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Deregulation of microRNA (miRNA) profile has been reportedly linked to the aging process, which is a dominant risk factor for many pathologies. Among the miRNAs with documented roles in aging-related cardiac diseases, miR-18a, -21a, -22, and -29a were mainly associated with hypertrophy and/or fibrosis; however, their relationship to aging was not fully addressed before. The purpose of this paper was to evaluate the variations in the expression levels of these miRNAs in the aging process. To this aim, multiple organs were harvested from young (2–3-months-old), old (16–18-months-old), and very old (24–25-months-old) mice, and the abundance of the miRNAs was evaluated by quantitative real-time (RT)-PCR. Our studies demonstrated that miR-21a, miR-22, and miR-29a were upregulated in the aged heart. Among them, miR-29a was highly expressed in many other organs, i.e., the brain, the skeletal muscle, the pancreas, and the kidney, and its expression was further upregulated during the natural aging process. Western blot, immunofluorescence, and xCELLigence analyses concurrently indicated that overexpression of miR-29a in the muscle cells decreased the collagen levels as well as cell migration and proliferation. Computational prediction analysis and overexpression studies identified SERPINH1, a specific chaperone of procollagens, as a potential miR-29a target. Corroborating to this, significantly downregulated SERPINH1 levels were found in the skeletal muscle, the heart, the brain, the kidney, and the pancreas harvested from very old animals, thereby indicating the role of the miR-29a-SERPINH1 axis in the aging process. In vitro analysis of miR-29a effects on fibroblast and cardiac muscle cells pointed toward a protective role of miR-29a on aging-related fibrosis, by reducing cell migration and proliferation. In conclusion, our study indicates an adaptive increase of miR-29 in the natural aging process and suggests its role as a transcriptional repressor of SERPINH1, with a potential therapeutic value against adverse matrix remodeling and aging-associated tissue fibrosis.

Aim The present work investigated serum levels of miR-29a, miR-122 and sestrin2 in obese children with/without type-2-diabetes mellitus (T2DM), and their correlations with inflammatory, metabolic and anthropometric parameters. Methods The study included 298 children, divided into: G1 (control, n = 136), G2 (obese without diabetes, n = 90) and G3 (obese with T2DM, n = 72). Metabolic and anthropometric parameters, miR-29a, miR-122 relative expressions, and sestrin2, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were measured by their specific methods. The data was processed and analyzed by SPSS V.26 using the corresponding tests. After testing the variables’ normality, Kruskal–Wallis one-way-ANOVA, Spearman correlations coefficient were used. Results Significant higher serum miR-29a, miR-122, IL-6, hsCRP and TNF-α and lower sestrin2 levels were found in G2 and G3 than G1 and in G3 than G2 (p= > 0.001 for all). Especially in G3, miR-29a and miR-122 levels correlated positively while sestrin2 levels correlated negatively with waist circumference and BMI percentiles, serum levels of LDL-cholesterol, triacylglycerol, total cholesterol, HbA1c%, glucose, insulin, c-peptide, homeostatic model assessment-insulin resistance (HOMA-IR), IL-6, hsCRP and TNF-α. Conclusion The change in the serum miR-29a, miR-122 and sestrin2 levels in obese children with/without T2DM may suggest a possible role of these biomarkers in the pathogenesis of childhood obesity and their accompanied complications e.g. inflammations and T2DM. Also, further studies are required to test drugs that antagonize the action miR-29a and miR-122 or upregulate sestrin2 in the management of these cases.

WOS: 000473057000001 PubMed ID: 31159615 In the last years, miRNAs have been associated with molecular pathways of cancer and other diseases. The change of expression level of miRNA has an inhibitory role in tumorigenesis. Nevertheless, the poor bioavailability of miRNA due to the rapid enzymatic degradation is a critical handicap in cancer therapy. In this study, we designed dextran-coated iron oxide-based nanoparticle for the delivery of miR-29a to breast cancer cells and analyzed its therapeutic efficacy in vitro. Results indicated that the presence of dextran-coated magnetic nanoparticles, loaded with miR29a, enhanced the selective delivery of miR-29a. Further, miR-29a complex nanoparticles caused down-regulation of anti-apoptotic genes. These results pave the way for further investigations into the possible use of miR-29a complex magnetic nanoparticles for breast cancer therapy.

Background: The molecular mechanisms underlying the contribution of human arterial smooth muscle cells (HASMCs), one of the most important components of the arterial wall, to the pathogenesis of arteriosclerosis obliterans (ASO) remain elusive. Methods: The expression levels of miR-29a in arterial walls were analyzed via real-time-polymerase chain reaction. An ASO cell model was established to investigate the expression of miR-29a on HASMCs. The interaction between miR-29a and platelet-derived growth factor receptor B (PDGFRB) was detected by luciferase reporter assay, and the alteration of the expression of PDGFRB was determined in platelet-derived growth factor‑BB (PDGF-BB)-stimulated HASMCs transfected with miR-NC, miR-29a mimics, and miR-29a inhibitors. Further, HASMCs cell proliferation was investigated by cell counting kit-8 and EdU assays, and cell migrations were evaluated by Transwell and wound closure assays. Results: The expression of miR-29a was remarkably downregulated in the arterial walls of ASO patients compared with normal arterial walls. Furthermore, expression of miR-29a in HASMCs under PDGF-BB stimulation was lower than vehicle control. PDGFRB was identified as a target of miR-29a in HASMCs, and miR-29a inhibited the proliferation and migration in PDGF-BB-induced HASMCs, via regulating the expression of PDGFRB. Conclusion: This study showed that miR-29a is downregulated in the arterial wall of ASO patients, as well as in the PDGF-BB-stimulated HASMCs. This alteration of miR-29a could upregulate target genes PDGFRB and inhibits the proliferation and migration of HASMCs. These findings discovered new mechanisms of ASO pathogenesis, and the miR-29a/PDGFRB axis could serve as potential therapy target of ASO.

