Development of m6A/m5C/m1A regulated lncRNA signature for prognostic prediction, personalized immune intervention and drug selection in LUAD.

Research indicates that there are links between m6A, m5C and m1A modifications and the development of different types of tumours. However, it is not yet clear if these modifications are involved in the prognosis of LUAD. The TCGA-LUAD dataset was used as for signature training, while the validation cohort was created by amalgamating publicly accessible GEO datasets including GSE29013, GSE30219, GSE31210, GSE37745 and GSE50081. The study focused on 33 genes that are regulated by m6A, m5C or m1A (mRG), which were used to form mRGs clusters and clusters of mRG differentially expressed genes clusters (mRG-DEG clusters). Our subsequent LASSO regression analysis trained the signature of m6A/m5C/m1A-related lncRNA (mRLncSig) using lncRNAs that exhibited differential expression among mRG-DEG clusters and had prognostic value. The model's accuracy underwent validation via Kaplan-Meier analysis, Cox regression, ROC analysis, tAUC evaluation, PCA examination and nomogram predictor validation. In evaluating the immunotherapeutic potential of the signature, we employed multiple bioinformatics algorithms and concepts through various analyses. These included seven newly developed immunoinformatic algorithms, as well as evaluations of TMB, TIDE and immune checkpoints. Additionally, we identified and validated promising agents that target the high-risk mRLncSig in LUAD. To validate the real-world expression pattern of mRLncSig, real-time PCR was carried out on human LUAD tissues. The signature's ability to perform in pan-cancer settings was also evaluated. The study created a 10-lncRNA signature, mRLncSig, which was validated to have prognostic power in the validation cohort. Real-time PCR was applied to verify the actual manifestation of each gene in the signature in the real world. Our immunotherapy analysis revealed an association between mRLncSig and immune status. mRLncSig was found to be closely linked to several checkpoints, such as IL10, IL2, CD40LG, SELP, BTLA and CD28, which could be appropriate immunotherapy targets for LUAD. Among the high-risk patients, our study identified 12 candidate drugs and verified gemcitabine as the most significant one that could target our signature and be effective in treating LUAD. Additionally, we discovered that some of the lncRNAs in mRLncSig could play a crucial role in certain cancer types, and thus, may require further attention in future studies. According to the findings of this study, the use of mRLncSig has the potential to aid in forecasting the prognosis of LUAD and could serve as a potential target for immunotherapy. Moreover, our signature may assist in identifying targets and therapeutic agents more effectively.

LncRNAs involvement in pathogenesis of immune-related disease via regulation of T regulatory cells, an updated review.

The pathophysiology of several illnesses, including cancer and autoimmune diseasesdepends on human regulatory T cells (Tregs), and abnormalities in these cells may function as triggers for these conditions. Cancer and autoimmune, and gynecological diseases are associated with the differentiation of the proinflammatory T cell subset TH17 and its balance with the production of Treg. Recently, long non-coding RNAs (lncRNAs) have become important regulatory molecules in a wide range of illnesses. During epigenetic regulation, they can control the expression of important genes at several levels by affecting transcription, post-transcriptional actions, translation, and protein modification. They might connect with different molecules, such as proteins, DNA and RNA, and their structural composition is intricate. Because lncRNAs regulatebiological processes, including cell division, death, and growth, they are linked to severaldiseases. A notable instance of this is the lncRNA NEAT1, which has been the subject of several investigations to ascertain its function in immune cell development. In the context of immune cell development, several additional lncRNAs have been connected to Treg cell differentiation. In this work, we summarize current findings about the diverse functions of lncRNAs in Treg cell differentiation and control of the Th17/Treg homeostasis in autoimmune disorders, cancers, as well as several gynecological diseases where Tregs are key players.

Knockdown of NEAT1 restricts dengue virus replication by augmenting interferon alpha-inducible protein 27 via the RIG-I pathway.

