miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor.

The activation of hepatic stellate cells (HSCs) is regarded as the primary driving factor of liver fibrosis. miR-192, a miRNA associated with hepatocellular carcinoma and enriched in HSCs, has an undisclosed role in HSC activation and liver fibrosis. In this study, a CCl4-induced rat liver fibrosis model and transforming growth factor-beta 1 (TGF-ß1)-treated HSC lines (LX-2 and HSC-T6) were used to detect miR-192 and Rictor levels in vivo and in vitro. Bioinformatic analysis and a dual luciferase assay were used to predict and confirm the interaction of Rictor with miR-192. Gain- and/or loss-of-function methods evaluated molecular changes and HSC activation phenotypes, detected by quantitative real-time PCR, western blotting, and immunofluorescence. We observed a gradual downregulation of miR-192 and upregulation of Rictor during CCl4-induced liver fibrosis/cirrhosis in rats. Enriched miR-192 was downregulated, while Rictor was upregulated in TGF-ß1-activated HSCs. miR-192 inhibited the activation of HSCs by directly targeting Rictor. High miR-192/low Rictor expression attenuated the fibrotic-related gene expression by AKT/mTORC2 signaling. In conclusion, miR-192 could inhibit the activation of HSCs by directly targeting Rictor in the AKT/mTORC2 signaling pathway. This study provides insights into potential therapeutic targets for liver fibrosis and cirrhosis.

Rictor mediates p53 deactivation to facilitate the malignant transformation of hepatocytes and promote hepatocarcinogenesis.

BACKGROUND: Mutations in TP53 gene is considered a main driver of hepatocellular carcinoma (HCC). While TP53 mutations are the leading cause of p53 dysfunction, their occurrence rates may drop to approximately 10% in cohorts without hepatitis B virus and aflatoxin exposure. This observation suggests that the deactivation of wild-type p53 (p53wt) may be a critical factor in the majority of HCC cases. However, the mechanism undermining p53wt activity in the liver remains unclear. METHODS: Microarray analysis and luciferase assay were utilized to confirm target associations. Gain- and/or loss-of-function methods were employed to assess alterations in signaling pathways. Protein interactions were analyzed by molecular immunological methods and further visualized by confocal microscopy. Bioinformatic analysis was performed to analyze clinical significance. Tumor xenograft nude mice were used to validate the findings in vivo. RESULTS: Our study highlights the oncogenic role of Rictor, a key component of the mammalian target of rapamycin complex 2 (mTORC2), in hepatocytes. Rictor exerts its oncogenic function by binding to p53wt and subsequently blocking p53wt activity based on p53 status, requiring the involvement of mTOR. Moreover, we observed a dynamic nucleocytoplasmic distribution pattern of Rictor, characterized by its translocation from the nucleus (in precancerous lesions) to the cytoplasm (in HCCs) during malignant transformation. Notably, Rictor is directly targeted by the liver-enriched microRNA miR-192, and the disruption of the miR-192-Rictor-p53-miR-192 signaling axis was consistently observed in both human and rat HCC models. Clinical analysis associated lower miR-192/higher Rictor with shorter overall survival and more advanced clinical stages (P < 0.05). In mice, xenograft tumors overexpressing miR-192 exhibited lower Rictor expression levels, leading to higher p53 activity, and these tumors displayed slower growth compared to untreated HCC cells. CONCLUSIONS: Rictor dynamically shuttles between the nucleus and cytoplasm during HCC development. Its pivotal oncogenic role involves binding and inhibiting p53wt activity within the nucleus in early hepatocarcinogenesis. Targeting Rictor presents a promising strategy for HCC based on p53 status.

METTL3-mediated maturation of miR-192-5p targets ATG7 to prevent Schwann cell autophagy in peripheral nerve injury.

