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Recently, more and more data have been accumulating indicating the role of long noncoding RNAs (lncRNAs) in the regulation of biological processes in cells, as well as in the mechanisms of cancer development and progression. Aberrant methylation of promoter regions of both protein genes and lncRNA genes can disrupt their expression and functional activity. Using bioinformatics databases, six lncRNA genes (GAS5, HOTAIR, LINC00472, LINC00886, SNHG17, and TUG1) with CpG islands differentially expressed and presumably hypermethylated in tumors of patients with ovarian cancer (OC) were selected. Using a sample of 93 OC samples, real-time methylation specific PCR showed a statistically significant (p < 0.05) increase in the level of methylation in tumors. Moreover, for the genes LINC00472, LINC00886, SNHG17, and TUG1, hypermethylation in OC was detected for the first time. Five genes (except SNHG17) showed a further increase in methylation levels at a more advanced stage, and four genes (except SNHG17 and LINC00886) showed a significant association with metastasis. Using real-time RT-PCR, differential changes in the expression level of the GAS5, HOTAIR, SNHG17, and TUG1 genes and a significant correlation of methylation with expression for the GAS5 gene were shown. Thus, hypermethylation associated with the progression and/or development of OC was detected for six lncRNA genes, which is important for elucidating the epigenetic processes involved in the pathogenesis of OC and can be used as new biomarkers of OC. [ABSTRACT FROM AUTHOR]

Considering the effect of SIRT1 on improving myocardial fibrosis and GAS5 inhibiting occurrence and development of myocardial fibrosis at the cellular level, the aim of the present study was to investigate whether LncRNA GAS5 could attenuate cardiac fibrosis through regulating mir-217/SIRT1, and whether the NLRP3 inflammasome activation was involved in this process. Isoprenaline (ISO) was given subcutaneously to the male C57BL/6 mice to induce myocardial fibrosis and the AAV9 vectors were randomly injected into the left ventricle of each mouse to overexpress GAS5. Primary myocardial fibroblasts (MCFs) derived from neonatal C57BL/6 mice and TGF-β1 were used to induce fibrosis. And the GAS5 overexpressed MCFs were treated with mir-217 mimics and mir-217 inhibitor respectively. Then the assays of expression levels of NLRP3, Caspase-1, IL-1β and SIRT1 were conducted. The findings indicated that the overexpression of GAS5 reduced the expression levels of collagen, NLRP3, Capase-1, IL-1β and SIRT1 in ISO treated mice and TGF-β1 treated MCFs. However, this effect was significantly weakened after mir-217 overexpression, but was further enhanced after knockdown of mir-217. mir-217 down-regulates the expression of SIRT1, leading to increased activation of the NLRP3 inflammasome and subsequent pyroptosis. LncRNA GAS5 alleviates cardiac fibrosis induced via regulating mir-217/SIRT1 pathway. [ABSTRACT FROM AUTHOR]

The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) level was demonstrated as involved in pediatric inflammatory bowel disease (IBD) pathogenesis. Since its antisense transcript GAS5-AS1 has never been investigated in IBD, this study aims to detect whether GAS5-AS1 and GAS5 levels are related to IBD clinical parameters and investigate their correlation in vitro. Twenty-six IBD pediatric patients were enrolled; paired inflamed and non-inflamed intestinal biopsies were collected. We evaluated GAS5 and GAS5-AS1 levels by real-time PCR. The role of GAS5 and GAS5-AS1 was assessed in vitro by transient silencing in THP1-derived macrophages. GAS5-AS1 and GAS5 levels were associated with patients' clinical parameters; GAS5-AS1 expression was downregulated in inflamed tissues and inversely correlated with disease activity. A positive correlation between GAS5-AS1 and GAS5 levels was observed in non-inflamed biopsies. On THP1-derived macrophages, a reduced amount of both GAS5-AS1 and GAS5 was observed; accordingly, matrix metalloproteinase (MMP) 9 was increased. After GAS5-AS1 silencing, a downregulation of GAS5 was found, whereas no effect was detected on GAS5-AS1 after GAS5 silencing. Conclusion: This study provided for the first time new insights into the potential role of GAS5-AS1 in IBD. GAS5-AS1 modulates GAS5 levels in vitro and may serve as a potential IBD diagnostic biomarker. What is Known: • GAS5 is involved in regulating intestinal MMP-2 and MMP-9 in pediatric patients with IBD; • GAS5-AS1 has never been investigated in the context of IBD; • GAS5-AS1 regulates the expression of GAS5, increasing its stability in tissues and in vitro cell models of cancer. What is New: • GAS5-AS1 correlated with GAS5 and IBD clinical parameters; • GAS5-AS1 can modulate GAS5 levels in macrophages; • GAS5-AS1 may serve as potential IBD diagnostic biomarker. [ABSTRACT FROM AUTHOR]

Thousands of lncRNAs have been found in zebrafish embryogenesis and adult tissues, but their identification and organogenesis-related functions have not yet been elucidated. In this study, high-throughput sequencing was performed at three different organogenesis stages of zebrafish embryos that are important for zebrafish muscle development. The three stages were 10 hpf (hours post fertilization) (T1), 24 hpf (T2), and 36 hpf (T3). LncRNA gas5, associated with muscle development, was screened out as the next research target by high-throughput sequencing and qPCR validation. The spatiotemporal expression of lncRNA gas5 in zebrafish embryonic muscle development was studied through qPCR and in situ hybridization, and functional analysis was conducted using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9, CRISPR/Cas9). The results were as follows: (1) A total of 1486 differentially expressed lncRNAs were identified between T2 and T1, among which 843 lncRNAs were upregulated and 643 were downregulated. The comparison with T3 and T2 resulted in 844 differentially expressed lncRNAs, among which 482 lncRNAs were upregulated and 362 lncRNAs were downregulated. A total of 2137 differentially expressed lncRNAs were found between T3 and T1, among which 1148 lncRNAs were upregulated and 989 lncRNAs were downregulated, including lncRNA gas5, which was selected as the target gene. (2) The results of spatiotemporal expression analysis showed that lncRNA gas5 was expressed in almost all detected embryos of different developmental stages (0, 2, 6, 10, 16, 24, 36, 48, 72, 96 hpf) and detected tissues of adult zebrafish. (3) After lncRNA gas5 knockout using CRISPR/Cas9 technology, the expression levels of detected genes related to muscle development and adjacent to lncRNA gas5 were more highly affected in the knockout group compared with the control group, suggesting that lncRNA gas5 may play a role in embryonic muscle development in zebrafish. (4) The results of the expression of the skeletal myogenesis marker myod showed that the expression of myod in myotomes was abnormal, suggesting that skeletal myogenesis was affected after lncRNA gas5 knockout. The results of this study provide an experimental basis for further studies on the role of lncRNA gas5 in the embryonic skeletal muscle development of zebrafish. [ABSTRACT FROM AUTHOR]

This study explored the inhibitory effect of miR-223-3p on the proliferation of brain glioma cells and its potential mechanism in relation to growth arrest-specific transcripts (GAS5). We utilized the StarBase tool to predict the binding of GAS5 to miR-223-3p, further confirming the binding relationship between GAS5 and miR-223-3p through a dual luciferase reporter assay and RNA immunoprecipitation. In vitro cultured U87 brain glial cells were categorized into four groups: the control group, quercetin group, GAS5 inhibition group, and quercetin + si-GAS5 group. We analyzed and compared the impacts of quercetin on GAS5/miR-223-3p and pyroptotic proteins (NLRP3, ASC, caspase-1, GSDMD, and GSDME), as well as the proliferative capacity of U87 cells. StarBase's predictions indicated that GAS5 bound to miR-223-3p. This was corroborated by the dual luciferase reporter assay and RNA immunoprecipitation assay, which demonstrated a direct binding between GAS5 and miR -223-3p. Quercetin was observed to enhance GAS5 expression, inhibit the expression of miR-223-3p and pyroptotic proteins (NLRP3, ASC, caspase-1, GSDMD, and GSDME), and suppress the proliferation and invasion of U87 cells (P < 0.05). Downregulation of GAS5 expression correlated with an increase in the expression of miR-223-3p and pyroptotic proteins (NLRP3, ASC, caspase-1, GSDMD, and GSDME), promoting the proliferation and invasion of RC-4B/C cells (P < 0.05). Quercetin was able to reverse the increase in miR-223-3p expression and pyroptotic proteins (NLRP3, ASC, caspase-1, GSDMD, and GSDME) induced by the downregulation of GAS5, thereby inhibiting the proliferation and invasion of U87 cells (P < 0.05). In conclusion, quercetin might inhibit the proliferation of U87 brain glioma cells by promoting the expression of GAS5, which in turn competitively inhibited miR-223-3p and suppressed the pyroptotic signaling pathway. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs have been shown to be involved in a myriad of physiological and pathological pathways. To date, malignant pleural mesothelioma (MPM) is considered an extremely aggressive cancer. One reason for this is the late diagnosis of the disease, which can occur within 30–40 years of asbestos exposure. There is an immense need for the development of new, sensitive, inexpensive and easy methods for the early detection of this disease other than invasive methods such as biopsy. The aim of this study was to determine the expression of circulating lncRNAs in mesothelioma patient plasma to identify potential biomarkers. Ten previously identified lncRNAs that were shown to be aberrantly expressed in mesothelioma tissues were selected as candidates for subsequent validation. The expression of the ten selected candidate lncRNAs was verified via quantitative PCR (qPCR) in human plasma samples from mesothelioma patients versus healthy controls. The expression levels of circulating GAS5, SNHG8 and MALAT1 were significantly greater in plasma samples from patients than in those from controls. The ROC analysis of both MALAT1 and SNHG8 revealed 88.89% sensitivity and 66.67% specificity. The sensitivity of these markers was greater than that of GAS5 (sensitivity 72.22% and specificity 66.67%). The regression model for GAS5 was statistically significant, while that for SNHG8 and MALAT1 was not significant due to the small sample size. The area under the curve (AUC) of the three ROC curves was acceptable and significant: 0.7519 for GAS5, 0.7352 for SNHG8 and 0.7185 for MALAT1. This finding confirmed their ability to be used as markers. The three lncRNAs were not affected by age, sex or smoking status. The three lncRNAs showed great potential as independent predictive diagnostic biomarkers. Although the prediction model for MALAT1 did not significantly differ, MALAT1 was significantly expressed in patients more than in controls (p = 0.0266), and the recorded sensitivity and specificity were greater than those of GAS5. [ABSTRACT FROM AUTHOR]