The lncRNA NEAT1 plays a vital role in mitochondrial function and antiviral response. We have previously identified NEAT1 as dysregulated lncRNAs and found an inverse correlation with interferon alpha-inducible protein 27 (IFI27) expression associated with developing dengue severity. However, the role of NEAT1 in dengue virus (DV) infection remains elusive. Here, we undertook a study to evaluate the functional consequences of NEAT1 and IFI27 modulation on antiviral response and viral replication in dengue infection. We observed that the knockdown of NEAT1 augmented IFI27 expression and antiviral response via the RIG-I pathway. Increased antiviral response leads to a decrease in dengue viral replication. Further study suggested that the knockdown of IFI27 augmented expression of the activating transcription factor 3 (ATF3), a negative regulator of antiviral response, and increased dengue virus replication suggesting an important role played by IFI27 in mediating antiviral response. RNA sequencing study confirmed several mitochondrial genes significantly altered upon knockdown of NEAT1 in DV-infected cells. We further verified the effect of NEAT1 knockdown on mitochondrial functions. We observed a reduced level of phospho-DRP1(S616) expression along with elongated mitochondria in DV2-infected cells. Further, NEAT1 knockdown or ectopic expression of IFI27 increased mitochondrial ROS production and cell death via activation of caspase 3. Our study points to the crucial role of NEAT1 and IFI27 in mediating antiviral response and mitochondrial dysfunction in dengue infection.

Clinical Value and Mechanism of Long Non-Coding RNA UCA1 in Acute Respiratory Distress Syndrome Induced by Cardiopulmonary Bypass.

AIM: Long non-coding RNA (lncRNA) can be used as a biological marker for the diagnosis and treatment of various diseases. The study aimed to detect changes in the expression of lncRNA for urothelial carcinoma associated 1 (UCA1) in patients with cardiopulmonary bypass (CPB)-induced acute respiratory distress syndrome (ARDS). Clinical values and cell function in ARDS were explored. METHOD: In total, 195 patients without CPB-induced ARDS were included in the control group, and 85 patients with ARDS were included in the ARDS group. Serum UCA1 levels were measured by quantitative real-time polymerase chain reaction. A549 was used for the cell experiments by establishing oxygen-glucose deprivation/reperfusion (OGD/R) cell models, and the cell viability and apoptosis were tested. The concentration of inflammatory factors was tested by an enzyme-linked immunosorbent assay. A luciferase reporting assay was applied for target gene analysis. RESULTS: Quantitative real-time polymerase chain reaction revealed a gradual increase in serum UCA1 in both control and ARDS cases, and patients with ARDS had higher levels of UCA1 than those in the control group. Serum UCA1 was positively correlated with serum tumour necrosis factor-α and interleukin-6 concentration in patients with ARDS. UCA1 had the ability to distinguish patients with ARDS from those without it. UCA1 inhibition protected against lung injury and inhibited cell inflammation in vitro. MicroRNA (miR-182-5p) was downregulated in OGD/R-induced cell models and sponged by UCA1. CONCLUSIONS: Elevated expression of UCA1 may be associated with the occurrence of ARDS after CPB surgery. The regulatory role of UCA1 in ARDS might be related to inflammation and downregulated miR-182-5p in alveolar epithelial cells.

tRNA-like Transcripts from the NEAT1-MALAT1 Genomic Region Critically Influence Human Innate Immunity and Macrophage Functions.

The evolutionary conserved NEAT1-MALAT1 gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found NEAT1-/- and MALAT1-/- mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell-cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their NEAT1-MALAT1 region of origin appears as archetype of a functionally highly integrated RNA processing system.

LncRNA IL21-AS1 interacts with hnRNPU protein to promote IL21 overexpression and aberrant differentiation of Tfh cells in systemic lupus erythematosus.

