RNA Metastasis-associated Lung Adenocarcinoma Transcript Research Articles

Predictive value of peripheral blood leukocytes-based methylation of Long non-coding RNA MALAT1 and H19 in the chemotherapy effect and prognosis of gastric cancer

BackgroundThe predictive value of the methylation of Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and H19 promoters in peripheral blood leukocytes as a non-invasive biomarker for the chemotherapy effect and prognosis gastric cancer (GC) is unclear. MethodsThe DNA methylation of H19 and MALAT1 between chemotherapy-sensitive and non-sensitive groups and between groups with better and worse survival of GC was compared using regression analyses. Several predictive nomograms were constructed. The genetic alteration of MALAT1 and H19 and the association between gene expression and immune status in GC were also investigated using bioinformatics analysis. ResultsHigher genetic methylations in peripheral blood were noticed in GC groups with poorer survival. The constructed nomograms presented strong predictive values for the chemotherapy effect and 3-year survival of disease-free survival, progression-free survival, and overall survival, with the area under the curve as 0.838, 0.838, 0.912, and 0.925, respectively. Significant correlations between MALAT1 or H19 expression and marker genes of immune checkpoints and immune pathways were noticed. The high infiltration of macrophages in H19-high and low infiltration of CD8+ T cells in MALAT1-high groups were associated with worse survival of GC. ConclusionsMALAT1 and H19 have the potential to predict the chemotherapy response and clinical outcomes of GC.

Expression and diagnostic value of lncRNA MALAT1 and NLRP3 in lower limb atherosclerosis in diabetes

ObjectiveThis study aimed to examine the diagnostic predictive value of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1(MALAT1) and NOD-like receptor protein 3(NLRP3) expression in patients with type 2 diabetes mellitus(T2DM) and lower extremity atherosclerosis disease (LEAD).MethodsA total of 162 T2DM patients were divided into T2DM with LEAD group (T2DM + LEAD group) and T2DM alone group (T2DM group). The lncRNA MALAT1 and NLRP3 expression levels were measured in peripheral blood, and their correlation was examined. Least absolute shrinkage and selection operator (LASSO) regression model was used to screen for the best predictors of LEAD, and multivariate logistic regression was used to establish a predictive model and construct the nomogram. The effectiveness of the nomogram was assessed using the receiver operating characteristic (ROC) curve, area under the curve (AUC), calibration curve, and decision curve analysis (DCA).ResultsThe levels of the lncRNA MALAT1 and NLRP3 in the T2DM + LEAD group were significantly greater than those in the T2DM group (P <0.001), and the level of the lncRNA MALAT1 was positively correlated with that of NLRP3 (r = 0.453, P<0.001). The results of the LASSO combined with the logistic regression analysis showed that age, smoking, systolic blood pressure (SBP), NLRP3, and MALAT1 were the influencing factors of T2DM with LEAD(P<0.05). ROC curve analysis comparison: The discriminatory ability of the model (AUC = 0.898), MALAT1 (AUC = 0.804), and NLRP3 (AUC = 0.794) was greater than that of the other indicators, and the predictive value of the model was the greatest. Calibration curve: The nomogram model was consistent in predicting the occurrence of LEAD in patients with T2DM (Cindex = 0.898). Decision curve: The net benefit rates obtained from using the predictive models for clinical intervention decision-making were greater than those obtained from using the individual factors within the model.ConclusionMALAT1 and NLRP3 expression increased significantly in T2DM patients with LEAD, while revealing the correlation between MALAT1 and NLRP3. The lncRNA MALAT1 was found as a potential biomarker for T2DM with LEAD.

Expression Pattern and Prognostic Significance of the Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 in Chronic Lymphocytic Leukemia.

