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This study aimed to investigate the relationship between the IL-28B SNP rs8099917 genotype, miRNA-122 expression, and the immune mechanism of ACR after LT using anti-HCV antibody calibration. A total of 45 patients with HCV received LT. IL-28B SNP rs8099917 genotyping was used to divide patients into TT and GT groups. The relative expression levels of miRNA-122 were calculated by quantitative PCR. Anti-HCV titers before and after LT were tracked to observe the relationship with ACR. The ACR rates were 27.6% for genotype TT and 62.5% for genotype GT, indicating a significantly higher rate in the GT group compared to the TT group (p = 0.024). In the rs8099917 genotype, TT was significantly associated with higher serum miRNA-122 levels than GT (p < 0.001). The TT group had significantly better outcomes than the GT group (p = 0.005). The Mann–Whitney U test showed significant differences in pre-LT and post-LT anti-HCV titers between the IL-28B genotypes (TT and GT) (p values of 0.006 and 0.027, respectively). These results suggested that the IL-28B rs8099917 genotype TT may play a significant role in modulating immune responses, both in terms of anti-HCV titers and the risk of ACR, possibly mediated through miRNA-122 levels.

microRNA-122 (miR-122) plays crucial yet contrasting roles in hepatocellular carcinoma (HCC) and breast cancer (BC), two prevalent and aggressive malignancies. This review synthesizes current research on miR-122’s functions in these cancers, focusing on its potential as a diagnostic, prognostic, and therapeutic target. A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus databases. In HCC, miR-122 is downregulated in most cases, suppressing oncogenic pathways and reducing tumor growth and metastasis. Restoring miR-122 levels has shown promising therapeutic potential, increasing sensitivity to treatments like sorafenib. In contrast, in BC, miR-122 plays a pro-metastatic role, especially in triple-negative breast cancer (TNBC) and metastatic lesions. miR-122′s ability to influence key pathways, such as the Wnt/β-catenin and NF-κB pathways in HCC, and its role in enhancing the Warburg effect in BC underline its significance in cancer biology. miR-122, a key factor in breast cancer radioresistance, suppresses tumors in radiosensitive cells. Inhibiting miR-122 could reverse resistance and potentially overcome radiotherapy resistance. Given its context-dependent functions, miR-122 could serve as a potential therapeutic target, where restoring or inhibiting its expression may help in treating HCC and BC, respectively. The dual roles of miR-122 underscore its significance in cancer biology and its potential in precision medicine.

Aim: To evaluate the diagnostic significance of the relationship between the level of microRNA-122 expression and liver fibrosis during HDV infection.Materials and methods. The expression of microRNA-122 was determined in 203 blood samples. Blood sampling was done from 53 patients with chronic viral hepatitis D, 49 patients with liver cirrhosis of HDV etiology, and 69 patients with newly diagnosed HBs antigenemia. The control group consisted of practically healthy individuals (n=32).Results. In patients with negative RNA HDV levels, the level of microRNA-122 in the blood serum was significantly higher than in samples with positive RNA HDV levels (14.0±2.8 2^-ΔΔCt and 1.6±0.17 2^-ΔΔCt) (p ˂ 0.005). Meanwhile, in healthy individuals, the expression of microRNA-122 was statistically significantly lower – 1.3±0.03 2^-ΔΔCt (p ˂ 0.005). Undetectable levels of HDV RNA in the serum were accompanied by a high HBV viral load and a significantly higher level of microRNA-122, which was 8.7 times higher than in the group of HDV RNA-positive patients (p ˂ 0.005). In patients with liver fibrosis F1, the expression of microRNA-122 was higher than in patients with liver fibrosis F2, F3, F4 (p = 0.0001). The lowest levels of microRNA-122 were observed in liver fibrosis F4.Conclusion. The expression level of microRNA-122 in blood serum during HDV infection decreases as liver fibrosis progresses. The development of cirrhosis is accompanied by a 3.7-fold drop in the level of microRNA-122 compared to the group of patients with chronic hepatitis D. MicroRNA-122 can be used in laboratory monitoring of patients with various stages of HDV infection as an indicator of the activity of the process, assessing the severity of liver damage and the rate of progression of liver fibrosis.

The article presents a study on the tissue specificity of cardiac genome editing using adeno-associated virus (AAV) vectors. The researchers discovered that the commonly used AAV9-Tnnt2 system had some gene expression leakage in the liver. To address this issue, they incorporated microRNA-122 target sequences (miR122TS) into the AAV9-Tnnt2 vectors, which effectively reduced liver leakage without affecting cardiac gene expression. The study emphasizes the need to improve the tissue specificity of gene editing techniques for cardiovascular research and gene therapy applications. [Extracted from the article]

A three-dimensional (3D) self-assembled AuNPs/Ti3C2 MXene hydrogel (AuNPs/Ti3C2 MXH) nanocomposite was prepared for the fabrication of a novel microRNA-122 electrochemical biosensor. The 3D hydrogel structure was gelated from two-dimensional MXene nanosheets with the assistance of graphite oxide and ethylenediamine. MXene hydrogels supported the in situ formation of Au nanoparticles (AuNPs) that predominantly exploring the (111) facet, and these AuNPs are utilized as carriers for hairpin DNA (hpDNA) probes, facilitating DNA hybridization. MXene acted as both a reductant and stabilizer, significantly improving the electrochemical signal. In addition, the conjugation of PAMAM dendrimer-encapsulated AuNPs and H-DNA worked as an ideal bridge to connect targets and efficient electrochemical tags, providing a high amplification efficiency for the sensing of microRNA-122. A linear relationship between the peak currents and the logarithm of the concentrations of microRNA-122 from 1.0 × 10−2 to 1.0 × 102 fM (I = 1.642 + 0.312 lgc, R2 = 0.9891), is obtained. The detection limit is 0.8 × 10−2 fM (S/N = 3). The average recovery for human serum detection ranged from 97.32 to 101.4% (RSD < 5%). [ABSTRACT FROM AUTHOR]

Objective: To explore the value of echocardiography combined with serum microRNA-122 (miR-122) in evaluating left ventricular function changes caused by essential hypertension (EH). Methods: 58 EH patients admitted to our hospital from January 2020 to June 2022 were selected as the study group, and 62 healthy persons in the same period were selected as the control group. All subjects were examined by echocardiography and serum miR-122. The differences of quantitative parameters of echocardiography and serum miR-122 levels between the two groups were compared, and the correlation between serum miR-122 and left ventricular function indexes was analyzed. The optimal diagnostic threshold of the quantitative parameters of echocardiography, serum miR-122 alone for to diagnose left ventricular function changes caused by EH, as well as the corresponding sensitivity and specificity were analyzed by drawing the receiver operating characteristic curve (ROC) and calculating the area under the curve (AUC). The joint diagnosis uses multivariate logistic regression analysis and draws ROC curves to evaluate its diagnostic efficacy. Results: In the study group, left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septum end diastolic thickness (IVSD), left ventricular posterior wall end diastolic thickness (LVPWD), the ratio of E to the mean value of the early diastolic velocity of the mitral annulus at the interventricular septum and side wall, e ’interventricular septum and e’ side wall (E/e ’), left ventricular end diastolic volume (EDV) and left ventricular end systolic volume (ESV), serum miR-122 level was significantly higher than the control group (P＜0. 05),and the ratio of early diastolic blood flow velocity E to late diastolic blood flow velocity A (E/A) was significantly lower than the control group (P＜0. 05). However,there was no statistically significant difference in left ventricular ejection fraction (EF) between the two groups (P＞0. 05). The serum miR-122 level was positively correlated with LVEDD, LVESD, EDV, and ESV (P＜0. 05), but not significantly correlated with other quantitative parameters of echocardiography IVSD, LVPWD, EF, E/A, E/e’ (P＜0. 05). Compared with individual diagnosis,the combination of quantitative parameters of echocardiography and serum miR-122 has the highest AUC, Jordan index, sensitivity,and specificity in diagnosing left ventricular function changes caused by EH (P＜0. 05). Conclusion: Echocardiography combined with serum miR-122 can accurately evaluate the changes of left ventricular function caused by EH, which is helpful to guide the selection of clinical treatment plan. [ABSTRACT FROM AUTHOR]

