Identification of region-specific amino acid signatures for doxorubicin-induced chemo brain.

Doxorubicin (DOX) is a cornerstone of chemotherapy for solid tumors and leukemias. DOX-induced cognitive impairment, termed chemo brain, has been reported in cancer survivors, whereas its mechanism remains poorly understood. Here we initially evaluated the cognitive impairments of mice treated with clinically relevant, long-term, low-dosage of DOX. Using HILIC-MS/MS-based targeted metabolomics, we presented the changes of 21 amino acids across six anatomical brain regions of mice with DOX-induced chemo brain. By mapping the altered amino acids to the human metabolic network, we constructed an amino acid-based network module for each brain region. We identified phenylalanine, tyrosine, methionine, and γ-aminobutyric acid as putative signatures of three regions (hippocampus, prefrontal cortex, and neocortex) highly associated with cognition. Relying on the reported mouse brain metabolome atlas, we found that DOX might perturb the amino acid homeostasis in multiple brain regions, similar to the changes in the aging brain. Correlation analysis suggested the possible indirect neurotoxicity of DOX that altered the brain levels of phenylalanine, tyrosine, and methionine by causing metabolic disorders in the liver and kidney. In summary, we revealed the region-specific amino acid signatures as actionable targets for DOX-induced chemo brain, which might provide safer treatment and improve the quality of life among cancer survivors.

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

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

Identification of the regulatory role of lncRNA HCG18 in myasthenia gravis by integrated bioinformatics and experimental analyses.

BACKGROUND: Long non-coding RNAs (lncRNAs), functioning as competing endogenous RNAs (ceRNAs), have been reported to play important roles in the pathogenesis of autoimmune diseases. However, little is known about the regulatory roles of lncRNAs underlying the mechanism of myasthenia gravis (MG). The aim of the present study was to explore the roles of lncRNAs as ceRNAs associated with the progression of MG. METHODS: MG risk genes and miRNAs were obtained from public databases. Protein-protein interaction (PPI) network analysis and module analysis were performed. A lncRNA-mediated module-associated ceRNA (LMMAC) network, which integrated risk genes in modules, risk miRNAs and predicted lncRNAs, was constructed to systematically explore the regulatory roles of lncRNAs in MG. Through performing random walk with restart on the network, HCG18/miR-145-5p/CD28 ceRNA axis was found to play important roles in MG, potentially. The expression of HCG18 in MG patients was detected using RT-PCR. The effects of HCG18 knockdown on cell proliferation and apoptosis were determined by CCK-8 assay and flow cytometry. The interactions among HCG18, miR-145-5p and CD28 were explored by luciferase assay, RT-PCR and western blot assay. RESULTS: Based on PPI network, we identified 9 modules. Functional enrichment analyses revealed these modules were enriched in immune-related signaling pathways. We then constructed LMMAC network, containing 25 genes, 50 miRNAs, and 64 lncRNAs. Through bioinformatics algorithm, we found lncRNA HCG18 as a ceRNA, might play important roles in MG. Further experiments indicated that HCG18 was overexpressed in MG patients and was a target of miR-145-5p. Functional assays illustrated that HCG18 suppressed Jurkat cell apoptosis and promoted cell proliferation. Mechanistically, knockdown of HCG18 inhibited the CD28 mRNA and protein expression levels in Jurkat cells, while miR-145-5p inhibitor blocked the reduction of CD28 expression induced by HCG18 suppression. CONCLUSION: We have reported a novel HCG18/miR-145-5p/CD28 ceRNA axis in MG. Our findings will contribute to a deeper understanding of the molecular mechanism of and provide a novel potential therapeutic target for MG.

Inhibition of microglial receptor-interacting protein kinase 1 ameliorates neuroinflammation following cerebral ischaemic stroke.

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.

Xanthohumol protects neuron from cerebral ischemia injury in experimental stroke.

Treatment of antioxidants is necessary to protect ischemic stroke associated neuronal damage. Xanthohumol (XN), a natural flavonoid extracted from hops, has been reported to have potential function as an antioxidant and can be used for neuro protection. However, the role of XN in ischemic stroke remains unclear. Here, we studied the neuroprotective effects of XN through experimental stroke models. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) was used as in vivo and in vitro model, respectively. We found that the treatment of XN improved MCAO-induced brain injury by reducing infarct size, improving neurological deficits, reversing neuronal damage, reducing oxidative stress injury and cell apoptosis. Further experimental studies showed that XN could revive neuronal apoptosis induced by OGD by preventing oxidative stress injury. In addition, our study suggested that these effects were related to the inhibition of phosphorylation of p38-MAPK and the mediation of nuclear Nrf2 activation. In conclusion, the neuroprotective effects of XN showed in this study make XN a promising supplement for ischemic stroke protection.

