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Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by inflammatory back pain and bony fusion of vertebral joints. Genetic associations and environmental factors have been proposed to explain the immunopathogenesis of AS. In the past few years, there have been major advances in understanding T cell dysfunction in AS. Clinically, targeting interleukin-17A, a major cytokine secreted by T helper 17 cells, has been approved for treating patients with active AS. Non-coding RNAs (ncRNAs) are RNA transcripts that do not translate into proteins. The ncRNAs regulate both innate and adaptive immunity and participate in the pathogenesis of autoimmune diseases, including AS. The main purpose of this article is to review the up-to-date studies investigating the aberrant expression of ncRNAs in T cells from patients with AS and to summarize their roles in its pathogenesis. After searching PubMed for studies published between January 2013 and June 2024, nine studies investigating the expression of ncRNAs in AS T cells were included. We found that aberrantly expressed ncRNAs in AS T cells could cause abnormal cytokine release, cell signaling abnormalities, and dysregulated cell proliferation and death, which contribute to the immunopathogenesis of AS. We discussed some limitations of these studies and suggested several research fields for further investigation. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer is one of the most common diseases worldwide that affects women of reproductive age. miR-221 and miR-222 are two highly homogeneous microRNAs that play pivotal roles in many cellular processes and regulate the Wnt/β-catenin signaling pathway. Curcumin (CUR), a yellow polyphenolic compound, targets numerous signaling pathways relevant to cancer therapy. The main aim of this study was to compare the ability of chitosan curcumin nanoparticle (CC-CUR) formulation with the curcumin in modulating miR-221 and miR-222 expression through Wnt/β-catenin signaling pathway in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cell lines. Method Chitosan-cyclodextrin-tripolyphosphate containing curcumin nanoparticles (CC-CUR) were prepared. Cytotoxicity of the CUR and CC-CUR was evaluated. Experimental groups including CC-CUR, CUR and negative control were designed. The expression of miR-221 and miR-222 and Wnt/β-catenin pathway genes was measured. Results The level of miR-221 and miR-222 and β-catenin genes decreased in MCF-7 and MDA-MB-231 cells and WIF1 gene increased in all cells in CC-CUR group. However, the results in SK-BR-3 cell line were unexpected; since miRs and WIF1 gene expressions were increased following CC-CUR administration and β-catenin decreased by administration of CUR. Conclusion Although the composite form of curcumin decreased the expression of miR-221 and miR-222 in MCF-7 and MDA cells, with significant decreasing of β-catenin and increasing of WIF1 gene in almost all three cell lines, we can conclude than this formulation exerts its effect mainly through the Wnt/β-catenin pathway. These preliminary findings may pave the way for the use of curcumin nanoparticles in the treatment of some known cancers.

Objectives: We previously found that the pluripotency factor OCT4 is reactivated in smooth muscle cells (SMC) in human and mouse atherosclerotic plaques and plays an atheroprotective role. Loss of OCT4 in SMC in vitro was associated with decreases in SMC migration. However, molecular mechanisms responsible for atheroprotective SMC-OCT4-dependent effects remain unknown. Methods: Since studies in embryonic stem cells demonstrated that OCT4 regulates long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), making them candidates for OCT4 effect mediators, we applied an in vitro approach to investigate the interactions between OCT4-regulated lncRNAs, mRNAs, and miRNAs in SMC. We used OCT4 deficient mouse aortic SMC (MASMC) treated with the pro-atherogenic oxidized phospholipid POVPC, which, as we previously demonstrated, suppresses SMC contractile markers and induces SMC migration. Differential expression of lncRNAs, mRNAs, and miRNAs was obtained by lncRNA/mRNA expression array and small-RNA microarray. Long non-coding RNA to mRNA associations were predicted based on their genomic proximity and association with vascular diseases. Given a recently discovered crosstalk between miRNA and lncRNA, we also investigated the association of miRNAs with upregulated/downregulated lncRNA-mRNA pairs. Results: POVPC treatment in SMC resulted in upregulating genes related to the axon guidance and focal adhesion pathways. Knockdown of Oct4 resulted in differential regulation of pathways associated with phagocytosis. Importantly, these results were consistent with our data showing that OCT4 deficiency attenuated POVPC-induced SMC migration and led to increased phagocytosis. Next, we identified several up- or downregulated lncRNA associated with upregulation of the specific mRNA unique for the OCT4 deficient SMC, including upregulation of ENSMUST00000140952-Hoxb5/6 and ENSMUST00000155531-Zfp652 along with downregulation of ENSMUST00000173605-Parp9 and, ENSMUST00000137236-Zmym1. Finally, we found that many of the downregulated miRNAs were associated with cell migration, including miR-196a-1 and miR-10a, targets of upregulated ENSMUST00000140952, and miR-155 and miR-122, targets of upregulated ENSMUST00000155531. Oppositely, the upregulated miRNAs were anti-migratory and pro-phagocytic, such as miR-10a/b and miR-15a/b, targets of downregulated ENSMUST00000173605, and miR-146a/b and miR-15b targets of ENSMUST00000137236. Conclusion: Our integrative analyses of the lncRNA-miRNA-mRNA interactions in SMC indicated novel potential OCT4-dependent mechanisms that may play a role in SMC phenotypic transitions. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are relatively new members of the RNA world and can contribute to crucial biological functions. CircRNAs have tissue-specific expression profiles depending on cell type and developmental stage. In Sistan region cultivated grapes are seedless but have small berries. The compact clusters are another notable characteristic of these grape cultivars, which negatively impacts their marketability. In this study, we aimed to identify the circRNAs that are active in cluster formation and investigated the effects of gibberellin treatment on their expression. Eight detection tools were used to predict the expressed circRNAs. Reliable circRNAs were used to identify potential functions of differentially expressed circRNAs by gene ontology (GO) analysis and prediction of target microRNAs (miRNAs). Of the 28 157 circRNAs detected, 3 715 were reliable. 900 differently expressed circRNAs were identified in the three developmental stages of the cluster under gibberellin treatment. Among the 503 target miRNAs found, 12 miRNAs were selected based on the number and expression of their circRNA sponges. Of the 29 circRNAs in the circRNAs-miRNAs-mRNAs interaction network, 12 circRNAs are highly conserved. Our results suggest that circRNAs in grape may play a key role in developmental and environmental adaptation in perennial plants.

Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by inflammatory back pain and bony fusion of vertebral joints. Genetic associations and environmental factors have been proposed to explain the immunopathogenesis of AS. In the past few years, there have been major advances in understanding T cell dysfunction in AS. Clinically, targeting interleukin-17A, a major cytokine secreted by T helper 17 cells, has been approved for treating patients with active AS. Non-coding RNAs (ncRNAs) are RNA transcripts that do not translate into proteins. The ncRNAs regulate both innate and adaptive immunity and participate in the pathogenesis of autoimmune diseases, including AS. The main purpose of this article is to review the up-to-date studies investigating the aberrant expression of ncRNAs in T cells from patients with AS and to summarize their roles in its pathogenesis. After searching PubMed for studies published between January 2013 and June 2024, nine studies investigating the expression of ncRNAs in AS T cells were included. We found that aberrantly expressed ncRNAs in AS T cells could cause abnormal cytokine release, cell signaling abnormalities, and dysregulated cell proliferation and death, which contribute to the immunopathogenesis of AS. We discussed some limitations of these studies and suggested several research fields for further investigation.

Abstract Objective To systematically identify and narratively synthesize the evidence surrounding liposomal delivery of gene therapy and the outcome for ovarian cancer. Methods An electronic database search of the Embase, MEDLINE and Web of Science from inception until July 7, 2023, was conducted to identify primary studies that investigated the effect of liposomal delivery of gene therapy on ovarian cancer outcomes. Retrieved studies were assessed against the eligibility criteria for inclusion. Results The search yielded 564 studies, of which 75 met the inclusion criteria. Four major types of liposomes were identified: cationic, neutral, polymer-coated, and ligand-targeted liposomes. The liposome with the most evidence involved cationic liposomes which are characterized by their positively charged phospholipids (n = 37, 49.3%). Similarly, those with neutrally charged phospholipids, such as 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, were highly researched as well (n = 25, 33.3%). Eight areas of gene therapy research were identified, evaluating either target proteins/transcripts or molecular pathways: microRNAs, ephrin type-A receptor 2 (EphA2), interleukins, mitogen-activated protein kinase (MAPK), human-telomerase reverse transcriptase/E1A (hTERT/EA1), suicide gene, p53, and multidrug resistance mutation 1 (MDR1). Conclusion Liposomal delivery of gene therapy for ovarian cancer shows promise in many in vivo studies. Emerging polymer-coated and ligand-targeted liposomes have been gaining interest as they have been shown to have more stability and specificity. We found that gene therapy involving microRNAs was the most frequently studied. Overall, liposomal genetic therapy has been shown to reduce tumor size and weight and improve survivability. More research involving the delivery and targets of gene therapy for ovarian cancer may be a promising avenue to improve patient outcomes.

