microRNA-181a contributes to gastric hypersensitivity in rats with diabetes by regulating TLR4 expression.

Aim: The aim of this study is to investigate the mechanism and interaction of microRNA-181a (miR-181a), toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) in gastric hypersensitivity in diabetic rats. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in female SD rats. Gastric balloon distension technique was used to measure diabetic gastric hypersensitivity. Gastric-specific (T7-T10) dorsal root ganglion (DRG) neurons were acutely dissociated to measure excitability with patch-clamp techniques. Western blotting was employed to measure the expressions of TLR4, TRAF6 and NF-κB subunit p65 in T7-T10 DRGs. The expressions of microRNAs in T7-T10 DRGs were measured with quantitative real-time PCR and fluorescence in situ hybridization. Dual-luciferase reporter gene assay was used to detect the targeting regulation of microRNAs on TLR4. Results: (1) Diabetic rats were more sensitive to graded gastric balloon distention at 2 and 4 weeks. (2) The expression of TLR4 was significantly up-regulated in T7-T10 DRGs of diabetic rats. Intrathecal injection of CLI-095 (TLR4-selective inhibitor) attenuated diabetic gastric hypersensitivity, and markedly reversed the hyper-excitability of gastric-specific DRG neurons. (3) The expressions of miR-181a and miR-7a were significantly decreased in diabetic rats. MiR-181a could directly regulate the expression of TLR4, while miR-7a couldn't. (4) Intrathecal injection of miR-181a agomir down-regulated the expression of TLR4, reduced the hyper-excitability of gastric-specific neurons, and alleviated gastric hypersensitivity. (5) p65 and TLR4 were co-expressed in Dil-labeled DRG neurons. (6) Inhibition of p65 attenuated diabetic gastric hypersensitivity and hyper-excitability of gastric-specific DRG neurons. (7) The expression of TRAF6 was significantly up-regulated in diabetic rats. CLI-095 treatment also reduced the expression of TRAF6 and p65. Conclusion: The reduction of microRNA-181a in T7-T10 DRGs might up-regulate TLR4 expression. TLR4 activated NF-κB through MyD88-dependent signaling pathway, increased excitability of gastric-specific DRG neurons, and contributed to diabetic gastric hypersensitivity.

[Circular RNA in Diabetes and its Complications].

Circular RNA (circRNA) is a special group of non-coding RNA.Unlike linear RNA,circRNA is a closed circular structure formed by reverse splicing of pre-mRNA,with highly stable expression and wide distribution in eukaryotes.CircRNA has multiple functions by acting as microRNA sponges or binding with RNA-binding proteins.They can be used as biomarkers for many diseases.The latest research shows that circRNA plays a role in the pathogenesis of diabetes mellitus and the related chronic complications.In this review,we summarized the current progress and underlying mechanisms of circRNA in diabetes mellitus and the related complications.

Efficacy of Probiotics and Synbiotics in Patients with Nonalcoholic Fatty Liver Disease: A Meta-Analysis.

BACKGROUND AND AIM: Extensive epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is the primary chronic liver disease worldwide. However, some studies have showed conflicting results on the effects of probiotics and synbiotics supplementation. Therefore, we conducted a systematic review and meta-analysis to investigate the effectiveness of the supplementation in subjects with NAFLD. METHODS: We searched systematically PubMed, Cochrane, and Embase databases up to April 2018 and checked manually the bibliography of the original articles. The quality of the studies was evaluated using the Cochrane Risk of Bias Tool. RESULTS: This study analyzed 15 randomized, controlled trials involving 782 patients with NAFLD. Probiotics and synbiotics supplementation could significantly improve liver steatosis, alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein, homeostasis model assessment-insulin resistance, liver stiffness and tumor necrosis factor-alpha (all P < 0.05). But the supplementation could not ameliorate body mass index (mean difference [MD] = -0.00; 95% confidence interval [CI]: -0.22 to 0.22, P = 0.99), waist circumference (MD = -0.01; 95% CI -0.03 to 0.02, P = 0.57) and fasting blood sugar (standard mean difference [SMD] = -0.10; 95% CI -0.32 to 0.12, P = 0.39). CONCLUSION: We present clear evidence for the benefit of probiotics and synbiotics supplementation for liver steatosis, liver enzymes, lipid profiles and liver stiffness in patients with NAFLD.