Dysregulated expression of the long non-coding RNA MALAT1 has been implicated in the pathogenesis and progression of a variety of cancers, including hematological malignancies, but it has been poorly investigated in chronic lymphocytic leukemia (CLL). In this study, the expression of MALAT1 was measured using a quantitative reverse-transcriptase polymerase chain reaction in the peripheral blood mononuclear cells of 114 unselected, newly diagnosed CLL patients in order to analyze its association with clinical, laboratory, and molecular patients' characteristics at diagnosis, as well as its prognostic relevance. MALAT1 was found to be upregulated in CLL patients in comparison to healthy controls, and expression levels were not related to age, leukocyte, lymphocyte and platelet count, serum β2-microglobulin, and IGHV somatic hypermutational status. On the other hand, high MALAT1 expression was associated with several favorable prognostic markers (high hemoglobin, low serum lactate dehydrogenase, earlier clinical stages, CD38-negative status), but also with unfavorable cytogenetics. Furthermore, an association between high MALAT1 levels and longer time to first treatment and overall survival in IGHV-unmutated CLL subtype was observed. In summary, our results imply that high MALAT1 expression at diagnosis may be a predictor of better prognosis and point to MALAT1 expression profiling as a candidate biomarker potentially useful in clinical practice.

Micro electrical fields induced MSC-sEVs attenuate neuronal cell apoptosis by activating autophagy via lncRNA MALAT1/miR-22-3p/SIRT1/AMPK axis in spinal cord injury

Spinal cord injury (SCI) is a traumatic condition of the central nervous system that causes paralysis of the limbs. Micro electric fields (EF) have been implicated in a novel therapeutic approach for nerve injury repair and regeneration, but the effects of human umbilical cord mesenchymal stem cell-derived small extracellular vesicles that are induced by micro electric fields (EF-sEVs) stimulation on SCI remain unknown. The aim of the present study was to investigate whether EF-sEVs have therapeutic effects a rat model of SCI. EF-sEVs and normally conditioned human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (CON-sEVs) were collected and injected intralesionally into SCI model rats to evaluate the therapeutic effects. We detect the expression of candidate long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA-MALAT1) in EF-sEVs and CON-sEVs. The targets and downstream effectors of lncRNA-MALAT1 were investigated using luciferase reporter assays. Using both in vivo and in vitro experiments, we demonstrated that EF-sEVs increased autophagy and decreased apoptosis after SCI, which promoted the recovery of motor function. We further confirmed that the neuroprotective effects of EF-sEVs in vitro and in vivo correlated with the presence of encapsulated lncRNA-MALAT1 in sEVs. lncRNA-MALAT1 targeted miR-22-3p via sponging, reducing miR-22-3p’s suppressive effects on its target, SIRT1, and this translated into AMPK phosphorylation and increased levels of the antiapoptotic protein Bcl-2. Collectively, the present study identified that the lncRNA-MALAT1 in EF-sEVs plays a neuroprotective role via the miRNA-22-3p/SIRT1/AMPK axis and offers a fresh perspective and a potential therapeutic approach using sEVs to improve SCI.

Circ-MALAT1 accelerates cell proliferation and epithelial mesenchymal transformation of colorectal cancer through regulating miR-506-3p/KAT6B axis.

Colorectal cancer (CRC) is a prevalent malignant tumor of the digestive tract. Circular RNAs may play important roles in the progression of CRC. In this study, we investigated the roles and mechanisms of action of circ-MALAT1 in CRC. Gene expression and protein abundance were determined using qRT-PCR and western blot, respectively. Cell proliferation and migration were assessed by MTT, clone formation, and wound-healing assays. The interactions among the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (circ-MALAT1), miR-506-3p, and lysine acetyltransferase 6B (KAT6B) were predicted using the StarBase software and confirmed by the luciferase activity assay. Circ-MALAT1 and KAT6B were upregulated, while miR-506-3p was downregulated in CRC cells. We validated that knocking down of circ-MALAT1 suppressed proliferation, migration, and epithelial-mesenchymal transition (EMT) of CRC cells, and these effects were abolished by miR-506-3p downregulation or KAT6B sufficiency. Our study suggests that circ-MALAT1 could sponge miR-506-3p to regulate the expression of KAT6B. Moreover, KAT6B sufficiency could neutralize miR-506-3p-dependent growth arrest, migration, and EMT. Circ-MALAT1 promotes cell proliferation, migration, and EMT of CRC cells via the miR-506-3p/KAT6B axis, thereby acting as a novel potential therapeutic target for the treatment of colorectal cancer.

Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promotes HIV-1 Replication through Modulating microRNAs in Macrophages.