The inhibition of miR-192-5p can promote nerve repair in rats with peripheral nerve injury (PNI) but the precise mechanisms underlying this effect remain unclear. Schwann cell (SC) autophagy mediated by autophagy-related gene (ATG) proteins has a key role in PNI but it is uncertain whether miR-192-5p affects the involvement of SC autophagy in PNI. In this study, we investigated the impact of methyltransferase-like protein 3 (METTL3)/miR-192-5p/ATG7 on SC autophagy in a rat PNI model and in an SC oxygen and glucose deprivation model. The results revealed that METTL3 stimulated miR-192-5p maturation via m6A methylation to depress ATG7 and SC autophagy and aggravate PNI. These findings provide a new target and potential basis for the treatment of patients with PNI.

Roles of microRNA-192 in diabetic nephropathy: the clinical applications and mechanisms of action.

Diabetic nephropathy (DN) is one of the most common and intractable microvascular complications of diabetes worldwide, serving as the main cause of terminal renal disease. Due to the lack of early specific symptoms and diagnostic markers, DN severely threatens the sufferer's life. MicroRNA-192 (miR-192) was early identified in human renal cortical tissue and stored and excreted in urine as microvesicles. MiR-192 was found to be involved in the development of DN. For the first time, the present review summarized all the current evidence on the topic of the roles of miR-192 in DN. Finally, 28 studies (ten clinical trials and eighteen experimental studies) were eligible for thorough reviewing. Most of the clinical trials (7/10, 70%) indicated miR-192 might be a protective factor for DN development and progression, while the majority of experimental studies (14/18, 78%) suggested miR-192 might be a pathogenic factor for DN. Mechanistically, miR-192 interacts with various direct targeted proteins (i.e., ZEB1, ZEB2, SIP1, GLP1R, and Egr1) and signaling cascades (i.e., SMAD/TGF-ß and PTEN/PI3K/AKT), together contribute to the pathogenesis of DN through epithelial-to-mesenchymal transition (EMT), extracellular matrix deposition, and fibrosis formation. The current review highlights the dual role of miR-192 in the development of DN. Low serum miR-192 expression could be applied for the early prediction of DN (the early stage of DN), while the high miR-192 level in renal tissues and urine may imply the progression of DN (the late stage of DN). Further investigations are still warranted to illustrate this inconsistent phenomenon, which may facilitate promoting the therapeutic applications of miR-192 in predicting and treating DN.

Circulating miRNA-192 and miR-29a as Disease Progression Biomarkers in Hepatitis C Patients with a Prevalence of HCV Genotype 3.

MicroRNAs miR-29a and miR-192 are involved in inflammatory and fibrotic processes of chronic liver disease, and circulating miR-29a is suggested to diagnose fibrosis progression due to hepatitis C virus (HCV) infection. This study aimed to evaluate the expression profile of circulating miR-192 and 29a in a patient cohort with a high frequency of HCV genotype-3. A total of 222 HCV blood samples were collected and serum were separated. Patients were classified into mild, moderate, and severe liver injury based on their Child-Turcotte-Pugh CTP score. RNA was isolated from the serum and used for quantitative real-time PCR. The HCV genotype-3 (62%) was the predominant HCV genotype. In HCV patients, the serum miR-192 and miR-29a levels were significantly upregulated in comparison to healthy controls (p = 0.0017 and p = 0.0001, respectively). The progression rate of miR-192 and 29a in the patient group with mild was highly upregulated compared to patients with moderate and severe hepatitis infection. The ROC curve of miR-192 and miR-29a of moderate liver disease had a significant diagnostic performance compared to the other HCV-infected groups. The increase in miR-29a and miR-192 serum levels was even slightly higher in patients with HCV genotype-3 than in non-genotype-3 patients. In conclusion, serum miR-192 and miR-29a levels significantly increased during the progression of chronic HCV infection. The marked upregulation in patients with HCV genotype-3 suggests them as potential biomarkers for hepatic disease, independently of the HCV genotype.

Modulation of miR-192/NF-κB/ TGF-ß/ E-cadherin by thymoquinone protects against diethylnitrosamine /carbon tetrachloride hepatotoxicity.

