In this study, a composite cell model for evaluation of idiosyncratic drug-induced liver injury (IDILI) was established in vitro from the perspective of immune inflammation. And this model was used to evaluate the risk of IDILI for 2, 3, 5, 4'-tetrahydroxy-cis-stilbene-2-O-β-glucoside (Cis-SG) and 2, 3, 5, 4'-tetrahydroxy-trans-stilbene-2-O-β-glucoside (Trans-SG). To determine the low, medium, and high dosage of Cis-SG and Trans-SG, CellTiter-Glo^® 3D Cell Viability Assay was used to detect the effects of Cis-SG and Trans-SG on cell viability of HepG2 cells in three dimensional (3D) culture, and MTT assay was used to detect the effects of Cis-SG and Trans-SG on cell viability of THP-1 derived macrophages. THP-1 derived macrophages were incubated by Cis-SG and Trans-SG directly or supernatants from HepG2 cells incubated with them. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of interleukin-1β (IL-1β) in the supernatants of the THP-1 derived macrophages. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine the expression of apoptosis-associated speck-like protein (ASC), Nod-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase-1 (caspase-1), and IL-1β in THP-1 derived macrophages. The results showed that there was no effect on the secretion of IL-1β in THP-1 derived macrophages incubated by Cis-SG and Trans-SG directly. However, the secretion of IL-1β, the protein and mRNA expression of ASC, NLRP3, caspase-1, and IL-1β significantly increased in THP-1 derived macrophages incubated by supernatants from HepG2 cells incubated with 1, 5, and 25 μmol·L^-1 Cis-SG or 25 μmol·L^-1 Trans-SG. In summary, the composite cell model for evaluation of IDILI established in vitro has been successfully applied in testing Cis-SG and Trans-SG. This composite cell model is helpful to evaluate and screen drugs with IDILI risk in vitro preliminarily, which provides methods for predicting and solving the idiosyncratic liver toxicity of drugs.

With a deepening understanding of cancer treatment, immune checkpoint inhibitors are recognized widely as a novel fundamental remedy for various malignancies with effectiveness and safety. With the development of pharmacometrics, model-informed drug development (MIDD) has emerged to accelerate the process of clinical research for new drugs and improve the accuracy of decision-making in new drug research, especially for immune checkpoint inhibitors. As a typical illustration, the research development of pembrolizumab is presented in this review to highlight the application of MIDD, which may provide a reference for the development of other new antitumor drugs.

Compared with crystalline drugs, their amorphous forms present long-range disordered molecular arrangements, and often exhibit higher apparent solubility and dissolution. However, several small molecule amorphous drugs may exhibit gelation phenomenon during the dissolution process, and show abnormal dissolution behavior with significantly lower dissolution than crystalline drugs. The current study aims to discover the relationship between the gelation of amorphous drugs and their abnormal dissolution, and further explore the internal gelation mechanism. Amorphous simvastatin (SIM), carvedilol (CAR), and irbesartan (IRB) were prepared by melt cooling method and characterized via X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR). Gel formation causes the dissolution of these three amorphous drugs to be significantly lower than their crystalline state. The formed gels were characterized as three-dimensional dense network structures by scanning electron microscope (SEM). Furthermore, amorphous SIM, CAR and IRB showed the critical gel temperature at 8-15℃, 25-30℃ and 45-50℃, and amorphous CAR and IRB showed the critical gel pH at 1 and 0.25. The mechanism of gel formation was proposed to be closely related to the transformation of amorphous drugs into the supercooled liquid state (as the important driving force) and the protonation induced self-assembling under acidic conditions. In addition, the wettability and properties of amorphous drugs also affect the formation of gelation.

Sempervirine, a yohimbane-type alkaloid isolated from Gelsemium elegans, was found to significantly inhibit the cellular proliferation of U251 cells in vitro and in vivo in a dose-dependent manner. U251 cells were treated with 0-16 μmol·L^-1 of sempervirine for 24, 48 or 72 h. An MTT assay and clone formation assay were used to investigate cell survival and clone formation. Hoechst staining and Annexin V-FITC/PI staining were used to measure cell apoptosis. The expression of PI3K, AKT, p-AKT, Bax, Bcl-2, caspase-3 and cleaved caspase-3 was determined by Western blot analysis. The antitumor effect of sempervirine in vivo was investigated by inoculating nude mice with U251 cells. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Fujian Medical University (Fujian, China). The results show that sempervirine significantly inhibits the proliferation and induces the apoptosis of U251 cells, promotes cleavage of caspase-3, down-regulates the protein expression of PI3K and Bcl-2/Bax, and inhibits phosphorylation of AKT in vitro. Intraperitoneal injection of 4 or 8 mg·kg^-1·day^-1 of sempervirine inhibits U251 cells tumor growth in the xenograft nude mice, and tumor weight decreased by 44.76% and 61.26%, respectively. Our study shows that sempervirine significantly inhibits the proliferation of U251 cells in vitro and in vivo, laying a foundation for further research and development of its anti-glioma effect.

Selective activation or inhibition of the angiotensin Ⅱ type 2 (AT₂) receptor can cause vasodilation, decrease cell proliferation, promote neurite outgrowth and block neuronal excitability. The AT₂ receptor can be used as a potential drug target for the treatment of cardiovascular diseases, fibrosis, inflammation, neuronal diseases and tumors. Research and development of new drugs that selectively act on the AT₂ receptor and the mechanism of intracellular signal transduction involving the AT₂ receptor is a challenging but worthy endeavor. We review research progress on the AT₂ receptor and compounds that act on the AT₂ receptor, along with structure-activity relationship analysis, to provide reference and guidance for further research in this field.

