Bioactive hyaluronic acid fragments inhibit lipopolysaccharide-induced inflammatory responses via the Toll-like receptor 4 signaling pathway / 医学前沿

The high- and the low-molecular weight hyaluronic acids (HMW-HA and LMW-HA, respectively) showed different biological activities in inflammation. However, the role of LMW-HA in inflammatory response is controversial. In this study, we aimed to investigate the effect of bioactive hyaluronan (B-HA) on lipopolysaccharide (LPS)-induced inflammatory responses in human macrophages and mice. B-HA was produced from HA treated with glycosylated recombinant human hyaluronidase PH20. Human THP-1 cells were induced to differentiate into macrophages. THP-1-derived macrophages were treated with B-HA, LPS, or B-HA + LPS. The mRNA expression and the production of inflammatory cytokines were determined using quantitative real-time PCR and enzyme-linked immunosorbent assay. The phosphorylation levels of proteins in the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and IRF-3 signaling pathways were measured using Western blot. The in vivo efficacy of B-HA was assessed in a mouse model of LPS-induced inflammation. Results showed that B-HA inhibited the expression of TNF-α, IL-6, IL-1, and IFN-β, and enhanced the expression of the antiinflammatory cytokine IL-10 in LPS-induced inflammatory responses in THP-1-derived macrophages and in vivo. B-HA significantly suppressed the phosphorylation of the TLR4 signaling pathway proteins p65, IKKα/β, IκBα, JNK1/2, ERK1/2, p38, and IRF-3. In conclusion, our results demonstrated that the B-HA attenuated the LPS-stimulated inflammatory response by inhibiting the activation of the TLR4 signaling pathway. B-HA could be a potential anti-inflammatory drug in the treatment of inflammatory disease.

Biological characteristics of high-mobility group box-1 and its role in the development, progression, and treatment of hepatitis B virus-related liver diseases / 临床肝胆病杂志

High-mobility group box-1 (HMGB1) is a member of the high-mobility group proteins and is present in eukaryotic cells. HMGB1 is not only a nuclear protein but also a pro-inflammatory factor, and the increase in HMGB1 level in the body indicates cell destruction and inflammatory response. Hepatitis B virus (HBV) infection is a major cause of chronic hepatitis B, liver cirrhosis, and hepatocellular carcinoma in the world. In recent years, the role of HMGB1 in HBV-related liver diseases has attracted more and more attention, especially the important role of HMGB1 in the progression of liver inflammation and liver cancer. This article reviews the recent research advances in the role of HMGB1 in the development, progression, and treatment of HBV-related liver diseases.

Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir combined with ribavirin in Asian adult patients with chronic HCV genotype 1b infection and compensated cirrhosis / 中华肝脏病杂志

Objective@#To evaluate the efficacy and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily and dasabuvir (DSV) 250 mg twice daily combined with ribavirin in adult patients of Mainland China with chronic HCV genotype 1b infection and compensated cirrhosis. @*Methods@#An open-label, multicenter, phase 3 clinical trial study was conducted in mainland China, Taiwan, and South Korea. Adult patients with compensated cirrhosis (Metavir score =F4) who were newly diagnosed and treated for hepatitis C virus genotype 1b infection with ombitasvir/paritaprevir/ritonavir and dasabuvir combined with ribavirin for 12 weeks were included. Assessed SVR rate of patients obtained at 12 and 24 weeks after drug withdrawal. Efficacy and safety were evaluated in patients who received at least one time study drugs. @*Results@#A total of 63 patients from mainland China were enrolled, 62 of whom (98.4%) had a baseline Child-Pugh score of 5 points. The overall rate of SVR12 and SVR24 in patients was 100% (95% CI: 94.3% to 100.0%). Most of the adverse events that occurred were mild. The incidence of common (≥10%) adverse events and laboratory abnormalities included elevated total bilirubin (36.5%), weakness (19.0%), elevated unconjugated bilirubin (19.0%) and conjugated bilirubin (17.5%), and anemia (14.3%). Three cases (4.8%) of patients experienced Grade ≥ 3 adverse events that were considered by the investigators to be unrelated to the study drug. None patients had adverse events leading to premature drug withdrawal. @*Conclusion@#Mainland Chinese patients with chronic HCV genotype 1b infection and compensated cirrhosis who were treated with OBV/PTV/r plus DSV combined with RBV for 12 weeks achieved 100 % SVR at 12 and 24 weeks after drug withdrawal. Tolerability and safety were good, and majority of adverse events were mild.

