Serum miR-34a Research Articles

MiR-34a in serum is involved in mild-to-moderate COPD in women exposed to biomass smoke

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities. The main causes of COPD are Gene-environment interactions associated with tobacco smoking (COPD-TS) and biomass smoke (COPD-BS). It is well know that microRNAs (miRNAs) participate in the control of post-transcriptional regulation and are involved in COPD-TS; nevertheless, those miRNAS are participating in the COPD-BS are unidentified. Thus, we studied which miRNAs are involved in COPD-BS (GOLD stages I–II).MethodsIn the screening phase, the profile of the miRNAs was analyzed in serum samples (n = 3) by means of a PCR array. Subsequently, the miRNAs were validated with RT-qPCR (n = 25) in the corresponding study groups. Additionally, the serum concentration of Notch1 was measured comparing COPD-BS vs COPD-TS.ResultsmiR-34a was down-regulated in COPD- BS vs COPD-TS. In the other study groups, three miRNAs were differentially expressed: miR-374a was down-regulated in COPD-BS vs C, miR-191-5p was up-regulated in COPD-BS vs H-BS, and miR-21-5p was down-regulated in COPD-TS compared to the C group. Moreover, the serum concentration of Notch1, one of the targets of miR-34a, was increased in COPD-BS compared to women with COPD-TS.ConclusionsThis is the first study in patients with COPD due to biomass that demonstrates miRNA expression differences between patients. The observations support the concept that COPD by biomass has a different phenotype than COPD due to tobacco smoking, which could have important implications for the treatment of these diseases.

Gallic acid protects the liver in rats against injuries induced by transient ischemia-reperfusion through regulating microRNAs expressions.

Objective(s):Gallic acid (GA) is a highly effective antioxidant, which its beneficial effects are well known, but its impact on expression of microRNAs (miRs) following hepatic ischemia-reperfusion (I/R) is not well recognized. Therefore, the current research was designed to specify the beneficial effect of GA on miRs (122 and 34a), liver functional tests, and histopathological alterations beyond I/R-induced hepatic injury. Materials and Methods:Thirty-two rats were randomly divided into four groups (8 per group) including: sham-operated (S), I/R, and GA+I/R pretreated groups. Rats in sham-operated group received physiologic saline (N/S, 2 ml/kg), on a weekly basis, once a day via intraperitoneally route), then a midline abdominal surgery was performed. IR, and GA+IR pretreated groups received physiologic saline (2 ml/kg), and GA (50, and 100 mg per kg) for same time, IP, respectively, before induction of transient ischemia. One hour after reperfusion, biochemical, and histopathological evaluations were performed and expression of miRs were evaluated.Results:The results showed that GA reduced the concentrations of liver enzymes, miR-122, and miR-34a in serum, and preserved liver cells changes induced by I/R injury.Conclusion:These findings showed that GA has beneficial effect on liver damage induced by I/R. Therefore, it is suggested that GA can be administered as an anti-miR before elective hepatic surgeries for prevention of this complication.

MicroRNA-34a promotes hypertension-induced vascular injury by targeting B-lymphocytoma-2