MicroRNA-29a is a key regulon that regulates hepatic stellate cells (HSCs) and mitigates liver fibrosis. However, the mechanism by which it does so remains largely undefined. The inhibition of bromodomain-4 protein (BRD4) represents a novel therapeutic target in hepatic fibrosis. Therefore, the purpose of this study is to investigate the miR-29a regulation of BRD4 signaling in a bile duct-ligation (BDL) animal model with regard to developing cholestatic liver fibrosis. Hepatic tissue in miR-29a transgenic mice (miR-29aTg mice) displayed weak fibrotic matrix, as shown by α-smooth muscle actin staining within affected tissues compared to wild-type mice. miR-29a overexpression reduced the BDL exaggeration of BRD4 and SNAI1 expression. Increased miR-29a signaling caused the downregulation of EZH2, MeCP2, and SNAI1, as well as the upregulation of PPAR-γ expression, in primary HSCs. We further demonstrated that the administration of JQ1, a BRD4 inhibitor, could inhibit BRD4, C-MYC, EZH2, and SNAI1 expression, while both JQ1 and a miR-29a mimic could inhibit the migration and proliferation of HSCs. In short, our research demonstrates that miR-29a negatively regulates HSC activation by inhibiting BRD4 and EZH2 function, thus making it a promising target for the pharmacologic treatment of hepatic fibrosis.

Recently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s11658-021-00266-9.

Background: To investigate the expression levels of miRNA-29a (miR-29a), tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) in peripheral blood of pulmonary tuberculosis patients and their correlation with clinical and pathological features. Methods: A prospective analysis was performed on 192 pulmonary tuberculosis patients (pulmonary tuberculosis group) and 186 healthy patients (control group) who were admitted to Beijing Chest Hospital, Capital Medical University, Beijing, China from Jun 2015 to Jun 2019. Real-time quantitative PCR was used to detect the expression levels of miR-29a, and ELISA to detect the concentrations of TNF-α and VEGF in serum. The diagnostic value of miR-29a, TNF-α and VEGF in tuberculosis was analyzed using receiver operating characteristic curve (ROC). The correlation of the expression levels of miR-29a, TNF-α and VEGF with gender, age, low-grade fever, expectoration, hemoptysis and pulmonary tuberculosis classification was analyzed. Results: The expression levels of miR-29a, TNF-α and VEGF in pulmonary tuberculosis group were significantly higher than those in control group (P

Purpose: Numerous studies have demonstrated the important relationship of TUG1 with tumorigenesis. The present study investigated the role of TUG1 and its downstream genes miR-29a and IFITM3 in the occurrence and development of hepatocellular carcinoma (HCC). We found that both TUG1 and IFITM3 genes are highly expressed in HCC, whereas the expression of miR-29a is low in HCC. Downregulation of TUG1 reduces cell invasion, metastasis, and cell proliferation ability and promotes cell apoptosis. Simultaneous downregulation of miR-29a reverses this effect. Moreover, IFITM3, as the target gene of miR-29a, is positively regulated by TUG1. However, the adjustment relationship between these three components is still unknown and thus warrants further investigation. The objective of this study was to investigate the regulatory relationship between TUG1, miR-29a, and IFITM3 in human liver cancer. Patients and methods: The expression of TUG1 and miR-29a in tumor tissues and adjacent non-tumor tissues of 65 patients with HCC was detected by real-time quantitative polymerase chain reaction (RT-qPCR). The migration and invasion of liver cancer cells were studied by the wound healing assay and the Transwell method, respectively. The apoptosis rate of HCC cells was detected by flow cytometry, and the proliferation rate of hepatoma cells was detected by the 5-ethynyl-2'-deoxyuridine (EdU) method. Immunofluorescence was used to detect the expression of TUG1 and IFITM3 in HCC-LM3 and HL-7702 cell lines. The relationship between TUG1 and miR-29a was detected using a double luciferase reporter assay and fluorescence in situ hybridization (FISH). Tumors were established in vivo by subcutaneous injection of HCC cells into nude mice and injection of these cells into the tail vein. Western blotting was used to quantify the biomarkers. Results: The expression of TUG1 increased significantly in tumor tissues and HCC cells. Moreover, the expression of miR-29a in liver cancer tissues was significantly lower than that in normal human liver tissues. The expression of TUG1 in liver cancer tissue was negatively correlated with miR-29a. Knockdown of TUG1 weakened the invasion, migration, and proliferation of HCC cells, and enhanced their apoptosis. A simultaneous knockdown of miR-29a enhanced cell invasion, metastasis, and cell proliferation, whereas the apoptosis ability decreased. As a target gene of miR-29a, IFITM3 is not only negatively regulated by miR-29a, but also positively regulated by TUG1. Therefore, TUG1 regulates IFITM3 in HCC cells by competitively binding to miR-29a, thus affecting cell invasion, migration, proliferation, and apoptosis. Conclusion: As a CeRNA, TUG1 competitively binds to miR-29a to regulate IFITM3 and promote the development of liver cancer. Downregulation of TUG1 can significantly inhibit the migration, invasion, and proliferation of liver cancer cells. Based on these results, we conclude that TUG1 could serve as a key gene to improve the prognosis of patients with HCC.

Changes in the cellular microRNA (miRNA) expression profile in response to HIV infection, replication or latency have been reported. Nevertheless, little is known concerning the abundance of miRNA in extracellular vesicles (EVs). In the search for a reliable predictor of viral rebound, we quantified the amount of miR-29a, miR-146a, and miR-155 in two types of plasma extracellular vesicles. Venous blood was collected from 235 ART-treated and ART-naive persons living with HIV (85 with ongoing viral replication, ≥20 copies/mL) and 60 HIV-negative participants at five HIV testing or treatment centers in Burkina Faso. Large and small plasma EVs were purified and counted, and mature miRNA miR-29a, miR-146a, and miR-155 were measured by RT-qPCR. Diagnostic performance of miRNA levels in large and small EVs was evaluated by a receiver operating characteristic curve analysis. The median duration of HIV infection was 36 months (IQR 14–117). The median duration of ART was 34 months (IQR 13–85). The virus was undetectable in 63.8% of these persons. In the others, viral load ranged from 108 to 33,978 copies/mL (median = 30,032). Large EVs were more abundant in viremic participants than aviremic. All three miRNAs were significantly more abundant in small EVs in persons with detectable HIV RNA, and their expression levels in copies per vesicle were a more reliable indicator of viral replication in ART-treated patients with low viremia (20–1000 copies/mL). HIV replication increased the production of large EVs more than small EVs. Combined with viral load measurement, quantifying EV-associated miRNA abundance relative to the number of vesicles provides a more reliable marker of the viral status. The expression level as copies per small vesicle could predict the viral rebound in ART-treated patients with undetectable viral loads.