Clinical effect and safety of 144-week treatment with entecavir capsules in treatment-naïve HBeAg-positive patients with chronic hepatitis B / 中华肝脏病杂志

Objective@#To investigate the clinical effect and safety of entecavir capsules in the treatment of treatment-naïve HBeAg-positive patients with chronic hepatitis B (CHB).@*Methods@#A total of 158 HBeAg-positive CHB patients were given oral entecavir capsules at a dose of 0.5 mg/time once a day for 144 weeks. Clinical outcome and safety were evaluated at baseline and at 24, 48, 72, 96, 120, and 144 weeks of treatment respectively. The Fisher’s exact test was used for the analysis of categorical data.@*Results@#After 144 weeks of treatment, 90.91% of all patients achieved virologic response (< 69 IU/ml), the normalization rate of alanine aminotransferase was 88.18%, the clearance rate of HBeAg was 33.33%, and the seroconversion rate of HBeAg was 24.07%. Of all patients, 2 dropped out due to adverse events and 5 experienced serious adverse reactions.@*Conclusion@#Entecavir capsules can inhibit viral replication and have good safety in treatment-naïve HBeAg-positive CHB patients.

Clinical effect and safety of pegylated interferon-α-2b injection (Y shape, 40 kD) in treatment of HBeAg-positive chronic hepatitis B patients / 中华肝脏病杂志

Objective@#To investigate the clinical effect and safety of long-acting pegylated interferon-α-2b (Peg-IFN-α-2b) (Y shape, 40 kD) injection (180 μg/week) in the treatment of HBeAg-positive chronic hepatitis B (CHB) patients, with standard-dose Peg-IFN-α-2a as positive control.@*Methods@#This study was a multicenter, randomized, open-label, and positive-controlled phase III clinical trial. Eligible HBeAg-positive CHB patients were screened out and randomized to Peg-IFN-α-2b (Y shape, 40 kD) trial group and Peg-IFN-α-2a control group at a ratio of 2:1. The course of treatment was 48 weeks and the patients were followed up for 24 weeks after drug withdrawal. Plasma samples were collected at screening, baseline, and 12, 24, 36, 48, 60, and 72 weeks for centralized detection. COBAS® Ampliprep/COBAS® TaqMan® HBV Test was used to measure HBV DNA level by quantitative real-time PCR. Electrochemiluminescence immunoassay with Elecsys kit was used to measure HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe). Adverse events were recorded in detail. The primary outcome measure was HBeAg seroconversion rate after the 24-week follow-up, and non-inferiority was also tested. The difference in HBeAg seroconversion rate after treatment between the trial group and the control group and two-sided confidence interval (CI) were calculated, and non-inferiority was demonstrated if the lower limit of 95% CI was > -10%. The t-test, chi-square test, or rank sum test was used according to the types and features of data.@*Results@#A total of 855 HBeAg-positive CHB patients were enrolled and 820 of them received treatment (538 in the trial group and 282 in the control group). The data of the full analysis set showed that HBeAg seroconversion rate at week 72 was 27.32% in the trial group and 22.70% in the control group with a rate difference of 4.63% (95% CI -1.54% to 10.80%, P = 0.1493). The data of the per-protocol set showed that HBeAg seroconversion rate at week 72 was 30.75% in the trial group and 27.14% in the control group with a rate difference of 3.61% (95% CI -3.87% to 11.09%, P = 0.3436). 95% CI met the non-inferiority criteria, and the trial group was non-inferior to the control group. The two groups had similar incidence rates of adverse events, serious adverse events, and common adverse events.@*Conclusion@#In Peg-IFN-α regimen for HBeAg-positive CHB patients, the new drug Peg-IFN-α-2b (Y shape, 40 kD) has comparable effect and safety to the control drug Peg-IFN-α-2a.

