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Fibrosis is the endpoint of pathological remodeling involving different expressions of non-coding RNA(ncRNA) including long non-coding RNA growth arrest-specific 5 (lncRNA Gas5). Up to now, many studies have demonstrated that lncRNA Gas5 may play a vital regulatory role in the occurrence and development of organ fibrosis including liver, renal and cardiac fibrosis et al. Furthermore, Gas5 may also serve as a biomarker in diagnostic settings for fibrosis diseases. Structurally, IncRNA Gas5 impacts fibrosis via its distinct structural modules. In response to various external stresses, distinct functional complexes on different parts of Gas5 sequence influence cell proliferation and survival, thus affecting the inflammatory process and deposition of extracellular matrix(ECM) in organ fibrosis. However, there is no consensus on the role of Gas5 in fibrosis and its changed expression under various circumstances. In this review, we present an overview of what is known about the effect of Gas5 in organ fibrosis so far and for the first time explain its mechanism in the progression of fibrosis based on its unique structure. [Display omitted] • Different changes of lncRNA Gas5 expression in different organ fibrosis models. • We present an overview of what is known about the effect of Gas5 in organ fibrosis. • We explain the mechanism of lncRNA Gas5 in the progression of fibrosis based on its unique structure for the first time. [ABSTRACT FROM AUTHOR]

• Innovative Mechanism Unveiled: Our study reveals that GAS5 functions as a molecular sponge for miR-455-5p, thereby regulating PTEN expression. • Epigenetic Modulation by Resveratrol: We discovered that resveratrol upregulates DNMT1, which in turn downregulates the GAS5-mediated miR-455-5p/PTEN axis. • GAS5 Effects: GAS5 counteracts resveratrol's effectiveness in reducing apoptosis and ROS by downregulating miR-455-5p. • Role of DNMT1 in Cellular Defense: DNMT1 enhances resveratrol's defense against DDP-triggered apoptosis and ROS in HEI-OCI cells via GAS5 methylation. • In Vivo Protective Effects: DNMT1 also amplifies resveratrol's protective impact against DDP-induced ototoxicity in vivo through GAS5 methylation. Our previous research demonstrated that resveratrol counters DDP-induced ototoxicity by upregulating miR-455-5p, which targets PTEN. This study aimed to elucidate the underlying mechanisms involving GAS5 and DNA methyltransferase 1 (DNMT1) in resveratrol's protective action. A luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to study the binding between GAS5 and miR-455-5p, as well as between miR-455-5p and PTEN. HEI-OC1 cells treated with DDP were transfected with vectors for GAS5, si-GAS5, DNMT1, si-DNMT1, and miR-455-5p mimics, as well as PTEN. Subsequently, they were treated with resveratrol and exposed to DDP, both separately and in combination. The distribution of CpG islands in the GAS5 promoter was identified using MethyPrimer, and methylation-specific PCR (MSP) was conducted to determine the methylation levels of GAS5. Chromatin immunoprecipitation (ChIP) was utilized to examine the interaction between DNMT1 and GAS5. The viability of HEI-OC1 cells, catalase (CAT) activity, apoptosis, and ROS levels were assessed using the CCK-8 assay, CAT assay, TUNEL staining, and flow cytometry, respectively. An in vivo mouse model was developed to measure auditory brainstem response (ABR) thresholds, while RT-qPCR and Western blot analysis were employed to evaluate molecular levels. Our study discovered that GAS5 acts as a sponge for miR-455-5p, thereby increasing PTEN expression in DDP-treated HEI-OC1 cells. This process was reversed upon treatment with resveratrol. Importantly, DNMT1 promoted the methylation of the GAS5 promoter, leading to the suppression of GAS5 expression. This suppression enhanced the effectiveness of resveratrol in combating DDP-induced apoptosis and ROS in HEI-OC1 cells and amplified its protective effect against DDP's ototoxicity in vivo. Our research emphasizes the significance of the DNMT1/GAS5/miR-455-5p/PTEN axis as a promising new route to boost resveratrol's effectiveness against DDP-induced ototoxicity. [ABSTRACT FROM AUTHOR]