The GAS5 gene encodes a long non-coding RNA (lncRNA) and intron-located small nucleolar RNAs (snoRNAs). Its structure, splice variants, and diverse functions in mammalian cells have been thoroughly investigated. However, there are still no data on a successful knockout of GAS5 in human cells, with most of the loss-of-function experiments utilizing standard techniques to produce knockdowns. By using CRISPR/Cas9 to introduce double-strand breaks in the terminal intronic box C/D snoRNA genes (SNORDs), we created monoclonal cell lines carrying continuous deletions in one of the GAS5 alleles. The levels of GAS5-encoded box C/D snoRNAs and lncRNA GAS5 were assessed, and the formation of the novel splice variants was analyzed. To comprehensively evaluate the influence of specific SNORD mutations, human cell lines with individual mutations in SNORD74 and SNORD81 were obtained. Specific mutations in SNORD74 led to the downregulation of all GAS5-encoded SNORDs and GAS5 lncRNA. Further analysis revealed that SNORD74 contains a specific regulatory element modulating the maturation of the GAS5 precursor transcript. The results demonstrate that the maturation of GAS5 occurs through the m6A-associated pathway in a SNORD-dependent manner, which is a quite intriguing epitranscriptomic mechanism. [ABSTRACT FROM AUTHOR]

Long non-coding (lnc)RNAs are a highly diverse collection of RNAs with a broad spectrum of regulatory mechanisms and functions. Among those, small nucleolar (sno)RNA host genes (SNHGs), which are often highly expressed and include snoRNAs in their introns, are emerging as key players in several biological processes. Both coding and noncoding SNHGs display unique features compared with regular mRNAs and, thus, noncoding SNHGs also have special features compared with other lncRNAs. Some noncoding SNHGs, such as GAS5 , ZFAS1, and SNHG5 , were shown to have important functions in addition to hosting snoRNAs, and some have even evolved functional open reading frames, thus harboring at least three distinct functional features. Mammalian genomes are pervasively transcribed into different noncoding (nc)RNA classes, each one with its own hallmarks and exceptions. Some of them are nested into each other, such as host genes for small nucleolar RNAs (snoRNAs), which were long believed to simply act as molecular containers strictly facilitating snoRNA biogenesis. However, recent findings show that noncoding snoRNA host genes (ncSNHGs) display features different from those of 'regular' long ncRNAs (lncRNAs) and, more importantly, they can exert independent and unrelated functions to those of the encoded snoRNAs. Here, we review and summarize past and recent evidence that ncSNHGs form a defined subclass among the plethora of lncRNAs, and discuss future research that can further elucidate their biological relevance. [ABSTRACT FROM AUTHOR]

This work aimed to investigate the effects of curcumin (Cur) encapsulated in triblock copolymer nanomicelles on lncRNA GAS5 expression and NF-κB signalling pathway in ischemic stroke rats. Using polycaprolactone (PCL), polyethylene (mPEG), polyglutamic acid (PLG), and Cur as raw materials, Cur-PLG-mPEG-PCL nanoparticles were prepared. Its morphology, particle size, and Zeta potential were analyzed. Then seventy-two SD rats were randomly divided into control (Ctrl) group, model group, model + blank nanomicelles (M + BNM) group, model +80 mg/mL Cur (M + C) group, model +40 mg/mL Cur-nanomicelles (M + CNM (40 mg/mL)) group, and model +80 mg/mL Cur nanomicelle (M + CNM (80 mg/mL)) group. The results showed that mean particle size of Cur-PLG-mPEG-PCL was (148.27 ± 27.44) nm, and mean Zeta potential was (−1.97 ± 0.21) mV. The evaluation time of intelligent optimization algorithm based on Single Shot MultiBox Detector (SSD) was significantly shortened, and average EEG power spectrum of ischemic cerebral pawns was significantly lower than that of the control group at θ, α, β, and γ bands for 4h (p < 0.01). These results indicate that the computer intelligent algorithm can be used to evaluate the behaviour of rats, EEG can reflect the changes of cerebral cortical function, and Cur-PLG-mPEG-PCL can improve neurological function and degree of brain injury. [ABSTRACT FROM AUTHOR]

Although, by definition, long noncoding RNAs (lncRNAs) are not translated, they are sometimes associated with ribosomes. In fact, some estimates suggest the existence of more than 50 K lncRNA molecules that could encode for small peptides. We examined the effects of an ethanol and Poly-ADP Ribose Polymerase (PARP) inhibitor (ABT-888) on ribosome-bound lncRNAs. Mice were administered via intraperitoneal injection (i.p.) either normal saline (CTL) or ethanol (EtOH) twice a day for four consecutive days. On the fourth day, a sub-group of mice administered with ethanol also received ABT-888 (EtOH+ABT). Ribosome-bound lncRNAs in CaMKIIα-expressing pyramidal neurons were measured using the Translating Ribosome Affinity Purification (TRAP) technique. Our findings show that EtOH altered the attachment of 107 lncRNA transcripts, while EtOH+ABT altered 60 lncRNAs. Among these 60 lncRNAs, 49 were altered by both conditions, while EtOH+ABT uniquely altered the attachment of 11 lncRNA transcripts that EtOH alone did not affect. To validate these results, we selected eight lncRNAs (Mir124-2hg, 5430416N02Rik, Snhg17, Snhg12, Snhg1, Mir9-3hg, Gas5, and 1110038B12Rik) for qRT-PCR analysis. The current study demonstrates that ethanol-induced changes in lncRNA attachment to ribosomes can be mitigated by the addition of the PARP inhibitor ABT-888. [ABSTRACT FROM AUTHOR]

Retinal endothelial cell activation is a central event in non-infectious posterior uveitis. There is recent interest in long non-coding (lnc)RNA-targeted therapeutics for retinal diseases. We aimed to identify human retinal endothelial cell lncRNAs that might be involved in activation. Eleven candidate lncRNAs were identified: GAS5, KCNQ1OT1, LINC00294, MALAT1, MEG3, MIR155HG, NEAT1, NORAD, OIP5-AS1, SENCR, TUG1. Expression was assessed by RT-PCR in human retinal endothelial cells, at baseline and following activation with interleukin (IL)-1β and tumor necrosis factor (TNF)-α. IL-1β significantly upregulated MEG3 and SENCR at 4 and 24 hours; LINC00294, NORAD, OIP5-AS1 and TUG1 at 24 hours; and MIR155HG at 4, 24 and 48 hours; but downregulated GAS5 at 24 and 48 hours. TNF-α significantly upregulated KCNQ1OT1, LINC00294, MEG3, NORAD and SENCR at 4 hours; SENCR and TUG1 at 24 hours; and MIR155HG at all time points. Future studies involving manipulation of MIR155HG may be warranted to explore potential therapeutic applications for non-infectious posterior uveitis. [ABSTRACT FROM AUTHOR]