Set-Membership Global Estimation of Networked Systems.

This article is concerned with set-membership global estimation for a networked system under unknown-but-bounded process and measurement noises. First, a group of local set-membership estimators is deployed to obtain the local ellipsoidal estimate of the true system state. Each estimator is capable of communicating with its neighbors within its communication range. Second, a global estimation approach is proposed which generates a trace-maximal ellipsoid within the intersection of all the local estimation sets with an aim to improve the difference of the local estimate at each time instant. Sufficient conditions for providing a global estimate under both complete and incomplete measurement transmissions are derived. Third, as an application, a modified distributed photovoltaic grid-connected generation system is provided to verify the effectiveness of the developed set-membership global estimation approach. Furthermore, an islanding fault detection scheme is derived based on the calculated global ellipsoidal estimate. Finally, simulation verification of the obtained theoretical results on the distributed generation system is presented.

A Variable Search Space Strategy Based on Sequential Trust Region Determination Technique.

The complexity of an optimization problem is determined by its decision and objective spaces. Over the past few decades, a large number of works have focused on the performance improvement of metaheuristic algorithms via the objective space, whereas studies related to the decision space have attracted little attentions. Moreover, metaheuristic algorithms may not obtain satisfactory results within an entire feasible region, even if sufficient computational resources are available. Therefore, reducing the search space (i.e., finding a trust region) may be an effective method to ensure that the convergence is sufficiently close to the global optimal region. However, inappropriate subspace size may also weaken the performance of algorithms except for ones with a sufficiently small search space. To alleviate aforementioned problems, a variable search space (VSS) strategy based on a sequential trust region determination approach is proposed in this paper. In the VSS, the entire optimization process is divided into two stages: the first stage is to use an optimization approach for sequentially finding the trust domain of each variable and then determine the best-matched subspace; the second stage is to employ the optimization method for searching an optimal/near-optimal solution within the found trust region. The effectiveness of the VSS is evaluated using two widely used test suites, that is, IEEE CEC2014 and BBOB2012. Experimental results indicate that improving the algorithm performance is an important method for tackling problems, but locating a trust region is also beneficial for metaheuristic algorithms to improve the solution precision, especially for complex optimization problems.

Distributed H∞-Consensus Filtering for Attitude Tracking Using Ground-Based Radars.

This paper is concerned with the distributed H ∞ -consensus filtering problem on attitude tracking over a radar filter network subject to switching topology and random packet dropouts occurring in the data transmission from both the Sun sensor and the filters. Since ground-based radars cannot directly measure the satellite attitude, a Sun sensor is deployed at the satellite side and its measurements are transmitted to radar filters through different network communication channels while suffering from random packet dropouts with different probabilities. In the radar filter network, each radar filter receives data not only from the Sun sensor but also from its local neighboring radar filters in accordance with a switching network topology. A delicate distributed H ∞ -consensus filtering algorithm, which incorporates the effects of switching network topology and random packet dropouts, is adopted to estimate attitude and attitude-rate. The algorithm guarantees H ∞ -consensus attenuation performance for the estimation deviations among radar filters, and the robustness against the switching network topology and packet dropouts for the radar filter network. The illustrative examples are given to verify the effectiveness of the proposed distributed H ∞ -consensus filtering algorithm.

Bioinformatics Analysis of Candidate Genes and Pathways Related to Hepatocellular Carcinoma in China: A Study Based on Public Databases.

