Daclatasvir plus Asunaprevir in Interferon (± Ribavirin)- Ineligible/Intolerant Asian Patients with Chronic HCV Genotype-1b Infection

( Lai Wei ),( Mingxiang Zhang ),( Min Xu ),( Wan-Long Chuang ),( Wei Lu ),( Wen Xie ),( Zhansheng Jia ),( Guozhong Gong ),( Yueqi Li ),( Si Hyun Bae ),( Yong-Feng Yang ),( Qing Xie ),( Shumei Lin ),( 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The efficacy/safety of daclatasvir (pan-genotypic NS5A inhibitor) plus asunaprevir (NS3 protease inhibitor) in interferon (± ribavirin)- ineligible/intolerant patients with chronic HCV genotype-1b infection from mainland China, Korea and Taiwan was investigated in a phase 3, open-label study. Methods: Patients received daclatasvir 60 mg (tablet) once daily plus asunaprevir 100 mg (soft capsule) twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment Week 24 (SVR24). Results: This study treated 159 patients from mainland China (80%), Korea (11%) and Taiwan (9%), including patients with cirrhosis (33%), IL28B non-CC genotypes (40%), and aged ≥70 years (4%). SVR24 was achieved by 91% of patients (100% concordance with SVR12) and was similarly high in all subgroups, e.g. cirrhotic patients (90%), and in patients from mainland China (91%), Korea (94%) and Taiwan (87%). SVR24 was higher in patients without baseline NS5A (L31M/Y93H) resistance-associated variants (RAVs) (n=137/139 [99%]), regardless of the presence (98%) or absence (99%) of cirrhosis, and lower in patients with baseline NS5A RAVs (n=8/19 [42%]). All serious adverse events (AEs) (n=5/159 [3.1%]), grade 4 laboratory abnormalities (n=3/159 [1.9%]) and deaths (n=1/159 [0.6%]) that occurred on-treatment were unrelated to the study drugs; two patients discontinued due to AEs. Treatment was generally well tolerated regardless of cirrhosis status. Conclusions: Daclatasvir plus asunaprevir achieved a high SVR24 rate of 91%, rising to 99% in patients without baseline NS5A RAVs, and was generally well tolerated in cirrhotic and non-cirrhotic interferon (± ribavirin)-ineligible/intolerant patients with HCV genotype-1b infection from mainland China, Korea and Taiwan.

TGF-β-activated Kinase-1: A Potential Prognostic Marker for Clear Cell Renal Cell Carcinoma

Wei, Can,Lai, Yong-Qing,Li, Xian-Xin,Ye, Jiong-Xian Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.1

Background: TGF-${\beta}$-activated kinase-1 (TAK1) has been found to be over-expressed in a variety of solid malignancies and related to tumor growth. The aim of this study was to evaluate the expression level of TAK1 in clear cell renal cell carcinoma (ccRCC) and assess its value as a novel prognostic marker. Methods: TAK1 mRNA was assessed in 51 paired ccRCC tissues and adjacent normal tissues (ADTs) by real-time PCR. Tissue TAK1 protein was also assessed in 91 ADTs and 177 samples of ccRCC immunohistochemically for evaluation of relationships with clinical characteristics. Results: RT-PCR showed that TAK1 RNA level was significantly higher in ccRCC tissues than in the paired ADTs and immunohistochemistry confirmed higher expression of TAK1 protein in ccRCC samples compared with ADTs. TAK1 protein expression in 177 ccRCC samples was significantly correlated with T stage, N classification, metastasis, recurrence and Fuhrman grade, but not age and gender. Patients with low TAK1 levels had a better survival outcome. TAK1 expression and N stage were independent prognosis factors for the overall survival of ccRCC patients. Conclusions: Overexpression of TAK1 predicts a poor prognosis in patients with ccRCC, so that TAK1 may serve as a novel prognostic marker.

