Early clinical efficacy of pegylated interferon treatment in patients with different phases of chronic HBV infection: A real-world analysis.

Although there are therapeutic advantages for hepatitis B virus (HBV) withpegylated interferon alpha (peg-IFNα) treatment compared with nucleos(t)ide analog (NAs) therapy, the effect difference in infected population at different phases has not been well established. We studied the clinical efficacy of peg-IFNα in two populations with HBV infection, including inactive HBsAg carrier (IHC) and chronic hepatitis B (CHB). A total of 328 HBV-infected patients were included in this real-world analysis. Patients were divided into two groups according to the infected stages. Peg-IFNα monotherapy or combination therapy with NAs were used in IHCs, and peg-IFNα added-on NAs therapy was applied to patients with CHB. The primary efficacy endpoint was HBsAg loss at Week 24. Results: The Kaplan-Meier cumulative rates of HBsAg loss were 39.50% (n = 47/119) in IHC group and 28.71% (n = 60/209) in CHB group at Week 24 (p < .05). After Propensity Score Matching (PSM), the HBsAg loss rates were 36.84% (n = 35/95) and 32.63% (n = 31/95), respectively (p > .05). Patients with baseline HBsAg level < 100 IU/ml achieved higher rates of HBsAg clearance in IHC and CHB group (before PSM: 47.44% vs. 42.86%, after PSM: 49.12% vs. 45.83%, all p values > .05). Baseline HBsAg level and its level decline from baseline to Week 12 can be as the predictors for HBsAg loss at Week 24 in both groups. Hence, the efficacy of HBsAg clearance was broadly similar between IHCs and NA-treated CHB patients during the early peg-IFNα therapy. A significant downward trend of HBsAg level was observed in both groups during peg-IFNα therapy.

A novel biocompatible Eu-based coordination polymers of cytarabine anticancer drug: Preparation, luminescence properties and in vitro anticancer activity studies.

In this study, we use cytarabine anticancer drug to synthesize a new rare earth complex with Europium ion. The study work is an attempt to investigate luminescence and biological properties of the Eu-based coordination polymers of cytarabine (Eu-CP-Ara) anticancer drug which have been prepared by us. Eu-CP-Ara has luminescence properties with emission centering at about 619 nm excited with 394 nm. We study cytarabine and Eu-CP-Ara in vitro cytotoxicity. Cytotoxicity of Eu-CP-Ara against lung cancer cells (A549) could even be comparable to the inhibitory effect of cytarabine ligands, showing the advantage of antitumor activity. In addition, Eu-CP-Ara showed lower cytotoxicity to normal liver cells (L02). At the same, from the CLSM images, Eu-CP-Ara has successfully entered the A549 cell. Hence, Eu-CP-Ara can be used as a potential anticancer drug. Eu-CP-Ara may be an effective strategy for the tracking cytarabine against tumours and might impart better accurate treatment effect and therapeutic efficiency.

LncRNA LIFR-AS1 overexpression suppressed the progression of serous ovarian carcinoma.