Scientific efforts have been made for a better understanding of the pathogenesis of hepatocellular carcinoma (HCC). We investigated the possible role of miR-192/nuclear factor-κB (NF-κB)/transforming growth factor-ß (TGF-ß)/E-cadherin in hepatic tumorigenesis. We expected a modulatory impact of thymoquinone. Thirty adult male rats were assigned into 3 groups (n = 10); (1) Control group. Group (2): Experimental HCC induced by intraperitoneal injection of diethylnitrosamine (DENA) followed by carbon tetrachloride (CCl4). Group (3): Thymoquinone 20 mg kg-1/oral supplementation starting from the model induction to the end of the 8th week. The HCC (DENA-CCL4) model was confirmed by elevated serum levels of alpha-fetoprotein and transaminases (ALT, AST) and by histopathological examination which denoted marked cellular atypia and features of neoplasia. Suppressed hepatic miR-192 and E-cadherin expression were detected in the HCC (DENA-CCL4) group accompanied by elevated tumor necrosis factor (TNF-α), interleukin (IL6)/NF-κB & TGF-ß1. Thymoquinone treatment protected the rat livers from hepatic tumorigenesis. Thymoquinone diminished (P < 0.001) alpha-fetoprotein and improved ALT, AST. It preserved hepatic miR-192 and normal E-cadherin expression. Thymoquinone-treated rats showed abrogated TNF-α, IL6/NF-κB/TGF-ß. Thymoquinone increased cell apoptosis markers Bax/Bcl2 and diminished cellular atypia. Pearson's correlations revealed positive association between miR-192 expression and E-cadherin and Bax/Bcl2 as well, and it was negatively correlated to alpha-fetoprotein, NF-κB and TGF-ß and the cellular atypia score. In conclusion, thymoquinone protected the liver tissues through preserving miR-192 and E-cadherin and aborting NF-κB & TGF-ß signaling. The current results highlight a new role for thymoquinone in preventing hepatic tumorigenesis.

Down-Regulated microRNA-192-5p Protects Against Hypoxic-Ischemic Brain Damage via Regulation of YAP1-Mediated Hippo Signaling Pathway.

Hypoxic-ischemic brain damage (HIBD) is a familiar neurological disorder. Emerging reports manifest that microRNAs (miRs) are related to the progression of HIBD. The goal of this study is to explore the mechanism of miR-192-5p in HIBD via regulation of Yes-associated protein 1 (YAP1)-mediated Hippo signaling pathway. The miR-192-5p, YAP1, and Hippo pathway-related factors Phospho (p)-Triaminoguanidinium azide (TAZ) in hippocampal tissues and neurons were detected. The regulatory relationship between miR-192-5p and YAP1 was verified. Neonatal hypoxic ischemia and oxygen-glucose deprivation (OGD) were used to simulate HIBD in vivo and in vitro. The neurobehavioral impairment, neuronal damage and vascular endothelial growth factor (VEGF) expression of neonatal rats in each group were detected. The viability, apoptosis and VEGF expression of hippocampal neurons in each group were also examined. MiR-192-5p expression was elevated while YAP1 expression was reduced in hippocampal tissues of HIBD rats in vivo and OGD neurons in vitro. MiR-192-5p had a targeting relation with YAP1. Suppressed miR-192-5p or overexpressed YAP1 in HIBD rats alleviated neurobehavioral impairment and neuronal damage, and decreased the expression levels of p-TAZ and VEGF expression in vivo. Reduced miR-192-5p or augmented YAP1 decelerated the neuron apoptosis, decreased the p-TAZ level and VEGF level and promoted cell viability of OGD hippocampal neurons in vitro. The study highlights that inhibited miR-192-5p protects against HIBD via regulation of YAP1 and Hippo signaling pathway, which is beneficial for HIBD treatment.

MiR-192-5p inhibits proliferation, migration, and invasion in papillary thyroid carcinoma cells by regulation of SH3RF3.

