Downregulation Of MALAT1 Research Articles

The effect of adipose-derived mesenchymal stem cells against high fructose diet induced liver dysfunction and dysbiosis.

High fructose diet (HFrD) has been approved to be involved in the pathogenesis of insulin resistance. Mesenchymal stem cells have a vital role in the treatment of various diseases including metabolic disturbances. We investigated the effect of Adipose-derived mesenchymal stem cells (ADMSCs) against HFrD-induced metabolic disorders and the molecular mechanisms for this effect. Rats were divided into 3 groups; control, HFrD, and combined HFrD with ADMSCs. We assessed liver functions, gut microbiota activity, oxidative stress, adiponectin, and IL10 levels. Also, we measured SREBP-1, IRS-1 expression using Western blot, and Malat1 expression using rt-PCR. ADMSCs antagonized metabolic abnormalities induced by HFrD in the form of improvement of liver functions and alleviation of oxidative stress. In addition, ADMSCs ameliorated gut microbiota activity besides the elevation of adiponectin and IL10 levels. ADMSCs attenuated insulin resistance through upregulation of IRS1 and downregulation of SREBP-1 and Malat1. ADMSCs can protect against HFrD-induced metabolic hazards.

Regulation of mitochondrial autophagy by lncRNA MALAT1 in sepsis-induced myocardial injury

BackgroundSepsis-induced myocardial injury (SIMI) is a severe complication of sepsis, contributing significantly to mortality. Mitochondrial dysfunction and dysregulated autophagy are implicated in SIMI pathogenesis. Long non-coding RNA MALAT1 has been associated with various diseases, including sepsis, but its role in SIMI remains unclear.ObjectiveThis study aimed to investigate the role of lncRNA MALAT1 in SIMI, specifically in the regulation of mitochondrial autophagy.MethodsA sepsis-induced cardiomyopathy model was established in mice, and the cardiac tissues were analyzed. The expression of lncRNA MALAT1 was modulated and its effects on mitochondrial autophagy, myocardial injury, inflammation, and apoptosis were assessed. Furthermore, the interaction between MALAT1 and miR-146a was explored, as well as the involvement of the TLR4/NF-kB/MAPK signaling pathway.ResultsActivation of mitochondrial autophagy by urolithin A (UA) alleviated SIMI, inflammation, and cardiac dysfunction. Downregulation of MALAT1 enhanced mitochondrial autophagy, stabilized the mitochondrial membrane potential, and inhibited mitochondrial reactive oxygen species (ROS) production, leading to improved cell viability and reduced myocardial injury. Furthermore, MALAT1 interacted with miR-146a, and their modulation influenced mitochondrial autophagy, myocardial injury, and inflammation. The TLR4/NF-kB/MAPK signaling pathway was implicated in these processes.ConclusionOur findings suggest that lncRNA MALAT1 plays a crucial role in SIMI by modulating miR-146a-mediated mitochondrial autophagy and the TLR4/NF-kB/MAPK signaling pathway. These results provide new insights into the pathogenesis of SIMI and potential therapeutic targets.

Schistosoma japonicum infection-mediated downregulation of lncRNA Malat1 contributes to schistosomiasis hepatic fibrosis by the Malat1/miR-96/Smad7 pathway