Objective To investigate the level of microRNA (miRNA, miR)-34a in serum of hypertensive patients and its effect on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) by targeting B cell lymphoma/leukemia-2 (bcl-2), and clarify the underlying mechanism of hypertension-induced vascular injury. Methods Real-time quantitative polymerase chain reaction (qPCR) was used to detect the level of miR-34a in serum of 98 hypertensive patients and 65 healthy controls; the potential targets of miR-34a was predicted by TargetScan; the interaction between miR-34a and bcl-2 was measured by dual luciferase reporter assay, western blot and qPCR; the effect of miR-34a on proliferation and apoptosis of HUVECs was detected by methyl thiazol tetrazolium (MTT) and flow cytometry. Results The level of miR-34a in serum of 98 hypertensive patients (2.432±0.201) was significantly higher than that of 65 healthy controls (0.996±0.112, P 0.05). The protein and mRNA level of bcl-2 in HUVECs after overexpressing miR-34a (0.403±0.041, 0.206±0.018) decreased significantly than that in Blank group (1.000±0.098, 1.000±0.067) and miR-NC group (0.996±0.087, 1.012±0.049). The proliferation of HUVECs after overexpressing miR-34a (48 h: 0.269±0.021, 72 h: 0.324±0.028) decreased significantly than that of the Blank group (48 h: 0.324±0.025, 72 h: 0.458±0.044) and miR-NC group (48 h: 0.335±0.028, 72 h: 0.469±0.051, P<0.05), and apoptosis (23.54±2.65) was significantly higher than that of Blank (6.45±0.42) and miR-NC (7.32±0.54, P<0.05). Conclusion MiR-34a is overexpressed in serum of hypertensive patients. Overexpressing miR-34a can inhibit proliferation of HUVECs by targeting bcl-2 expression, which may be one of the potential mechanisms of vascular injury in hypertensive patients and provide experimental basis for using miR-34a as a new target to diagnose and treat hypertension in the future. Key words: MicroRNA-34a; B cell lymphoma/leukemia-2; Hypertension; Vascular injury

Identification of serum miR-34a as a potential biomarker in acute myeloid leukemia.

MicroRNA-34a (miR-34a), as a tumor-suppressive miRNA, has been found to induce cell apoptosis in acutemyeloid leukemia (AML). However, the diagnostic and prognostic significance of miR-34a in AML remains largely unknown. We aimed to explore its associations with clinical characteristics and prognosis of AML patients. This study detected serum miR-34a level in 117diagnosed AML patients and 60control subjects by using qRT-PCR, and results were compared to clinical features and patient outcome. Since cytogenetically-normal AML (CN-AML) has a good uniformity of cytogenetics and provides a perfect platform for detectionof AML biomarkers, we further analyzed miR-34a expression in 56CN-AML subjects. We found that miR-34a was significantly downregulated in AML and CN-AML patients. MiR-34a underexpression was commonly observed in AML patients with intermediate/poor risk cytogenetic, and M5 subtype. ROC analysis demonstrated that serum miR-34a could well identify AML/CN-AML patients from healthy individuals. More importantly, miR-34a expression was found negatively correlated with aggressive clinical variable, and served as an independent prognostic indicator. In addition, AML/CN-AML patients with low miR-34a expression displayed shorter overall and recurrence free survival. Altogether, miR-34a might have an application as a diagnostic and prognostic indicator for AML patients.

Alcohol-mediated miR-34a modulates hepatocyte growth and apoptosis.

MicroRNAs (miRs) have been recently shown to be heavily involved in the development of alcoholic liver disease (ALD) and suggested as a potential therapeutic target in ALD. The miR‐34a was consistently reported to be significantly elevated in several ALD rodent models, but it remains unclear how miR‐34a modulates the cellular behaviours of hepatocytes in ALD development and progression. This study aims to characterize alcohol‐induced miR‐34a impact on hepatocytes growth and apoptosis. The miRNA array was performed to assess changes in miRNA after chronic alcohol feeding. Liver and blood samples were used to examine ALD progression. The miR‐34a was overexpressed in human hepatocytes to evaluate its impact on cell growth and apoptosis. Real‐time quantitative PCR and Western blot were used to determine the growth and apoptosis molecular signalling pathways associated with miR‐34a. Alcohol feeding significantly promoted fatty liver progression, serum ALT levels, apoptosis and miR‐34a expression in rat liver. Overexpression of miR‐34a in human hepatocytes suppressed cell growth signallings, including c‐Met, cyclin D1 and cyclin‐dependent kinase 6 (CDK6). The miR‐34a might also inhibit the expression of sirtuin 1 (Sirt1) and its target, B‐cell lymphoma 2. Interestingly, the expression of miR‐34a reverses the suppressive effects of ethanol on cell growth. But, miR‐34a promotes hepatocyte senescence and apoptosis. Although the miR‐34a‐mediated down‐regulation of cell growth‐associated genes may contribute to cell growth retardation, other miR‐34a targets, such as Sirt1, may reverse this phenotype. Future studies will be needed to clarify the role of miR‐34a in ALD progression.

