Background/Aims: Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics, and antiviral activity of three doses of EDP-514 in treatment-naive viremic patients with HBeAgpositive or -negative chronic HBV infection. Methods: Patients with HBsAg detectable at screening and at least 6 months previously were eligible. HBeAg-positive and -negative patients had a serum/plasma HBV DNA level ≥20,000 and ≥2,000 IU/mL, respectively. Twenty-five patients were randomized to EDP-514 200 (n=6), 400 (n=6) or 800 mg (n=7) or placebo (n=6) once daily for 28 days. Results: A dose-related increase in EDP-514 exposure (AUClast and Cmax) was observed across doses. At Day 28, mean reductions in HBV DNA were –2.9, –3.3, –3.5 and –0.2 log10 IU/mL with EDP-514 200 mg, 400 mg, 800 mg, and placebo groups, respectively. The corresponding mean change from baseline for HBV RNA levels was –2.9, –2.4, –2.0, and –0.02 log10 U/mL. No virologic failures were observed. No clinically meaningful changes from baseline were observed for HBsAg, HBeAg or HBcrAg. Nine patients reported treatment emergent adverse events of mild or moderate severity with no discontinuations, serious AEs or deaths. Conclusions In treatment-naïve viremic patients, oral EDP-514 was generally safe and well-tolerated, displayed PK profile supportive of once-daily dosing, and markedly reduced HBV DNA and HBV RNA.

Background/Aims: Diagnosis of isolated laryngopharyngeal reflux symptoms (ILPRS), ie, without concomitant typical reflux symptoms (CTRS), remains difficult. Mean nocturnal baseline impedance (MNBI) reflects impaired mucosal integrity. We determined whether esophageal MNBI could predict pathological esophagopharyngeal reflux (pH+) in patients with ILPRS. Methods: In this cross-sectional study conducted in Taiwan, non-erosive or low-grade esophagitis patients with predominant laryngopharyngeal reflux symptoms underwent combined hypopharyngeal multichannel intraluminal impedance-pH monitoring when off acid suppressants. Participants were divided into the ILPRS (n = 94) and CTRS (n = 63) groups. Asymptomatic subjects without esophagitis (n = 25) served as healthy controls. The MNBI values at 3 cm and 5 cm above the lower esophageal sphincter (LES) and the proximal esophagus were measured. Results: Distal but not proximal esophageal median MNBI values were significantly lower in patients with pH+ than in those with pH– (ILPRS in pH+ vs pH–: 1607 Ω vs 2709 Ω and 1885 Ω vs 2563 Ω at 3 cm and 5 cm above LES, respectively; CTRS in pH+ vs pH–: 1476 vs 2307 Ω and 1500 vs 2301 Ω at 3 cm and 5 cm above LES, respectively, P < 0.05 for all). No significant differences of any MNBI exist between any pH– subgroups and healthy controls. The areas under the receiver operating characteristic curve in the ILPRS group were 0.75 and 0.80, compared to the pH– subgroup and healthy controls (P < 0.001 for both), respectively. Interobserver reproducibility was good (Spearman correlation 0.93, P < 0.0001). Conclusion Distal esophageal MNBI predicts pathological reflux in patients with ILPRS.

Sarglanoids A-F, six new sesquiterpenoids belonging to eudesmane (1-5) and eremophilane (6) types, were isolated from the leaves of Sarcandra glabra, a famous traditional Chinese medicine (TCM). Their structures including absolute configurations were elucidated through extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. Compounds 1-2 were rare N-containing eudesmane-type sesquiterpenoids. Compound 3 exhibited inhibitory activity against nitric oxide (NO) production in lipopolysaccharides (LPS)-induced RAW 264.7 cells with IC₅₀ values at 20.00 ± 1.30 μmol·L^-1. These findings provide scientific evidence for sesquiterpenoids as the material foundation of S. glabra.
Molecular Structure ; Plant Leaves ; Polycyclic Sesquiterpenes ; Seeds ; Sesquiterpenes/pharmacology*

OBJECTIVE: To construct the RNA interference(RNAi) lentiviral vector of suppressor of variegation 3-9 homolog 1(Suv39 h1) and verify its interfering efficiency by transfecting it to the bone marrow-derived mesenchymal stem cells(BMSCs). METHODS: The oligonucleotides of RNA plasmid were designed and synthesized according to the gene sequence of Suv39 h1 and short hairpin RNA design principles. Three kinds of LV-Suv39 h1-RNAi recombinant plasmids with different lentivirus knockdown targets(KD1, KD2 and KD3) were constructed. After identification by restriction analysis and sequencing, the packaged lentivirus vectors with the three kinds of Suv39 h1 gene were transfected into rat BMSCs at logarithmic growth stage, and were named KD1, KD2 and KD3 transfection groups. The control group was transfected with the negative control virus. After 72 hours transfection, the transfection efficiency was evaluated, and the relative mRNA levels of Suv39 h1 were determined by quantitative real-time polymerase chain reaction(qPCR). RESULTS: Sequencing analysis demonstrated that three kinds of LV-Suv39 h1-RNAi recombinant plasmids were constructed correctly. The results of transfection efficiency evaluation showed that more than 80.00% green fluorescence was expressed in the BMSCs transfected with the three lentiviral vectors with a multiplicity of infection of 20. These results indicated that lentivirus was successfully constructed and transfection efficiency was high. The results of qPCR showed that the relative expression of Suv39 h1 mRNA in BMSCs of KD1, KD2 and KD3 transfection groups was lower than that in the control group(all P<0.05), and the relative expression of Suv39 h1 mRNA in KD1 and KD3 transfection groups was lower than that in KD2 transfection group(both P<0.05). However, there was no significant difference in the relative expression of Suv39 h1 mRNA between KD1 and KD3 transfection groups(P>0.05). CONCLUSION: The constructed lentiviral vector with low expression of Suv39 h1 was constructed successfully. This vector can be expressed in rat BMSCs, which lays a foundation to study the effect of Suv39 h1 gene in acute myeloid leukemia.