Prevalence of Anti-deamidated Gliadin Peptide Antibodies in Asian Patients With Irritable Bowel Syndrome

( Wei Lu ),( Kok Ann Gwee ),( Kewin Tien Ho Siah ),( Jin Yong Kang ),( Ru Min Lee ),( Cecilia Cheng Lai Ngan ) 대한소화기기능성질환·운동학회 2014 Journal of Neurogastroenterology and Motility (JNM Vol.20 No.2

Background/AimsNon-celiac gluten sensitivity has been increasingly recognized as a predisposing factor for irritable bowel syndrome (IBS)-likesymptoms in Western populations where celiac disease (CD) is relatively common. In Asia where CD is rare, we wish to determinethe prevalence of gluten protein associated serology in IBS patients, which has not been formally studied, and its relationto histological and human leukocyte antigen (HLA) markers. MethodsWe reviewed a consecutive cohort of Asian patients with IBS, who had undergone serologic testing for IgA against deamidatedgliadin peptide antibodies (IgA DGP) and IgA anti-endomysium antibodies, and who also had duodenal biopsies during clinicalworkup. In addition, a subset of Chinese patients with positive serology was further tested for HLA-DQ2 and HLA-DQ8. ResultsOf 186 patients, 34 (18%) were positive for IgA DGP; bloating, abdominal pain, belching and diarrhea were the most com -monly reported symptoms but diarrhea as the most bothersome symptom was significantly more common in IgA DGP positivepatients. Mildly increased intra-epithelial lymphocytes on duodenal biopsy was also more common (29% vs. 9%, P = 0.001). Nine of 21 Chinese patients tested as IgA DGP positive undertook HLA-DQ2/DQ8 testing, with only 2 being positive forHLA-DQ8. All patients with positive IgA DGP reported symptom improvement with gluten withdrawal. ConclusionsWe have described a series of Asian, mainly Chinese, patients with IBS who were tested positive for IgA DGP, and improvedon a gluten exclusion diet. We believe this is the first report of non-celiac gluten sensitivity in Asia, a region where CD isuncommon

Determination of Ammonia-N in Environmental Water by Air-segmented FIA

Feng, Yong-Lai,Tian, Li-Ching,Wang, Wei,Wu, Qiao-Znen 한국분석과학회 1995 분석과학 Vol.8 No.4

A method for determination of ammonia-N in environmental water by air-segmented flow injection analysis using the colour reaction of phenol and sodium hypochlorite with ammonia was described in this paper. When the reaction temperature is $70^{\circ}C$ and the reaction residence time is 5 minutes, a sample frequency of $60-90h^{-1}$ can be achieved. The detection limit and relative deviation are $0.05mg.ml^{-1}$ and 4%, respectively. The recovery of this method is 96 - 110%, and the determination results of the method are greatly agreement with standard colorimetric method.

Slide Session : OS-GAS-04 ; Gastroenterology : Uric Acid Regulates Hepatic Steatosis and Insulin Sig-naling Through the NLRP3 Infl ammasome Dependent Mechanism

( Wan Xing Yong ),( Xu Cheng Fu ),( Lu Chao ),( Yu Wei Lai ),( Zhu Hua Tuo ),( Yu Chao Hui ),( Li You Ming ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: Serum uric acid is strongly associated with nonalcoholic fatty liver disease (NAFLD) and insulin resistance in patients. However, whether this association is causally or coincidentally with NAFLD and insulin resistance remains uncertain, neither the mechanisms behind this association are unclear so far. Methods: We first analyzed the impact of uric acid on development of hepatic steatosis in mice and two cell models (HepG2 and HL7702), and then explored the effect of uric acid on insulin signaling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt in HepG2 and HL7702 cells. Further, we studied the role of NLRP3 inflammasome in regulation of hepatic steatosis and insulin signaling. Results: Uric acid directly induced hepatocyte fat accumulation both in vivo and in vitro. Further, uric acid treatment decreased insulin-induced phospho-Akt (ser437) and enhanced the phospho-IRS1(ser307) in HepG2 and HL7702 cells. Then, we found significant increases of NLRP3 inflammasome-related molecules, both mRNA and protein levels, including NLPR3, caspase-1, IL-1ß, and IL-18, in HepG2 and HL7702 cells stimulated with uric acid. We also found that uric acid induced significant elevations of IL-1ß and IL-18 levels in culture supernatants of HepG2 and HL7702 cells. Consistent with in vitro results, mice fed 8 weeks of hyperuricemia-inducing diet resulted in significant up-regulation of hepatic mRNA and protein expressions of NLPR3, caspase-1, IL-1ß and IL-18, and elevation of serum IL-1ß and IL-18 levels. Further experiments indicated that silencing NLRP3 expression significantly alleviated uric acid-induced fat accumulation in vitro. Moreover, inhibition of NLRP3 expression ameliorated uric acid induced insulin signaling impairing, confirmed by increased insulin- induced phospho-Akt (ser437) and reduced the phospho-IRS1(ser307) in vitro. Conclusions: Our results suggest that uric acid contributes to hepatic steatosis and impairs insulin signaling through the NLRP3 inflammasome dependent mechanism.