The long noncoding RNA growth arrest-specific 5 (lncRNA Gas5) is implicated in various kidney diseases. In this study, we investigated the lncRNA Gas5 expression profile and its critical role as a potential biomarker in the progression of chronic kidney disease. Subsequently, we assessed the effect of lncRNA Gas5 deletion on renal fibrosis induced by unilateral ureteral obstruction (UUO). The results indicated that loss of lncRNA Gas5 exacerbates UUO-induced renal injury and extracellular matrix deposition. Notably, the deletion of lncRNA Gas5 had a similar effect on control mice. The fibrogenic phenotype observed in mice lacking lncRNA Gas5 correlates with peroxisome proliferator-activated receptor (PPAR) signaling pathway activation and aberrant cytokine and chemokine reprogramming. Single-cell RNA sequencing analysis revealed key transcriptomic features of fibroblasts after Gas5 deletion, revealing heterogeneous cellular states suggestive of a propensity for renal fibrosis. Our findings indicate that lncRNA Gas5 regulates the differentiation and activation of immune cells and the transcription of key genes in the PPAR signaling pathway. These data offer novel insights into the involvement of lncRNA Gas5 in renal fibrosis, potentially paving the way for innovative diagnostic and therapeutic targets. • lncRNA Gas5 is a potential biomarker in chronic kidney disease. • Loss of lncRNA Gas5 exacerbates renal injury and extracellular matrix deposition in UUO-induced renal fibrosis. • We explain the role of lncRNA Gas5 in renal fibrosis based on the integration of scRNA-Seq and Bulk RNA-Seq analysis for the first time. • lncRNA Gas5 could regulate the differentiation and activation of immune cells and transcription of key genes in PPAR signal pathway. [ABSTRACT FROM AUTHOR]

• GAS5 and PTEN was downregulated in glioma and miR-106b was opposite. • GAS5 regulated the EMT process of glioma cells. • GAS5 directly targeted miR-106b in glioma. • PTEN was a target of miR-106b for regulating EMT process of glioma cells. LncRNA growth arrest special 5 (GAS5) and microRNA-106b (miR-106b) have been reported to be involved in the regulation of gliomas. However, their precise mechanisms in regulating the progression and development of gliomas remain unclear. We aimed to investigate the interaction between GAS5 and miR-106b, and their influence on the proliferation, migration, and invasion of gliomas cells. Western blotting and qRT-PCR were applied for measuring expression of protein and mRNA, respectively. The proliferation, migration, and invasion of cells were measured by MTT, wound healing, and transwell assays, respectively. Dual luciferase reporter assay was applied for confirming the binding site between miR-106b and GAS5, miR-106b and PTEN. Significant higher expression of miR-106b, and lower expression of GAS5 and PTEN in the glioma tissues were observed. The binding sites between GAS5 and miR-106b, miR-106b and PTEN were identified. GAS5 could regulate the expression of PTEN through targeting miR-106b, and further influence EMT process, and the proliferation, migration, and invasion of gliomas cells. Meanwhile, PTEN could remarkably inhibited the proliferation, migration and invasion of glioma cells. The influence of PTEN on glioma cells and EMT was similar to GAS5. GAS5 could regulate the EMT process, and the migration of gliomas cells through miR-106b targeting PTEN. Therefore, our findings may provide a new thought for the study of pathogenesis and treatment of glioma. [ABSTRACT FROM AUTHOR]

• Spinal cord ischemia-reperfusion injury affects nerve function through apoptosis and inflammation. • Downregulation of lncRNAGas5 and MMP-7 inhibit apoptosis and inflammation after SCII. • LncRNA Gas5 plays an important role in SCII, perhaps by inhibiting MMP-7, cleaved caspase-3 and IL-1β. • Downregulation of lncRNA Gas5 and MMP-7 may be a promising therapeutic approach in the treatment of SCII. Spinal cord ischemia-reperfusion injury(SCII)affects nerve function through many mechanisms, which are complex and not fully understood. Recently, accumulating evidence has indicated that long noncoding RNAs (lncRNAs) play an increasingly important role in SCII. We investigated the role of lncRNA growth arrest-specific 5(Gas5) in a rat SCII model, and its effects on apoptosis and inflammation possibly by modulating MMP-7, cleaved caspase-3 and IL-1β. LncRNA Gas5 and MMP-7 were knocked down by intrathecal siRNA injection. Neurological assessment and TUNEL assay were performed. The RNA and protein expression levels of lncRNA Gas5, MMP-7, cleaved caspase-3 and IL-1β were determined by PCR and Western blotting, respectively. MMP-7 localization was visualized by double-immunofluorescence. SCII induced functional impairment in the hind limb, and the expression of lncRNA Gas5 was highest at 24 h after SCII. LncRNA Gas5 downregulation inhibited the RNA and protein expression of MMP-7, as well as the protein expression of cleaved caspase-3 and IL-1β. LncRNA Gas5 downregulation reduced the number of TUNEL-positive and MMP-7-positive double-labeled cells. Therefore, lncRNA Gas5 downregulation alleviated hind limb functional impairment and improved neuronal apoptosis after SCII. MMP-7 downregulation also inhibited apoptosis and inflammation and alleviated damage. Pretreatment with intrathecal injection of si-lncRNA Gas5 and si-MMP-7 reduced the expression levels of cleaved caspase-3 and IL-1β, protecting nerve function after SCII. These results show that lncRNA Gas5 plays an important role in SCII, perhaps by inhibiting MMP-7, cleaved caspase-3 and IL-1β. LncRNA Gas5 downregulation could be a promising therapeutic approach in the SCII treatment. [ABSTRACT FROM AUTHOR]