Aims: Detection and characterization of idiosyncratic drug‐induced liver injury (DILI) currently rely on standard liver tests, which are suboptimal in terms of specificity, sensitivity and prognosis. Therefore, DILI diagnosis can be delayed, with important consequences for the patient. In this study, we aimed to evaluate the potential of osteopontin, cytokeratin‐18 (caspase‐cleaved: ccK18 and total: K18), α‐glutathione‐S‐transferase and microRNA‐122 as new DILI biomarkers. Methods: Serial blood samples were collected from 32 DILI and 34 non‐DILI acute liver injury (ALI) cases and a single sample from 43 population controls without liver injury (HLC) and analysed using enzyme‐linked immunosorbent assay (ELISA) or single‐molecule arrays. Results: All biomarkers differentiated DILI and ALI from HLC with an area under receiver operator characteristic curve (AUC) value of >0.75 but were less efficient in distinguishing DILI from ALI, with ccK18 (0.79) and K18 (0.76) demonstrating highest potential. However, the AUC improved considerably (0.98) for ccK18 when comparing DILI and a subgroup of autoimmune hepatitis cases. Cytokeratin‐18, microRNA‐122 and α‐glutathione‐S‐transferase correlated well with traditional transaminases, while osteopontin correlated most strongly with the international normalized ratio (INR). Conclusions: ccK18 appears promising in distinguishing DILI from autoimmune hepatitis but less so from other forms of acute liver injury. Osteopontin demonstrates prognostic potential with higher levels detected in more severe cases regardless of aetiology. [ABSTRACT FROM AUTHOR]

Aim: Serum microRNA‐122 (miR‐122) is a novel biomarker for drug‐induced liver injury, with good sensitivity in the early diagnosis of paracetamol‐induced liver injury. We describe miR‐122 concentrations in participants with antituberculosis drug‐induced liver injury (AT‐DILI). We explored the relationship between miR‐122 and alanine aminotransferase (ALT) concentrations and the effect of N‐acetylcysteine (NAC) on miR‐122 concentrations. Methods: We included participants from a randomized placebo‐controlled trial of intravenous NAC in AT‐DILI. ALT and miR‐122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR‐122 concentrations and described changes in ALT and miR‐122 concentrations between sampling occasions. Results: We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre‐ and post‐infusion biomarker specimens was 68 h (47‐77 h). The median pre‐infusion ALT and miR‐122 concentrations were 420 U/L (238‐580) and 0.58 pM (0.18‐1.47), respectively. Pre‐infusion ALT and miR‐122 concentrations were correlated (Spearman's ρ =.54, P =.0001). Median fold‐changes in ALT and miR‐122 concentrations between sampling were 0.56 (0.43‐0.69) and 0.75 (0.23‐1.53), respectively, and were similar in the NAC and placebo groups (P =.40 and P =.68 respectively). Conclusions: miR‐122 concentrations in our participants with AT‐DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR‐122 concentrations. Further research is needed to determine the utility of miR‐122 in the diagnosis and management of AT‐DILI. [ABSTRACT FROM AUTHOR]

Background: Infection with hepatitis C virus frequently progresses to cirrhosis and liver cell cancer. Objectives: The objective of this study was testing the usefulness of miR-122 as a marker for diagnosis of cirrhosis in chronic infection with hepatitis C virus (CHC) and as a diagnostic tool for early detection of hepatocellular cancer. Methods: This study included 118 patients; the first group included eighty-eight patients with chronic hepatitis C (CHC) and HCV related cirrhosis, the second group included thirty patients with HCC on to of chronic HCV infection, and the third one included twenty controls. Quantification of the viral RNA by real-time-PCR. MicroRNA-122 expression level was measured by RTPCR. Results: The mean serum levels of miR-122 were much higher in CHC, compensated cirrhosis and decompensated cirrhosis patients' than in controls, while they were less in HCC patients than control group (p = 0.0001). Serum miR-122 revealed gradual decrease in levels with progression of fibrosis stage, with more significant decrease in late fibrosis stages including F3 and F4 (p=0.01). Conclusion: The mean levels of serum miR-122 decreased in patients of HCC thus can differentiate HCC from CHC and liver cirrhosis. MicroRNA -122 had high efficiency compared to other noninvasive indices in prediction of HCV, and progression towards HCC. [ABSTRACT FROM AUTHOR]

We examined the role of hepatocyte micro-RNA-122 and hypothalamic neuropeptides, in weanling (21d) female rats exposed to calorie restriction induced growth restriction either prenatally (IUGR), postnatally (PNGR) or both (IPGR) vs. ad lib fed controls (CON). IUGR were hyperinsulinemic, hyperleptinemic and dyslipidemic with high circulating miR-122. In contrast, PNGR and IPGR displayed insufficient glucose, insulin and leptin amidst high ketones with a dichotomy in circulating miR-122 of PNGR

The purpose of this study was to evaluate the effect of curcumin, an active polyphenol, on the leptin induced lowering of miR-122 in Hepatic stellate cells (HSCs) in vivo and an animal model. Gene expression was evaluated by transfection assay, real-time PCR, or Western blot analysis. The liver fibrosis model of leptin deficient mouse was used for in vivo experiment. As a result, curcumin showed inhibitory effect on leptin induced lowering of the miR-122 in HSCs. Curcumin suppressed leptin induced sonic hedgehog (Shh) expression and blocked leptin induced Shh signaling pathway, which was essential for curcumin inhibition of the negative role of leptin in miR-122 expression in HSCs. The influence of curcumin on the negative effect of leptin on miR-122 level was followed by the attenuation of liver fibrosis caused by leptin in leptin-deficient mouse model. In conclusion, curcumin could reduce the decrease of miR-122 level in HSCs induced by leptin and inhibit liver fibrosis induced by leptin. These data may have potential implications to treat with liver fibrosis by elevating the expression of leptin in humans especially obese patients. [ABSTRACT FROM AUTHOR]

Background and purpose: MicroRNA-122 (miR-122) is the most abundant liver–specific miRNA. It has been reported that miR-122 plays several biological roles such as iron homeostasis, tumor suppressor, hepatic fatty acid regulation, and in hepatocyte differentiation. The Purpose of this study was to investigate changes in liver miR-122 gene expression and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzymes after resistance training and boldenone undecylenate (boldenone) steroid injection in male rats. Materials and methods: Twenty male Wistar rats were randomly divided into four groups: control (n=5), resistance training (n=5), resistance training+ boldenone injection (n=5), and boldenone injection (n=5). Resistance training was performed three sessions a week for eight weeks. Boldenone was injected twice per week (2mg/kg). Seventy-two hours after last training, blood and tissue samples were collected. Serum levels of ALT and AST were measured via photometric method and miR-122 gene expression in the liver was assessed by real-time PCR. Statistical analysis was conducted using SPSS V16. Results: Reduced expression of liver miR-122 was found in boldenone group, while the expression of miR-122 was higher in resistance training group, however, the difference was not significant (P= 0.514). Also, no significant difference was found in serum AST and ALT levels between the experimental groups (P= 1.00 and P= 0.527, respectively). Conclusion: In this study, liver miR-122 responded differently to resistance training and boldenone injection. However, clear understanding of its mechanism requires further studies.