Objectives: We previously found that the pluripotency factor OCT4 is reactivated in smooth muscle cells (SMC) in human and mouse atherosclerotic plaques and plays an atheroprotective role. Loss of OCT4 in SMC in vitro was associated with decreases in SMC migration. However, molecular mechanisms responsible for atheroprotective SMC-OCT4-dependent effects remain unknown.Methods: Since studies in embryonic stem cells demonstrated that OCT4 regulates long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), making them candidates for OCT4 effect mediators, we applied an in vitro approach to investigate the interactions between OCT4-regulated lncRNAs, mRNAs, and miRNAs in SMC. We used OCT4 deficient mouse aortic SMC (MASMC) treated with the pro-atherogenic oxidized phospholipid POVPC, which, as we previously demonstrated, suppresses SMC contractile markers and induces SMC migration. Differential expression of lncRNAs, mRNAs, and miRNAs was obtained by lncRNA/mRNA expression array and small-RNA microarray. Long non-coding RNA to mRNA associations were predicted based on their genomic proximity and association with vascular diseases. Given a recently discovered crosstalk between miRNA and lncRNA, we also investigated the association of miRNAs with upregulated/downregulated lncRNA-mRNA pairs.Results: POVPC treatment in SMC resulted in upregulating genes related to the axon guidance and focal adhesion pathways. Knockdown of Oct4 resulted in differential regulation of pathways associated with phagocytosis. Importantly, these results were consistent with our data showing that OCT4 deficiency attenuated POVPC-induced SMC migration and led to increased phagocytosis. Next, we identified several up- or downregulated lncRNA associated with upregulation of the specific mRNA unique for the OCT4 deficient SMC, including upregulation of ENSMUST00000140952-Hoxb5/6 and ENSMUST00000155531-Zfp652 along with downregulation of ENSMUST00000173605-Parp9 and, ENSMUST00000137236-Zmym1. Finally, we found that many of the downregulated miRNAs were associated with cell migration, including miR-196a-1 and miR-10a, targets of upregulated ENSMUST00000140952, and miR-155 and miR-122, targets of upregulated ENSMUST00000155531. Oppositely, the upregulated miRNAs were anti-migratory and pro-phagocytic, such as miR-10a/b and miR-15a/b, targets of downregulated ENSMUST00000173605, and miR-146a/b and miR-15b targets of ENSMUST00000137236.Conclusion: Our integrative analyses of the lncRNA-miRNA-mRNA interactions in SMC indicated novel potential OCT4-dependent mechanisms that may play a role in SMC phenotypic transitions.

Micro RNAs (miRNAs) are short non-coding RNAs that act as post-transcriptional gene expression regulators. Genes regulated in vertebrates include those affecting growth and development or stress and immune response. Pikeperch (Sander lucioperca) is a species that is increasingly being considered for farming in recirculation aquaculture systems. We characterized the pikeperch miRNA repertoire to increase the knowledge of the genomic mechanisms affecting performance and health traits by applying small RNA sequencing to different developmental stages and organs. There were 234 conserved and 8 novel miRNA genes belonging to 104 families. A total of 375 unique mature miRNAs were processed from these genes. Many mature miRNAs showed high relative abundances or were significantly more expressed at early developmental stages, like the miR-10 and miR-430 family, let-7, the miRNA clusters 106-25-93, and 17-19-92. Several miRNAs associated with immune responses (e.g., slu-mir-731-5p, slu-mir-2188-5p, and slu-mir-8159-5p) were enriched in the spleen. The mature miRNAs slu-mir-203a-3p and slu-mir-205-5p were enriched in gills. These miRNAs are similarly abundant in many vertebrates, indicating that they have shared regulatory functions. There was also a significantly increased expression of the disease-associated miR-462/miR-731 cluster in response to hypoxia stress. This first pikeperch miRNAome reference resource paves the way for future functional studies to identify miRNA-associated variations that can be utilized in marker-assisted breeding programs. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether or not the application of a stem cell-derived exosome-laden collagen patch (EXP) during coronary artery bypass grafting (CABG) can recover cardiac function by modulating mitochondrial bioenergetics and myocardial inflammation in hibernating myocardium (HIB), which is defined as myocardium with reduced blood flow and function that retains viability and variable contractile reserve. In vitro methods involved exposing H9C2 cardiomyocytes to hypoxia followed by normoxic coculture with porcine mesenchymal stem cells. Mitochondrial respiration was measured using Seahorse assay. GW4869, an exosomal release antagonist, was used to determine the effect of mesenchymal stem cells-derived exosomal signaling on cardiomyocyte recovery. Total exosomal RNA was isolated and differential micro RNA expression determined by sequencing. In vivo studies comprised 48 Yorkshire-Landrace juvenile swine (6 normal controls, 17 HIB, 19 CABG, and 6 CABG + EXP), which were compared for physiologic and metabolic changes. HIB was created by placing a constrictor on the proximal left anterior descending artery, causing significant stenosis but preserved viability by 12 weeks. CABG was performed with or without mesenchymal stem cells-derived EXP application and animals recovered for 4 weeks. Before terminal procedure, cardiac magnetic resonance imaging at rest, and with low-dose dobutamine, assessed diastolic relaxation, systolic function, graft patency, and myocardial viability. Tissue studies of inflammation, fibrosis, and mitochondrial morphology were performed posttermination. In vitro data demonstrated improved cardiomyocyte mitochondrial respiration upon coculture with MSCs that was blunted when adding the exosomal antagonist GW4869. RNA sequencing identified 8 differentially expressed micro RNAs in normoxia vs hypoxia-induced exosomes that may modulate the expression of key mitochondrial (peroxisome proliferator-activator receptor gamma coactivator 1-alpha and adenosine triphosphate synthase) and inflammatory mediators (nuclear factor kappa-light-chain enhancer of activated B cells, interferon gamma, and interleukin 1β). In vivo animal magnetic resonance imaging studies demonstrated regional systolic function and diastolic relaxation to be improved with CABG + EXP compared with HIB (P =.02 and P =.02, respectively). Histologic analysis showed increased interstitial fibrosis and inflammation in HIB compared with CABG + EXP. Electron microscopy demonstrated increased mitochondrial area, perimeter, and aspect ratio in CABG + EXP compared with HIB or CABG alone (P <.0001). Exosomes recovered cardiomyocyte mitochondrial respiration and reduced myocardial inflammation through paracrine signaling, resulting in improved cardiac function. [Display omitted] [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDDs) and neuropsychiatric disorders (NPDs) are two common causes of death in elderly people, which includes progressive neuronal cell death and behavioral changes. NDDs include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and motor neuron disease, characterized by cognitive defects and memory impairment, whereas NPDs include depression, seizures, migraine headaches, eating disorders, addictions, palsies, major depressive disorders, anxiety, and schizophrenia, characterized by behavioral changes. Mounting evidence demonstrated that NDDs and NPDs share an overlapping mechanism, which includes post-translational modifications, the microbiota–gut–brain axis, and signaling events. Mounting evidence demonstrated that various drug molecules, namely, natural compounds, repurposed drugs, multitarget directed ligands, and RNAs, have been potentially implemented as therapeutic agents against NDDs and NPDs. Herein, we highlighted the overlapping mechanism, the role of anxiety/stress-releasing factors, cytosol-to-nucleus signaling, and the microbiota–gut–brain axis in the pathophysiology of NDDs and NPDs. We summarize the therapeutic application of natural compounds, repurposed drugs, and multitarget-directed ligands as therapeutic agents. Lastly, we briefly described the application of RNA interferences as therapeutic agents in the pathogenesis of NDDs and NPDs. Neurodegenerative diseases and neuropsychiatric diseases both share a common signaling molecule and molecular phenomenon, namely, pro-inflammatory cytokines, γCaMKII and MAPK/ERK, chemokine receptors, BBB permeability, and the gut–microbiota–brain axis. Studies have demonstrated that any alterations in the signaling mentioned above molecules and molecular phenomena lead to the pathophysiology of neurodegenerative diseases, namely, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and neuropsychiatric disorders, such as bipolar disorder, schizophrenia, depression, anxiety, autism spectrum disorder, and post-traumatic stress disorder. [ABSTRACT FROM AUTHOR]

Depression is a psychiatric disorder accountable for high death, morbidity, destructive health behaviors, missing occupation efficiency, and enlarged health care consumption. The presence of miRNAs in brain tissues and the potential of postmortem brain samples to recognize the severity of depressive and peripheral tissues provide a promising approach for the wide regulatory use of miRNA. Because of the inherent restrictions associated with obtaining brain tissue in vivo, the use of postmortem brain tissue may confuse by an unlimited postmortem gap and prior medication exposure. Therefore, this review aims to assess the potential broad applications of micro-RNA and its current advancement in depression. [ABSTRACT FROM AUTHOR]