BACKGROUND: The aberrant differentiation of T follicular helper (Tfh) cells plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of regulating Tfh cells differentiation remains unclear. Long noncoding RNAs (lncRNAs) act as important regulators in the processes of innate and adaptive immune response. Whether lncRNAs are involved in regulating Tfh cell differentiation and autoimmune responses need to be further identified. METHODS: The characters and functions of human IL21-AS1 and its mouse homologous lncRNA (mIl21-AS) were investigated by a series of biochemical assays and cell transfection assay. mIl21-AS1 regulating humoral immune response in vivo was explored by keyhole limpet haemocyanin (KLH) and chronic graft versus host disease (cGVHD) model. RESULTS: Human IL21-AS1 and its mouse homologous lncRNA (mIl21-AS) were identified and cloned. We uncovered that IL21-AS1 was highly expressed in CD4+ T cells of SLE patients and Tfh cells, which promoted differentiation of Tfh cells. Mechanistically, IL21-AS1 bound heterogeneous nuclear ribonucleoprotein U and recruited acetyltransferases CREB-binding protein to the promoter of IL21, leading to the transcriptional activation of IL21 and Tfh cells differentiation through increasing Histone H3 acetylation level on IL21 promoter. Moreover, Tfh proportion and antibodies production were significantly increased in mIl21-AS knock-in mice immunized with KLH. mIl21-AS1 overexpression also exacerbated the lupus-like phenotype in cGVHD mice model. CONCLUSIONS: Our results demonstrate that IL21-AS1 activates IL21 transcription via epigenetic mechanism to promote germinal centre response, adding insight into the molecular regulation of autoimmune pathogenesis and providing a novel target for SLE treatment.

Long noncoding RNA uc.230/CUG-binding protein 1 axis sustains intestinal epithelial homeostasis and response to tissue injury.

Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.

Downregulation of LEMD1-AS1 and Its Influences on the Diagnosis, Prognosis, and Immune Infiltrates of Epithelial Ovarian Cancer.

Previous studies have confirmed long noncoding RNA LEMD1-AS1 (LEMD1-AS1) as a functional factor in several tumors. The present work is aimed at exploring the prognostic and diagnostic values of LEMD1-AS1 in patients with epithelial ovarian cancer (EOC). We examined the expressions of LEMD1-AS1 in pan-cancer from TCGA microarray datasets and GTEx Project. The expressions of LEMD1-AS1 were detected by qRT-PCR in EOC specimens and normal ovarian specimens from 30 EOC patients. The χ 2 test was applied to compare the clinicopathological characteristics of different groups. ROC curves were established to determine the diagnostic values of LEMD1-AS1 in screening EOC tissues. The association of LEMD1-AS1 expression with clinical outcome was determined by the Kaplan-Meier methods and COX assays. A decreased expression of LEMD1-AS1 was observed in EOC tissues compared to matched normal specimens (p < 0.01). Low LEMD1-AS1 expression could be used to distinguish EOC from adjacent normal specimens. A clinical study revealed that patients with low LEMD1-AS1 expression have a shorter overall survival (p = 0.035) and progress-free interval (p = 0.041) than those with high LEMD1-AS1 expression. The Spearman correlation test revealed that LEMD1-AS1 expressions were negatively associated with the expressions of neutrophil and myeloid dendritic cell. Overall, our finding suggested that LEMD1-AS1 may have potential roles as a potential biomarker and/or a therapeutic target in EOC.

Whole-transcriptome analysis of periodontal tissue and construction of immune-related competitive endogenous RNA network.

BACKGROUND: In periodontitis, noncoding RNAs may play a regulatory role in the immune microenvironment through competitive endogenous RNA. We aimed to profile noncoding RNA expression and construct immune-related ceRNA network in periodontitis. METHODS: Five inflamed periodontal tissue and five healthy gingivae were collected for whole-transcriptome sequencing. Differential gene, functional enrichment, and protein-protein interaction network analysis were performed to explore the function of differentially expressed genes. CIBERSORTx was used to analyze level of immune cell infiltration in the periodontal tissue. An immune-related competitive endogenous RNA network was constructed and expression of key regulators in the network was validated. RESULTS: Compared with healthy gingiva, 200 mRNAs, 90 long noncoding RNAs, 65 microRNAs, and 518 circular RNAs were differentially expressed, and cell chemotaxis was significantly enhanced in inflamed periodontal tissue. Immune cell infiltration analysis showed that neutrophils, macrophages M1, T follicular helper cells, and naive B cells were significantly increased in periodontitis. Key regulators including JUN, FOS, THBS1, KLF2, WIF1, were identified and their expression was then validated. CONCLUSION: We constructed an immune-related competitive endogenous RNA network in periodontal tissue, which provided new insights into immune homeostasis in periodontitis and laid a foundation for further study of noncoding RNAs. Key regulators in this network may be promising targets for future periodontitis treatment.