This study aimed to investigate the effects of hepatic microRNA-122 (miR-122) on Sortilin-mediated apolipoprotein B100 (apoB-100) secretion, and on aortic lipid deposition and atherosclerosis (AS) lesions and to clarify the antiatherosclerotic mechanism of 6-methylcoumarin (6-MC) via the modulation of miR-122. Bioinformatics analysis revealed that miR-122 was putatively overexpressed in a liver-specific manner and was downregulated in steatotic livers. miR-122 was shown to suppress the expression of Sortilin by complementarily pairing to the 3′-untranslated region (3'-UTR) of Sortilin mRNA via bioinformatics and dual-luciferase reporter assays, impeding Sortilin-mediated apoB-100 secretion from HepG2 cells. Administration of 6-MC significantly upregulated hepatocellular miR-122 levels, reducing Sortilin expression and apoB-100 secretion in HepG2 cells. The miR-122 mimic vigorously enhanced 6-MC-depressed Sortilin expression, while miR-122 inhibitor repealed the inhibitory effect of 6-MC on Sortilin expression to some extent in HepG2 cells. After internal intervention with the miR-122 precursor, and 6-MC supplementation alone or in combination with the miR-122 sponge led to the reduction in blood triglyceride (TG) levels, low-density lipoprotein-cholesterol (LDL-C) and apoB-100 and a reduction in aortic lipid deposition and AS lesions in apolipoprotein E -deficient (ApoE−/−) mice fed a high fat diet (HFD). The hepatic levels of Sortilin and apoB-100 expression were also decreased in these treated mice. In conclusion, miR-122 suppresses Sortilin expression and Sortilin-mediated apoB-100 secretion to resist circulating LDL production and aortic AS development, which is enhanced by 6-MC-upregulated miR-122 in the liver. • miR-122 is lowly expression in lipoprotein metabolism in lipid-loaded hepatocytes. • miR-122-improved lipoprotein metabolism through complementarily targeting to the 3'-UTR of Sortilin mRNA. • 6-MC upregulates miR-122 expression and inhibits Sortilin-mediated apoB-100 secretion. • 6-MC-induced miR-122 upregulation can alleviate aortic atherosclerosis lesions in ApoE−/− mice by suppressing Sortilin-mediated apoB-100 secretion from the liver. [ABSTRACT FROM AUTHOR]

Aim: Our previous study demonstrated miR-122 mimic decreased NOS2 expression in blood leucocytes and improved stroke outcomes when given immediately after middle cerebral artery occlusion (MCAO) in rats. Since NOS2 is associated with neuro-inflammation in stroke and decreasing NOS2 expression alone in leucocytes is insufficient to improve stroke outcomes, we hypothesized that miR-122 mimic may also decrease NOS2 expression in brain microvascular endothelial cells (BMVECs) even at extended time windows. Methods: We administered PEG-liposome wrapped miR-122 mimic (2.4 mg/kg, i.v.) 0 or 6 h after MCAO, and assessed stroke volume and NOS2 expression in BMVECs 24 h following MCAO in rats. Luciferase reporter assays were used to determine if miR-122 binds to 3' untranslated regions (3'UTR) of NOS2. Results: The data showed that miR-122 mimic decreased infarct volumes and decreased MCAO-induced NOS2 over-expression in BMVECs. However, miR-122 did not bind to 3'UTR of NOS2 in the luciferase assays. Conclusion: The data show the 6-h period of therapeutic efficacy of miR-122 mimic which could relate to indirect knockdown of NOS2 in both BMVECs and leucocytes.

Wu Y, Gao Z, Zhang J. Neuropsychiatr Dis Treat. 2020;16:2633–2647. At the authors request, the Editor and Publisher of Neuropsychiatric Disease and Treatment are retracting the published article. The authors informed the journal that they were unable to verify the reported findings and requested to retract the article. Given that additional concerns had also been raised about the reliability of the findings, the Editor agreed with the authors decision. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Objective: This study aimed to determine the roles of microRNA (miR)-122 in the activation of hepatic stellate cells (HSCs) and liver cirrhosis. Methods: Rat primary HSCs were incubated with transforming growth factor-beta (TGF-b), during which miR-122 and EphB2 expression was measured. miR-122 mimic and/or pcDNA3.1 EphB2 was transfected into TGF-b-induced HSCs. A mouse model of liver cirrhosis was established via an intraperitoneal injection of carbon tetrachloride (CCl4), followed by the injection of miR-122 agomir. Levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. Fibronectin (FN), alpha smooth muscle actin (a-SMA), Collagen I, miR-122, and EphB2 expression was evaluated in liver tissues and HSCs. Cell proliferation was measured using CCK-8 assay. Interactions between miR-122 and EphB2 were assessed using dual luciferase reporter assay. Results: miR-122 (0.15-fold) was downregulated and EphB2 (mRNA: 5.06-fold; protein: 2.35-fold) was upregulated after TGF-b induction of HSCs. Overexpressed miR-122 decreased proliferation and EphB2 (mRNA: 0.46-fold; protein: 0.62-fold), FN (mRNA: 0.45-fold; protein: 0.64-fold), a-SMA (mRNA: 0.48-fold; protein: 0.51-fold), and Collagen I (mRNA: 0.44-fold; protein: 0.51-fold) expression in HSCs, which was abrogated by EphB2 upregulation. miR-122 expression was reduced by 0.21-fold and serum ALT and AST levels were enhanced in mice following 8-week CCl4 induction along with increased expression of FN, a-SMA, and Collagen I in liver tissues, which was blocked by miR-122 overexpression. Moreover, EphB2 was a target gene of miR-122. Conclusion: miR-122 curtails HSC proliferation and activation by targeting EphB2 and suppresses liver cirrhosis in mice. [ABSTRACT FROM AUTHOR]

Purpose: The main purpose of our study is to research the potential of circulating microRNA-122 (miR-122)as a marker for hepatocellular carcinoma. Materials and Methods: Circulating miR-122 levels were measured by real-time polymerase chain reaction in patients with varied stages of hepatocellular carcinoma. In addition, various other laboratory and clinical data of the participants were evaluated in order to observe the correlation between these data and serum miR-122 levels. Results: Serum miR-122 levels were found significantly higher in hepatocellular carcinoma patients compared to the control group. (median miR-122 (min. – max.); patients: 0.0104 (0-0.262); controls: 0.00187 (0-0.100), p

Purpose: Little is known about the relations between changes in circulating microRNA-122 (miR-122) and liver fat in response to weight-loss interventions. We aimed to investigate the association between miR-122 and changes of hepatic fat content during 18-month diet and physical activity interventions. Methods: The CENTRAL trial is an 18-month randomized, controlled trial among adults with abdominal obesity or dyslipidemia. Subjects were randomly assigned to a low-fat diet or a Mediterranean/low-carbohydrate diet. After 6 months of dietary intervention, each diet group was further randomized into added physical activity groups or no added physical activity groups for the following 12 months of intervention. The current study included 220 participants at baseline and 134 participants with repeated measurements on serum miR-122 and hepatic fat content over 18 months. Results: Serum miR-122 significantly increased from baseline to 18 months, while no difference was observed across the 4 intervention groups. We found a significant association between miR-122 and hepatic fat content at baseline, as per unit increment in log-transformed miR122 was associated with 3.79 higher hepatic fat content (P < 0.001). Furthermore, we found that higher elevations in miR-122 were associated with less reductions in hepatic fat percentage during 18-month interventions (β = 1.56, P = 0.002). We also found a significant interaction between changes in miR-122 and baseline fasting plasma glucose with hepatic fat content changes in 18 months (P interaction = 0.02). Conclusions: Our data indicate that participants with higher elevation in serum miR-122 may benefit less in reduction of hepatic fat content in response to diet and physical activity interventions. [ABSTRACT FROM AUTHOR]

Because our recent studies have demonstrated that miR-122 decreased in whole blood of patients and in whole blood of rats following ischemic stroke, we tested whether elevating blood miR-122 would improve stroke outcomes in rats. Young adult rats were subjected to a temporary middle cerebral artery occlusion (MCAO) or sham operation. A polyethylene glycol-liposome-based transfection system was used to administer a miR-122 mimic after MCAO. Neurological deficits, brain infarction, brain vessel integrity, adhesion molecule expression and expression of miR-122 target and indirect-target genes were examined in blood at 24 h after MCAO with or without miR-122 treatment. miR-122 decreased in blood after MCAO, whereas miR-122 mimic elevated miR-122 in blood 24 h after MCAO. Intravenous but not intracerebroventricular injection of miR-122 mimic decreased neurological deficits and brain infarction, attenuated ICAM-1 expression, and maintained vessel integrity after MCAO. The miR-122 mimic also down-regulated direct target genes (e.g. Vcam1, Nos2, Pla2g2a) and indirect target genes (e.g. Alox5, Itga2b, Timp3, Il1b, Il2, Mmp8) in blood after MCAO which are predicted to affect cell adhesion, diapedesis, leukocyte extravasation, eicosanoid and atherosclerosis signaling. The data show that elevating miR-122 improves stroke outcomes and we postulate this occurs via downregulating miR-122 target genes in blood leukocytes.

