Methyl butyrate attenuates concanavalin A-induced autoimmune hepatitis by inhibiting Th1-cell activation and homing to the liver.

Con A-induced hepatitis is the most commonly used animal model for simulating autoimmune hepatitis (AIH). In this study, we investigated whether methyl butyrate (MB) alleviates Con A-induced hepatitis and how it affects Con A-stimulated lymphocytes. MB improves liver function in AIH mice, reducing the expression of several inflammatory cytokines and Th1 cell-associated chemokines in the liver, while significantly inhibiting toll-like receptor signaling pathway. Also in the liver, we verified that infiltrating Th1 cells were fewer after MB treatment. In vitro, we found that the activation of both human and mouse Th1 cells by Con A were inhibited by MB and the human-derived cells were even more sensitive. And MB caused a reduction in IFN-γ secretion together with TNF-α and IL-6. The above findings suggest that MB inhibits the activation and homing of Th1 cells to the liver, thereby attenuating Con A-induced liver injury, and may be a potential therapeutic agent for AIH.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double-blind, double-dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty-seven (71 in group A) patients with HBeAg-positive CHB and 46 (21 in group A) patients with HBeAg-negative CHB completed the 240-week treatment and follow-up. Baseline characteristics were well balanced between the two groups. For the HBeAg-positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg-negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long-term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Optical effect and pre-forming temperature field of in situ laser-assisted micro-stamping by a diamond indenter.

During in situ laser-assisted micro-stamping (In-LAS) using a diamond indenter, the temperature of the machined area cannot be accurately predicted because of the coupling of the beam with the diamond indenter. This study uses geometrical optics and wave optics to determine the effect of the taper angle on laser direction, the light intensity distribution at the diamond indenter tip, and the temperature field of the machined area. This research provides data support and a theoretical basis for the selection of related process parameters of In-LAS and delivers a feasible theoretical method for a similar in situ laser-assisted machining.

Association Between Negative Results From Tests for HBV DNA and RNA and Durability of Response After Discontinuation of Nucles(t)ide Analogue Therapy.

BACKGROUND & AIMS: There is no satisfactory way to identify patients who will maintain a response after discontinuation of nuleos(t)ide analogue therapy for chronic hepatitis B virus (HBV) infection. We investigated whether patients with negative results from tests for HBV DNA and HBV RNA (double negative) at the end of treatment maintain a long-term response to treatment. METHODS: We performed a post-hoc analysis of data from a 2-year multi-center randomized controlled trial, and its long-term extension trials, on 130 patients with chronic HBV infection who were positive for the HB e antigen (HBeAg-positive; mean age, 30.8 ± 6.9 years; 72.3% male) and received telbivudine with or without adefovir and stopped therapy after they had HBeAg seroconversion and levels of HBV DNA <300 copies/mL for at least 48 weeks (evaluation cohort). Clinical and laboratory assessments were made every 12 or 16 weeks until clinical relapse (defined as HBV DNA > 2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal) or until 4 years off treatment. We validated our findings in a cohort of 40 HBeAg-positive patients (36.5 ± 9.4 years old; 72.5% male) treated with entecavir or tenofovir, and followed after discontinuation for up to 5.5 years. Patients were considered to be negative for HBV DNA if it was not detected in the COBAS Taqman assay. Patients were considered to be negative for HBV RNA if it was not detected by quantitative real-time PCR with 2 different pairs of primers. RESULTS: After 4 years off treatment, in the evaluation cohort, 30.8% of patients had a clinical relapse, 54.7% had virologic relapse (HBV DNA >2000 IU/mL in 2 tests), and 16.8% had reappearance of HBeAg in 2 tests (reversion). A significantly lower proportion of double negative patients had a clinical relapse 4 years later (2/35; 8.0%) than of patients who tested positive for either HBV DNA or RNA (32/102; 31.4%; P = .018). In the validation cohort, after 5.5 years of follow up, a lower proportion of double negative patients had clinical relapse (2/13; 15.4%) than of patients who tested positive for either HBV DNA or RNA at the end of treatment (9/27; 33.3%; P = .286) CONCLUSIONS: In an analysis of data from 2 independent cohorts, we associated negative results from tests for HBV DNA and RNA (double negative) at the end of treatment with continued response 4 or more years after discontinuation of therapy in HBeAg-positive patients. These results might be used to identify the best candidates for discontinuation of nuleos(t)ide analogue therapy.