Background: Red Blood cells (RBCs) bring about harmful consequences during storage. MicroRNA (miRNA) dysregulation in stored RBCs could represent potential biomarkers of storage lesions. Although leukoreduction prevents damage to RBCs, it is uncertain whether leukoreduction of RBCs would impact the dysregulation of miRNAs during storage. This study evaluated the potential role of miRNAs for any alteration of leukoreduced (LR) and non‐leukoreduced (NLR) RBCs till 21 days of storage. Study Design and Methods: In this prospective study, thirty male volunteers' blood was equally divided into leukoreduced RBCs (LR) and NLR RBC (NLR) bags and stored till Day 21 at 4‐60c. Selected miRNAs were quantified on Days 0 and 21. Further, bioinformatic tools were used to analyze the selected miRNAs and their predicted target genes (mRNAs) and identify the miRNA‐mRNA regulatory relationships. Results: A significantly higher fold change values of three miRNAs (miR‐96‐5p, miR‐197‐3p, miR‐769‐3p) were observed in NLR RBCs (p <.05). A significantly higher (p <.05) expression levels of miR‐150‐5p and miR‐197‐3p were observed in NLR RBCs till 21 days of storage. Further, the correlation with mRNA quantification confirmed the regulatory role of these miRNAs upon functional pathway enrichment analysis. Discussion: A higher level of dysregulation of miRNAs was observed in NLR RBCs. Validation from In‐Silico analysis suggested the regulatory role of miRNAs in cell apoptosis, senescence, and RBC‐related signaling pathways. This indicated that stored LR RBCs would likely have better in vivo survival and function following transfusion. However, an in vivo study of miRNA in RBCs is warranted for conclusive evidence. [ABSTRACT FROM AUTHOR]

Objective: To systematically identify and narratively synthesize the evidence surrounding liposomal delivery of gene therapy and the outcome for ovarian cancer. Methods: An electronic database search of the Embase, MEDLINE and Web of Science from inception until July 7, 2023, was conducted to identify primary studies that investigated the effect of liposomal delivery of gene therapy on ovarian cancer outcomes. Retrieved studies were assessed against the eligibility criteria for inclusion. Results: The search yielded 564 studies, of which 75 met the inclusion criteria. Four major types of liposomes were identified: cationic, neutral, polymer-coated, and ligand-targeted liposomes. The liposome with the most evidence involved cationic liposomes which are characterized by their positively charged phospholipids (n = 37, 49.3%). Similarly, those with neutrally charged phospholipids, such as 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, were highly researched as well (n = 25, 33.3%). Eight areas of gene therapy research were identified, evaluating either target proteins/transcripts or molecular pathways: microRNAs, ephrin type-A receptor 2 (EphA2), interleukins, mitogen-activated protein kinase (MAPK), human-telomerase reverse transcriptase/E1A (hTERT/EA1), suicide gene, p53, and multidrug resistance mutation 1 (MDR1). Conclusion: Liposomal delivery of gene therapy for ovarian cancer shows promise in many in vivo studies. Emerging polymer-coated and ligand-targeted liposomes have been gaining interest as they have been shown to have more stability and specificity. We found that gene therapy involving microRNAs was the most frequently studied. Overall, liposomal genetic therapy has been shown to reduce tumor size and weight and improve survivability. More research involving the delivery and targets of gene therapy for ovarian cancer may be a promising avenue to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal cancer (NPC) has a high incidence in Southern China and Asia, and its survival is extremely poor in advanced patients. MiRNAs play critical roles in regulating gene expression and serve as therapeutic targets in cancer. This study sought to disclose key miRNAs and target genes responsible for NPC prognosis and endocrine metabolism. Materials and methods: Three datasets (GSE32960, GSE70970, and GSE102349) of NPC samples came from Gene Expression Omnibus (GEO). Limma and WGCNA were applied to identify key prognostic miRNAs. There were 12 types of miRNA tools implemented to study potential target genes (mRNAs) of miRNAs. Univariate Cox regression and stepAIC were introduced to construct risk models. Pearson analysis was conducted to analyze the correlation between endocrine metabolism and RiskScore. Single-sample gene set enrichment analysis (ssGSEA), MCP-counter, and ESTIMATE were performed for immune analysis. The response to immunotherapy was predicted by TIDE and SubMap analyses. Results: Two key miRNAs (miR-142-3p and miR-93) were closely involved in NPC prognosis. The expression of the two miRNAs was dysregulated in NPC cell lines. A total of 125 potential target genes of the key miRNAs were screened, and they were enriched in autophagy and mitophagy pathways. Five target genes (E2F1, KCNJ8, SUCO, HECTD1, and KIF23) were identified to construct a prognostic model, which was used to divide patients into high group and low group. RiskScore was negatively correlated with most endocrine-related genes and pathways. The low-risk group manifested higher immune infiltration, anticancer response, more activated immune-related pathways, and higher response to immunotherapy than the high-risk group. Conclusions: This study revealed two key miRNAs that were highly contributable to NPC prognosis. We delineated the specific links between key miRNAs and prognostic mRNAs with miRNA–mRNA networks. The effectiveness of the fivegene model in predicting NPC prognosis as well as endocrine metabolism provided a guidance for personalized immunotherapy in NPC patients. [ABSTRACT FROM AUTHOR]

Stem cell therapy provides a hope to no option heart disease patient group. Stem cells work via different mechanisms of which paracrine mechanism is reported to justify most of the effects. Therefore, identifying the control arms for paracrine cocktail production is necessary to tailor stem cell functions in disease contextual manner. In this study, we describe a novel paracrine cocktail regulatory axis, in stem cells, to enhance their cardioprotective abilities. We identified that HSF1 knockout resulted in reduced cardiac regenerative abilities of mesenchymal stem cells (MSCs) while its overexpression had opposite effects. Altered exosome biognesis and their miRNA cargo enrichment were found to be underlying these altered regenerative abilities. Decreased production of exosomes by MSCs accompanied their loss of HSF1 and vice versa. Moreover, the exosomes derived from HSF1 depleted MSCs showed significantly reduced candidate miRNA expression (miR-145, miR-146, 199-3p, 199b and miR-590) compared to those obtained from HSF1 overexpressing MSCs. We further discovered that HSF1 mediates miRNAs' enrichment into exosomes via Y binding protein 1 (YBX1) and showed, by loss and gain of function strategies, that miRNAs' enrichment in mesenchymal stem cell derived exosomes is deregulated with altered YBX1 expression. It was finally demonstrated that absence of YBX1 in MSCs, with normal HSF1 expression, resulted in significant accumulation of candidate miRNAs into the cells. Together, our data shows that HSF1 plays a critical role in determining the regenerative potential of stem cells. HSF1 does that by affecting exosome biogenesis and miRNA cargo sorting via regulation of YBX1 gene expression. [ABSTRACT FROM AUTHOR]

Abstract Background Monocytes -key regulators of the innate immune response- are actively involved in the pathogenesis of systemic lupus erythematosus (SLE). We sought to identify novel compounds that might serve as monocyte-directed targeted therapies in SLE. Results We performed mRNA sequencing in monocytes from 15 patients with active SLE and 10 healthy individuals. Disease activity was assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Leveraging the drug repurposing platforms iLINCS, CLUE and L1000CDS2, we identified perturbagens capable of reversing the SLE monocyte signature. We identified transcription factors and microRNAs (miRNAs) that regulate the transcriptome of SLE monocytes, using the TRRUST and miRWalk databases, respectively. A gene regulatory network, integrating implicated transcription factors and miRNAs was constructed, and drugs targeting central components of the network were retrieved from the DGIDb database. Inhibitors of the NF-κB pathway, compounds targeting the heat shock protein 90 (HSP90), as well as a small molecule disrupting the Pim-1/NFATc1/NLRP3 signaling axis were predicted to efficiently counteract the aberrant monocyte gene signature in SLE. An additional analysis was conducted, to enhance the specificity of our drug repurposing approach on monocytes, using the iLINCS, CLUE and L1000CDS2 platforms on publicly available datasets from circulating B-lymphocytes, CD4+ and CD8+ T-cells, derived from SLE patients. Through this approach we identified, small molecule compounds, that could potentially affect more selectively the transcriptome of SLE monocytes, such as, certain NF-κB pathway inhibitors, Pim-1 and SYK kinase inhibitors. Furthermore, according to our network-based drug repurposing approach, an IL-12/23 inhibitor and an EGFR inhibitor may represent potential drug candidates in SLE. Conclusions Application of two independent - a transcriptome-reversal and a network-based -drug repurposing strategies uncovered novel agents that might remedy transcriptional disturbances of monocytes in SLE.

microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females (n = 6) before and after a single submaximal bout of endurance exercise ('reference training'). Subsequently, participants were subjected to a structured training program, consisting of six weeks of moderate-intensity continuous endurance training (MICT) and six weeks of high-intensity interval training (HIIT) in randomized order. In vastus lateralis muscle, we found significant downregulation of myomiRs, specifically miR-1, 133a-3p, and -5p, -133b, and -499a-5p. Similarly, exercise-associated miRs-23a-3p, -378a-5p, -128-3p, -21-5p, -107, -27a-3p, -126-3p, and -152-3p were significantly downregulated, whereas miR-23a-5p was upregulated. Furthermore, in an untargeted approach for differential expression in response to acute exercise, we identified n = 35 miRs that were downregulated and n = 20 miRs that were upregulated by factor 4.5 or more. Remarkably, KEGG pathway analysis indicated central involvement of this set of miRs in fatty acid metabolism. To reproduce these data in a larger cohort of all-female subjects (n = 29), qPCR analysis was carried out on n = 15 miRs selected from the microarray, which confirmed their differential expression. Furthermore, the acute response, i.e., the difference between miR concentrations before and after the reference training, was correlated with changes in maximum oxygen uptake (V̇O2max) in response to the training program. Here, we found that miRs-199a-3p and -19b-3p might be suitable acute-response candidates that correlate with individual degrees of training adaptation in females. [ABSTRACT FROM AUTHOR]

Micro RNAs (miRNAs) are 19–23 nucleotides-long non-coding RNA which have been identified as important biomarkers for many diseases, including cancers. Here, we report an ultrasensitive, highly specific, label-free, and without nucleic acid amplification (NAA) detection of miRNAs using paper-based single-walled carbon nanotubes (SWNTs) field-effect transistor (FET) biosensors. The strategy involved a two-step protocol starting with direct hybridization of the target miRNA with a specific RNA probe immobilized on SWNTs networks deposited on the paper substrate to generate the first response, followed by the recognition of the resulting RNA/miRNA duplexes with the Carnation Italian ringspot virus p19 protein (p19) in a size-dependent manner, giving the second electrical response that magnified the biosensor sensitivity. As a demonstration, we detected the miRNA-122a, a promising biomarker for the diagnosis of early-stage hepatocellular carcinoma (HCC) in various sample matrices, including phosphate buffers, human serum, and synthetic saliva. We achieved the lowest detection of 0.1 aM and a wide dynamic range of 0.1 aM–1 fM, that demonstrated its potential for rapid, facile, low-cost, and point-of-care detection of miRNAs for early cancer diagnosis.

Background: Monocytes -key regulators of the innate immune response- are actively involved in the pathogenesis of systemic lupus erythematosus (SLE). We sought to identify novel compounds that might serve as monocyte-directed targeted therapies in SLE. Results: We performed mRNA sequencing in monocytes from 15 patients with active SLE and 10 healthy individuals. Disease activity was assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Leveraging the drug repurposing platforms iLINCS, CLUE and L1000CDS2, we identified perturbagens capable of reversing the SLE monocyte signature. We identified transcription factors and microRNAs (miRNAs) that regulate the transcriptome of SLE monocytes, using the TRRUST and miRWalk databases, respectively. A gene regulatory network, integrating implicated transcription factors and miRNAs was constructed, and drugs targeting central components of the network were retrieved from the DGIDb database. Inhibitors of the NF-κB pathway, compounds targeting the heat shock protein 90 (HSP90), as well as a small molecule disrupting the Pim-1/NFATc1/NLRP3 signaling axis were predicted to efficiently counteract the aberrant monocyte gene signature in SLE. An additional analysis was conducted, to enhance the specificity of our drug repurposing approach on monocytes, using the iLINCS, CLUE and L1000CDS2 platforms on publicly available datasets from circulating B-lymphocytes, CD4+ and CD8+ T-cells, derived from SLE patients. Through this approach we identified, small molecule compounds, that could potentially affect more selectively the transcriptome of SLE monocytes, such as, certain NF-κB pathway inhibitors, Pim-1 and SYK kinase inhibitors. Furthermore, according to our network-based drug repurposing approach, an IL-12/23 inhibitor and an EGFR inhibitor may represent potential drug candidates in SLE. Conclusions: Application of two independent - a transcriptome-reversal and a network-based -drug repurposing strategies uncovered novel agents that might remedy transcriptional disturbances of monocytes in SLE. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a common cancer all over the world that affects women. BC is one of the leading causes of cancer mortality in women, which today has decreased with the advancement of technology and new diagnostic and therapeutic methods. BCs are histologically divided into in situ and invasive carcinoma, and both of them can be divided into ductal and lobular. The main function after the diagnosis of invasive breast cancer is which patient should use chemotherapy, which patient should receive adjuvant therapy, and which should not. If the decision is for adjuvant therapy, the next challenge is to identify the most appropriate treatment or combination of treatments for a particular patient. Addressing the first challenge can be helped by prognostic biomarkers, while addressing the second challenge can be done by predictive biomarkers. Among the molecular markers related to BC, ER, PR, HER2, and the Mib1/Ki-67 proliferation index are the most significant ones and are tightly confirmed in the standard care of all primary, recurrent, and metastatic BC patients. CEA and CA-15–3 antigens are the most valuable markers of serum tumors in BC patients. Determining the series of these markers helps monitor response to the treatment and early detection of recurrence or metastasis. miRNAs have been demonstrated to be intricate in mammary gland growth, proliferation, and formation of BC known to be incriminated in BC biology. By combining established prognostic factors with valid prognostic/predicted biomarkers, we can start the journey to personalized treatment for every recently diagnosed BC patient. [ABSTRACT FROM AUTHOR]

Diagnosis of echinococcosis is difficult and usually performed based on clinical findings, imaging, and serological test. However, all of them have limitations, especially in follow-up approaches. Detection of cell-free DNA (cfDNA) and micro-RNA (miRNA) is currently a hot topic for diagnosis of echinococcosis diseases. For detecting cell-free DNA in echinococcosis patient's samples such as sera, some techniques are based on next-generation sequencing (NGS), DNA-deep sequencing, some are based on PCR-based methods, and a few works related to the detection of miRNA for the diagnosis of human echinococcosis. In the detection of cell-free DNA in echinococcosis patient' samples, NGS and DNA-deep sequencing have shown high level of sensitivity, but are not suitable for routine clinical examination as they are expensive and inaccessible in the majority of endemic areas. However, PCR-based methods have shown a sensitivity of about 20–25%. To improve the sensitivity of these tests, improving the DNA extraction method, designing appropriate primers for detecting short-length fragments of circulating DNA, using a higher volume of a serum sample, and application of more sensitive PCR methods are recommended. In the field of miRNA detection, further works are recommended. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated thrombocytopenia and variable phenotype as some patients suffer no bleeding whilst others have bleeding from mild to severe, which may be fatal. This variability probably reflects the disease's complex pathophysiology; a dysregulated hyperreactive immune effector cell response involving the entire adaptive immune system (e.g. B and T cell subsets) that leads to platelet and megakaryocyte (MK) destruction. It appears that these effector responses are due to a breakdown in immune tolerance, and this is characterized by defects in several immunosuppressive cell types. These include defective T regulatory cells (Tregs), B regulatory cells (Bregs) and Myeloid-derived suppressor cells (MDSC), all of which are all intimately associated with antigen presenting cells (APC) such as dendritic cells (DC). The loss of this immunosuppressive axis allows for the activation of unchecked autoreactive T cells and B cells, leading to the development of autoantibodies and cytotoxic T cells (CTL), which can directly destroy platelets in the periphery and inhibit MK platelet production in the bone marrow (BM). This review will focus on the effector cell mechanisms in ITP and highlight the defective immunosuppressive axis that appears responsible for this platelet-specific immune hyperreactivity. • ITP is initiated by abnormal antigen presenting events by macrophages and dendritic cells to autoreactive Th0 cells. • Activated Th0 cells differentiate into several T cell subsets such as Th1, Th17, and Th22 cells which propagate autoimmunity. • The T cell subsets lead to IgG autoantibody and CTL production which mediate destruction of platelets and megakaryocytes. • The platelet autoimmunity is due to faulty immunosuppressive mechanisms axis involving Tregs, Bregs, and MDSC. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons. Currently, there are no effective biomarkers and fundamental therapies for this disease. Dysregulation in RNA metabolism plays a critical role in the pathogenesis of ALS. With the contribution of Next Generation Sequencing, the functions of non-coding RNAs (ncRNAs) have gained increasing interests. Especially, micro RNAs (miRNAs), which are tissue-specific small ncRNAs of about 18–25 nucleotides, have emerged as key regulators of gene expression to target multiple molecules and pathways in the central nervous system (CNS). Despite intensive recent research in this field, the crucial links between ALS pathogenesis and miRNAs remain unclear. Many studies have revealed that ALS-related RNA binding proteins (RBPs), such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS), regulate miRNAs processing in both the nucleus and cytoplasm. Of interest, Cu2+/Zn2+ superoxide dismutase (SOD1), a non-RBP associated with familial ALS, shows partially similar properties to these RBPs via the dysregulation of miRNAs in the cellular pathway related to ALS. The identification and validation of miRNAs are important to understand the physiological gene regulation in the CNS, and the pathological implications in ALS, leading to a new avenue for early diagnosis and gene therapies. Here, we offer a recent overview regarding the mechanism underlying the functions of multiple miRNAs across TDP-43, FUS, and SOD1 with the context of cell biology, and challenging for clinical applications in ALS.