A liver-specific microRNA, miR-122, anneals to the hepatitis C virus (HCV) genomic 59 terminus and is essential for virus replication in cell culture. However, bicistronic HCV replicons and full-length RNAs with specific mutations in the 59 untranslated region (UTR) can replicate, albeit to low levels, without miR-122. In this study, we have identified that HCV RNAs lacking the structural gene region or having encephalomyocarditis virus internal ribosomal entry site (EMCV IRES)-regulated translation had reduced requirements for miR-122. In addition, we found that a smaller proportion of cells supported miR-122-independent replication compared a population of cells supporting miR-122-dependent replication, while viral protein levels per positive cell were similar. Further, the proportion of cells supporting miR-122-independent replication increased with the amount of viral RNA delivered, suggesting that establishment of miR-122-independent replication in a cell is affected by the amount of viral RNA delivered. HCV RNAs replicating independently of miR-122 were not affected by supplementation with miR-122, suggesting that miR-122 is not essential for maintenance of an miR-122-independent HCV infection. However, miR-122 supplementation had a small positive impact on miR-122-dependent replication, suggesting a minor role in enhancing ongoing virus RNA accumulation. We suggest that miR-122 functions primarily to initiate an HCV infection but has a minor influence on its maintenance, and we present a model in which miR-122 is required for replication complex formation at the beginning of an infection and also supports new replication complex formation during ongoing infection and after infected cell division. IMPORTANCE The mechanism by which miR-122 promotes the HCV life cycle is not well understood, and a role in directly promoting genome amplification is still debated. In this study, we have shown that miR-122 increases the rate of viral RNA accumulation and promotes the establishment of an HCV infection in a greater number of cells than in the absence of miR-122. However, we also confirm a minor role in promoting ongoing virus replication and propose a role in the initiation of new replication complexes throughout a virus infection. This study has implications for the use of anti-miR-122 as a potential HCV therapy. [ABSTRACT FROM AUTHOR]

Androgenetic alopecia (AGA) is the most common pattern of hair loss resulting from the effects of androgen on hair follicles. MicroRNAs (miRs) serve imperative roles in the regulation of many biological processes of hair follicles. However, the exact molecular mechanism of AGA remains to be elucidated. In the present study, we found miR‐122, which is mainly recognized as a tumor suppressor, was highly overexpressed in the bulb of balding hair follicles in comparison with nonbalding ones in AGA. Moreover, miR‐122 induces apoptosis of human dermal papilla cells (hDPCs) with miR‐122 mimics in vitro, and the expression of insulin‐like growth factor 1 receptor (IGF1R) in hDPCs was reduced following upregulation of miR‐122. Mechanistically, dual‐luciferase reporter assay confirmed that miR‐122 directly targeted the 3′‐untranslated region of IGF1R. These findings suggested that upregulation of miR‐122 induces apoptosis, potentially via the repression of IGF1R in hDPCs of AGA, providing a novel insight into the potential pathological mechanism of miR‐122 in AGA DPCs. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have emerged as essential regulators that could have pivotal roles in cardiac homeostasis and pathological remodeling of various cardiovascular diseases. We previously demonstrated that miRNA-122-5p overexpression exacerbated the process of vascular hypertrophy, fibrosis, and dysfunction in hypertensive rats and rat aortic adventitial fibroblasts. However, the exact roles and underlying mechanisms of miRNA-122-5p in myocardial fibroblasts remain largely unknown. In this work, neonatal rat cardiofibroblasts (CFs) were isolated and primarily cultured from the hearts of 2- to 3-d-old Sprague–Dawley rats. Stimulation of angiotensin II (Ang II) resulted in marked increases in cellular proliferation and migration and levels of collagen I, collagen III, CTGF, and TGF-β1 in cultured CFs. Furthermore, Ang II led to promoted expression of P62, Bax, and phosphorylated mTOR as well as downregulation of LC3II, beclin-1, and AMPK-phosphorylated levels, thereby contributing to imbalance of autophagy and apoptosis, and cellular injury in CFs, which were significantly ameliorated by treatment with miRNA-122-5p inhibitor. These changes were associated with decreased levels of collagen I, collagen III, CTGF, and TGF-β1. Furthermore, Ang II–induced loss of autophagy and promotion of apoptosis in CFs were prevented by the treatment with Pyr1-apelin-13 or AMPK agonist AICAR or mTOR inhibitor rapamycin, respectively. In contrast, administration of miRNA-122-5p mimics and autophagy inhibitor 3-methylademine reversed beneficial roles of Pyr1-apelin-13. Collectively, these data indicated that miRNA-122-5p is an essential regulator of autophagy and apoptosis in rat CFs via the apelin/AMPK/mTOR signaling pathway, which may be potentially used as a therapeutic target in myocardial fibrosis and related diseases. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS), a prevalent aggressive malignancy in the bone, has limited therapeutic targets and diagnostic biomarkers. In the current investigation, RT-qPCR showed that CDKN2B-AS1 was enhanced in OS samples and cells. This research was set to examine the modulation of CDKN2B-AS1 in OS. The expression of CDKN2B-AS1 and downstream molecules was analyzed by RT-qPCR method. CCK8, EdU staining along with Transwell assays were applied to evaluate cell proliferation and invasion. Those in vitro investigations specified that silencing of CDKN2B-AS1 with shRNAs obviously impeded the proliferation and invasion of MG63 cells. To authenticate the relationships between CDKN2B-AS1 and microRNA-122-5p (miR-122-5p) or cyclin G1 (CCNG1) and miR-122-5p, we next employed luciferase reporter assay. We displayed that CDKN2B-AS1 repressed miR-122-5p to restore CCNG1 expression. All in all, our findings substantiated the indispensable function of CDKN2B-AS1 in OS progression and the possible molecular mechanism. [ABSTRACT FROM AUTHOR]

Introduction: It is unclear whether the relationships between changes in fibrosis and circulating microRNA-122 (miR-122) dynamics might influence the prognosis of nonalcoholic fatty liver disease (NAFLD). Methods: This study investigates the impact of serum miR-122 dynamics and histological changes on the incidence of liver cancer and mortality in 81 Japanese NAFLD patients who underwent serial liver biopsies. The median interval between the first and second liver biopsies was 2.9 years. Results: The fibrosis stage scores indicated progression, no change, and improvement (a decrease of one point or more) in 21.0%, 56.8%, and 22.2% of the patients, respectively. There were 64 patients in the high-risk group who had no improvement in stage scores. Among these, the miR-122 levels were significantly lower in 7 patients with liver cancer than those of the 54 patients who had no liver cancer at the second liver biopsy. The cumulative rates of liver cancer were significantly higher in cases with miR-122 ratios <0.5 (serum miR-122 level at second biopsy to that at first biopsy) than those with ratios ≥0.5. The cumulative survival rates in cases with miR-122 ratios <0.5 tended to be lower than those with ratios ≥0.5. Of the 64 high-risk patients, 39 indicated stage 2 or greater (severe fibrosis stage) at the first liver biopsy and also showed similar results of cumulative liver cancer and survival rates. Conclusions: Longitudinal examination of serial liver biopsies indicated that the circulating miR-122 dynamics might be useful in predicting the prognosis for NAFLD patients with severe fibrosis stage and no improvement of the stage scores. [ABSTRACT FROM AUTHOR]