BACKGROUND: Serous ovarian carcinoma (SOC) is a common malignant tumor in female reproductive system. Long noncoding RNA (lncRNA) LIFR-AS1 is a tumor suppressor gene in colorectal cancer, but its effect and underlying mechanism in SOC are still unclear. Therefore, this study focuses on unveiling the regulatory mechanism of LIFR-AS1 in SOC. METHODS: The relationship between LIFR-AS1 expression and prognosis of SOC patients was analyzed by TCGA database and Starbase, and then, the LIFR-AS1 expression in SOC tissues and cells was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Besides, the relationship between LIFR-AS1 and clinical characteristics was analyzed. Also, the effects of LIFR-AS1 on the biological behaviors of SOC cells were measured by Cell Counting Kit-8, colony formation, and wound-healing and Transwell assays, respectively. Western blot and qRT-PCR were employed to determine the protein expressions of genes related to proliferation (PCNA), apoptosis (cleaved caspase-3), epithelial-mesenchymal transition (E-cadherin, N-cadherin, and Snail). RESULTS: LIFR-AS1 was lowly expressed in SOC, which was correlated with the poor prognosis of SOC patients. Low expression of LIFR-AS1 in SOC was associated with the tumor size, clinical stage, lymph node metastasis, and distant metastasis. LIFR-AS1 overexpression promoted the expressions of cleaved caspase-3 and E-cadherin while suppressing the malignant behaviors (proliferation, migration, and invasion) of SOC cells, the expressions of PCNA, N-cadherin, and Snail. Besides, silencing LIFR-AS1 exerted the effects opposite to overexpressed LIFR-AS1. CONCLUSION: LIFR-AS1 overexpression inhibits biological behaviors of SOC cells, which may be a new therapeutic method.

Obese rats intervened with Rhizoma coptidis revealed differential gene expression and microbiota by serum metabolomics.

BACKGROUND: Integrating systems biology is an approach for investigating metabolic diseases in humans. However, few studies use this approach to investigate the mechanism by which Rhizoma coptidis (RC) reduces the effect of lipids and glucose on high-fat induced obesity in rats. METHODS: Twenty-four specific pathogen-free (SPF) male Sprague-Dawley rats (80 ± 10 g) were used in this study. Serum metabolomics were detected by ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry. Liver tissue and cecum feces were used for RNA-Seq technology and 16S rRNA gene sequencing, respectively. RESULTS: We identified nine potential biomarkers, which are differential metabolites in the Control, Model and RC groups, including linoleic acid, eicosapentaenoic acid, arachidonic acid, stearic acid, and L-Alloisoleucine (p < 0.01). The liver tissue gene expression profile indicated the circadian rhythm pathway was significantly affected by RC (Q ≤ 0.05). A total of 149 and 39 operational taxonomic units (OTUs), which were highly associated with biochemical indicators and potential biomarkers in the cecum samples (FDR ≤ 0.05), respectively, were identified. CONCLUSION: This work provides information to better understand the mechanism of the effect of RC intervention on hyperlipidemia and hypoglycemic effects in obese rats. The present study demonstrates that integrating systems biology may be a powerful tool to reveal the complexity of metabolic diseases in rats intervened by traditional Chinese medicine.

Development of an In Vivo Predictive Dissolution Methodology of Topiroxostat Immediate-Release Tablet Using In Silico Simulation.

The main objective of this study was to develop an in vivo predictive dissolution (IVPD) model for topiroxostat immediate-release (IR) formulation by the combination of mechanistic absorption model (MAM) deconvolution method with time shifting factor (TSF) adjustment. The in vitro dissolution profiles in different biorelevant dissolution media containing different concentrations of sodium lauryl sulfate (SLS) were obtained from dissolution testing with the paddle method of the US Pharmacopeia, while the human pharmacokinetic profile was taken from the published experimental results. The GastroPlus™ software was used to observe the linear relationship between in vitro drug dissolution and in vivo absorption. The pharmacokinetic profile of topiroxostat IR tablet was first deconvoluted through the MAM method to obtain the fraction absorbed in vivo. Next, Levy plot was constructed to estimate the TSF, and the time scale for both processes of dissolution and absorption was then adjusted to be superimposable. The IVPD modelling was subsequently established with data between in vitro dissolution profiles and fraction absorbed in vivo. Finally, the dissolution profiles of topiroxostat IR tablet were translated into a pharmacokinetic curve in terms of convolution method. The comparison between translated and observed pharmacokinetic data will validate the performance of the developed IVPD model. This new linear IVPD model with high predictive power for the tablet can predict the in vivo pharmacokinetic differences through in vitro dissolution data, and it can be utilized as a risk-control tool for the formulation development of the topiroxostat IR tablet and the quality control of product batches.