Circular RNAs (circRNAs) are relatively new members of the RNA world and can contribute to crucial biological functions. CircRNAs have tissue-specific expression profiles depending on cell type and developmental stage. In Sistan region cultivated grapes are seedless but have small berries. The compact clusters are another notable characteristic of these grape cultivars, which negatively impacts their marketability. In this study, we aimed to identify the circRNAs that are active in cluster formation and investigated the effects of gibberellin treatment on their expression. Eight detection tools were used to predict the expressed circRNAs. Reliable circRNAs were used to identify potential functions of differentially expressed circRNAs by gene ontology (GO) analysis and prediction of target microRNAs (miRNAs). Of the 28 157 circRNAs detected, 3 715 were reliable. 900 differently expressed circRNAs were identified in the three developmental stages of the cluster under gibberellin treatment. Among the 503 target miRNAs found, 12 miRNAs were selected based on the number and expression of their circRNA sponges. Of the 29 circRNAs in the circRNAsmiRNAs-mRNAs interaction network, 12 circRNAs are highly conserved. Our results suggest that circRNAs in grape may play a key role in developmental and environmental adaptation in perennial plants. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the expression pattern of micro RNAs (miRNAs) on a surface with nanotopography compared with a smooth surface (control). Materials and Methods: Human mesenchymal stem cells (hMSCs) were plated on different surfaces and compared at 3, 7 and 14 days for alkaline phosphatase (ALP) activity, expression of genes (osterix [OSX], runt-related transcription factor 2 [RUNX2], bone morphogenetic protein 2 [BMP2], and ALP), and expression of miRNAs. Western blot was also used to detect osteogenic proteins (BMP2, OSX, and osteocalcin [OCN]). Scanning electron microscopy of cells plated onto the surfaces was obtained. Results: ALP activity on different surfaces was significantly greater in the nanotopography surface. At day 14, there was a 3.5-fold and a 9-fold increase for the RUNX2 and OSX genes, respectively. BMP2 and ALP also increased by fourfold and sevenfold compared with the control. Protein levels for OSX and BMP2 were also upregulated compared with the control group. Using RNA sequencing technology (RNA-Seq), a total of 117 miRNAs were found to be differentially expressed comparing the control (day 7) with the nanosurface (day 14). Forty-five miRNAs were upregulated, and 72 were downregulated. Several of the miRNAs that were differently expressed regulate osteogenic genes. For example, hsa-miR-135b-5p targets OCN, BSP, RUNX2, COL15A1, and OSX; hsa-miR-122-5p targets OPN; hsa-miR-196a-5p targets BMP4; hsa-miR-26b-5p targets BMP2 and hsa-miR-148b-3p targets OPN. Conclusion: Surfaces with nanotopography have the potential to improve the osseointegration response in order to reduce the osseointegration time and also increase bone formation around the implants, improving areas with low bone quality. Within the limitation of this study, nanotopography surfaces affected MSC differentiation to osteoblasts. Several miRNAs were differentially regulated by surface topography. These miRNAs could be related to the differentiation response to help control the osseointegration process. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are single-stranded non-coding RNA sequences with about 22 nucleotides that regulate gene expression posttranscriptionally. miRNAs play a crucial role as gene regulators; nevertheless, they also have an influence on the etiology of many disorders, including cancer. Both population-based and functional studies have investigated the function of miRNAs in the onset and progression of cancer. However, research on the impact of miRNA polymorphisms on human cancer susceptibility to initiation, development, and prognosis is still growing. The pri-miR-26a-1 may have an impact on miR-26, which has been hypothesized to have a tumor-suppressive function in the genesis of cancer. Early study has shown cancer risk associated with the pri-miR-26a-1 rs7372209 C >T polymorphism in molecular epidemiology research. The data regarding the impact of pri-miR-26a-1 rs7372209 C >T polymorphism on cancer risk among the Saudi population lacks. The present study sought to determine the allelic frequency and distribution of the pri-miR-26a-1 rs7372209 C >T polymorphism in the Saudi Arabian population and to compare it to populations from other parts of the world. Data from epidemiological studies conducted in various ethnic groups were extracted using PUBMED (Medline) and other similar web databases. An estimated 12.25 percent of the Saudi population harbors the pri-miR-26a-1 rs7372209 variant allele (T). When the Saudi prevalence is compared to that of other populations, it is observed that China, the USA, and South Africa (black ancestry) have significantly different frequencies (p<.0001). Only one South African report with participants of mixed ancestry from the Western Cape and a population with significant ancestral components from the indigenous Khoisan, Bantuspeaking Africans, Europeans, and Asians revealed comparable pri-miR-26a-1 rs7372209 frequency (p=0.34). Clearly, the pri-miR-26a-1 rs7372209 polymorphism variant allele has a very unique pattern in the Saudi Arabian population, which may be a result of racial differences. The findings could assist in the risk assessment of people carrying pri-miR-26a-1 rs7372209 TT mutant predisposed to develop different types of cancers in the Saudi population. [ABSTRACT FROM AUTHOR]

Sphingolipid molecules have recently attracted attention as signaling molecules in allergic inflammation diseases. Sphingosine-1-phosphate (S1P) is synthesized by two isoforms of sphingosine kinases (SPHK 1 and SPHK2) and is known to be involved in various cellular processes. S1P levels reportedly increase in allergic inflammatory diseases, such as asthma and anaphylaxis. FcεRI signaling is necessary for allergic inflammation as it can activate the SPHKs and increase the S1P level; once S1P is secreted, it can bind to the S1P receptors (S1PRs). The role of S1P signaling in various allergic diseases is discussed. Increased levels of S1P are positively associated with asthma and anaphylaxis. S1P can either induce or suppress allergic skin diseases in a context-dependent manner. The crosstalk between FcεRI and S1P/SPHK/S1PRs is discussed. The roles of the microRNAs that regulate the expression of the components of S1P signaling in allergic inflammatory diseases are also discussed. Various reports suggest the role of S1P in FcεRI-mediated mast cell (MC) activation. Thus, S1P/SPHK/S1PRs signaling can be the target for developing anti-allergy drugs. [ABSTRACT FROM AUTHOR]

Bovine mastitis is one of the most troublesome and costly problems in the modern dairy industry, which is not only difficult to monitor, but can also cause economic losses while having significant implications on public health. However, efficacious preventative methods and therapy are still lacking. Moreover, new drugs and therapeutic targets are in increasing demand due to antibiotic restrictions. In recent years, noncoding RNAs have gained popularity as a topic in pathological and genetic studies. Meanwhile, there is growing evidence that they play a role in regulating various biological processes and developing novel treatment platforms. In light of this, this review focuses on two types of noncoding RNAs, micro RNAs and circular RNAs, and summarizes their characterizations, relationships, potential applications as selection markers, diagnostic or treatment targets and potential applications in RNAbased therapy, in order to shed new light on further research. [ABSTRACT FROM AUTHOR]

Background: The dysregulation of microRNAs (miRNAs) has been detected in patients with gastric cancer (GC), which inspired the use of miRNAs as a novel biomarker for GC. In this study, we investigated the previously reported miRNA dysfunction in cancer tissues as a potential plasma biomarker for GC using quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Methods: The published miRNA abnormalities were searched in the microRNA Cancer Association Database. Plasma samples were collected from patients with GC (n = 26) and controls (n = 17). The sensitivity and specificity of polyadenylation RT-PCR (PA-RT) and stem-loop RT-PCR (SL-RT) were compared. Statistical comparisons between patients with GC and controls were performed to identify miRNA biomarkers, and correlation analyses between the threshold cycle (Ct) values of miRNAs and various blood biochemical parameters were performed to elucidate the confounding factors. Results: mir-17, mir-21, mir-31, mir-99b, mir-222, and U6 were selected. PA-RT showed greater sensitivity and lower specificity than SL-RT (PA-RT vs. SL-RT, mean Ct: 19.6 vs. 29.2; coefficient of variation: 0.42 vs. 0.10). Adopting SL-RT owing to its higher specificity, only mir-222 was significantly upregulated in patients with GC (GC vs. control, miRNA expression: 15.4 vs. 5.27, p = 0.0098). Regarding the correlation between blood biochemical parameters and cells with miRNA expression, mir-31 and mir-99b were correlated with blood urea nitrogen, mir-17, mir-21, and mir-99b were negatively correlated with platelets, and mir-21 was correlated with neutrophils. No obvious correlations were noted between mir-222 expression and blood parameters. Receiver operating characteristic (ROC) curve analysis indicated that mir-222 identified GC patients with a maximum area under the curve (0.73, 95% confidence interval 0.57-0.89). Conclusions: Plasma mir-222 was confirmed to be dysregulated in patients with GC, irrespective of blood biochemical parameters.