Abstract 4440: New predictive and preventive biomarkers for preclinical hepatocellular carcinoma in Egyptian population by detection of serum miRNAs

Abstract The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and carries a poor survival rate. Prognosis, survival and management of patients at risk for developing HCC remain challenging in Egypt and worldwide. Furthermore, poor prognosis of patients with symptomatic (HCC) diagnosed clinically at advanced stages suggests an urgent need for new biomarkers detection that can be used for pre-clinical screening for early detection of premalignant lesions and tumors in high risk to hepatitis C infection. In the present study we used novel formulated anticancer compound(s), combined with or without Sorafenib treatment to exert their antiproliferative effects by eliciting concomitant expression of known or novel biomarkers, including different serum miRNAs, which can be quantitatively analyzed for differences in the levels of metabolites and proteins in the blood and liver tissues of treated HCC xenografts and liver cirrhosis animal models. In addition, circulating miRNAs levels were measured as promising markers in 12 month interval-serum samples that were collected from normal, chronic hepatitis C virus infected patient cohorts at the pre-malignant or pre-clinical stages and liver cirrhotic patients that did not develop cancer. Different serum miRNAs, including miR-21, miR-142, let-7a, let-7b, miR-429 and miR-34a were detected in pre-clinical HCC patients and have the potential to screen for hepatitis C virus infected patients at high risk to develop HCC 12 months after miRNAs detection. Our data of detected serum miRNAs from animal models and patient samples can be used to confirm and correlate histological and histochemical results at various time points with serum or imaging biomarkers, which may have a great promise for the prediction and prevention of HCC in high risk Egyptian populations. Citation Format: Sara Salama Ghazy, Amira S. Fyala, Ahmed S. Sultan. New predictive and preventive biomarkers for preclinical hepatocellular carcinoma in Egyptian population by detection of serum miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4440. doi:10.1158/1538-7445.AM2017-4440

Relation of MiR-34a Expression in Diffuse Large B Cell Lymphoma with Clinical Prognosis

To investigate the expression of miR-34a in serum of DLBCL patients, and to analyze its correlation with the expression of BCL-2 protein and clinical prognosis. The clinical data of 65 DLBCL patients and 22 cases of lymphonode reactive hyperplasia (RH) were collected, the serum expressions of miR-34a and BCL-2 were detected by real-time fluorescence quantitative PCR, and the relationship of miR-34a and BCL-2 expression with clinical pathological features and prognosis was analyzed. The miR-34a lowly expressed in DLBCL and the BCL-2 highly expressed in DLBCL, the miR-34a expression level correlated negatively with BCL-2 expression (P<0.01). The survival time of patients with high expression of miR-34a was significantly longer than that of patients with miR-34a low expression. Multivariate Cox regression analysis revealed that the expression of miR-34a (P<0.01) and BCL-2 (P<0.01) as well as clinical staging (P<0.01) were independent factors influencing the prognosis of patients with DLBCL. The low expression of miR-34a in DLBCL patients may be involved in the occurrence and development of diffuse large B cell lymphoma, the MiR-34a is correlated with prognosis of diffuse large B cell lymphoma.

