lncRNA Expression Profiles Research Articles

Integrated analysis reveals ceRNA network of cardiac remodeling by SGLT2 inhibitor in middle-aged hypertensive rats

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent an innovative class of antidiabetic agents that have demonstrated promise in mitigating cardiac remodeling. However, the transcriptional regulatory mechanisms underpinning their impact on blood pressure and the reversal of hypertension-induced cardiac remodeling remain largely unexplored. Given this context, our study concentrated on comparing the cardiac expression profiles of lncRNAs and mRNAs between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). To validate our results, we performed blood pressure measurements, tissue staining, and qRT-PCR. The treatment led to a significant reduction in systolic blood pressure and improved cardiac remodeling by reducing myocardial fibrosis and regulating the inflammatory response. Our examination disclosed that ventricular tissue mRNA, regulated by hypertension, was primarily concentrated in the complement and coagulation cascades and cytokine-cytokine receptor interactions. Compared with SHR, the SGLT2i treatment group was associated with myocardial contraction. Investigation into the lncRNA-mRNA regulatory network and competing endogenous RNA (ceRNA) network suggested that the potential roles of these differentially expressed (DE) lncRNAs and mRNAs were tied to processes such as collagen fibril organization, inflammatory response, and extracellular matrix (ECM) modifications. We found that the expression of Col3a1, C1qa, and lncRNA NONRATT007139.2 were altered in the SHR group and that SGLT2i treatment reversed these changes. Our results suggest that dapagliflozin effectively reverses hypertension-induced myocardial remodeling through a lncRNA-mRNA transcriptional regulatory network, with immune cell-mediated ECM deposition as a potential regulatory target. This underlines the potentiality of SGLT2i and genes related to immunity as promising targets for the treatment of hypertension.

LncRNA and Protein Expression Profiles Reveal Heart Adaptation to High-Altitude Hypoxia in Tibetan Sheep.

The Tibetan sheep has an intricate mechanism of adaptation to low oxygen levels, which is influenced by both genetic and environmental factors. The heart plays a crucial role in the adaptation of Tibetan sheep to hypoxia. In the present study, we utilized transcriptomic and proteomic technologies to comprehensively analyze and identify the long non-coding RNAs (lncRNAs), genes, proteins, pathways, and gene ontology (GO) terms associated with hypoxic adaptation in Tibetan sheep at three different altitudes (2500 m, 3500 m, and 4500 m). By integrating the differentially expressed (DE) lncRNA target genes, differentially expressed proteins (DEPs), and differentially expressed genes (DEGs), we were able to identify and characterize the mechanisms underlying hypoxic adaptation in Tibetan sheep. Through this integration, we identified 41 shared genes/proteins, and functional enrichment analyses revealed their close association with lipid metabolism, glycolysis/gluconeogenesis, and angiogenesis. Additionally, significant enrichment was observed in important pathways such as the PPAR signaling pathway, glycolysis/gluconeogenesis, the oxoacid metabolic process, and angiogenesis. Furthermore, the co-expression network of lncRNAs and mRNAs demonstrated that lncRNAs (MSTRG.4748.1, ENSOART00020025894, and ENSOART00020036371) may play a pivotal role in the adaptation of Tibetan sheep to the hypoxic conditions of the plateau. In conclusion, this study expands the existing database of lncRNAs and proteins in Tibetan sheep, and these findings may serve as a reference for the prevention of altitude sickness in humans.

Maimendong and Qianjinweijing Tang combined with cisplatin suppressed lung cancer through targeting lncRNA-p21

Ethnopharmacological relevanceMaimendong and Qianjinweijing Tang (Jin formula) is a traditional Chinese medicine formula that has been proven effective in the treatment of lung cancer in long-term clinical practice. Aim of the studyTo evaluate the anti-tumor effects of Jin formula combined with cisplatin (JIN + DDP) in vivo and in vitro, as well as to explore the role of long non-coding RNA (lncRNA) in the anti-lung cancer mechanism of its action. Materials and methodsA Lewis lung cancer model was established in C57 BL/6 mice to study the in vivo anti-tumor effect of Jin formula combined with cisplatin. TUNEL staining and western blot were applied to study the effects of Jin formula combined cisplatin on apoptosis. The in vitro anti-cancer function of Jin formula combined with cisplatin was explored by cell viability assay, flow cytometry, wound healing assay and transwell assay. The changes in lncRNA expression profiles were determined by lncRNA microarray, and the differentially expressed lncRNA-p21 was verified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. The expression differences of lncRNA-p21 in tumor and normal tissues were analyzed by bioinformatics, and the expression differences of lncRNA-p21 in tumor cells and normal cells were detected by qRT-PCR. The role of lncRNA-p21 in the anti-cancer effect of Jin formula combined cisplatin was investigated by knockdown or overexpression of lncRNA-p21 and a series of cell experiments. The expression of MAPK pathway-related proteins was analyzed by western blot. ResultsJin formula combined with cisplatin (JIN + DDP) can suppress tumor growth and promote apoptosis in Lewis lung cancer mouse model. LncRNA-p21 was significantly up-regulated in the JIN and JIN + DDP groups, and the expression of lncRNA-p21 in lung cancer tissues and cells was lower than that in normal tissues and cells. In vitro, JIN + DDP significantly induced apoptosis and inhibited the proliferation, migration, and invasion of H460 and H1650 lung cancer cells. The above effects can be enhanced by the overexpression of lncRNA-p21 and eliminated by knock-down of lncRNA-p21. Further studies revealed that JIN + DDP inhibited the expression of mitogen-activated protein kinase (MAPK) pathway-related proteins, whereas knock-down of lncRNA-p21 abrogated the inhibition of the MAPK signaling pathway. ConclusionsThis study showed that Jin formula combined with cisplatin could effectively inhibit the progression of lung cancer partially through targeting lncRNA-p21.