Macrophages can serve as a reservoir for human immunodeficiency-1 (HIV-1) virus in host cells, constituting a barrier to eradication, even in patients who are receiving antiretroviral therapy. Although many noncoding RNAs have been characterized as regulators in HIV-1/AIDS-induced immune response and pathogenesis, only a few long noncoding RNAs (lncRNAs) have demonstrated a close association with HIV-1 replication, and the molecular mechanisms remain unknown. In this study, we investigated how lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), related microRNAs, and key inflammatory genes alter HIV-1 replication in macrophages. Our data show that HIV-1 infection modulates the expression of miR-155 and miR-150-5p in a time-dependent manner, which is regulated by MALAT1. MALAT1 induced suppressor of cytokine signaling 1 (SOCS1) expression by sponging miR-150-5p in HIV-1-infected macrophages and stimulated inflammatory mediators triggering receptor expressed on myeloid cells/cold inducible RNA binding protein (TREM 1/CIRP) ligand/receptor. The RNA immunoprecipitation (RIP) assay validated the direct interaction within the MALAT1/miR-150-5p/SOCS1 axis. HIV-1 infection-mediated upregulation of MALAT1, SOCS1, and HIV-1 Gag was attenuated by SN50 (an NF-кB p50 inhibitor). MALAT1 antisense oligonucleotides (ASOs) suppressed HIV-1 p24 production and HIV-1 Gag gene expression and decreased expression of miR-155 and SOCS1, as well as the production of proinflammatory cytokines by HIV-1-infected macrophages. In conclusion, HIV-1 infection induces MALAT1, which attenuates miR-150-5p expression and increases SOCS1 expression, promoting HIV-1 replication and reactivation. These data provide new insights into how MALAT1 alters the macrophage microenvironment and subsequently promotes viral replication and suggest a potential role for targeting MALAT1 as a therapeutic approach to eliminate HIV-1 reservoirs. IMPORTANCE Viral reservoirs constitute an obstacle to curing HIV-1 diseases, despite antiretroviral therapy. Macrophages serve as viral reservoirs in HIV infection by promoting long-term replication and latency. Recent studies have shown that lncRNAs can modulate virus-host interactions, but the underlying mechanisms are not fully understood. In this study, we demonstrate how lncRNA MALAT1 contributes to HIV-1 replication through modulation of the miR-150/SOCS1 axis in human macrophages. Our findings have the potential to identify new therapies for eliminating HIV-1 reservoirs in immune cells.

The long non-coding RNA MALAT1 regulates intestine host-microbe interactions and polyposis.

The long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) maintains the integrity of the intestinal epithelial barrier and regulates local inflammation. However, its influences on intestinal microbial communities and tissue susceptibility to cancer development remain unexplored. Here, we report that MALAT1 regulates host anti-microbial response gene expression and the composition of mucosal-associated microbial communities in a region-specific manner. In the APC mutant mouse model of intestine tumorigenesis, knocking out MALAT1 results in higher polyp counts in the small intestine and colon. Interestingly, intestine polyps that developed in the absence of MALAT1 were smaller in size. These findings highlight the unexpected bivalent role of MALAT1 in restricting and promoting cancer progression at different disease stages. Among the 30 MALAT1-targets shared by both the small intestine and colon, ZNF638 and SENP8 levels are predictive of colon adenoma patient overall survival and disease-free survival. Genomic assays further revealed that MALAT1 modulates intestinal target expression and splicing through both direct and indirect mechanisms. This study expands the role of lncRNAs in regulating intestine homeostasis, microbial communities, and cancer pathogenesis.

Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1: Epigenetic Regulation of PTEN in Mediating Vascular Smooth Muscle Cell Proliferation and Apoptosis

This study investigated the regulatory role of long non-coding RNA (lncRNA) MALAT1 in HA-VSMCs proliferation and apoptosis through mediating PTEN level. HA-VSMCs were induced with different doses of ox-LDL for various time points, and the relative level of MALAT1 was determined. MALAT1 was upregulated in a time- and dose-dependent manner. Overexpression of MALAT1 increased viability and proliferative rate, and decreased apoptotic rate of HA-VSMCs induced with 100 mg/L ox-LDL for 24 h, which was reversed by si-MALAT1 transfection. PTEN protein level was downregulated by ox-LDL induction and upregulated by si-MALAT1. MALAT1 was mainly distributed in the nucleus, and it interacted with EZH2. Silencing of MALAT1 attenuated EZH2 binding on PTEN promoter region. Knockdown of PTEN reversed the decreased proliferative ability and increased apoptotic rate in ox-LDL-induced HA-VSMCs transfected with si-MALAT1. These results indicate that MALAT1 accelerates HA-VSMCs proliferation by recruiting EZH2 to mediate PTEN level. Overall, MALAT1 may play a crucial role in the progression of atherosclerosis and may be a potential therapeutic target.

Effect of Exosomal lncRNA MALAT1/miR-370-3p/STAT3 Positive Feedback Loop on PI3K/Akt Pathway Mediating Cisplatin Resistance in Cervical Cancer Cells.

Exosomes can encapsulate lncRNA to mediate intercellular communication in cancer progression. Our study devoted to research the effect that long noncoding RNA Metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) influence on cervical cancer (CC). MALAT1 and miR-370-3p levels in CC was assessed using qRT-PCR. CCK-8 assay and flow cytometry were devoted to confirm the influence on MALAT1 influencing the proliferation in cisplatin-resistant CC cells. Futher more, MALAT1, combined with miR-370-3p was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. In CC tissues, MALAT1 turned into substantially expressed, cisplatin-resistant cell lines, as well as exosomes. Cell proliferation was restrained and cisplatin-induced apoptosis was promoted by way of Knockout MALAT1. And promoted the miR-370-3p level, MALAT1 targeted miR-370-3p. Promoting effect of MALAT1 on cisplatin resistance of CC was partially reversed through miR-370-3p. In addition, STAT3 may induce up-regulation of MALAT1 expression in cisplatin-resistant CC cells. It was further confirmed that the effect of MALAT1 on cisplatin-resistant CC cells was achieved by activating PI3K/Akt pathway. The positive feedback loop of exosomal MALAT1/miR-370-3p/STAT3 mediates the cisplatin resistance of cervical cancer cells affecting PI3K/Akt pathway. Exosomal MALAT1 may become a promising therapeutic target for treating cervical cancer.

Regulation of the Inflammatory Response, Proliferation, Migration, and Epithelial-Mesenchymal Transition of Human Lens Epithelial Cells by the lncRNA-MALAT1/miR-26a-5p/TET1 Signaling Axis.

The ocular inflammatory microenvironment has been reported to be closely associated with the occurrence and progression of highly myopic cataract (HMC). Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) could alter the biological properties of mammalian cells by modulating the expression of inflammatory mediators; therefore, it may contribute to the development of HMC. To investigate the function of MALAT1 in the inflammatory response, proliferation, migration, and epithelial-mesenchymal transition (EMT) of inflammatory and injured human lens epithelial cells (HLECs) and to reveal the underlying molecular signals. Patients with HMC and age-related cataract (ARC) with an axial length of more than 26 mm were selected, and the anterior capsular tissue was obtained during cataract surgery. TNF-α (20 ng/mL) was chosen to induce inflammatory damage in HLECs to simulate the inflammatory microenvironment in HMC eyes. Specific siRNAs, inhibitors, and mimics were used to suppress or enhance the functions of MALAT1 and miR-26a-5p. RT-qPCR and Western blot analysis were performed to measure gene and protein expression, respectively. The expression of MALAT1 and the inflammatory mediators IL-6, MMP-2, and MMP-9 were significantly higher in HMC anterior capsule tissues than in ARC. TNF-α treatment increased the expression of MALAT1, while it also promoted the proliferation, migration, and EMT of HLECs. MALAT1 interference decreased the expression of IL-6 and MMP-2 and inhibited the aforementioned processes. Furthermore, MALAT1 negatively regulated the expression of miR-26a-5p and then promoted TET1 expression. TET1 was identified as a direct target of miR-26a-5p, and the promoting effect of MALAT1 on TET1 expression could be reversed by miR-26a-5p mimics. The inflammatory environment and MALAT1 expression could be reciprocally induced in HLECs. MALAT1 may act as a ceRNA via the "sponge" miR-26a-5p and target TET1 to regulate the inflammatory response, proliferation, migration, and EMT processes in HLECs.

