs targeting NOD-like receptors in bladder cancer: preliminary results.

Exosomes are membrane vesicles secreted by both cancerous and normal cells which play important roles during intercellular communications and oncogenic transformation. Many reports highlight the importance of exosomal microRNAs (miRNAs) as pro-tumorigenic mediators during carcinogenesis, since they regulate all these pathways at the post-transcriptional level. Since bladder cancer cells have a high immunogenic potential, from one hand, and inflammation process is intimately connected to carcinogenesis, from the other, the interest in analyzing inflammasome-related exo-miRNAs is apparent. The modulation of miRNAs targeting NOD-like receptor mRNAs in patients harboring bladder cancer has been assessed in our previous studies. In the present report, we characterized the previously selected miRNAs in the soluble fraction of the same bladder cancer patient cohort, stratified according to the risk of recurrence and progression. Exosome precipitation and isolation were performed; the expression levels of exosomal miRNAs were compared with their cellular counterparts. An up-regulation of exosomal miR-141-3p and miR-19a-3p with respect to urine sediment was reported. Linear regression analysis showed a significant negative correlation for the same miRNAs. Moreover, exosomal miRNAs increased in low risk compared to high risk patients, which was opposite to that observed for urine sediment. Our work demonstrated the inverse correlation between exosomal and cellular miRNAs in patients with bladder cancer. The fact that these miRNAs were higher in exosomal than cellular fraction allowed us to hypothesize their active compartmentalization during cancer progression, suggesting their potential role as cancer messengers.

MiRspongeR: an R/Bioconductor package for the identification and analysis of miRNA sponge interaction networks and modules

BackgroundA microRNA (miRNA) sponge is an RNA molecule with multiple tandem miRNA response elements that can sequester miRNAs from their target mRNAs. Despite growing appreciation of the importance of miRNA sponges, our knowledge of their complex functions remains limited. Moreover, there is still a lack of miRNA sponge research tools that help researchers to quickly compare their proposed methods with other methods, apply existing methods to new datasets, or select appropriate methods for assisting in subsequent experimental design.ResultsTo fill the gap, we present an R/Bioconductor package, miRspongeR, for simplifying the procedure of identifying and analyzing miRNA sponge interaction networks and modules. It provides seven popular methods and an integrative method to identify miRNA sponge interactions. Moreover, it supports the validation of miRNA sponge interactions and the identification of miRNA sponge modules, as well as functional enrichment and survival analysis of miRNA sponge modules.ConclusionsThis package enables researchers to quickly evaluate their new methods, apply existing methods to new datasets, and consequently speed up miRNA sponge research.

Anticancer Activity and Underlying Mechanism of Phytochemicals against Multiple Myeloma.

Multiple myeloma (MM)—a common hematologic malignancy of plasma cells—accounts for substantial mortality and morbidity rates. Due to the advent of novel therapies such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs), response rates were increased and free survival and overall survival have been elevated. However, adverse events including toxicity, neuropathy or continuous relapse are still problems. Thus, development of novel drugs which have less side effects and more effective is needed. This review aims to recapitulate the pharmacologic anti-MM mechanisms of various phytochemicals, elucidating their molecular targets. Keywords related to MM and natural products were searched in PUBMED/MEDLINE. Phytochemicals have been reported to display a variety of anti-MM activities, including apoptosis, cell cycle arrest, antiangiogenesis, and miRNA modulation. Some phytochemicals sensitize the conventional therapies such as dexamethasone. Also, there are clinical trials with phytochemicals such as agaricus, curcumin, and Neovastat regarding MM treatment. Taken together, this review elucidated and categorized the evidences that natural products and their bioactive compounds could be potent drugs in treating MM.

The Influence of Diet on MicroRNAs that Impact Cardiovascular Disease.