Yunxia Wu, Zhiqiang Gao, Jiang Zhang Department of Neurology, Linyi Central Hospital, Linyi, Shandong 276400, People’s Republic of ChinaCorrespondence: Jiang Zhang Department of Neurology, Linyi Central Hospital, No. 17, Jiankang Road, Yishui County, Linyi 276400, Shandong, People’s Republic of ChinaTel/Fax +86-0539-22260223Email Jiangzhang3241@163.comBackground: It has been documented that microRNAs (miRs) assume a pivotal role in the development of ischemic stroke (IS). However, it remains poorly identified about the role of miR-122 in IS. Herein, this study was intended to explore the mechanism of E2F1-orchestrated miR-122 in IS.Patients and Methods: E2F1, miR-122, and SPRY2 expression in serum from patients with IS and oxygen-glucose deprivation (OGD)-treated N2a cells was detected by RT-qPCR. After gain- and loss-of-function approaches in OGD-induced N2a cells, GAFP staining, flow cytometry, and Western blot analysis were adopted to assess neuronal viability, cell cycle and apoptosis, and expression of apoptosis- and autophagy-related proteins, respectively. Meanwhile, mice with IS were induced, in which E2F1, miR-122, and SPRY2 were overexpressed, followed by evaluation of neurological deficit and cerebral infarction area. The MAPK pathway activity in tissues of mice and cells was determined.Results: miR-122 was down-regulated, and E2F1 and SPRY2 were up-regulated in IS patients and OGD-induced N2a cells. E2F1 inhibited miR-122 transcription, while miR-122 targeted SPRY2. Overexpression (OE) of miR-122 or down-regulation of E2F1 or SPRY2 increased viability, but decreased apoptosis, cell cycle arrest, and autophagy in OGD-induced N2a cells. In IS mice, the neurological deficit score and cerebral infarction area were elevated, which was aggravated by up-regulating E2F1 or SPRY2 but attenuated by overexpressing miR-122. E2F1/miR-122/SPRY2 axis mediated the MAPK pathway in vivo and in vitro.Conclusion: Collectively, E2F1 reduced miR-122 transcription to up-regulate SPRY2, which inactivated MAPK pathway and promoted neurological deficit in IS.Keywords: ischemic stroke; IS, E2F1, microRNA-122, SPRY2, MAPK pathway, neurological injury

Osteoporosis is characterized by the reduction of bone mineral density and deterioration of bone quality which leads to high risk of fractures. Some microRNAs (miRNAs) have been confirmed as potential modulators of osteoblast differentiation to maintain bone mass maintenance. We aimed to clarify whether miR-122 could regulate osteoblast differentiation in ovariectomized rats with osteoporosis. miR-122 was upregulated and Purkinje cell protein 4 (PCP4) was downregulated in ovariectomized rats. PCP4 was identified as a target of miR-122 by dual-luciferase reporter gene assay. We transfected isolated osteoblasts from ovariectomized rats with miR-122 mimic or inhibitor or PCP4 overexpression vectors. Proliferation and differentiation of osteoblasts were repressed by the overexpression of miR-122 but enhanced by overexpression of PCP4. miR-122 could induce the activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway, while PCP4 blocked this pathway. Rescue experiments further demonstrated that the inhibiting effects of miR-122 on osteoblast differentiation could be compensated by activation of the PCP4 or inhibition of JNK signaling pathway. Collectively, our data imply that miR-122 inhibits osteoblast proliferation and differentiation in rats with osteoporosis, highlighting a novel therapeutic target for osteoporotic patients.

MicroRNAs (miRNAs) are small non‑coding RNAs that serve key roles in cell proliferation, migration, invasion and apoptosis by regulating gene expression. In malignant tumors, miRNA‑122 serves either as a tumor suppressor or oncogene, influencing tumor progression via downstream gene targeting. However, the precise role of miRNA‑122 in cancer remains unclear. miRNA‑122 is a potential biomarker and modulator of radiotherapy and chemotherapy. The present review aimed to summarize the roles of miRNA‑122 in cancer, its potential as a biomarker for diagnosis and prognosis and its implications in cancer therapy, including radiotherapy and chemotherapy, alongside strategies for systemic delivery.

Hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT) remains problematic. The genetic and molecular characteristics of patients may affect HCC recurrence. We evaluated the effects of microRNA-122 (miR-122) and interleukin-28B (IL-28B) genetic polymorphisms on patients with HCC following LDLT in 60 patients. MiR-122 and IL-28B polymorphisms were evaluated in plasma and liver tissues after LDLT. HBV, HCV, dual HBV/HCV infection, and non-B non-C were detected in 26, 22, 3, and 9 patients, respectively, over a median follow-up time of 20.5 (10-33) months. miR-122 was significantly higher in the liver than in the plasma of patients with HBV, HCV, dual HBV/HCV, and non-B non-C. Hepatic miR-122 expression was significantly higher for genotype TT and genotype TT plus GT (p = 0.005) compared with genotype GG of IL-28B rs8099917 and significantly higher in > 6% fatty liver than in < 5% or no fatty liver. In conclusion, high hepatic miR-122 was correlated with the IL-28B rs8099917 genotypes TT and GT and with > 6% fatty liver and, thus, may play a major role in HCC. [ABSTRACT FROM AUTHOR]

Purpose: The main purpose of our study is to research the potential of circulating microRNA-122 (miR-122)as a marker for hepatocellular carcinoma. Materials and Methods: Circulating miR-122 levels were measured by real-time polymerase chain reaction in patients with varied stages of hepatocellular carcinoma. In addition, various other laboratory and clinical data of the participants were evaluated in order to observe the correlation between these data and serum miR-122 levels. Results: Serum miR-122 levels were found significantly higher in hepatocellular carcinoma patients compared to the control group. (median miR-122 (min. – max.); patients: 0.0104 (0-0.262); controls: 0.00187 (0-0.100), p <0.001). For the cut-off value of serum miR-122 levels (0.0038), the area under the receiver operating characteristic curve analysis revealed 67.4% sensitivity and 74.4% specificity in hepatocellular carcinoma diagnosis. At this cut-off value, 1-year, 3-year and 5-year overall survival rates were not statistically different between patients with above or below this value. Conclusion: Our results show that only serum miR-122 is not a suitable biomarker for the hepatocellular carcinoma. Thus, using other diagnostic indicators together with serum miR-122 may be clinically meaningful for which large-scale studies are warranted. [ABSTRACT FROM AUTHOR]

Background Many lncRNAs have been recognized as critical regulatory factors in acute myocardial infarction (AMI). Herein, we further tested the influence of long non-coding RNA urothelial carcinoma associated 1 (UCA1) on cardiomyocytes injury in AMI, along with the role of microRNA-122 (miR-122) in this influence.Methods Cardiomyocytes H9c2 was subjected to oxygen-glucose deprivation (OGD) stimulation. Cell viability and apoptosis were assessed. The UCA1 and miR-122 expressions were measured by qRT-PCR. Plasmids and miRNAs transfection were utilized to elevate UCA1 and miR-122 expressions. Subsequently, the influences of UCA1 and/or miR-122 overexpression on OGD-aroused H9c2 cell viability inhibition and apoptosis were probed. The AKT/mTOR and JNK/p38MAPK pathways in cells were analyzed.Results OGD aroused H9c2 cell injury by suppressing cell viability and elevating cell apoptosis. Followed by OGD stimulation, the UCA1 expression was lowered in H9c2 cells. Overexpression of UCA1 weakened H9c2 cell injury aroused by OGD and declined miR-122 expression. Moreover, miR-122 attended to the influence of UCA1 overexpression on OGD-aroused H9c2 cell injury. Overexpression of UCA1 weakened OGD-aroused AKT/mTOR pathway inactivation and JNK/p38MAPK pathway activation by declining miR-122.Conclusion UCA1-relieved OGD-aroused H9c2 cell injury might be achieved via declining miR-122 and then promoting AKT/mTOR pathway and suppressing JNK/p38MAPK pathway.

microRNAs (miRNAs) are small non-coding RNAs that regulate various biological processes by targeting mRNAs and affecting their stability or translation. miR-122 is a major miRNA in mammalian liver but its function in poultry liver has not been studied. Therefore, the objective of the current study was to determine the function of miR-122 in the chicken liver. Through bioinformatics, we found P4HA1 was a candidate target of miR-122. P4HA1 mRNA and protein expression were increased in hepatocytes when miR-122 was knocked down by locked nucleic acid (LNA)-antisense-miR-122 (LNA-122). Reporter gene analyses confirmed that P4HA1 was a target of miR-122. Because P4HA1 is known to play an important role in liver metabolism, these findings suggest that miR-122 may be involved in liver metabolism in the chicken by regulating the P4HA1 expression.Highlights The predicted target site of miR-122 in chicken P4HA1 is conserved among species. P4HA1 mRNA and protein are upregulated in miR-122 knockdown chicken hepatocytes. miR-122 targets P4HA1 in chicken.