LncNFYB promotes the proliferation of rheumatoid arthritis fibroblast-like synoviocytes via LncNFYB/ANXA2/ERK1/2 axis

Long noncoding RNAs (lncRNAs) are specifically expressed in different diseases and regulate disease progression. To explore the functions of rheumatoid arthritis (RA)- specific lncRNA, we determined the lncRNA expression profile of fibroblast-like synoviocytes (FLS) obtained from patients with RA and osteoarthritis (OA) using an LncRNA microarray and identified up-regulated LncNFYB in RA as a potential therapeutic target. Using gain- and loss-of-function studies, LncNFYB was proved promoting FLS proliferation and cell cycle progress, but not affecting their invasion, migration, and apoptotic abilities. Further investigation discovered that LncRNA could combine with annexin A2 (ANXA2) and enhanced the level of phospho-ANXA2 (Tyr24) in the plasma membrane area, which induced the activation of ERK1/2 to promoting proliferation. These findings provide new insights into the biological functions of LncNFYB on modification of FLS, which may be exploited for the therapy of RA.

Identification and functional prediction of long non-coding RNA and mRNA related to connective tissue disease-associated interstitial lung diseases.

Recently, the role of long non-coding RNA (lncRNA) in rheumatic immune diseases has attracted widespread attention. However, knowledge of lncRNA in connective tissue disease-associated interstitial lung disease (CTD-ILD) is limited. This study explored the expression profile and possible mechanisms of lncRNA and mRNA in peripheral blood mononuclear cells (PBMCs) of CTD-ILD patients, especially systemic sclerosis (SSc)-ILD and rheumatoid arthritis (RA)-ILD. LncRNA microarray analysis identified 240 diferentially expressed lncRNAs and 218 diferentially expressed mRNA in the CTD-ILD group and the connective tissue disease without associated interstitial lung disease (CTD-NILD) group. The bioinformatics analysis of diferential genes has identified several important biological processes and signal pathways, including nuclear factor kappa B (NF-kappa B) signaling pathway, interleukin 17 (IL-17) signaling pathway, B cell receptor signaling pathway. Relative expression levels of five diferentially expressed lncRNAs and one mRNA in 120 SSc and RA patients with or without ILD were detected by quantitative reverse-transcription (PCR). The ENST00000604692 expression level was significantly higher in the ILD than the without interstitial lung disease (NILD) group; T311354 and arginase-1 were significantly higher in SSc than RA group. These data suggest that the specific profile of lncRNA in PBMCs of CTD-ILD patients and the potential signal pathways related to the pathogenesis of CTD-ILD, which may provide newfound insights for the diagnosis and treatment of CTD-ILD patients.

Long non-coding RNA expression in PBMCs of patients with active pulmonary tuberculosis.

Mycobacterium tuberculosis (Mtb) infection is the primary cause of the chronic infectious illness tuberculosis (TB). Long non-coding RNAs (lncRNAs) are functional RNA molecules that cannot be translated into proteins and play a crucial role in regulating the immune system's innate and adaptive responses. It has been demonstrated that the dysregulation of lncRNA expression is associated with various human diseases. However, the mechanism underlying the involvement of so many lncRNAs in the immune response to TB infection remains unclear. The objective of our current study was to identify a number of significantly differentially expressed lncRNAs in peripheral blood mononuclear cells (PBMCs) from TB patients and to select the most indicative lncRNAs as potential biomarkers for active pulmonary tuberculosis. Microarray analysis was performed to determine the lncRNA and mRNA expression profiles in TB patients using a case-control model. The differentially expressed lncRNAs were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to investigate potential roles and pathways associated with the pathogenesis of TB infection, and to screen lncRNAs specifically linked to TB infection. Using real-time fluorescence quantitative PCR (QRT-PCR), specific lncRNAs were identified in TB patients and latent infections. Our findings revealed that various signaling pathways were differentially expressed in TB-infected individuals, suggesting a potential role for lncRNAs in the immunological responses driven by TB infection. This study provides crucial guidelines for future functional research. Upregulated lncRNAs were mainly enriched in Neutrophil extracellular trap formation and Chemokine signaling pathways, while downregulated lncRNAs were enriched in Neuroactive ligand-receptor interaction and Cushing syndrome in TB PBMCs. Furthermore, we found that lnc-XPNPEP1-5, lnc-CASKIN2-2, lnc-HSPA13-6, lnc-CLIC5-1, and LINC02502 were significantly downregulated in TB-infected patients, while LINC00528, lnc-SLC45A4-3, and LINC00926 were significantly upregulated in TB patients and latent infections. These eight lncRNAs, identified as novel biological marker candidates for diagnosing TB infection, were validated by real-time fluorescence quantitative PCR (QRT-PCR). The abnormally expressed lncRNAs identified in this research may provide crucial information for understanding the pathophysiological characteristics of TB patients and the dysfunction of PBMCs. Our findings reveal potential targets for early TB diagnosis and therapy, as well as offer new insights into the mechanisms underlying TB infection.