Long noncoding RNA MALAT1 inhibition attenuates sepsis-induced acute lung injury through modulating the miR-129-5p/PAX6/ZEB2 axis.

This research aimed to investigate the role of the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-129-5p (miR-129-5p)/paired box gene 6 (PAX6) axis in sepsis-induced acute lung injury (ALI). MLE-12 cells and C57BL/6 mice were induced by LPS to establish lung injury in in vitro and in vivo models. Cell viability and apoptosis were measured by cell counting kit-8 assay and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) staining, respectively. Levels of inflammatory cytokines in cell supernatants and bronchoalveolar lavage fluid (BALF) were detected by ELISA. Lung injury was evaluated by lung wet weight-to-dry weight ratio and hematoxylin-eosin staining. MALAT1, PAX6, and zinc finger E-box-binding homeobox 2 (ZEB2) expression was elevated and miR-129-5p expression was reduced in the serum of patients with sepsis-induced ALI, LPS-induced MLE-12 cells, and lung tissues of ALI mice. MALAT1 interference delayed the LPS-induced cell proliferation decrease, apoptosis increase, and inflammatory factor increase. miR-129-5p inhibition could reverse the delaying effect of MALAT1 interference on LPS-induced lung cell injury. PAX6 overexpression (oe) reversed the inhibitory effect of miR-129-5p oe on LPS-induced lung cell injury. Downregulating MALAT1 reduced pulmonary edema, inflammatory cytokine levels, lung injury, and apoptosis in ALI mice. Moreover, miR-129-5p suppression or PAX6 oe reversed the delaying effect of MALAT1 interference on sepsis-induced ALI. MALAT1 aggravates sepsis-induced ALI via the miR-129-5p/PAX6/ZEB2 axis.

Association study of serum LncRNA MALAT1 and SAA with type 2 diabetic kidney disease

To investigate the correlation of serum long noncoding RNA-metastasis associated lung adenocarcinoma transcript 1(LncRNA MALAT1) and serum amyloid A(SAA) with diabetic kidney disease. Retrospective research was used, and 40 patients with type 2 diabetes and 80 patients with type 2 diabetic kidney disease patients who were treated in Tianjin Medical University Chu Hsien-I Memorial Hospital from August 2021 to February 2022 were selected, and 40 healthy subjects were selected during the same period. Reverse transcription-polymerase chain reaction(RT-PCR) was used to detect serum LncRNA MALAT1. SAA were detected with enzyme linked immunosorbent assay (ELISA). Automatic biochemistry analyzer was used to detect serum creatinine (CREA) and low-density lipoprotein cholesterol(LDL-C),automatic blood glucose analyzer to detect serum fasting plasma glucose (FPG), automatic glycated hemoglobin analyzer to detect hemoglobin A1C (HbA1c), and automatic immunoassay analyzer to detect urinary albumin to creatinine ratio(UACR). Differences between groups were compared by t test and analysis of variance. Pearson analysis was used to analyze the correlation between MALAT1, SAA and other indicators. Receiver operating characteristic curve(ROC) was used to evaluate the auxiliary diagnostic value of MALAT1 and SAA for diabetic kidney disease. The results showed that MALAT1 and SAA in the diabetic kidney disease with mass albuminuria group were higher than those in the type 2 diabetes mellitus group (q=8.57, P<0.01; q=11.09, P<0.01) and the diabetic kidney disease with microalbuminuria group (q=3.96, P<0.05; q=7.85, P<0.01). MALAT1 had a high correlation with UACR, CREA, SAA, HbA1c and FPG (r value was 0.706, 0.643, 0.578, 0.553, and 0.524, all P<0.01), and SAA had a high correlation with UACR, HbA1c and FPG (r value was 0.664, 0.617, and 0.595, all P<0.01). ROC curve analysis of the diagnostic value of LncRNA MALAT1 and protein SAA for diabetic kidney disease showed that the areas under curve (AUC) were 0.741 and 0.744, respectively. The combined diagnostic value of the two was the greatest (AUC=0.801). In summary, MALAT1 and SAA were elevated in the serum of patients with type 2 diabetes. Their concentrations in the serum of group with diabetic kidney disease were higher than that in the type 2 diabetes group, and the serum concentrations of MALAT1 and SAA in group with mass albuminuria are higher than the group with microalbuminuria. MALAT1 and SAA were both closely related to UACR and HbA1c, and there is a correlation between them. Both of them may have ancillary diagnostic value for diabetic kidney disease.

