Berberine is one of the most studied original natural drugs in China in recent years. It is a new lipid-lowering drug with completely different mechanism from statins, which has been used in the multi-center clinical trials. However, berberine is poorly absorbed in the intestinal tract after oral administration leading a significant pharmacokinetic characteristic of low blood concentration (1%) and bioavailability (< 5%). That is to say, it is difficult to explain the therapeutical effect in vivo by the current pharmacokinetic results. In fact, this phenomenon also exists in a number of clinically effective natural drugs. This review introduces the pharmacokinetic characteristic of berberine by focusing on the gut microbiota to mediate the metabolic process of berberine in vivo. Meanwhile, taking berberine as an example, we emphasized the important role of intestinal bacteria on the pharmacokinetic study on the oral chemical drugs, and put forward a new research mode of drug PK-PD mediated by the gut microbiota.

Hepatic fibrosis is an important pathological process in the development of liver cirrhosis and liver cancer from chronic liver damage. So far there is no effective chemical drug in clinic for treatment of hepatic fibrosis. Therefore, the research in anti-hepatic fibrosis drugs is a hot topic. For drugs currently under research and development, most of the mechanisms of action are related to inhibition of factors that could cause or deteriorate liver fibrosis, including activation and proliferation of hepatic stellate cells, inflammation, oxidative stress and production of extracellular matrix, et al. In this review, we briefly analyze targets and drugs related to the mechanisms mentioned above in order to provide a reference to the future research and development of anti-hepatic fibrosis drugs.

Tumor microenvironment (TME) is the internal environment of tumor. As a functional unit, the microenvironment determines the occurrence and development of tumors. Hypoxia, inflammation and immunosuppression are three major characteristics of TME. Hypoxia signals involve in multiple immunosuppressive pathway. There is communication among the gut microbiota, chronic inflammation and immunity. The three characteristics are associated with each other to form a complex network affecting the metastasis of the tumor. TME also influences the development of immunotherapy and efficacy of drugs in solid tumor. Therefore, it is important to identify the valuable biomarkers to predict disease progression, to elucidate the mechanistic networks in the microenvironment, to develop microenvironment targeting drugs and effective drug combination strategies to improve the drug efficacy. All of these have a profound clinical value.

Neural stem cell is a cell type with the ability of self-renewing and the potential to differentiate into neurons, astrocytes or oligodendrocytes. Neurogenesis is beneficial for the recovery of many neurological diseases, such as stroke, Alzheimer's disease and so on. Neurogenesis capacity can maintain through the whole life, which includes the proliferation, migration and differentiation of neural stem cell, as well as the incorporation into the neuronal network of newborn neurons. The self-renewal and differentiation activities of neural stem cell are regulated by the microenvironment, which is defined as neural stem cell niche. Components of neural stem cell niche include cell-cell interactions, cytokines, extracellular matrix and vascular niche. Illustration of neural stem cell niche impact is far more significant for the treatment of certain nervous system diseases. This review summarizes the current understanding of the relationship between neural stem cell niche and the fate of neural stem cell.

HIV-1 reverse transcriptase (RT) plays an important role in HIV-1 life cycle. At present, the listed NRTIs and NNRTIs targeting the RT showed high efficiency as clinical first-line drugs. However, the rapid emergence of multidrug-resistant viruses and significant cumulative drug toxicities compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, there is an urgent demand for new types of RT inhibitors with novel mechanism of action to address this challenge. In recent years, additional inhibitors with novel mechanism of action have been reported, including nucleic acid competitive inhibitors, reverse transcriptase-directed mutagenesis inhibitors, primers/templates-competitive reverse transcriptase inhibitors, polymerase-RNase H inhibitors, reverse transcription initiation process inhibitors, peptide inhibitors etc., which have brought new hope to the development of novel anti-HIV drugs. This article focuses on the development of these inhibitors.