An Integrative Analysis Revealing ZFHX4-AS1 as a Novel Prognostic Biomarker Correlated with Immune Infiltrates in Ovarian Cancer.

Ovarian cancer (OC) is the main cause of deaths worldwide in female reproductive system malignancies. Growing studies have indicated that eRNAs could regulate cellular activities in various tumors. Yet the potential roles of eRNAs in OC progression have not been elucidated. Thus, comprehensive assays were needed to screen the critical eRNAs and to explore their possible function in OC. We used Kaplan-Meier methods to identify survival-associated eRNAs in OC based on TCGA datasets. The levels of ZFHX4-AS1 were examined using TCGA datasets. Further exploration was carried out based on the following assays: clinical and survival assays, GO terms, and KEGG assays. TIMER was applied to delve into the relationships between ZFHX4-AS1 and tumor immune infiltration. In this research, we observed 71 survival-related eRNAs in OC patients. ZFHX4-AS1 was highly expressed in OC specimens and predicted a poor prognosis of OC patients. In addition, high ZFHX4-AS1 expression was positively related to the advanced stages of OC specimens. Multivariate assays revealed that ZFHX4-AS1 was an independent prognostic factor for overall survival of OC patients. KEGG analysis indicated that ZFHX4-AS1 may play a regulatory effect on TGF-beta signaling, PI3K-Akt signaling, and proteoglycans in cancer. The pan-cancer validation indicated that ZFHX4-AS1 was related to survival in eight tumors, namely, UCEC, STAD, SARC, OV, ACC, KICH, KIRC, and BLCA. The expression of ZFHX4-AS1 was correlated with the levels of B cells, T cell CD8+, neutrophil, macrophage, and myeloid dendritic cells. Simultaneously, ZFHX4-AS1 may be a prognostic biomarker and a distinctly immunotherapy-related eRNA in OC.

lncRNA FR215775 Regulates Th2 Differentiation in Murine Allergic Rhinitis.

To identify the effect of long noncoding RNA (lncRNA) FR215775 in regulating CD4+ T cells on murine models of allergic rhinitis (AR), the expression of lncRNA FR215775 in primary Th2 cells was detected through qRT-PCR. After knocking down the expression of lncRNA FR215775 via Sh-FR215775-Ads, Cell Counting Kit-8, cytometric bead array, and fluorescence-activated cell sorting were performed to determine its functions in vitro. Moreover, lncRNA FR215775-silencing or nonsilencing cells were injected intravenously into AR mice. Then, hematoxylin and eosin, Alcian blue-periodic acid Schiff, and toluidine blue staining were performed, and the levels of IL-2, IL-4, IL-5, IL-6, IL-10, IL-17A, IFN-γ, and TNF in the AR mice were also determined. We found that the expression of lncRNA FR215775 was specifically higher in the murine primary Th2 cells. After the knockdown of lncRNA FR215775, the proliferation of CD4+ T cells was inhibited, and the expressions of IL-4 and IL-5 in the cell culture supernatant were significantly decreased (P < 0.001), along with the percentage of Th2 cells (P < 0.05). The lncRNA FR215775-silencing AR group showed less serious allergic symptoms and a low level of ovalbumin-specific immunoglobulin E (P < 0.01). Meanwhile, the eosinophilia inflammation, goblet cell hyperplasia, and mast cell inflammation in the nasal mucosa all decreased, which indicated attenuated allergic inflammation in the lncRNA FR215775-silencing AR group. In addition, the Th2-related cytokines IL-4 and IL-5 were downregulated in the serum and nasal lavage fluid of this group (P < 0.01). In conclusion, lncRNA FR215775 may play a vital role in the function and differentiation of Th2 cells, which may encourage allergic inflammation. These results may provide significant insights into AR pathogenesis and offer new treatment targets for alleviating AR.