Serum microRNA Expression Profiling: Potential Diagnostic Implications of a Panel of Serum microRNAs for Clear Cell Renal Cell Cancer

To study the expression profiles of 5 microRNAs in tissue and serum of patients with clear cell renal cell cancer (ccRCC) and evaluate their diagnostic and prognostic potential. We prospectively analyzed 30 patients of histologically proven ccRCC and collected 3 mL of serum preoperatively and small pieces of tumor and adjacent non-tumor renal tissue intraoperatively. Control serum samples were obtained from 15 patients of non-renal benign diseases. We analyzed 5 miRNAs-miR-34a, miR-141, miR-200c, miR-1233, and miR-21-2. Freshly collected samples were immediately frozen in liquid nitrogen and total RNA was extracted. cDNA was synthesized by reverse transcription, and quantitative polymerase chain reaction was performed to determine relative miRNA expression. In the renal tissue and serum samples, 3 out of 5 miRNAs were differentially expressed; that is, the expression levels of miR-34a and miR-141 were significantly decreased, whereas that of miR-1233 was significantly increased. Serum miR-34a, miR-141, and miR-1233 were able to diagnose ccRCC with a sensitivity of 80.76%, 75%, and 93.33%, and specificity of 80%, 73.33%, and 100%, respectively, as compared to histopathology. Using a panel of 2 serum miRNAs (miR-141 and miR-1233) ccRCC can be diagnosed with 100% sensitivity and 73.3% specificity. miRNAs are differentially expressed in serum of patients with ccRCC and can be used to diagnose ccRCC with high sensitivity and specificity. Diagnostic sensitivity can be further improved by using a panel of miRNAs and has the potential to serve as novel diagnostic markers of ccRCC.

Changes of serum miR34a expression during neoadjuvant chemotherapy predict the treatment response and prognosis in stage II/III breast cancer

To investigate the predictive value of serum miR34a (ser-miR34a) expression for the neoadjuvant chemotherapy (NACT) response and prognosis in breast cancer patients. This study included 86 diagnosed stage II/III breast cancer patients and 20 healthy volunteers. Peripheral blood from every participant was collected before the start, at the end of the second cycle, and at the end of NACT. The expression of ser-miR34a was examined by qRT-PCR and its association with the chemotherapy response and prognosis was analyzed. The expression of ser-miR34a in breast cancer patients before NACT was significant higher than that of healthy volunteers. During the NACT, the changes in ser-miR34a expression were significantly associated with treatment response and disease-free survival (DFS). In responding patients, ser-miR34a levels at the end of the second cycle and at the end of NACT were significantly lower than before NACT (P=0.016 and P=0.002, respectively), and in non-responding patients, the changes were insignificant. Survival analyses showed that the patients with decreased ser-miR34a expression from the end of the second cycle and the end of NACT to before NACT had improved DFS compared with that of the patients with increasing ser-miR34a expression (P<0.001 for both). Cox regression analyses showed that the changes of ser-miR34a expression were independent prognostic indicators. Ser-miR34a is a novel, noninvasive predictive marker for NACT response and prognosis in breast cancer patients.

Serum microRNA-34a is potential biomarker for inflammation in nonalcoholic fatty liver disease

Abstract Background MicroRNA-34a (miR-34a) contributes to liver injury through an apoptosis pathway. Objective To determine the correlation between serum miR-34a and liver inflammation as assessed by nonalcoholic fatty liver disease (NAFLD) activity score (NAS). Method We included a cross-selectional study of 50 patients with NAFLD in this observational study and confirmed diagnosis by liver biopsy, with NAS grading. A control group comprised 23 healthy individuals without chronic liver disease. Serum miR-34a was assayed using a real-time quantitative PCR (Applied Biosystems). Result The mean age of NAFLD patients was 46.0 ± 13.7 years, and 52% were female. Metabolic syndrome was found in 76%. Liver histopathology showed that 54% of patients had NAS ≥4 and significant fibrosis (≥2) was found in 22%. Serum levels of miR-34a were significantly correlated with NAS (r = 0.39, P = 0.005), and the degree of steatosis (r = 0.28, P = 0.049), ballooning (r = 0.30, P = 0.034), and fibrosis (r = 0.39, P = 0.005). Serum miR-34a in patients with NAS ≥4 was significantly higher than in those with NAS &lt;4 (P = 0.011) and controls (P &lt; 0.001). There was no significant correlation between serum miR-34a and other variables. The area under receiver operating characteristic curve for serum miR-34a comparing patients with NAS ≥4 and with NAS &lt;4 was 0.67 (95% CI 0.52, 0.82). Conclusion Serum level of miR-34a has a significant fair to good correlation with NAS and may serve as a biomarker of liver inflammation and fibrosis in patients with NAFLD.