Nagilactone E (NLE), a natural product with anticancer activities, is isolated from Podocarpus nagi. In this study, we reported that NLE increased programmed death ligand 1 (PD-L1) expressions at both protein and mRNA levels in human lung cancer cells, and enhanced its localization on the cell membrane. Mechanistically, NLE increased the phosphorylation and expression of c-Jun, and promoted the localization of c-Jun in the nucleus, while silencing of c-Jun by small interfering RNA (siRNA) reduced NLE-induced PD-L1. Further study showed that NLE activated the c-Jun N-terminal kinases (JNK), the upstream of c-Jun, and its inhibitor SP600125 reversed the NLE-increased PD-L1. Moreover, NLE-induced PD-L1 increased the binding intensity of PD-1 on the cell surface. In summary, NLE upregulates the expression of PD-L1 in lung cancer cells through the activation of JNK-c-Jun axis, which has the potential to combine with the PD-1/PD-L1 antibody therapies in lung cancer.

OBJECTIVE: To compare the bonding durability of three different self-etch adhesives to primary enamel and dentin, and to investigate the effect of mild salivary contamination followed by air drying on the bonding durability. METHODS: Two hundred and forty enamel specimens were divided randomly into 16 groups (n=15/group)according to the adhesive system [self-etch adhesives: Clearfil SE Bond(SE), AdperTM Easy One (EO), Scotchbond Universal (SBU); total-etch adhesive: AdperTM Single Bond Plus(SL)], contamination status (non-contaminated vs. salivary-contaminated) and storage condition (stored in distilled water for 24 h vs. aging mode 5 000 thermal cycles in 5 ℃ and 55 ℃). Two hundred and forty dentin specimens were assigned in the same way. Shear bond strength for 12 specimens in each group were measured. The adhesive interface for the residual specimens in each group was observed by scanning electron microscopy(SEM). Data were analyzed by three-way analysis of variance and Tukey test(P < 0.05). RESULTS: For primary enamel, total-etch adhesive showed higher initial shear bond strength values (28.92±1.83) MPa and shear bond strength values (27.27±3.03) MPa after thermal cycles compared with the other groups, and the difference between the groups was statistically significant (P < 0.01). Shear bond strength values of EO decreased significantly in salivary-treated groups, regardless of storage conditions, and the difference was statistically significant (P < 0.01). For primary dentin, shear bond strength values of EO decreased significantly in salivary-treated groups after 24 h (P < 0.01). After 5 000 thermal cycles, total-etch adhesive showed significantly lower shear bond strength values (14.31±1.97) MPa compared with the other groups, and the difference between the groups was statistically significant (P < 0.01), and shear bond strength values of EO were significantly lower than those in SE and SBU groups (P < 0.01), regardless of contamination status. CONCLUSION Total-etch adhesive SL has better bonding durability to primary enamel. SE and SBU have better bonding durability to primary dentin and have a certain resistance to salivary contamination, while the bonding performance of EO is compromised greatly by mild salivary contamination followed by air drying.
Acid Etching, Dental ; Adhesives ; Dental Bonding ; Dentin ; Dentin-Bonding Agents ; Materials Testing ; Resin Cements ; Shear Strength ; Tooth, Deciduous