Fluorinated compounds, which now make up 20%-25% of all marketed chemical drugs, are playing significant role and showing great potential in medicinal chemistry. Fluorine substitution is always utilized to change the physicochemical properties of the compounds to improve the ADME/T properties. In addition, fluorine substitution leads to improvement of the ligand binding affinity. With respect to molecular level, organofluorine can form various intermolecular interactions with the target proteins, e.g., hydrogen bond, halogen bond, C-F…π interaction, polar interaction and so on. These interactions display unique properties or nature due to the specificity of fluorine atom, which are at the center of attention. This paper reviews the related research background, followed by the research progress of hydrogen bond, halogen bond, C-F…π interaction, polar interaction and some other interactions involved organofluorine.

Primary hepatocellular carcinoma as the main pathological type of liver cancer is one of the common malignant tumors in our country. Liver cancer stem cells (LCSCs) have the characteristics of multidrug resistance, anti-radiotherapy and high tumorigenicity in addition to the characteristics of stem cells, namely, self-renewal, multi-directional differentiation and unlimited proliferation. Based on the above features, relapse and metastasis often occur after the patients being treated with conventional methods, which results in poor prognosis. Effective treatment targeting LCSCs has the potential to cure hepatocellular carcinoma (HCC) completely. This article reviews the common biomarkers used in identification of LCSCs and development of stem cell-targeted therapy for HCC.

Mesoporous silica nanoparticles (MSNs) have been widely used as drug carriers in the diagnosis and treatment of diseases due to their specific characteristics, which include a large surface area, ordered mesoporous structures, easy surface modification and feasible sustained release action for encapsulated drugs. With the research development of MSNs, the biodegradability and removability of mesoporous silica nanomaterials have attracted considerable attention in the clinical application of the MSNs-based formulations. This paper was prepared to emphasize the preparation approaches of biodegradable mesoporous silica nanoparticles through the metal oxide doping method and the organic compound doping method. We discussed the biodegradable mechanism and process of such nanoparticles, and finally, provided an insightful and helpful review of the prospective application of the biodegradable mesoporous silica nanoparticles in medical field.

Intestinal permeability is one of key factors determing absorption of oral drug products. It is a big challenge to assess permeability of compounds with high accuracy and high efficacy during research and development process. In this review, the principles, strengths, weaknesses and advances of common intestinal permeability models are summarized, with focus on Ussing chamber and parallel artificial membrane permeability assay. In addition, future trends of permeability models are briefly discussed. This review may provide a reference to accessing permeability of lead compounds.

Arenaviruses are enveloped RNA viruses. The genus mammarenavirus contains nine members that are known to be human pathogens, and eight of them cause human hemorrhagic fever. Lassa hemorrhagic fever, caused by Lassa virus (LASV) infection, is the most prevalent arenavirus hemorrhagic fever with potential to cause major epidemics. LASV belongs to category A agents, and biosafety level-4 (BSL-4) facility is required for live virus experiments. Currently there are few specific treatments available for arenavirus diseases. Here, we established efficient cell-based pseudovirus infection models using an HIV-1 core (pNL4-3.Luc.R^-E^-) packed with arenavirus glycoproteins. Nine recombinant arenaviruses (arenavirus-GP/HIV-luc) were generated, and 17 cell lines were tested for susceptibilities to these viruses. These pseudovirus infection models were further validated by known arenavirus entry inhibitors. The models are safe and specific to pseudovirus infection, which are readily used for pharmacodynamic evaluation of arenavirus entry inhibitors in BSL-2 laboratory. The models will facilitate screening of the anti-arenavirus drugs and vaccines.

Shengmaiyin is widely used in the treatment of arrhythmia and has achieved a good effect. Due to the complexity of traditional Chinese medical formula, the pharmacological mechanism of Shengmaiyin in the treatment of arrhythmia is unclear. In this study, we used the internet-based Computation Platform (www.tcmip.cn) to explore the molecular mechanism. Shengmaiyin was found to treat the arrhythmia by modulating the pathway related to energy metabolism such as carbon metabolism, purine metabolism, carbohydrate metabolism, or by regulating the level of ATP. In this study, we find that the main active drug component in Shengmaiyin may be ginseng.