Novel ultrastructural findings on cardiac mitochondria of huddling Brandt's voles in mild cold environment.

Reduced ambient temperature has a damaging effect on mammalian myocardium. Huddling as a cooperative behavior has evolved in social mammals as a strategy to maximize adaptation to environmental cooling. Here, we studied the effects of huddling behavior on mitochondrial morphology, number, and function in the myocardia of Brandt's voles (Lasiopodomys brandtii) under cool environmental temperatures (15 °C). Results showed (1) mitochondrial swelling and cristae disruption in the cool huddling group (CH) and cool separated group (CS). Compared to the control group (CON, 22 °C), damaged mitochondria in the cool huddling and separated groups reached >90%; however, total number of mitochondria in the CH group was similar to that in the CON group. (2) ATP synthase activity was lowest in the CS group, whereas citrate synthetase activity was maintained among the three treatment groups. (3) Bax/bcl2 protein expression in the CH and CS groups was higher than that in the CON group, whereas DNA fragmentation, nuclear number, and caspase3 activity showed no significant differences among the three groups. (4) The protein expression levels of dynamin-related protein1 and mitochondrial fission factor were highest in the CH group. (5) Both protein expression of PINK1 and phosphorylation ratio of Parkin showed the pattern CS > CH > CON. (6) Total number of mitochondria was higher in males than in females. In general, the increased mitochondrial fission level observed in huddling voles partially counteracted the decrease in myocardial mitochondria caused by the increase in autophagy.

The long noncoding RNA MALAT-1 functions as a competing endogenous RNA to regulate MSL2 expression by sponging miR-338-3p in myasthenia gravis.

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.

Integrating multiple-level molecular data to infer the distinctions between glioblastoma and lower-grade glioma.

Glioblastomas (GBMs) and lower-grade gliomas (LGGs) are the most common malignant brain tumors. Despite extensive studies that have suggested that there are differences between the two in terms of clinical profile and treatment, their distinctions on a molecular level had not been systematically analyzed. Here, we investigated the distinctions between GBM and LGG based on multidimensional data, including somatic mutations, somatic copy number variants (SCNVs), gene expression, lncRNA expression and DNA methylation levels. We found that GBM patients had a higher mutation frequency and SCNVs than LGG patients. Differential mRNAs and lncRNAs between GBM and LGG were identified and a differential mRNA-lncRNA network was constructed and analyzed. We also discovered some differential DNA methylation sites could distinguish between GBM and LGG samples. Finally, we identified some key GBM- and LGG-specific genes featuring multiple-level molecular alterations. These specific genes participate in diverse functions; moreover, GBM-specific genes are enriched in the glioma pathway. Overall, our studies explored the distinctions between GMB and LGG using a comprehensive genomics approach that may provide novel insights into studying the mechanism and treatment of brain tumors.

Associations of BAFF rs2893321 polymorphisms with myasthenia gravis susceptibility.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune diseases characterized by fatigue and weakness of skeletal muscles. B-lymphocyte-activating factor (BAFF), an essential factor for B cell differentiation and development, is important in the progression of MG. The current study aimed to investigate the association between single nucleotide polymorphism rs2893321 in BAFF with MG susceptibility in Chinese Han population. METHODS: One hundred forty-nine patients with MG and 148 healthy controls were recruited. Using improved multiple ligase detection reaction technology, the polymorphisms of rs2893321 between groups and among MG subgroups have been compared. RESULTS: A significant differences between the MG group and the healthy control group was observed. Additionally, rs2893321 was found to be associated with gender and age in patients with MG. CONCLUSION: Genetic variations of rs2893321 in BAFF might be associated with susceptibility to MG in the Chinese Han population.

NSDNA: a manually curated database of experimentally supported ncRNAs associated with nervous system diseases.

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.

MSGD: a manually curated database of genomic, transcriptomic, proteomic and drug information for multiple sclerosis.