Interaction of lncRNA-CR33942 with Dif/Dorsal Facilitates Antimicrobial Peptide Transcriptions and Enhances Drosophila Toll Immune Responses.

The Drosophila Toll signaling pathway mainly responds to Gram-positive (G+) bacteria or fungal infection, which is highly conserved with mammalian TLR signaling pathway. Although many positive and negative regulators involved in the immune response of the Toll pathway have been identified in Drosophila, the roles of long noncoding RNAs (lncRNAs) in Drosophila Toll immune responses are poorly understood to date. In this study, our results demonstrate that lncRNA-CR33942 is mainly expressed in the nucleus and upregulated after Micrococcus luteus infection. Especially, lncRNA-CR33942 not only modulates differential expressions of multiple antimicrobial peptide genes but also affects the Drosophila survival rate during response to G+ bacterial infection based on the transiently overexpressing and the knockdown lncRNA-CR33942 assays in vivo. Mechanically, lncRNA-CR33942 interacts with the NF-κB transcription factors Dorsal-related immunity factor/Dorsal to promote the transcriptions of antimicrobial peptides drosomycin and metchnikowin, thus enhancing Drosophila Toll immune responses. Taken together, this study identifies lncRNA-CR33942 as a positive regulator of Drosophila innate immune response to G+ bacterial infection to facilitate Toll signaling via interacting with Dorsal-related immunity factor/Dorsal. It would be helpful to reveal the roles of lncRNAs in Toll immune response in Drosophila and provide insights into animal innate immunity.

Involvement of blood lncRNA UCA1 in sepsis development and prognosis, and its correlation with multiple inflammatory cytokines.

BACKGROUND: Sepsis is a highly life-threatening disease. Long non-coding RNA urothelial carcinoma associated 1 (lncRNA UCA1) participates in the processes of inflammation and organ injury in several diseases, whereas its role in sepsis patients is still unclear. The aim was to explore the clinical value of lncRNA UCA1 in sepsis patients. METHODS: One hundred seventy-four sepsis patients and 100 age and gender-matched controls were enrolled. LncRNA UCA1 in peripheral blood mononuclear cell samples was examined, and the level of inflammatory cytokines in serum samples was assessed. RESULTS: LncRNA UCA1 was highly expressed in sepsis patients compared with controls. LncRNA UCA1 was positively correlated with tumor necrosis factor-α, interleukin (IL)-6, IL-17, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in sepsis patients, while it was not correlated with these inflammatory cytokines in controls. lncRNA UCA1 upregulation was related to raised APACHE II score and SOFA score in sepsis patients. Moreover, lncRNA UCA1 was increased in sepsis deaths compared with sepsis survivors and was independently correlated with increased 28-day sepsis mortality risk. Further receiver operating characteristic curves presented that lncRNA UCA1 had a good value to predict 28-motality risk, while its combination with other independent factors (including age, history of chronic kidney disease, G+ bacterial infection, Fungus infection, C-reactive protein, and APACHE II score) exerted a great predictive value for 28-day mortality risk. CONCLUSION: LncRNA UCA1 is upregulated and correlates with multiple pro-inflammatory cytokines, terrible disease severity, and poor prognosis in sepsis patients.

The correlation of lncRNA SNHG16 with inflammatory cytokines, adhesion molecules, disease severity, and prognosis in acute ischemic stroke patients.