Five cadinane-type sesquiterpenoids were isolated from the n-hexane extract of Commiphora myrrha by using various chromatographic techniques, including silica gel, ODS and semi-preparative HPLC. Their structures were identified by physicochemical properties and spectroscopic data. These compounds were defined as (3S, 4R)-3, 9-dimethoxymyrrhone (1), 9-methoxymyrrhone (2), myrrhone (3), commiterpene B (4) and comosone Ⅱ (5). Compound 1 is a new compound, of which the absolute configuration was established by single crystal X-ray crystallographic analysis. Compound 5 is firstly isolated from the Commiphora genus.

The permeation and pharmacodynamics of ocular drugs are influenced by the corneal barrier. Here, a hard-soluble drug, brinzolamide, was selected as the model drug and used for preparation of minimally invasive dissolving microneedles. Brinzolamide was dissolved in ethanol and polyvinylpyrrolidone (PVP) K90 was added and dissolved. The mixture solution was casted into the dissolving microneedles mold and dried and brinzolamide dissolving microneedles (BMN) were obtained after demolding. The stereoscopic and scanning electron microscopic images showed that BMN were conical needles with the height of 750 μm, the bottom diameter of 300 μm, and the inter-tip distance of 500 μm. The dissolving microneedles patch was composed of 10×10 arrays with the area of 1 cm² and the high drug load of 7.3 mg·cm^-2. BMN showed a rapid in vitro drug release with 93% accumulative release at 2 h and the high drug corneal permeation amount of 877±105 μg. BMN exhibited the high mechanical strength of 0.32 N/needle, leading to easy rat corneal insertion with the depth of 200 μm. Moreover, BMN were rapidly dissolved in the cornea, and more importantly, the damaged cornea were quickly self-healed within 24 h. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical and the experiments were conducted in accordance with relevant guidelines and regulations. Ocular minimally invasive dissolving microneedles have the advantages of corneal minimal wounds and rapid healing, high drug loading, and high permeability, favoring the treatment of ocular diseases.

Dengue virus (DENV) is the most rapidly transmitted mosquito-borne pathogen, which is the main cause of seasonal outbreaks of dengue fever and dengue hemorrhagic fever in tropical and subtropical regions, and may cause serious life-threatening diseases. There is an urgent need to develop effective vaccines or antiviral therapies. In this paper, we found that a podocarpane-type diterpenoid, (3α, 5β, 10α)-13-methoxypodocarpa-8, 11, 13-triene-3, 12-diol (MPTD), isolated from the stems and leaves of Aleurites moluccana, showed good effect against DENV. The anti-DENV activity of MPTD against four different DENV serotypes was studied by plaque assay. The cytotoxicity of MPTD in Vero and Huh7 cells was tested by MTT assay. qRT-PCR and Western blot assays were used to investigate the anti-DENV activity of MPTD at RNA and protein levels, respectively. The results showed that MPTD greatly reduced the virus titer in DENV infected Vero cells, and its 50% effective concentration (EC₅₀) for DENV (1-4) were 2.72±0.39, 10.99±5.18, 18.72±0.21, and 0.48±0.28 μmol·L^-1, respectively. The results showed that MPTD inhibits DENV RNA level and the expression of E protein. In addition, MPTD may inhibit the early stage of DENV replication and exert antiviral activity. Further studies showed that the inhibitory effect of MPTD against DENV infection is not targeting the viral entry stage. Therefore, MPTD has a significant anti-dengue virus effect, and is an anti-DENV compound with potential application value.

In order to provide a scientific basis for the establishment of a Daphnes Cortex medicinal material fungus library and the screening of endophytic fungi that promote the growth of Daphnes Cortex and increase the content of daphnetin, we used Illumina high-throughput testing technology to analyze 9 Daphnes Cortex samples from Gansu and Shanxi provinces. A total of 632 766 valid sequences were obtained, including 348 OTUs, 4 phyla, 20 classes, 48 orders, 108 families, 154 genera, and 208 species. The sum of the first 3 fungal genera account for more than 65% of the total abundance, with the highest reaching 98.4%. Alternaria and Phoma are the main genuses of Daphne giraldii Nitsche, and Altemaria is the dominant genus. The endophytic fungi community of Daphnes Cortex is rich in diversity, and the order of fungal diversity in different producing areas is: Gangu County > Wutai County > Tanchang County.

This study integrates metabolomics and network pharmacology techniques to systematically analyze the possible mechanism of Pudilan Xiaoyan oral liquid (PDL) in the treatment of acute respiratory infections. GC-MS metabolomics analysis found 8 endogenous metabolites, 3-phosphoglycerate, α-aminoadipate, D-ribulose-5-phosphate, β-mannosylglyceric acid, D-fructose, urea, D-maltose and ornithine in the serum of mice with acute respiratory infection induced by LPS; these substances can be used as biomarkers for PDL use in the treatment of acute respiratory infections. Biological network studies revealed 10 potential targets for intervention by PDL in the glycolysis and pentose phosphate pathways, including GPI, G6PD, H6PD, PFKM, TALDO1, TKT, GAPDH, HK1, PKLR and TPI1. All animal experiments were carried out with approval of the Animal Ethics Committee of Nanjing University of Chinese Medicine. Our findings indicate that the strategy of combining metabolomics and network analysis can provide information on the possible mechanism of PDL in acute respiratory infections, and reveal that PDL may ameliorate the pathological process of acute respiratory infections by regulating disordered metabolic pathways.