To explore the protective effect of protropine in Corydalis humosa Migo. on lipopolysaccharide-induced acute kidney injury in mice (AKI), an approach that used ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q/TOF-MS) coupled with a multivariate analytical platform was established. The BALB/c mice were divided into normal group (CON), model group (LPS), and protropine group (PRO). Mice were injected intraperitoneally with lipopolysaccharide solution to replicate the AKI model. Three hours after modeling, mice were given the protropine solution by gavage. Protropine was a monomer compound isolated in the laboratory, and protropine solution was prepared by dissolving protropine in sterilized distilled water. Administration was performed twice a day for three days. After modeling and administration, serum samples were collected. UHPLC-Q/TOF-MS was used to generate metabolomics data. Multivariate statistical analysis and online databases were used to screen potential biomarkers and enrich metabolic pathways. The heatmap of relative quantitative biomarker data was generated through Mev software. Animal experiments were approved by the Animal Experimentation Ethics Committee of Henan University of Chinese Medicine (No. SYXK2015-0005). The results show that the metabolic profile of mice in the LPS group was significantly altered by intervention with protropine, and clustered towards the CON group. 70 biomarkers were identified from the CON group vs LPS group (35 in positive source mode, 35 in negative source mode), and 67 biomarkers were identified from the LPS group vs PRO group (37 in positive source mode, 30 in negative source mode). A total of 34 common markers (18 in positive source mode, 16 in negative source mode) were obtained from the two comparison groups. The enrichment of all biomarkers resulted in 8 metabolic pathways including linoleic acid metabolism, D-glutamine and D-glutamate metabolism, arginine and proline metabolism, and arachidonic acid metabolism. The results show that protropine in Corydalis rhizoma ameliorates the kidney damage, insufficient energy supply, and inflammation in AKI mice by regulating amino acid metabolism, energy metabolism, and lipid metabolism in AKI mice.

In this study, a novel nano-drug delivery system, namely hybrid exosome, was constructed via membrane self-assembly of pancreatic cancer cell-derived exosomes with liposomes, which inherits the functionalities of exosomes, including high affinity, good stability and low immunogenicity, but also unites the characteristic of liposomes (e.g., long circulation time, high loading ability) to achieve precise drug navigation and minimum adverse effects. Specifically, two different preparation methods—repeated freeze-thawing and 37 ℃ incubation were used to fabricate hybrid exosomes at laboratory scale. Comparative analysis and characterization of these synthesized samples were performed based upon size, zeta potential and membrane fusion efficiency. The results showed that the highest exosome yield was attainted after culture for 48 h, with the exosome yield of 0.83 ± 0.07 mg/10⁸ cells for HuP-T3 cell line and 0.79 ± 0.10 mg/10⁸ cells for Panc0403 cell line. Hybrid exosomes obtained by freeze-thaw method were shown to have higher membrane fusion rate, lower size and polydispersity index (PDI), higher zeta potential and relative more stable, as compared with that made by incubation at 37 ℃ for 12 h, indicating the former approach is more suitable to construct hybrid exosomes with desirable physicochemical properties. This result may provide a preliminary experimental basis for the subsequent delivery of different anticancer drugs for the treatment of solid tumors such as pancreatic cancer.

Silk fibroin is a kind of natural biodegradable polymer, which is stable, non-toxic, cheap and easy to obtain, and has no inflammatory reaction. Silk fibroin shows satisfactory degradability and biocompatibility, widely used as a promising material for biological tissue engineering and drug delivery carrier in the biomedical field. This review introduces the structure and constituent of silk fibroin, summarizes the research progress and methods of evaluating biodegradability and biocompatibility in vivo and in vitro, which provides reference for further research and application of silk fibroin.

The development of the manufacturing process may require considerable time and resources from an economic perspective, which may result from the lack of cost-effective and reliable modeling tools of unit operation development in the pharmaceutical industry, in contrast to other chemical industries. Therefore, it is necessary to apply the modeling tools to the process, not only to overcome the challenges of regulatory and economic aspects but also to develop a more efficient and robust process. In response to this necessity, the modeling of the manufacturing process has been become increasingly important, as it can be applied to equipment design, improving process efficient, scale-up and unit operation development in the pharmaceutical industry. Discrete element method is a numerical method for predicting mechanical dynamics, such as position, velocity and motion of individual particles. First of all, the input parameters related to particle contact should be clearly defined. In this work, a calibration method of discrete element parameters was established and then elucidated the effects of different testing methods on repose angle of microcrystalline cellulose (MCC), from mesoscale angle. This experiment was composed of three parts: ① Angle of repose measured by the lifting cylinder method (θ) was regarded as the response value of the model, and then discrete element simulation parameters were screened and optimized by Plackett-Burman, steepest climb and Box-Behnken test designs; ② The robustness of previous model was assessed by angle of repose measured by the funnel injection method (α) and the shear box method (φ) to obtain the best parameter combination generated from the model; ③ Based on accurate and reliable microscopic parameters, the formation mechanism of angle of repose was comprehensively investigated from the mesoscopic-angle perspective. The calibration results showed a robust and reliable parameter combination. Moreover, the lifting speed of lifting cylinder method and the height of funnel injection method all had a certain impact on the measurement results of angle of repose. Interesting, the evolution of force chains in the process of stacking with different angle of repose revealed a certain law in the perspective of mesoscopic-angle. Thus, the objective of present work is to provide a reference for discrete element simulation parameter calibration of other solid preparations and accurate simulation of materials in the pharmaceutical process such as mixing, transferring and tablet pressing.