Objective To explore the predictive efficiency of microRNA-122a（miR-122a）expression and high-mo‐ bility group protein 1（HMGB1）level in serum on the prognosis of children with sepsis-associated liver injure（SALI）. Methods Totally 198 children with sepsis were divided into the liver injury group（80 cases，in which 37 cases were se‐ vere，23 cases were moderate and 20 cases were mild ）and non-liver injury group（118 cases）according to whether they had liver injury. Totally 60 healthy children were taken as the control group. Peripheral venous blood of children was collected to detect the expression of miR-122a and level of HMGB1 in serum. The influencing factors for poor prognosis in children with SALI were analyzed by multivariate Logistics regression analysis. The receiver operating characteristic curve （ROC）was drawn to analyze the predictive value of miR-122a expression and HMGB1 level in serum on the poor prognosis of the children with SALI. Results Compared with the control group，the expression of miR-122a and level of HMGB1 in serum increased in the liver injury group. Compared with the non-liver injury group and the control group，the expression of miR-122a and level of HMGB1 in serum in the liver injury group increased（all P<0. 05）. Compared with the mild group，the expression of miR-122a and the level of HMGB1 in serum of the moderate group were higher（both P<0. 05）. The expression of miR-122a and level of HMGB1 in serum of the severe group were higher than those in the medium group and the mild group（all P<0. 05）. Severe liver injury（OR=2. 535，95%CI：1. 345－5. 293），miR-122a（OR=1. 807，95%CI：1. 375－2. 466）and HMGB1（OR=1. 367，95%CI：1. 035－1. 806）were independent risk factors for poor prog‐ nosis in children with SALI（all P<0. 05）. The sensitivity and specificity of miR-122a+HMGB1（AUC=0. 921，95%CI： 0. 839－0. 970）in predicting poor prognosis of children with SALI were higher than those of miR-122a（AUC=0. 793， 95%CI：0. 688－0. 875）and HMGB1（AUC=0. 788，95%CI：0. 682－0. 871）. Conclusions With the severity of liver injury，the miR-122a expression and HMGB1 level in serum of children with sepsis increase. The independent risk factors for poor prognosis in children with SALI were are liver injury, increased miR-122a expression and HMGB1 level. Com bined detection of miR-122a expression and HMGB1 level in serum can be used to predict the poor prognosis of children with SALI. [ABSTRACT FROM AUTHOR]

aimaa A Hassanein,3 Samar M Kamaleldeen,4 Fatma E Ahmed,5 Mahmoud Rizk,6 Abdelnaser A Gadallah,7 Soma E Ajlan,8 Ahmed S Sief91Tropical Medicine Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 2Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 3Diagnostic Radiology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 4Clinical Pathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 5Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 6Internal Medicine Department, Faculty of Medicine, Banha University, Banha, Egypt; 7Internal Medicine Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 8Microbiology and Immunology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt; 9Hepatology and Gastroenterology Department, Shebin Elkom Teaching Hospital, Menoufia, EgyptCorrespondence: Safaa I TayelMedical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia, 32511, EgyptTel +20 1003383097Email [email protected] Background: Treatment response to antiviral drugs is a challenging issue in patients with chronic hepatitis C virus (HCV) infection. Although microRNA-122 represents the majority of the microRNA content in hepatic tissues, few studies have evaluated its role in the treatment response, so we aimed to study its role in chronic HCV patients and in predicting the treatment response to direct-acting antivirals (DAAs). Methods: The study included 125 chronic HCV patients (89 naïve and 36 with a prior failed peginterferon/ribavirin response) and 50 apparently healthy subjects. Complete blood count, liver function, α-fetoprotein, lipid profiles, serum creatinine, abdominal ultrasound, and FibroScan® were assessed. Viral markers, HCV antibodies, and hepatitis B surface antigen were measured by enzyme-linked fluorescent immunoassay, with quantitative estimation of HCV RNA and microRNA-122 levels by real-time PCR. Results: The microRNA-122 level in HCV patients (those with a sustained virologic response 12 weeks after finishing therapy [SVR12] and non-responders) was significantly increased compared with controls and expressed more in non-responders versus SVR12 (p=0.042). ROC curve analysis of microRNA-122 for differentiating HCV patients from healthy controls revealed that a cut-off point of > 1.45 had a sensitivity of 67.20%, specificity of 94.0%, AUC=0.861, and p< 0.001; and for predicting response to treatment a cut-off point ≤ 5.66 could significantly (p=0.022) predict the occurrence of SVR, with a sensitivity of 60.34%, specificity of 66.67%, and AUC=0.729. Logistic regression analysis showed significant values for microRNA-122 in multivariate and univariate analysis for the prediction of response to DAAs. Conclusion: The results demonstrated the possible function of microRNA-122 as an indicative tool for distinguishing chronic HCV patients from controls and in the assessment of the therapeutic reaction to DAAs. [ABSTRACT FROM AUTHOR]

• Loss of miR-122 increases the levels of proinflammatory chemokines and RelB in the liver • miR-122 regulates Relb expression via binding to 3′-UTR. • Macrophages from miR-122 knockout (KO) mice are hypersensitive to LPS. • miR-122 KO mice exhibit increased mortality and inflammation in response to LPS. MicroRNA-122 (miR-122) is the most abundant miRNA in the liver and it plays an important role in regulating liver metabolism and tumor formation. Previous studies also reveal an anti-inflammatory function of miR-122; however, relatively little is known about the mechanisms by which miR-122 suppresses inflammation. This study aims to search the effect of miR-122 on proinflammatory chemokines/cytokines production in mice. Quantitative real-time PCR, Western blot analysis, and ELISA were performed to examine gene expression. TargetScan, miRanda, and microT v3.0 were used to search for possible miR-122 target sites in the 3′-untranslated regions (3′-UTR) of candidate genes. Luciferase reporter assay and site-directed mutagenesis were applied to verify miR-122 target sequences. LPS was applied to peritoneal macrophages and mice to evaluate inflammatory response. The expression of proinflammatory chemokines, including Ccl2, Ccl4, Ccl20, Cxcl2, and Cxcl10 , and Relb in the livers of miR-122 knockout (KO) mice was increased. We identified Relb as a direct miR-122 target. Overexpressing RelB in the mouse liver increased the expression of Ccl2, Ccl4, Ccl20, Cxcl2, and Cxcl10. Peritoneal macrophages from miR-122 KO mice had a higher level of RelB, and they showed a stronger NF-κB activation and more TNF-α and IL-6 secretion after LPS stimulation. Overexpression of RelB in a macrophage cell line augmented LPS-induced TNF-α and IL-6 production. miR-122 KO mice showed a greatly increased mortality rate and generated a stronger and lasting inflammatory response to LPS. Deletion of miR-122 caused an upregulation of proinflammatory chemokines and RelB in the liver. Increased RelB may contribute to increases in these chemokine in the liver. Intriguingly, deletion of miR-122 also enhanced the sensitivity of macrophages and mice to LPS. Our results reveal that reducing RelB expression is a new mechanism by which miR-122 regulates inflammation. [ABSTRACT FROM AUTHOR]