BackgroundSchistosoma japonicum infection causes hepatic fibrosis, a primary cause of morbidity and mortality associated with the disease, and effective treatments are still lacking. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenic process of various tissue fibroses. However, the role of lncRNAs in schistosomiasis hepatic fibrosis (HF) is poorly understood. Understanding the role of lncRNAs in schistosomiasis HF will enhance knowledge of disease processes and aid in the discovery of therapeutic targets and diagnostic biomarkers.MethodsDifferentially expressed lncRNA profiles in primary hepatic stellate cells (HSCs) of mice infected with S. japonicum were identified using high-throughput lncRNA sequencing. Primary HSCs were isolated from infected mice using collagenase digestion and density-gradient centrifugation, cultured in DMEM with 10% fetal bovine serum. Dual-luciferase reporter assays, nuclear cytoplasm fractionation and RIP assays were employed to assess the relationship between Malat1 and miRNA-96. Malat1 lentivirus and ASO-Malat1 were constructed for forced expression and downregulated expression of Malat1. The Malat1-KO mouse was constructed by CRISPR/Cas9 technology. Pathological features of the liver were evaluated by hematoxylin-eosin (HE), Masson’s trichrome staining and immunohistochemistry (IHC). The expression levels of fibrosis-related genes were determined by quantitative real-time PCR (qRT-PCR) and Western blot.ResultsA total of 1561 differentially expressed lncRNAs were identified between infected and uninfected primary HSCs. Among the top altered lncRNAs, the downregulated Malat1 was observed in infected HSCs and verified by qPCR. Treatment of infected mice with praziquantel (PZQ) significantly increased the Malat1 expression. Elevated Malat1 expression in infected primary HSC reduced the expressions of profibrogenic genes, whereas Malat1 knockdown had the opposite effect. Moreover, Malat1 was found to interact with miR-96, a profibrotic miRNA, by targeting Smad7. Forced Malat1 expression reduced miR-96 levels in infected primary HSCs, attenuating fibrogenesis and showing negative correlation between Malat1 expression and the expression levels of miR-96 and profibrogenic genes α-SMA and Col1α1. Notably, in Malat1-KO mice, knockout of Malat1 aggravates schistosomiasis HF, while restored Malat1 expression in the infected HSCs reduced the expression of profibrogenic genes.ConclusionsWe demonstrate that lncRNA is involved in regulation of schistosomiasis HF. Elevated lncRNA Malat1 expression in infected HSCs reduces fibrosis via the Malat1/miR-96/Smad7 pathway, thus providing a novel therapeutic target for schistosomiasis HF. Furthermore, Malat1 expression is sensitive to PZQ treatment, thus offering a potential biomarker for assessing the response to chemotherapy.Graphical abstract

MALAT1 Knockdown Inhibits the Proliferation, Migration, and Collagen Deposition of Human Hypertrophic Scar Fibroblasts via Targeting miR-29a-3p/Smurf2 Axis.

Hypertrophic scarring (HS) is commonly described as an abnormal post-traumatic tissue repair characterized by excessive hypercellularity and extracellular matrix (ECM) deposition. Mounting evidence suggests that MALAT1 is maladjusted in many fibrotic diseases, but its contribution to HS progression remains poorly understood. Hence, we sought to elucidate the fundamental role of MALAT1 in HS. The expression of MALAT1, miR-29a-3p, and Smurf2 in skin tissues and fibroblasts was assessed by RT-qPCR and Western blotting. Furthermore, lentiviruses, RNAi, or plasmids were utilized to transfect hypertrophic scar fibroblasts (HSFs) for gene overexpression or downregulation. The biological behaviors of HSFs were quantified by the CCK-8 assay, wound healing assay, transwell assay, and flow cytometry. Mechanistically, bioinformatics analysis, dual-luciferase reporter assays, and rescue experiments were performed to verify the relationship between miR-29a-3p and MALAT1 or Smurf2. Our data indicate that MALAT1, Smurf2 were overexpressed while miR-29a-3p was suppressed in HS tissues and fibroblasts. Downregulation of MALAT1 may lead to decreased proliferation, migration, and invasion of fibroblasts, accompanied by enhanced apoptosis, reduced TGF-β signal transduction, and ECM accumulation in HSFs, by enhancing miR-29a-3p and suppressing Smurf2 expression. Mechanistically, MALAT1 acted as a sponge for miR-29a-3p, while miR-29a-3p directly targeted Smurf2. More importantly, rescue experiments suggested that MALAT1 downregulation induced impact on the proliferation, migration, and invasion of HSFs could be partially overturned through miR-29a-3p knockdown or Smurf2 overexpression. MALAT1 knockdown inhibits the proliferation, migration, invasion, and collagen deposition of HSFs via targeting the miR-29a-3p/Smurf2 axis, which may reveal a promising therapeutic exploitable vulnerability to HS.

Air-Liquid Interface Microfluidic Monitoring Sensor Platform for Studying Autophagy Regulation after PM2.5 Exposure.