Radiation-induced lung injury (RILI) is one of the most serious complications of thoracic radiation and TGF-β1 is a central regulator of RILI. However, the molecular mechanism underlying the fine tuning of TGF-β1 signaling in RILI has not been fully understood. In the current study, differentially expressed long non-coding RNAs (LncRNAs) among human lung fibroblasts cell lines HFL-1 and WI-38 treated with TGF-β1, were identified by microarray and validated by real time PCR. LncRNA-RP11 was found to be the most increased LncRNA and it mediated the promotion of fibrogenic activity in human lung fibroblasts after TGF-β1 treatment. Bioinformatic analysis revealed that TGF-β1 may be associated with the component and structure of extracellular matrix in lung fibroblasts cells, and LncRNA-RP11 was predicted and confirmed to be a competing endogenous RNA by directly binding to miR-29a. Functional experiments investigating the biological role of LncRNA-RP11/miR-29a axis in RILI, were then carried out in human fibroblasts. The results showed that radiation promoted the expression of LncRNA-RP11, but regressed the expression of miR-29a. Furthermore, radiation elevated the expression of various common collagenic proteins, which could be abolished by overexpression of miR-29a.

Background As a highly malignant tumor, cholangiocarcinoma poses a serious threat to human life and health, so exploring the mechanisms of its development and progression at a molecular level is of great significance to the diagnosis and treatment of the disease. Objective This study was aimed at investigating the effects and related mechanisms of LncRNA TUG1 on cholangiocarcinoma cells. Methods Cholangiocarcinoma tissues and adjacent tissues (n=82 each), human cholangiocarcinoma cell lines (RBE, QBC939, HuH28), and a human normal biliary epithelial cell line (HIBE) were collected. miR-29a-mimics, miR-29a-inhibitor, miR-NC, si-TUG1, pcDNA3.1 TUG1, and NC were transfected into the cholangiocarcinoma cells. qRT-PCR was performed to detect TUG1 and miR-29a expression in the cholangiocarcinoma tissues and cells. Western blotting (WB) was conducted to detect the expression of Bax, Caspase-3, and Bcl-2 in the cells. CCK-8 assay, Transwell, and flow cytometry were carried out to detect cell proliferation, invasion, and apoptosis. Dual luciferase reporter gene assay (DLRGA) was performed to confirm the correlation of TUG1 with miR-29a. Results TUG1 was highly expressed while miR-29a was poorly expressed in cholangiocarcinoma cells. TUG1 expression was negatively correlated with miR-29a expression, and TUG1 had a relatively high diagnostic value for cholangiocarcinoma. Cell experiments showed that inhibiting TUG1 expression or up-regulating miR-29a expression could inhibit cholangiocarcinoma cells from proliferation and invasion, and promote their apoptosis, while up-regulating TUG1 or inhibiting miR-29a could promote the proliferation and invasion but inhibit the apoptosis. Rescue experiment showed that overexpressing miR-29a could reverse the effects of high TUG1 expression on cholangiocarcinoma cells. DLRGA confirmed that there was a regulatory relationship between TUG1 and miR-29a. Conclusion TUG1 is highly expressed in cholangiocarcinoma tissues. It can promote the growth and metastasis of cholangiocarcinoma cells by inhibiting miR-29a, so it may be a new target for diagnosing and treating cholangiocarcinoma.

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. Methods In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing and control human PSCs (hPSCs). Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top miR-29a candidate targets in hPSCs transfected with miR-29a mimic or scramble control. Results RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. Conclusions Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-cancer cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.

Due to their aggressive behavior, local recurrence and distant metastasis, survival rate of advanced stage of the patients with head and neck squamous cell carcinoma (HNSCC) is very poor. Currently available epidermal growth factor receptor (EGFR)-targeted therapies are not considered curative for HNSCC. Therefore, novel approaches for identification of therapeutic targets in HNSCC are needed. All members of the miRNA-29 family (miR-29a, miR-29b, and miR-29c) were downregulated in HNSCC tissues by analysis of RNA-sequencing based microRNA (miRNA) expression signature. Ectopic expression of mature miRNAs demonstrated that the miR-29 family inhibited cancer cell migration and invasion by HNSCC cell lines. Comprehensive gene expression studies and in silico database analyses were revealed that integrin β1 (ITGB1) was regulated by the miR-29 family in HNSCC cells. Overexpression of ITGB1 was confirmed in HNSCC specimens, and high expression of ITGB1 significantly predicted poor survival in patients with HNSCC (p = 0.00463). Knockdown of ITGB1 significantly inhibited cancer cell migration and invasion through regulating downstream of ITGB1-mediated oncogenic signalling. In conclusion, regulation of the antitumor miR-29 family affected integrin-mediated oncogenic signalling to modulate HNSCC pathogenesis; these molecules may be novel therapeutic targets for HNSCC.

Background: Plasma microRNAs (miRNAs) are promising non-invasive biomarkers for colorectal cancer (CRC) prognosis. However, the published studies to date have yielded conflicting and inconsistent results for specific plasma miRNAs. Methods: We have conducted a study using robust assays to assess a panel of nine miRNAs for CRC prognosis and early detection of recurrence. Plasma samples from 144 patients in a prospective CRC cohort study were collected at diagnosis, 6, 12, and 24 months after diagnosis. miRNAs were assayed by Taqman qRT–PCR to generate miRNA normalised copy numbers. Results: Preoperative high plasma miRNA levels were associated with increased recurrence risk for miR-200b (HR [95% CI]=2.04 [1.00, 4.16], P=0.05), miR-203 (HR=4.2 [1.48, 11.93], P=0.007), miR-29a (HR=2.61 [1.34,5.07], P=0.005), and miR-31 (HR=4.03 [1.76, 9.24], P=0.001). Both plasma miR-31 (AUC: 0.717) and miR-29a (AUC: 0.703) could discriminate recurrence from these patients without recurrence. In addition, high levels of miR-31 during surveillance was associated with a three-fold increased risk of recurrence across all time points. Dynamic postoperative plasma miR-141 and 16 levels correlated with recurrence in the surveillance samples. Conclusions: Pre-operative plasma miR-29a, 200b, 203, and 31 are potential CRC prognosis biomarkers. In addition, dynamic postoperative miR-31, 141 and 16 levels are potential biomarkers for the early detection of recurrence during CRC surveillance.