BACKGROUND: Long non-coding RNA small nucleolar RNA host gene 16 (lncRNA SNHG16) is involved in the pathogenesis of acute ischemic stroke (AIS) through the regulation of brain endothelial cell viability, inflammation, atherosclerotic plaque formation, and neural apoptosis. This study aimed to evaluate the prognostic value of lncRNA SNHG16 in AIS patients. METHODS: Newly diagnosed AIS patients (N = 120) were serially recruited. Their lncRNA SNHG16 expressions in peripheral blood mononuclear cells (PBMCs) were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR); serum inflammatory cytokines and adhesion molecules were determined using enzyme-linked immunosorbent assay (ELISA). The accumulating recurrence-free survival (RFS) and overall survival (OS) were analyzed. Moreover, controls (N = 60) were recruited and their lncRNA SNHG16 expressions in PBMCs were detected. RESULTS: LncRNA SNHG16 was declined in AIS patients compared to controls (p < 0.001). Moreover, lncRNA SNHG16 was not related to any comorbidities in AIS patients (all p > 0.05). Interestingly, lncRNA SNHG16 was negatively related to tumor necrosis factor alpha (TNF-α) (p < 0.001), interleukin 6 (IL-6) (p = 0.013), and intracellular cell adhesion molecule-1 (ICAM-1) (p = 0.024), while positively correlated with interleukin 10 (IL-10) (p = 0.022) in AIS patients. Besides, lncRNA SNHG16 was inversely associated with the National Institutes of Health Stroke Scale (NIHSS) score in AIS patients (p = 0.003). During the follow-up period, in 14 (11.7%) patients occurred recurrence and 5 (4.2%) patients died. Unexpectedly, lncRNA SNHG16 was not associated with accumulating RFS (p = 0.103) or OS (p = 0.150) in AIS patients. CONCLUSION: LncRNA SNHG16 relates to lower inflammatory cytokines, adhesion molecules, and milder disease severity, but fails to predict prognosis in AIS patients.

LncRNA GAS5 relates to Th17 cells and serves as a potential biomarker for sepsis inflammation, organ dysfunctions and mortality risk.

BACKGROUND: Long noncoding RNA GAS5 (lnc-GAS5) is able to regulate macrophage M1 polarization and Th17 cell differentiation, also engaged in sepsis-induced inflammation and organ injury. This study aimed to further evaluate its linkage with Th1 cells and Th17 cells, as well as its clinical value in sepsis management. METHODS: About 101 sepsis patients were enrolled followed by peripheral blood mononuclear cell (PBMC) and serum samples collection. PBMC lnc-GAS5 was detected by RT-qPCR; Th1 cells and Th17 cells in PBMC CD4+ T cells were detected by flow cytometry; serum IFN-γ and IL-17A were detected by ELISA. Besides, PBMC lnc-GAS5 was also detected in 50 health controls (HCs). RESULTS: Lnc-GAS5 was reduced in sepsis patients than in HCs (p < 0.001), which also well-distinguished sepsis patients from HCs with AUC 0.860. Lnc-GAS5 did not relate to Th1 cells (p = 0.059) or IFN-γ (p = 0.192); while negatively linked with Th17 cells (p = 0.002) and IL-17A (p = 0.019) in sepsis patients. Interestingly, lnc-GAS5 negatively correlated with SOFA score (p = 0.001), SOFA-Respiratory system score (p = 0.001), SOFA-Coagulation score (p = 0.015), and SOFA-Renal system score (p = 0.026), but not SOFA-Liver score (p = 0.080), SOFA-Cardiovascular system score (p = 0.207) or SOFA-Nervous system score (p = 0.182) in sepsis patients. Furthermore, lnc-GAS5 was negatively related to CRP (p = 0.002) and APACHE II score (p = 0.004) in sepsis patients. Finally, lnc-GAS5 was decreased in dead sepsis patients compared to survivors (p = 0.007), which also distinguished sepsis deaths from survivors with AUC 0.713. CONCLUSION: Lnc-GAS5 relates to Th17 cells and serves as a potential biomarker for sepsis severity and mortality risk.

Competitive Endogenous RNA Network Activates Host Immune Response in SARS-CoV-2-, panH1N1 (A/California/07/2009)-, and H7N9 (A/Shanghai/1/2013)-Infected Cells.