Interleukin-6 (IL-6)/janus kinase (JAK)/signal transducers and activators of transcription 3 (STAT3) is a pivotal signaling pathway in the regulation of cell proliferation, survival, differentiation and T cell activation. Aberration of this pathway is involved in multiple autoimmunity diseases and cancers, therefore the pathway is considered as a hot target for drug development. In our study, we validated a cell-based model of IL-6/JAK/STAT3 and used it in screening of its inhibitors. HEK-Blue IL-6 cells of Invivogen Inc. were used to stably express IL-6 receptor and STAT3-induced secreted embryonic alkaline phosphatase (SEAP) report gene. After stimulation by IL-6, SEAP was secreted from cells and reacted with QUANTI-Blue. The product can be detected at 655 nm. The inhibitory effect of compounds on STAT3 signaling showed as IC₅₀ was calculated by OD value. The results shown that IL-6 specifically activated the cells, which could be applied to screen the inhibitors for IL-6/JAK/STAT3 signaling pathway. The optimized screening conditions were described as below:50 000 cells/well, 1 ng·mL^-1 IL-6 incubation for 20 h and reaction with QUANTI-Blue for 1 h. Based on this condition, we screened 14 natural products based on this cell model and arctigenin, cryptotanshinone and curcumin showed potential inhibitory activities on STAT3 signaling pathway with IC₅₀ of 1.28, 2.96 and 6.61 μmol·L^-1. Our study suggests that HEK-Blue IL-6 cells were suitable for screening inhibitors for the IL-6/JAK/STAT3 signaling pathway.

Nobiletin is a kind of polymethoxyflavonoid with many pharmacological effects, such as antiinflammatory and antioxidation activities. This study was carried out to investigate the inhibitory effects of nobiletin on P-glycoprotein (P-gp) in vitro and in vivo. The molecular mechanism for structure-inhibition relationships of nobiletin with P-gp was investigated. Nobiletin exhibited significant inhibition (IC₅₀=2.21 μmol·L^-1) on P-gp in MDR1-MDCKⅡ cells. In the cell toxicity test, the paraquat-treated cell viability was decreased with nobiletin by inhibiting P-gp activity. In the rats PK study, the AUC_0-t of digoxin was increased 2.02 folds while the C_max of digoxin was increased 3.29 folds, when nobiletin was used in the pretreatment of SD rats. Molecular docking analysis elucidated that the formation of Pi-Pi bonds with Phe974 was the key factor for P-gp inhibition. The research findings provide important guideline for prediction of potential interaction between nobiletin and P-gp.

The hepatotoxicity of gefitinib is an important factor limiting its clinical application. In order to control the toxicity, we conducted this study to find the gene variation that can explain and predict the occurrence and severity of hepatotoxicity of gefitinib. Ninety patients with non-small cell lung cancer were included in the retrospective clinical study. Detailed hepatotoxicity induced by gefitinib and epidemiological characteristics were recorded. Twenty-six candidate single-nucleotide polymorphisms of molecular targets, metabolic enzymes, transporters and chemokines were genotyped by matrix-assisted laser desorption/ionization time-of-flight platform. Various confounding factors, such as age, gender and smoking status, were included in the follow-up analysis and variability in the extent of hepatotoxicity was best explained by a multivariate logistic regression model incorporating. The severity of hepatotoxicity was associated with mitogen-activated protein kinase 1 rs13515 (OR=9.467, P=0.074). The research about pharmacogenomic of gefitinib identified the determinants of the drug-induced liver injury. These findings provide a basis to design clinical trials targeting a particular toxicity of gefitinib or similarly targeted agents to benefit patients on long-term gefitinib treatment.

The study was designed to investigate the effect of IMPDH1 gene polymorphism on the pharmacodynamics of mycophenolic acid in the renal transplant patients. 315 patients with renal transplantation were treated with triple immunotherapy (mycophenolic acid + tacrolimus + prednisone). The Agena MassARRAY assay was used to detect the IMPDH1 genotypes in patients above. The plasma drug concentration of mycophenolic acid (MPA) and its main metabolite mycophenolic acid glucuronide (MPAG) was detected by high performance liquid chromatography (HPLC). The correlation between IMPDH1 gene polymorphism (rs10954183, rs12536006, rs13242340, rs2278293, rs2288549) and rejection and postoperative infection in renal transplant recipients were analyzed by SPSS 21 software. The result showed that IMPDH1 rs2288549 GG is a risk factor for acute rejection after renal transplantation (P < 0.05), and IMPDH1 rs2278293 CT is a risk factor for infection after renal transplantation (P < 0.05). Above all, IMPDH1 rs2288549 is an important factor of acute rejection after renal transplantation, IMPDH1 rs2278293 is an important factor affecting the emergence of infection after renal transplantation. The SNPs may help to optimize clinical medication to reduce the incidence of adverse reaction.