Studies have reported goat Polled Intersex Syndrome(PIS) a 11.7-kb deletion triggers intersexuality and polledness in goats. To determine the effect of PIS region on horned phenotype of Guanzhong dairy goats, four specific primers (PIS1-1, PIS1-2, PIS2 and PIS3) covering PIS fragment were designed, and four DNA fragment were amplifed and sequenced. A 12.814kb sequence was assembled containing the whole goat PIS region both in horned goats and in polled goats, which mean there were no 11.7 kb deletion in the Guanzhong dairy goats.The polymorphisms sites in PIS region of horned and polled Guanzhong dairy goats were identified, and a total of 30 polymorphisms sites were confirmed (A648T, T652C, G1107C, T2594C, G2820A, G3556A, A3573G, T3621C, A5329T, T5392G, G5878A, C5996T, A6187G, C6228A, G6969T, G7045T, T7057C, C7266G, C7417T, T8327G, T9029G, C10034A, A10846G, del 10861-10862TT, G11842A, G12157A, G12104A, del 12431-12432AT, G12665A and del 12771-12772TT) in the 12.814 kb sequence. The further annotation results showed that a tRNA was located at 4218-4290bp, STR1 (TGTGTGTGTGTG) and STR2 (ATATATATATAT) were located at 9473-9484bp and 12451- 12462bp, respectively. Three micro RNAs, dme-mir-1, dme-mir-263a and cbr-mir-354 were confermed to locate at 3002-3023bp, 9078-9094bp and 10866-10882bp, respectively. There is a CpG island at 4390- 4540 bp. Our results showed that the PIS regions have no effect on polled phenotype of Guanzhong dairy goat, genetic diversity in PIS region of the goat were identified and the key gene polymorphism sites still waiting to be determined. [ABSTRACT FROM AUTHOR]

Background: Non-coding RNA played one pivotal role in NSCLC in terms of pathogenesis and progression. We aimed to determine the LncRNA, which can be one new potential target for NSCLC treatment and its possible mechanisms from Jan 2017 to Aug 2020. Methods: Gene LOC285758, which produced new cells in tumor cellular system, was knocked out. Its specific effects were tested in terms of cellular phenotype. LOC285758 was chosen to target for miRNA as well as downstream mRNA targeted by miRNA, which verified the combination predicted before. Specific impacts brought from miRNA on NSCLC cells were examined. At last, dynamic impacts produced through miRNA and LOC285758 on mRNA expression and NSCLC cellular phenotype were examined. Results: LOC285758 expression was up-regulated in tissues and cells from NSCLC. Knocking out gene LOC285758 could repress cellular survival and migration of A549 and H292 cells. miRNA-204 was repressed via LOC285758 targeting. miRNA-204 over-expressing repressed invasion ability of NSCLC cells and CDK6 targeted by miRNA-204. CDK6 knocking out suppressed survival and migration of NSCLC cells. The influence brought from gene LOC285758 knocking out could be reversed through suppressing miRNA-204, causing up-regulated CDK6 as well as LOC285758 expression in NSCLC tissues. miRNA-204 was negatively correlated with CDK6 as well as LOC285758, respectively. Nonetheless, CDK6 possessed the positive relationship with LOC285758. Conclusion: An axis of lncRNA LOC285758/miRNA-204/CDK6 can modulate NSCLC cells in terms of migration as well as survival.

Abstract Japan faces an increasing incidence of heart disease, owing to a shift towards a westernized lifestyle and an aging demographic. In cases where conventional interventions are not appropriate, regenerative medicine offers a promising therapeutic option. However, the use of stem cells has limitations, and therefore, “direct cardiac reprogramming” is emerging as an alternative treatment. Myocardial regeneration transdifferentiates cardiac fibroblasts into cardiomyocytes in situ. Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 (GMT) can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. The three main approaches to improving reprogramming efficiency are (1) improving direct cardiac reprogramming factors, (2) improving cell culture conditions, and (3) regulating epigenetic factors. miR-133 is a potential candidate for the first approach. For the second approach, inhibitors of TGF-β and Wnt signals, Akt1 overexpression, Notch signaling pathway inhibitors, such as DAPT ((S)-tert-butyl 2-((S)-2-(2-(3,5-difluorophenyl) acetamido) propanamido)-2-phenylacetate), fibroblast growth factor (FGF)-2, FGF-10, and vascular endothelial growth factor (VEGF: FFV) can influence reprogramming. Reducing the expression of Bmi1, which regulates the mono-ubiquitination of histone H2A, alters histone modification, and subsequently the reprogramming efficiency, in the third approach. In addition, diclofenac, a non-steroidal anti-inflammatory drug, and high level of Mef2c overexpression could improve direct cardiac reprogramming. Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.

microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females (n = 6) before and after a single submaximal bout of endurance exercise (‘reference training’). Subsequently, participants were subjected to a structured training program, consisting of six weeks of moderate-intensity continuous endurance training (MICT) and six weeks of high-intensity interval training (HIIT) in randomized order. In vastus lateralis muscle, we found significant downregulation of myomiRs, specifically miR-1, 133a-3p, and -5p, -133b, and -499a-5p. Similarly, exercise-associated miRs-23a-3p, -378a-5p, -128-3p, -21-5p, -107, -27a-3p, -126-3p, and -152-3p were significantly downregulated, whereas miR-23a-5p was upregulated. Furthermore, in an untargeted approach for differential expression in response to acute exercise, we identified n = 35 miRs that were downregulated and n = 20 miRs that were upregulated by factor 4.5 or more. Remarkably, KEGG pathway analysis indicated central involvement of this set of miRs in fatty acid metabolism. To reproduce these data in a larger cohort of all-female subjects (n = 29), qPCR analysis was carried out on n = 15 miRs selected from the microarray, which confirmed their differential expression. Furthermore, the acute response, i.e., the difference between miR concentrations before and after the reference training, was correlated with changes in maximum oxygen uptake (V̇O2max) in response to the training program. Here, we found that miRs-199a-3p and -19b-3p might be suitable acute-response candidates that correlate with individual degrees of training adaptation in females.

Osteoarthritis (OA) is a chronic degenerative joint disease with multiple causative factors such as aging, mechanical injury, and obesity. Autophagy is a complex dynamic process that is involved in the degradation and modification of intracellular proteins and organelles under different pathophysiological conditions. Autophagy, as a cell survival mechanism under various stress conditions, plays a key role in regulating chondrocyte life cycle metabolism and cellular homeostasis. Non-coding RNAs (ncRNAs) are heterogeneous transcripts that do not possess protein-coding functions, but they can act as effective post-transcriptional and epigenetic regulators of gene and protein expression, thus participating in numerous fundamental biological processes. Increasing evidence suggests that ncRNAs, autophagy, and their crosstalk play crucial roles in OA pathogenesis. Therefore, we summarized the complex role of autophagy in OA chondrocytes and focused on the regulatory role of ncRNAs in OA-associated autophagy to elucidate the complex pathological mechanisms of the ncRNA-autophagy network in the development of OA, thus providing new research targets for the clinical diagnosis and treatment of OA. • Autophagy is a double-edged sword in regulating the survival or death of OA chondrocytes. • NcRNAs act as key regulators of chondrocytes autophagy to modulate OA development. • Novel strategies and challenges in targeting the ncRNAs-autophagy axis for OA treatment are discussed. [ABSTRACT FROM AUTHOR]