Undoubtedly, a deep understanding of PM2.5-induced tumor metastasis at the molecular level can contribute to improving the therapeutic effects of related diseases. However, the underlying molecular mechanism of fine particle exposure through long noncoding RNA (lncRNA) regulation in autophagy and, ultimately, lung cancer (LC) metastasis remains elusive; on the other hand, the related monitoring sensor platform used to investigate autophagy and cell migration is lacking. Herein, this study performed an air-liquid interface microfluidic monitoring sensor (AIMMS) platform to analyze human bronchial epithelial cells after PM2.5 stimulation. The multiomics analysis [RNA sequencing (RNA-seq) on lncRNA and mRNA expressions separately] showed that MALAT1 was highly expressed in the PM2.5 treatment group. Furthermore, RNA-seq analysis demonstrated that autophagy-related pathways were activated. Notably, the main mRNAs associated with autophagy regulation, including ATG4D, ATG12, ATG7, and ATG3, were upregulated. Inhibition or downregulation of MALAT1 inhibited autophagy via the ATG4D/ATG12/ATG7/ATG3 pathway after PM2.5 exposure and ultimately suppressed LC metastasis. Thus, based on the AIMMS platform, we found that MALAT1 might become a promising therapeutic target. Furthermore, this low-cost AIMMS system as a fluorescence sensor integrated with the cell-monitor module could be employed to study LC migration after PM2.5 exposure. With the fluorescence cell-monitoring module, the platform could be used to observe the migration of LC cells and construct the tumor metastasis model. In the future, several fluorescence probes, including nanoprobes, could be used in the AIMMS platform to investigate many other biological processes, especially cell interaction and migration, in the fields of toxicology and pharmacology.

Transcriptional alteration of NF-κB-associated long noncoding RNAs in the stomach of Helicobacter pylori-infected and non-infected patients.

Helicobacter pylori could colonize the gastric mucosa and cause gastritis, ulcers and cancer. Numerous virulence factors have been identified in this bacterium that play important roles in promoting gastric disorders. Although the interaction of long noncoding RNAs (lncRNAs) with transcription, processing, and translation of genes associated with different diseases are described, their interaction with the inflammatory genes and H. pylori infection in the gastric tissue is not well known. This study compared changes in common NF-κB-regulatory lncRNAs in the gastric tissue of H. pylori-infected and non-infected patients with gastritis. Moreover, a link between the virulence entity of the strains and the transcriptional changes was analyzed. Two groups of infected and non-infected patients with chronic gastritis were included in the study. Genotyping of the H. pylori strains was done by PCR and relative changes in the expression of NF-κB and regulatory lncRNAs, lincRNA-p21, MALAT1, NKILA, were measured by relative quantitative real time-PCR. Transcriptional levels of MALAT1, lincRNA-p21, and NKILA genes decreased in the infected patients compared with the non-infected patients, which was significantly linked with increased NF-κB gene expression. Our results showed that a hypervirulent strain of H. pylori with oipA"on"/HP-NAP+/iceA1+/iceA2+/vacA s1m1/s1m2+/cagA+ genotype can promote a higher level of NF-κB transcription in the inflamed tissue. H. pylori infection could promote down-regulation of lincRNA-p21, MALAT1 and NKILA in the infected gastric tissue in correlation with NF-κB upregulation. More detailed studies are needed to show a link between the virulence genes and their impact on the regulation of lncRNAs in the stomach.

Downregulation of MALAT1 in triple-negative breast cancer cells

BackgroundMALAT1 is one of the most abundant nuclear long non-coding RNAs, which has been found to be elevated in various types of cancers. However, conflicting reports on MALAT1 in breast cancer cell lines challenge understanding of MALAT1's involvement in breast cancer progression. AimMeasurement of normalized relative quantity (NRQ) of MALAT1 transcripts in cell lines representing triple-negative breast cancer (TNBC) and luminal breast cancer. Materials and methodsThe studies were performed using cell lines representing luminal breast cancer (T47D, MCF-7), TNBC (MDA-MB-468, CAL-51, MDA-MB-231), and MCF-10A cell line of normal breast epithelial cells. Total RNA was isolated from six independent cell cultures of each line, treated with DNase I, and used to synthesize complementary DNA, which was used in quantitative real-time PCR (qPCR) assays. Four MALAT1 fragments and reference genes CCSER2, ANKRD17, PUM1, GAPDH were amplified. ResultsGeometric means of the NRQ of MALAT1 in breast cancer cell lines had the shortest 95% confidence intervals when CCSER2 was used for normalization. MALAT1 major transcript levels thus estimated in TNBC cell lines were found to be statistically significantly reduced compared to levels in both MCF-10A cells and luminal breast cancer cell lines, while MALAT1 minority splice variants were found to be increased in almost all breast cancer cell lines. ConclusionCCSER2-normalized qPCR results indicate MALAT1 downregulation in cell lines representing the more aggressive breast cancer subtype compared to both the normal breast epithelial cell line and the estrogen receptor-positive breast cancer cell lines.