LncRNA MALAT1 Targets miR-9-3p to Upregulate SAP97 in the Hippocampus of Mice with Vascular Dementia.

Vascular dementia (VaD) is the second most common subtype of dementia, but the precise mechanism underlying VaD is not fully understood. Long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) can act as a key regulator in physiological and pathological processes, including neurological disorders, but whether it is correlated with VaD has not been elucidated. In this study, we established a mouse model of VaD by the transient bilateral common carotid artery occlusion surgery. As expected, the Morris water maze showed that VaD mice had significant deficits in spatial learning and memory. MALAT1 was elevated in the hippocampus of VaD mice. Additionally, we found that microRNA (miR)-9-3p was downregulated in the VaD hippocampus. By performing a dual-luciferase report assay, we verified the binding relationship between MALAT1 and miR-9-3p. Interestingly, synapse-associated protein-97 (SAP97), a well-known gene related to synaptic functions, was found upregulated in the hippocampus of VaD mice. In vitro experiments performed on hippocampal neurons demonstrated that miR-9-3p negatively regulated SAP97 expression. The downregulation of MALAT1 in hippocampal neurons increased miR-9-3p and reduced SAP97, whereas miR-9-3p inhibition rescued the MALAT1 downregulation-mediated SAP97 reduction. In conclusion, the present study reported the alterations in the expression levels of MALAT1, miR-9-3p, and SAP97 in the hippocampus of VaD mice, suggesting that MALAT1 targets miR-9-3p to upregulate SAP97 in the hippocampus of mice with VaD. This work will be helpful for understanding the molecular mechanisms of VaD.

Impact of Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 on the Susceptibility of High Glucose-Treated Cardiomyocytes to Hypoxia/Reoxygenation

To estimate the effect of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on susceptibility of high glucose (HG)-treated cardiomyocytes (CMs) to hypoxia/reoxygenation (H/R). Forty healthy rats were assigned to the control, diabetes mellitus (DM), DM + ischemia/reperfusion injury (IRI) control, and DM IRI groups (n = 10 for each group). Rat CMs (H9C2) were subjected to HG and H/R treatments. LncRNA MALAT1 and cyclic-AMP responsive element modulator (CREM) mRNA levels were measured using quantitative polymerase chain reaction, and protein levels of CREM, myeloid differentiation primary response protein 88 (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor associated factor 6 (TRAF6), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were quantified using western blotting. Flow cytometry was applied for detection of apoptosis, and a cell viability analyzer determined the number of living cells. IRI induced myocardial apoptosis and elevated lncRNA MALAT1, CREM, and MyD88/IRAK1/TRAF6 levels in DM group mice. In H9C2 cells, HG treatment downregulated CREM expression, which resulted in the downregulation of lncRNA MALAT1 expression, reducing the susceptibility to H/R, increasing cell viability and apoptosis, decreasing the activity of the MyD88/IRAK1/TRAF6 signaling pathway, and suppressing TNF-α and IL-6 expression. LncRNA MALAT1 regulates the susceptibility of HG-treated CMs to H/R through the MyD88 signaling pathway.

Long non-coding RNA MALAT1 promotes Th2 differentiation by regulating microRNA-135b-5p/GATA-3 axis in children with allergic rhinitis.