• Expression levels of GAS5 is decreased in CD4+ T cells and plasma from SLE patients. • LncRNA GAS5 inhibits activation of normal CD4+ T cells and attenuates the self-reactivity of SLE CD4+T. • E4BP4 is involved in GAS-mediated inhibition of CD4+ T cells activation. • GAS5 upregulates E4BP4 by inhibiting miR-92. Increasing evidence reveals that long noncoding RNAs (lncRNAs) are associated with autoimmune and inflammatory diseases, such as systemic lupus erythematosus (SLE). In this study, we aimed to explore the role of lncRNA growth arrest specific 5 (GAS5) in the pathogenesis of SLE. We found that lncRNA GAS5 was decreased in CD4+ T cells and plasma from SLE patients. Overepression of GAS5 inhibited activation of normal CD4+ T cells and attenuated the self-reactivity of SLE CD4+ T cells. Additionally, we demonstrated that adenovirus E4 binding protein 4 (E4BP4) was involved in lncRNA GAS5-mediated inhibition of CD4+ T cell activation. GAS5 could upregulate E4BP4 by inhibiting miR-92a-3p. Taken together, our results indicate that the GAS5/miR-92a-3p/E4BP4 pathway plays an important role in inhibiting CD4+ T cell activation in SLE, thus providing a potential therapeutic target for SLE treatment. [ABSTRACT FROM AUTHOR]

The rapid progress of gastric cancer (GC) is mainly due to metastasis. Long non-coding RNA (lncRNA) GAS5 has been identified as a tumor suppressor in numerous cancers, and its downregulation in GC has already been reported. In this study, we planned to investigate the role of GAS5 in GC metastasis. Gene expressions were detected by qRT-PCR. ISH staining was applied to assess GAS5 level in clinical tissues. Gain-of-function assays were conducted to evaluate the function of GAS5 in GC metastasis. RNA pull down, RIP and cycloheximide assays were performed to confirm the relationship between GAS5 and p53 protein. GAS5 expression was markedly decreased in GC tissues and cell lines, and its low expression was strongly related to GC metastasis and unsatisfactory prognosis. GAS5 overexpression repressed GC cell migration and invasion by targeting p53. Intriguingly, GAS5 relied on the exon 12 to interact with and stabilize p53 protein. Our data implied that GAS5 is a suppressor in GC metastasis via modulating p53 signaling, suggesting GAS5 as a potential therapeutic target for GC, especially for patients with metastasis. [ABSTRACT FROM AUTHOR]

