Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized, controlled, phase 3, non-inferiority TALENT study / 中华医学杂志(英文版)

BACKGROUND@#Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs.@*METHODS@#We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%.@*RESULTS@#At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group.@*CONCLUSIONS@#The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure.@*TRIAL REGISTRATION@#ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx.

Dendrobium officinale Kimura et Migo and American ginseng mixture: A Chinese herbal formulation for gut microbiota modulation / 中国天然药物

Dendrobium officinale Kimura et Migo (D. officinale) is a famous traditional Chinese medicine (TCM). A mixture of D. officinale and American ginseng has been shown to enhance cell-mediated immunity, humoral immunity, and monocyte/macrophage functions in mice. Here, the effects of a D. officinale and American ginseng mixture on the structure of gut microbial community in dogs were examined using high-throughput 16S rRNA gene amplicon sequencing. The data revealed that while the mixture did not change the diversity of gut microbial community significantly, differences among individuals were significantly reduced. Furthermore, the mixture-responsive operational taxonomic units (OTUs) exhibited a phase-dependent expression pattern. Fifty-five OTUs were found to exhibit a mixture-induced expression pattern, among which one third were short-chain fatty acid (SCFA)-producing genera and the others were probiotic genera included Lactobacillus spp., Sutterella, Alistipes, Anaerovorax, Bilophila, Coprococcus, Gordonibacter, Oscillibacter, among others. By contrast, 36% of the OTUs exhibiting a mixture-repressed expression pattern were disease-associated microorganisms, and six genera, namely Actinomyces, Escherichia/Shigella, Fusobacterium, Slackia, Streptococcus and Solobacterium, were associated with cancer. In addition, five genera were closely associated with diabetes, namely Collinsella, Rothia, Howardella, Slackia and Intestinibacter. Our results indicate that this D. officinale and American ginseng mixture may be used as a prebiotic agent to enhance SCFA-producing genera and prevent gut dysbiosis.

Clinical Efficacy of Gandouling Decoction in Improving Hepatic Function with Phlegm and Blood Stasis Type Wilson' s Disease / 中国实验方剂学杂志

Objective::To observe the clinical efficacy of Gandouling decoction on hepatic function of patients with phlegm and blood stasis type Wilson's disease. Method::From January 2015 to December 2017, totally 72 cases of phlegm and blood stasis type Wilson's disease admitted to Encephalopathy Center in the First Affiliated Hospital of Anhui University of Chinese Medicine were randomly divided into treatment group and control group, with 36 cases in each group. Patients in both groups were injected with sodium dimercaptopropane sulfonate for routine treatment. At the same time, patients in control group received Hugan Tablets, and patients in treatment group received Gandouling decoction for a total of 6 treatment courses. Before and after treatment, traditional Chinese medicine(TCM)syndrome effective rate, serum enzyme index [alanine aminotransferase(ALT), aspartate aminotransferase (AST), alkaline phosphatase(AKP)], bilirubin metabolism index [total bilirubin(TBIL)], liver fibrosis index [laminin(LN), hyaluronic acid(HA), collagen type IV(CⅣ), procollagen type Ⅲ peptide(PⅢP)]and blood coagulation index [fibrinogen (FBG), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) ]were observed. Result::TCM syndrome effective rates of treatment group and control group were 86.11%(31/36) and 63.98%(23/36) respectively, with a significant difference between two groups (P<0.05). ALT, AST, AKP, TBIL decreased in two groups after treatment (P<0.01), and the effects of ALT, AST, AKP, TBIL in treatment group were significantly better than those in control group (P<0.01), liver fibrosis index decreased in both groups after treatment (P<0.01), and the effect in treatment group was significantly better than that in control group (P<0.01). Blood coagulation indexes were improved to different degrees in both groups (P<0.05, P<0.01), and there were significant differences between treatment group and control group in decreasing PT, APTT, TT levels (P<0.05, P<0.01) and increasing FBG level (P<0.01). Conclusion::Gandouling decoction can significantly improve hepatic function of patients with phlegm and blood stasis type Wilson's disease, which is manifested in improving serum enzymes and bilirubin indexes, reversing liver fibrosis, promoting clotting factors and reducing bleeding tendency, in order to delay the progress of the disease and improve the life quality of patients.

Effects of ginseng and ligusticum drug containing serum on the ERK pathway, proliferation, and vitality of neural stem cells undergoing oxygen-glucose deprivation/reoxygenation culture / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the effects of ginseng and Ligustrazine drug containing serum on the proliferation, vitality, and extracellular-signal-responsive kinase (ERK) pathway in neural stem cells undergoing in vitro oxygen-glucose deprivation/reoxygenation culture.</p><p><b>METHODS</b>The cultured neural stem cells were randomly divided into 5 groups, i.e., the normal control group (Group A), the oxygen-glucose deprivation/reoxygenation group (Group B), the oxygen-glucose deprivation/reoxygenation +ginseng serum group (Group C), the oxygen-glucose deprivation/reoxygenation + Ligustrazine serum group (Group D), and oxygen-glucose deprivation/reoxygenation +ginseng and Ligustrazine drug serum group (Group E).The protein expression levels of ERK and phosphorylated ERK (p-ERK) were observed using immunoblotting. The proliferation of neural stem cells was observed using 5-bromodeoxyuridine (BrdU) incorporation assay. The vitality of neural stem cells was detected using methyl thiazolyl tetrazolium (MTT) colorimetry.</p><p><b>RESULTS</b>The p-ERK level increased transiently at 10 min and 30 min after reoxygenation, but it decreased to the normal level at 4 h, 6 h, and 1 day, respectively. Compared with Group B, the p-ERK level at 6 h after reoxygenation could be elevated in Group C, D, and E. The proliferation and the vitality of neural stem cells at 1 day after reoxygenation could be enhanced. Furthermore, the effects of combination of ginseng and Ligusticum were better than those of using ginseng or Ligusticum alone.</p><p><b>CONCLUSIONS</b>Combination of ginseng and Ligusticum could promote the proliferation and vitality of rats' neural stem cells undergoing oxygen-glucose deprivation/reoxygenation culture through ERK signal pathway. Its effects was better than that of using ginseng or Ligusticum alone.</p>