Early steep decline of liver stiffness predicts histological reversal of fibrosis in chronic hepatitis B patients treated with entecavir.

It is unknown whether dynamic changes of liver stiffness measurement (LSM) can predict the reversibility of fibrosis. Therefore, we evaluated the utility of LSM changes in predicting histological changes of fibrosis in patients with chronic hepatitis B (CHB) on antiviral therapy. In a prospective cohort of CHB patients treated with entecavir, virological measurement and biochemical measurement along with LSM were measured at baseline and every 6 months. Liver biopsies were conducted at baseline and month 18 of treatment. Fibrosis regression was defined by the following two criteria: (a) Ishak score decrease ≥1 stage, (b) Ishak score decrease ≥1 stage or predominantly regressive by post-treatment PIR classification. The dynamic changes of LSM and its predictive value for histological reversibility were evaluated with piecewise linear mixed-effects model and ROC analysis. We found that at month 18 of antiviral therapy, liver fibrosis was reserved in 86 of 212 (40.6%) CHB patients by Ishak reversal criterion. Overall, a decline in LSM was associated with attenuation of Ishak score. The rate of LSM decline in the first 6 months was significantly faster in patients with fibrosis reversal (ΔLSM%Ishak  = -2.19%/month, P = 0.0025; ΔLSM%Ishak/PIR  = -2.56%/month, P = 0.0004). The predictive model based on baseline FIB-4 and Ishak score as well as baseline LSM, PLT, albumin and their changes during the first 6 months could predict histological reversal (AUROCIshak  = 0.74, 95% CI: 0.67-0.80; AUROCIshak/PIR  = 0.81, 95% CI: 0.74-0.87). We conclude that in CHB patients, changes in LSM during the first 6 months of entecavir therapy can predict histological reversibility of liver fibrosis at month 18 of antiviral therapy.

Comparison of non-invasive models for predicting liver damage in chronic hepatitis B patients.

INTRODUCTION: Inexpensive blood tests have been well established as alternatives to liver biopsies to evaluate liver fibrosis in CHB patients. Here, we aim to compare their diagnostic accuracy in assessing liver fibrosis and necroinflammation. PATIENTS AND METHODS: A retrospective study was performed to evaluate the predictive value of non-invasive models in chronic hepatitis B patients with liver fibrosis by the area under receiver operating characteristic curve (AUROC). The clinical data of 160 patients were collected from medical records. RESULTS: Of the 160 consecutive treatment-naïve CHB patients, 29 (16%) had significant fibrosis and 34 (21%) had severe necroinflammation. The AUROC of the gamma-glutamyl transpeptidase to platelet ratio (GPR) (0.761, 95% CI 0.671-0.850) for predicting significant fibrosis was significantly higher than that of the aspartate transaminase-to-platelet ratio index (APRI) (0.680, 95% CI 0.585-0.774, p=0.034), but comparable with the fibrosis index based on four factors (Fib-4) (0.746, 95% CI 0.656-0.836, p=0.703), while for predicting severe necroinflammation, the performance of the GPR (AUROC=0.869, 95% CI 0.800-0.937) was better than the APRI (AUROC=0.816, 95% CI 0.740-0.892, p=0.085) and Fib-4 (0.792, 95% CI 0.711-0.873, p=0.023). DISCUSSION: GPR is a satisfactory model to stage liver fibrosis and to grade necroinflammation activity, representing a convenient non-invasive alternative to liver biopsy in China.

Association of baseline vitamin D level with genetic determinants and virologic response in patients with chronic hepatitis B.