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Upon investigation, it was discovered that 5 figures contain fabrication. Figures 1C, 3D, 5C, 5D, and 6G contain manipulated and/or duplicated data. The authors requested a corrigendum be published, however, due to the large number of corrections applied (figures 3, 6, 7, 8 and S3), it cannot be concluded that these changes would not alter the conclusions of the paper. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (LncRNAs) are aberrantly expressed in many diseases including cardiac fibrosis. LncRNA growth arrest-specific 5 (GAS5) is reported as a significant mediator in the control of cell proliferation and growth; however, the role and function in cardiac fibrosis remain unknown. In this study, we confirmed that GAS5 was lowly expressed in cardiac fibrosis tissues as well as activated cardiac fibroblast. Overexpression of GAS5 inhibited the proliferation of cardiac fibroblast. Moreover, microRNA-21 (miR-21) has been reported to be overexpressed in cardiac fibrosis tissues as well as activated cardiac fibroblast, which is responsible for the progression of cardiac fibrosis. We found that up-regulated GAS5 decreased the expression of miR-21 significantly. Furthermore, GAS5 that upregulated or downregulated the expression of PTEN through miR-21 in cardiac fibroblasts. Taken together, GAS5 plays a suppressive role in cardiac fibrosis via negative regulation of miR-21. These results indicated that GAS5 may be a novel therapeutic target for further research of cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Intracerebral hemorrhage (ICH) is the most devastating stroke subtype. Transcription factor Forkhead box O1 (FoxO1) is extensively implicated in cerebral injury. This study investigated the mechanism of FoxO1 in neurological function recovery in ICH mice.Methods: A murine model of ICH was established. The modified neurological severity score (mNSS), forelimb placement test, and corner turn test were adopted to evaluate the neurological function of mice. The brain water content was measured and the pathological changes of cerebral tissues were observed. The levels of IL-1β, IL-6, and TNF-α were determined. The expressions of FoxO1, lncRNA GAS5, miR-378a-5p, and heat shock 70 kDa protein 5 (Hspa5) in mouse cerebral tissues were examined. The binding relationships among FoxO1, lncRNA GAS5, miR-378a-5p, and Hspa5 were validated. Functional rescue experiments were designed to verify the role of lncRNA GAS5/miR-378a-5p/Hspa5 axis in neurological function recovery in ICH mice.Results: FoxO1 was highly expressed in cerebral tissues of ICH mice. FoxO1 silencing facilitated neurological function recovery in ICH mice, evidenced by decreased mNSS, improved forelimb placement rate, reduced turning defects, declined brain water content, relieved edema, intracellular vacuoles, and inflammatory cell infiltration, and reduced IL-1β, IL-6, and TNF-α levels. FoxO1 enhanced lncRNA GAS5 expression by binding to its promoter. LncRNA GAS5 facilitated Hspa5 transcription by sponging miR-378a-5p. Intervention of lncRNA GAS5/miR-378a-5p/Hspa5 axis reversed the promoting effect of FoxO1 silencing on the neurological function recovery in ICH mice.Conclusion: FoxO1 silencing facilitated neurological function recovery in ICH mice via the lncRNA GAS5/miR-378a-5p/Hspa5 axis. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) is a progressive and potentially serious lung disease, defined by an abnormal elevation of pulmonary arterial pressure. PH occurs for many reasons, and hypoxia is considered as an important stimulus for the disease. Proliferation and migration of pulmonary artery smooth muscular cells (PASMCs) in the small peripheral pulmonary arteries are common characteristic features in hypoxia-induced PH (HPH). However, the mechanisms involved in the hypoxia-induced cell proliferation and migration are not clear. The aim of the present study was to investigate the role of lncRNA Gas5 in the hypoxia-stimulated proliferation and migration of human PASMCs (hPASMCs). We found that the expression of Gas5 was down-regulated in a rat model with hypoxia and in cultured hypoxic hPASMCs, and silence of Gas5 significantly promoted hPASMCs proliferation and migration in both normal and hypoxia condition. Subsequent studies revealed that miR-23b-3p interacted with Gas5 by directly targeting the miRNA-binding site in the Gas5 sequence, and qRT-PCR results showed miR-23b-3p and Gas5 could affect each other's expression, respectively. Further study demonstrated that Gas5 acted as a competing endogenous RNA (ceRNA) for miR-23b-3p to modulate the KCNK3 expression, and these interactions led to promotion of hPASMCs proliferation and migration. This study identified that Gas5/miR-23b-3p/KCNK3 axis may be a mechanism that hypoxia-induced PASMCs proliferation and migration, providing a strategy for clinical treatment of HPH in the future. [ABSTRACT FROM AUTHOR]

Long non coding RNA growth arrest-specific transcript 5 (LncRNA GAS5) participate in the formation of fibrosis diseases. However, the key role of LncRNA GAS5 in the development of cardiac fibrosis remains unclear. Accumulating evidence suggests that DNA methylation alterations play a central role in cardiac fibroblast activation. In this study, we explored MeCP2 inactivation of LncRNA GAS5 leads to down regulation of LncRNA GAS5 expression in cardiac fibrosis. Gain and loss function of LncRNA GAS5 and MeCP2 was analyzed. The expression of LncRNA GAS5 was significantly decreased in cardiac fibrosis tissues, while MeCP2 was significantly increased. Moreover, the expression of MeCP2 was increased in TGF-β1 induced cardiac fibroblasts, while the expression of LncRNA GAS5 was decreased. Down regulation of LncRNA GAS5 resulted in increasing cellular proliferation. In contrast, exogenous over expression of LncRNA GAS5 in cardiac fibroblasts inhibited cell proliferation. 5-AzadC or knockdown of MeCP2 treatment significantly restored LncRNA GAS5 expression in cardiac fibroblasts, while over expression of MeCP2 treatment significantly inhibited LncRNA GAS5 expression in cardiac fibroblasts. In summary, these results suggested that MeCP2 silencing of LncRNA GAS5 triggers cardiac fibroblasts activation in cardiac fibrosis. Unlabelled Image • LncRNA GAS5 controls cardiac fibroblast activation and fibrosis. • MeCP2 inactivation of LncRNA GAS5 in activated cardiac fibroblast. • MeCP2 and GAS5 regulate cardiac fibroblast activation via Smad3 axis. [ABSTRACT FROM AUTHOR]