Identification of a Novel lncRNA in Diagnosis of Sepsis-Induced Cardiomyopathy Using a Comprehensive Analysis of lncRNA-mRNA Network

Abstract Objective Long noncoding RNAs (lncRNAs) have been implicated in various biological processes, particularly in the regulation of inflammatory responses and myocardial injuries. Notably, the role of lncRNAs in sepsis-induced cardiomyopathy (SIC) has been highlighted. However, a comprehensive analysis investigating the specific circulating lncRNAs associated with SIC has yet to be conducted. Therefore, we conducted a study involving samples from healthy controls, sepsis patients without myocardial injuries, individuals with cardiac dysfunction following heart surgery, and those with SIC, aiming to identify the distinct lncRNAs involved in SIC. Methods A total of 12 blood samples were collected, including healthy controls, sepsis patients without myocardial injuries, patients with cardiac surgery-related myocardial injuries, and patients with SIC, who were aged from 10 to 22 months. Transcriptome sequencing was conducted to identify differentially expressed (DE) lncRNAs and mRNAs. Venn plots were employed to identify the DE RNAs specific to SIC. Subsequently, enrichment analyses were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms. A coexpression network between lncRNAs and mRNAs was constructed, focusing on protein–protein interaction features. Then, further validation had been done in a consecutive larger cohort. Results We identified independent DE mRNAs and lncRNAs specific to SIC patients. The analysis of DE mRNAs revealed that immune activation, particularly innate immune activity, was the primary distinction between sepsis with or without myocardial injuries. Furthermore, cytokine production, particularly interleukin-1 secretion, played a significant role in inducing SIC. The expression profiles of DE lncRNAs showed considerable enrichment in shared topics with mRNAs. Subsequently, we identified lncRNAs targeting the DE mRNAs, many of which were involved in immune responses and cytokine production. We established a coexpression network between lncRNAs and mRNAs, leading to the discovery of a novel lncRNA (TCONS_00136255). Finally, we successfully validated TCONS_00136255, demonstrating its acceptable diagnostic accuracy and its role in regulating major molecular processes involved in SIC. Conclusion lncRNAs actively participate in the significant biological changes associated with immune responses in sepsis-induced myocardial injuries. These lncRNAs interact with mRNAs to modulate inflammation activity and cytokine production. Notably, the identification of the novel lncRNA (TCONS_00136255) highlights its crucial regulatory role in SIC.

The diagnostic value of serum lncRNA CATG00000112921.1 as a marker of multiple myeloma

Multiple myeloma (MM) is a malignant plasma cell disease. At present, numerous studies have shown that lncRNA plays a very important role in the occurrence, development and even drug resistance of multiple myeloma. It may become a potential diagnostic and prognostic marker of multiple myeloma and provide new ideas for targeted therapy. Based on the above research background, this study used gene chip technology to screen out the differentially expressed lncRNA in the serum of MM patients and healthy people, and verified more clinical serum samples to screen out the lncRNA with the largest difference as a biomarker for further research. In this research, the data of hospitalized patients diagnosed with MM and healthy people in the Affiliated Hospital of Guangdong Medical University were retrospectively collected. The lncRNA expression profile of serum samples from patients with multiple myeloma and healthy controls was analyzed by lncRNA chip technology. The serum samples were verified by real-time fluorescence quantitative PCR, and the candidate diagnostic markers were screened out. The ROC working curve was drawn to evaluate the diagnostic efficacy of the candidate markers and to determine their stability at different temperatures and time. A total of 44 MM patients and 37 healthy people were involved in this research. Among them, 4 patients with MM and 4 patients with HD were sent for microarray analysis. According to Fold Change ≥ 2 and P < 0.05, a total of 17 differentially expressed lncRNA molecules were screened, of which 9 were up-regulated RNA molecules and 8 were down-regulated RNA molecules. Through real-time fluorescence quantitative PCR verification, it was found that lncRNA CATG00000112921.1 was highly expressed in the healthy control group and diminished in patients with multiple myeloma, P < 0.001. The ROC curve demonstrated that the area under the curve (AUC) was 0.749, the sensitivity was 0.636, the specificity was 0.789, and the 95 % CI was 0.636-0.862 (P < 0.001). In addition, in order to verify the effects of temperature, time and repeated freezing and thawing on lncRNA, it was placed at 25°C, 4°C, -20°C, -80°C for 0h, 24h, 48h, 72h, and placed at-80°C repeated freezing and thawing 0 times, 2 times, 4 times, 8 times, and the expression level was not significantly changed. Serum lncRNA CATG00000112921.1 may be a potential candidate diagnostic marker for multiple myeloma. The ROC curve shows that it has good diagnostic value, and its high stability at different temperatures and different times is a required condition for becoming a diagnostic marker. As far as we know, this is the first study in the world to find differential expression of lncRNA CATG00000112921.1 in peripheral serum of healthy people and newly diagnosed multiple myeloma patients. This study also highlights the application of gene chip technology in screening differentially expressed genes.