Deregulation of miR-34a and Its Chaperon Hsp70 in Hepatitis C virus-Induced Liver Cirrhosis and Hepatocellular Carcinoma Patients

Background:MicroRNA deregulation may occur during hepatocellular carcinoma (HCC) genesis and progression stages. MicroRNA-34a (miR-34a) functions as a tumor suppressor and is down-regulated or silenced in a variety of human cancers, while heat shock proteins (Hsps) play important roles in assisting protein folding and preventing both protein aggregation and transport across membranes. The present study aimed to evaluating serum expression of miR-34a and its target Hsp70 for early detection of HCC in patients with liver cirrhosis (LC), focusing on correlations with clinicopathological features.Methods:A total of 180 patients were included: 120 with HCC on top of LC (60 with either early or late HCC) and 60 patients with HCV-related LC. In addition, 60 healthy individuals were considered as controls. Real-time polymerase chain reactions were performed for expression profiling of serum miR-34a and Hsp70 and for allelic discrimination of the promotor variant (rs2763979, C/T). In addition, in silico analysis was carried out.Results:All participants were heterozygote for the promotor polymorphism. miR-34a serum levels were significantly under-expressed in LC and especially HCC patients as compared to controls. Associations with a high Child-Turcotte-Pugh (CTP) score, advanced cancer stage, and number of masses were noted. In contrast the target Hsp70 was significantly overexpressed in cancer patients but not in LC group and inversely correlated with miR-34a levels.Conclusion:Utility of circulating miRNAs as biomarkers for early detection of HCC was raised. Future large-scale studies are warranted to confirm the current findings.

MicroRNA-34a expression levels in serum and intratumoral tissue can predict bone metastasis in patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. We screened a microRNA (miRNA) microarray to identify potential serum biomarkers for BM in HCC patients. A miRNA microarray was used to screen for BM-related miRNAs in paired serum samples from HCC patients with BM and from HCC patients without BM. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to quantify candidate miRNAs in serum samples from 106 independent HCC patients. Levels of candidate miRNAs in tissue samples from an independent cohort of 296 HCC patients were evaluated by in situ hybridization and intratumoral tissue microarray. The migration and invasion capabilities of HCCLM3 and SMMC-7721 cells were evaluated following treatment with a mimic and an inhibitor of miR-34a. Ninety miRNAs were differentially expressed in sera from HCC patients with BM when compared with sera from non-BM HCC patients (P < 0.05). Only miR-34a and miR-498 had false discovery rates (FDRs) < 0.05. In cohorts of 106 and 296 HCC patients, we found that reduced serum and intratumoral miR-34a expression levels were independent risk factors for developing BM. Migration and invasion experiments indicated that a reverse correlation existed between miR-34a and HCC tumor migration and invasion. This study demonstrates the potential for the use of miR-34a as a serum and intratumoral tissue biomarker for predicting the risk of BM in HCC patients.

Human serum miR-34a as an indicator of exposure to ionizing radiation.

Radiation exposure in industrial accidents or nuclear device attacks is a major public health concern. There is an urgent need for markers that rapidly identify people exposed to ionizing radiation (IR). Finding a blood-based marker is advantageous because of the ease of sample collection. This study was designed to test the hypothesis that serum miR-34a could serve as an indicator of exposure to IR. Therefore, 44 women with breast cancer, where radiotherapy was part of their therapeutic protocol, were investigated in this study. After demonstrating the appropriateness of our microRNA (miRNA) extraction efficiency and miRNA assay in human serum, we analyzed the miR-34a level in paired serum samples before and after radiotherapy. Fifty Gy X-ray irradiation in daily dose fractions of 2Gy, 5days per week, was used in this study. We demonstrated that IR significantly increased serum level of miR-34a. By measuring miR-34a in serum, we could distinguish irradiated patients with sensitivity of 65% and specificity of 75%. According to this study, serum miR-34a has the potential to be used as an indicator of radiation exposure.