An integrated in silico-in vitro investigation to assess the skin sensitization potential of 4-Octylphenol

One of the major challenges in chemical toxicity testing is the possibility to protect human health against adverse effects with non-animal methods. In this paper, 4-Octylphenol (OP) was tested for skin sensitization and immunomodulatory effects using an integrated in silico-in vitro test approach. In silico tools (QSAR TOOLBOX 4.5, ToxTree and VEGA) were used together with several in vitro tests including HaCaT cells (quantification of IL-6; IL-8; IL-1α and IL-18 by ELISA and expression of genes TNF, IL1A, IL6 and IL8 by RT- qPCR), RHE model (quantification of IL-6; IL-8; IL-1α and IL-18 by ELISA) and THP-1 activation assay (CD86/CD54 expression and IL-8 release). Additionally, the immunomodulatory effect of OP was investigated using lncRNAs MALAT1 and NEAT1 expression and LPS-induced THP-1 activation (CD86/CD54 expression and IL-8 release). The in silico tools predicted OP as a sensitizer. In vitro tests are also concordant with the in silico prediction. OP increased IL-6 expression (HaCaT cells); IL-18 and IL-8 expressions (RHE model). An irritant potential was also shown by a great expression of IL-1α (RHE model); and increased expression of CD54 marker and IL-8 in THP-1 cells. Immunomodulatory effects of OP were demonstrated by the downregulation of NEAT1, MALAT1 (epigenetic markers), IL6 and IL8; and an increase in LPS-induced CD54 and IL-8 expressions. Overall, results indicate that OP is a skin sensitizer, being positive in three key events of the AOP for skin sensitization, also showing immunomodulatory effects.

Downregulation of MALAT1 is a hallmark of tissue and peripheral proliferative T cells in COVID-19.

T cells play key protective but also pathogenic roles in COVID-19. We studied the expression of long non-coding RNAs (lncRNAs) in COVID-19 T-cell transcriptomes by integrating previously published single-cell RNA sequencing datasets. The long intergenic non-coding RNA MALAT1 was the most highly transcribed lncRNA in T cells, with Th1 cells demonstrating the lowest and CD8+ resident memory cells the highest MALAT1 expression, amongst CD4+ and CD8+ T-cells populations, respectively. We then identified gene signatures that covaried with MALAT1 in single T cells. A significantly higher number of transcripts correlated negatively with MALAT1 than those that correlated. Enriched functional annotations of the MALAT1- anti-correlating gene signature included processes associated with T-cell activation such as cell division, oxidative phosphorylation, and response to cytokine. The MALAT1 anti-correlating gene signature shared by both CD4+ and CD8+ T-cells marked dividing T cells in both the lung and blood of COVID-19 patients. Focussing on the tissue, we used an independent patient cohort of post-mortem COVID-19 lung samples and demonstrated that MALAT1 suppression was indeed a marker of MKI67+ proliferating CD8+ T cells. Our results reveal MALAT1 suppression and its associated gene signature are a hallmark of human proliferating T cells.

Haplotype-GGGT in long non-coding RNA MALAT1 inhibits brain metastatic lung cancer and lymph nodes of lung cancer via the MALAT1/miR-328/KATNB1.

The up-regulation of Katanin P8 has been reported to be correlated with a larger tumor size and lymph node metastasis in non-small-cell lung cancer (NSCLC) patients. And lncRNA MALAT1 was demonstrated to promote the proliferation of chronic myeloid leukemia cells via modulating miR-328. 135 lung cancer patients were divided into 6 groups according to their genotypes of MALAT1. The expression of KATNB1 was negatively correlated with the GGGT genotype of MALAT1. Decreased lymph node size and tumor size of brain metastatic lung were observed in patients with GGGT genotype of MALAT1. The luciferase activities of MALAT1 and KATNB1 were remarkably suppressed by miR-328 in A549 and H460. And the down-regulation of MALAT1 or up-regulation of miR-328 significantly repressed the KATNB1 expression in A549 and H460 cells. MALAT1 expression was reduced in patients carrying haplotype GGGT. A signaling pathway of MALAT1/miR-328/KATNB1 was established to explain the down-regulation of KATNB1 mRNA in patients carrying haplotype GGGT and reduced lymph node size in lung cancer and tumor size in brain metastatic lung cancer.