Profiling and Bioinformatics Analyses of Hypoxia-Induced Differential Expression of Long Non-coding RNA in Glioblastoma Multiforme Cells.

Hypoxic microenvironments are intricately linked to malignant characteristics of glioblastoma multiforme (GBM). Long non-coding ribonucleic acids (lncRNAs) have been reported to be involved in the progression of GBM and closely associated with hypoxia. Nevertheless, the differential expression profiles as well as functional roles of lncRNAs in GBM cells under hypoxic conditions remain largely obscure. We explored the expression profiles of lncRNAs in hypoxic U87 cells as well as T98G cells using sequencing analysis. The effect of differentially expressed lncRNAs (DElncRNAs) was assessed through bioinformatic analysis. Furthermore, the expression of lncRNAs significantly dysregulated in both U87 and T98G cells was further validated using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Relevant cell functional experiments were also conducted. We used predicted RNA-binding proteins (RBPs) to construct an interaction network via the interaction prediction module. U87 and T98G cells showed dysregulation of 1115 and 597 lncRNAs, respectively. Gene Ontology (GO) analysis indicated that altered lncRNA expression was associated with nucleotide-excision repair and cell metabolism in GBM cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed the association between dysregulated lncRNAs and the Hippo signaling pathway under hypoxia. The dysregulation of six selected lncRNAs (ENST00000371192, uc003tnq.3, ENST00000262952, ENST00000609350, ENST00000610036, and NR_046262) was validated by qRT-PCR. Investigation of lncRNA-microRNA (miRNA)-mRNA networks centered on HIF-1α demonstrated cross-talk between the six validated lncRNAs and 16 related miRNAs. Functional experiments showed the significant inhibition of GBM cell proliferation, invasion, and migration by the knockdown of uc003tnq.3 in vitro. Additionally, uc003tnq.3 was used to construct a comprehensive RBP-transcription factor (TF)-miRNA interaction network. The expression of LncRNAs was dysregulated in GBM cells under hypoxic conditions. The identified six lncRNAs might exert important effect on the development of GBM under hypoxic microenvironment.

Expression profiles of lncRNAs, miRNAs, and mRNAs and interaction analysis indicate their potential involvement during testicular fusion in Spodoptera litura

Testicular fusion of Spodoptera litura occures during metamorphosis, which benefits sperms development. Previous research identified involvement of ECM-integrin interaction pathways, MMPs in testicular fusion, but the regulatory mechanism remains unclear. RNA-seq was performed to analyze long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in testes, aiming to uncover potential regulatory mechanisms of testicular fusion. 2150 lncRNAs, 2742 targeted mRNAs, and 347 miRNAs were identified in testes at three different developmental stages. Up-regulated DElncRNAs and DEmRNAs, as well as down-regulated DEmiRNAs, were observed during testicular fusion, while the opposite expression pattern was observed after fusion. Enrichment analysis of DEmRNAs revealed that cAMP signal pathway, ECM remodeling enzymes, ECM-integrin interaction pathways, and cell adhesion molecules were potentially associated with testicular fusion. The identified DElncRNA-DEmiRNA-DEmRNA regulatory network related to cAMP signal pathway, ECM remodeling enzymes suggests their roles during testicular fusion. Our research will provide new targets for studying the mechanism of testicular fusion.

Expression profiles of oviductal mRNAs and lncRNAs in the follicular phase and luteal phase of sheep (Ovis aries) with 2 fecundity gene (FecB) genotypes.