Background and Objective: Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor of the digestive system worldwide. Chronic hepatitis B virus (HBV) infection and aflatoxin exposure are predominant causes of HCC in China, whereas hepatitis C virus (HCV) infection and alcohol intake are likely the main risk factors in other countries. It is an unmet need to recognize the underlying molecular mechanisms of HCC in China. Methods: In this study, microarray datasets (GSE84005, GSE84402, GSE101685, and GSE115018) derived from Gene Expression Omnibus (GEO) database were analyzed to obtain the common differentially expressed genes (DEGs) by R software. Moreover, the gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by using Database for Annotation, Visualization and Integrated Discovery (DAVID). Furthermore, the protein-protein interaction (PPI) network was constructed, and hub genes were identified by the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape, respectively. The hub genes were verified using Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier Plotter online databases were performed on the TCGA HCC dataset. Moreover, the Human Protein Atlas (HPA) database was used to verify candidate genes' protein expression levels. Results: A total of 293 common DEGs were screened, including 103 up-regulated genes and 190 down-regulated genes. Moreover, GO analysis implied that common DEGs were mainly involved in the oxidation-reduction process, cytosol, and protein binding. KEGG pathway enrichment analysis presented that common DEGs were mainly enriched in metabolic pathways, complement and coagulation cascades, cell cycle, p53 signaling pathway, and tryptophan metabolism. In the PPI network, three subnetworks with high scores were detected using the Molecular Complex Detection (MCODE) plugin. The top 10 hub genes identified were CDK1, CCNB1, AURKA, CCNA2, KIF11, BUB1B, TOP2A, TPX2, HMMR and CDC45. The other public databases confirmed that high expression of the aforementioned genes related to poor overall survival among patients with HCC. Conclusion: This study primarily identified candidate genes and pathways involved in the underlying mechanisms of Chinese HCC, which is supposed to provide new targets for the diagnosis and treatment of HCC in China.

Comparison of diagnostic accuracy of 3 diagnostic criteria combined with refined pathological scoring system for drug-induced liver injury.

Drug-induced liver injury (DILI) is difficult in diagnose, criteria used now are mostly based on history review. We tried to evaluate the value of these criteria and histopathology features in DILI to perform a method diagnosing DILI more definitely.We enrolled 458 consecutive hospitalized DILI patients from January 1, 2012 to December 31, 2018, using Roussel-Uclaf Causality Assessment Method (RUCAM), Maria & Victorino scale (M&V), and Digestive Disease Week-Japan criterion (DDW-J) combined with refined pathological scoring system respectively to perform the evaluation.A total of 458 DILI patients were enrolled, the area under receiver operating characteristics (AUROC) of the 3 clinical diagnostic criteria were 0.730 (95% confidence interval [CI]: 0.667-0.793), 0.793 (95% CI: 0.740-0.847), and 0.764 (95% CI: 0.702-0.826) respectively. Three hundred two DILI patients' liver biopsies were included: steatosis in 204 cases (67.5%), cholestasis in 151 cases (50%), cell apoptosis in 139 cases (46%), eosinophil granulocyte infiltration in 131 cases (43.4%), central and/or portal phlebitis in 103 cases (34.1%), iron deposition in 90 cases (29.8%), and pigmented macrophages in 92 cases (30.5%). The AUROC of refined pathological scale combined with 3 criteria were 0.843 (95% CI: 0.747-0.914), 0.907 (95% CI: 0.822-0.960), and 0.881 (95% CI: 0.790-0.942) respectively. In hepatocellular type, the AUROCs were 0.894 (95% CI: 0.787-0.959), 0.960 (95% CI: 0.857-0.994), and 0.940 (95% CI: 0.847-0.985); in cholestatic type, the AUROCs were 0.750 (95% CI: 0.466-0.931), 0.500 (95% CI: 0.239-0.761), and 0.500 (95% CI: 0.239-0.761); in mixed type, the AUROCs were 0.786 (95% CI: 0.524-0.943), 0.869 (95% CI: 0.619-0.981), and 0.762 (95% CI: 0.498 to -0.930).Combined with pathological scale can significantly improve the accuracy of clinical diagnostic criteria, no matter in alone or combined condition, M&V might be more accurate in diagnosing DILI from suspected patients.

Circular RNA profile in diabetic peripheral neuropathy: analysis of coexpression networks of circular RNAs and mRNAs.

