Idiosyncratic drug-induced liver injury(IDILI)is an adverse drug reaction that occurs only in a minority of the population. IDILI also has many characteristics such as unpredictable and low morbidity, its occurrence has often not been clearly correlated with the dose, route, or duration of drug administration. Several studies have shown that IDILI is a synergistic effect which was caused by body diathesis, environment and drugs. In addition, evidence also suggests that most IDILIs are mediated by immunity. Chemical medicines-related IDILIs have been extensively studied, and a variety of immunological mechanism hypotheses have also emerged to explain the pathogenesis and characteristics of chemical medicines-related IDILIs. However, the traditional Chinese medicine(TCM)-related IDILI has always been neglected due to the complexity and specificity of TCM. In recent years, TCM-related IDILI has been gradually confirmed by researchers, and formed a new hypothesis, a immunological stress-mediated tri-elements synergetic mechanism hypothesis, which can reveal the pathogenesis and clinical characteristics of TCM-related IDILI. This paper is prepared to summarize the immunological mechanism hypotheses of chemical medicine-related IDILI and TCM-related IDILI to provide a scientific basis for guiding IDILI research and establishing its clinical risk prevention and control measures.

The drug hepatotoxicity assessment method in vitro was established by 3D organoid model of HepaRG cell line in combination with high content imaging analysis. HepaRG cells were differentiated into hepatocyte-like morphology and bile canaliculus-like structures by treatment with hydrocortisone and dimethyl sulfoxide(DMSO), inducing the expressions of drug-metabolizing enzymes, transporters, nuclear receptors and hepatocyte-specific protein albumin(ALB)genes, finally forming the stable organoids with closely resembling liver function in vitro. Through the high content imaging analysis and the specific, multi-targets fluorescent dye, the number of live/dead cells, mitochondrial membrane potential(MMP), intracellular reactive oxygen species(ROS)were analyzed for the drug hepatotoxicity evaluation. The results showed that the organoids evaluation model of HepaRG cells in vitro could be used to assess accurately the difference between hepatotoxicity positive control drugs of amiodarone(AMD), cyclosporin(CSP)and the negative control drug of aspirin(ASP): AMD and CSP concentration-dependently decreased the number of total and live organoid cells. The number of dead organoid cells was increased sharply when the concentration of AMD was more than 50 μmol·L^-1, while no significant changes was observed for ASP. AMD and CSP concentration-dependently caused the MMP declined and the ROS increased, with AMD showing a greater degree than CSP and ASP presenting no markedly effect. In conclusion, the organoid evaluation method of HepaRG cells in combination with high content imaging analysis can be used for the drug hepatotoxicity assessment in vitro. It displays the advantages of multi-target, high throughput, intuitive results as well as quantitatively.

To study the chemical constituents of the fruits of Fructus carotae, silica gel column chromatography and preparative HPLC were used to isolate and purify the extract of Fructus carotae. The structures of obtained compounds were elucidated on the basis of physicochemical property and spectral data. Nine guaiane-type sesquiterpenes were isolated and identified as 8β-angeloyloxy-11-hydroxy-4-guaien-3-one(1), 11-acetoxy-4-guaien-3-one(2), 11-acetoxy-8β-isobutyryl-4-guaien-3-one(3), 11-acetoxy-8β-propionyl-4-guaien-3-one(4), 11-hydroxy-4-guaien-3-one(5), 11-acetoxy-8β-angeloyloxy-1β-hydroxy-4-guaien-3-one(6), 11-acetoxy-8β-angeloyloxy-4-guaien-3-one(7), 11-acetoxy-8β-hydroxy-4-guaien-3-one(8)and 8β, 11-dihydroxy-4-guaien-3-one(9). Compound 1 is a new compound, compound 5 is a new natural product, and compounds 2-4 were isolated from this genus for the first time.

Nanoparticles hold great potential in the improvement of the therapeutic activities of many drugs. Synthetic approaches are dominant in the conventional approach for nanoparticles design and engineering strategies. However, combination of synthetic nanoparticles with natural biomaterials have recently gained much attention. By taking inspiration from nature, cell-derived nanomedicine delivery system has been created, which is a biomimetic platform consisting of a nanoparticulate core coated with cell or cell membrane. Compared to the conventional drug delivery systems, this novel system combines the unique functionalities of cells and engineering versatility of synthetic nanomaterials for effective delivery of therapeutic agents. With existing of cell, nanomedicine has significantly improved the biocompatibility, accurate delivery and long half-life in circulation as well as reduced the toxicity and side effect of drugs. Moreover, the delivery system can interact with the incredibly complex biological systems that exist within the body, such as actively targeting the inflammatory sites and tumors. Hence, it can be applied to drug delivery, tumor radiotherapy, and vaccine preparation. The cell-derived nanomedicine delivery system emerging as a novel delivery strategy, have the potential to significantly advance the nanomedicine to improve the therapeutic efficacy. The recent research in characteristics, preparation and application of erythrocyte, mononuclear phagocyte, bacteria and tumor cell as nanomedicine delivery carrier are reviewed.

Heat shock protein 90(HSP90), as an essential molecular chaperone, regulates the folding, assembly and maturation of a wide range of oncogenic client proteins. The process of adenosine triphosphate(ATP)binding and adenosine diphosphate(ADP)/ATP exchange act as a conformational switch to regulate the chaperone function of HSP90. Furthermore, this process is controlled by a range of accessory proteins(as referred to co-chaperones), such as Hop, CDC37, p23, AHA1, PP5, etc. This article describes the structure and function of several co-chaperones, and their roles in tumor progress.