Food quality and nutritional habits strongly influence human health status. Extensive research has been conducted to confirm that foods rich in biologically active nutrients have a positive impact on the onset and development of different pathological processes, including cardiovascular diseases. However, the underlying mechanisms by which dietary compounds regulate cardiovascular function have not yet been fully clarified. A growing number of studies confirm that bioactive food components modulate various signaling pathways which are involved in heart physiology and pathology. Recent evidence indicates that microRNAs (miRNAs), small single-stranded RNA chains with a powerful ability to influence protein expression in the whole organism, have a significant role in the regulation of cardiovascular-related pathways. This review summarizes recent studies dealing with the impact of some biologically active nutrients like polyunsaturated fatty acids (PUFAs), vitamins E and D, dietary fiber, or selenium on the expression of many miRNAs, which are connected with cardiovascular diseases. Current research indicates that the expression levels of many cardiovascular-related miRNAs like miRNA-21, -30 family, -34, -155, or -199 can be altered by foods and dietary supplements in various animal and human disease models. Understanding the dietary modulation of miRNAs represents, therefore, an important field for further research. The acquired knowledge may be used in personalized nutritional prevention of cardiovascular disease or the treatment of cardiovascular disorders.

Noncoding RNAs as Molecular Targets of Resveratrol Underlying Its Anticancer Effects.

Cancer is a significant disease burden worldwide. Chemotherapy is the mainstay of cancer treatment. Clinically used chemotherapeutic agents may elicit severe side effects. Remarkably, most of cancer cells develop chemoresistance after a period of treatment. Therefore, it is imperative to seek more effective agents without side effects. In recent years, increasing research efforts have attempted to identify natural agents that may be used alone or in combination with traditional therapeutics for cancer management. Resveratrol is a natural polyphenolic phytoalexin that can be found in various foods including blueberries, peanuts, and red wine. As a natural food ingredient, resveratrol possesses antioxidant, anti-inflammatory, and cardioprotective properties. Moreover, resveratrol exhibited promising effects in suppressing the initiation and progression of cancers. Noncoding RNAs (ncRNAs) have been universally accepted as vital regulators in cancer pathogenesis. The modulation of miRNAs and lncRNAs by resveratrol has been described. Thus, the mechanism involving the domination of ncRNA function is one of the keys to understand the anticancer effects of resveratrol. In this review, we focus on the antagonistic effects of resveratrol on cancer progression through regulation of miRNAs and lncRNAs. We also discuss the potential application of resveratrol in cancer management.

WWOX Inhibits Metastasis of Triple-Negative Breast Cancer Cells via Modulation of miRNAs.

Triple-negative breast cancer (TNBC) is a heterogeneous, highly aggressive, and difficult to treat tumor type. The tumor suppressor WWOX spans FRA16D, a common fragile site that is commonly altered in breast cancer. Despite recent progress, the role of WWOX in TNBC metastasis is unknown. Here we report that WWOX inactivation correlates with advanced stages of TNBC and that its levels are frequently altered in TNBC cells. Ectopic restoration of WWOX in WWOX-negative TNBC cells inhibited metastasis while its depletion in WWOX-positive TNBC cells promoted metastasis. WWOX was a negative regulator of c-MYC, which regulated miR-146a expression and consequently fibronectin levels, contributing to an epithelial status of the cell. Treatment of TNBC cells with anti-miR-146a rescued the WWOX antimetastatic phenotype. Moreover, overexpression of MYC in WWOX-expressing TNBC cells overrode WWOX effects on miR-146a and fibronectin levels. Altogether, our data uncover an essential role for WWOX in antagonizing TNBC progression and highlight its potential use as a biomarker for metastasis. SIGNIFICANCE: These findings highlight the mechanism by which the tumor suppressor WWOX regulates metastasis of triple-negative breast cancer.See related commentary by Sharma, p. 1746.

Phytochemical Modulation of MiRNAs in Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of death in the United States. Chemotherapy and radiotherapy are some of the most commonly used treatments, but are often associated with severe side effects, and are not entirely curative. It is therefore important to consider other preventative treatment options. Phytochemicals are naturally occurring bioactive compounds which have been shown to play a role in cancer prevention and treatment, especially in regards to a person’s lifestyle and diet. Recent evidence has shown that phytochemicals may exert their chemopreventative effects by targeting micro RNAs (miRNAs), which regulate the downstream expression of tumor suppressors and oncogenes. MiRNAs are small, endogenous, noncoding RNAs that regulate several biological processes through post-translational regulation. The dysregulation of miRNA expression has been shown to be associated with colorectal cancer. In this review, we will summarize and discuss several phytochemicals, which have been shown to exert chemopreventative effects in colorectal cancer by the modulation of miRNA expression.

