Glioblastoma multiforme (GBM) is a highly malignant brain tumor associated with a poor prognosis. Cross-talk between competitive endogenous RNAs (ceRNAs) plays a critical role in tumor development ...and physiology. In this study, we present a multi-step computational approach to construct a functional GBM long non-coding RNA (lncRNA)-mediated ceRNA network (LMCN) by integrating genome-wide lncRNA and mRNA expression profiles, miRNA-target interactions, functional analyses, and clinical survival analyses. LncRNAs in the LMCN exhibited specific topological features consistent with a regulatory association with coding mRNAs across GBM pathology. We determined that the lncRNA MCM3AP-AS was involved in RNA processing and cell cycle-related functions, and was correlated with patient survival. MCM3AP-AS and MIR17HG acted synergistically to regulate mRNAs in a network module of the competitive LMCN. By integrating the expression profile of this module into a risk model, we stratified GBM patients in both the The Cancer Genome Atlas and an independent GBM dataset into distinct risk groups. Finally, survival analyses demonstrated that the lncRNAs and network module are potential prognostic biomarkers for GBM. Thus, ceRNAs could accelerate biomarker discovery and therapeutic development in GBM.
Microglia are rapidly activated following ischaemic stroke and participate in the induction of neuroinflammation, which exacerbates the injury of ischaemic stroke. However, the mechanisms regulating ...ischaemic microglia remain unclear. In the present study, middle cerebral artery occlusion and oxygen and glucose deprivation models were established for in vivo and vitro monitoring of experimental stroke. We applied recombinant human thioredoxin‐1 (rhTrx‐1) and Necrostatin‐1 (Nec‐1, inhibitor of RIPK1) to examine the role of receptor‐interacting protein kinase 1 (RIPK1) in the development of inflammation in ischaemic microglia via explored the inflammatory responses and the associated mechanisms. Molecular docking results indicated that rhTrx‐1 could directly bind to RIPK1. In vivo and vitro data revealed that rhTrx‐1 reduced necroptosis, mitochondrial membrane potential damage, reactive oxygen species accumulation and NLR Family, pyrin domain‐containing 3 protein (NLRP3) inflammasome activation and regulated the microglial M1/M2 phenotypic changes by inhibiting RIPK1 expression in ischaemic microglia. Consistent with these findings, further in vivo experiments revealed that rhTrx‐1 treatment attenuated cerebral ischaemic injury by inhibiting the inflammatory response. Our data demonstrated the role of RIPK1 in microglia‐induced neuroinflammation following cerebral ischaemia. Administration of rhTrx‐1 provides neuroprotection in ischaemic stroke‐induced microglial neuroinflammation by inhibiting RIPK1 expression.
Myasthenia gravis (MG) is a cell‐dependent autoimmune disease commonly associated with thymic pathology. Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT‐1) has been associated with gene ...regulation and alternative splicing. It has shown relationship with proliferation, apoptosis, migration, and invasion. In this study, we found that MALAT‐1 expression was downregulated in MG. The level of the miR‐338‐3p was increased in peripheral blood mononuclear cells from MG patients compared with those from control subjects. MALAT‐1 competed for binding to miR‐338‐3p with male‐specific lethal 2 (MSL2) in luciferase reporter assays. We confirmed the MALAT‐1‐miR‐338‐3p‐MSL2 interaction network in MG in vitro. Thus, MALAT‐1 directly induced MSL2 expression in MG by acting as a competing endogenous RNA for miR‐338‐3p, suggesting that it may serve as a therapeutic target for MG treatment.
We confirmed the MALAT‐1‐miR‐338‐3p‐MSL2 interaction network in myasthenia gravis (MG) in vitro. Thus, metastasis‐associated lung adenocarcinoma transcript 1 (MALAT‐1) directly induced male‐specific lethal 2 (MSL2) expression in MG by acting as a competing endogenous RNA (ceRNA) for miR‐338‐3p, suggesting that it may serve as a therapeutic target for MG treatment.