It is investigated that the hepatotoxicity of Polygonum multiflorum (PM)was attenuated by its processed products of nine times steaming and nine times sunning(RPM)based on immunological stress-mediated animal model by using metabolomics method. Sprague-Dawley(SD)rats were intragastrically administered with(5.4 g crude drug per kg body weight)of 50% alcohol extracts of PM and its processed products of nine times steaming and nine times sunning respectively or co-treated with non-toxic dose of lipopolysaccharide(LPS, 2.8 mg·kg^-1)via tail vein injection. The plasma alanine aminotransferase(ALT)and aspartate aminotransferase(AST)activities were assayed and the isolated livers were evaluated for histopathological changes. Global metabolomics profiling, multivariate analysis and data base searching were performed to discover common differential metabolites for idiosyncratic liver injury. The results showed that co-treatment with non-toxic dose of LPS and PM could result in significant liver injury, indicated by the elevation of plasma ALT and AST activities, as well as obvious liver histologic damage; whereas RPM failed to induce detectable liver injury. Furthermore, 10 potential metabolomics biomarkers that differentially expressed in LPS/PM group compared with LPS/RPM without liver injury were identified by untargeted metabolomics, mainly involved ten pathways: sphingolipid metabolism, linoleic acid metabolism, taurine and hypotaurine metabolism, steroid hormone biosynthesis, galactose metabolism, steroid biosynthesis, metabolism of xenobiotics by cytochrome P450, pyrimidine metabolism, biosynthesis of unsaturated fatty acids, primary bile acid biosynthesis. This work illustrated the idiosyncratic hepatotoxicity of heshouwu and provided a metabolomic insight into diosyncratic liver injury of PM and RPM.

The methylation of histone lysine plays a pivotal role in epigenetic regulation of gene expression. Histone lysine methylation modifications have 5 sites within histone H3(K4, K9, K27, K36, K79) and 1 site within histone H4(K20). Methylation at various sites has been shown to lead to transcriptional activation or silencing. Histone lysine methyltransferases(HKMTs)and histone lysine demethylases(HKDMs)collectively regulate the methylation modification state of histone lysine. It was reported that the mis-regulation of HKDMs is associated with the occurring and resistance of numerous malignant tumors, so more and more attention are received to HKDMs. Therefore, it is great significant in the study and development of HKDMs inhibitors. The inhibitors could be served not only as a tool in the investigation of the biological function, but also could be used as novel anti-cancer agents in the anticancer therapy. In this review, we provide a short summary of the HKDMs inhibitors recently reported and their potential in the treatment of diseases.

The objective of this study was to examine the antimetastatic effects of cordycepin and elucidate its molecular mechanism using MHCC97H cells in vitro and in vivo. Cellular proliferation was detected with MTT assay. The migration and metastatic potential were measured with scratch wound healing as well as transwell migration assays in vitro. Protein expression was detected by Western blotting. Antitumor and antimetastatic effects of cordycepin were evaluated by subcutaneous xenograft and lung metastatic model in vivo. The results demonstrated that cordycepin significantly inhibited MHCC97H cells proliferation and metastasis which was due to the down-regulation of AKT, p-AKT, p-GSK-3β, β-catenin, N-cadherin, MMP-7, MMP-9 and up-regulation the expression of E-cadherin. Furthermore, cordycepin inhibited tumor growth and metastasis in a dose-dependent manner in vivo. Cordycepin(40 and 20 mg·kg^-1)and 5-fluorouracil group significantly inhibited the tumor weights to 0.38 ± 0.04, 0.61 ± 0.08 and 0.65 ± 0.07 g, respectively, comparing with the control group(1.52 ± 0.46 g)(P < 0.01), but not 10 mg·kg^-1 cordycepin group(1.13 ± 0.36 g)(P > 0.05); the lung metastasis nodus numbers showed the same results, which in all group above(48.9 ± 7.2, 67.2 ± 9.4, 73.6 ± 8.6, respectively)were fewer than the control group(123.5 ± 14.5)(P < 0.01), except 10 mg·kg^-1 cordycepin(106.4 ± 11.3)(P > 0.05). Collectively, cordycepin inhibited MHCC97H cell proliferation and metastasis in vivo and in vitro.

In this study, eleven containing gallic acid moiety derivatives of Matijin-Su(MTS)were synthesized and evaluated for their anti-HBV activities in HepG2 2.2.15 cells in an effort to find novel effective anti-hepatitis B virus(HBV)agents. Compounds 5c, 6c and 6d exhibited significant anti-HBV activity with IC₅₀ values of 6.12, 8.44 and 9.86 μmol·L^-1, respectively. Incorporation of gallic acid moiety into MTS derivatives can lead to profound changes in their anti-HBV activity, and could be worth of further research.

An ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF/MS)method has been established to analyze the bioactive components of the aqueous extract of Euodiae Fructusand detect the metabolites in rats after oral administration of the aqueous extract. Compounds were detected by analyzing their retention times, high resolution mass data, mass spectra and comparing with the reference substances. As a result, 27 compounds were characterized from the aqueous extract of Euodiae Fructus, and 25 compounds were identified on the basis of the reference substances. 16 parent compounds and 35 metabolites were detected in rats' plasma, urine and feces samples, and all of the parent compounds were determined unambiguously through comparison with the reference substances. Four classes of compounds were identified from the aqueous extract of Euodiae Fructus, including phenolic acids, limonins, flavonoid glycosides and alkaloids. Phenolic acids, flavonoid glycosides and alkaloids were detected in rats' plasma, urine and feces, while limonins were detected in the urine and feces. The main metabolism pathways of these compounds in rats might include hydroxyl, hydrogenation, methylation, sulfating, glucuronidation, and so on. The results of this study provide references in the material basis of Euodiae Fructus in vivo.