Down-regulation of MALAT1 is a hallmark of tissue and peripheral proliferative T cells in COVID-19

Down-regulation of MALAT1 is a hallmark of tissue and peripheral proliferative T cells in COVID-19

A cutting-edge immunomodulatory interlinkage between HOTAIR and MALAT1 in tumor-associated macrophages in breast cancer: A personalized immunotherapeutic approach.

Breast cancer (BC) is one of the most common cancers, accounting for 2.3 million cases worldwide. BC can be molecularly subclassified into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These molecular subtypes differ in their prognosis and treatment strategies; thus, understanding the tumor microenvironment (TME) of BC could lead to new potential treatment strategies. The TME hosts a population of cells that act as antitumorigenic such as tumor-associated eosinophils or pro-tumorigenic such as cancer-associated fibroblasts (CAFs), tumor-associated neutrophils (TANs), monocytic-derived populations such as MDSCs, or most importantly "tumor-associated macrophages (TAMs)," which are derived from CD14+ monocytes. TAMs are reported to have the pro-inflammatory phenotype M1, which is found only in the very early stages of tumor and is not correlated with progression; however, the M2 phenotype is anti-inflammatory that is correlated with tumor progression and metastasis. The current study focused on controlling the anti-inflammatory activity in TAMs of hormonal, HER2+, and TNBC by epigenetic fine-tuning of two immunomodulatory proteins, namely, CD80 and mesothelin (MSLN), which are known to be overexpressed in BC with pro-tumorigenic activity. Long non-coding RNAs are crucial key players in tumor progression whether acting as oncogenic or tumor suppressors. We focused on the regulatory role of MALAT1 and HOTAIR lncRNAs and their role in controlling the tumorigenic activity of TAMs. This study observed the impact of manipulation of MALAT1 and HOTAIR on the expression of both CD80 and MSLN in TAMs of BC. Moreover, we analyzed the interlinkage between HOTAIR and MALAT1 as regulators to one another in TAMs of BC. The current study reported an upstream regulatory effect of HOTAIR on MALAT1. Moreover, our results showed a promising use of MALAT1 and HOTAIR in regulating oncogenic immune-modulatory proteins MSLN and CD80 in TAMs of HER2+ and TNBC. The downregulation of MALAT1 and HOTAIR resulted in the upregulation of CD80 and MSLN, which indicates that they might have a cell-specific activity in TAMs. These data shed light on novel key players affecting the anti-inflammatory activity of TAMs as a possible therapeutic target in HER2+ and TNBC.

Expression of lncRNA MALAT1 through miR-144-3p in Osteoporotic Tibial Fracture Rats and Its Effect on Osteogenic Differentiation of BMSC under Traction.

Objective To investigate the expression of lncRNA MALAT1 and miR-144-3p in osteoporotic (OP) tibial fracture rats and analyze their targeting relationship and effects on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSC) under traction. Methods The OP tibial fracture model was established, and the rats were divided into a sham group and a model group. The tibial tissue of these rats was taken. BMSC of cultured rats with good growth was purchased and grouped according to the presence or absence of transfection of si-MALAT1 and miR-144-3p-mimic. The expression of MALAT1 and miR-144-3p in each group was detected. The bioinformatics website and double luciferase were used to predict the targeting relationship between MALAT1 and miR-144-3p and to detect the expression of genes related to bone differentiation (collagen I, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP)) of each component, and ALP staining and AR staining were used to detect the formation of BMSC calcium nodules. Results The levels of ALP and TRAP in the model group were higher than that in the sham group (P < 0.05). qRT-PCR results showed that the relative expression level of MALAT1 in the model group was higher than that in the sham group, and the relative expression level of miR-144-3p was lower than that in the sham group (P < 0.05). MALAT1 has a targeting relationship with miR-144-3p. qRT-PCR results showed that the relative expression level of MALAT1 in the tension-MSC group was higher than the MSC group, and the relative expression level of miR-144-3p was lower than the MSC group (P < 0.05). The expressions of collagen I, OCN, OPN, and ALP proteins in the si-MALAT1 group were higher than those of the si-NC group (P < 0.05). The results of ALP staining showed that BMSCs of the si-MALAT1 group had stronger osteogenic differentiation capacity and higher ALP activity than those of the si-NC group. The results of AR staining showed that compared with the si-NC group, the mineralization degree of cells in the si-MALAT1 group was higher, the number of calcium nodules was more, and the cells were more deeply stained. The expressions of collagen I, OCN, OPN, and ALP proteins in the miR-144-3p-mimic group were higher than the mimic-NC group (P < 0.05). ALP staining results showed that BMSCs in the miR-144-3p-mimic group had strong osteogenic differentiation capacity and high ALP activity compared with the mimic-NC group. The results of AR staining showed that, compared with the mimic-NC group, the mineralization degree of cells in the miR-144-3p-mimic group was higher, the number of calcium nodules was more and the cells were more deeply stained. Conclusion In the OP rat model with the tibial fracture, the expression of MALAT1 is upregulated and that of miR-144-3p is downregulated. MALAT1 has a targeting relationship with miR-144-3p, and downregulation of MALAT1 and upregulation of miR-144-3p can promote the osteogenic differentiation of BMSC under traction.