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system. 'Omics' technologies (genomics, transcriptomics, proteomics) and associated drug information have begun reshaping our understanding of multiple sclerosis. However, these data are scattered across numerous references, making them challenging to fully utilize. We manually mined and compiled these data within the Multiple Sclerosis Gene Database (MSGD) database, intending to continue updating it in the future. We screened 5485 publications and constructed the current version of MSGD. MSGD comprises 6255 entries, including 3274 variant entries, 1175 RNA entries, 418 protein entries, 313 knockout entries, 612 drug entries and 463 high-throughput entries. Each entry contains detailed information, such as species, disease type, detailed gene descriptions (such as official gene symbols), and original references. MSGD is freely accessible and provides a user-friendly web interface. Users can easily search for genes of interest, view their expression patterns and detailed information, manage gene sets and submit new MS-gene associations through the platform. The primary principle behind MSGD's design is to provide an exploratory platform, aiming to minimize filtration and interpretation barriers while ensuring highly accessible presentation of data. This initiative is expected to significantly assist researchers in deciphering gene mechanisms and improving the prevention, diagnosis and treatment of MS. Database URL: http://bio-bigdata.hrbmu.edu.cn/MSGD.

Construction of ceRNA network mediated by circRNAs screening from microarray and identification of novel biomarkers for myasthenia gravis.

BACKGROUND: Recent studies have revealed that circRNA can serve as ceRNA to participate in multiple autoimmune diseases. Our study aims to explore the key circRNA as ceRNA and biomarker for MG. METHODS: We used circRNA microarray to explore differentially expressed circRNAs (DECs) from MG and compare with control. Then, we predicted the target miRNA associated with DECs and screened miRNAs by the algorithm of random walk with restart (RWR). Next, we constructed the circRNA-miRNA-mRNA ceRNA regulated network (CMMC) to identify the hub objects. Following, we detected the expression of hub-circRNAs by RT-PCR. We verify has_circ_0004183 (circFRMD4) sponging miR-145-5p regulate cells proliferation using luciferase assay and CCK-8. RESULTS: We found that the expression level of circFRMD4 and has_circ_0035381 (circPIGB) were upregulated and has_circ_0089153(circ NUP214) had the lowest expression level in MG. Finally, we proved circFRMD4 sponging miR-145-5p regulate Jurkat cells proliferation. CircFRMD4 take part in the genesis and development of MG via circFRMD4/miR145-5p axis. CONCLUSIONS: We found that circFRMD4, circPIGB and circNUP214 can be considered as valuable potential novel biomarkers for AchR + MG. CircFRMD4 participate in the development of AchR + MG via targeting binding with miR-145-5p.

RNA2Immune: A Database of Experimentally Supported Data Linking Non-coding RNA Regulation to The Immune System.

Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as important regulators of the immune system and are involved in the control of immune cell biology, disease pathogenesis, as well as vaccine responses. A repository of ncRNA-immune associations will facilitate our understanding of ncRNA-dependent mechanisms in the immune system and advance the development of therapeutics and prevention for immune disorders. Here, we describe a comprehensive database, RNA2Immune, which aims to provide a high-quality resource of experimentally supported database linking ncRNA regulatory mechanisms to immune cell function, immune disease, cancer immunology, and vaccines. The current version of RNA2Immune documents 50,433 immune-ncRNA associations in 42 host species, including (1) 6690 ncRNA associations with immune functions involving 31 immune cell types; (2) 38,672 ncRNA associations with 348 immune diseases; (3) 4833 ncRNA associations with cancer immunology; and (4) 238 ncRNA associations with vaccine responses involving 26 vaccine types targeting 22 diseases. RNA2Immune provides a user-friendly interface for browsing, searching, and downloading ncRNA-immune system associations. Collectively, RNA2Immune provides important information about how ncRNAs influence immune cell function, how dysregulation of these ncRNAs leads to pathological consequences (immune diseases and cancers), and how ncRNAs affect immune responses to vaccines. RNA2Immune is available at http://bio-bigdata.hrbmu.edu.cn/rna2immune/home.jsp.

Study of molecular patterns associated with ferroptosis in Parkinson's disease and its immune signature.

Parkinson's disease is the second most common neurodegenerative disease in the world. We downloaded data on Parkinson's disease and Ferroptosis-related genes from the GEO and FerrDb databases. We used WCGAN and Random Forest algorithm to screen out five Parkinson's disease ferroptosis-related hub genes. Two genes were identified for the first time as possibly playing a role in Braak staging progression. Unsupervised clustering analysis based on hub genes yielded ferroptosis isoforms, and immune infiltration analysis indicated that these isoforms are associated with immune cells and may represent different immune patterns. FRHGs scores were obtained to quantify the level of ferroptosis modifications in each individual. In addition, differences in interleukin expression were found between the two ferroptosis subtypes. The biological functions involved in the hub gene are analyzed. The ceRNA regulatory network of hub genes was mapped. The disease classification diagnosis model and risk prediction model were also constructed by applying hub genes based on logistic regression. Multiple external datasets validated the hub gene and classification diagnostic model with some accuracy. This study explored hub genes associated with ferroptosis in Parkinson's disease and their molecular patterns and immune signatures to provide new ideas for finding new targets for intervention and predictive biomarkers.