FecB (also known as BMPR1B) is a crucial gene in sheep reproduction, which has a mutation (A746G) that was found to increase the ovulation rate and litter size. The FecB mutation is associated with reproductive endocrinology, such mutation can control external estrous characteristics and affect follicle-stimulating hormone during the estrous cycle. Previous researches showed that the FecB mutation can regulate the transcriptomic profiles in the reproductive-related tissues including hypothalamus, pituitary, and ovary during the estrous cycle of small-tailed Han (STH) sheep. However, little research has been reported on the correlation between FecB mutation and the estrous cycle in STH sheep oviduct. To investigate the coding and noncoding transcriptomic profiles involved in the estrous cycle and FecB in the sheep oviduct, RNA sequencing was performed to analyze the transcriptomic profiles of mRNAs and long noncoding RNAs (lncRNAs) in the oviduct during the estrous cycle of STH sheep with mutant (FecBBB) and wild-type (FecB++) genotypes. In total, 21,863 lncRNAs and 43,674 mRNAs were screened, the results showed that mRNAs had significantly higher expression levels than the lncRNAs, and the expression levels of these screened transcripts were lower in the follicular phase than they were in the luteal phase. Among them, the oviductal glycoprotein gene (OVGP1) had the highest expression level. In the comparison between the follicular and luteal phases, 57 differentially expressed (DE) lncRNAs and 637 DE mRNAs were detected, including FSTL5 mRNA and LNC_016628 lncRNA. In the comparison between the FecBBB and FecB++ genotypes, 26 DE lncRNAs and 421 DE mRNAs were detected, including EEF1D mRNA and LNC_006270 lncRNA. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis indicated that the DE mRNAs were enriched mainly in terms related to reproduction such as the tight junction, SAGA complex, ATP-binding cassette, nestin, and Hippo signaling pathway. The interaction network between DE lncRNAs and DE mRNAs indicated that LNC_018420 may be the key regulator in sheep oviduct. Together, our results can provide novel insights into the oviductal transcriptomic function against a FecB mutation background in sheep reproduction.

RNA Sequencing and Bioinformatics Analysis to Reveal Potential Biomarkers in Patients with Combined Allergic Rhinitis and Asthma Syndrome.

Combined allergic rhinitis and asthma syndrome (CARAS) is a concurrent clinical or subclinical allergic symptom of diseases of the upper and lower respiratory tract. This study is the first to explore the expression profiles of mRNA, lncRNA, and circRNA in CARAS using RNA sequencing, which may provide insight into the mechanisms underlying CARAS. Whole blood samples from nine participants (three CARAS patients, three AR patients, and three normal control participants) were subjected to perform RNA sequencing, followed by identification of differentially expressed lncRNAs (DElncRNAs), circRNAs (DEcircRNAs) and mRNAs (DEmRNAs). Then, lncRNA/circRNA-mRNA regulatory pairs were constructed, followed by functional analysis, immune infiltration analysis, drug prediction, and expression validation with RT-qPCR and ELISA. The results showed that 61 DEmRNAs, 23 DElncRNAs and 3 DEcircRNAs may be related to the occurrence and development of CARAS. KRT8 may be implicated in the development of AR into CARAS. Three immunity-related mRNAs (IDO1, CYSLTR2, and TEC) and two hypoxia-related mRNAs (TKTL1 and VLDLR) were associated with the occurrence and development of CARAS. TEC may be considered a drug target for Dasatinib in treating CARAS. Several lncRNA/circRNA-mRNA regulatory pairs were identified in CARAS, including LINC00452/MIR4280HG/hsa_circ_0007272/hsa_circ_0070934-CLC, HEATR6-DT/LINC00639/LINC01783/hsa_circ_0008903-TEC, RP11-71L14.3-IDO1/SMPD3, RP11-178F10.2-IDO1/HRH4, and hsa_circ_0008903-CYSLTR2, which may indicate potential regulatory effects of lncRNAs/circRNAs in CARAS. Dysregulated levels of immune cell infiltration may be closely related to CARAS. The regulating effect of lncRNA/circRNA-immunity/hypoxia-related mRNA regulatory pairs may be involved in the occurrence and development of CARAS.

Novel PBMC LncRNA signatures as diagnostic biomarkers for colorectal cancer

The expression of long non-coding RNAs (LncRNAs) in peripheral blood mononuclear cell (PBMC) and its clinical relevance in colorectal cancer (CRC) remains largely uncharacterized. To address these gaps, we investigated the expression profiles of lncRNAs in PBMC from CRC and healthy controls (HC) by RNA sequencing. The expression level of differentially expressed lncRNAs (DElncRNAs) were evaluated by quantitative PCR in PBMC samples from CRC patients and HC. A total of 447 DElncRNAs were identified, with 178 elevated lncRNAs and 269 decreased lncRNAs in PBMC from CRC patients as compared with that from HC. RT-PCR results supported a significant elevation of NEAT1:11, lnc-PDZD8-1:5 and LINC00910:16 in 98 CRC patients and 82 HC. The clinical implication of NEAT1:11, lnc-PDZD8-1:5 and LINC00910:16 as CRC diagnostic biomarker were determined by receiver operating characteristic (ROC) curve, showing sensitivity 74.5% and specificity 84.5% for joint detection the three lncRNAs. Notably, NEAT1:11 was closely related with the size and extent of primary tumor, with higher relative expression of NEAT1:11 in higher T stage (P=0.0047). Moreover, NEAT1:11 was related with grade (P=0.012). Collectively, PBMC from patients with CRC show significantly variable expression profiles of lncRNAs, and detection of these differential expression lncRNAs may provide useful information for basic and clinical research.

Comprehensive Analysis of Disulfidptosis-Related LncRNAs in Molecular Classification, Immune Microenvironment Characterization and Prognosis of Gastric Cancer.