LncRNA metastasis-associated lung adenocarcinoma transcript-1 promotes osteogenic differentiation of bone marrow stem cells and inhibits osteoclastic differentiation ofMø in osteoporosis via the miR-124-3p/IGF2BP1/Wnt/β-catenin axis.

Osteoporosis is defined as a skeletal disorder characterized by impairment in bone strength. The potential application of lncRNAs as therapeutic targets for osteoporosis has been unveiled. This study investigated the regulatory mechanism of lncRNA MALAT1 in the differentiation of bone marrow stem cells (BMSCs) and macrophages (Mø) in osteoporosis. MALAT1 expression in peripheral blood of elderly osteoporosis patients and healthy volunteers was detected. BMSCs and mononuclear Mø were isolated and cultured. Osteogenic differentiation of BMSCs and osteoclastic differentiation of Mø were induced. BMSCs and Mø were transfected with si-MALAT1, miR-124-3p mimics, miR-124-3p inhibitor, or pcDNA IGF2BP1, followed by detection of cell differentiation. The target microRNAs (miRs) and downstream genes and signaling pathways of MALAT1 were examined. The ovariectomy-induced mouse model of osteoporosis was established, and the mice were injected with pcDNA-MALAT1. MALAT1 was downregulated in osteoporosis patients, increased in BMSCs after osteogenic differentiation, and diminished in Mø after osteoclastic differentiation. Downregulation of MALAT1 repressed osteogenic differentiation of BMSCs and facilitated osteoclastic differentiation of Mø. MALAT1 upregulated IGF2BP1 expression by competitively binding to miR-124-3p. miR-124-3p silencing reversed the effect of si-MALAT1 on BMSCs and Mø differentiation, and IGF2BP1 upregulation averted the effect of overexpressed-miR-124-3p by activating the Wnt/β-catenin pathway. Upregulation of MALAT1 activated the Wnt/β-catenin pathway and attenuated bone injury in mice. In conclusion, lncRNA MALAT1 promoted the osteogenic differentiation of BMSCs and inhibited osteoclastic differentiation of Mø in osteoporosis via the miR-124-3p/IGF2BP1/Wnt/β-catenin axis.

Intelligent Bio-Responsive Fluorescent Au–shRNA Complexes for Regulated Autophagy and Effective Cancer Bioimaging and Therapeutics