• GAS5 expression was downregulated both in PBMCs of ITP patients and spleen tissues of ITP mice. • GAS5 accelerated the degradation of STAT3 via promoting TRAF6-mediated ubiquitination. • Overexpressing GAS5 suppressed Th17 differentiation in vitro and alleviated ITP in vivo via reducing STAT3. The increased differentiation of T helper 17 cells (Th17) accelerates the development of immune thrombocytopenia (ITP), which is a common autoimmune disease with limited therapeutic methods. Recent studies have revealed that long non-coding RNAs (lncRNAs) play a critical role in autoimmune diseases, thus this study aims to investigate the effect of lncRNA GAS5 on the differentiation of Th17 cells in ITP. The expression of GAS5 in peripheral blood mononuclear cells (PBMCs) of ITP patients and spleen tissues of ITP mice was measured by qRT-PCR. The percentage of Th17 cells in CD4+ cells was measured by flow cytometry. The combination between GAS5 and STAT3 was confirmed by RNA pull-down assay and RNA Binding Protein Immunoprecipitation (RIP). The ubiquitination of STAT3 was detected by ubiquitination assay and the interaction between STAT3 and TRAF6 was measured by Co-Immunoprecipitation (Co-IP). Finally, the effect of GAS5 on Th17 differentiation was investigated in vitro and in vivo using lentivirus (lenti)-GAS5. GAS5 expression was downregulated both in PBMCs of ITP patients and spleen tissues of ITP mice. Overexpression of GAS5 suppressed Th17 differentiation while had no effect on Treg differentiation in naïve CD4+ cells. RNA pull-down and RNA immunoprecipitation assays confirmed the interaction between GAS5 and STAT3. Further studies showed GAS5 accelerated the degradation of STAT3 via promoting TRAF6-mediated ubiquitination. Overexpressing GAS5 suppressed Th17 differentiation in vitro and alleviated ITP in vivo via reducing STAT3. LncRNA GAS5 inhibited Th17 differentiation through promoting the TRAF6-mediated ubiquitination of STAT3, thus relieving ITP. [ABSTRACT FROM AUTHOR]

• AS-IV attenuates hypoxia-induced H9c2 cell injury. • AS-IV down-regulates lncRNA GAS5 expression in H9c2 cells. • AS-IV alleviates hypoxia-induced H9c2 cell injury via down-regulating lncRNA GAS5. • AS-IV down-regulates lncRNA GAS5 via the PI3K/mTOR pathway in H9c2 cells. Poor understanding of the regulatory mechanisms of astragaloside IV (AS-IV) in cardiovascular protection limits clinical application of AS-IV in heart failure. Hypoxia is an important stimulus in the progression of heart failure. We investigated the role of AS-IV in hypoxia-treated cardiomyoblast H9c2 cells. Cell viability and apoptotic cells in hypoxia-treated H9c2 cells were detected by CCK-8 assay and flow cytometry, respectively. Expression of proteins associated with proliferation and apoptosis was measured by Western blot. Then effects of AS-IV on hypoxia-induced cell injury were explored, and the alteration of lncRNA growth arrest specific 5 (GAS5) level under AS-IV treatment was determined by RT-qPCR. Whether AS-IV affected hypoxia-treated H9c2 cells via lncRNA GAS5 was subsequently testified. Besides, whether AS-IV regulated lncRNA GAS5 expression was via modulating the PI3K/mTOR pathway was investigated. Hypoxia-induced decreasing cell viability, increasing apoptotic cells, and proteins associated with proliferation and apoptosis were all attenuated by AS-IV treatments. Then, we found that lncRNA GAS5 expression was down-regulated by AS-IV treatment, and AS-IV might affect hypoxia-stimulated H9c2 cells through lncRNA GAS5. Finally, we found that inhibition of PI3K/mTOR or mTOR could reverse the AS-IV-induced down-regulation of lncRNA GAS5 in H9c2 cells. AS-IV protected H9c2 cells against hypoxia through down-regulating lncRNA GAS5. Besides, AS-IV might repress lncRNA GAS5 expression via activation of the PI3K/mTOR pathway. [ABSTRACT FROM AUTHOR]