In vitro evaluation of 9-(2-phosphonylmethoxyethyl)adenine ester analogues, a series of anti-HBV structures with improved plasma stability and liver release

Sha Liao,Shi-Yong Fan,Qin Liu,Chang-Kun L,Jia Chen,Jing-Lai Li,Zhi-Wei Zhang,Zhen-Qing Zhang,Bo-Hua Zhong,Jian-Wei Xie 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.11

Chronic hepatitis B virus (HBV) infection maylead to liver cirrhosis and hepatocellular carcinoma, butfew drugs are available for its treatment. Acyclic nucleosidephosphonates (ANPs) have remarkable antivirusactivities but are not easily absorbed from the gastrointestinaltract and accumulate in the kidneys, resulting innephrotoxicity. Therefore, there is a need to find effectiveliver site-specific prodrugs. The dipivaloyloxymethyl esterof 9-(2-phosphonylmethoxyethyl)adenine (PMEA)—adefovirdipivoxil (ADV)—is a first-line therapy drug forchronic hepatitis B with a low therapeutic index because ofrenal toxicity and low hepatic uptake. In this study, a seriesof PMEA derivatives were synthesized to enhance plasmastability and liver release. The metabolic stability of ADV(Chemical I) and its two analogues (Chemicals II and III)was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC–UV method and a hybridion trap and high-resolution time-of-flight mass spectrometry(LC-IT-TOF-MS) were used to evaluate the degradationrate of the analogues and to identify their intermediatemetabolites, respectively. Chemicals I and II were hydrolyzedby cleavage of the C–O bond to give monoesters. Sufficient enzymatic activation in the liver homogenatethrough a relatively simple metabolic pathway, in additionto a favorable stability profile in rat plasma, made ChemicalII an optimal candidate. Next, six analogues based onthe structure of Chemical II were synthesized and evaluatedin plasma and liver homogenate. Compared toChemical II, these compounds generated less active PMEAlevels in rat liver homogenate. Therefore, chemical modificationof Chemical II may lead to new promising PMEAderivatives with enhanced plasma stability and liveractivation.

Two New Natural Products from the Fruits of Alpinia oxyphylla with Inhibitory Effects on Nitric Oxide Production in Lipopolysaccharide- Activated RAW264.7 Macrophage Cells

Zhang Jun Qing,Duan Jin Ao,Wang Yong,Li Yong Hui,Lai Wei Yong,Li Hai Long,Pei Li Xia 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.12

Chemical investigation of the fruits of Alpinia oxyphylla led to an isolation of the two new natural products, 9-hydroxy epinootkatol (1) and (S)-2-pentanol-2-O-β-D-glucopyranoside (2), in addition to the nine known compounds, pinocembrin (3), tectochrysin (4), izalpinin (5), nookatone (6), yakuchinone A (7), protocatechuic acid (8), β-sitosterol (9), daucosterol (10) and β-sitosterol palmitate (11). Their structures were elucidated on the basis of physicochemical constants and NMR spectral data analysis. The effects of the isolated components on nitric oxide production in LPS-induced RAW 264.7 macrophages were examined. The two new natural compounds showed inhibitory activities with IC50 values of 21.8 and 32.8 μg/mL, respectively.