The long non-coding RNA (lncRNA) MALAT1 acts as an oncogene. RNA interference (RNAi) is an effective method to control the expression of specific genes and can be used for the treatment of tumors, but an effective and safe carrier system is a significant obstacle to gene therapy. Herein, we explored the possibility of constructing an in situ bio-responsive self-assembled fluorescent gold-short hairpin RNA nanocomplex (Au–shRNA NCs) delivery system by co-incubating gold and MALAT1-shRNA for precise hepatocellular carcinoma (HCC) imaging and treatment. Due to the characteristics of the cancer microenvironment, Au–shRNA NCs self-assembled in HCC cells (HepG2) but did not occur in control cells (L02) under the same conditions. The in situ bio-responsive self-assembled Au–shRNA NCs delivery system can realize cancer cell bioimaging and promote cell uptake and endosomal escape mechanism, thereby realizing effective transfection. They effectively silenced target gene MALAT1, and with the downregulation of MALAT1, we found that several molecules involved in autophagic flux were also regulated. In vitro and tumor-bearing mouse model experiments demonstrated that the as-prepared fluorescent Au–shRNA NCs can readily realize tumor bioimaging and effectively silence the target gene MALAT1, and those autophagy-related pathway molecules were significantly downregulated, thereby exerting a tumor suppressor efficiency. This raises the possibility of realizing accurate multi-scale bio-imaging from the molecular-level with targeted gene-recognition to cancer cell imaging as well as in vivo tumor tissue imaging for the simultaneous precise cancer therapy.

Expression of Linear and Circular lncRNAs in Alzheimer's Disease.

Alzheimer's disease is a neurodegenerative disorder of the elderly described by progressive cognitive debility. Recent studies have displayed the significance of linear and circular long non-coding RNAs (lncRNAs) in the pathobiology of Alzheimer's disease. These studies have reported the downregulation of MALAT1, while the upregulation of NEAT1, RP11-543N12.1, SOX21-AS1, BDNF-AS, BACE1-AS, ANRIL, XIST, and some other linear lncRNAs in clinical samples are obtained from these patients or animal models of Alzheimer's disease. A number of circRNAs such as ciRS-7, ciRS-7, circNF1-419, circHDAC9, circ_0000950,and circAβ-a have been shown to partake in the pathogenesis of this disorder. In the present manuscript, we provide a review of the impact of linear and circular lncRNAs in the pathobiology of Alzheimer's disease and their potential application as markers for this neurodegenerative condition.

Down-regulation of MALAT1 aggravates polycystic ovary syndrome by regulating MiR-302d-3p-mediated leukemia inhibitory factor activity

AimsAccumulating evidence have shown the important roles of long noncoding RNA (lncRNA) in controlling different diseases. In the present study, we tried to explore the role which lncRNA MALAT1 plays in polycystic ovary syndrome (PCOS) with the involvement of microRNA-302d-3p (miR-302d-3p) and leukemia inhibitory factor (LIF). MethodsA PCOS rat model was established and characterized, followed by treatment with si-MALAT1, oe-MALAT1, miR-302d-3p mimic, or miR-302d-3p inhibitor constructs. Serum hormonal levels were detected to evaluate endocrine conditions. The effect of MALAT1 and miR-302d-3p on activities of ovarian granulosa cells was assessed, as well as the involvement of LIF. ResultsMALAT1 expression was shown to be downregulated in ovarian tissue of PCOS rats. Overexpression of MALAT1 in vitro promoted proliferation and inhibited apoptosis of ovarian granulosa cells. Overexpression of MALAT1 in vivo reduced the ovarian tissue injury and endocrine disorders accompanied with decreased level of FSH and elevated serum levels of E2, T, and LH in the PCOS rat. Overexpression of MALAT1 also promoted the expression of LIF, which could be reversed by overexpression of miR-302d-3p, indicating that MALAT1 up-regulated the expression of LIF via miR-302d-3p. Furthermore, overexpression of MALAT1 reduced endocrine disorders and ovarian tissue damage via the miR-302d-3p/LIF axis. ConclusionOur study highlighted that MALAT1 plays a protective role in reducing ovarian tissue damage and endocrine disorder in PCOS by regulating the miR-302d-3p/LIF axis.

Quercetin Can Inhibit Angiogenesis via the Down Regulation of MALAT1 and MIAT LncRNAs in Human Umbilical Vein Endothelial Cells.