siRNAs targeting La, hVAP-33, eIF2Bgamma, and HCV IRES inhibit the replication and expression of HCV in Huh7 cells / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the in vivo functional roles of the La autoantigen (La), the human homologue of the 33-kDa vesicle-associated membrane protein-associated protein (hVAP-33), and the subunit gamma of the human eukaryotic initiation factors 2B (eIF2Bgamma) as co-infection factors supporting chronic infection with hepatitis C virus (HCV).</p><p><b>METHODS</b>Small interfering (si)RNAs were designed against the HCV internal ribosome entry site (IRES) and transfected into Huh7 cells chronically infected with the HCV pseudovirus (designated as Huh7-HCV cells). The IRES siRNA producing the most effective silencing was selected for further analysis by fluorescence quantitative polymerase chain reaction (qPCR). siRNAs designed against La, hVAP-33, and eIF2Bgamma and the IRES-specific siRNA were then transfected, respectively or in various combinations, into the Huh7-HCV cell line for 48 h. The delta CT values were calculated and used to compare the HCV inhibitive efficacies of the siRNAs in isolation or in combination. Western blotting analysis was used to compare the quantity of core protein expression in each group.</p><p><b>RESULTS</b>The four gene-specific siRNAs, in isolation or in combination, caused inhibition of HCV replication and gene and protein expressions to varying degrees. The combination of La + IRES siRNAs produced the strongest inhibition of HCV core antigen expression. The combinations of hVAP-33 + IRES siRNAs and eIF2Bgamma + IRES siRNAs produced stronger inhibitions of HCV replication and gene and protein expressions than either hVAP-33 siRNA or eIF2Bgamma siRNA alone.</p><p><b>CONCLUSION</b>La, hVAP-33, and eIF2Bgamma act as co-infection factors of HCV chronic infection in vivo. HCV replication and gene and protein expression can be inhibited significantly by RNA interference of these co-infection factors and/or HCV IRES.</p>

Inhibition of HCV replication by HCV specific U1 small nuclear RNA chimeric ribozyme in vivo / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To determine the advantage of U1 small nuclear RNA as a ribozyme vector (U1-Rz) to inhibit HCV replication in vivo.</p><p><b>METHODS</b>The 3rd stem-loop was substituted by HCV core specific ribozyme to construct an U1-Rz eucaryotic expression plasmid. Then it was co-transfected with pCMV/T7-NCRC Delta-luc into Huh7 cell line mediated by lipofectin. The cell lysis supernatant was subjected to Western blot and lumenometer to determine the luciferase levels.</p><p><b>RESULTS</b>A U1 snRNA chimeric ribozyme was constructed successfully. Both Rz and U1-Rz inhibited luciferase expression in Huh7 by 48.64% and 87.46%, respectively.</p><p><b>CONCLUSION</b>Rz has more efficacy in cells when using U1 snRNA delivery system. U1 can be an efficient vector for HCV specific ribozyme.</p>

Study on the cleavage activity of U1 small nuclear RNA chimeric ribozyme against HCV RNA in vitro / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the cleavage activity on the HCV RNA of a chimeric recombinant of HCV specific ribozyme and U1 small nuclear RNA, which compartmentalizes within the nucleolus.</p><p><b>METHODS</b>The third stem-loop sequence of human U1 snRNA (position 95-116) within pBSIISK+ U1 was substituted by hammerhead ribozyme against HCV RNA by PCR and cloning methods, and the constructed plasmid was named pBSIISK+ (U1-Rz). Then the whole gene fragment of the chimeric ribozyme was cloned into a pGEM-T vector under the control of T7 promoter, and the constructed plasmid was named pGEM- (U1-Rz). The pGEM- (U1-Rz) and pGEM-Rz (containing the same ribozyme sequence as that in U1-Rz) transcripts as enzyme were transcribed in vitro. Also the (32)P-labeled pCMV/T7-NCRC luc (containing the gene sequence of the whole 5'-NCR and part core of HCV RNA) transcripts as target-RNAs were transcribed in vitro. The enzymes were incubated with the target RNAs under different conditions and autoradiographed after denaturing gel-electrophoresis.</p><p><b>RESULTS</b>The sequencing result showed that the construction of U1 snRNA chimeric ribozyme was correct. Compared with the ribozyme alone, both of them were active at 37 degree C and with Mg2+ (10 mmol/L) and TrisCl (10 mmol/L, pH7.9), and there was no remarkable difference between them. The cleavage activity of the chimeric ribozyme increased with the prolongation of reaction time and increment of enzyme concentration.</p><p><b>CONCLUSION</b>Both ribozyme and U1 snRNA chimeric ribozyme exhibited specifically catalytic activity against HCV RNA in vitro. There was no remarkable difference between their cleavage efficiencies.</p>