Disulfidptosis is a novel form of programmed cell death that unveils promising avenues for the exploration of tumor treatment modalities. Gastric cancer (GC) is a malignant tumor characterized by high incidence and mortality rate. However, there has been no systematic study of disulfidptosis-related long noncoding RNAs (DRLs) signature in GC patients. The lncRNA expression profiles containing 412 GC samples were acquired from the Cancer Genome Atlas (TCGA) database. Differential expression analysis was performed alongside Pearson correlation analysis to identify DRLs. Prognostically significant DRLs were further screened using univariate COX regression analysis. Subsequently, LASSO regression and multifactorial COX regression analyses were employed to establish a risk signature composed of DRLs that exhibit independent prognostic significance. The predictive value of this risk signature was further validated in a test cohort. The ESTIMATE, CIBERSORT and ssGSEA methodologies were utilized to investigate the tumor immune microenvironment of GC populations with different DRLs profiles. Finally, the correlation between DRLs and various GC drug responses was explored. We established a prognostic signature comprising 12 disulfidptosis-related lncRNAs (AC110491.1, AL355574.1, RHPN1-AS1, AOAH-IT1, AP001065.3, MEF2C-AS1, AC016394.2, LINC00705, LINC01952, PART1, TNFRSF10A-AS1, LINC01537). The Kaplan-Meier survival analysis revealed that patients in the high-risk group exhibited a poor prognosis. Both univariate and multivariate COX regression models demonstrated that the DRLs signature was an independent prognostic indicator in GC patients. Furthermore, the signature exhibited accurate predictions of survival at 1-, 3- and 5- years with the area under the curve (AUC) values of 0.708, 0.689 and 0.854, respectively. In addition, we also observed significant associations between the DRLs signature and various clinical variables, distinct immune landscape and drug sensitivity profiles in GC patients. The low-risk group patients may be more likely to benefit from immunotherapy and chemotherapy. Our study investigated the role and potential clinical implications of DRLs in GC. The risk model constructed by DRLs demonstrated high accuracy in predicting the survival outcomes of GC and improving the treatment efficacy for GC patients.

The Ancestry-Related Landscape of Long Non-Coding RNAs (LncRNAs) in Acute Myeloid Leukemia (AML) and Its Impact on Patient (Pt) Survival

Background In addition to molecular genetic and cytogenetic findings, gene expression profiles provide independent prognostic information in AML. Aberrant expression of non-coding RNAs, including lncRNAs, further inform pt prognosis. However, non-coding expression profiles and their clinical relevance in AML almost exclusively stem from studies of pts of European ancestry (hereafter referred to as White). Given the inferior survival of African-American (hereafter referred to as Black) AML pts, we hypothesized that aberrant, possibly ancestry-associated lncRNA expression may contribute to survival disparities. Hence, we set out to (1) characterize the lncRNA landscape of African-American ancestry, (2) delineate associations of lncRNAs with clinical and molecular characteristics and (3) assess the prognostic significance of ancestry-associated lncRNAs in AML. Methods We used diagnostic samples from 681 adult AML pts (&amp;lt;60y) treated similarly on Alliance frontline protocols (White, n=616; Black, n=65) for RNAseq, mutational profiling and centrally reviewed karyotyping. A negative binomial model was fit to identify lncRNAs differentially expressed between Black and White pts. To determine prognostic relevance of identified lncRNAs, 10-fold cross-validation repeated 1000 times was performed on LASSO penalized Cox proportional hazards model to overall survival (OS). LncRNAs appearing in at least 900 of the 1000 models were retained and coefficient estimates were averaged then applied to form the “lncRNA score.” Ancestry-associated SNPs in regulatory regions of select lncRNAs were identified using the ENCODE registry for cCREs, SNP2TFBS and population allele frequency data from NCBI ALFA. Results Comparing Black and White AML pts, 135 lncRNAs were upregulated and 55 lncRNAs were downregulated. The differentially expressed lncRNAs were equally distributed throughout the genome and no lncRNA was ancestry-exclusive in its expression, indicating high conservation. lncRNAs with the highest differential expression include several lncRNAs previously implicated in cancer/leukemia, but also thus far unstudied lncRNAs. Using the 190 aberrantly expressed lncRNAs identified from comparison of Black and White pts, we derived a prognostic score (lncRNA score) consisting of 13 lncRNAs. LncRNA High strongly associated with inferior OS in all pts ( Fig. 1). In all pts combined, presence of lncRNA High positively associated with several adverse-risk features, and negatively associated with core-binding factor AML and CEBPA bZIP mutations. Notably, select genetic features differed in their lncRNA score associations based on ancestry, including a relative paucity of cytogenetically normal AML (29% vs 57%), NPM1 (13% vs 40%) and CEBPA bZIP (8% vs 17.5%) mutations in Black pts compared to White pts in the lncRNA Low group. lncRNA score was an independent prognosticator of worse OS in both Black and White pts that refined the prognostication of the European LeukemiaNet 2022 Favorable (P=.004) and Intermediate (P&amp;lt;.001) genetic risk groups. It also provided further prognostic information to the LSC17 score in both low (P&amp;lt;.001) and high (P&amp;lt;.001) LSC17 groups. Examination of the genomic context of regulatory regions within the 13 lncRNAs revealed multiple ancestry-associated SNPs that putatively altered transcription factor / chromatin regulator binding sites in cis-regulatory regions, including rs58515841 (MAF White vs Black, 24% vs 9%, CTCF binding site within ENSG00000284052) and rs1400262 (MAF, 62% vs 10%, REST binding site upstream of NCK1-DT). Conclusions We show an ancestry-related landscape of lncRNAs in AML, including an ancestry-associated expression profile of lncRNAs and evidence of ancestry-associated SNPs as expression modulators. A prognosis-associated lncRNA score based on differentially expressed lncRNAs in Black versus White AML pts carries prognostic significance irrespective of ancestry and refines both mutation/cytogenetically-based (ELN 2022) and gene-expression-based (LSC17) prognostic algorithms. Our findings highlight the importance of ancestry-diverse populations in the establishment of prognostic scoring systems to provide ancestry-connected survival prediction. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org. Clinicaltrials.gov Ids: NCT00048958, NCT00899223, NCT00900224