BACKGROUND: The decreased level of miR-192-5p has been reported in several kinds of cancers, including bladder, colon, ovarian, and non-small cell lung cancer. However, the expression and function of miR-192-5p in papillary thyroid carcinoma/cancer (PTC) remains unknown. OBJECTIVE: The present study aimed to explore the function and underlying mechanism of miR-192-5p in PTC development. METHODS: PTC tissues and relative normal controls from PTC patients were collected. qRT-PCR analysis was performed to measure miR-192-5p and SH3RF3 mRNA level in PTC tissues and cell lines. CCK-8 method and FCM assay were used to test cell proliferation and apoptosis in TPC-1 cells, respectively. The abilities of cell migration and invasion were detected by wound healing and transwell assays, respectively. The protein expression was evaluated by Western blot. The interaction between miR-192-5p and Src homology 3 (SH3) domain containing ring finger 3 (SH3RF3) were confirmed by dual-luciferase reporter assay. RESULTS: MiR-192-5p level was obviously decreased in PTC tissues and cell lines. Overexpression of miR-192-5p suppressed proliferation, migration, invasion, and EMT process, while induced apoptosis in TPC-1 cells. In addition, miR-192-5p negatively modulated SH3RF3 expression by binding to its 3'-untranslated region (3'UTR). Silencing SH3RF3 inhibited the migration, invasion, and EMT of TPC-1 cells. In the meantime, matrine, an alkaloid extracted from herb, exerted its anti-cancer effects in PTC cells dependent on increase in miR-192-5p expression and decrease in SH3RF3 expression. CONCLUSION: We firstly declared that miR-192-5p played a tumor suppressive role in PTC via targeting SH3RF3. Moreover, matrine exerted its anti-cancer effects in PTC via regulating miR-192-5p/SH3RF3 pathway.

Effect of intestinal microbiota imbalance associated with chronic hepatitis B virus infection on the expression of microRNA­192 and GLP­1.

It has been reported that hepatitis B virus (HBV) infection has an impact on intestinal microbiota imbalance to induce diabetes mellitus (DM), but the underlying mechanisms still remain to be explored. The present study aimed to investigate the regulatory role of microRNA­192 (miR­192­5p) and glucagon­like peptide­1 (GLP­1) in intestinal microbiota imbalance by recruiting patients with DM infected with HBV. In the present study, patients with HBV infection and different levels of alanine transaminase (ALT) were recruited and divided into three groups. Intestinal microbiota analysis was performed to evaluate the fecal bacterial composition of patients in various groups. Quantitative PCR was performed to explore the differential expression of miR­192­5p and GLP­1 in the feces, peripheral blood and intestinal mucosal tissue samples of each patient. Immunohistochemistry was used to assess the expression of GLP­1 protein in the intestinal mucosal tissue samples. Luciferase assays were performed by cell transfection of miR­192­5p mimics/precursors/inhibitors to study the inhibitory effect of miR­192­5p on GLP­1 expression. Intestinal microbiota imbalance was observed in hepatitis B surface antigen (HBsAg)­positive patients with high ALT. The expression of miR­192­5p was significantly elevated in the feces, peripheral blood and intestinal mucosal tissue samples of HBsAg­positive patients with high ALT along with decreased GLP­1 mRNA and protein expression. Luciferase activity of GLP­1 vector was inhibited by miR­192­5p mimics and promoted by miR­192­5p inhibitors. Transfection of miR­192­5p precursors resulted in upregulation of miR­192­5p and downregulation of GLP­1, while miR­192­5p inhibitors remarkably suppressed the expression of miR­192­5p and notably induced the expression of GLP­1. These results showed a regulatory network involving HBV infection, intestinal microbiota imbalance, and miR­192­5p and GLP­1 expression.

MicroRNA-192-5p inhibits migration of triple negative breast cancer cells and directly regulates Rho GTPase activating protein 19.