Two novel Mannich base derivatives of silybin, SLB-DEA and DHSLB-PIP, were designed and synthesized. All the structures of new Mannich base derivatives of silybin were characterized by ¹H NMR and HR-MS. Their protective action against CCl₄-induced liver injury in mice were investigated. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) were determined and the histopathological changes in liver tissues were examined. Pretreatment with a higher dosage of DHSLB-PIP (40 mg·kg^-1) prevented CCl₄-induced liver injury as indicated by the reduced levels of ALT, AST, LDH and TG. Meanwhile, liver histopathological improvement was observed in the model groups. The pharmacokinetics study in rats showed that the relative bioavailability of SLB-DEA and DHSLB-PIP were 172.5% and 259.8% compared with silybin. All the results suggest that SLB-DEA and DHSLB-PIP may protect liver against injury by CCl₄ and the relative bioavailability was significantly increased, which is worth of further investigation for their druggability.

The chemical constituents of Sabia limoniacea var. ardisioides were investigated using chromatographic methods, such as silica gel, Sephadex LH-20 and preparative HPLC. Eight compounds were isolated and their structures were elucidated by spectral data and physicochemical properties, which were identified as 5-methoxy-1, 2-methylenedioxyl oxoaporphine (1), fuseine (2), N-p-feruloyltyramine (3), N-trans-coumaroyl tyramin (4), quercetin (5), rutin (6), mutabiloside (7), and protocatechuic acid (8). Among those, compound 1 is a new compound, compounds 2-8 were isolated from this plant for the first time.

This study was designed to explore the intervention of muscle fatigue in rats with Astragali Radix using ¹H NMR metabolomics methods. The fatigue model was induced in rats by forced swimming plus food restriction, and the effects of Astragali Radix (3, 6 and 12 g·kg^-1) were investigated using the exhaustive time of rat swimming. After 3 weeks, the gastrocnemius was collected for ¹H NMR detection, and the anti-fatigue effects of Astragali Radix were explored using multivariate statistical analysis. Astragali Radix significantly improved the exhaustive swimming time of rats. Compared with control group, the levels of isoleucine, leucine, creatine, phosphatidylcholine, trimethylamine oxide, taurine, guanidinoacetate, AMP, inosine, histidine, hypoxanthine, anserine in rat gastrocnemius of model group were increased. While the levels of lactate, acetone, choline, glycerophosphocholine, glycine were decreased. These 6, 11, 5 potential biomarkers could be reversely regulated by treatment with Astragali Radix (high dose, middle dose, low dose), respectively. Metabolomics analysis revealed that Astragali Radix has a certain anti-fatigue effects and the mechanism may be related to regulation of amino metabolism.

The study was designed to explore the influence of high-fat diet on the metabolism profile of feces and intestinal contents of golden hamster to provide new information for the mechanism of drug action. Twelve golden hamsters fed with high-fat diet and twelve golden hamsters fed with normal diet were used as model group and control group, respectively. Serum samples were collected from the normal group and the model group at 2 weeks, 4 weeks and 8 weeks after the induction of high-fat diet. Serum biochemical parameters were measured in the control and model groups. The levels of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) levels in model group were higher than the control group. After 8 weeks, the feces and intestine contents were taken. The intestine was divided into four sections:jejunum, ileum, cecum and colon. The changes of endogenous metabolites in intestinal contents were analyzed by ¹H NMR based metabolomics combined with multivariate statistical analysis to find the significant differences in metabolites. The metabolic profiles of hyperlipidemia model group and control group were significantly distinguished by the othorgonal partial least squares-discriminate analysis, (OPLS-DA). Compared with the control group, the endogenous metabolites in feces such as amino acids, fatty acids, tricarboxylic acid cycle intermediates and nucleotides related to intestinal microflora were changed significantly (P < 0.05), and the amino acid metabolites, protein spoilage products and choline metabolites in intestinal contents had significant changes (P < 0.05). The data suggest that the intestinal microflora plays an important role in the development of hyperlipidemia in golden hamsters from the molecular level of metabolites. This result provides useful information for the clinical treatment of hyperlipidemia and development of hyperlipidemia drug.