Background: To investigate the diagnostic value of serum lncRNA growth arrest-specific transcript 5 (lncRNA GAS5) and microRNA-21 (miR-21) in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), and elucidate their roles in the pathogenesis. Methods: A microarray technology was used asses lncRNA GAS5 and miR-21 expression profiles in non-anticoagulant blood from 44 patients including T2DM without DN group (DM), T2DM with DN group (DN), and healthy controls group (N), followed by real-time PCR validation. Logistic regression and receiver operating characteristic (ROC) curves were applied to evaluate the clinical indicators among normal, T2DM, and DN patients. Results: The serum lncRNA GAS5 expression in T2DM and DN patients was significantly down-regulated compared with the N group, while the expression of miR-21 was significantly up-regulated (all P < 0.05). Fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) were negatively correlated with serum lncRNA GAS5, and FBG was independently correlated with serum lncRNA GAS5. Urinary microalbumin, total cholesterol (TC), creatinine (Cr), urea, and systolic blood pressure (SBP) were significantly positively correlated with serum miR-21. Glomerular filtration rate (GFR) and albuminuria (ALB) were negatively correlated with serum miR-21, and ALB was independently correlated with serum miR-21. Serum lncRNA GAS5, miR-21 and lncRNA GAS5/miR-21 showed good diagnostic efficiency as the "diagnostic signature" of T2DM and DN. Conclusion: The lncRNA GAS5/miR-21 diagnostic signature may be a more effective non-invasive biomarker for detecting T2DM. In addition, miR-21 alone may be a more accurate serum biomarker for the early screening of DN patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Our previous animal experiments have shown that Rongjin Niantong Fang can affect the decomposition and anabolism of cartilage matrix through long non-coding RNA (LncRNA) growth arrest-specific transcript 5 (GAS5)/miR-21, thereby preventing and treating knee osteoarthritis. Whether LncRNA GAS5/miR-21 can be used as a target for the prevention and treatment of knee osteoarthritis still needs to be verified at the cellular level. OBJECTIVE: To explore the mechanism of Rongjin Niantong Fang in the treatment of knee osteoarthritis at the cellular level. METHODS: (1) Forty 8-week-old SPF male Sprague-Dawley rats were randomly divided into blank serum group, Rongjin Niantong Fang-containing serum group, and glucosamine hydrochloride capsule-containing serum group. 0.9% normal saline, Rongjin Niantong Fang (0.45 g/mL), and glucosamine hydrochloride capsule (0.015 g/mL) were intragastrically given to the rats in the corresponding groups to collect drug containing serum. (2) Cells were treated with interleukin-1β to induce degenerative chondrocyte model. (3) Chondrocytes from the knee joint of Sprague-Dawley rats were isolated and cultured. Passage 2 chondrocytes were obtained and divided into blank group (blank serum), and model group (interleukin-1β+blank serum), treatment group (interleukin1β+Rongjin Niantong Fang-containing serum), and control group (interleukin-1β+glucosamine hydrochloride capsule-containing serum). After 48 hours of intervention, the gene and protein expressions of LncRNA GAS5, miR-21, tissue inhibitor of metalloproteinases 3 (TIMP-3), matrix metalloproteinase (MMP)- 3, MMP-9, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-5) were detected by real-time PCR and western blot, respectively. (4) Chondrocytes were transfected with LncRNA GAS5 overexpression lentiviral vector. Then, the transfected cells were divided into LncRNA GAS5 empty vector + blank serum group, LncRNA GAS5 empty vector + Rongjin Niantong Fang-containing serum group, LncRNA GAS5 overexpression + blank serum group, and LncRNA GAS5 overexpression + Rongjin Niantong Fang-containing serum group. The gene expressions of LncRNA GAS5, miR-21, TIMP-3, MMP-9, MMP-13, and ADAMTS-5 were detected using real-time PCR. RESULTS AND CONCLUSION: Culture with the serum containing 10% Rongjin Niantong Fang and 15% glucosamine hydrochloride capsule for 48 hours significantly increased the activity of chondrocytes. Compared with the model group, Rongjin Niantong Fang-containing serum and glucosamine hydrochloride capsule-containing serum could inhibit the gene expression of LncRNA GAS5, MMP-3, MMP-9, MMP-13, and ADAMTS-5 (P < 0.05) and promote the gene and protein expression of miR-21 and TIMP-3 (P < 0.05). Compared with the blank group, the gene expression of LncRNA GAS5, MMP-3, MMP-9, MMP-13, and ADAMTS-5 in the LncRNA GAS5 overexpression group increased significantly (P < 0.05), while the gene expression of miR-21 and TIMP-3 decreased significantly (P < 0.05). Compared with the LncRNA GAS5 overexpression+blank serum group, the gene expression of MMP-9, MMP-13, and ADAMTS-5 was significantly decreased in the LncRNA GAS5 overexpression+Rongjin Niantong Fang-containing serum group (P < 0.05), while the gene expression of miR-21 and TIMP-3 were significantly increased (P < 0.05). To conclude, Rongjin Niantong Fang could delay the degradation of cartilage extracellular matrix by promoting TIMP-3 expression and inhibiting the expression of MMP-3, MMP-9, MMP-13 and ADAMTS-5 through regulating LncRNA GAS5/miR-21, thereby preventing and treating knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Background: This study explores the association between growth arrest-specific 5 (GAS5) rs145204276, nuclear paraspeckle assembly transcript 1 (NEAT1) rs512715, and Maternally Expressed 3 (MEG3) rs4081134 polymorphisms and their impact on susceptibility to papillary thyroid carcinoma (PTC), considering differential expression of long noncoding RNAs (lncRNAs) in PTC. Methods: A case-control study involving 125 papillary thyroid carcinoma (PTC) patients and 125 controls was conducted. Genotyping of polymorphisms was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. Results: No significant association was found between the two groups regarding genotypes and allelic frequencies of GAS-5 145204276 and MEG3 rs4081134 polymorphisms. Genetic models also showed the same results. Regarding NEAT1 rs512715, The PTC group had more GC genotypes and over-dominant models of NEAT1 rs512715 than controls, while controls showed a higher frequency of recessive models. Conclusion: GAS5 rs145204276 and MEG3 rs4081134 polymorphisms showed no significant association with papillary thyroid carcinoma (PTC) risk. In contrast, NEAT1 rs512715 exhibited a significant impact on PTC development. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) patients suffer from severe disability and premature death because of failure in prognosis, diagnosis, and treatment. Although neural mechanisms of bipolar have not been fully discovered, studies have shown long noncoding RNAs (lncRNAs) can play an important role in signaling pathways such as PI3K/AKT pathway. There has been little study on deregulated lncRNAs and the lncRNAs' mode of action in the BD. Hence, we aimed to investigate the expression of PI3K/AKT pathway-related lncRNAs named TUG1, GAS5, and FOXD3-AS1 lncRNAs in the PMBC in 50 bipolar patients and 50 healthy controls. Our results showed that FOXD3-AS1 and GAS5 under-expressed significantly in bipolar patients compared to healthy controls (P = 0.0028 and P < 0.0001 respectively). Moreover, after adjustment, all P values remained significant (q value < 0.0001). According to the ROC curve, AUC (area under the curve), specificity, and sensitivity of these lncRNAs, GAS5 and FOXD3-AS1 might work as BD candidate diagnostic biomarkers. Taken together, the current results highlight that the dysregulation of FOXD3-AS1 and GAS5 may be associated with an increased risk of BD. [ABSTRACT FROM AUTHOR]

Previous studies indicated long non-coding RNAs (lncRNAs) participated in the pathogenesis of atrial fibrillation (AF). However, little is known about the role of lncRNAs in AF-induced electrical remodeling. This study aimed to investigate the regulatory effect of lncRNA GAS5 (GAS5) on the electrical remodeling of neonatal rat cardiomyocytes (NRCMs) induced by rapid pacing (RP). RNA microarray analysis yielded reduced GAS5 level in NRCMs after RP. RT-qPCR, western blot, and immunofluorescence yielded downregulated levels of Nav1.5, Kv4.2, and Cav1.2 after RP, and whole-cell patch-clamp yielded decreased sodium, potassium, and calcium current. Overexpression of GAS5 attenuated electrical remodeling. Bioinformatics tool prediction analysis and dual luciferase reporter assay confirmed a direct negative regulatory effect for miR-27a-3p on lncRNA-GAS5 and HOXa10. Further analysis demonstrated that either miR-27a-3p overexpression or the knockdown of HOXa10 further downregulated Nav1.5, Kv4.2, and Cav1.2 expression. GAS5 overexpression antagonized such effects in Nav1.5 and Kv4.2 but not in Cav1.2. These results indicate that, in RP-treated NRCMs, GAS5 could restore Nav1.5 and Kv4.2 expression via the miR-27a-3p/HOXa10 pathway. However, the mechanism of GAS5 restoring Cav1.2 level remains unclear. Our study suggested that GAS5 regulated cardiac ion channels via the GAS5/miR-27a-3p/HOXa10 pathway and might be a potential therapeutic target for AF. [ABSTRACT FROM AUTHOR]