Crude Dietary Polysaccharide Fraction Isolated from Jackfruit Enhances Immune System Activity in Mice

Yin-Feng Tan,Hai-Long Li,Wei-Yong Lai,Jun-Qing Zhang 한국식품영양과학회 2013 Journal of medicinal food Vol.16 No.7

Crude polysaccharides (PSs) were isolated from the fruit pulp of jackfruit, and their chemical composition determined and evaluated for an immune regulatory activity in mice. The PSs were isolated from water extracts of jackfruit pulp ( JFP) using the ethanol precipitation method. The resulting precipitates were further purified by dialysis and protein depletion by the Sevage method. The phenol–sulfuric method was used to determine the content of the PSs. The composition of PSs was determined by the Sephadex-G200 column chromatography and high-performance liquid chromatography methods. The thymus index and macrophage phagocytic function methods in mice were used to evaluate the immune regulatory activity of JFP-PSs. The JFP-PSs content in jackfruit was about 21% (w/w) and the yield of crude PSs was 3.91%. The single molecular mass weight PS was the main constituent of JFP-PSs. The major monosaccharide residues were rhamnose, glucose, galactose, and arabinose. The JFP-PSs enhanced the thymus weight index and the phagocytic rate after 30 days of subchronic p.o. administration to mice at 4.5 mg/kg. The JFP contains single molecular PS and JFP-PS has immunestimulating activities in mice. These data suggest that at least some of the traditional uses of JFP can be ascribed to its immunomodulatory effects.

Low-dose diethylhexyl phthalate exposure does not impair the expressive patterns of epigenetics-related genes and DNA methylation of breast cancer-related genes in mouse mammary glands

Shun-Feng Cheng,Ling Li,Bo Li,Jing-Cai Liu,Fang-Nong Lai,Yong Zhao,Xi-Feng Zhang,Wei Shen,Lan Li 대한독성 유전단백체 학회 2018 Molecular & cellular toxicology Vol.14 No.2

Backgrounds: Di-(2-ethylhexyl) phthalate (DEHP), as an endocrine-disrupting chemical (EDC), is widely used in plasticizer and other productions. Ubiquitous human exposure to DEHP has been proposed to be a potential risk to public health. Developmental exposure to DEHP could alter epigenetic programming and result in adult-onset disease. Methods: In this study, we investigated whether DEHP exposure to pregnant mice affected epigenetic changes as a result of increase in breast cancer incidence. Results: Our results showed that the expression of total 143 epigenetics-related genes in mammary gland cells, have no significantly altered after short time and low-dose treated with DEHP from 0.5 days post-coitum (dpc) to 3.5 dpc of pregnant mice. DNA methylation status of some neoplastic development genes, such as EGFr, Esr1, Pgr, Fos and Rassf5 also had no obvious change. Conclusion: These finding showed no impact of DEHP on the expressive patterns of epigenetics-related genes and DNA methylation of breast cancer-related genes in pregnant mouse mammary gland cells.

Probiotic supplements alleviate gestational diabetes mellitus by restoring the diversity of gut microbiota: a study based on 16S rRNA sequencing

Zheng Qing-Xiang,Jiang Xiu-Min,Wang Hai-Wei,Ge Li,Lai Yu-Ting,Jiang Xin-Yong,Chen Fan,Huang Ping-Ping 한국미생물학회 2021 The journal of microbiology Vol.59 No.9

Probiotics effectively prevent and improve metabolic diseases such as diabetes by regulating the intestinal microenvironment and gut microbiota. However, the effects of probiotics in gestational diabetes mellitus are not clear. Here, we showed that probiotic supplements significantly improved fasting blood glucose in a gestational diabetes mellitus rat model. To further understand the mechanisms of probiotics in gestational diabetes mellitus, the gut microbiota were analyzed via 16S rRNA sequencing. We found that compared with the normal pregnant group, the gestational diabetes mellitus rats had decreased diversity of gut microbiota. Moreover, probiotic supplementation restored the diversity of the gut microbiota in gestational diabetes mellitus rats, and the gut microbiota structure tended to be similar to that of normal pregnant rats. In particular, compared with gestational diabetes mellitus rats, the abundance of Firmicutes and Actinobacteria was higher after probiotic supplementation. Furthermore, activating carbohydrate metabolism and membrane transport pathways may be involved in the potential mechanisms by which probiotic supplements alleviate gestational diabetes mellitus. Overall, our results suggested that probiotic supplementation might be a novel approach to restore the gut microbiota of gestational diabetes mellitus rats and provided an experimental evidence for the use of probiotic supplements to treat gestational diabetes melitus.