Background:Angiogenesis is an important step in cancer metastasis since it enables the growing tumor to receive nutrients and oxygen. Quercetin is a generic flavonoid and has been investigated for its ability to inhibit angiogenesis in different types of cancers. MALAT1 and MIAT lncRNAs are associated with the angiogenesis process. MALAT1 induces hypoxia-driven angiogenesis via the overexpression of angiogenic genes. Down regulation of MIAT1 could inhibit the proliferation of endothelial cells, tube formation, and migration. In this study, we assessed the anti-angiogenic activity of quercetin on human umbilical vein endothelial cells (HUVEC) via the expression of MALAT1 and MIAT genes.Methods:In the present study, HUVEC cells were incubated with various concentrations of quercetin for 24, 48, and 72 h. Cell proliferation was then evaluated by MTT assay. RNA was extracted by TRIzol and cDNA synthesis. The expression levels of MALAT1 and MIAT genes relative to the GAPDH gene were quantified using the highly sensitive real-time PCR method.Results:Our results demonstrated that quercetin has an inhibitory impact on the cell viability of HUVEC cells. The IC50 values of quercetin after 24, 48, and 72 h were 282.05 μM, 228.25 μM, and 131.65 μM, respectively. The MALAT1/GAPDH ratio was computed as 0.21 for 24h, 0.18 for 48h, and 0.29 for 72 h. The MIAT/GAPDH ratio was computed as 0.82 for 24h, 0.84 for 48h, and 0.78 for 72 h.Conclusions:In conclusion, quercetin treatment had an anti-angiogenic effect on HUVEC cells, at least partially via the down regulation of MALAT1 and MIAT LncRNAs gene expression.

LncRNA MALAT1 promotes breast cancer progression and doxorubicin resistance via regulating miR-570–3p

BackgroundMetastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that regulates disease progression in various types of cancers. The aim of this study was to explore the role of MALAT1 in breast cancer (BC) progression and doxorubicin resistance. MethodsReal-time polymerase chain reaction (RT-PCR) was used to determine the expression of MALAT1 in BC tissues and cells; MTT and Transwell assay were used to detect the proliferation, migration and invasion of BC cells, respectively; drug resistance test was performed to assess the sensitivity of BC cells to doxorubicin; dual-luciferase reporter gene assay was conducted to verify the interaction between MALAT1 and miR-570–3p. ResultsMALAT1 was highly expressed in BC tissues compared with normal tissues adjacent to cancer as well as in BC cells. In addition, inhibition the expression of MALAT1 could significantly suppress the proliferation, migration and invasion of BC cells. Meanwhile, down-regulation of MALAT1 sensitized BC cells to doxorubicin. Moreover, bioinformatics analysis suggested that miR-570–3p was the potential downstream target of MALAT1. Dual-luciferase reporter gene assay confirmed that MALAT1 could directly target miR-570–3p. Additionally, miR-570–3p was lowly expressed in BC tissues and cells. Up-regulation of miR-570–3p not only significantly inhibited the proliferation, metastasis, and invasion of BC cells, but also increased the sensitivity of BC cells to doxorubicin. ConclusionMALAT1 functions as a novel oncogenic lncRNA in regulating the progression and doxorubicin resistance of BC by targeting miR-570–3p.

Long Noncoding RNA MALAT1 and Regulation of the Antioxidant Defense System in Diabetic Retinopathy.

The retina experiences increased oxidative stress in diabetes, and the transcriptional activity of Nrf2, which is critical in regulating many antioxidant genes, is decreased. The nuclear movement/transcriptional activity of Nrf2 is mediated by its intracellular inhibitor Keap1, and retinal Keap1 levels are increased in diabetes. Gene expression is also regulated by long noncoding RNAs (LncRNAs). Our aim was to investigate the role of LncRNA MALAT1 in the regulation of Keap1-Nrf2-antioxidant defense in diabetic retinopathy. LncRNA MALAT1 expression (quantitative real-time PCR, immunofluorescence, and RNA sequencing), its interactions with Keap1 (FACS), Keap1-Nrf2 interactions, and transcription of the antioxidant response genes (immunofluorescence and nuclear RNA sequencing) were investigated in retinal endothelial cells exposed to high glucose. Glucose increased LncRNA MALAT1 levels by increasing Sp1 transcription factor binding at its promoter. Downregulation of LncRNA MALAT1 by its siRNA prevented glucose-induced increase in Keap1 and facilitated Nrf2 nuclear translocation and antioxidant gene transcription. Retinal microvessels from streptozotocin-induced diabetic mice and human donors with diabetic retinopathy also presented similar increases in LncRNA MALAT1 and its interactions with Keap1 and decreases in Nrf2-mediated antioxidant defense genes. Thus, LncRNA MALAT1, via Keap1-Nrf2, regulates antioxidant defense in diabetic retinopathy. Inhibition of LncRNA MALAT1 has potential to protect the retina from oxidative damage and to prevent or slow down diabetic retinopathy.