Fibrotic diseases cause annually more than 800,000 deaths worldwide, where of the majority accounts for cardiovascular fibrosis, which is characterized by endothelial dysfunction, myocardial stiffening and reduced dispensability. MicroRNAs (miRs), small noncoding RNAs, play critical roles in cardiovascular dysfunction and related disorders. Intriguingly, there is a critical link among miR-122, cardiovascular fibrosis, sirtuin 6 (SIRT6) and angiotensin-converting enzyme 2 (ACE2), which was recently identified as a coreceptor for SARS-CoV2 and a negative regulator of the rennin-angiotensin system. MiR-122 overexpression appears to exacerbate the angiotensin II-mediated loss of autophagy and increased inflammation, apoptosis, extracellular matrix deposition, cardiovascular fibrosis and dysfunction by modulating the SIRT6-Elabela-ACE2, LGR4-β-catenin, TGFβ-CTGF and PTEN-PI3K-Akt signaling pathways. More importantly, the inhibition of miR-122 has proautophagic, antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic effects. Clinical and experimental studies clearly demonstrate that miR-122 functions as a crucial hallmark of fibrogenesis, cardiovascular injury and dysfunction. Additionally, the miR-122 level is related to the severity of hypertension, atherosclerosis, atrial fibrillation, acute myocardial infarction and heart failure, and miR-122 expression is a risk factor for these diseases. The miR-122 level has emerged as an early-warning biomarker cardiovascular fibrosis, and targeting miR-122 is a novel therapeutic approach against progression of cardiovascular dysfunction. Therefore, an increased understanding of the cardiovascular roles of miR-122 will help the development of effective interventions. This review summarizes the biogenesis of miR-122; regulatory effects and underlying mechanisms of miR-122 on cardiovascular fibrosis and related diseases; and its function as a potential specific biomarker for cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA‐122 (miR‐122) is specifically expressed in the liver. This study focuses on the role of miR‐122 in MC‐LR‐induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 μg/kg·BW MC‐LR, 25 μg/kg·BW MC‐LR, Negative control agomir and 25 μg/kg·BW MC‐LR + miR‐122 agomir). The results show that MC‐LR decreases the expressions of miR‐122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR‐122 agomir pretreatment improves MC‐LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR‐122 agomir can prevent the accumulation of hepatic iron induced by MC‐LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL‐6/STAT signaling pathways. [ABSTRACT FROM AUTHOR]

Objectives: To explore the value of ultrasomics in temporal monitoring of tumor changes in response to gene therapy in hepatocellular carcinoma compared with methods according to the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). Methods: Hepatocellular carcinoma–bearing mice were injected intratumorally with microRNA‐122 (miR‐122) mimics and an miR‐122 negative control in the treatment and control groups, respectively. The injections were performed every 3 days for 5 times (on days 0, 3, 6, 9, and 12). Before each injection and at the experiment ending, 2‐dimensional ultrasound imaging was performed for tumor size measurement with RECIST and computing a quantitative imaging analysis with ultrasomics. To analyze the tumor perfusion by mRECIST, perfusion parameters were analyzed offline based on dynamic contrast‐enhanced ultrasound image videos using SonoLiver software (TomTec, Unterschleissheim, Germany) on day 13. Tumor miR‐122 expression was then analyzed by real‐time reverse transcription–polymerase chain reaction experiments. Results: Tumors in mice treated with miR‐122 mimics demonstrated a mean ± SD 763‐ ± 60‐fold increase in miR‐122 levels compared with tumors in the control group. With RECIST, a significant therapeutic response evaluated by tumor size changes was detected after day 9 (days 9, 12, and 13; P <.001). With mRECIST, no parameters showed significant differences (P >.05). Significant different features of the 2‐dimensional ultrasound images between the groups were detected by the ultrasomics analysis, and the model could be successfully built. The ultrasomics score values between the groups were statistically significant after day 6 (days 6, 9, 12, and 13; P <.05). Conclusions: Ultrasomics revealed significant changes after the second injection of miR‐122, showing the potential as an important imaging biomarker for gene therapy. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B (CHB) infection remains worldwide health problem. Antiviral treatment options for CHB patients include nucleos(t)ide analogs (NAs) and interferon. Most of the current biomarkers for predicting treatment response are virus-dependent. MicroRNA-122 is the most abundant liver-specific miRNA and has been identified involved in multiple liver physiology and pathology including hepatotropic virus infection. To identify the role of miR-122 in NA therapy, 80 CHB patients with high viral load (HVL) were enrolled and serum miR-122 levels at baseline, week 12 and week 24 were measured. Serum miR-122 levels were significantly lower in patients who developed virological response (VR), compared with non-VR group. Levels of miR-122 at week 12 and week 24 were determined to be independent prognostic indicators for a VR with satisfactory AUROC values at 0.812 and 0.800, respectively. During NA therapy, serum miR-122 level deceased steadily and an earlier reduction was observed in VR group, indicating early reduction of miR-122 level might increase the possibility of developing virological response. In conclusion, we identified the dynamic change of serum miR-122 level and miR-122 levels at week 12 and week 24 as independent predictors for VR in CHB patients with HVL treated with NAs.

Background: Many lncRNAs have been recognized as critical regulatory factors in acute myocardial infarction (AMI). Herein, we further tested the influence of long non-coding RNA urothelial carcinoma associated 1 (UCA1) on cardiomyocytes injury in AMI, along with the role of microRNA-122 (miR-122) in this influence. Methods: Cardiomyocytes H9c2 was subjected to oxygen-glucose deprivation (OGD) stimulation. Cell viability and apoptosis were assessed. The UCA1 and miR-122 expressions were measured by qRT-PCR. Plasmids and miRNAs transfection were utilized to elevate UCA1 and miR-122 expressions. Subsequently, the influences of UCA1 and/or miR-122 overexpression on OGD-aroused H9c2 cell viability inhibition and apoptosis were probed. The AKT/mTOR and JNK/p38MAPK pathways in cells were analyzed. Results: OGD aroused H9c2 cell injury by suppressing cell viability and elevating cell apoptosis. Followed by OGD stimulation, the UCA1 expression was lowered in H9c2 cells. Overexpression of UCA1 weakened H9c2 cell injury aroused by OGD and declined miR-122 expression. Moreover, miR-122 attended to the influence of UCA1 overexpression on OGD-aroused H9c2 cell injury. Overexpression of UCA1 weakened OGD-aroused AKT/mTOR pathway inactivation and JNK/p38MAPK pathway activation by declining miR-122. Conclusion: UCA1-relieved OGD-aroused H9c2 cell injury might be achieved via declining miR-122 and then promoting AKT/mTOR pathway and suppressing JNK/p38MAPK pathway. [ABSTRACT FROM AUTHOR]

MicroRNAs are deemed as key regulators of gene expression. In particular, the elevated expression of excision repair cross‐complementing 1 (ERCC1) significantly reduced the effectiveness of gastric cancer treatment by cisplatin (CDDP)‐based therapies. In this paper, qRT‐PCR and western blot were adopted to measure miR‐122 and ERCC1 messenger RNA (mRNA) expression in all samples. Luciferase assay was carried out to verify the role of ERCC1 as a target of miR‐122. The CCK‐8 assay was carried out to study the effect of ERCC1 and miR‐122 on cell survival and apoptosis. The results demonstrated that miR‐122 expression was reduced in cisplatin‐resistant gastric cancer. Using bioinformatic analysis, miR‐122 was shown to target the 3′‐UTR of human ERCC1. A dual‐luciferase assay demonstrated that miR‐122 downregulated ERCC1 expression, while the mutations in ERCC1 3′‐UTR abolished its interaction with miR‐122. Transfection of miR‐122 mimics decreased the levels of ERCC1 mRNA and protein expression, while the transfection of miR‐122 inhibitors increased the levels of both ERCC1 mRNA and protein expression. Furthermore, we found that overexpressed miR‐122 promoted the proliferation of MKN74 cells and reduced their apoptotic by targeting ERCC1. In addition, the levels of miR‐122 and ERCC1 were negatively correlated in gastric cancer samples. In summary, the reduced miR‐122 expression may play an essential role in the induction of cisplatin‐resistance by increasing ERCC1 expression. [ABSTRACT FROM AUTHOR]