// Zhuo Xi 1, 2 , Ping Wang 3 , Yixue Xue 3 , Chao Shang 3 , Xiaobai Liu 1, 2 , Jun Ma 3 , Zhiqing Li 3 , Zhen Li 1, 2 , Min Bao 1, 2 , Yunhui Liu 1, 2 1 Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of China 2 Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang 110004, People’s Republic of China 3 Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People’s Republic of China Correspondence to: Yunhui Liu, email: neurosurgery_sj@163.com Keywords: miR-29a, QKI-6, WTAP, glioma, glioblastoma stem cells Received: May 05, 2016 Accepted: January 23, 2017 Published: February 15, 2017 ABSTRACT Glioblastoma is the most common type of malignant primary brain tumor and has high recurrence and lethality rates. Glioblastoma stem cells (GSCs), a subpopulation of glioblastoma cells, may promote rapid tumor recurrence and therapy resistance. Because altered microRNA (miR) expression in GSCs may lead to glioblastoma progression, we assessed the effects of miR-29a expression on the oncogenic behavior of GSCs. MiR-29a expression was lower in GSCs than non-GSCs, and overexpression of miR-29a in GSCs inhibited cell proliferation, migration and invasion, but promoted apoptosis. MiR-29a directly inhibited the expression of Quaking gene isoform 6 ( QKI-6 ) by binding to its 3’-UTR, and thus inhibited GSC malignant behavior. In addition, Wilms’ tumor 1-associating protein ( WTAP ) was identified as a downstream target of QKI-6. Overexpression of miR-29a in GSCs inhibited expression of WTAP and suppressed both phosphoinositide 3-kinase/AKT and extracellular signal-related kinase pathways by downregulating QKI-6, thereby inhibiting cell proliferation, migration, and invasion but promoting apoptosis. We have characterized a novel miR-29a/QKI-6/WTAP axis in GSCs, which may provide theoretical support for the treatment of glioblastoma with miR-29a agomirs.

Background: miR-29a, a downstream factor of Wnt/β-catenin signaling, promotes the activity of the Wnt/β-catenin signaling in a positive feedback loop. Our previous work showed that 5,7,3ʹ,4ʹ-tetramethoxyflavone (TMF), a major constituent from Murraya exotica L., exhibited chondroprotective activity by inhibiting the activity of Wnt/β-catenin signaling. Purpose: To investigate whether TMF showed the inhibitory effects on miR-29a/β-catenin signaling by up regulation of Foxo3a expression. Methods: Rat knee OA models were duplicated by using Hulth’s method. TMF (5 μg/mL and 20 μg/mL) was used for administration to cultured cells, which were isolated from the rat cartilages. Analysis of chondrocytes apoptosis, gene expression, and protein expression were conducted. In addition, miR-29a mimics and pcDNA3.1(+)-Foxo3a vector were used for transfection, luciferase reporter assay for detecting the activity of Wnt/β-catenin signaling, and co-immunoprecipitation for determining proteins interaction. Results: TMF down regulated miR-29a/β-catenin signaling activity and cleaved caspase-3 expression and up regulated Foxo3a expression in OA rat cartilages. In vitro, miR-29a mimics down regulated the expression of Foxo3a and up regulated the activity of Wnt/β-catenin signaling and cleaved caspase-3 expression. TMF ameliorated miR-29a/β-catenin-induced chondrocytes apoptosis by up regulation of Foxo3a expression. Conclusion: TMF exhibited chondroprotective activity by up regulating Foxo3a expression and subsequently inhibiting miR-29a/Wnt/β-catenin signaling activity.

MicroRNA-29 (miR-29) has been found to reduce liver inflammation and fibrosis following a liver injury. Meanwhile, DNA methyltransferase has been reported to participate in the development of non-alcoholic steatohepatitis (NASH). The aim of this study is to investigate the miR-29a regulation of methyltransferase signaling and epigenetic program in NASH progression. Methods: miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates were subjected to the methionine-choline-deficient (MCD) diet-induced animal model of NASH. Primary hepatic stellate cells were transfected with a miR-29a mimic and antisense inhibitor. We then analyzed gene expressions with qRT-PCR, immunohistochemical stain, Western blot, and luciferase reporter assay. The results demonstrated that increased miR-29a alleviated the MCD diet-induced body weight loss and steatosis and decreased aspartate aminotransferase (AST) levels in mice. Furthermore, hepatic tissue in miR-29aTg mice displayed a weak fibrotic matrix, as shown with Sirius Red staining concomitant with low fibrotic &alpha, SMA expression within affected tissues compared to the wild-type mice fed the MCD diet. Forced miR-29a expression reduced the MCD diet exaggeration of reactive oxygen species (ROS) production by immunohistochemically staining 8-OHdG. Increased miR-29a signaling also resulted in the downregulation of DNMT3b, TGF-&beta, IL-6, heme oxygenase-1 (HO-1), p-SMAD3, PI3K, and L3BII expression within the liver tissue. An in vitro luciferase reporter assay further confirmed that miR-29a mimic transfection reduced DNMT3b expression in primary HSCs. Our data provide new insights that miR-29a improves MCD diet-induced liver inflammation, steatosis and fibrosis, and highlight the potential of miR-29a targeted therapy for treating NASH.