Introduction: Myocardial hypoxia is an important factor causing myocardial infarction (MI). Interestingly, many unknown factors in the molecular mechanism of MI remain unclear. Our study explored the role of lncRNA growth arrest‐specific 5 (GAS5) in cell injury under hypoxia. Methods: AS5 expression was assessed in MI and human cardiomyocytes under hypoxia through RT‐qPCR assay. Methyl thiazolyl tetrazolium assay, flow cytometry assay, and transwell assay was carried out for cell viability, cell apoptosis, cell migration, and invasion, respectively. The regulatory target of GAS5 was explored through a dual‐luciferase reporter assay. Results: Our findings indicated that the upregulation of GAS5 was related to hypoxia. Downregulation of GAS5 expression could decrease hypoxia‐induced cell apoptosis and increase cell migration and invasion. Moreover, GAS 5 targeted miR‐21, which regulated the phosphatase and tension homology deleted on chromosome ten gene (PTEN) expression. Furthermore, the knockdown of miR‐21 eliminated the effect of GAS5 silencing on cell injury. Conclusion: These results indicated that lncRNA GAS5 silencing decreased cardiomyocyte injury by hypoxia‐induced through regulating miR‐21/PTEN. [ABSTRACT FROM AUTHOR]

Background/Aim. Prostate carcinoma (PCa) is second occurring carcinoma that affects the male population. Although PCa incidence rates are high, most cases have a favorable prognosis, with comfortable long-term life quality. The aim of the study was to compare long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) plasma levels between healthy individuals and patients with PCa, and also between PCa patients with different prognostic scores. Methods. The present study included a total of 40 patients with PCa and a control group of 20 healthy individuals. PCa patients were divided into two subgroups (20 patients each) based on the prognostic criteria of the American Joint Committee on Cancer. The patient data were collected and analyzed; lncRNA GAS5 levels were quantified using the real-time polymerase chain reaction method. Statistical analysis was conducted using the IBM SPSS Statistics 26.0 computer program (IBM, USA, 2019). Results. The relative quantification of lncRNA GAS5 expression levels showed downregulation in PCa patients compared to healthy individuals; however, the difference was marginally statistically significant (p = 0.056). With further analysis of the given results, we concluded that the expression level of lncRNA GAS5 was not significantly different in the first patient subgroup and the healthy individuals (p = 0.268). Patients from the second subgroup had significantly lower plasma levels of lncRNA GAS5 than healthy individuals (p = 0.033). The difference in the level of lncRNA GAS5 expression between patients with favorable prognoses (Group 1) and the ones with worse prognostic scores (Group 2) did not indicate statistical significance (p = 0.275). In both Group 1 (p = 0.805) and Group 2 (p = 0.454), the plasma levels of lncRNA GAS5 were not significantly different in comparison to the age (≤ 65 vs. > 65 years). Conclusion. One of the main objectives of PCa research is identifying novel and more efficient biomarkers. Conducted research provides strong evidence about the significance of lncRNAs GAS5 in PCa, as well as the correlation between decreased expression of lncRNA GAS5 and poor prognosis in various tumors. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a worldwide disease with rapidly increasing prevalence. This complex disorder caused by interplay between genetic predisposition factors, early developmental elements, diet and inactive lifestyle. Several researches have shown impact of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in the pathogenesis of this disorder. Several miRNAs such as miR-126, miR-222-3p, miR-182, let-7b-5p, and miR-1-3p have been down-regulated in different biological sources of patients with T2DM. Some other miRNAs including miR-21, miR-30d, miR-148a-3p, miR-146b and miR-486 have the opposite trends. In addition, a number of lncRNAs such as LY86-AS, HCG27_201, VIM‐AS1, CTBP1‐AS2, CASC2, GAS5, LINC-PINT, and MALAT1 have been altered in the peripheral blood, serum samples or tissues obtained from patients with T2DM. Taken together, both miRNAs and lncRNAs contribute to the development of T2DM and might be applied as markers or therapeutic molecules for this disorder. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous entity encompassing distinct endotypes and varying phenotypes, characterized by common clinical manifestations, such as shortness of breath, wheezing, and variable airflow obstruction. Two major asthma endotypes based on molecular patterns are described: type 2 endotype (allergic-asthma) and T2 low endotype (obesity-related asthma). Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides in length, currently involved in many diverse biological functions, such as chromatin remodeling, gene transcription, protein transport, and microRNA processing. Despite the efforts to accurately classify and discriminate all the asthma endotypes and phenotypes, if long noncoding RNAs could play a role as biomarkers in allergic asthmatic and adolescent obesity-related asthma, adolescents remain unknown. To compare expression levels of lncRNAs: HOTAIRM1, OIP5-AS1, MZF1-AS1, and GAS5 from whole blood of Healthy Adolescents (HA), Obese adolescents (O), allergic asthmatic adolescents (AA) and Obesity-related asthma adolescents (OA). We measured and compared expression levels from the whole blood of the groups mentioned above through RT-q-PCR. We found differentially expressed levels of these lncRNAs between the groups of interest. In addition, we found a discriminative value of previously mentioned lncRNAs between studied groups. Finally, we generated an interaction network through bioinformatics. Expression levels of OIP5-AS1, MZF1-AS1, HOTAIRM1, and GAS5 in whole blood from the healthy adolescent population, obese adolescents, allergic asthma adolescents, and obesity-related asthma adolescents are differently expressed. Moreover, these lncRNAs could act as molecular biomarkers that help to discriminate between all studied groups, probably through molecular mechanisms with several genes and miRNAs implicated. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) have been reported to be involved in the pathogenesis of neurodegenerative diseases. It has also been hypothesized that plasma exosomal lncRNAs may be used as Alzheimer's disease (AD) biomarkers. In this systematic review, we compiled all studies on the subject to evaluate the accuracy of lncRNAs in identifying AD cases through meta-analysis. Methods: A PRISMA-compliant systematic search was conducted in PubMed/MEDLINE, EMBASE, and Web of Science databases for English publications till September 2022. We included all observational studies published which investigated the sensitivity and specificity of various lncRNAs in plasma samples of AD diagnosis. Our search strategy included lncRNA and all the related spelling and abbreviation variations combined with the keyword Alzheimer's disease. Methodological quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-II) tool. The meta-analysis was carried out using the area under the Receiver Operator Characteristic (ROC) curves (AUC) and sensitivity and specificity values to assess the accuracy of the identified lncRNAs in AD diagnosis. To account for the predicted heterogeneity of the study, a random-effects model was used. All the statistical analyses and visualizations were conducted using Stata 17.0 software. Results: A total of seven studies (AD patients = 553, healthy controls = 513) were included in the meta-analysis. Three lncRNAs were upregulated (RNA BACE-AS1, RNA NEAT1, RNA GAS5), and one lncRNA (MALAT1) was downregulated in plasma samples of AD patients. RNA 51A and RNA BC200 were reported to have variable expression patterns. A lncRNA (RNA 17A) was not significantly different between AD and control groups. The pooled sensitivity, specificity, and AUC values of lncRNAs in identifying AD were (0.74; 95% CI [0.63, 0.82], I2 = 79.2%), (0.88; 95% CI [0.75, 0.94], I2 = 88.9%), and 0.86; 95% CI [0.82, 0.88], respectively. In addition, the pooled diagnostic odds ratio (DOR) of the five individual lncRNAs in AD diagnosis was 20. Conclusion: lncRNAs had high accuracy in identifying AD and must be seen as a promising diagnostic biomarker of the disease. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a condition that may cause persistent pulmonary damage. The transformation of pericytes into myofibroblasts has been recognized as a key player during IPF progression. This study aimed to investigate the functions of lncRNA growth arrest-specific transcript 5 (GAS5) in myofibroblast transformation during IPF progression. Methods: We created a mouse model of pulmonary fibrosis (PF) via intratracheal administration of bleomycin. Pericytes were challenged with exogenous transforming growth factor-β1 (TGF-β1). To determine the expression of target molecules, we employed quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical and immunofluorescence staining. The pathological changes in the lungs were evaluated via H&E and Masson staining. Furthermore, the subcellular distribution of GAS5 was examined using FISH. Dual-luciferase reporter assay, ChIP, RNA pull-down, and RIP experiments were conducted to determine the molecular interaction. Results: GAS5 expression decreased whereas PDGFRα/β expression increased in the lungs of IPF patients and mice with bleomycin-induced PF. The in vitro overexpression of GAS5 or silencing of PDGFRα/β inhibited the TGF-β1-induced differentiation of pericytes to myofibroblasts, as evidenced by the upregulation of pericyte markers NG2 and desmin as well as downregulation of myofibroblast markers α-SMA and collagen I. Further mechanistic analysis revealed that GAS5 recruited KDM5B to promote H3K4me2/3 demethylation, thereby suppressing PDGFRα/β expression. In addition, KDM5B overexpression inhibited pericyte–myofibroblast transformation and counteracted the promotional effect of GAS5 knockdown on pericyte–myofibroblast transformation. Lung fibrosis in mice was attenuated by GAS5 overexpression but promoted by GAS5 deficiency. Conclusion: GAS5 represses pericyte–myofibroblast transformation by inhibiting PDGFRα/β expression via KDM5B-mediated H3K4me2/3 demethylation in IPF, identifying GAS5 as an intervention target for IPF. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the second most common cancer and cause of death in women. In recent years many studies investigated the association of long non-coding RNAs (lncRNAs), as novel genetic factors, on BC risk, survival, clinical and pathological features. Recent studies also investigated the roles of metformin treatment as the firstline treatment for type 2 diabetes (T2D) played in lncRNAs expression/regulation or BC incidence, outcome, mortality and survival, separately. This comprehensive study aimed to review lncRNAs associated with BC features and identify metformin-regulated lncRNAs and their mechanisms of action on BC or other types of cancers. Finally, metformin affects BC by regulating five BC-associated lncRNAs including GAS5, HOTAIR, MALAT1, and H19, by several molecular mechanisms have been described in this review. In addition, metformin action on other types of cancers by regulating ten lncRNAs including AC006160.1, Loc100506691, lncRNA-AF085935, SNHG7, HULC, UCA1, H19, MALAT1, AFAP1-AS1, AC026904.1 is described. [ABSTRACT FROM AUTHOR]