MicroRNAs and nervous system diseases: network insights and computational challenges.

The nervous system is one of the most complex biological systems, and nervous system disease (NSD) is a major cause of disability and mortality. Extensive evidence indicates that numerous dysregulated microRNAs (miRNAs) are involved in a broad spectrum of NSDs. A comprehensive review of miRNA-mediated regulatory will facilitate our understanding of miRNA dysregulation mechanisms in NSDs. In this work, we summarized currently available databases on miRNAs and NSDs, star NSD miRNAs, NSD spectrum width, miRNA spectrum width and the distribution of miRNAs in NSD sub-categories by reviewing approximately 1000 studies. In addition, we characterized miRNA-miRNA and NSD-NSD interactions from a network perspective based on miRNA-NSD benchmarking data sets. Furthermore, we summarized the regulatory principles of miRNAs in NSDs, including miRNA synergistic regulation in NSDs, miRNA modules and NSD modules. We also discussed computational challenges for identifying novel miRNAs in NSDs. Elucidating the roles of miRNAs in NSDs from a network perspective would not only improve our understanding of the precise mechanism underlying these complex diseases, but also provide novel insight into the development, diagnosis and treatment of NSDs.

Exosomal miRNAs as Novel Pharmacodynamic Biomarkers for Cancer Chemopreventive Agent Early Stage Treatments in Chemically Induced Mouse Model of Lung Squamous Cell Carcinoma.

Background: Chemopreventive agent (CPA) treatment is one of the main preventive options for lung cancer. However, few studies have been done on pharmacodynamic biomarkers of known CPAs for lung cancer. Materials and methods: In this study, we treated mouse models of lung squamous cell carcinoma with three different CPAs (MEK inhibitor: AZD6244, PI-3K inhibitor: XL-147 and glucocorticoid: Budesonide) and examined circulating exosomal miRNAs in the plasma of each mouse before and after treatment. Results: Compared to baselines, we found differentially expressed exosomal miRNAs after AZD6244 treatment (n = 8, FDR < 0.05; n = 55, raw p-values < 0.05), after XL-147 treatment (n = 4, FDR < 0.05; n = 26, raw p-values < 0.05) and after Budesonide treatment (n = 1, FDR < 0.05; n = 36, raw p-values < 0.05). In co-expression analysis, we found that modules of exosomal miRNAs reacted to CPA treatments differently. By variable selection, we identified 11, 9 and nine exosomal miRNAs as predictors for AZD6244, XL-147 and Budesonide treatment, respectively. Integrating all the results, we highlighted 4 miRNAs (mmu-miR-215-5p, mmu-miR-204-5p, mmu-miR-708-3p and mmu-miR-1298-5p) as the key for AZD6244 treatment, mmu-miR-23a-3p as key for XL-147 treatment, and mmu-miR-125a-5p and mmu-miR-16-5p as key for Budesonide treatment. Conclusions: This is the first study to use circulating exosomal miRNAs as pharmacodynamic biomarkers for CPA treatment in lung cancer.

Endogenous and Exogenous Modulation of Nrf2 Mediated Oxidative Stress Response in Bovine Granulosa Cells: Potential Implication for Ovarian Function.