Ischemic stroke is the main cause of brain injury and results in a high rate of morbidity, disability and mortality. In the present study, we aimed to determine whether miR‑29a played a protective role in oxygen glucose deprivation (OGD) injury via regulation of the water channel protein aquaporin 4 (AQP4). Real‑time PCR and western blotting were used to assess miR‑29a levels and AQP4 protein levels, respectively. Apoptosis was detected by flow cytometry, and lactate dehydrogenase (LDH) was determined by enzyme‑linked immunosorbent assay (ELISA). Overexpression of miR‑29a was significantly downregulated in OGD‑induced primary astrocytes, and transfection with a miR‑29a mimic decreased LDH release and apoptosis, and improved cell health in OGD‑induced astrocytes. AQP4 was the target of miR‑29a, which suppressed AQP4 expression, and knockdown of AQP4 mitigated OGD‑induced astrocyte injury. Furthermore, miR‑29a regulated AQP4 expression in OGD‑induced astrocytes. AQP4 exacerbated astrocyte injury following ischemic stroke, and knockdown of AQP4 protected OGD/RX‑induced primary cultured astrocytes against injury. The effect of miR‑29a inhibitor on primary astrocytes was lost following AQP4 knockdown. These findings indicated that miR‑29a prevented astrocyte injury in vitro by inhibiting AQP4. Thus, miR‑29a may protect primary cultured astrocytes after OGD‑induced injury by targeting AQP4, and may be a potential therapeutic target for ischemic injury of astrocytes.

Hepatocellular carcinoma (HCC) remains one of the most lethal human cancer globally. For advanced HCC, curable plan for advanced HCC is yet to be established, and the prognosis remains poor. The detail mechanisms underlying the progression of HCC tumorigenicity and the corruption of tumor microenvironment (TME) is complex and inconclusive. A growing body of studies demonstrate microRNAs (miRs) are important regulators in the tumorigenicity and TME development. Notably, mounting evidences indicate miR-29a play a crucial role in exerting hepatoprotective effect on various types of stress and involved in the progression of HCC, which elucidates their potential theragnostic implications. In this review, we reviewed the advanced insights into the detail mechanisms by which miR-29a dictates carcinogenesis, epigenetic program, and metabolic adaptation, and implicated in the sponging activity of competitive endogenous RNAs (ceRNA) and the TME components in the scenario of HCC. Furthermore, we highlighted its clinical significance in diagnosis and prognosis, as well as the emerging therapeutics centered on the activation of miR-29a.

Background/Aims: Atherosclerosis is a chronic inflammatory condition associated with a variety of vascular diseases. Previous studies showed that both miR-29a and oxidized low density lipoprotein (ox-LDL) were vital in the development of atherosclerosis. However, the relationship between miR-29a and ox-LDL remains unknown. This study was designed to investigate the association of miR-29a and ox-LDL and to test whether circulating miR-29a and ox-LDL levels could predict atherosclerosis. Methods: In 170 participants, plasma levels of miR-29a were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) while plasma ox-LDL levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. The relationship between miR-29a level and ox-LDL and carotid intima-media thickness (cIMT) was assessed using the Spearman correlation coefficient and multiple liner regression. Results: Compared with the normal cIMT group, the increased cIMT group had higher levels of ox-LDL (0.47 ± 0.08 vs 0.29 ± 0.06 ng/ml, p = 0.003) and miR-29a (32.93 ± 4.26 vs 26.37 ± 1.04, p < 0.001). A positive correlation was found between ox-LDL and miR-29a (r = 0.695, p < 0.001), and both the ox-LDL (r = 0.857, p < 0.001) and the miR-29a (r = 0.753, p < 0.001) were positively related to cIMT. Furthermore, multiple liner regression indicated that a significant correlation between ox-LDL and cIMT (β = 0.768, p < 0.001), as well as between miR-29a and cIMT (β = 0.686, p

Lung cancer remains the most frequent cause of cancer-related death in developed countries. A recent molecular-targeted strategy has contributed to improvement of the remarkable effect of adenocarcinoma of the lung. However, such treatment has not been developed for squamous cell carcinoma (SCC) of the disease. Our recent studies of microRNA (miRNA) expression signatures of human cancers showed that the microRNA-29 family (miR‑29a, miR‑29b and miR‑29c) significantly reduced cancer tissues compared to normal tissues. These findings suggest that miR‑29s act as tumor-suppressors by targeting several oncogenic genes. The aim of the study was to investigate the functional significance of miR‑29s in lung SCC and to identify miR‑29s modulating molecular targets in lung SCC cells. Restoration of all mature members of the miR‑29s inhibited cancer cell migration and invasion. Gene expression data combined in silico analysis and luciferase reporter assays demonstrated that the lysyl oxidase-like 2 (LOXL2) gene was a direct regulator of tumor‑suppressive miR‑29s. Moreover, overexpressed LOXL2 was confirmed in lung SCC clinical specimens, and silencing of LOXL2 inhibited cancer cell migration and invasion in lung SCC cell lines. Our present data suggested that loss of tumor-suppressive miR‑29s enhanced cancer cell invasion in lung SCC through direct regulation of oncogenic LOXL2. Elucidation of the novel lung SCC molecular pathways and targets regulated by tumor-suppressive miR‑29s will provide new insights into the potential mechanisms of oncogenesis and metastasis of the disease.

Objective To evaluate serum microRNA (miR)-29a/b expression in gestational diabetes mellitus (GDM) and its influence on neonatal prognosis. Methods This was a retrospective study including 68 pregnant women with GDM (GDM group) and 55 healthy pregnant women of similar age range and gestation period (healthy group). Results The area under the curve was 0.829 for the diagnosis of GDM using serum miR-29a expression, 0.857 for diagnosis using serum miR-29b expression, and 0.944 for combined diagnosis (using both miR-29a and miR-29b). The fasting insulin (FINS) level of the GDM group was significantly lower than that of the healthy group; levels of fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), and glycated hemoglobin (HbA1c) were significantly higher in the GDM group than in the healthy group. Both miR-29a and miR-29b were positively correlated with FINS levels and negatively correlated with FPG, 2hPG, and HbA1c levels. Serum miR-29a/b expression in pregnant women with GDM was not correlated with neonatal weight, premature delivery, or asphyxia but was correlated with pathologic jaundice. Conclusions Serum miR-29a/b expression was downregulated in pregnant women with GDM and correlated with neonatal pathologic jaundice, showing good individual (miR-29a or miR-29b) diagnostic value and excellent combined (miR-29a and miR-29b) diagnostic value.