AIM: The role of vitamin D in individuals with chronic hepatitis B (CHB) is unclear. We aimed to explore the association of baseline vitamin D level with genetic determinants and week-104 treatment outcome in CHB patients. METHODS: Baseline serum 25-hydroxycholecalciferol (25(OH)D) levels and genetic polymorphism within GC, DHCR7, and CYP2R1 were determined in stored serum of 560 patients who were enrolled into a multicenter, randomized, controlled study and completed 104 weeks of telbivudine monotherapy or telbivudine-based optimized therapy. Virologic response was defined as hepatitis B virus DNA <300 copies/mL (52 IU/mL) at week 104. RESULTS: The mean 25(OH)D value was 29.64 ng/mL. The percentage of patients with vitamin D insufficiency (<30 ng/mL) and vitamin D deficiency (<20 ng/mL) were 55.0% and 20.9%, respectively. Gender, season, latitude, and GC rs2282679 polymorphism were independent factors of vitamin D status. Patients with sufficient vitamin D (≥30 ng/mL) achieved a higher virologic response rate than those with vitamin D insufficiency (81.7% vs. 67.2%, P < 0.001). The area under the curve of 25(OH)D to predict virologic response was 0.65 (P < 0.001; 95% confidence interval, 0.62-0.67). On multivariate analysis, 25(OH)D level was an independent predictor of virologic response, but not associated with hepatitis B envelope antigen (HBeAg) seroconversion or alanine aminotransferase (ALT) normalization. CONCLUSIONS: Vitamin D insufficiency was highly prevalent in treatment-naïve CHB patients in mainland China. Latitude and genetic determinants affect vitamin D status. Baseline vitamin D level can predict week-104 virologic response, but not HBeAg seroconversion or ALT normalization.

Analysis of the influence of installation tilt error on the tool setting accuracy by laser diffraction.

In the ultra-precision machining process, it is important to detect the tool-workpiece distance by the laser diffraction effect. However, there is no absolute ideal situation for the tool setting of laser diffraction. It is necessary to consider the influence of installation tilt error on the tool setting accuracy and its compensation. In this paper, referring to the ideal optical axis, the influences of the incident laser tilt, CCD tilt, and rectangular orifice tilt on the peak position of the diffraction fringes in the CCD phase are modeled and analyzed to determine the relative effects on the tool setting accuracy for tool-workpiece distance detection. The tilt angle of the incident laser is measured by extracting the CCD pixel position, where the central peak point is located. The CCD tilt angle is detected by extracting the CCD pixel positions, where the first-degree peak points are located. The inclination direction and the inclination angle of the rectangular orifice are detected by extracting the bending direction and the bending degree of the fringes in the horizontal direction, and the error compensation is performed according to the inclination angle. This study establishes a compensation method for installing tilt error, and the optimized installation process parameters can be acquired under certain experimental conditions according to the experimental data to ensure the results' accuracy.

MicroRNA-548j inhibits type I interferon production by targeting ZBTB11 in patients with chronic hepatitis B.

Type I IFNs play crucial roles in antiviral immune responses. By inducing cellular resistance to viral infection and apoptosis of virus-infected cells, they impair virus replication and eliminate the invading pathogens. However, in CHB patients, generation of type I IFN was significantly impaired and the underlying mechanisms have not been fully understood. MicroRNA-548 family has been implicated in regulating antiviral response upon various infections. Here we explored the potential role of miR-548j in modulating type I IFN production in CHB. We found that miR-548j expression increased in MoDCs from CHB patients than that from healthy volunteers and transient transfection of miR-548j mimic led to a marked decrease of IFN-α/ß production in MoDCs from healthy volunteers while blockade of miR-548j by anti-miR-548j significantly restored IFN-α/ß secretion in MoDCs from CHB patients. In addition, Zinc finger and BTB domain containing 11 (ZBTB11) was predicted and finally confirmed to be a target of miR-548j. Forced expression of ZBTB11 also restored IFN-α/ß secretion in MoDCs from CHB patients. These results indicate the involvement of miR-548j in aberrant production of type I IFN in CHB patients, and provide a potential target for developing anti-HBV therapies.

Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues.