Objective: To observe the hypoglycemic effect of Uygur medicine Ziya Biti tablet on the type 2 diabetic rats, and analyze the hypoglycemic mechanism based on metabolomic techniques. Method: According to the results of clinical research about different origins of Ziya Biti tablet, the optimal composition was screened out; type 2 diabetic rats were taken as an experimental object in the pharmacodynamic experiments;the control group and model group were given the same dose of normal saline, Ziya Biti bablet group was given 300 mg·kg^-1, the metformin group was given 300 mg·kg^-1 metformin hydrochloride. The fasting blood and weight changes of the experimental group after the treatment were recorded and compared with normal group; ultra-high performance liquid chromatography-linear ion trap/electrostatic field orbit trap combined-type high resolution mass spectrometry (UHPLC-LTQ/Orbitrap MS) technology was used to conduct the metabolomics analysis on the rat serum, and principal component analysis (PCA), partial least squares discriminant analysis (OPLS-DA) on different groups of rat serum metabolites were performed to identify potential biomarkers. Result:Compared with the model group, the rats in the Uygur medicine Ziya Biti tablet showed a healthy states, and the blood glucose were decreased(P<0.05), which indicated that Uygur medicine Ziya Biti tablet had a certain hypoglycemic effect on type 2 diabetic rats. Eight biomarkers were finally obtained according to the results. Compared with model group, L-valine and propionylcarnitine in the Uygur medicine group were decreased(P<0.05), while sphingosine-1-phosphate, LPC (16:1/0:0), LPC (18:0/0:0), LPC (18:2/0:0), LPC 20:1/0:0), PC (19:0/0:0) were elevated(P<0.05). Conclusion:The experimental results showed that Uygur medicine Ziya Biti tablet can reduce the blood glucose of type 2 diabetic rats and allivate general physiological characteristics. The mechanism of action may be related to the improvement of amino acid metabolism and lipid metabolism.

Objective To explore the experience of infantile liver transplantation ,reconstructing portal vein (PV) and avoid the higher incidence of portal vein low flow and complications .Methods The clinical data were reviewed for 152 infantile liver transplantations performed by a single surgery group .And 114 cases with PV risk factors underwent customized PV reconstructions .All of them were diagnosed as cholestatic liver diseases and 106 (93％ ) belonged to biliary atresia .Forty-two cases (36％ ) had 2 or more risk factors .Results Most cases (n= 106 ,93％ ) underwent living donor transplantations using lateral left graft while another 8 cases had deceased donor transplantations . Four types of PV reconstructions were adopted based upon individual conditions :left/right branch of PV trunk (n= 103) ,autogenous patch PV venoplastic reconstruction (n= 3) ,duct-to-duct of PV trunk (n= 5) and donor PV duct-to-recipient confluence of SMV/CV and SV (n= 3) .Graft size reduction was performed when GRWR > 4 .5％ (n= 16) .During a median follow-up period of 6 .5 (1 .5-13) months ,there were 3 LPVF (2 .6％ ) ,2PVS (1 .7％ ) and 1 PVT (0 .8％ ) .Three LPVF cases was corrected by PV stenting ,two cases of PVS were stable after anticoagulation therapy while one PVT case undergoing thromboectomy plus PV stenting resumed a normal PV flow .Conclusions PV reconstruction of high-risk infants require comprehensive risk evaluations ,precise surgical skills and customized strategies .For PV complications ,stenting is both safe and feasible .

The study is aimed to assess the genetic diversity and genetic relationship of 18 Sarcandra glabra resources from different populations,and guide parent selection of cross breeding between these resources. The molecular marker technique ISSR was used to investigate the genetic diversity of the 18 resources. Data was analyzed by POPGEN 32, and a cluster diagram was presented by UPGMA. One hundred and ninety-eight amplified fragments were obtained using 23 ISSR primers. One hundred and eighty-four polymorphic loci were identified. Nei's genetic diversity index (h) was 0.32, Shannon diversity index (I) was 0.485 4. The genetic similarity coefficient among the resources ranged from 0.383 8 to 0.878 8 in an average of 0.661 2. The genetic distance between sample S2 and sample S18 was the farthest, so as between sample S3 and sample S18 both Nei's genetic distance was 0.957 5, The genetic distance between sample S4 and sample S5 was the closest, the Nei's genetic distance was 0.129 2,and the sample S1, S2, S3, S7, S10 were significantly different from the others based on the clustering analysis, the three groups S2 vs S3, S2 vs S6, S2 vs S18 were the best parent group selection. There was a middle level of genetic differentiation in the resources. The genetic distance between resources gives useful information to guide parent selection of cross breeding.
Conservation of Natural Resources ; DNA Primers ; genetics ; Genetic Variation ; Magnoliopsida ; classification ; genetics ; Microsatellite Repeats ; Phylogeny

The paper is aimed to identify SNP in Sarcandra glabra and Chloranthus spicatus, and authenticate S. glabra from Ch. spicatus and the mixture by using PCR amplification of specific alleles. SNPs in the ITS sequences of S. glabra and Ch. spicatus were found by ClustulX 2. 1 program and Bioedit software. Primers for authentic S. glabra and Ch. spicatus was designed according to the SNP site, and ITS sequence universal primers plus to the authentic primer to construct a multi-PCR reaction system, and then optimized the PCR reaction system. Five hundred and eighty band special for S. glabra and 470 bp band special for Ch. spicatus were found by using multi-PCR reaction. The multi-PCR reaction system could be applied to identify S. glabra and Ch. spicatus's leaves.
DNA, Plant ; analysis ; genetics ; DNA, Ribosomal ; genetics ; DNA, Ribosomal Spacer ; analysis ; genetics ; Magnoliopsida ; classification ; genetics ; Plant Leaves ; genetics ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; RNA, Ribosomal ; genetics ; RNA, Ribosomal, 18S ; genetics ; RNA, Ribosomal, 5.8S ; genetics ; Species Specificity