Nrf2 is a redox sensitive transcription factor regulating the expression of antioxidant genes as defense mechanism against various stressors. The aim of this study is to investigate the potential role of noncoding miRNAs as endogenous and quercetin as exogenous regulators of Nrf2 pathway in bovine granulosa cells. For this cultured granulosa cells were used for modulation of miRNAs (miR-28, 153 and miR-708) targeting the bovine Nrf2 and supplementation of quercentin to investigate the regulatory mechanisms of the Nrf2 antioxidant system. Moreover, cultured cells were treated with hydrogen peroxide to induce oxidative stress in those cells. Our results showed that, oxidative stress activated the expression of Nrf2 as a defense mechanism, while suppressing the expression of those miRNAs. Overexpression of those miRNAs resulted in downregulation of Nrf2 expression resulted in higher ROS accumulation, reduced mitochondrial activity and cellular proliferation. Quercetin supplementation showed its protective role against oxidative stress induced by H2O2 by inducing the expression of antioxidant enzymes. In conclusion, this study highlighted the involvement of miR-153, miR-28 and miR-708 in regulatory network of Nrf2 mediated antioxidant system in bovine granulosa cells function. Furthermore, quercetin at a low dose played a protective role in bovine granulosa cells against oxidative stress damage.

A Novel OsteomiRs Expression Signature for Osteoblast Differentiation of Human Amniotic Membrane-Derived Mesenchymal Stem Cells.

Human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) are a potential source of cells for therapeutic applications in bone regeneration. Recent evidence reveals a role for microRNAs (miRNAs) in the fine-tuning regulation of osteogenesis (osteomiRs) suggesting that they can be potential targets for skeleton diseases treatment. However, the functions of osteomiRs during differentiation of hAM-MSCs to osteogenic lineage are poorly understood. In this investigation, we discovered a novel miRNAs expression signature corresponding to the matrix maturation (preosteoblast) and mineralization (mature osteoblast) stages of dexamethasone-induced osteoblastic differentiation of hAM-MSCs. Comprehensive miRNAs profiling using TaqMan Low Density Arrays showed that 18 miRNAs were significantly downregulated, whereas 3 were upregulated in the matrix maturation stage (7 days after osteogenic induction) in comparison to undifferentiated cells used as control. Likewise, 47 miRNAs were suppressed and 25 were overexpressed at mineralization stage (14 days after osteogenic induction) in comparison to osteoprogenitors cells. Five out 93 miRNAs (miR-19b-3p, miR-335-3p, miR-197-3p, miR-34b-39, and miR-576-3p) were regulated at both 7 and 14 days suggesting a role in coordinated guidance of osteoblastic differentiation. Exhaustive bioinformatic predictions showed that the set of modulated miRNAs may target multiple genes involved in regulatory networks driving osteogenesis including key members of BMP, TGF-β, and WNT/β-catenin signaling pathways. Of these miRNAs, we selected miR-204, a noncoding small RNA that was expressed at matrix maturation phase and downregulated at maturation stage, for further functional studies. Interestingly, gain-of-function analysis showed that restoration of miR-204 using RNA mimics at the onset of mineralization stage dramatically inhibited deposition of calcium and osteogenic maturation of hAM-MSCs. Moreover in silico analysis detected a conserved miR-204 binding site at the 3′UTR of TGF-βR2 receptor gene. Using luciferase assays we confirmed that TGF-βR2 is a downstream effector of miR-204. In conclusion, we have identified a miRNAs signature for osteoblast differentiation of hAM-MSCs. The results from this study suggested that these miRNAs may act as potential inhibitors or activators of osteogenesis. Our findings also points towards the idea that miR-204/TGF-βR2 axis has a regulatory role in differentiation of hAM-MSCs committed to osteoblastic lineage.

Exposure to enriched environment rescues anxiety-like behavior and miRNA deregulated expression induced by perinatal malnutrition while altering oligodendrocyte morphology