Stroke has become the most common cause of death among residents in China, among which ischemic stroke accounts for the vast majority reaching 70% to 80%. It is of great importance to actively investigate the protective mechanism of cerebral ischemia injury after IS (ischemic stroke). We constructed cerebral ischemia injury models in vivo MACO rat and in vitro (oxygen-glucose deprivation cell model) and set up different interference groups. RT-PCR (reverse transcription PCR) was conducted to detect the expression of lncRNA in neuronal cells, brain tissue, and plasma of different groups, and ELISA (enzyme-linked immunosorbent assay) and western blot were used to detect the expression of the protein in neuronal cells, brain tissue, and plasma of different groups. Cell activity was detected by the CCK-8 assay, while cell apoptosis was examined by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay. In the rats' neuronal cells and brain tissue, curcumin can inhibit the expression of lncRNA GAS5 (long noncoding RNA growth arrest-specific 5). In oxygen-glucose-deprived neuronal cells in vitro, curcumin and low-expressed lncRNA GAS5 can enhance cell activity and decline cell apoptosis, but the addition of curcumin and overexpressed lncRNA GAS5 can make this phenomenon disappear. In neuronal cells, plasma, and brain tissue, curcumin and the low-expressed lncRNA GAS5 can inhibit the expression of IL-1β (interleukin 1 beta), TNF-α (tumor necrosis factor alpha), IL-6 (interleukin 6), Sox2 (SRY-box transcription factor 2), Nanog, and Oct4 (octamer-binding transcription factor 4). However, overexpressed lncRNA GAS5 and curcumin made the inhibitory effect disappear. In conclusion, this study demonstrated that curcumin could inhibit the expression of lncRNA GAS5, thereby inhibiting the expression of inflammation-related factors IL-1β, TNF-α, and IL-6, and ultimately achieve the purpose of attenuating cerebral ischemic cell damage. However, curcumin and lncRNA GAS5 may not alleviate cerebral ischemic cell damage by affecting stem cell differentiation. [ABSTRACT FROM AUTHOR]

Although the imbalance of circulating levels of Thyroid Hormones (THs) affects female fertility in vertebrates, its involvement in the promotion of Premature Ovarian Aging (POA) is debated. Therefore, altered synthesis of THs in both thyroid and ovary can be a trait of POA. We investigated the relationship between abnormal TH signaling, dysthyroidism, and POA in evolutionary distant vertebrates: from zebrafish to humans. Ovarian T3 signaling/metabolism was evaluated by measuring T3 levels, T3 responsive transcript, and protein levels along with transcripts governing T3 availability (deiodinases) and signaling (TH receptors) in distinct models of POA depending on genetic background and environmental exposures (e.g., diets, pesticides). Expression levels of well-known (Amh, Gdf9, and Inhibins) and novel (miR143/145 and Gas5) biomarkers of POA were assessed. Ovarian dysthyroidism was slightly influenced by genetics since very few differences were found between C57BL/6J and FVB/NJ females. However, diets exacerbated it in a strain-dependent manner. Similar findings were observed in zebrafish and mouse models of POA induced by developmental and long-life exposure to low-dose chlorpyrifos (CPF). Lastly, the T3 decrease in follicular fluids from women affected by diminished ovarian reserve, as well as of the transcripts modulating T3 signaling/availability in the cumulus cells, confirmed ovarian dysthyroidism as a common and evolutionary conserved trait of POA. [ABSTRACT FROM AUTHOR]

Introduction: Globally, one of the major causes of cancer related deaths in women is breast cancer. Although metabolic pattern is altered in cancer patients, robust metabolic biomarkers with a potential to improve the screening and disease monitoring are lacking. A complete metabolome profiling of breast cancer patients may lead to the identification of diagnostic/prognostic markers and potential targets. Objectives: The aim of this study was to analyze the metabolic profile in the serum from 43 breast cancer patients and 13 healthy individuals. Materials & methods: We used 1H NMR spectroscopy for the identification and quantification of metabolites. q-RT-PCR was used to examine the relative expression of lncRNAs. Results: Metabolites such as amino acids, lipids, membrane metabolites, lipoproteins, and energy metabolites were observed in the serum from both patients and healthy individuals. Using unsupervised PCA, supervised PLS-DA, supervised OPLS-DA, and random forest classification, we observed that more than 25 metabolites were altered in the breast cancer patients. Metabolites with AUC value > 0.9 were selected for further analysis that revealed significant elevation of lactate, LPR and glycerol, while the level of glucose, succinate, and isobutyrate was reduced in breast cancer patients in comparison to healthy control. The level of these metabolites (except LPR) was altered in advanced-stage breast cancer patients in comparison to early-stage breast cancer patients. The altered metabolites were also associated with over 25 signaling pathways related to metabolism. Further, lncRNAs such as H19, MEG3 and GAS5 were dysregulated in the breast tumor tissue in comparison to normal adjacent tissue. Conclusion: The study provides insights into metabolic alteration in breast cancer patients. It also provides an avenue to examine the association of lncRNAs with metabolic patterns in patients. [ABSTRACT FROM AUTHOR]

In this report, changes in the levels of various long non-coding RNAs (lncRNAs) were demonstrated for the first time in fibroblasts derived from patients suffering from 11 types/subtypes of mucopolysaccharidosis (MPS). Some kinds of lncRNA (SNHG5, LINC01705, LINC00856, CYTOR, MEG3, and GAS5) were present at especially elevated levels (an over six-fold change relative to the control cells) in several types of MPS. Some potential target genes for these lncRNAs were identified, and correlations between changed levels of specific lncRNAs and modulations in the abundance of mRNA transcripts of these genes (HNRNPC, FXR1, TP53, TARDBP, and MATR3) were found. Interestingly, the affected genes code for proteins involved in various regulatory processes, especially gene expression control through interactions with DNA or RNA regions. In conclusion, the results presented in this report suggest that changes in the levels of lncRNAs can considerably influence the pathomechanism of MPS through the dysregulation of the expression of certain genes, especially those involved in the control of the activities of other genes. [ABSTRACT FROM AUTHOR]

Lately, the interest in long non-coding RNAs (lncRNAs) as potential drug targets and predictive markers in the context of HIV-1 has peaked, but their in vivo expression and regulation remains largely unexplored. Therefore, the present study examined lncRNA expression patterns during a clinical antiretroviral treatment interruption (ATI) trial. Peripheral blood mononuclear cells were isolated from ten patients at four timepoints: prior to ATI, 7–15 days after stop, at viral rebound and 3 months post antiretroviral therapy re-initiation. RNA was extracted and RT-qPCR on five known HIV-1-related lncRNAs (HEAL, MALAT1, NEAT1, GAS5 and NRON) was performed and correlated with HIV-1 and host marker expression. All lncRNAs correlated stronger with interferon stimulated genes (ISGs) than with HIV-1 reservoir and replication markers. However, one lncRNA, HEAL, showed significant upregulation at viral rebound during ATI compared to baseline and re-initiation of therapy (p = 0.0010 and p = 0.0094, respectively), following a similar viral-load-driven expression pattern to ISGs. In vitro knockdown of HEAL caused a significant reduction in HIV-1 infection levels, validating HEAL's importance for HIV-1 replication. We conclude that the HIV-1-promoting lncRNA HEAL is upregulated at viral rebound during ATI, most likely induced by viral cues. [ABSTRACT FROM AUTHOR]