Favipiravir in the treatment of patients with SARS-CoV-2 RNA recurrent positive after discharge: A multicenter, open-label, randomized trial.

BACKGROUND: The clinical characteristics and treatment of patients who tested positive for COVID-19 after recovery remained elusive. Effective antiviral therapy is important for tackling these patients. We assessed the efficacy and safety of favipiravir for treating these patients. METHODS: This is a multicenter, open-label, randomized controlled trial in SARS-CoV-2 RNA re-positive patients. Patients were randomly assigned in a 2:1 ratio to receive either favipiravir, in addition to standard care, or standard care alone. The primary outcome was time to achieve a consecutive twice (at intervals of more than 24 h) negative RT-PCR result for SARS-CoV-2 RNA in nasopharyngeal swab and sputum sample. RESULTS: Between March 27 and May 9, 2020, 55 patients underwent randomization; 36 were assigned to the favipiravir group and 19 were assigned to the control group. Favipiravir group had a significantly shorter time from start of study treatment to negative nasopharyngeal swab and sputum than control group (median 17 vs. 26 days); hazard ratio 2.1 (95% CI [1.1-4.0], p = 0.038). The proportion of virus shedding in favipiravir group was higher than control group (80.6% [29/36] vs. 52.6% [10/19], p = 0.030, respectively). C-reactive protein decreased significantly after treatment in the favipiravir group (p = 0.016). The adverse events were generally mild and self-limiting. CONCLUSION: Favipiravir was safe and superior to control in shortening the duration of viral shedding in SARS-CoV-2 RNA recurrent positive after discharge. However, a larger scale and randomized, double-blind, placebo-controlled trial is required to confirm our conclusion.

Metabolite Profile Changes in Different Regions of Rat Brain Affected by Ephedra sinica.

Ephedra sinica Stapf (EP) has a long medication history dating back centuries in the world. There were some reports of adverse effects in the central nervous system (CNS) resulting from administration of a drug containing EP or ephedrine. Compared with alkaloid monomer compounds, the effects of EP on the CNS are usually neglected. It is necessary to explore CNS affection which is helpful to use EP rationally. However, the affection and the changes of substances by EP in the brain are still unknown because the effects of drug on the brain also exhibit different tendency and distribution and usually lead to diversity of metabolite alteration in different regions. In this study, metabolomics based on different brain regions was used to investigate the affection mechanism of EP in the CNS. The metabolites in 6 brain regions from a rat that underwent oral administration with EP for 14 days were determined by UPLC/Q-TOF-MS. Brain histological examinations showed that there were no obvious lesions in EP administration groups. Partial least square-discriminant analysis (PLS-DA) displayed that there were significant separations between control and EP administration groups. 7 CNS biomarkers were found and identified in different regions. 3 metabolic pathways were disturbed by EP, including amino acid metabolism, phospholipid metabolism, and amino sugar metabolism. Furthermore, all biomarkers were significantly changed in the cortex after administration. This study may be helpful to understand the affection mechanism of EP in the CNS and improve cognition of brain regional characteristics.

Yttrium(iii) coordination polymer micro/nanospheres with single ligand and dual ligands.

In this work, yttrium(iii) coordination polymer (Y-CP) ball-flower-shaped microparticles with diameters ranging from 5 µm to 10 µm were synthesized using vanillin and asparagine as ligands under solvothermal conditions at 150 °C for 24 h. Then, we investigated the reaction influencing factors such as the concentration of reactants (involving vanillin, asparagine, and rare earth), reaction temperature, and reaction time. Both uniform and sphere-like nanoparticles with an average size of ∼50 nm were obtained using vanillin as a ligand at 120 °C for 12 h. Furthermore, the products were characterized and the results of cytotoxicity research demonstrated that the nanoparticles had low cytotoxicity and the coordination polymer nanospheres were perfectly biocompatible.