Maternal malnutrition is one of the major early-life adversities affecting the development of newborn's brain and is associated with an increased risk to acquire cognitive and emotional deficiencies later in life. Studies in rodents have demonstrated that exposure to an enriched environment (EE) can reverse the negative consequences of early adversities. However, rescue of emotional disorders caused by perinatal malnutrition and the mechanisms involved has not been determined. We hypothesized that exposure to an EE may attenuate the anxiety-like disorders observed in mice subjected to perinatal protein malnutrition and that this could be mediated by epigenetic mechanisms. Male CF-1 mice were subject to perinatal protein malnutrition until weaning and then exposed to an EE for 5 weeks after which small RNA-seq was performed. In parallel, dark–light box and elevated plus maze tests were conducted to evaluate anxiety traits. We found that exposure to an EE reverses the anxiety-like behavior in malnourished mice. This reversal is paralleled by the expression of three miRNAs that become dysregulated by perinatal malnutrition (miR-187-3p, miR-369-3p and miR-132-3p). The predicted mRNA targets of these miRNAs are mostly related to axon guidance pathway. Accordingly, we also found that perinatal malnutrition leads to reduction in the cingulum size and altered oligodendrocyte morphology. These results suggest that EE-rescue of anxiety disorders derived from perinatal malnutrition is mediated by the modulation of miRNAs associated with the regulation of genes involved in axonal guidance.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Bifidobacterium longum Suppresses Murine Colorectal Cancer through the Modulation of oncomiRs and Tumor Suppressor miRNAs

The modulatory role of the Bifidobacterium longum (BL), isolated from women breast milk, on some oncogenic and tumor suppressor miRNAs as well as IL-1β and IL6 targeted-miRNAs was investigated using murine colorectal cancer (CRC) induced on the top of inflammatory ulcerative colitis model. The investigation of the oncomiRs miR-21a and miR-155, which regulate IL-6 and IL-1β expression, indicated that both was depressed by BL-administration in healthy and in CRC-mice. BL-administration induced the tumor suppressor miRNAs (miR-145 and miR-15a) expression in both of the healthy and in CRC-mice. The miR-146a expression, which regulates both of IL-1β and IL-6 expression, was decreased after the BL-administration in both of the healthy and in CRC-mice. In CRC-mice, NF-Kb concentration was elevated, however this NF-Kb induction was diminished after the treatment with BL. BL highly enhanced the IL-1β and IL-6 mRNA and protein concentrations in healthy mice. The administration of BL to CRC-mice resulted in a dramatic increase in IL-1β mRNA and IL-1β concentration, which in contrast was accompanied with a decrease in the IL-6 mRNA and IL-6 concentration. BL-administration resulted in a drop in the aberrant crypt foci number in CRC-mice and increased necrosis and fibrosis of the colon cells. The modulatory influence of B. longum on microRNAs may provide an important therapeutic impact in CRC through inhibition of the proliferation, invasion, apoptosis, and cell cycle of tumor cells.

CeModule: an integrative framework for discovering regulatory patterns from genomic data in cancer

BackgroundNon-coding RNAs (ncRNAs) are emerging as key regulators and play critical roles in a wide range of tumorigenesis. Recent studies have suggested that long non-coding RNAs (lncRNAs) could interact with microRNAs (miRNAs) and indirectly regulate miRNA targets through competing interactions. Therefore, uncovering the competing endogenous RNA (ceRNA) regulatory mechanism of lncRNAs, miRNAs and mRNAs in post-transcriptional level will aid in deciphering the underlying pathogenesis of human polygenic diseases and may unveil new diagnostic and therapeutic opportunities. However, the functional roles of vast majority of cancer specific ncRNAs and their combinational regulation patterns are still insufficiently understood.ResultsHere we develop an integrative framework called CeModule to discover lncRNA, miRNA and mRNA-associated regulatory modules. We fully utilize the matched expression profiles of lncRNAs, miRNAs and mRNAs and establish a model based on joint orthogonality non-negative matrix factorization for identifying modules. Meanwhile, we impose the experimentally verified miRNA-lncRNA interactions, the validated miRNA-mRNA interactions and the weighted gene-gene network into this framework to improve the module accuracy through the network-based penalties. The sparse regularizations are also used to help this model obtain modular sparse solutions. Finally, an iterative multiplicative updating algorithm is adopted to solve the optimization problem.ConclusionsWe applied CeModule to two cancer datasets including ovarian cancer (OV) and uterine corpus endometrial carcinoma (UCEC) obtained from TCGA. The modular analysis indicated that the identified modules involving lncRNAs, miRNAs and mRNAs are significantly associated and functionally enriched in cancer-related biological processes and pathways, which may provide new insights into the complex regulatory mechanism of human diseases at the system level.