OBJECTIVE: The investigation regarding the clinical significance of quantitative hepatitis B core antibody (anti-HBc) during chronic hepatitis B (CHB) treatment is limited. The aim of this study was to determine the performance of anti-HBc as a predictor for hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive CHB patients treated with peginterferon (Peg-IFN) or nucleos(t)ide analogues (NUCs), respectively. DESIGN: This was a retrospective cohort study consisting of 231 and 560 patients enrolled in two phase IV, multicentre, randomised, controlled trials treated with Peg-IFN or NUC-based therapy for up to 2 years, respectively. Quantitative anti-HBc evaluation was conducted for all the available samples in the two trials by using a newly developed double-sandwich anti-HBc immunoassay. RESULTS: At the end of trials, 99 (42.9%) and 137 (24.5%) patients achieved HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. We defined 4.4 log10 IU/mL, with a maximum sum of sensitivity and specificity, as the optimal cut-off value of baseline anti-HBc level to predict HBeAg seroconversion for both Peg-IFN and NUC. Patients with baseline anti-HBc ≥4.4 log10 IU/mL and baseline HBV DNA <9 log10 copies/mL had 65.8% (50/76) and 37.1% (52/140) rates of HBeAg seroconversion in the Peg-IFN and NUC cohorts, respectively. In pooled analysis, other than treatment strategy, the baseline anti-HBc level was the best independent predictor for HBeAg seroconversion (OR 2.178; 95% CI 1.577 to 3.009; p<0.001). CONCLUSIONS: Baseline anti-HBc titre is a useful predictor of Peg-IFN and NUC therapy efficacy in HBeAg-positive CHB patients, which could be used for optimising the antiviral therapy of CHB.

Response-guided peginterferon therapy in patients with HBeAg-positive chronic hepatitis B: A randomized controlled study.

BACKGROUND & AIMS: Response-guided therapy has been confirmed to be an effective strategy for the treatment of chronic hepatitis C in the pegylated interferon (PegIFN) era, but no randomized trial utilizing this strategy has been conducted in chronic hepatitis B. METHODS: In this open-label, multicenter, randomized trial, HBeAg positive patients were treated with PegIFN (180µg/week) for 24weeks. Early responders (HBsAg <1500IU/ml and HBV DNA <10(5)copies/ml at week 24) received PegIFN for a further 24weeks (arm A), while non-early responders were randomized to PegIFN for another 24weeks (arm B), another 72weeks (arm C) or PegIFN for another 72weeks plus adefovir for 36weeks (arm D). The primary endpoint was the change of quantitative HBsAg from baseline to the end of follow-up (EOF). RESULTS: For non-early responders, 96-week PegIFN monotherapy did not lead to a greater reduction of HBsAg from baseline to EOF, compared with 48-week PegIFN (-0.71 vs. -0.67log10IU/ml, P=0.407). The rate of HBeAg seroconversion with HBV DNA <2000IU/ml at EOF were similar for arms B, C and D (17.9%, 23.9% and 25.0% respectively). For patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24, 38.4% and 37.0% achieved HBeAg seroconversion with HBV DNA <2000IU/ml at EOF respectively. CONCLUSIONS: Patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24 would benefit from continued PegIFN treatment. Extending the duration of PegIFN with or without adding adefovir did not show superiority over 48weeks PegIFN monotherapy. LAY SUMMARY: Extending the duration of pegylated interferon (PegIFN) alfa-2a is not recommended in HBeAg positive patients as treatment extension beyond 48weeks did not show convincing benefit. Patients who achieved HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml after 24-week PegIFNα-2a showed satisfactory outcome after the withdrawal of finite PegIFNα-2a treatment. CLINICAL TRIAL NUMBER: NCT01086085.

The 104-week efficacy and safety of telbivudine-based optimization strategy in chronic hepatitis B patients: a randomized, controlled study.

UNLABELLED: An optimization strategy based on the Roadmap concept is supposed to improve the clinical outcomes of patients with suboptimal antiviral response. The aim of this study was to prove the concept with a multicenter, open-label, randomized, controlled study. In all, 606 hepatitis B e antigen (HBeAg)-positive, nucleos(t)ide-naive chronic hepatitis B patients were randomized to the Optimize or Mono group. Patients in the Optimize group were treated with telbivudine for 24 weeks, after which those suboptimal responders with HBV DNA ≥300 copies/mL at week 24 received telbivudine plus adefovir until week 104, while the early virological responders continued telbivudine monotherapy. Patients in the Mono group received telbivudine monotherapy. All patients with telbivudine monotherapy had adefovir added if viral breakthrough developed. Sixty-eight percent (204/300) of patients in the Optimize group had adefovir added due to suboptimal response. At week 104, compared to the Mono group, more patients in the Optimize group achieved HBV DNA <300 copies/ml (76.7% versus 61.2%, P < 0.001) with less genotypic resistance (2.7% versus 25.8%, P < 0.001). The rates of HBeAg seroconversion and alanine aminotransferase (ALT) normalization were comparable between the two groups (23.7% versus 22.1%; 80.7% versus 79.2%). For week 24 suboptimal responders, telbivudine plus adefovir showed an additive antiviral potency, with 71.1% achieving virological response at week 104 and only 0.5% developing genotypic resistance, compared with 46.6% who achieved virological response and 37.8% who developed genotypic resistance with telbivudine monotherapy. Both treatment regimens were well tolerated, with an observed persistent increase of the glomerular filtration rate. CONCLUSION: For suboptimal virological responders to telbivudine at week 24, adjusting the treatment strategy is recommended. Adding adefovir can benefit these patients with additive antiviral potency and low resistance without increased side effects.