Prediction of the pharmacokinetics and pharmacodynamics of topiroxostat in humans by integrating the physiologically based pharmacokinetic model with the drug-target residence time model.

Topiroxostat is a selective xanthine oxidoreductase (XOR) inhibitor for the management of hyperuricemia in patients with or without gout. In this work, we aim to employ the physiologically based pharmacokinetic (PBPK) model with the drug-target residence time model to predict and characterize both the pharmacokinetics (PK) and pharmacodynamics (PD) of topiroxostat in humans. The plasma concentration-time profile of topiroxostat was simulated based on drug properties and human physiology parameters. The predictive power of this PBPK model was then demonstrated by comparison of stimulated to observed pharmacokinetic parameters. The utility of the model was further demonstrated through predicting the oral absorption and disposition characteristics of topiroxostat in humans. Finally, by combining the PBPK model and the drug-target residence time model, we successfully predicted the target occupancy and built the relationship between PK and PD using in vitro, in vivo and in silico information. The results showed that topiroxostat exhibited significant in vivo pharmacological activity even after the complete clearance of this drug from the liver (target site), which may be due to the long residence time of the binary topiroxostat-XOR complex. This work may be helpful to guide future investigations of topiroxostat and also provides a novel strategy for PK/PD studies.

Utilizing the Combination of Binding Kinetics and Micro-Pharmacokinetics Link in Vitro α-Glucosidase Inhibition to in Vivo Target Occupancy.

Many compounds with good inhibitory activity (i.e., high affinity) within in vitro experiments failed in vivo studies due to a lack of efficacy from limited target occupancy (TO) in the drug discovery process. Recently, it was found that rate constants of the formation and dissociation of the binary drug-target complex, rather than affinity, often govern in vivo efficacy. Therefore, the binding kinetics (BK) properties of compound-target interaction are emerging as a pivotal parameter. However, it is obvious that BK rate constants of the compound against target would not be directly linked to the in vivo TO unless the compound concentration in the target vicinity at any time point (TPK) can be evaluated. Here, we developed a novel simulation model to quantitate the dynamic change of target engagement over time in rat with a combined use of BK and TPK features of Epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) on the basis of α-glucosidase (AGH). Analysis of the results displayed that the percent of maximum AGH occupancies by the ECG were varied significantly from 48.9 to 95.3% and by the EGCG slightly from 96 to 99.8%; that the time course of above 70% engagement by ECG spanned a range from 0 to 0.64 h and by EGCG a range of 1.5 to 8.9 h in four different intestinal segments of the rat. It was clearly analyzed how each parameter in the simulation model effected on the in vivo the AGH engagement by ECG and EGCG. Our results provide a novel approach for assessing the potential inhibitory activity of the compounds against AGH.

Suppression of murine B-cell lymphoma growth by trichosanthin through anti-angiogenesis.

Studies have suggested trichosanthin (TCS) exerts antitumor activity mainly through direct cytotoxicity toward cancer cells and immune regulation. In this study, we conducted the proliferation and apoptosis assay on A20 cells and endothelial cells (ECs) with different concentrations of TCS and investigated the levels of gene expression linked to angiogenesis. Herein, a new mechanism that TCS inhibits murine B-cell lymphoma growth by anti-angiogenesis was reported. First, TCS inhibit tumor growth and prolonged survival significantly in vivo, and TCS depressed the formation of new blood vessels around the tumor in a dose-dependent manner. Further studies showed that the platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31)-positive endothelial cell numbers, and the serum levels of MMP-2 and MMP-9 were also lower in the study group than controls. However, TCS did neither change the ratio of T cells and NK cells in the spleen of treated mice nor affect the proliferation and apoptosis of A20 cells in vitro. Additionally, the newly formed blood vessels in chorioallantoic membranes treated with TCS were significantly reduced. Last, TCS may suppress the proliferation, induce apoptosis and decrease tube formation and migration of endothelial cells (ECs). And, the mRNA and protein levels of VEGF in ECs treated with TCS were lower than that in the control group. These findings confirm that inhibitory effect of TCS on A20 murine B-cell lymphoma growth is mediated via anti-angiogenesis, and which may be associated with the down-regulation of VEGF and MMPs expression. This is an indication that TCS may represent a natural anti-angiogenic drug for lymphoma therapy.