The Nervous System Disease NcRNAome Atlas (NSDNA) (http://www.bio-bigdata.net/nsdna/) is a manually curated database that provides comprehensive experimentally supported associations about nervous ...system diseases (NSDs) and noncoding RNAs (ncRNAs). NSDs represent a common group of disorders, some of which are characterized by high morbidity and disabilities. The pathogenesis of NSDs at the molecular level remains poorly understood. ncRNAs are a large family of functionally important RNA molecules. Increasing evidence shows that diverse ncRNAs play a critical role in various NSDs. Mining and summarizing NSD-ncRNA association data can help researchers discover useful information. Hence, we developed an NSDNA database that documents 24 713 associations between 142 NSDs and 8593 ncRNAs in 11 species, curated from more than 1300 articles. This database provides a user-friendly interface for browsing and searching and allows for data downloading flexibility. In addition, NSDNA offers a submission page for researchers to submit novel NSD-ncRNA associations. It represents an extremely useful and valuable resource for researchers who seek to understand the functions and molecular mechanisms of ncRNA involved in NSDs.
Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy and frequently evolving drug resistance. Although there is growing consensus that noncoding ribonucleic acids (ncRNAs) are ...modulators of TLE, the knowledge about the deoxyribonucleic acid (DNA) methylation patterns of ncRNAs in TLE remains limited. In the current study, we constructed DNA methylation profiles from 30 TLE patients and 30 healthy controls for ncRNAs, primarily focusing on long ncRNAs (lncRNAs) and microRNAs (miRNAs), by reannotating data of DNA methylation BeadChip. Statistics analyses have revealed a global hypermethylation pattern in miRNA and lncRNA gene in TLE patients. Bioinformatic analyses have found aberrantly methylated miRNAs and lncRNAs are related to ion channel activity, drug metabolism, mitogen-activated protein kinase (MAPK) signaling pathway, and neurotrophin signaling pathway. Aberrantly methylated ncRNA and pathway target might be involved in TLE development and progression. The methylated and demethylated ncRNAs identified in this study provide novel insights for developing TLE biomarkers and potential therapeutic targets.
Given the high disability rate of multiple sclerosis (MS), there is a need for safer and more effective therapeutic agents. Existing literature highlights the prominent roles of miRNA in MS ...pathophysiology. Nevertheless, there are few studies that have explored the usefulness of existing drugs in treating MS through potential miRNA-modulating abilities.The current investigation identifies genes that may exacerbate the risk of MS due to their respective miRNA associations. These findings were then used to determine potential drug candidates through the construction of miRNA-regulated drug-pathway network through genes. We uncovered a total of 48 MS risk pathways, 133 MS risk miRNAs, and 186 drugs that can affect these pathways. Potential MS risk miRNAs that are also regulated by therapeutic candidates were hsa05215 and hsa05152. We analyzed the properties of the miRNA-regulated drug-pathway network through genes and uncovered a number of novel MS agents by assessing their respective Z-values.A total of 20 likely drug candidates were identified, including human immunoglobulin, aspirin, alemtuzumab, minocycline, abciximab, alefacept, palivizumab, bevacizumab, efalizumab, tositumomab, minocycline, etanercept, catumaxomab, and sarilumab. Each of these agents were then explored with regards to their likely mechanism of action in treating MS.The current investigation provides a fresh perspective on MS biological mechanisms as well as likely treatment strategies.
Abstract
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • We provide the first worldwide association study. • We found no association between SNPs of CACNA1A , 1C , and 1H and drug-resistant epilepsy. • We calculated a meaningful haplotype of ...CACNA1A.
Myasthenia gravis (MG) is an autoimmune disorder resulting from antibodies against the proteins at the neuromuscular junction. Emerging evidence indicates that long non-coding RNAs (lncRNAs), acting ...as competing endogenous RNAs (ceRNAs), are involved in various diseases. However, the regulatory mechanisms of ceRNAs underlying MG remain largely unknown. In this study, we constructed a lncRNA-mediated ceRNA network involved in MG using a multi-step computational strategy. Functional annotation analysis suggests that these lncRNAs may play crucial roles in the immunological mechanism underlying MG. Importantly, through manual literature mining, we found that lncRNA SNHG16 (small nucleolar RNA host gene 16), acting as a ceRNA, plays important roles in the immune processes. Further experiments showed that SNHG16 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from MG patients compared to healthy controls. Luciferase reporter assays confirmed that SNHG16 is a target of the microRNA (miRNA) let-7c-5p. Subsequent experiments indicated that SNHG16 regulates the expression of the key MG gene interleukin (IL)-10 by sponging let-7c-5p in a ceRNA manner. Furthermore, functional assays showed that SNHG16 inhibits Jurkat cell apoptosis and promotes cell proliferation by sponging let-7c-5p. Our study will contribute to a deeper understanding of the regulatory mechanism of MG and will potentially provide new therapeutic targets for MG patients.
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