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing, as is research on the molecular mechanisms underlying cellular infection by coronaviruses, with the hope of developing therapeutic agents against this pandemic. Other important respiratory viruses such as 2009 pandemic H1N1 and H7N9 avian influenza virus (AIV), influenza A viruses, are also responsible for a possible outbreak due to their respiratory susceptibility. However, the interaction of these viruses with host cells and the regulation of post-transcriptional genes remains unclear. In this study, we detected and analyzed the comparative transcriptome profiling of SARS-CoV-2, panH1N1 (A/California/07/2009), and H7N9 (A/Shanghai/1/2013) infected cells. The results showed that the commonly upregulated genes among the three groups were mainly involved in autophagy, pertussis, and tuberculosis, which indicated that autophagy plays an important role in viral pathogenicity. There are three groups of commonly downregulated genes involved in metabolic pathways. Notably, unlike panH1N1 and H7N9, SARS-CoV-2 infection can inhibit the m-TOR pathway and activate the p53 signaling pathway, which may be responsible for unique autophagy induction and cell apoptosis. Particularly, upregulated expression of IRF1 was found in SARS-CoV-2, panH1N1, and H7N9 infection. Further analysis showed SARS-CoV-2, panH1N1, and H7N9 infection-induced upregulation of lncRNA-34087.27 could serve as a competitive endogenous RNA to stabilize IRF1 mRNA by competitively binding with miR-302b-3p. This study provides new insights into the molecular mechanisms of influenza A virus and SARS-CoV-2 infection.

MALAT-1/p53/miR-155/miR-146a ceRNA circuit tuned by methoxylated quercitin glycoside alters immunogenic and oncogenic profiles of breast cancer.

Triple-Negative Breast Cancer (TNBC) is one of the most aggressive and hot BC subtypes. Our research group has recently shed the light on the utility of natural compounds as effective immunotherapeutic agents. The aim of this study is to investigate the role of a methoxylated quercetin glycoside (MQG) isolated from Cleome droserifolia in harnessing TNBC progression and tuning the tumor microenvironment and natural killer cells cytotoxicity. Results showed that MQG showed the highest potency (IC50 = 12 µM) in repressing cellular proliferation, colony-forming ability, migration, and invasion capacities. Mechanistically, MQG was found to modulate a circuit of competing endogenous RNAs where it was found to reduce the oncogenic MALAT-1 lncRNA and induce TP53 and its downstream miRNAs; miR-155 and miR-146a. Accordingly, this leads to alteration in several downstream signaling pathways such as nitric oxide synthesizing machinery, natural killer cells' cytotoxicity through inducing the expression of its activating ligands such as MICA/B, ULBP2, CD155, and ICAM-1 and trimming of the immune-suppressive cytokines such as TNF-α and IL-10. In conclusion, this study shows that MQG act as a compelling anti-cancer agent repressing TNBC hallmarks, activating immune cell recognition, and alleviating the immune-suppressive tumor microenvironment experienced by TNBC patients.

The long noncoding RNA MIR122HG is a precursor for miR-122-5p and negatively regulates the TAK1-induced innate immune response in teleost fish.

Long noncoding RNAs (lncRNAs) are a diverse subset of RNA species of noncoding transcripts that are usually longer than 200 nt. However, the biological role and function of many lncRNAs have not been fully identified. It has been shown that one potential function of lncRNAs is to act as a precursor miRNA and promote the production of multiple miRNAs. However, the function of the miiuy croaker lncRNA MIR122HG has not been explored. In the present study, we show that this differentially expressed teleost fish lncRNA can act as the host gene of miR-122-5p, regulate its expression, and indirectly regulate the expression of potential inflammatory target protein transforming growth factor-ß-activated kinase 1. We show that MIR122HG can negatively regulate the transforming growth factor-ß-activated kinase 1-triggered NF-κB and interferon regulatory factor 3 signaling pathways and subsequently attenuate the innate immune response. In addition, MIR122HG can promote the replication of Siniperca chuatsi rhabdovirus and exacerbate the pathological effects caused by viral infection. We conclude that the study of lncRNA-miRNA-mRNA interaction through bioinformatics analysis or experimental-supported analysis can provide information for further elucidation of the functions of fish lncRNAs in innate immunity.