In-depth analyses of lncRNA and circRNA expression in the hippocampus of LPS-induced AD mice by Byu d Mar 25.

Byu d Mar 25 (BM25) has been verified to have neuroprotective effects in Alzheimer's disease (AD) mice. However, the molecular mechanism remains unclear. We aimed to investigate the expression profiling of lncRNAs and circRNAs by microarray analysis. Six hippocampus from LPS-mediated AD mice model treated with (normal saline (NS) (n = 3) and AD mice model treated with BM25 (n = 3) were selected. Microarray analysis was performed to detect the expression profiles of lncRNAs and circRNAs in hippocampus. Differentially expressed (DE) lncRNAs, mRNAs and circRNAs were identified through scatter plot and volcano plot filtering with a threshold of fold-change ≥2 and P ≤ 0.05. Co-expression network is analyzed by Circos software. Cis - and Trans - regulation were analyzed using RIsearch-2.0 and FEELNC softwares. LncRNA-transcription factors (TFs) and LncRNA-Target-TFs network were analyzed by Clusterprofiler software. The prediction of miRNAs bind to circRNAs were performed with miRNAbase. A total of 113 DElncRNAs, 117 DEmRNAs, and 4 DEcircRNAs were detected. The pathway analysis showed the mRNAs that correlated with lncRNAs were involved in apoptosis, inflammatory mediator regulation of TRP channels, NF-kappa B and PI3K-Akt signaling pathway. The lncRNA-TFs network analysis suggested the lncRNAs were mostly regulated by Ncoa1, Phf5a, Klf6, Lmx1b, and Pax3. Additionally, lncRNA-target-TFs network analysis indicated the GATA6, Junb, Smad1, Twist1, and Mafb mostly regulate the same lncRNAs: XR_001783430.1 and NR_051982.1. Furthermore, 480 miRNAs were predicted binding to 4 identified circRNAs. The BM25 may affect AD by regulating the expression of lncRNAs and circRNAs, which could regulate the expressions of mRNAs or miRNAs by LncRNA-Target-TFs network.

Astragalus polysaccharide promotes autophagy and alleviates diabetic nephropathy by targeting the lncRNA Gm41268/PRLR pathway

Background Astragalus polysaccharide (APS) is a major bioactive component of the Chinese herb astragalus, with well-established protective effects on the kidney. However, the effect of APS on diabetic nephropathy (DN) is unclear. Methods Long non-coding RNA (lncRNA) expression profiles in kidney samples from control, db/db, and APS-treated db/db mice were evaluated using RNA high-throughput sequencing techniques. Additionally, rat renal tubular epithelial (NRK-52E) cells were cultured in high glucose (HG) media. We inhibited the expression of Gm41268 and prolactin receptor (PRLR) by transfecting NRK-52E cells with Gm41268-targeting antisense oligonucleotides and PRLR siRNA. Results We found that APS treatment reduced 24-h urinary protein levels and fasting blood glucose and improved glucose intolerance and pathological renal damage in db/db mice. Furthermore, APS treatment enhanced autophagy and alleviated fibrosis in the db/db mice. We identified a novel lncRNA, Gm41268, which was differentially expressed in the three groups, and the cis-regulatory target gene PRLR. APS treatment induced autophagy by reducing p62 and p-mammalian target of rapamycin (mTOR) protein levels and increasing the LC3 II/I ratio. Furthermore, APS alleviated fibrosis by downregulating fibronectin (FN), transforming growth factor-β (TGF-β), and collagen IV levels. In addition, APS reversed the HG-induced overexpression of Gm41268 and PRLR. Reduction of Gm41268 decreased PRLR expression, restored autophagy, and ameliorated renal fibrosis in vitro. Inhibition of PRLR could enhance the protective effect of APS. Conclusions In summary, we demonstrated that the therapeutic effect of APS on DN is mediated via the Gm41268/PRLR pathway. This information contributes to the exploration of bioactive constituents in Chinese herbs as potential treatments for DN.