Objective: To study the changes and significance of mi RNA expression profile in the prefrontal cortex of mice with generalized anxiety disorder induced by chronic restraint stress (CRS).Methods: After 7 days of CRS, the mice were tested by open field experiment and elevated plus maze experiment to detect whether the mice can show nervous and anxious behaviors. High-throughput sequencing was used to quantitatively analyze the expression levels of mi RNAs in the prefrontal cortex of mice in the control and model groups, and to study the molecular expression profiles related to anxiety induced by CRS. The differentially expressed mi RNAs in the sequencing results were verified by RT-PCR. Results: In mice in the CRS-induced generalized anxiety disorder model group, the total distance of activities in the model group increased (P<0.05), the average speed (P<0.05) increased, the central residence decreased (P<0.05), and the percentage of open arm entry times (P<0.01) and residence time of the open arm (P<0.01)are reduced. Compared with the control group, the results were statistically significant, indicating that the GAD mice were successfully modeled. Based on the results of high-throughput sequencing and bio-informatics analysis, compared with the control group, there were 28 up-regulated mi RNAs and 34down-regulated mi RNAs in the model group and 5388 target genes participated in the changes. In the up/down-regulated mi R-GO analysis results, they are mainly involved in the development of the nervous system, postsynaptic density, neuron projection, protein serine/threonine kinase activity and other processes ;in the up/down-regulated mi R-KEGG results, they participate in common pathways Mainly include axon guidance, neurotrophic factor signaling pathway, cAMP signaling pathway, dopaminergic synapse, MAPK signaling pathway and so on. Conclusion: The changes of mi R-7a-5p, mi R-124-3p, mi R-141-3p, mi R-183-5p and other mi RNAs in the prefrontal cortex are involved in the pathogenesis of generalized anxiety disorder, and may regulate and affect nerve conduction functions. [ABSTRACT FROM AUTHOR]

Background: One of the important molecular pathways in breast cancer is the PTEN-PI3K-AKT pathway. Any change in the activity of the PTEN gene can alter the PI3K-AKT pathway. Moreover, there are subsets of genes and pathways their expression changes by post-transcriptional regulations. For instance, gene regulation alters by non-coding RNAs such as micro-RNAs as post-transcriptional regulators that prevent the expression of the target transcript. Therefore, it is essential to assess the related alterations in micro-RNA expression patterns to find out the possible causes of conversions in related transcripts and pathways such as the PTEN-PI3K-AKT pathway in breast cancer. Methods: To determine the expression level of miR-181a and miR-30d in 30 breast tumor samples and 30 adjacent normal samples, the RNA extraction, and cDNA synthesis was performed by RiboEx (GeneAll, Korea). Finally, the Real-Time PCR method was used for quantitative analysis of the expression levels of these miRNAs. all the experimental part of the project in done at Islamic Azad University in 2017. Results: After analyzing comparisons in the expression level of miR-181a and miR-30d in tumor and normal tissues, there was a significant increase in the expression level of miR-181a in tumor samples compared with normal samples. Moreover, the expression level of miR-30d in tumor samples reported a significant decrease in comparison with normal samples (P

Abstract Background Planarians reliably regenerate all body parts after injury, including a fully functional head and central nervous system. But until now, the expression dynamics and functional role of miRNAs and other small RNAs during the process of head regeneration are not well understood. Furthermore, little is known about the evolutionary conservation of the relevant small RNAs pathways, rendering it difficult to assess whether insights from planarians will apply to other taxa. Results In this study, we applied high throughput sequencing to identify miRNAs, tRNA fragments and piRNAs that are dynamically expressed during head regeneration in Dugesia japonica. We further show that knockdown of selected small RNAs, including three novel Dugesia-specific miRNAs, during head regeneration induces severe defects including abnormally small-sized eyes, cyclopia and complete absence of eyes. Conclusions Our findings suggest that a complex pool of small RNAs takes part in the process of head regeneration in Dugesia japonica and provide novel insights into global small RNA expression profiles and expression changes in response to head amputation. Our study reveals the evolutionary conserved role of miR-124 and brings further promising candidate small RNAs into play that might unveil new avenues for inducing restorative programs in non-regenerative organisms via small RNA mimics based therapies.

Abstract Background Beside common risk factors for stroke such as diabetes and hypertension, single-nucleotide variants occurring within micro RNA genes have been identified as susceptibility loci for ischemic stroke risk. Objectives Investigate the possible association of two variants in pre miRNA sequences, rs11614913 within miR-196a2 C > T and rs2292832 within miR-149 T > C, with ischemic stroke. Subjects and methods One hundred ischemic stroke patients and 100 age and sex-matched controls having > 1 risk factor for atherosclerosis were enrolled in a case-control study. Degree of atherosclerosis was assessed using ultrasonography. Micro RNA variants were assessed by real-time PCR TaqMan probe assay. Results The TT genotype and T allele frequencies of miR-196a2 C > T were protective against ischemic stroke (OR 0.168, P 0.001; OR 0.482, P < 0.001 respectively). While among miR-149 T > C variants, CC genotype was associated with increased risk by threefold (OR 3.061, P 0.005) and C allele was associated with about 1.9 fold risk of stroke (OR 1.909, P 0.002). Haplotypes analysis revealed miR-196a2T/-149 T allele combination was significantly lower among stroke patients than the controls (P < 0.001) with a protective effect (OR 0.196, 95% CI 0.083-0.466). Conclusion A decrease in the incidence of ischemic stroke is associated with miR-196a2 TT genotype and T allele and increases in the likelihood risk of ischemic stroke are associated with CC genotype and C allele within miR-149, and the two miRNAs under study are closely associated with vascular damage responses.

ABSTRACT Severe acute respiratory syndrome coronavirus (SARS-CoV) and the closely related SARS-CoV-2 are emergent highly pathogenic human respiratory viruses causing acute lethal disease associated with lung damage and dysregulated inflammatory responses. SARS-CoV envelope protein (E) is a virulence factor involved in the activation of various inflammatory pathways. Here, we study the contribution of host miRNAs to the virulence mediated by E protein. Small RNAseq analysis of infected mouse lungs identified miRNA-223 as a potential regulator of pulmonary inflammation, since it was significantly increased in SARS-CoV-WT virulent infection compared to the attenuated SARS-CoV-ΔE infection. In vivo inhibition of miRNA-223-3p increased mRNA levels of pro-inflammatory cytokines and NLRP3 inflammasome, suggesting that during lung infection, miRNA-223 might contribute to restrict an excessive inflammatory response. Interestingly, miRNA-223-3p inhibition also increased the levels of the CFTR transporter, which is involved in edema resolution and was significantly downregulated in the lungs of mice infected with the virulent SARS-CoV-WT virus. At the histopathological level, a decrease in the pulmonary edema was observed when miR-223-3p was inhibited, suggesting that miRNA-223-3p was involved in the regulation of the SARS-CoV-induced inflammatory pathology. These results indicate that miRNA-223 participates in the regulation of E protein-mediated inflammatory response during SARS-CoV infection by targeting different host mRNAs involved in the pulmonary inflammation, and identify miRNA-223 as a potential therapeutic target in SARS-CoV infection. IMPORTANCE The SARS-CoV-2 pandemic has emphasized the need to understand the mechanisms of severe lung inflammatory pathology caused by human deadly coronaviruses in order to design new antiviral therapies. Here, we identify miRNA-223-3p as a host miRNA involved in the regulation of lung inflammatory response mediated by envelope (E) protein during SARS-CoV infection. miRNAs downregulate the expression of cellular mRNAs and participate in complex networks of mRNA–miRNA interactions that regulate cellular processes. The inhibition of miRNA-223 in infected mice by intranasal administration of antisense RNAs led to changes in the expression of host factors involved in inflammation (cytokines, chemokines, and NLRP3 inflammasome) and in the resolution of lung edema ion transporter CFTR. These results confirmed the contribution of miRNA-223 to the regulation of SARS-CoV-induced pathogenic processes and support the therapeutic potential of inhibiting miRNAs during coronavirus infection using RNA interference approaches.

Autophagy and apoptosis are two crucial self-destructive processes that maintain cellular homeostasis, which are characterized by their morphology and regulated through signal transduction mechanisms. These pathways determine the fate of cellular organelle and protein involved in human health and disease such as neurodegeneration, cancer, and cardiovascular disease. Cell death pathways share common molecular mechanisms, such as mitochondrial dysfunction, oxidative stress, calcium ion concentration, reactive oxygen species, and endoplasmic reticulum stress. Some key signaling molecules such as p53 and VEGF mediated angiogenic pathway exhibit cellular and molecular responses resulting in the triggering of apoptotic and autophagic pathways. Herein, based on previous studies, we describe the intricate relation between cell death pathways through their common genes and the role of various stress-causing agents. Further, extensive research on autophagy and apoptotic machinery excavates the implementation of selective biomarkers, for instance, mTOR, Bcl-2, BH3 family members, caspases, AMPK, PI3K/Akt/GSK3β, and p38/JNK/MAPK, in the pathogenesis and progression of neurodegenerative diseases. This molecular phenomenon will lead to the discovery of possible therapeutic biomolecules as a pharmacological intervention that are involved in the modulation of apoptosis and autophagy pathways. Moreover, we describe the potential role of micro-RNAs, long non-coding RNAs, and biomolecules as therapeutic agents that regulate cell death machinery to treat neurodegenerative diseases. Mounting evidence demonstrated that under stress conditions, such as calcium efflux, endoplasmic reticulum stress, the ubiquitin–proteasome system, and oxidative stress intermediate molecules, namely p53 and VEGF, activate and cause cell death. Further, activation of p53 and VEGF cause alteration in gene expression and dysregulated signaling pathways through the involvement of signaling molecules, namely mTOR, Bcl-2, BH3, AMPK, MAPK, JNK, and PI3K/Akt, and caspases. Alteration in gene expression and signaling cascades cause neurotoxicity and misfolded protein aggregates, which are characteristics features of neurodegenerative diseases. Excessive neurotoxicity and misfolded protein aggregates lead to neuronal cell death by activating death pathways like autophagy and apoptosis. However, autophagy has a dual role in the apoptosis pathways, i.e., activation and inhibition of the apoptosis signaling. Further, micro-RNAs and LncRNAs act as pharmacological regulators of autophagy and apoptosis cascade, whereas, natural compounds and chemical compounds act as pharmacological inhibitors that rescue neuronal cell death through inhibition of apoptosis and autophagic cell death. [ABSTRACT FROM AUTHOR]