Objective: This study aims to investigate the effect of miR-29a targeting the regulation of DNMT3A on the development of cardiac fibrosis in Sprague-Dawley (SD) rats. Methods: In vivo experiment: SD rats were randomly divided into model and control groups. The cardiac and left ventricular indices in each group were calculated. The pathological changes of the myocardium were observed. The expression levels of miR-29a, CollA1, α-SMA, and DNMT3A in the myocardium of each group were detected. In vitro experiment: The cardiac fibroblasts (CFs) of SD rats were isolated from the myocardial tissue of SD rats and cultured. The miR-29a mimics, inhibitors, DNMT3A-siRNA, and control-siRNA were transfected into CFs. The expression levels of miR-29a, DNMT3A, CollA1, and α-SMA were detected, and the proliferation of CFs after transfection was observed. Results: The heart weight index of the rats in the model group increased significantly compared with that in the control group. Obvious collagen deposition was observed in the myocardial tissue of the model group. The expression levels of CollA1, α-SMA, and DNMT3A in the model group were significantly higher than those in the control group (p

IL-13 is a proinflammatory cytokine associated with multiple pathological conditions and the promotion of metastasis in lung cancer. Previous studies have demonstrated that IL-13 and YY1 are associated with PI3K/AKT signaling. In addition, miR-29a has been found to play a critical role in cell invasion in lung cancer. However, the molecular mechanism of miR-29a underlying its involvement in IL-13-induced lung cancer cell invasion remains largely unknown. In the present study, we aimed to investigate the role of miR-29a in cell invasion mediated by IL-13 in lung cancer. By using MTT and wound-scratch assays, we assessed cell proliferation and migration induced by IL-13, and identified activation of the PI3K/AKT/YY1 pathway. Inhibition of PI3K/AKT by LY294002 downregulated IL-13-induced YY1 expression. Furthermore, we found that miR-29a directly targets YY1 and suppressed its expression in lung cancer. By using MTT, flow cytometry and Transwell assays, overexpression of miR-29a restricted both YY1 and N-cadherin expression, and inhibited IL-13-induced invasion of lung cancer A549 cells. Taken together, these findings demonstrate that PI3K/AKT/YY1 is involved in the regulation of lung cancer cell behavior induced by IL-13, and miR-29a represents a promising therapeutic target.

Background and Objective: Various cellular factors affect the process of HIV activity. One of these cellular factors are structures known as microRN that are expected to be involved in controlling HIV replication and infectivity. The expression of one or a set of them may represent the patientchr('39')s clinical conditions. In this study, the expression of miR-29a and miR-29b involved in regulating viral genes’ expression was evaluated in three HIV-positive groups and a healthy control group. Later, the expression level of these microRNAs was compared between the cases and controls. Methods: Total RNA extraction was performed on the collected samples using RNx-plus kit and then the microRNA expression levels were evaluated using Relative Real-time PCR. The obtained data was entered into SPSS 22 and Graphpad softwares and analyzed using Kruskal-Wallis and Man-Whitney tests. P-value of less than 0.05 was considered as statistical significance level. Results: The expression level of miR-29a was reduced in patients under treatment and drug-resistant patients ( P ≤ 0.05) . All three HIV-positive groups including people without drug treatment, patients under treatment and drug-resistant patients showed reduced miR-29b expression level compared to control group (P ≤ 0.05). Conclusion: the decreased expression of miR-29a and miR-29b in patients under treatment and drug-resistant patients indicates an increased viral replication and reduced CD4 cell count. It may be possible to predict the progression of the disease by miRNA measurement or control viral replication using these mir-RNAs that requires further studies. Keywords: HIV, expression, mir-29a, mir-29b.

Background: MicroRNAs (miRNAs) have emerged as gene expression regulators in the progression of ischemia-reperfusion injury (IRI). Accumulating evidences have indicated miR-29a play roles in myocardial and cerebral IRI. However, the role of miR-29a in testicular IRI has not been elucidated. Methods: Changes in expression of miR-29a and Transient Receptor Potential Vanilloid 4 (TRPV4) in animal samples and GC-1 spermatogenic cells were examined. The effects of miR-29a on spermatogenic cell apoptosis in testicular IRI were analyzed both in vitro and in vivo. Results: The expression of MiR-29a was negatively correlated with the expression of TRPV4 and significantly downregulated in animal samples and GC-1 cells as testicular IRI progressed. Further studies revealed TRPV4 as a downstream target of miR-29a. Inhibition of miR-29a expression increased the expression of TRPV4 and promoted spermatogenic cell apoptosis, whereas overexpression of miR-29a downregulated TRPV4 expression and suppressed spermatogenic cell apoptosis caused by testicular IRI in vitro and in vivo. Conclusion: Our results suggest that miR-29a suppresses apoptosis induced by testicular IRI by directly targeting TRPV4.

AIM To investigate the functional role and underlying molecular mechanism of miR-29a in hepatitis B virus (HBV) expression and replication. METHODS The levels of miR-29a and SMARCE1 in HBV-infected HepG2.2.15 cells were measured by quantitative real-time PCR and western blot analysis. HBV DNA replication was measured by quantitative PCR and Southern blot analysis. The relative levels of hepatitis B surface antigen and hepatitis B e antigen were detected by enzyme-linked immunosorbent assay. The Cell Counting Kit-8 (CCK-8) was used to detect the viability of HepG2.2.15 cells. The relationship between miR-29a and SMARCE1 were identified by target prediction and luciferase reporter analysis. RESULTS miR-29a promoted HBV replication and expression, while SMARCE1 repressed HBV replication and expression. Cell viability detection indicated that miR-29a transfection had no adverse effect on the host cells. Moreover, SMARCE1 was identified and validated to be a functional target of miR-29a. Furthermore, restored expression of SMARCE1 could relieve the increased HBV replication and expression caused by miR-29a overexpression. CONCLUSION miR-29a promotes HBV replication and expression through regulating SMARCE1. As a potential regulator of HBV replication and expression, miR-29a could be a promising therapeutic target for patients with HBV infection.