Among the different breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with a poor prognosis, low survival rates, and high expression of histone deacetylases. Treatment with histone deacetylase inhibitor trichostatin A (TSA) leads to an increased expression of potential tumor-suppressive miRNAs. Characterization of these miRNAs can help to find new molecular targets for treatment of TNBC. We identified differentially expressed miRNAs by microarray analyses after treatment with TSA in the TNBC cell lines HCC38, HCC1395, and HCC1935. The gene locus of hsa-miRNA-192-5p (miR-192) and hsa-miR-194-2 (miR-194-2) with its host gene, long noncoding RNA miR-194-2HG, has been linked to inhibition of migration in different tumor types. Therefore, we examined tumor-relevant functional effects using WST-1-based proliferation, capsase-3/7-based apoptosis, and trans-well migration assays after transfection with miRNA mimics or specific siRNAs. We demonstrated the tumor-suppressive capacity of miR-192 in TNBC cells, which was exerted through inhibition of proliferation, induction of apoptosis, and reduction of migration. Gene expression and bioinformatics analyses of TNBC cell lines transfected with miR-192 mimics, identified a number of genes involved in migration including the Rho GTPase Activating Protein ARHGAP19. Through RNA immunoprecipitation we demonstrated the direct binding of miR-192 and ARHGAP19. Downregulation of ARHGAP19 expression by either miR-192 or siRNA inhibited migration of TNBC cells significantly. Our findings demonstrate that overexpression of epigenetically deregulated miR-192 decreases proliferation, promotes apoptosis, and inhibits migration of TNBC cell lines.

Altered expressions of circulating microRNAs 122 and 192 during antitubercular drug induced liver injury indicating their role as potential biomarkers.

Drug induced liver toxicity is a serious health complication leading to high mortality rates and post marketing withdrawal of drugs. Although considered to be the gold standard biomarkers; aspartate aminotransferase, alanine aminotransferase, total bilirubin and alkaline phosphatase have been found to have specificities beyond liver, therefore more specific and predictive markers for the detection of antitubercular drug mediated liver damage are required. Unfortunately, the effectiveness of currently used first line antitubercular drugs namely isoniazid, rifampicin, pyrazinamide is often accompanied with liver injury, impeding the cure of patients. Keeping in view, the prognostic and diagnostic applications of microRNAs in various diseases, we tried to assess the importance of microRNAs 122 and 192 in antitubercular drug associated liver injuries. The study included subjects having tuberculosis of any type with antitubercular drug induced liver injury; naïve or newly diagnosed tuberculosis patients, tuberculosis patients on drugs not having toxicity and healthy controls. Observations from this study revealed that expression levels of miR-122 and miR-192 were significantly decreased in the serum of antitubercular drug induced liver injury patients only. Therefore, these microRNAs or the pathways associated with them can be used as a tool to predict or cure antitubercular drug associated liver injury in future.

Adipose mesenchymal stem cells-secreted extracellular vesicles containing microRNA-192 delays diabetic retinopathy by targeting ITGA1.

Diabetic retinopathy (DR) has characteristics of early loss of capillary pericytes, contributing to aberrant endothelial proliferation and angiogenesis. The function of extracellular vesicles (Evs) derived from mesenchymal stem cells (MSCs) in angiogenesis and endothelial proliferation were investigated in the present study. In particular, the role of microRNA-192 (miR-192) was described. Firstly, the GSE60436 data set was applied to screen out that integrin subunit α1 (ITGA1) was overexpressed in DR. Subsequently, streptozotocin (STZ) was used to induce diabetes in rats, which was later subjected to intravitreal injection of targeted shRNAs. ITGA1 knockdown alleviated inflammation and angiogenesis in STZ-induced diabetic retina. Evs were extracted from MSCs and injected into rat vitreous. Meanwhile, human retinal microvascular endothelial cells, Müller cells, and retinal pigment epithelium cells were exposed to high glucose. MSC-derived Evs relieved inflammatory response and angiogenesis by shuttling miR-192. miR-192 targeted and negatively regulated ITGA1, thereby ameliorating diabetic retinal damage. Our study established that miR-192 released by Evs from MSCs could delay the events of the inflammatory response and angiogenesis in DR and may represent a possible therapeutic approach for the treatment of DR.

miR­192­5p upregulation mediates the suppression of curcumin in human NSCLC cell proliferation, migration and invasion by targeting c­Myc and inactivating the Wnt/ß­catenin signaling pathway.