Allergic rhinitis (AR) threatens patient survival. CD4+ T cells play key roles in AR progression. Long non-coding RNAs (lncRNAs) are key regulators of cell differentiation. Therefore, we investigated the molecular mechanism of the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in AR. Expression levels of MALAT1, microRNA (miR)-135b-5p, interleukin-4 (IL-4), and GATA-binding protein 3 (GATA-3) in the nasal mucosa of AR patients were quantified. CD4+ T cells were isolated from the peripheral blood of healthy volunteers and treated with ovalbumin (OVA) and Th2 inducers. After MALAT1 and miR-135b-5p levels changed in CD4+ T cells, the proportion of IL-4-expressing cells and the levels of IL-4 and GATA-3 in OVA-induced CD4+ T cells were determined. Binding relationships among MALAT1, miR-135b-5p, and GATA-3 were predicted and verified. Rescue experiments were performed to confirm the role of the MALAT1/miR-135b-5p/GATA-3 axis in Th2 differentiation of CD4+ T cells. MALAT1, IL-4, and GATA-3 expression was upregulated, whereas miR-135b-5p expression was downregulated, in patients with AR. MALAT1 knockdown or miR-135b-5p overexpression in CD4+ T cells notably decreased the proportion of IL-4-expressing cells and downregulated GATA-3 and IL-4 expression in OVA-induced CD4+ T cells. MALAT1 and GATA-3 exhibited competitive binding toward miR-135b-5p. MALAT1 facilitated CD4+ T cell Th2 differentiation via the miR-135b-5p/GATA-3 axis. MALAT1 facilitated AR development by facilitating CD4+ T cell Th2 differentiation via the miR-135b-5p/GATA-3 axis. This study may provide guidance for clinical treatment of AR.

Malat1 deficiency prevents hypoxia-induced lung dysfunction by protecting the access to alveoli.

Hypoxia is common in lung diseases and a potent stimulator of the long non-coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1). Herein, we investigated the impact of Malat1 on hypoxia-induced lung dysfunction in mice. Malat1-deficient mice and their wild-type littermates were tested after 8 days of normoxia or hypoxia (10% oxygen). Hypoxia decreased elastance of the lung by increasing lung volume and caused in vivo hyperresponsiveness to methacholine without altering the contraction of airway smooth muscle. Malat1 deficiency also modestly decreased lung elastance but only when tested at low lung volumes and without altering lung volume and airway smooth muscle contraction. The in vivo responsiveness to methacholine was also attenuated by Malat1 deficiency, at least when elastance, a readout sensitive to small airway closure, was used to assess the response. More impressively, in vivo hyperresponsiveness to methacholine caused by hypoxia was virtually absent in Malat1-deficient mice, especially when hysteresivity, a readout sensitive to small airway narrowing heterogeneity, was used to assess the response. Malat1 deficiency also increased the coefficient of oxygen extraction and decreased ventilation in conscious mice, suggesting improvements in gas exchange and in clinical signs of respiratory distress during natural breathing. Combined with a lower elastance at low lung volumes at baseline, as well as a decreased propensity for small airway closure and narrowing heterogeneity during a methacholine challenge, these findings represent compelling evidence suggesting that the lack of Malat1 protects the access to alveoli for air entering the lung.

Synthesis and physical and biological properties of 1,3-diaza-2-oxophenoxazine-conjugated oligonucleotides

The artificial nucleobase 1,3-diaza-2-oxophenoxazine (tCO) and its derivative G-clamp strongly bind to guanine and, when incorporated into double-stranded DNA, significantly increase the stability of the latter. As the phenoxazine skeleton is a constituent of major pharmaceuticals, we hypothesized that oligonucleotides (ONs) containing phenoxazine bases would induce property changes related to intracellular uptake and migration in tissues. In this study, we designed and synthesized a novel G-clamp-linker antisense oligonucleotide (ASO) in which a G-clamp base with a flexible linker was introduced into the 5′-end of an ASO targeting mouse long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (mMALAT1). Compared to unconjugated ASO, the G-clamp-linker ASO induced significantly more effective knockdown of mMALAT1 in mouse skeletal muscle. The ASOs conjugated with 2′-deoxyribonucleotide(s) bearing a tCO nucleobase at the 5′-end exhibited a similar knockdown effect in skeletal muscle. Thus, it may be possible to improve therapeutic effects against skeletal muscle diseases, such as muscular dystrophy, by using ONs with incorporated phenoxazine nucleobases.