Efficacy and safety of pegylated interferon α-2b injection (Y shape, 40 kD) in treatment of patients with genotype 1/6 chronic hepatitis C / 中华肝脏病杂志

Objective@#To investigate the efficacy and safety of the new investigational drug pegylated interferon α-2b (Peg-IFN-α-2b) (Y shape, 40 kD) injection (180 µg/week) combined with ribavirin in the treatment of patients with genotype 1/6 chronic hepatitis C (CHC), with standard-dose Peg-IFN-α-2a combined with ribavirin as a positive control.@*Methods@#A multicenter, randomized, open-label, and positive-controlled phase III clinical trial was performed. Eligible patients with genotype 1/6 CHC were screened out and randomly divided into Peg-IFN-α-2b(Y shape, 40kD) group and Peg-IFN-α-2a group at a ratio of 2:1. The patients in both groups were given oral ribavirin for 48 weeks in addition and then followed up for 24 weeks after drug withdrawal. Abbott Real Time HCV Genotype II was used to determine HCV genotype, and Cobas TaqMan quantitative real-time PCR was used to measure HCV RNA level at 0, 4, 12, 24, 48, and 72 weeks. Adverse events were recorded in detail. The primary efficacy endpoint was sustained virological response (SVR), and a non-inferiority test was also performed.@*Results@#A total of 561 patients with genotype 1/6 CHC were enrolled, among whom 529 received treatment; 90.9% of these patients had genotype 1 CHC. The data of the full analysis set showed that SVR rate was 69.80% (95% CI 65.00%-74.60%) in the trial group and 74.16% (95% CI 67.73%-80.59%) in the control group (P = 0.297 0). The data of the per protocol set (PPS) showed that SVR rate was 80.63% (95% CI 76.04%-85.23%) in the trial group and 81.33% (95% CI 75.10%-87.57%) in the control group (P = 0.849 8), and the 95% CI of rate difference conformed to the non-inferiority standard. The analysis of the PPS population showed that of all subjects, 47.9% achieved rapid virologic response, with a positive predictive value of 93.8%. The incidence rate of adverse events was 96.30% in the trial group and 94.94% in the control group, and the incidence rate of serious adverse events was 5.13% in the trail group and 5.06% in the control group.@*Conclusion@#In the regimen of Peg-IFN-α combined with ribavirin for the treatment of genotype 1/6 CHC, the new investigational drug Peg-IFN-α-2b(Y shape, 40 kD) has comparable clinical effect and safety to the control drug Peg-IFN-α-2a.

Progress of toll-like receptor 4 signaling pathway / 医学研究生学报

[Abstract ] Toll like receptor 4 (TLR4) is a key member of the Toll like receptor family , and is a major receptor for lipopo-lysaccharide ( LPS) .After stimulating with LPS , TLR4 activation could cause the release of a series of inflammatory factors , and acti-vate the immune response of the organism .In recent years , LPS/TLR4 signal transduction has been widely studied , and it has become the most important research hotspot in the inflammatory reaction and its control method .In this paper , we review the recent progress of molecules involved in TLR 4 signaling pathway and their regulatory mechanisms .

RUCAM scale-based diagnosis, clinical features and prognosis of 140 cases of drug-induced liver injury / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To analyze the etiology, clinical features and prognosis of liver injuries caused by different drugs.</p><p><b>METHODS</b>The types of suspected drugs related to liver injury, clinical manifestations, liver biochemical parameters, clinical outcomes and other associated data were retrospectively assessed for 140 patients with drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method (RUCAM) was used to assess the causality between drugs and liver injury.</p><p><b>RESULTS</b>The most prevalent agents inducing DILI were Chinese traditional drugs (62.1%), followed by antipyretic analgesic drugs (10%) and antibiotics (5%). The ratio of male to female patients in the study cohort was 1:1.69, with 71 of the total patients (50.7%) being between the ages of 40 and 60 years-old. The RUCAM scale was not less than 3 points for any of the patients.In general, the clinical manifestations and biochemical results were not specific. The percentages of hepatocellular injury type, cholestatic injury type and mixed injury type were 51.4%, 30.7% and 17.9% respectively. The median age of patients with cholestatic liver injury was 55.6 years, which was older than that of patients with hepatocellular injury (47.1 years) or mixed injury (49.9 years).</p><p><b>CONCLUSION</b>Although antipyretic analgesics and antibiotics are considered as common drugs that can induce DILI, Chinese traditional drugs have emerged as another important group of liver injurious agents. Cholestatic DILI was found to occur more often in elderly patients than in younger patients.</p>