This study was designed to investigate the impacts of particle shape of micelles on cell uptake and tumor imaging applications. We designed and synthesized an ultra-pH sensitive PEG-iPDPA diblock polymer, and prepared it into wormlike micelles and spherical micelles by thin-film dispersion method and modified solvent evaporation method, respectively. Firstly, the pH responsiveness of two kinds of micelles was investigated in vitro. Both forms of micelles responded to pH sensitively, and each of them could reach 100 times of ON/OFF fold after conjugated with BDP fluorescent probe. Moreover, the cellular uptake of two forms of micelles depended on the concentration and incubation time. However, the amount of cellular uptake of spherical micelles was much higher than that of the wormlike micelles, which proved that the shape of nanoparticles had a great influence on the cellular uptake. The results of in vivo imaging revealed that the spherical micelles had a better tumor accumulation as well as tumor imaging outcomes. Finally, the biosafety of micelles was tested by MTT assay and H & E staining, which indicated that none of the two kinds of micelles had obvious toxicity. Collectively, these results suggest that the spherical micelles could be a better carrier compared with wormlike micelles in terms of cellular uptake, tumor accumulation and tumor detection.

In this study, multivariate statistical analysis was applied to characterize the flowability of different types of microcrystalline cellulose (MCC), and the visualization of R language was used to explore the intrinsic correlation on its performances. To verify the operability of multivariate statistical analysis, we compared the results of the conventional methods such as repose angle method, Hausner ratio method, Carr's index method and the parameter a of Kawakita equation to determine whether there are significant differences between the conventional ones and multivariate statistical analysis. Moreover, the fillibility and compressibility were characterized by parameters 1/b of Kawakita equation and the means of pressure-tensile strength and compressibility curve method, respectively. The data was analyzed through R language for visualizing the correlation among the performance parameters of MCC. The flowability of the series of microcrystalline cellulose PH (MCCPH) were superior to the series of microcrystalline cellulose WJ (MCCWJ), the compressibility of MCCPH-302 was optimum, and the flowability and fallibility of MCCPH-102 were better than others. The results of conventional methods were consistent with multivariate statistical analysis. The fillibility was positively correlated with flowability, both negatively correlated with compressibility by analyzing correlation coefficient diagram, which was statistically significant (P < 0.01). It is reasonable that adopting multivariate statistical analysis to character the flowability of powders, which is more objective than the traditional approach. The correlation visualization of performance parameters of powders provides convenience for screening preparation material via the visualization of R language.

Jasmonic acid (JA) can promote the biosynthesis of artemisinin.To have an insight into the JA signaling in Artemisia annua, two new genes belonging to JAZ family, namely AaJAZ5 and AaJAZ6, were cloned from Artemisia annua, which might be the negative regulators involved in the JA signaling pathway.Bioinformatic analysis showed that AaJAZ5 and AaJAZ6 contained the conserved domains of ZIM and Jas specific to JAZ family.According to tissue profile analysis, AaJAZ5 had the highest expression level in leaf and AaJAZ6 had the highest expression level in root.The expression levels of both AaJAZ5 and AaJAZ6 were markedly elevated by methyl jasmonate and mechanical wounding.The BiFC results indicated that AaJAZ5, as well as AaJAZ6, physically interacted with AaMYC2.Importantly, only AaJAZ5 could interact with AaCOI1.The interaction assays given by BiFC suggested that AaJAZ5 might play a crucial role in JA signaling.This study facilitated the further analysis of the functional divergence of JAZ-family members and the understanding of molecular mechanism on JA signaling to regulate the artemisinin biosynthesis.