Randomized, three-arm study to optimize lamivudine efficacy in hepatitis B e antigen-positive chronic hepatitis B patients.

BACKGROUND AND AIM: Data about the efficacy of de novo combination therapies, or optimization strategy by adding the other drug based on the virological response at week 24 of low genetic barrier antiviral agents is still limited. This study aimed to compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE). METHODS: Adult patients without antiviral therapy within 6 months before screening with hepatitis B virus (HBV)-DNA ≥ 10(5) copies/mL, alanine aminotransferase 1.3-10 times upper limit of normal and compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV-DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued MONO until week 104. For all the patients receiving MONO, ADV would be added if virological breakthrough was confirmed. RESULTS: At week 104, more patients in COMBO and OPTIMIZE groups achieved HBV-DNA < 300 copies/mL (53.3% [64/120] and 48.3% [58/120]), with less lamivudine resistance (0.8% and 6.7%) compared with MONO group (HBV-DNA < 300 copies/mL 34.8% [41/118], lamivudine resistance 58.5%). Patients under MONO with early virological response showed superior efficacy at week 104 (HBV-DNA < 300 copies/mL 73.1% [38/52], HBeAg seroconversion 40.4% [21/52]). All regimens were well tolerated. CONCLUSION: Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg-positive CHB patients. In lamivudine-treated patients with suboptimal virological response at week 24, promptly adding on ADV is necessary to prevent resistance development.

The function of MicroRNA in hepatitis B virus-related liver diseases: from Dim to Bright.

MicroRNAs represent a class of non-coding RNA molecules that negatively regulate gene expression either by repressing translation or by inducing degradation of messenger RNA. Studies have shown that, as regulators of gene expression, microRNAs are widely involved in various human diseases, including hepatitis B virus-related liver diseases. By modulating hepatitis B virus replication, regulating extracellular matrix formation, as well as silencing tumor suppressor genes, these small molecules are implicated in the development of chronic hepatitis, liver fibrosis/cirrhosis, and hepatocellular carcinoma caused by hepatitis B virus infection. In addition, current researches indicated a potential role of microRNA as diagnostic markers and therapeutic targets. In conclusion, microRNAs are promising tools in the diagnosis and treatment of hepatitis B virus -related liver diseases.

[A meta-analysis of diammonium glycyrrhizinate enteric-coated capsules versus diammonium glycyrrihizinate in patients with chronic viral hepatitis].

OBJECTIVE: To systematically evaluate the efficacy and safety of diammonium glycyrrhizinate enteric-coated capsules versus diammonium glycyrrihizinate in patients with chronic viral hepatitis. METHODS: The Chinese Biomedical Literature Database (CBM on CD-ROM) and the China Academic Journals Full-Text Database (Chinese National Knowledge Infrastructure, CNKI) were searched for randomized controlled trials (RCTs) that compared the efficacy and safety of diammonium glycyrrhizinate entetic-coated capsules versus diammonium glycyrrihizinate in treatment (less than 2 months) of chronic viral hepatitis published between 2005 and 2012. A meta-analysis was performed on the selected RCTs to determine the effects on alanine aminotransferase (ALT) normalization, serum levels of ALT, aspartate aminotransferase (AST), total bilirubin (TBil) and albumin, as well as rates of adverse reactions. RESULTS: Nine RCTs, involving 687 patients, were included in the meta-analysis. Compared to the patients treated with diammonium glycyrrihizinate, the patient treated with diammonium glycyrrhizinate enteric-coated capsules had a significantly better recovery rate of ALT (relative risk (RR) =4.15, 95% confidence interval (CI):1.55 to 11.15, P less than 0.01) and significantly more robust decreases in ALT (weighted mean difference (WMD) = -32.75, 95% CI:-46.67 to-18.83, P less than 0.01) and AST (WMD = -12.70, 95% CI:-21.13 to-4.27, P less than 0.01). In contrast, the patients treated with diammonium glycyrrihizinate showed more robust improvements in the TBil level (WMD = -0.74, 95% CI:3.98 to 2.49, P =0.653) and albumin (WMD =1.03, 95% CI:-1.03 to 3.09, P =0.326), but the differences did not reach the threshold for statistical significance (P less than 0.05). Only four adverse reactions were reported, all of which were related to the lipid complex nature of the diammonium glycyrrhizin enteric-coated capsules and were mild, including dry mouth, dizziness and mild gastrointestinal discomfort and reactions. CONCLUSION: Diammonium glycyrrhizinate enteric-coated capsules elicited superior anti-inflammatory and liver protection effects than diammonium glycyrrihizinate, and produced only mild side effects that are tolerable to the patients.