MicroRNAs (miRNAs) are endogenously expressed small, non-coding transcripts that regulate protein expression. Substantial evidences suggest that miRNAs are enriched in central nervous system, where they are hypothesized to play pivotal roles during neural development. In the present study, we analyzed miRNAs expression in mice cerebral cortex and hippocampus at different developmental stages and found miR-29a increased dramatically at postnatal stages. In addition, we provided strong evidences that miR-29a is enriched in mature neurons both in vitro and in vivo. Further investigation demonstrated that the activation of glutamate receptors induced endogenous miR-29a level in primary neurons. Moreover, we showed that miR-29a directly regulated its target protein Doublecortin (DCX) expression, which further modulated axon branching in primary culture. Together, our results suggested that miR-29a play an important role in neuronal development of mice cerebrum. Electronic supplementary material The online version of this article (doi:10.1007/s13238-014-0022-7) contains supplementary material, which is available to authorized users.

Background: Growing evidence suggests that miR-29a has an important role in regulating tumourigenesis and development of various types of cancer. However, the role and the underlying mechanism of miR-29a in colorectal cancer (CRC) remain largely unknown. Methods: MiR-29a targeted gene was identified by the luciferase assay and western blot. MiR-29a function was analysed by invasion assays and the orthotopic transplantation mouse model. The miR-29a pathway was assayed by real-time PCR, western blot and chip analysis. Results: KLF4 was identified as a direct target gene of miR-29a. MiR-29a promoted CRC cell invasion, which was blocked by re-expression of KLF4. In addition, MMP2 was identified as a novel direct target of KLF4. Both miR-29a overexpression and KLF4 knockdown promoted MMP2 expression but inhibited E-cadherin expression. Furthermore, clinical data indicated that both miR-29a high expression and KLF4 mRNA low expression were associated with metastasis and poor prognosis in CRC patients, and KLF4 protein expression was inversely correlated with MMP2 but positively correlated with E-cad protein expression. Conclusion: Increased expression of miR-29a promoted CRC metastasis by regulating MMP2/E-cad through direct targeting KLF4, which highlights the potential of the miR-29a inhibitor as a novel agent against CRC metastasis.

Our recent studies of microRNA (miRNA) expression signatures indicated that microRNA-29a (miR-29a) was significantly downregulated in several types of human cancers, suggesting that miR-29a may be a putative tumor-suppressive miRNA in human cancers. The aim of this study was to investigate the functional significance of miR-29a in cervical squamous cell carcinoma (SCC) and to identify novel miR-29a-regulated cancer pathways and target genes involved in cervical SCC oncogenesis and metastasis. Restoration of miR-29a in cervical cancer cell lines (CaSKi, HeLa, ME180 and Yumoto) revealed that this miRNA significantly inhibited cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that heat-shock protein 47 (HSP47), a member of the serpin superfamily of serine proteinase inhibitors and a molecular chaperone involved in the maturation of collagen molecules, was a potential target of miR-29a regulation. Luciferase reporter assays showed that miR-29a directly regulated HSP47. Moreover, silencing of the HSP47 gene significantly inhibited cell migration and invasion in cancer cells and the expression of HSP47 was upregulated in cancer tissues and cervical intraepithelial neoplasia (CIN), as demonstrated by immunostaining. Downregulation of miR-29a was a frequent event in cervical SCC and miR-29a acted as a tumor suppressor by directly targeting HSP47. Recognition of tumor-suppressive miRNA-regulated molecular targets provides new insights into the potential mechanisms of cervical SCC oncogenesis and metastasis and suggests novel therapeutic strategies for treatment of this disease.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate target gene expression by binding to the 3′ untranslated region (3′ UTR) of the target mRNA. MiRNAs regulate a large variety of genes, including those involved in liver biology and disease. Here, we report for the first time that miR-29a post-transcriptionally regulates stearoyl-CoA desaturase (SCD) by binding to its 3′ UTR in genetically improved farmed tilapia (GIFT), Oreochromis niloticus, as shown by a 3′ UTR luciferase reporter assay. miR-29a antagomir treatment in vivo resulted in significant upregulation of SCD expression. We found that miR-29a expression was negatively correlated with SCD expression in GIFT liver. Inhibition of miR-29a led to a significant increase in SCD expression on day 60 induced by a saturated fatty acid diet, thereby increasing conversion of 16:0 and 18:0 to 16:1 and 18:1, respectively, and activating serum insulin, which would favor glucose and lipid uptake by the liver. These results indicate that miR-29a regulates SCD levels by binding to its 3′ UTR, and this interaction affects saturated fatty acid stress induction and insulin and lipid accumulation in serum. Our results suggest that miR-29a is critical in regulating lipid metabolism homeostasis in GIFT liver, and this might provide a basis for understanding the biological processes and therapeutic intervention encountered in fatty liver., Summary: miR-29a targets SCD 3′ UTR directly. Inhibition of miR-29a could mediate conversion of C16:0 and C18:0 to C16:1 and C18:1, respectively, and activate serum insulin and glucose uptake in GIFT by increasing SCD.

Breast cancer is the most commonly occurring cancer among women. MicroRNAs as noncoding small RNA molecules play pivotal roles in cancer-related biological processes. Increased levels of microRNA-29a in the serum of breast cancer patients have been reported. Since heat shock proteins (HSPs) play important roles in cell events, the quantitative fluctuations in their cellular levels could be deemed as key indicators of how the exerted treatment alters cell behavior. In this regard, using an antisense small RNA, we attempted to investigate the effects of miR-29a knockdown on the expression of HSPs genes in the MCF-7 breast cancer cell line. MCF-7 cells were cultured in high-glucose Dulbecco’s modified Eagle’s medium with 10% FBS. Studied cells were subdivided into five groups: treated with scramble, anti-miR-29a, anti-miR-29a + Taxol, Taxol, and control. Taxol was added 24 h post-anti-miR transfection and RNA extraction, and cDNA synthesis was done 48 h later. The changes in expression of HSP27, HSP40, HSP60, HSP70, and HSP90 were evaluated by real-time PCR. Our results revealed that inhibitors of microRNA-29a promote apoptosis through upregulation of HSP60 level and downregulation of HSP27, HSP40, HSP70, and HSP90 levels and could be contemplated as a compelling alternative for Taxol employment with similar effects and/or to sensitize cancer cells to chemotherapy with fewer side effects.