Shifts in normal aging set stage for neurodegeneration and dementia affecting 1 in 10 adults. The study demonstrates that lncRNA GAS5 is decreased in aged and Alzheimer's disease brain. The role and targets of lncRNA GAS5 in the aging brain were elucidated using a GAS5-targeting small molecule NPC86, a frontier in lncRNA-targeting therapeutic. Robust techniques such as molecular dynamics simulation of NPC86 binding to GAS5, in vitro functional assays demonstrating that GAS5 regulates insulin signaling, neuronal survival, phosphorylation of tau, and neuroinflammation via toll-like receptors support the role of GAS5 in maintaining healthy neurons. The study demonstrates the safety and efficacy of intranasal NPC86 treatment in aged mice to improve cellular functions with transcriptomic analysis in response to NPC86. In summary, the study demonstrates that GAS5 contributes to pathways associated with neurodegeneration and NPC86 has tremendous therapeutic potential to prevent the advent of neurodegenerative diseases and dementias. [ABSTRACT FROM AUTHOR]

Background: Renin-angiotensin system (RAS) is prominently associated with renal pathophysiology in postmenopausal women. Long non-coding RNAs (lncRNAs) H19, GAS5, MIAT, and Rian have been linked to the pathogenesis of renal injury. Aims: This study aimed to evaluate the beneficial effects of daidzein on unilateral ureteral obstruction (UUO) induced-renal injury in ovariectomized (OVX) rats through interaction with angiotensin AT1, Mas receptors, and lncRNAs. Methods: 84 female rats were ovariectomized (OVX) two weeks before performing obstruction of the left kidney ureter (UUO). The animals were then randomly divided into four main groups (n=21): Sham+DMSO, UUO+DMSO, UUO+17ß-Estradiol (E2) (positive control), and UUO+daidzein. Each main group comprised three subgroups (n=7) and were treated with saline, A779 (MasR antagonist), or losartan (AT1R antagonist) for 15 days. On day 16, the animals were euthanized, and the left kidneys were harvested for histopathology and lncRNAs expression assays. Results: UUO significantly increased kidney tissue damage score (KTDS) in the UUO rats, increased the expression of H19 and MIAT, and decreased the expression of GAS5 and Rian. Daidzein alone and in cotreatment with losartan or A779 reversed these effects. Daidzein with 1 mg/kg dose was more effective than E2. Conclusion: Daidzein alone and in co-treatment with A779 and losartan improved renal injury in UUO rats and recovered dysregulated expression of UUOrelated lncRNAs through modulating MasR and AT1R receptors, associating with modulation of the expression of lncRNAs. Daidzein could be considered a renoprotective phytoestrogen substitute for E2 therapy in postmenopausal women suffering from renal diseases. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR), designated as the blunted response of insulin target tissues to physiological level of insulin, plays crucial roles in the development and progression of diabetes, nonalcoholic fatty liver disease (NAFLD) and other diseases. So far, the distinct mechanism(s) of IR still needs further exploration. Long non-coding RNA (lncRNA) is a class of non-protein coding RNA molecules with a length greater than 200 nucleotides. LncRNAs are widely involved in many biological processes including cell differentiation, proliferation, apoptosis and metabolism. More recently, there has been increasing evidence that lncRNAs participated in the pathogenesis of IR, and the dysregulated lncRNA profile played important roles in the pathogenesis of metabolic diseases including obesity, diabetes and NAFLD. For example, the lncRNAs MEG3, H19, MALAT1, GAS5, lncSHGL and several other lncRNAs have been shown to regulate insulin signaling and glucose/lipid metabolism in various tissues. In this review, we briefly introduced the general features of lncRNA and the methods for lncRNA research, and then summarized and discussed the recent advances on the roles and mechanisms of lncRNAs in IR, particularly focused on liver, skeletal muscle and adipose tissues. [ABSTRACT FROM AUTHOR]

LncRNA growth arrest specific 5 (GAS5) has been confirmed to play an essential role in a number of biological processes, such as tumor regulation and gene transcription. GAS5 has been shown to be a tumor suppressor gene in many types of cancer, but its specific mechanism of action in bladder cancer (BC) remains to be elucidated. In this study, we explored the biological properties of GAS5 in BC and its mechanism of action in BC. We analyzed the expression of GAS5 in 50 pairs of BC tissues and found that GAS5 was low expressed in BC tissues compared with normal mucosal tissues. In vitro and in vivo experiments showed that GAS5 could affect the proliferation and migration of BC cells. Nucleoplasmic isolation assays and fluorescence in situ hybridization (FISH) assays demonstrated the localization of GAS5 in cell cytoplasm. Chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation (RIP) and luciferase assay demonstrated the target binding relationship of GAS5 with miR-18a-5p. Rescue experiments demonstrated that GAS5 promoted the proliferation and migration of BC cells through target binding of miR-18a-5p. Moreover, miR-18a-5p bound to its targets AXIN2 and GSK3β, which in turn affected the expression of Wnt/β-catenin pathway-related proteins. Our findings demonstrate that GAS5 regulates Wnt/β-catenin pathway activity by regulating the miR-18a-5p/AXIN2/GSK3β axis to modulate BC progression, providing a new potential therapeutic strategy for the treatment of BC. [ABSTRACT FROM AUTHOR]

Overexpression and knockdown experiments performed on Raji cells showed that lncRNA GAS5 overexpression reduces cell proliferation, promotes apoptosis, induces cell cycle arrest at G1 phase and decreases cell invasion. Given that miR-222 in CLL cells down-regulates the expression of p27, which prevents cell cycle progression, low level of lncRNA GAS5 in CLL could promote cell proliferation by inhibiting p27 [[88]]. Analyses of lincRNA-p21 expression in primary CLL cells in the context of DNA damage revealed its induction in a p53-dependent manner: the strongest induction was observed in TP53 SP wt sp cells, but was impaired in CLL cells with 11q deletion (which encompasses ATM gene) and TP53 SP del/mut sp . This was in line with the observed overexpression of miR-222 in CLL samples and the negative correlation between the levels of lncRNA GAS5 and miR-222 in both CLL samples and Raji cells overexpressing lncRNA GAS5 [[88]]. Leukemia Leukemias are malignant diseases of hematopoietic cells which result from abnormal proliferation and clonal expansion, aberrant differentiation and impaired apoptosis of the cell of origin, leading to the accumulation of leukemic cells in bone marrow and other hematopoietic tissues and suppression of normal blood cells' production. [Extracted from the article]

The lncRNA GAS5 acts as a tumor suppressor and is downregulated in gastric cancer (GC). In contrast, E2F1, an important transcription factor and tumor promoter, directly inhibits miR-34c expression in GC cell lines. Furthermore, in the corresponding GC cell lines, lncRNA GAS5 directly targets E2F1. However, lncRNA GAS5 and miR-34c remain to be studied in conjunction with GC. Here, we present a dynamic Boolean network to classify gene regulation between these two non-coding RNAs (ncRNAs) in GC. This is the first study to show that lncRNA GAS5 can positively regulate miR-34c in GC through a previously unknown molecular pathway coupling lncRNA/miRNA. We compared our network to several in-vivo/in-vitro experiments and obtained an excellent agreement. We revealed that lncRNA GAS5 regulates miR-34c by targeting E2F1. Additionally, we found that lncRNA GAS5, independently of p53, inhibits GC proliferation through the ATM/p38 MAPK signaling pathway. Accordingly, our results support that E2F1 is an engaging target of drug development in tumor growth and aggressive proliferation of GC, and favorable results can be achieved through tumor suppressor lncRNA GAS5/miR-34c axis in GC. Thus, our findings unlock a new avenue for GC treatment in response to DNA damage by these ncRNAs. [ABSTRACT FROM AUTHOR]

It has been reported that lncRNA GAS5 can inhibit LPS-induced inflammation, indicating its involvement in sepsis. We observed the downregulation of GAS5 in plasma of sepsis patients. In addition, expression levels of GAS5 were positively correlated with the expression levels of miR-214. In cardiomyocytes, overexpression of GAS5 upregulated the expression of miR-214, while its knockdown resulted in decreased expression levels of miR-124. Methylation-specific PCR (MSP) revealed that GAS5 negatively regulated the methylation of miR-124. Cell apoptosis showed that overexpression of GAS5 and miR-214 suppressed the apoptosis of cardiomyocytes induced by LPS. In addition, overexpression of miR-214 also reduced the enhancing effects of silencing of GAS5 on cell apoptosis. Therefore, GAS5 may upregulate miR-214 through methylation pathway to inhibit the apoptosis of cardiomyocytes in sepsis. [ABSTRACT FROM AUTHOR]

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]

Cardiac hypertrophy (CH) is a pathological phenotype of cardiomyopathy. Epigenetic modification is a mechanism associated with CH. Our study here investigated the histone demethylase KDM3C in relation to epigenetic regulation in CH. We found that KDM3C mRNA silencing alleviated CH, as evidenced by reduced ANP, BNP, and β‐MHC mRNAs, increased α‐MHC mRNA, decreased cell surface area, and reduced cellular protein/DNA ratios. Specifically, KDM3C upregulated miR‐200c‐3p expression through demethylation of H3K9me2, leading to enhanced binding of miR‐200c‐3p to GAS5 and suppression of GAS5 expression; these effects then led to reduced binding of GAS5 to miR‐495‐3p, increased miR‐495‐3p expression, and repression of PHF8 transcription. Through these mechanisms, our data indicate that KDM3C‐dependent epigenetic modification promotes CH. [ABSTRACT FROM AUTHOR]