Investigation of the epidemiological and clinical characteristics of an outbreak of tsutsugamushi disease in Anhui Province / 中华传染病杂志

Objective To investigate the epidemiological and clinical characteristics of an outbreak of tsutsugamushi disease in Chuzhou region, Anhui Province, and to clarify the new changes of epidemic focus of tsutsugamushi disease in China. Methods Field epidemiological investigation and analysis of clinical features were done. The detections of specific antibodies against Rickettsia tsutsugamushi were conducted to diagnose tsutsugamushi disease using colloidal gold immunochromatography assay combined with Well-Felix reaction. The geomorphic and climatic characteristics of the new epidemic focus were investigated. Results The outbreak occurred from October to November, 2007. The epidemic focus located on mountainous brushland regions, and the air temperature fluctuated from 20-4 ℃. Nineteen cases of tsutsugamushi disease in the new-found epidemic focus were finally diagnosed, 9 cases out of them were hospitalized, another 9 had recovered when diagnosed by serological tests; the remaining one had classical manifestations of tsutsugamushi disease but did not receive the serological test for certain cause. The main clinical symptoms were chilly in 14 cases, fever in 19 cases, headache in 15 cases; among the 9 hospitalized patients, the symptoms were lymphadenectasis in 8 inpatients, skin rash in 7 inpatients, splenomegaly in 4 inpatients and skin eschar and ulcer in 7 inpatients and Weil-Felix reaction by OXκantigen positive in 4 cases; the specific antibodies against Rickettsia tsutsugarnushi of 18 tested cases were all positive. No severe complications occurred in all patients. Before the first case was identified, all other cases were not diagnosed in time and did not receive correct antibiotic treatment. Nine hospitalized patients recovered rapidly with the treatment of doxycycline. Conclusions The outbreak of tsutsugamushi disease in Anhui Province in 2007 is type of emerged in autumn and transitional epidemic focus. There is epidemic focus of tsutsugamushi disease in northern region of Anhui Province. Doxycycline is rapid and effective for the treatment of tsutsugamushi disease.

Association of polymorphisms in transcription factor 7-like 2(TCF7L2) gene with type 2 diabetes in Chinese Han population / 中华内分泌代谢杂志

Objective To study the association of transcription factor 7-like 2(TCF7L2)polymorphisms with tvpe 2 diabetes mellitus in Chinese Han population. Methods Two polymorphisms (rs7903146 and rs12255372)of TCF7L2 gene were genotyped in 446 patients with type 2 diabetes mellitus(T2DM group)and 303 normal subiects (NC group) by PCR-restriction fragment length polymorphism(PCR-RFLP).Waist circumference.body mass index,plasma glucose,serum insulin,lipid profiles,high-sensitivity C-reactive protein and non-esterified fatty acid were measured.Homeostasis model assessment of insulin resistance(HOMA-IR)and β-cell function(HOMA-β)were calculated.Results (1) In T2DM group,T allele frequency and CT,TY geno tvpe frequeneies of rs7903146 were significantly higher than those in NC group(0.093,0.150,0.018 vs 0.043, 0.079,0.003,respectively,a11 P<O.O 1).Logistic regression analysis showed that the CT/TT genotype was a risk factor of tvpe 2 diabetes(OR=2.25,95%CI 1.39-3.62,P=0.001)and was associated with the decrease of insulin secretion. (2) No significant association was observed in vs12255372 alleles and genotypes with type 2 diabetes mellitus.Conclusion These results indicate that TCF7L2 might be one of the candidate genes for confe ring susceptibi lity to type 2 diabetes mellitus in the Chinese Han population.