Integrated analysis of differentially expressed genes and a ceRNA network to identify hub lncRNAs and potential drugs for multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease of the nervous system. However, the precise molecular mechanisms underlying MS have yet to be fully elucidated. In this study, our aim was to provide novel insight into the pathogenesis of MS and provide a resource for identifying new biomarkers and therapeutics for MS. METHODS: In this study, we analyzed the gene expression profiles (GSE21942) and miRNA expression profiles (GSE61741) of MS patient samples that were downloaded from the GEO database and identified differentially expressed mRNAs and miRNAs (DEmRNAs, DEmiRNAs). Next, we constructed a protein-protein interaction (PPI) network and a MS-specific ceRNA network (MCEN) by integrating expression profiles, interaction pairs of mRNA-miRNAs and lncRNA-miRNAs. Then, according to the modular structure of the PPI network, we identified hub DEmRNAs and generated a ceRNA subnetwork so that we could analyze the key lncRNAs that were associated with MS. RESULTS: We first identified 4 modules by constructing a PPI network using DEmRNAs. Functional enrichment analysis showed these modules were enriched in immune-related pathways. Then, we constructed the MCEN and the hub gene-associated ceRNA subnetwork using a comprehensive computational approach. We identified three key lncRNAs (LINC00649, TP73-AS1 and MALAT1) and further identified key lncRNA-mediated ceRNAs within the subnetwork. Finally, by analyzing LINC00649-miR-1275-CD20, we identified 6 drugs that may represent novel drugs for MS. CONCLUSION: Collectively, our results provide novel insight for the discovery of biomarkers and therapeutics for MS and provide a suitable foundation from which to design future investigations of the pathogenic mechanisms associated with MS.

Construction of miRNA-regulated drug-pathway network to screen drug repurposing candidates for multiple sclerosis.

ABSTRACT: 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.

LncRNA OIP5-AS1 modulates the proliferation and apoptosis of Jurkat cells by sponging miR-181c-5p to regulate IL-7 expression in myasthenia gravis.

Background: Myasthenia gravis (MG) is an antibody-mediated autoimmune disease. In recent years, accumulating evidence has indicated that long non-coding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs), contributing to the progression of various autoimmune diseases. Nevertheless, the regulatory roles of ceRNAs in MG pathogenesis remain unclear. In this study, we aimed to elucidate the role of lncRNA OIP5-AS1 as a ceRNA associated with MG progression. Methods: Real-time PCR was used to detect OIP5-AS1 levels in peripheral blood mononuclear cells (PBMCs) from patients with MG. Luciferase reporter assays were performed to validate the relationship between OIP5-AS1 and miR-181c-5p. CCK-8 and flow cytometry were performed to test the proliferation and apoptotic abilities of OIP5-AS1 in Jurkat cells. Furthermore, real-time PCR and Western blot assays were performed to explore the interactions between OIP5-AS1, miR-181c-5p, and IL-7. Results: The expression of OIP5-AS1 was up-regulated in patients with MG. Luciferase reporter assay indicated that OIP5-AS1 targeted the miR-181c-5p. Functional assays showed that OIP5-AS1 suppressed Jurkat cell apoptosis and promoted cell proliferation by sponging miR-181c-5p. Mechanistically, knockdown of OIP5-AS1 inhibited IL-7 expression at both the mRNA and protein levels in Jurkat cells, whereas the miR-181c-5p inhibitor blocked the reduction of IL-7 expression induced by OIP5-AS1 suppression. Conclusions: We confirmed that OIP5-AS1 serves as an endogenous sponge for miR-181c-5p to regulate the expression of IL-7. Our findings provide novel insights into MG processes and suggests potential therapeutic targets for patients with MG.

Construction Immune Related Feed-Forward Loop Network Reveals Angiotensin II Receptor Blocker as Potential Neuroprotective Drug for Ischemic Stroke.