Differential Expression of miRNAs, lncRNAs, and circRNAs between Ovaries and Testes in Common Carp (Cyprinus carpio).

Female common carp grow faster than male individuals, implying that rearing females could be more profitable in aquaculture. Non-coding RNAs (ncRNAs) serve as versatile regulators with multiple functions in diverse biological processes. However, the roles of ncRNAs in the sex differentiation of common carp are less studied. In this study, we investigated the expression profiles of ncRNAs, including miRNAs, lncRNAs, and circRNAs, in the gonads to comprehend the roles of ncRNAs in sex differentiation in common carp. A substantial number of differentially expressed (DE) ncRNAs in ovaries and testes were identified. Some miRNAs, notably miR-205, miR-214, and miR-460-5p, might modulate hormone synthesis and thus maintain sex. A novel miRNA, novel_158, was predicted to suppress the expression of foxl3. DE lncRNAs were associated with oocyte meiosis, GnRH signaling pathways, and steroid biosynthesis, while DE circRNA target genes were enriched in the WNT signaling pathway and MAPK signaling pathway. We also analyzed ncRNA-mRNA interactions to shed light on the crosstalk between competing endogenous RNAs (ceRNAs), which is the critical mechanism by which lncRNAs and circRNAs function. Some lncRNAs and circRNAs may be able to competitively bind novel_313, a new miRNA, and thus regulate hsd17β3. Our research will provide a valuable resource for understanding the genetic basis of gonadal differentiation and development in common carp.

Rotavirus-induced lncRNA SLC7A11-AS1 promotes ferroptosis by targeting cystine/glutamate antiporter xCT (SLC7A11) to facilitate virus infection

Rotavirus (RV) is the primary etiological agent of virus-associated gastroenteritis in infants, causing 200,000 childhood death annually. Despite the availability of vaccines, rotaviral diarrhea continues to be a severe issue in underdeveloped nations in Asia and Africa. The situation demands continual studies on host-rotavirus interactions to understand disease pathogenesis and develop effective antiviral therapeutics. Long non-coding RNAs (lncRNAs), which are a subset of non-coding RNAs of more than 200 nucleotides in length, are reported to play a regulatory function in numerous viral infections. Virus infection often alters the host transcriptome including lncRNA that are differentially expressed either to play an antiviral role or to be advantageous towards virus propagation. In the current study, qPCR array-based expression profiling of host lncRNAs was performed in rotavirus-infected HT-29 cells that identified the lncRNA SLC7A11-AS1 to be upregulated during RV infection. Knockdown of SLC7A11-AS1 conspicuously reduced RV titers implying its pro-viral significance. RV-induced SLC7A11-AS1 downregulates the gene SLC7A11/xCT that encodes the light chain subunit of the system XC− cystine-glutamate exchange transporter, leading to decrease in intracellular glutathione level and increase in lipid peroxidation, which are signature features of ferroptotic pathway. Ectopic expression of xCT also abrogated RV infection by reversing the virus optimized levels of intracellular GSH and lipid ROS levels. Cumulatively, the study reveals that RV infection triggers ferroptotic cell death via SLC7A11-AS1/xCT axis to facilitate its own propagation.

A microRNA sponge, LINC02193, promotes neutrophil activation by upregulating ICAM1 and is correlated with ANCA-associated vasculitis.

To investigate the pathogenic role and underlying mechanisms of long noncoding RNAs (lncRNAs) in ANCA-associated vasculitis (AAV). RNA-sequencing (RNA-seq) was applied to screen the expression profile of lncRNAs in peripheral leukocytes from five AAV patients and five healthy controls (HC). Candidate lncRNAs were preliminarily verified in peripheral leukocytes from 46 AAV patients and 35 HC by qRT-PCR. Then, the identified LINC02193 was further validated in peripheral neutrophils from 67 AAV patients, 45 HC and 64 disease controls. Correlation between LINC02193 levels and disease activity was analysed. Then, a loss-of-function study was conducted to investigate the role of LINC02193 in neutrophils activation. Furthermore, bioinformatics analysis, dual luciferase reporter and RNA immunoprecipitation assays were performed to explore the mechanism of LINC02193 regulating neutrophils activation. A total of 467 upregulated and 412 downregulated lncRNAs were identified in AAV patients. From the top five upregulated lncRNAs, an elevation of LINC02193 was validated in a larger sample of AAV patients, and positively correlated with disease activity. Knockdown of LINC02193 inhibited reactive oxygen species and nitric oxide production, neutrophil extracellular traps release and adhesion to endothelial cells of differentiated human promyelocytic leukaemia HL-60 cells, whereas overexpression of ICAM1 counteracted these effects. Mechanistic analysis demonstrated that LINC02193 acted as an miR-485-5p sponge to relieve the repressive effect of miR-485-5p on ICAM1, thus promoting ICAM1 expression. LINC02193, a novel lncRNA identified in AAV, could function as competing endogenous RNAs for miR-485-5p to promote ICAM1 expression and neutrophils activation, suggesting its potential as a therapeutic target of AAV.