Familial adenomatous patients with desmoid tumours show increased expression of miR-34a in serum and high levels in tumours.

Familial adenomatous polyposis (FAP) is rare affecting 1 in 10,000 people and a subset (10%) are at risk of myofibroblastic desmoid tumours (DTs) after colectomy to prevent cancer. DTs are a major cause of morbidity and mortality. The absence of markers to monitor progression and a lack of treatment options are significant limitations to clinical management. We investigated microRNAs (miRNA) levels in DTs and serum using expression array analysis on two independent cohorts of FAP patients (total, n=24). Each comprised equal numbers of patients who had formed DTs (cases) and those who had not (controls). All controls had absence of DTs confirmed by clinical and radiological assessment over at least three years post- colectomy. Technical qPCR validation was performed using an expanded cohort (29 FAP patients; 16 cases and 13 controls). The most significant elevated serum miRNA marker of DTs was miR-34a-5p and in-situ hybridisation (ISH) showed most DTs analysed (5/6) expressed miRNA-34a-5p. Exome sequencing of tumour and matched germline DNA did not detect mutations within the miR-34a-5p transcript sites or 3′-UTR of target genes that would alter functional miRNA activity. In conclusion, miR-34a-5p is a potential circulatory marker and therapy target. A large prospective world-wide multi-centre study is now warranted.

Association of Circulating Serum miR-34a and miR-122 with Dyslipidemia among Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of diseases from simple steatosis to non-alcoholic steatohepatitis, with approximately 20% risk of progressing to fibrosis and cirrhosis. The aim of this study was to compare the relative expression levels of circulating miR-21, miR-34a, miR-122, miR-125b and miR-375 between healthy controls and NAFLD patients, and to assess the feasibility of microRNAs as potential biomarkers for NAFLD. A cross-sectional study was conducted to evaluate circulating serum miRNAs as potential diagnostic markers for NAFLD. Twenty-eight clinically diagnosed and histologically-confirmed NAFLD patients, as well as 36 healthy controls were enrolled in this study. The relative expression of serum microRNAs were calculated using the comparative cycle threshold with spiked-in C. elegans miR-39 as exogenous internal control. Serum levels of miR-34a and miR-122 were significantly higher in NAFLD patients than in healthy controls (P = <0.0001). Positive correlations were observed between serum miR-34a with very low density lipoprotein cholesterol (VLDL-C) and triglyceride levels. However, the expression levels of miR-34a and miR-122 did not correlate with the histological features of NAFLD. Interestingly, receiver operating characteristic (ROC) curve analysis revealed that miR-34a and miR-122 are potential markers for discriminating NAFLD patients from healthy controls with an area under the curve (AUC) values of 0.781 and 0.858, respectively. Serum levels of miR-34a and miR-122 were found to be significantly higher among NAFLD patients, and were positively correlated with VLDL-C and triglyceride levels. Thus, circulating miR-34a and miR-122 can be used as potential biomarkers for discriminating NAFLD patients from healthy controls. Larger cohorts are required to validate the utility of miR-34a and miR-122 in monitoring liver injury.

Circulating miRNAs: Potential Novel Biomarkers for Hepatopathology Progression and Diagnosis of Schistosomiasis Japonica in Two Murine Models.