Background: Abdominal aortic aneurysm (AAA) is a disease commonly seen in the elderly. The aneurysm diameter increases yearly, and the larger the AAA the higher the risk of rupture, increasing the risk of death. However, there are no current effective interventions in the early stages of AAA. Methods: Four gene expression profiling datasets, including 23 normal artery (NOR) tissue samples and 97 AAA tissue samples, were integrated in order to explore potential molecular biological targets for early intervention. After preprocessing, differentially expressed genes (DEGs) between AAA and NOR were identified using LIMMA package. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were conducted using the DAVID database. The protein-protein interaction network was constructed and hub genes were identified using the STRING database and plugins in Cytoscape. A circular RNA (circRNA) profile of four NOR tissues versus four AAA tissues was then reanalyzed. A circRNA-miRNA-mRNA interaction network was constructed after predictions were made using the Targetscan and Circinteractome databases. Results: A total of 440 DEGs (263 up-regulated and 177 down-regulated) were identified in the AAA group, compared with the NOR group. The majority were associated with the extracellular matrix, tumor necrosis factor-a, and transforming growth factor-β. Ten hub gene-encoded proteins (namely IL6, RPS27A, JUN, UBC, UBA52, FOS, IL1B, MMP9, SPP1 and CCL2) coupled with a higher degree of connectivity hub were identified after protein-protein interaction network analysis. Our results, in combination with the results of previous studies revealed that miR-635, miR-527, miR-520h, miR-938 and miR-518a-5p may be affected by circ_0005073 and impact the expression of hub genes such as CCL2, SPP1 and UBA52. The miR-1206 may also be affected by circ_0090069 and impact RPS27A expression. Conclusions: This circRNA-miRNA-mRNA network may perform critical roles in AAA and may be a novel target for early intervention. [ABSTRACT FROM AUTHOR]

Plant-nematode associations are the most imperative area of study that forms the basis to understand their regulatory networks and coordinated functional aspects. Nematodes are highly parasitic organisms known so far, to cause relentless damage towards agricultural crops on a global scale. They pierce the roots of host plants and form neo-plastic feeding structures to extract out resources for their functional development. Moreover, they undergo re-differentiation within plant cells to form giant multi-nucleate feeding structures or syncytium. All these processes are facilitated by numerous transcriptomic, proteomic, metabolomic and epigenetic modifications, that regulate different biological attractions among plants and nematodes. Nevertheless, these mechanisms are quite remarkable and have been explored in the present review. Here, we have shed light on genomic as well as genetic approaches to acquire an effective understanding regarding plant-nematode associations. Transcriptomics have revealed an extensive network to unravel feeding mechanism of nematodes through gene-expression programming of target genes. Also, the regulatory circuits of epigenetic alterations through DNA-methylation, non-coding RNAs and histone modifications very well explain epigenetic profiling within plants. Since decades, research have observed many intricacies to elucidate the dynamic nature of epigenetic modulations in plant-nematode attractions. By this review, we have highlighted the functional aspects of small RNAs in inducing plant-nematode parasitism along with the putative role of miRNAs. These RNAs act as chief genetic elements to mediate the expressional changes in plants through post-transcriptional silencing of various effector proteins as well as transcriptional factors. A pragmatic role of miRNAs in modulating gene expression in nematode infection and feeding site development have also been reviewed. Hence, they have been considered master regulators for functional reprogramming the expression during establishment of feeding sites. We have also encapsulated the advancement of genome-broadened DNA-methylation and untangled the nematode mediated dynamic alterations within plant methylome along with assessing transcriptional activities of various genes and transposons. In particular, we have highlighted the role of effector proteins in stimulating epigenetic changes. Finally, we have emerged towards a molecular-based core understanding about plant-nematode associations. • Nematodes pierce plants to form neo-plastic feeding structures or syncytium. • Epigenetic modifications are substantial for regulating plant-nematode attractions. • Regulatory circuits are DNA-methylation, non-coding RNAs and histone modifications. • Small RNAs and micro RNAs are crucial for nematode parasitism in plants. • Plant methylome undergo transcriptional changes, unravelled by genome-based approaches. [ABSTRACT FROM AUTHOR]

Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has emerged as a multifaceted player in cancer biology. The functioning of PKM2 is intricately regulated at multiple levels, including controlling the gene expression via various transcription factors and non-coding RNAs, as well as adding post-translational modifications that confer distinct functions to the protein. Here, we explore the diverse functions of PKM2, encompassing newly emerging roles in non-glycolytic metabolic regulation, immunomodulation, inflammation, DNA repair and mRNA processing, beyond its canonical role in glycolysis. The ever-expanding list of its functions has recently grown to include roles in subcellular compartments such as the mitochondria and extracellular milieu as well, all of which make PKM2 an attractive drug target in the pursuit of therapeutics for cancer. • PKM2 is a central player in cancer and a regulator of Warburg effect. • Functioning is finely regulated at transcriptional, post-transcriptional and post-translational level. • PKM2 is involved in metabolic regulation beyond glucose. • Recently found to have roles in immunomodulation, inflammation, DNA repair, and mRNA processing. • Expanding list of roles in nucleus, mitochondria and extracellular milieu make PKM2 an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

Cinnamaldehyde (CA) is the main component extracted from the traditional Chinese medicine cinnamon. Recent studies revealed that CA has antiviral and anti-tumor effects. However, the effect and mechanism of CA on non-small cell lung cancer (NSCLC) through whole transcriptome sequencing integrated analysis have not been systematically investigated. In this study, whole transcriptome sequencing was used to identify differentially expressed messenger RNAs (mRNAs), micro RNAs (miRNAs), and long non-coding RNAs (lncRNAs) that were influenced by CA and screen regulatory pathways. The results showed that CA significantly inhibited proliferation, invasion, and migration, whereas it induced the apoptosis of NSCLC cells. CA inhibited tumor growth in vivo. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that these differentially expressed mRNAs were potentially implicated in the CA-suppressing malignant phenotypes of NSCLC. According to the competing endogenous RNA (ceRNA) hypothesis, a ceRNA network was constructed, including 13 mRNAs, 6 miRNAs, and 11 lncRNAs. Kyoto Encyclopedia of Genes and Genomes analysis of the 13 mRNAs in the ceRNA network showed that suppressors of cytokine signaling 1 (SOCS1), BTG anti-proliferation factor 2 (BTG2), and Bruton tyrosine kinase (BTK) were significantly enriched in the JAK/STAT signaling pathway, RNA degradation, and nuclear factor-κB (NF-κB) signaling pathway related to cancer. These findings indicated that SOCS1, BTG2, and BTK play an essential role in CA against NSCLC. Meanwhile, based on the ceRNA network, three lncRNAs (long intergenic non-protein coding RNA 1504 [LINC01504], LINC01783, and THUMPD3 antisense RNA 1 [THUMPD3-AS1]) and three miRNAs (has-miR-155-5p, has-miR-7-5p, and has-miR-425-5p) associated with SOCS1, BTG2, and BTK may be important in CA against NSCLC. Taken together, the present study demonstrated the activity of CA against lung cancer and its potential use as a therapeutic agent.

The germinal center (GC) reactions are critical for the production of high‐affinity antibodies that comprise the protective humoral response elicited by infection or vaccination. GCs are initiated through the interaction of B cells with T follicular helper (Tfh) cells. While the transcriptional regulation of Tfh differentiation has been studied in great detail, the impact of micro RNAs (miRNAs) on Tfh development and stability has been harder to address. It was previously shown that a complete deletion of miRNAs biogenesis prevents Tfh differentiation. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2021. 51: 408‐413], Zeiträg et al. use an inducible gene deletion approach to reveal that miRNAs are also required for the maintenance of Tfh cells induced following viral infection in mice. These results provide new clues to the regulation of GC responses through Tfh and T follicular regulatory cells. [ABSTRACT FROM AUTHOR]