Curcumin is a naturally active phenolic compound extracted from the rhizome of the plant Curcuma longa, which has been demonstrated to serve as an anticancer drug in different types of cancer, including non­small­cell lung cancer (NSCLC). Accumulating evidence has suggested that curcumin may exert epigenetic regulatory effects on microRNAs (miRs). Therefore, the present study aimed to investigate the role of miR­192­5p, and the effects of curcumin, in NSCLC, alongside the underlying mechanisms. Human NSCLC cells, A427 and A549, were treated with curcumin, and the expression levels of miR­192­5p and c­Myc were detected using reverse transcription­quantitative PCR and western blotting. Cellular proliferation was analyzed using Cell Counting Kit­8 assays and cell viability was determined using a MTT assay. Additionally, the migratory and invasive abilities of cells were analyzed using Transwell and Matrigel assays, respectively. The binding sites between miR­192­5p and c­Myc were predicted using TargetScanHuman software, and confirmed using a dual­luciferase reporter assay and RNA immunoprecipitation. Finally, the Wnt pathway regulator, ß­catenin, and cyclin D1 expression levels were determined using western blotting. Curcumin treatment inhibited NSCLC cell proliferation, migration, invasion and viability in a dose­dependent manner, in addition to promoting a dose­dependent increase in the expression levels of miR­192­5p and a reduction in c­Myc expression levels. Notably, the genetic knockdown of miR­192­5p blocked the inhibitory effects of curcumin on NSCLC progression and instead promoted NSCLC progression, which was observed to be partially reversed by c­Myc silencing; thus, c­Myc was suggested to be a direct target gene of miR­192­5p as demonstrated by the TargetScanHuman database, dual­lucierase and RIP assay results. In addition, the curcumin­induced decreased expression levels of ß­catenin, cyclin D1 and c­Myc were rescued following the genetic knockdown of miR­192­5p. In conclusion, these findings suggested that the upregulation of miR­192­5p may underlie the inhibitory effects of curcumin on NSCLC cells through targeting c­Myc and inactivating the Wnt/ß­catenin signaling pathway.

Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

Dysregulation of miR-192-5p in acute pancreatitis patients with nonalcoholic fatty liver and its functional role in acute pancreatitis progression.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a frequent metabolic disease and has been demonstrated to contribute to the severity of acute pancreatitis (AP). The present study aimed to investigate the aberrant expression of microRNA-192-5p (miR-192-5p) in AP patients with NAFLD, and further analyze the clinical significance and biological function of miR-192-5p in AP progression. METHODS: Expression of miR-192-5p was estimated using quantitative real-time PCR (qRT-PCR). Diagnostic value of miR-192-5p was evaluated by the receiver operating characteristic curve (ROC). The effects of miR-192-5p on cell proliferation, apoptosis and inflammatory response of pancreatic acinar cells were further assessed by CCK-8 assay, flow cytometry and enzyme-linked immunosorbent assay (ELISA). RESULTS: Circulating miR-192-5p was decreased in AP patients with NAFLD compared with those patients without NAFLD and healthy controls (P<0.05). The down-regulated expression of miR-192-5p had a relative high diagnostic accuracy to distinguish the AP patients with NAFLD from the cases without NAFLD. Furthermore, the overexpression of miR-192-5p in pancreatic acinar cells led to the decreased cell proliferation, increased cell apoptosis and suppressed inflammatory reaction (all P<0.05). CONCLUSION: Collectively, all data indicated that serum expression of miR-192-5p in AP patients with NAFLD is significantly decreased and serves as a candidate diagnostic biomarker. The up-regulation of miR-192-5p in pancreatic acinar cell leads to increased cell apoptosis and decreased inflammatory response, suggesting the potential of miR-192-5p as a therapeutic target of AP.