BackgroundSchistosomiasis remains a major public health issue, with an estimated 230 million people infected worldwide. Novel tools for early diagnosis and surveillance of schistosomiasis are currently needed. Elevated levels of circulating microRNAs (miRNAs) are commonly associated with the initiation and progression of human disease pathology. Hence, serum miRNAs are emerging as promising biomarkers for the diagnosis of a variety of human diseases. This study investigated circulating host miRNAs commonly associated with liver diseases and schistosome parasite-derived miRNAs during the progression of hepatic schistosomiasis japonica in two murine models.Methodology/Principal FindingsTwo mouse strains (C57BL/6 and BALB/c) were infected with a low dosage of Schistosoma japonicum cercariae. The dynamic patterns of hepatopathology, the serum levels of liver injury-related enzymes and the serum circulating miRNAs (both host and parasite-derived) levels were then assessed in the progression of schistosomiasis japonica. For the first time, an inverse correlation between the severity of hepatocyte necrosis and the level of liver fibrosis was revealed during S. japonicum infection in BALB/c, but not in C57BL/6 mice. The inconsistent levels of the host circulating miRNAs, miR-122, miR-21 and miR-34a in serum were confirmed in the two murine models during infection, which limits their potential value as individual diagnostic biomarkers for schistosomiasis. However, their serum levels in combination may serve as a novel biomarker to mirror the hepatic immune responses induced in the mammalian host during schistosome infection and the degree of hepatopathology. Further, two circulating parasite-specific miRNAs, sja-miR-277 and sja-miR-3479-3p, were shown to have potential as diagnostic markers for schistosomiasis japonica.Conclusions/SignificanceWe provide the first evidence for the potential of utilizing circulating host miRNAs to indicate different immune responses and the severity of hepatopathology outcomes induced in two murine strains infected with S. japonicum. This study also establishes a basis for the early and cell-free diagnosis of schistosomiasis by targeting circulating schistosome parasite-derived miRNAs.

Su1811 Sitagliptin Can Be Anti-Inflammatory Drug for the Development of NAFLD in Obese Diabetic OB/OB Mice Under Lipopolysaccharides Existence

the biopsy day. Serum miR-34a was analyzed by quantitative real time PCR method (Applied BiosynthesisTM) and expressed as copies/μL. Results: The mean age of NAFLD patients was 47.1 ± 13.6 year with female of 56%. Their mean body mass index (BMI) was 32.3 ± 16.4 kg/m2. Obesity was found in 74.4%, and metabolic syndrome was 76.4%. Liver histopathology showed that 55.8% of patients had NAS ≥4 and the remaining of 44.2% had NAS <4. Two-third of patients (67.4%) had histopathology compatible with NASH and significant fibrosis ( ≥ F2) was found in 25.6%. Serum level of miR-34a showed significant correlation with NAS (r = 0.44, P = 0.003) (Figure 1), degree of steatosis (r = 0.34, P = 0.026), degree of ballooning (r = 0.31, P = 0.043), and degree of fibrosis (r = 0.34, P = 0.002), whereas miR-34a was not correlated with the degree of lobular inflammation (r = 0.21, P = 0.178). Interestingly, serum miR-34a in patients with NAS ≥4 was significantly higher than those with NAS <4 (338.9 ± 353.2 vs 118.4 ± 154.9, P = 0.01) (Figure 2). There was no significant correlation between serum miR-34a and the other variables including age, body weight, height, and BMI. Conclusion: Serum level of microRNA-34a had significantly fair to good correlation with NAS and degree of fibrosis which represent the severity of inflammation. Additionally, serum miR-34a level in patients with NAS ≥4 was significantly higher than those with NAS <4. Thus, microRNA-34a may serve as a potential biomarker of liver inflammation and fibrosis in NAFLD patients.

Serum interferon-related microRNAs as biomarkers to predict the response to interferon therapy in chronic hepatitis C genotype 4.