Sepsis is mainly caused by infection, and inflammation plays a vital role in the progression of sepsis. Increasing evidence shows the regulatory mechanism of long non-coding RNA growth arrest-specific 5 (GAS5) in inflammatory response. However, the potential role of GAS5 in sepsis was not really clear. Here, we set to investigate the role and mechanism of GAS5 in the inflammatory response of lipopolysaccharide (LPS)-induced macrophages in vitro. Levels of GAS5, microRNA-520-3p, suppressor of cytokine signaling 3 (SOCS3) and inflammatory cytokines tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 and IL-1β were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Nitric oxide (NO) release was measured through flow cytometry. The levels of TNF-α, IL-6, and IL-1β were also detected using ELISA. Dual-luciferase reporter and RNA pull-down assays were performed to clarify the relationship between miR-520-3p and GAS5 or SOCS3. Western blot was carried out to assess SOCS3 protein expression in macrophages. GAS5 level was remarkably decreased in sepsis serum and it was inversely related to the severity of sepsis. Upregulation of GAS5 repressed inflammatory response in LPS-induced macrophages, and the inhibitory effect was returned by miR-520-3p mimics. Moreover, miR-520-3p inhibitor downregulated the levels of inflammatory factors of TNF-α, IL-6, and IL-1β, as well as suppressed NO release. Mechanically, GAS5 functioned as a sponge of miR-520-3p and miR-520-3p directly targeted SOCS3. GAS5 regulated inflammatory response by the miR-520-3p/SOCS3 axis in LPS-induced macrophages, which furnished a novel therapeutic idea in clinical treatment of inflammation-induced sepsis. [ABSTRACT FROM AUTHOR]

The long non-coding RNA (lncRNA) GAS5 can be a marker for early diagnosis and postoperative follow-up in the patients with prostate cancer, whereby lower levels of GAS5 correlate with tumorigenesis and unfavourable clinical course. Expression of the GAS5 can be affected by rs145204276 polymorphism, a 5 base pairs insertion-deletion polymorphism shown as „AGGCA/-". The aim of this study was to analyse the association between rs145204276 and prostate cancer susceptibility and prognosis. This study was included 121 healthy subjects and 70 patients with prostate cancer. Diagnosis of prostate cancer was established by histopathology after the surgery. Genotyping was performed by allelic discrimination method using the TaqMan® assay. In the healthy subjects, the obtained frequencies of GAS5 rs145204276 genotypes were 80.2% of ins/ins, 16.5% of ins/del and 3.3% of del/del. The allele frequencies were 88.5% of ins and 11.5% of del, respectively. In the patient group, the frequencies of ins/ins, ins/del and del/del genotypes were 70%, 20% and 10%, respectively; the frequency of ins allele was 80% and the frequency of del allele was 20%. Observed frequencies of GAS5 rs145204276 genotypes were not significantly different between healthy subjects and patients with prostate cancer, and also between prognostic groups of prostate cancer. This study demonstrate no significant association between GAS5 rs145204276 and sussceptibility/prognosis of prostate cancer. [ABSTRACT FROM AUTHOR]

Objective. This study is aimed at investigating the molecular mechanism of lncRNA GAS5-induced cell apoptosis in acute myeloid leukemia (AML) by targeting Nrf2. Methods. The RNA interfering technique was utilized to silence THP-1 in AML cell line, and lncRNA GAS5 expression in cell line was determined by real-time PCR. EdU experiment and flow cytometry were used to detect the apoptosis and proliferation ability of cells in different groups. PD-L1, STAT3, AKT, and MMP9 expressions were determined by Western blot. Results. The si-RNA significantly inhibited the expression of lncRNA GAS5 in THP-1 cells. Compared with the si-NC group, the difference in cell apoptosis between lncRNA GAS5 and Nrf2 groups was significant (P < 0.05). Compared with the lncRNA GAS5 group, the number of apoptotic cells in the lncRNA GAS5+Nrf2 group significantly reduced (P < 0.05). Compared with the si-NC group, the differences in the levels of four proteins between lncRNA GAS5 and Nrf2 groups were significant (P < 0.05). In lncRNA GAS5+Nrf2 and lncRNA GAS5 groups, PD-L1 expression increased, while the expression of STAT3, AKT, and MMP9 decreased. Conclusion. In AML cells, lncRNA GAS5 with Nrf2 could regulate the proliferation and apoptosis of AML cells. lncRNA GAS5 inhibited Nrf2 expression, regulated cell apoptosis and proliferation, and further inhibited the progression of AML disease. [ABSTRACT FROM AUTHOR]

Growth arrest‐specific 6 (GAS6) protein plays a key role in processes related to proliferation, inflammation, angiogenesis, and atherosclerotic plaque formation. In addition, it has been reported that plasma levels of GAS6 are related to cancer prognosis and other relevant pathologies, such as heart failure or sepsis. We report here the first electrochemical immunoplatform for the determination of GAS6, which has demonstrated to be competitive with other available methodologies in terms of cost, simplicity, and decentralized application. The developed immunoplatform involves a sandwich immunoassay using magnetic microparticles (MBs) and uses amperometric detection at disposable screen‐printed carbon electrodes (SPCEs). The MBs were modified with an antibody specific to GAS6 for its selective capture, which is further recognized by a biotinylated secondary antibody subsequently labeled with a streptavidin‐horseradish peroxidase (Strep‐HRP) conjugate. The electrochemical detection was carried out using the hydroquinone (HQ)/H2O2 system. The developed bioplatform exhibits a great selectivity and low limit of detection (27 pg/mL) that allowed the determination of the GAS6 circulating level in plasma samples from patients suffering heart failure (HF) and diagnosed with pancreatic ductal adenocarcinoma (PDAC), as well as the determination of the target protein in raw secretomes of human colorectal cancer cell lines. [ABSTRACT FROM AUTHOR]

• Pleural mesothelioma requires individual treatment concepts. • Biomarker combination can indicate risk for early tumor progression or recurrence. • Combination of MALAT1, GAS5, and calretinin as a promising approach for prediction of diasease progression. The role of cytoreductive surgery for epithelioid pleural mesothelioma within a multimodal treatment approach remains controversial. Carefully selected patients benefit from cytoreductive surgery and adjuvant chemotherapy, but there is no established biomarker to predict tumor recurrence or progression during the course of the disease. The aim of this study was to identify potential biomarkers to predict therapeutic response in terms of progression-free survival. Between 03/2014 and 08/2022, preoperative blood samples were collected from 76 patients with epithelioid pleural mesothelioma who underwent cytoreductive surgery as part of a multimodal treatment approach. Identification of potential biomarkers was performed by determination of mesothelin and calretinin, as well as specific long non-coding RNAs and microRNAs. Receiver operating characteristic analysis, Kaplan-Meier survival analysis, and Cox regression were used to assess the association between biomarker concentrations and patient recurrence status and survival. MALAT1, GAS5, and calretinin showed statistically significant increased biomarker levels in patients with recurrence in contrast to recurrence-free patients after surgical treatment (p < 0.0001, p = 0.0190, and p = 0.0068, respectively). The combination of the three biomarkers resulted in a sensitivity of 68 % and a specificity of 89 %. MALAT1, GAS5, and calretinin could be potential biomarkers for the prediction of tumor recurrence, improving the benefit from multimodal treatment including cytoreductive surgery. [ABSTRACT FROM AUTHOR]

The article titled "[Retracted] Downregulation of long non-coding RNA GAS5 promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma" has been retracted by the Editor of Oncology Letters due to concerns about the integrity of the data presented. An area of similarity was identified in the cellular data, and the western blots showed atypical and possibly anomalous protein bands. The authors were asked for an explanation but did not respond. The Editor apologizes for any inconvenience caused and thanks the concerned reader for bringing this matter to their attention. [Extracted from the article]