Diagnostic Value of Combination of MicroRNA-192 in Urinary Sediment and B-Ultrasound for Bladder Cancer.

OBJECTIVE: We aimed to explore the diagnostic value of microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer. METHODS: A total of 118 patients with bladder cancer and 120 patients with benign urinary system diseases were selected for collection of urinary sediment. Real-time quantitative polymerase chain reaction was applied to detect the microRNA-192 expression (normalized to U6 level) in urinary sediment. Besides, the relationship between microRNA-192 expression and clinicopathological characteristics was analyzed. Furthermore, receiver operating characteristic curve was performed to analyze clinical value of microRNA-192 expression alone and microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer. RESULTS: MicroRNA-192 expression was significantly downregulated in urinary sediment of patients with bladder cancer, which was related to tumor stage and tumor size (P < .05). The results of receiver operating characteristic curve analysis showed that the best critical value of microRNA-192 expression in urinary sediment for the diagnosis of bladder cancer was 0.785 with the sensitivity and specificity of 76.7% and 78.0%, respectively. The sensitivity and specificity of microRNA-192 expression in urinary sediment combined with B-ultrasound in the diagnosis of bladder cancer were 93.2% and 76.7%, respectively. The sensitivity of combined diagnosis (93.2%) was not significantly different from that of cystoscopy (93.2%; P > 0.05). There were significant differences between the expression of microRNA-192 in urinary sediment and the sensitivity of B-ultrasound examination alone with cystoscopy (P < .05). CONCLUSION: The downregulation of microRNA-192 expression in urinary sediment of patients with bladder cancer may be related to tumor progression. The microRNA-192 expression in urinary sediment is valuable in the diagnosis of bladder cancer, which shows high sensitivity in diagnosis of bladder cancer when combined with B-ultrasound.

microRNA-192-5p is involved in nerve repair in rats with peripheral nerve injury by regulating XIAP.

Objective: MicroRNAs (miRNAs) have been demonstrated to engage in the nerve injury, while the effect of microRNA-192-5p (miR-192-5p) on the nerve repair has not yet been well understood. This study is performed to investigate how miR-192-5p affects nerve repair in rats with peripheral nerve injury by regulating X-linked inhibitor of apoptosis protein (XIAP).Methods: The rat model of left sciatic nerve injury was established, and the expression of miR-192-5p was then detected. A series of experiments were conducted to investigate the role of miR-192-5p on nerve repair in rats with peripheral nerve injury. The expression of apoptosis-related proteins (Caspase-3, Bax and Bcl-2) and nerve repair factors (NGF, BDNF, and GAP-43) was measured. Bioinformatics analysis and dual-luciferase reporter gene assay confirmed the targeting relationship between miR-192-5p and XIAP.Results: MiR-192-5p inhibition promoted the recovery of sensory function and the recovery and regeneration in rats with sciatic nerve injury. MiR-192-5p inhibition promoted the recovery of muscle atrophy caused by nerve injury. MiR-192-5p inhibition inhibited neuronal apoptosis by affecting the expression of apoptosis-related proteins and promoted the recovery of nerve function by elevating the expression of nerve repair factors induced by peripheral nerve injury. Bioinformatics analysis and dual-luciferase reporter gene assay confirmed that XIAP was a target gene of miR-192-5p.Conclusion: This study demonstrates that miR-192-5p inhibition can up-regulate the expression of XIAP, decrease the apoptosis of nerve cells, and promote the repair and regeneration of peripheral nerve injury.