Cyclooxygenase-2 promotes hepatocellular apoptosis by interacting with TNF-α and IL-6 in the pathogenesis of nonalcoholic steatohepatitis in rats.

BACKGROUND AND PURPOSE: The underlying mechanisms of nonalcoholic steatohepatitis (NASH) are poorly understood, and little is known about hepatocellular apoptosis in NASH. Cyclooxygenase (COX)-2, the key enzyme in eicosanoid metabolism, is highly expressed in NASH. COX-2 can also regulate the release of mediators of inflammation, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6. The aim of our study was to evaluate the effects of COX-2 on hepatocellular apoptosis and the mechanism of the action in the pathogenesis of NASH in rats. METHODS: Sprague-Dawley rats were fed a high-fat diet (HFD) or standard diet for 8 and 12 weeks. COX-2 and cytokines expression in hepatic tissue and TNF-α and IL-6 levels in serum were measured at 8 and 12 weeks. Moreover, celecoxib (10 mg/kg body weight once a day) was administered to rats for 4 weeks to inhibit the expression of COX-2. Liver pathology was assessed by hematoxylin and eosin (H&E) stain and electron microscopy. Hepatocyte apoptosis was evaluated by TUNEL staining. RESULTS: COX-2 messenger RNA and protein were highly expressed in livers of HFD rats and were correlated with the severity of steatohepatitis (R = 0.82, p < 0.01). COX-2 upregulation was preceded by increases in TNF-α and IL-6. The level of hepatocellular apoptosis was significantly higher in HFD rats than in the control rats. The hepatocellular apoptosis was suppressed by the inhibition of COX-2. CONCLUSIONS: COX-2 may promote hepatocellular apoptosis by interacting with TNF-α and IL-6 in NASH in rats.

[Analysis of a randomized, double-blind, double-dummy, controlled, multicenter study confirmed the similar therapeutic efficacies of entecavir maleate and entecavir for treatment of HBeAg-positive chronic hepatitis B].

OBJECTIVE: To evaluate the efficacy and safety of entecavir maleate (ETV) versus ETV in Chinese patients with hepatitis B e antigen(HBeAg)-positive chronic hepatitis B(CHB). METHODS: The patient population of this previously published randomized, double-blind, double-dummy, controlled, multicenter study was expanded by patients in the 0.5 mg/day ETV maleate group (total n = 110) and patients in the 0.5 mg/day ETV group (total n = 108). At treatment weeks 12, 24 and 48, hepatitis B virus (HBV) DNA levels were measured by the Roche Cobas Ampliprep/Cobas Taqman PCR assay. Adverse events (AE) were recorded. RESULTS: As in the original analysis, the two treatment groups showed similar characteristics at baseline. In addition, the results for the all therapeutic effects showed identical trends to the results obtained in the original analysis, including the statistically similar effects of ETV and ETV maleate treatment-induced decreases in mean HBV DNA level at weeks 12, 24, and 48 (ETV: by 4.28, 5.00, and 5.53 log10 IU/ml vs. ETV maleate: by 4.46, 4.99, and 5.51 log10 IU/ml, respectively; all vs. baseline P more than 0.05), achievement of undetectable levels of serum HBV DNA ( less than 20 IU/ml) at week 48 (ETV: 38.18% vs. ETV maleate: 35.19%; P more than 0.05), HBeAg loss rates at week 48 (ETV: 10.91% vs. ETV maleate: 12.96%; P more than 0.05), HBeAg seroconversion rates at week 48 (ETV: 7.77% vs. ETV maleate: 10.38%; P more than 0.05), normalization of alanine aminotransferase at week 48 (ETV: 75.47% vs. ETV maleate: 82.86%; P more than 0.05), and overall incidence of AE (ETV: 18.02% vs. ETV maleate: 17.43%; P more than 0.05). CONCLUSION: Performing analysis of the therapeutic efficacies of entecavir maleate versus entecavir with a larger study population confirmed our original findings of similar efficacy and safety profiles for these two drugs in patients with HBeAg-positive CHB.