Impacts of long noncoding RNA MALAT1 on LPS-induced periodontitis via modulating miR-155/SIRT1 axis

Abstract Objectives Periodontitis, a dental disease that causes inflammation of gums is triggered by a bacterial infection. Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) has been reported to participate in inflammatory diseases. In the present study, we investigated the effects of lncRNA MALAT1 on periodontal ligament cells (PDLCs) with lipopolysaccharide (LPS) induction. Methods MALAT1, microRNA-155 (miR-155), Sirtuin 1 (SIRT1), Bax, and Bcl-2 RNA expressions were detected by using real-time quantitative polymerase chain reaction (RT-qPCR). PDLC viability and apoptosis were assessed by using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium salt (MTT) assay and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) assessed secretions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Luciferase reporter test was applied for confirming the binding of miR-155 with MALAT1 and SIRT1, respectively. Results Overexpression of MALAT1 facilitated the LPS-induced periodontitis while MALAT1 suppression restrained LPS-induced injury. Also, miR-155 was expressed in LPS-induced PDLCs. Moreover, MALAT1 negatively regulated miR-155 followed by the up-regulation of SIRT1 which in turn reduced the inflammation in LPS-induced PDLCs. Conclusions We concluded that upregulated lncRNA MALAT1 could accelerate periodontitis through the regulation of miR-155/SIRT1. Our findings suggested a novel MALAT1/miR-155/SIRT1 pathway for the treatment of periodontitis.

LncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis.

Objective The long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) are closely associated with the pathogenesis of diabetic nephropathy (DN). But a complete mechanism for MALAT1 in DN has yet to be identified. This study investigated the effect of MALAT1 on DN through the regulation of miR-15b-5p/TLR4 signaling. Method Renal tissues were collected from DN patients. Human renal tubular epithelial cells (HK-2) were used as a model of DN induced by high glucose (HG). We then measured the viability, apoptosis, and inflammatory cytokine levels of HK-2 cells using the corresponding assays. Following transfections of si-MALAT1, si-MALAT1+miR-15b-5p inhibitor, or si-MALAT1+vector TLR4 into HG-stimulated HK-2 cells, cell viability, apoptosis, and inflammatory cytokines were again measured. Furthermore, dual-luciferase reporter assay validated the interactions of MALAT1/miR-15b-5p and miR-15b-5p/TLR4. In addition, the interaction between MALAT1 and miR-15b-5p was investigated by RNA immunoprecipitation (RIP). Results A significant upregulation of MALAT1 was observed in DN kidney tissues, as well as in HG-stimulated HK-2 cells. MALAT1 knockdown attenuates the inhibition of cell viability, apoptosis, and inflammatory response induced by HG in HK-2 cells. Moreover, a miR-15b-5p inhibitor or TLR4 overexpression reversed the above effects induced by MALAT1 knockdown. Conclusion These results indicate that reduced MALAT1 ameliorates HG-stimulated HK-2 cell damage through an inhibition of the miR-15b-5p/TLR4 axis. MALAT1 may serve as a biomarker and potential therapeutic target for DN.

LncRNA MALAT1 Participates in Protection of High-Molecular-Weight Hyaluronan against Smoke-Induced Acute Lung Injury by Upregulation of SOCS-1.

Smoke-induced acute lung injury (ALI) is a grievous disease with high mortality. Despite advances in medical intervention, no drug has yet been approved by the Food and Drug Administration (FDA) for ALI. In this study, we reported that pretreatment with high-molecular-weight hyaluronan (1600 kDa, HA1600) alleviated pulmonary inflammation and injury in mice exposed to smoke and also upregulated long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as well as suppressor of cytokine signaling-1 (SOCS-1), in the lung tissues. Next, we overexpressed MALAT1 in the lungs by intratracheal administration of adenovirus cloned with MALAT1 cDNA and found that the survival of mice after smoke exposure was improved. Moreover, pulmonary overexpression of MALAT1 ameliorated smoke-induced ALI in mice and elevated the level of SOCS-1 in the lungs. In conclusion, the results pointed out that HA1600 exerted a protective effect against smoke-induced ALI through increasing the MALAT1 level and the subsequent SOCS-1 expression. Our study provides a potential therapeutic approach to smoke-induced ALI and a novel insight into the mechanism of action of HA1600.