Scientific efforts continue to concentrate on elucidating the complex molecular mechanisms underlying traumatic brain injury (TBI), and recent reports suggest that epigenetic regulation including long non-coding RNA (lncRNA) is involved. The present study aimed to investigate the plasma concentration of a long non-coding RNA, named growth arrest-specific 5 (GAS5), in a group of 45 patients with severe TBI (sTBI), and to analyze the correlations of GAS5 with TBI onset, injury severity, systemic inflammation, and early outcome of the patients. It was found that plasma GAS5 levels were substantially increased in sTBI patients compared with the relative controls (p < 0.001). Further, significantly higher expression of plasma GAS5 was observed in patients with a Glasgow Coma Scale (GCS) score of less than five (p = 0.002) or unfavorable outcome at discharge (p < 0.001). Circulating GAS5 expression had a negative correlation with GCS score (r = −0.406, p = 0.006), and positive correlations with white blood cell count (r = 0.473, p = 0.001), neutrophil count (r = 0.502, p < 0.001), and neutrophil/lymphocyte ratio (NLR) (r = 0.398, p = 0.007). Univariate and multivariate logistic regression analyses revealed that GCS score (OR = 0.318, 95% CI 0.132–0.767, p = 0.011) and GAS5 (OR = 2.771, 95% CI 1.025–7.494, p = 0.045) were the two independent predictors for early outcome of patients. The receiver operating characteristic (ROC) curves showed good prognostic values of GCS score (AUC = 0.856, 95% CI: 0.719–0.943) and GAS5 expression (AUC = 0.798, 95% CI: 0.651–0.903). Importantly, the combined use of them can improve the prognostic ability of TBI with an AUC of 0.895 (95% CI: 0.767–0.966). Collectively, our study indicated that the levels of lncRNA GAS5 in circulation were elevated following severe TBI and correlated well with injury severity and inflammatory parameters. In addition, GAS5 as well as GCS scores may have the potential to predict the early outcome of TBI patients. [ABSTRACT FROM AUTHOR]

In recent years, long non-coding RNAs (lncRNAs) have been shown to play important regulatory roles in cellular processes. Growth arrests specific transcript 5 (GAS5) is a lncRNA that is highly expressed during the cell cycle arrest phase but is downregulated in actively growing cells. Growth arrests specific transcript 5 was discovered to be downregulated in several cancers, primarily solid tumors, and it is known as a tumor suppressor gene that regulates cell proliferation, invasion, migration, and apoptosis via multiple molecular mechanisms. Furthermore, GAS5 polymorphism was found to affect GAS5 expression and functionality in a cell-specific manner. This review article focuses on GAS5's tumor-suppressive effects in regulating oncogenic signaling pathways, cell cycle, apoptosis, tumor-associated genes, and treatment-resistant cells. We also discussed genetic polymorphisms of GAS5 and their association with cancer susceptibility. [ABSTRACT FROM AUTHOR]

Background: Berberine (BBR) is an isoquinoline alkaloid found in the Berberis species. It was found to have protected effects in cardiovascular diseases. Here, we investigated the effect the regulatory function of long noncoding RNAs (lncRNAs) during the treatment of stable coronary heart disease (CHD) using BBR. We performed microarray analyses to identify differentially expressed (DE) lncRNAs and mRNAs between whole blood samples from 5 patients with stable CHD taking BBR and 5 no BBR volunteers. DE lncRNAs and mRNAs were validated by quantitative real-time PCR. Results: A total of 1703 DE lncRNAs and 912 DE mRNAs were identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated DE mRNAs might be associated with mammalian target of rapamycin and mitogen-activated protein kinase pathway. These pathways may be involved in the healing process after CHD. To study the relationship between mRNAs encoding transcription factors (DNA damage inducible transcript 3, sal-like protein 4 and estrogen receptor alpha gene) and CHD related de mRNAs, we performed protein and protein interaction analysis on their corresponding proteins. AKT and apoptosis pathway were significant enriched in protein and protein interaction network. BBR may affect downstream apoptosis pathways through DNA damage inducible transcript 3, sal-like protein 4 and estrogen receptor alpha gene. Growth arrest-specific transcript 5 might regulate CHD-related mRNAs through competing endogenous RNA mechanism and may be the downstream target gene regulated by BBR. Verified by the quantitative real-time PCR, we identified 8 DE lncRNAs that may relate to CHD. We performed coding and non-coding co-expression and competing endogenous RNA mechanism analysis of these 8 DE lncRNAs and CHD-related DE mRNA, and predicted their subcellular localization and N6-methyladenosine modification sites. Conclusion: Our research found that BBR may affect mammalian target of rapamycin, mitogen-activated protein kinase, apoptosis pathway and growth arrest-specific transcript 5 in the process of CHD. These pathways may be involved in the healing process after CHD. Our research might provide novel insights for functional research of BBR. [ABSTRACT FROM AUTHOR]

Background. Long noncoding RNA (lncRNA) is involved in the occurrence and development of diabetic kidney disease (DKD). It is necessary to identify the expression of lncRNA from DKD patients through systematic reviews, and then carry out silico analyses to recognize the dysregulated lncRNA and their associated pathways. Methods. The study searched Pubmed, Embase, Cochrane Library, WanFang, VIP, CNKI, and CBM to find lncRNA studies on DKD published before March 1, 2021. Systematic review of the literature on this topic was conducted to determine the expression of lncRNA in DKD and non-DKD controls. For the dysregulated lncRNA in DKD patients, silico analysis was performed, and lncRNA2Target v2.0 and starBase were used to search for potential target genes of lncRNA. The Encyclopedia of Genomics (KEGG) pathway enrichment analysis was performed to better identify dysregulated lncRNAs in DKD and determine the associated signal pathways. Results. According to the inclusion and exclusion criteria, 28 publications meeting the eligibility criteria were included in the systematic evaluation. A total of 3,394 patients were enrolled in this study, including 1,238 patients in DKD group, and 1,223 diabetic patients, and 933 healthy adults in control group. Compared with the control, there were eight lncRNA disorders in DKD patients (MALAT1, GAS5, MIAT, CASC2, NEAT1, NR_033515, ARAP1-AS2, and ARAP1-AS1). In addition, five lncRNAs (MALAT1, GAS5, MIAT, CASC2, and NEAT1) participated in disease-related signal pathways, indicating their role in DKD. Discussion. This study showed that there were eight lncRNAs in DKD that were persistently dysregulated, especially five lncRNAs which were closely related to the disease. Although systematic review included 28 studies that analyzed the expression of lncRNA in DKD-related tissues, the potential of these dysregulated lncRNAs as biomarkers or therapeutic targets for DKD remains to be further explored. Trial registration. PROSPERO (CRD42021248634). [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVD) such as myocardial ischemia, myocardial infarction, heart failure, atherosclerosis, hypertension, arrhythmia, and their complications diseases are associated with increased morbidity and mortality, it is necessary to develop new diagnostic markers for CVD. LncRNAs have become a new class of biomarkers in CVD with good development prospects. Numerous studies have confirmed lncRNAs feasibility as diagnostic, prognostic and predictive tools for different types of CVD. In this review, we summarized the available knowledge regarding the clinical application value and pathophysiological mechanism of circulating lncRNA as potential biomarkers of cardiovascular disease. We reviewed the scope of application and changes of circulating lncRNAs such as ZFAS1, CDR1AS, CHAST, UCA1, HOTAIR, MIAT, NEAT1, LIPCAR, H19, NRF, NRON, MHRT, PVT1, Heat2, CASC7, GAS5, MALAT1, APPAT, HIF1A-AS1, KCNQ1OT1, NEXN in different kinds of CVD and discussed their clinical application potential as biomarker, which can help us better understand the mechanism of CVD. • Cardiovascular diseases have increased morbidity and mortality, it is necessary to develop new diagnostic markers for CVD. • Accurate early diagnosis of CVD has important clinical significance. • LncRNAs have become a new class of biomarkers in CVD with good development prospects. • The combined application of lncRNA with miRNA may bring a breakthrough to the diagnosis and prognosis of MI. [ABSTRACT FROM AUTHOR]

The aim of this work was to appraise the potential associations of single nucleotide polymorphisms (SNPs) of long non-coding RNA growth arrest-specific 5 (GAS5) with diabetic retinopathy (DR) in a diabetes mellitus (DM) population. Two loci of the GAS5 SNPs (rs55829688 and rs145204276) were genotyped via TaqMan allelic discrimination in 449 non-DR patients and 273 DR subjects. The SNP rs145204276 Del/Del showed a significantly higher distribution in the DR group compared to the non-DR group (AOR: 2.487, 95% CI: 1.424–4.344, p = 0.001). During subgroup analyses, the non-proliferative diabetic retinopathy (NPDR) subgroup demonstrated a significantly higher ratio of the SNP rs145204276 Del/Del (AOR: 2.917, 95% CI: 1.574–5.406, p = 0.001) and Ins/Del + Del/Del (AOR: 1.242, 95% CI: 1.016–1.519, p = 0.034) compared to the non-DR population, while the proliferative diabetic retinopathy (PDR) subgroup did not reveal significant differences in either SNP rs145204276 or rs55829688 distributions compared to the non-DR group. Furthermore, patients with a GAS5 SNP rs145204276 Del/Del showed a significantly shorter DM duration than the wild type (Ins/Ins) (p = 0.021). In conclusion, our findings demonstrate that the GAS5 SNP rs145204276 Del/Del variant is associated with an increased susceptibility to DR in DM patients, particularly in those patients with NPDR. [ABSTRACT FROM AUTHOR]