Robust finite-time adaptive control for high performance voice coil motor-actuated fast steering mirror.

Fast steering mirror (FSM) is an efficient and reliable mechanical device in aerial optical image systems for controlling the beam direction with high precision. With the advantages of compact size, high speed, simple structure, and long linear stroke, voice coil motors are ideal actuators for FSM systems. However, model uncertainty can lead to poor performance or even system divergence, especially in environments with temperature variations, electromagnetic environment changes, etc. This paper proposes a novel finite-time adaptive control (FAC) algorithm for an FSM system to obtain high performance, i.e., positioning accuracy, dynamic performance, and robustness. In addition, the finite-time convergence of the controller is analyzed. In the experiments, the controller is implemented in a DSP-based microprocessor. The step response results show that the proposed algorithm has a shorter setting time, smaller overshoot, and smaller steady-state error compared to classical sliding mode control (SMC). The sinusoidal signal tracking accuracy of FAC + SMC has been improved by 19.8%. In addition, as the model uncertainty increases 10%, the root mean square errors (RMSEs) are 1.73″ and 1.18″ for SMC and FAC + SMC, respectively. With 20% model uncertainty, the RMSEs increase to 2.56″ and 1.85″, respectively. Extensive experiments demonstrate the general effectiveness of the proposed algorithm.

Methyl Butyrate Alleviates Experimental Autoimmune Encephalomyelitis and Regulates the Balance of Effector T Cells and Regulatory T Cells.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelinating neuropathy. The etiology of MS is not yet clear and its treatment remains a major medical challenge. While we search for drugs that can effectively treat experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we also hope to further explore its possible pathogenesis. In the present study, we investigated whether methyl butyrate (MB) could alleviate EAE and its potential mechanisms. In EAE mice, we found that administration of MB was effective in alleviating their clinical signs and improving histopathological manifestations of the CNS. In the CNS and intestinal lamina propria, we observed fewer effector T cells, including Th1 and Th17, in the MB-treated group. MB also increased the proportion of regulatory T cells and the secretion of IL-10 in peripheral immune organs. In vitro, MB led to suppression of Th1 cells and promotion of regulatory T cells in their differentiation. Given that MB had no direct effect on Th17 cell differentiation in vitro, we hypothesized that MB suppressed Th17 cells indirectly by inhibiting the secretion of IL-6, which was later confirmed both in vitro and in vivo. In addition, we found that MB treatment upregulated Maf gene expression in mice, which explained its promotion of IL-10 secretion. The above findings suggest that MB may provide new ideas for the study of the mechanism of MS and have positive implications for new drug development.

Induction and Diverse Assessment Indicators of Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a typical autoimmune disease of the central nervous system (CNS) characterized by inflammatory infiltration, demyelination, and axonal damage. Currently, there are no measures to cure MS completely, but multiple disease-modifying therapies (DMT) are available to control and mitigate disease progression. There are significant similarities between the CNS pathological features of experimental autoimmune encephalomyelitis (EAE) and MS patients. EAE has been widely used as a representative model to determine MS drugs' efficacy and explore the development of new therapies for MS disease. Active induction of EAE in mice has a stable and reproducible effect and is particularly suitable for studying the effects of drugs or genes on autoimmune neuroinflammation. The method of immunizing C57BL/6J mice with myelin oligodendrocyte glycoprotein (MOG35-55) and the daily assessment of disease symptoms using a clinical scoring system is mainly shared. Given the complex etiology of MS with diverse clinical manifestations, the existing clinical scoring system can't satisfy the assessment of disease treatment. To avoid the shortcomings of a single intervention, new indicators to assess EAE based on clinical manifestations of anxiety-like moods and osteoporosis in MS patients are created to provide a more comprehensive assessment of MS treatment.