Ischemic stroke (IS) accounts for the leading cause of disability and mortality in China. Increasing researchers are studying the effects of neuroprotective agents on IS. However, the molecular mechanisms of feed-forward loops (FFLs) associated with neuroprotection in the pathogenesis of IS need to be further studied. A protein-protein interaction (PPI) network of IS immune genes was constructed to decipher the characters and excavate 3 hub genes (PI3K, IL6, and TNF) of immunity. Then, we identified two hub clusters of IS immune genes, and the cytokine-cytokine receptor interaction pathway was discovered on the pathway enrichment results of both clusters. Combined with GO enrichment analysis, the cytokines participate in the inflammatory response in the extracellular space of IS patients. Next, a transcription factor (TF)-miRNA-immune gene network (TMIGN) was established by extracting four regulatory pairs (TF-miRNA, TF-gene, miRNA-gene, and miRNA-TF). Then, we detected 3-node regulatory motif types in the TMIGN network. According to the criteria we set for defining 3-node motifs, the motif with the highest Z-score (3-node composite FFL) was picked as the statistically evident motif, which was merged to construct an immune-associated composite FFL motif-specific sub-network (IA-CFMSN), which contained 21 3-node FFLs composed of 13 miRNAs, 4 TFs, 9 immune genes, and 1 TF& immune gene, among which TP53 and VEGFA were prominent TF and immune gene, respectively. In addition, the immune genes in IA-CFMSN were used for identifying associated pathways and drugs to further clarify the immune regulation mechanism and neuroprotection after IS. As a result, 5 immune genes targeted by 20 drugs were identified and the Angiotensin II Receptor Blockers (ARBs) target AGTR1 was found to be a neuroprotective drug for IS. In the present study, the construction of IA-CFMSN provides IS immune-associated FFLs for further experimental studies, providing new prospects for the discovery of new biomarkers and potential drugs for IS.

Identification of LINC00173 in Myasthenia Gravis by Integration Analysis of Aberrantly Methylated- Differentially Expressed Genes and ceRNA Networks.

Myasthenia gravis (MG) is an autoimmune disease associated with autoantibody production that leads to skeletal muscle weakness. The molecular mechanisms underlying MG are not fully understood. We analyzed the gene expression profile (GSE85452) and methylation profile (GSE85647) of MG samples from the GEO database to identify aberrantly methylated-differentially expressed genes. By integrating the datasets, we identified 143 hypermethylation-low expression genes and 91 hypomethylation-high expression genes. Then we constructed PPI network and ceRNA networks by these genes. Phosphatase and tensin homolog (PTEN) and Abelson tyrosine-protein kinase (ABL)1 were critical genes in both PPI networks and ceRNA networks. And potential MG associated lncRNAs were selected by comprehensive analysis of the critical genes and ceRNA networks. In the hypermethylation-low expression genes associated ceRNA network, sirtuin (SIRT)1 was the most important gene and the lncRNA HLA complex (HC) P5 had the highest connection degree. Meanwhile, PTEN was the most important gene and the lncRNA LINC00173 had the highest connection degree in the hypomethylation-high expression genes associated ceRNA network. LINC00173 was validated to be upregulated in MG patients by qRT-PCR (P = 0.005), which indicated LINC00173 might be a potential biomarker for MG. These results provide a basis for future studies on the molecular pathogenesis of MG.

Competitive endogenous RNA network and pathway-based analysis of LncRNA single-nucleotide polymorphism in myasthenia gravis.

Myasthenia gravis (MG) is a complex neurological autoimmune disease with a pathogenetic mechanism that has yet to be elucidated. Emerging evidence has revealed that genes, non-coding RNAs and genetic variants play significant roles in the pathogenesis of MG. However, the molecular mechanisms of single nucleotide polymorphisms (SNPs) located on lncRNAs could disturb lncRNA-mediated ceRNA regulatory functions still unclear in MG. In this study, we collated 276 experimentally confirmed MG risk genes and 192 MG risk miRNAs. We then constructed a lncRNA-mediated ceRNA network for MG based on multi-step computational strategies. Next, we systematically integrated risk pathways and identified candidate SNPs in lncRNAs for MG based on data acquired from public databases. In addition, we constructed a pathway-based lncRNA-SNP mediated network (LSPN) that contained 128 lncRNAs targeting 8 MG risk pathways. By analyzing network, we propose a latent mechanism for how the "lncRNA-SNP-mRNA-pathway" axis affects the pathogenesis of MG. Moreover, 25 lncRNAs and 51 SNPs on lncRNAs were extracted from the "lncRNA-SNP-mRNA-pathway" axis. Finally, functional analyses demonstrated lncRNA-SNPs mediated ceRNA regulation pairs associated with MG participated in the MAPK signaling pathway. In summary, we constructed MG-specific lncRNA-SNPs mediated ceRNA regulatory networks based on pathway in the present study, which was helpful to elucidate the roles of lncRNA-SNPs in the pathogenesis of MG and provide novel insights into mechanism of lncRNA-SNPs as potential genetic risk biomarkers of MG.