Bone marrow-derived mesenchymal stem cells-secreted exosomal microRNA-192-5p delays inflammatory response in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease closely correlated to synovial tissue inflammation. Exosomes are known to transfer microRNAs (miRNAs) between cells and have been validated as the vehicles for delivery of therapeutic molecules. AIM AND SCOPE: The current study was set to examine the functional values of bone marrow-derived mesenchymal stem cells (BMSCs)-secreted exosomal miR-192-5p (exo-miR-192-5p) on inflammation in RA. METHODS: Following the screening of differentially expressed genes in RA and miRNA-mRNA target prediction, BMSCs were infected with lentivirus expressing miR-192-5p to obtain miR-192-5p-overexpressed exosomes. To study the effect of exo-miR-192-5p on the expression of ras-related C3 botulinum toxin substrate 2 (RAC2), collagen-induced arthritis (CIA) rat models were established, and the clinical and histopathological changes were evaluated in the rats injected with exosomes. Subsequently, the expression patterns of pro-inflammatory factors were determined by ELISA. RESULTS: miR-192-5p was found to be down-regulated, while RAC2 was up-regulated in RA samples. Bioinformatics prediction revealed that the up-regulated RAC2 in RA may be regulated by miR-192-5p, which was further confirmed by dual luciferase reporter gene assay. The clinical arthritic scores, joint destruction, and inflammatory response were reduced after the injection of exosomes in rats with CIA targeting RAC2, and the treatment efficacy was even better with miR-192-5p-overexpressed exosomes. CONCLUSION: Our study established that the BMSCs-secreted exosomal miR-192-5p can delay the event of the inflammatory response in RA and may represent a possible therapeutic strategy for the treatment of RA.

Astragaloside IV inhibits excessive mesangial cell proliferation and renal fibrosis caused by diabetic nephropathy via modulation of the TGF-ß1/Smad/miR-192 signaling pathway.

Astragaloside IV (ASI) exhibits a wide variety of pharmacological effects in cardiovascular diseases, hepatitis and kidney disease and due to this, ASI has recently become an attractive research target. The present study aimed to determine the effect of ASI on renal fibrosis and the mechanisms underlying its therapeutic effects in diabetic nephropathy (DN). In vitro, ASI was added to rat mesangial cells (RMCs) and cultured with a high level of glucose (HG) to observe the effects exhibited on proliferation and fibrosis-related mRNA and protein expression. In vivo, a DN model was established using streptozotocin administration in rats, and renal injury was evaluated using renal histological examination. The expression levels of related mRNAs and proteins were analyzed using reverse transcription-quantitative PCR, western blot analysis and immunohistochemistry. ASI was demonstrated to downregulate miR-192 expression and inhibit excessive proliferation of RMCs, which was induced by HG, in a dose-dependent manner. Additionally, ASI exhibited a therapeutic effect on DN rats. ASI was also demonstrated to decrease the miR-192 expression and mRNA and protein expression of transforming growth factor-ß1 (TGF-ß1), Smad3, α-smooth muscle actin (α-SMA) and collagen type 1 (col1), and increase the mRNA and protein expression of Smad7 in vitro and in vivo. These results suggested that ASI exhibited a therapeutic effect on DN, possibly due to the inhibition of excessive mesangial proliferation and renal fibrosis via the TGF-ß1/Smad/miR-192 signaling pathway.

miR-192 is upregulated in T1DM, regulates pancreatic ß-cell development and inhibits insulin secretion through suppressing GLP-1 expression.

MicroRNAs (miRs) post-translationally regulate gene expression by specifically binding to the mRNA of their target genes. The aim of the present study was to determine the effect of miR-192 on pancreatic ß-cell development. The serum levels of miR-192 in type 1 diabetes mellitus (T1DM) and streptozotocin-induced rats were determined, and were revealed to be elevated compared with those in healthy patients and normal rats, respectively. Western blot and reverse transcription-quantitative polymerase chain reaction analysis indicated that miR-192 suppressed the expression of glucagon-like peptide-1 (GLP-1), a potent insulin secretagogue. Ectopic expression of miR-192 inhibited cell proliferation and promoted apoptosis of NIT-1 cells, while miR-192 inhibitor had the opposite effect. Collectively, the present results revealed that miR-192 was elevated in T1DM, and is implicated in pancreatic ß-cell development through regulation of cell proliferation and apoptosis, thereby suppressing insulin secretion. Furthermore, miR-192 suppressed GLP-1 expression, thereby further promoting T1DM. The present study suggested that miR-192 is a novel molecular target for the management or prevention of T1DM.