Variation and influential factors of high sensitive C-reactive protein level in type 2 diabetic family members / 中华内分泌代谢杂志

Objective To explore the variation and influential factors of high sensitive C-reactive protein (hs-CRP) level in type 2 diabetic family members. Methods A total of 427 type 2 diabetic patients, 377 non-diabetic first-degree relatives of type 2 diabetics and 135 normal control subjects without diabetic family history were recruited. Serum hs-CRP, clinical and biochemical parameters were measured. The relations among indicators were analyzed. Results Compared with normal control subjects, serum hs-CRP levels in type 2 diabetics and first-degree relatives were significantly increased (both P＜0.05), and the increment was even marked in type 2 diabetics than that in first-degree relatives (P＜0.01). The serum hs-CRP levels in type 2 diabetics and first-degree relatives were positively associated with body mass index, waist-hip ratio, abdominal circumference, postgrandial 2 h plasma glucose, fasting and postgrandial 2 h serum insulin, HOMA-IR, triglyceride, creatinine and negatively correlated with high density lipoprotein-cholesterol. In first-degree relatives, serum hs-CRP level was positively associated with systolic blood pressure and HOMA-β. Conclusion As in type 2 diabetic patients, there exists inflammatory reaction in the non-diabetic first-degree relatives of type 2 diabetics, which may play an important role in the pathogenesis of type 2 diabetes mellitus.

Non-esterified fatty acid level and metabolic characteristics in nondiabetic first-degree relatives of type 2 diabetics / 中华内分泌代谢杂志

Objective To investigate the change of serum non-esterified fatty acid (NEFA) level in nondiabetic first-degree relatives of type 2 diabetics, and to explore the related factors in the change.MethodsSerum lipid profile, plasma glucose and insulin levels were measured in 186 type 2 diabetic patients, 565 nondiabetic first-degree relatives of type 2 diabetics and 149 normal controls. Results (1) The fasting NEFA level in first-degree relatives was significantly lower than that of type 2 diabetic patients [(0.53±0.28 vs 0.63±0.31) mmol/L,P＜0.01]and HOMA-IR was significantly higher than that of normal controls (0.98±0.51 vs 0.89±0.47,P＜0.01). (2) The fasting NEFA level in the first-degree relatives with higher body mass index (BMI), plasma glucose or area under curve of glucose concentration (AUCglu) was higher than that in those with lower BMI, plasma glucose , blood pressure or AUCglu (all P＜0.05). (3) NEFA showed significantly positive correlations with BMI, systolic blood pressure, diastolic blood pressure (DBP), AUCglu in the first-degree relatives by correlative analysis (r=0.12, r=0.148, r=0.21 and r=0.281 respectively, all P＜0.05). Stepwise linear regression analysis showed that DBP, AUCglu and age were the independent risk factors of NEFA (all P＜0.01). Conclusion Insulin resistance exists in nondiabetic first-degree relatives of type 2 diabetics, which seems to be related to elevated NEFA levels.

Influencing factor of serum cortisoi levels in the type 2 diabetic pedigrees / 中华内分泌代谢杂志

Serum cortisol levels during oral glucose tolerance test (OGTY) were measured in subjects of type 2 diabetic pedigrees. The results showed that cortisol levels during OGTF were higher in type 2 diabetic patients than those in non-diabetic first-degree relatives and normal controls. Fasting cortisol level was positively correlated with fasting plasma glucose level in type 2 diabetic pedigree members. These results suggest that the dysregulation of hypothalamic-pituitary-adrenal axis may coexist in type 2 diabetic patients.

Association of FcRL3 gene polymorphism with autoimmune thyroid diseases / 中华内分泌代谢杂志

The polymorphism in the exon 4 of FcRL3 gene was evaluated by PCR-FPLR in 506 patients with Graves' disease (GD), 80 with Hashimoto thyroiditis (HT) and 261 normal subjects in Chongqing. The data suggest that 82G allele in exon 4 of FcRL3 gene may be susceptible to GD in male patients of Chongqing Hart nationality.

Correlation between AMPK?_2 subunit gene polymorphism and type 2 diabetes / 重庆医科大学学报

0.05).Conclusion:The polymorphism of rs857155 in PRKAA2 is not associated with T2DM in Han population from Chongqing.

Correlation between AMPK?2 subunit gene polymorphism and type 2 diabetes and related metabolism in Chongqing area / 解放军医学杂志

T) in PRKAA2 is not associated with T2DM in Han population in Chongqing area.