Aim: To study the expression pattern of circular RNAs in diabetic peripheral neuropathy. Materials & methods: Transmission electron microscopy was used to observe the ultrastructure of sciatic nerves and dorsal root ganglion (DRGs). circRNAs in DRGs were identified with high-throughput RNA sequencing. Whole-genome mRNAs were detected by a chip scan. Results: The ultrastructure of sciatic nerves and DRGs in diabetes mellitus mice changed significantly. A total of 11,004 circRNAs and 15 differentially expressed circRNAs, as well as 35,368 mRNAs and 133 differentially expressed mRNAs were identified in DRGs between wild-type and diabetes mellitus mice. 11 circRNAs and 14 mRNAs have a significant correlation using strict coexpression analysis. The expression of circRNA.4614 was validated to be upregulated significantly. Conclusion: Our study suggested that circRNAs might be involved in the regulation of mRNA expressions in diabetic peripheral neuropathy.

Alpha-lipoic acid downregulates TRPV1 receptor via NF-κB and attenuates neuropathic pain in rats with diabetes.

AIMS: Painful diabetic neuropathy (PDN) is a refractory complication of diabetes. The study aimed to investigate the role of α-lipoic acid (ALA) on the regulation of transient receptor potential vanilloid-1 (TRPV1) in dorsal root ganglion (DRG) neurons of rats with diabetes. METHODS: Whole-cell patch-clamp recordings were employed to measure neuronal excitability in DiI-labeled DRG neurons of control and streptozotocin (STZ)-induced diabetic rats. Western blotting and immunofluorescence assays were used to determine the expression and location of NF-κBp65 and TRPV1. RESULTS: STZ-induced hindpaw pain hypersensitivity and neuronal excitability in L4-6 DRG neurons were attenuated by intraperitoneal injection with ALA once a day lasted for one week. TRPV1 expression was enhanced in L4-6 DRGs of diabetic rats compared with age-matched control rats, which was also suppressed by ALA treatment. In addition, TRPV1 and p65 colocated in the same DRG neurons. The expression of p65 was upregulated in L4-6 DRGs of diabetic rats. Inhibition of p65 signaling using recombinant lentiviral vectors designated as LV-NF-κBp65 siRNA remarkably suppressed TRPV1 expression. Finally, p65 expression was downregulated by ALA treatment. CONCLUSION: Our findings demonstrated that ALA may alleviate neuropathic pain in diabetes by regulating TRPV1 expression via affecting NF-κB.

The diagnostic role of miR-122 in drug-induced liver injury: A systematic review and meta-analysis.

BACKGROUND: Drug-induced liver injury (DILI) is a potentially severe adverse drug reaction especially in susceptible patients. But there are no sensitive or specific parameters to detecting DILI. The specific expression of miR-122 in the liver has been a hotspot in the evaluation of hepatic toxicity due to its high stability and sensitivity. METHODS: We performed a systematic literature review through July 31, 2017 to identify studies which evolved DILI patients testing miR-122 without limiting a certain drug. According to the PRISMA statement, a meta-analysis: the diagnostic role of miR-122 in DILI was made. QUADAS-2 quality evaluation table was used to evaluate the quality of the documentary evidence, PRISMA flowchart and quality evaluation table were drawn with RevMan, use Stata to calculate the sensitivity and specificity of miR-122 in diagnosing DILI, ROC curve and Deeks funnel plot were also drawn by STATA. RESULTS: Eleven studies involved 194 DILI patients and 251 controls, all were tested miR-122 (fold change). Sensitivity of miR-122 in diagnosing DILI was [0.85 (95% CI, 0.75-0.91), I = 53.46%] and specificity was [0.93 (95% CI, 0.86-0.97), I = 65.10%], the area under ROC curve was 0.95 (95% CI, 0.93-0.97). While in acetaminophen (APAP)-induced liver injury, the sensitivity was [0.82 (95%CI, 0.67-0.91), I = 65.77%] specificity was [0.96 (95%CI, 0.88-0.99), I = 31.46%], AUROC was 0.97 (95% CI, 0.95-0.98). CONCLUSIONS: In this systematic review and meta-analysis, we found miR-122 have a high specificity in DILI, and a modest positive diagnostic effects. On the basis of the limited evidence, further research is needed to evaluate the long-term observation and more clinical data to testify miR-122 in diagnosing DILI.