Nitrogen-containing three-dimensional biomass porous carbon materials as an efficient enzymatic biosensing platform for glucose sensing.

A novel glucose biosensor was developed by immobilizing glucose oxidase (GOD) on a three-dimensional (3D) porous cane vine (wisteria) stem-derived carbon (3D-CVS), which was firstly proposed as novel support material for electrochemical biosensors using loaded biomolecules. Here, an integrated 3D-CVS electrode was fabricated by loading GOD molecule onto a whole piece of 3D-CVS electrode for a glucose biosensor. The morphologies of integrated 3D-CVS and 3D-CVS/GOD electrode were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). SEM results show the 3D macroporous structure of the integrated 3D-CVS electrode. TEM results show that there are some micro-holes and defects in the 3D-CVS electrode. Electrochemical behaviors and electrocatalytic performance of integrated 3D-CVS/GOD electrode were evaluated by cyclic voltammetry and electrochemical impedance spectroscopy. The effects of pH and scanning rate on the electrochemical response of biosensors have been studied in detail. The glucose biosensor showed a wide linear range from 0.58 µM to 16 mM, with a high sensitivity of 86.17 µA mM-1 and a low detection limit of 0.19 µM. Furthermore, the glucose biosensor exhibited high selectivity, good repeatability and nice stability.

Marsdenia tenacissima extract suppresses tumor growth and angiogenesis in A20 mouse lymphoma.

Marsdenia tenacissima (MT), a traditional Chinese medicine, has been utilized in the treatment of a variety of malignant conditions for decades, but the underlying mechanism remains unclear. Angiogenesis, new blood vessel formation by nearby endothelial cells (ECs) from pre-existing vessels, plays a key role in cancer growth. In the present study, the effects of MT extract (MTE) on EC proliferation and apoptosis in vitro, and on A20 mouse lymphoma growth and angiogenesis in vivo were investigated. MTE exhibited an anti-proliferative effect on the ECs, with a half maximal inhibitory concentration of 11.91±0.24 µl/ml. Acridine orange/propidium iodide staining indicated that cell apoptosis increased with MTE concentration. Flow cytometry revealed that the EC apoptosis rates induced by 0, 6.25, 12.5 and 25 µl/ml MTE were 4.8, 23.3, 49.8 and 92.3%, respectively. In vivo, the volume and weight of the A20 solid tumors were significantly inhibited following administration of 300 µl MTE per day for 14 days (P<0.05). MTE showed extended survivability and a satisfactory security. Subsequent to treatment with MTE, peritumorous angiogenesis was significantly reduced, with lower microvessel density (P<0.05) was quantified by hemotoxylin and eosin staining. Moreover, serum vascular endothelial growth factor, matrix metalloproteinase (MMP)-2 and MMP-9 expression at the protein level in the MTE-treated group, quantified using an ELISA, was significantly lower than that of the control (P<0.05). In a chick chorioallantoic membrane assay, 12.5 and 25 µl/ml MTE distinctly decreased the level of angiogenesis (P<0.05). In conclusion, MTE exhibited potent anti-lymphoma efficacy in vitro and this may be associated with its effects against tumor angiogenesis.

Total synthesis of (+/-)-paeonilide.

The total synthesis of paeonilide, a natural anti-PAF (platelet-activating factor) new skeleton monoterpenoid with an IC(50) value of 8 microg/mL, was achieved in 16 steps with 15% overall yield from commercially available 2-hydroxy-4-methylacetophenone. [reaction: see text]