MicroRNAs are messengers during interferon-virus interplay and are involved in antiviral immunity, however, little is known about interferon-related microRNAs regarding their detection in serum and their potential use as non-invasive diagnostic and prognostic biomarkers in chronic hepatitis C (CHC). To elucidate some of the molecular aspects underlying failure of pegylated interferon-α/ribavirin therapy, we investigated pretreatment expression profiles of seven selected interferon-related microRNAs (miR-146a, miR-34a, miR-130a, miR-19a, miR-192, miR-195, and miR-296) by quantitative RT-PCR custom array technology in serum of Egyptian CHC genotype 4 patients and whether their pretreatment levels would predict patient response to the combination therapy. One hundred and six CHC patients and forty matched healthy controls were included. Patients were divided into sustained virological response (SVR) and non-responder (NR) groups. Serum miR-34a, miR-130a, miR-19a, miR-192, miR-195, and miR-296 were upregulated, whereas serum miR-146a was downregulated in CHC compared to controls. Significant correlations were found between expression levels of studied microRNAs and also with clinical data. Pretreatment levels of miR-34a, miR-130a, and miR-195 were significantly higher, whereas miR-192 and miR-296 levels were significantly lower in SVR than NR patients. miR-19a and miR-146a levels were not significantly different between the two groups. miR-34a was superior to differentiate CHC from controls, whereas miR-296 was superior to discriminate SVR from NR patients by receiver operating characteristic analysis. Multivariate logistic analysis revealed miR-34a and miR-195 as independent predictors for SVR and miR-192 as an independent variable for non-response. In conclusion, pretreatment expression profiles of five interferon-related microRNAs are associated with treatment outcome in CHC. Of these, miR-34a, miR-195, and miR-192 could predict treatment response. The profiling results could be used as novel non-invasive diagnostic and prognostic pharmacogenetic biomarkers for treatment personalization in CHC and could help to identify new microRNA-based antivirals.

MicroRNA-34a Promotes Cardiomyocyte Apoptosis Post Myocardial Infarction Through Down-regulating Aldehyde Dehydrogenase 2

MicroRNA-34a (miR-34a) promotes apoptosis via down-regulating many anti-apoptotic proteins. Aldehyde dehydrogenase 2 (ALDH2) is an anti-apoptotic enzyme whose activity decline associates with myocardial injury. We tested hypothesis that miR-34a might play a pro-apoptotic role in myocardial infarction (MI) by down-regulating ALDH2. MiR-34a was highly increased while ALDH2 expression was decreased after experimental MI. Overexpression of miR-34a in neonatal rat cardiomyocyte could significantly enhance apoptosis and down-regulate ALDH2 expression. In 293 cells, luciferase reporter assay results demonstrated that ALDH2 was a direct target of miR-34a. Serum miR-34a levels in acute myocardial infarction (AMI) patients and rats were significantly higher than healthy subjects and sham rats. Our results proved that miR-34a could promote cardiomyocyte apoptosis via negatively regulating ALDH2 and circulating miR-34a was increased in the condition of MI. Thus, miR-34a may constitute a new therapeutic target and diagnostic marker for patients with MI.

MiR-34a in Age and Tissue Related Radio-Sensitivity and Serum miR-34a as a Novel Indicator of Radiation Injury

MiR-34a, a direct target of p53, has shown to exert potent anti-proliferative effects. It has also been found that miR-34a can be induced by irradiation in vitro and in vivo. However, the relationship between miR-34a and radio-sensitivity, and its potential diagnostic significance in radiation biology, remain unclear. This study found that differing responses to ionizing radiation (IR) of young and adult mice were related to miR-34a. First, we found that miR-34a could be induced in many organs by radiation of both young and adult mice. However, the level of miR-34a induced by young mice was much higher when compared to adult mice. Next, we found that miR-34a played a critical role in radio-sensitivity variations of different tissues by enhancing cell apoptosis and decreasing cell viability. We also found that the induction of miR-34a by radiation was in a p53 dependent manner and that one possible downstream target of miR-34a that lead to different radio-sensitivity was the anti-apoptosis molecular Bcl-2. However, over-expression of miR-34a and knockdown of Bcl-2 could significantly enhance the radio-sensitivity of different cells while inhibition of miR-34a could protect cells from radiation injury. Finally, we concluded that miR-34a could be stable in serum after IR and serve as a novel indicator of radiation injury. Taken together, this data strongly suggests that miR-34a may be a novel indicator, mediator and target of radiation injury, radio-sensitivity and radioprotection.