MicroRNAs have been reported to play an important role in diverse biological processes and progression of various cancers. MicroRNA-29a has been observed to be downregulated in human lung cancer tissues, but the function of microRNA-29a in lung cancer has not been well investigated. In this study, we demonstrated that the expression levels of microRNA-29a were significantly downregulated in 38 pairs of lung cancer tissues when compared to adjacent normal tissues. Overexpression of microRNA-29a inhibited the activity of cell proliferation and colony formation of lung cancer cells, H1299 and A549. Furthermore, microRNA-29a targeted NRAS proto-oncogene in lung cancer cells. In human clinical specimens, NRAS proto-oncogene was highly expressed in human lung cancer tissues compared to normal tissues. More interestingly, microRNA-29a also sensitizes lung cancer cells to cisplatin (CDDP[Please replace “CDDP” with its expansion in the abstract and also provide expansion for the same in its first occurrence in text, if appropriate.]) via its target, NRAS proto-oncogene. Thus, our results in this study demonstrated that microRNA-29a acted as a tumor suppressor microRNA, which indicated potential application of microRNAs for the treatment of human lung cancer in the future.

Here, we found that members of the microRNA-29 family (miR-29a/b/c; “miR-29s”) were significantly reduced in clear cell renal cell carcinoma (ccRCC) tissues, suggesting that they functioned as tumour suppressors. Restoration of all mature members of the miR-29 family inhibited cancer cell proliferation, migration and invasion. LOXL2 was a direct target gene of miR-29s, as shown by genome-wide gene expression analysis and luciferase reporter assay. Overexpressed LOXL2 was confirmed in ccRCC clinical specimens, and silencing of LOXL2 inhibited cancer cell migration and invasion in ccRCC cell lines. Our data demonstrated that the miR-29s-LOXL2 axis contributed to cancer cell migration and invasion in ccRCC.

MicroRNA-29 (miR-29) is found to modulate hepatic stellate cells’ (HSCs) activation and, thereby, reduces liver fibrosis pathogenesis. Histone methyltransferase regulation of epigenetic reactions reportedly participates in hepatic fibrosis. This study is undertaken to investigate the miR-29a regulation of the methyltransferase signaling and epigenetic program in hepatic fibrosis progression. miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates were subjected to bile duct-ligation (BDL) to develop cholestatic liver fibrosis. Primary HSCs were transfected with a miR-29a mimic and antisense inhibitor. Profibrogenic gene expression, histone methyltransferases and global genetic methylation were probed with real-time quantitative RT-PCR, immunohistochemical stain, Western blot and ELISA. Hepatic tissue in miR-29aTg mice displayed weak fibrotic matrix as evidenced by Sirius Red staining concomitant with low fibrotic matrix collagen 1α1 expression within affected tissues compared to the wild-type mice. miR-29a overexpression reduced the BDL exaggeration of methyltransferases, DNMT1, DNMT3b and SET domain containing 1A (SET1A) expression. It also elevated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling within liver tissue. In vitro, miR-29a mimic transfection lowered collagen 1α1, DNMT1, DNMT3b and SET1A expression in HSCs. Gain of miR-29a signaling resulted in DNA hypomethylation and high PTEN expression. This study shines a new light on miR-29a inhibition of methyltransferase, a protective effect to maintain the DNA hypomethylation state that decreases fibrogenic activities in HSC. These robust analyses also highlight the miR-29a regulation of epigenetic actions to ameliorate excessive fibrosis during cholestatic liver fibrosis development.

MicroRNAs have been shown to play an important role in insulin signaling but their biological function in insulin resistance induced by saturated fatty acids (SFA) remains largely unknown. Here, we report that SFA palmitate and high fat diet (HFD) significantly increase expression of miR-29a in myocytes. miR-29a targets IRS-1 3’UTR directly and represses IRS-1 expression at the translational level. Furthermore, the ectopic expression of miR-29a impairs insulin signaling and glucose uptake in myocytes through a substantial decrease in IRS-1. These findings suggest that the up-regulation of miR-29a by SFA is causally related to the development of insulin resistance in myocytes.

Accumulating evidence demonstrates that microRNA-29 (miR-29) expression is prominently decreased in patients with hepatic fibrosis, which consequently stimulates hepatic stellate cells’ (HSCs) activation. We used a cDNA microarray study to gain a more comprehensive understanding of genome-wide gene expressions by adjusting miR-29a expression in a bile duct-ligation (BDL) animal model. Methods: Using miR-29a transgenic mice and wild-type littermates and applying the BDL mouse model, we characterized the function of miR-29a with regard to cholestatic liver fibrosis. Pathway enrichment analysis and/or specific validation were performed for differentially expressed genes found within the comparisons. Results: Analysis of the microarray data identified a number of differentially expressed genes due to the miR-29a transgene, BDL, or both. Additional pathway enrichment analysis revealed that TGF-β signaling had a significantly differential activated pathway depending on the occurrence of miR-29a overexpression or the lack thereof. Furthermore, overexpression was found to elicit changes in Wnt/β-catenin after BDL. Conclusion: This study verified that an elevated miR-29a level could alleviate liver fibrosis caused by cholestasis. Furthermore, the protective effects of miR-29a correlate with the downregulation of TGF-β and associated with Wnt/β-catenin signal pathway following BDL.

A wealth of studies has highlighted the biological complexity of hematologic malignancies and the role of dysregulated signal transduction pathways. Along with the crucial role of genetic abnormalities, epigenetic aberrations are nowadays emerging as relevant players in cancer development, and significant research efforts are currently focusing on mechanisms by which histone post-translational modifications, DNA methylation and noncoding RNAs contribute to the pathobiology of cancer. As a consequence, these studies have provided the rationale for the development of epigenetic drugs, such as histone deacetylase inhibitors and demethylating compounds, some of which are currently in advanced phase of pre-clinical investigation or in clinical trials. In addition, a more recent body of evidence indicates that microRNAs (miRNAs) might target effectors of the epigenetic machinery, which are aberrantly expressed or active in cancers, thus reverting those epigenetic abnormalities driving tumor initiation and progression. This review will focus on the broad epigenetic activity triggered by members of the miR-29 family, which underlines the potential of miR-29s as candidate epi-therapeutics for the treatment of hematologic malignancies.