A prognostic model based on immune-related long noncoding RNAs for patients with epithelial ovarian cancer.

BACKGROUND: Long noncoding RNAs (lncRNAs) are important regulators of gene expression and can affect a variety of physiological processes. Recent studies have shown that immune-related lncRNAs play an important role in the tumour immune microenvironment and may have potential application value in the treatment and prognosis prediction of tumour patients. Epithelial ovarian cancer (EOC) is characterized by a high incidence and poor prognosis. However, there are few studies on immune-related lncRNAs in EOC. In this study, we focused on immune-related lncRNAs associated with survival in EOC. METHODS: We downloaded mRNA data for EOC patients from The Cancer Genome Atlas (TCGA) database and mRNA data for normal ovarian tissue from the Genotype-Tissue Expression (GTEx) database and identified differentially expressed genes through differential expression analysis. Immune-related lncRNAs were obtained through intersection and coexpression analysis of differential genes and immune-related genes from the Immunology Database and Analysis Portal (ImmPort). Samples in the TCGA EOC cohort were randomly divided into a training set, validation set and combination set. In the training set, Cox regression analysis and LASSO regression were performed to construct an immune-related lncRNA signature. Kaplan-Meier survival analysis, time-dependent ROC curve analysis, Cox regression analysis and principal component analysis were performed for verification in the training set, validation set and combination set. Further studies of pathways and immune cell infiltration were conducted through Gene Set Enrichment Analysis (GSEA) and the Timer data portal. RESULTS: An immune-related lncRNA signature was identified in EOC, which was composed of six immune-related lncRNAs (KRT7-AS, USP30-AS1, AC011445.1, AP005205.2, DNM3OS and AC027348.1). The signature was used to divide patients into high-risk and low-risk groups. The overall survival of the high-risk group was lower than that of the low-risk group and was verified to be robust in both the validation set and the combination set. The signature was confirmed to be an independent prognostic biomarker. Principal component analysis showed the different distribution patterns of high-risk and low-risk groups. This signature may be related to immune cell infiltration (mainly macrophages) and differential expression of immune checkpoint-related molecules (PD-1, PDL1, etc.). CONCLUSIONS: We identified and established a prognostic signature of immune-related lncRNAs in EOC, which will be of great value in predicting the prognosis of clinical patients and may provide a new perspective for immunological research and individualized treatment in EOC.

Constructing a Novel Signature Based on Immune-Related lncRNA to Improve Prognosis Prediction of Cervical Squamous Cell Carcinoma Patients.

We downloaded gene expression data, clinical data, and somatic mutation data of cervical squamous cell carcinoma (CSCC) patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Predictive lncRNAs were screened using univariate analysis and least absolute shrinkage and selection operator (LASSO) regression, and risk scores were calculated for each patient according to the expression levels of lncRNAs and regression coefficients to establish a risk model that could be a novel signature. We assessed the correlation between immune infiltration status, chemotherapeutics sensitivity, immune checkpoint proteins (ICP), and the signature. Therefore, we selected 11 immune-related lncRNAs (WWC2,AS2, STXBP5.AS1, ERICH6.AS1, USP30.AS1, LINC02073, RBAKDN, IL21R.AS1, LINC02078, DLEU1, LINC00426, BOLA3.AS1) to construct the risk model. Patients who were in the high-risk group had a shorter survival time than those in the low-risk group (p < 0.001). Risk scores in the signature were negatively correlated with macrophage M1, macrophage M2, and T cell CD8 + ; what's more, T cell CD8 + was higher in the low-risk group. The expression levels of ICP such as PD-L1, PD-1, CTLA-4, TIGIT, LAG-3, and TIM-3 were substantially higher in the low-risk group. For chemotherapeutic agents, high-risk scores were associated with higher half-inhibitory concentrations (IC50) of cisplatin. These findings suggested that the risk model can be a novel signature for predicting CSCC patients' prognosis, and it also can be used to formulate clinical treatment plans for CSCC patients.