A luminescent microRNA nanoprobe based on the target-triggered Ir(III)-solvent complex release has been fabricated. The complex is initially embedded into mesoporous silica nanoparticles (MSNs), and then is capped by single-stranded (ss) DNA. In the presence of the target microRNA, the ssDNA hybridize with the microRNA forming a rigid DNA/RNA heteroduplexes and leaving the surface of MSN. Thus, the capped Ir(III) solvent complex is released and re-coordinated with histidine (His) to form a new luminescent complex. The luminescence intensity of the nascent complex (with excitation/emission maxima at 340/570 nm) is positively correlated with the concentrations of the target microRNA in the range from 0.05 to 2 nM, and the detection limit of microRNA is estimated as 0.2 pM (S/N = 3). The ability of this nanoprobe to detect microRNA in cell extract further demonstrates its potential in practical application. [ABSTRACT FROM AUTHOR]

Aims In acute alcoholic liver injury, alcohol can directly or indirectly induce endoplasmic reticulum stress (ERS) to participate in liver injury, and it is found that the expression of serum exosomal miR-122 is significantly affected. Therefore, the present study investigated the effects of endoplasmic reticulum stress inhibition on the expression of serum exosomal miR-122 and acute liver injury. Methods The acute alcoholic liver injury models were established by the intragastric administration of ethanol (5 g/kg) in ICR mice. Intervention group received 4-phenylbutyric acid (PBA, endoplasmic reticulum stress inhibitor; 75 mg/kg and 150 mg/kg, intraperitoneal) 12 and 24 hours before intragastric administration. Mice treated with saline were used as controls. Results The ethanol treated mice exhibited significantly elevated hepatosomatic index (liver weight/body weight) and alanine aminotransferase (ALT), compared with those in the control group (P < 0.05). The ERS inhibitor 4-phenylbutyric acid protected against ethanol induced acute liver injury and hepatocyte necrosis, and PBA 150 mg/kg significantly attenuated ethanol induced hepatic ER stress-related proteins (GRP78, pIRE1α and pIF2α) (P < 0.05). Moreover, PBA 150 mg/kg markedly alleviated ethanol induced elevation of hepatic and serum exosomal miR-122 and pri-miR-122 (P < 0.05). Conclusions These findings suggest that ER stress inhibitor PBA attenuated ethanol induced acute liver injury and serum exosomal miR-122, and provides a potential therapy strategy for acute alcoholic liver injury. [ABSTRACT FROM AUTHOR]

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MicroRNA-122 (miR-122) has been reported to be involved in the pathogenesis of several types of malignancies; however, its role in prostate carcinoma remains unknown. Thus, the current study aimed to investigate the functionality of miR-122 in prostate carcinoma. Clinical data of 54 patients with prostate carcinoma who were diagnosed and treated in Union Hospital (Wuhan, China) between January 2011 and January 2013 were retrospectively analyzed. The expression levels of miR-122 and Rho-associated protein kinase 2 (ROCK2) in prostate tumor and adjacent healthy tissues of patients, as well as in the serum of prostate carcinoma patients and healthy controls, were detected by reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curve and survival curve analyses were used to examine the diagnostic and prognostic values of serum miR-122 for prostate carcinoma. In addition, miR-122 mimic was transfected into prostate carcinoma cells, and the effects on cell proliferation and ROCK2 expression were explored by Cell Counting Kit-8 and western blot assays, respectively. It was observed that miR-122 was downregulated and ROCK2 was upregulated in tumor tissues as compared with their levels in adjacent healthy tissues. miR-122 level in the serum was also markedly lower in prostate carcinoma patients in comparison with that in healthy controls. Furthermore, a low serum level of miR-122 was found to effectively distinguish the prostate carcinoma patients from healthy controls and to be an indicator of poor survival. In prostate carcinoma cells, miR-122 overexpression inhibited the proliferation and the expression of ROCK2. Taken together, miR-122 may inhibit the proliferation of prostate carcinoma cells possibly by downregulating ROCK2 expression. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non‐alcoholic fatty liver disease (NAFLD). Methods: In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 weeks and were evaluated by liver histology at pretreatment and at 24 weeks after the start of treatment. The primary outcome was histological improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metabolism was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA‐122 (miR‐122) as early predictors of histological improvement was investigated. Results: All of the nine patients achieved histological improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 weeks compared to the pretreatment, respectively. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR‐122 ratios (the ratio of miR‐122 levels at 1 day after treatment to that at baseline), showed histological improvement. Furthermore, one patient, who showed a decrease in exosome miR‐122 ratios regardless of the increase in extracellular miR‐122 ratios, also showed decreases in NAFLD activity score and fibrosis stage. Conclusion: A prospective study showed that SGLT2I for NAFLD complicated by DM improved histological features in connection with glucose metabolism. This trial was registered as clinical trial UMIN000018166. [ABSTRACT FROM AUTHOR]

The present study aimed to systematically analyze the value of microRNA-122 (miRNA-122) in the diagnosis and prognosis of hepatocellular carcinoma (HCC) and other types of cancer. First, the reverse transcription-quantitative polymerase chain reaction method was used to detect the expression levels of miRNA-122 in the serum samples of patients with HCC, benign lesions and healthy volunteers. Next, miRNA-seq data of miRNA-122 from The Cancer Genome Atlas database were used to analyze the differential expression and overall survival rate associated with a variety of types of cancer. Meanwhile, the target gene prediction of miRNA-122 was performed using four different software programs. Finally, 353 significant target genes were identified for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis. Finally, it was demonstrated that the expression levels of miRNA-122 in the HCC group were increased compared with the healthy group (P<0.001), but decreased with respect to the benign group (P<0.001). In addition, the combination of the miRNA-122 and a fetoprotein may further improve the diagnostic accuracy between the HCC and healthy groups (area under the curve, 0.980; 95% confidence interval, 0.958–1.000). It was also demonstrated that miRNA-122 exhibited significantly differential expression and the overall survival rate was predicted for various other types of cancer, including colorectal cancer, renal carcinoma, cholangiocarcinoma, prostate cancer and thyroid carcinoma. Functional enrichment analysis demonstrated that the target genes of miRNA-122 may contribute to the composition of the nucleus and cytoplasm, and regulate a variety of biological processes, including cardiac muscle cell differentiation and glucose metabolic processes via protein biosynthesis, estrogen and glucagon associated signaling pathways. These results revealed that miRNA-122 may be an indispensable biomarker for the diagnosis, prognostic evaluation and targeted therapy in pan-cancer. [ABSTRACT FROM AUTHOR]

This study investigated the effects of tanshinol (TAN) on lipopolysaccharide (LPS)-induced human keratinocytes inflammatory injury and underlying potential molecular mechanisms. Viability and apoptosis of HaCaT cells were assessed using MTT assay and Annexin V-FITC/PI staining, respectively. Quantitative reverse transcription-polymerase chain reaction was performed to measure the expression of microRNA-122 (miR-122) in HaCaT cells. Cell transfection was conducted to up-regulate the expression of miR-122. Western blotting was used to detect the protein expression levels of key factors involved in cell apoptosis, inflammatory response, c-Jun N-terminal kinase (JNK), and nuclear factor kappa B (NF-κB) pathways. We found that LPS treatment induced HaCaT cell inflammatory injury by inhibiting cell viability, promoting cell apoptosis, and enhancing the protein expression levels of cyclooxygenase 2 and inducible nitric oxide synthase. TAN treatment relieved LPS-induced HaCaT cell inflammatory injury. Moreover, TAN treatment attenuated LPS-induced activation of JNK and NF-κB pathways in HaCaT cells. Furthermore, TAN treatment alleviated LPS-induced up-regulation of miR-122. Overexpression of miR-122 reversed the effects of TAN on LPS-induced HaCaT cell inflammatory injury and activation of JNK and NF-κB pathways. In conclusion, TAN exerted anti-inflammatory and protective effects on keratinocytes injury. TAN relieved LPS-induced inflammatory injury of human HaCaT cells via down-regulating miR-122 and then inactivating JNK and NF-κB pathways. [ABSTRACT FROM AUTHOR]