To investigate the effect of ionic liquid based on choline and citronellic acid ([Cho] [CA], COCA) on the oral absorption of poorly soluble drug cyclosporin A (CsA), COCA was synthesized using choline and citronellic acid by one-step neutralization method, and then characterized by mass spectrometry, ¹H-NMR, and infrared spectrophotometry. Next, CsA-ionic liquid (CsA-COCA) was prepared by ultrasonic-assisted method and filled into enteric-coated capsules. After oral administration of CsA-COCA capsules or CsA suspension preparation in rats, CsA concentration in whole blood was assayed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and the pharmacokinetic parameters were calculated by DAS 2.0 software. All animal care and experiments followed the approval of Institutional Animal Care and Use Committee at Peking University Health Science Center. The results indicated that compared with oral administration of 10 mg·kg^-1 CsA suspension, the area under the curve (AUC), half-life time (T_1/2), and mean residence time (MRT) of CsA obtained by oral administration the same dose of CsA-COCA increased by 2.81, 4.41, and 1.77 times, respectively. The COCA prepared in this study can significantly promote the oral absorption of CsA in rats, and prolong the half-life. This study can provide reference for the study of oral formulation of insoluble drugs such as CsA.

This study aims to explore the mechanism of Arisaema cum Bile on epilepsy using combination of network pharmacology and patch clamp recording. Active ingredients of Arisaema cum Bile were collected from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and literatures. Epilepsy-related targets were identified from GeneCards and OMIM database. STRING platform was employed to perform protein-protein interaction (PPI), and David platform was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis. The drug-ingredient-target-pathway-disease network was constructed with Cytoscape software. The animal experiments were approved by the Laboratory Animal Ethical and Welfare Committee Hebei Medical University. Nine compounds were detected as the active ingredients of Arisaema cum Bile, including chenodeoxycholic acid (CDCA), deoxycholic acid and β-sitosterol, etc. A total of 22 key potential targets were identified, including 5-hydroxytryptamine transporter (SLC6A4), gamma-aminobutyric acid receptor type A subunit alpha 2 (GABRA2) and neuronal acetylcholine receptor subunit alpha-7 (CHRNA7). These targets were associated with biological processes of serotonergic synapse, GABAergic synapse and ion transmembrane transport. Brain slice electrophysiology experiments revealed that β-sitosterol and CDCA inhibited the action potential (AP) of CA1 pyramidal neurons in the mouse hippocampus. Both β-sitosterol and CDCA affected the properties of AP, such as rheobase, delay and depolarization duration. In addition, the inhibitory effect of AP was more prominent when the two compounds were given together. Combining with network pharmacology and electrophysiological experiments, our study reveals the potential mechanisms of Arisaema cum Bile for the treatment of epilepsy in a "multi-ingredients, multi-targets and multi-pathways" manner. Our study provides a reference for further studies of Arisaema cum Bile.

Totally 28 new 12N-substituted aloperine derivatives were designed, synthesized and evaluated for their down-regulating PD-L1 activities in breast cancer MDA-MB-231 cells. Among them, compound 7f could significantly down-regulate PD-L1 level in concentration- and time-dependent manners, and exhibit a low cytotoxicity. It activated the killing activity of co-cultured T cells against tumor cells in a concentration-dependent manner, showing the potential of tumor immunotherapy. Further study indicated that 7f mediated the degradation of PD-L1 through a lysosomal pathway. This study provides useful guidance for the development of aloperine compounds into new small molecule tumor immune suppressants.

The emergence of antibiotic-resistant strains seriously reduces the efficiency of traditional antibiotic therapy. The development of a new alternative antibiotic method to effectively eliminate this bacterial infection has become a critical issue. Photothermal therapy (PTT) has shown many advantages in tissue penetration, spatiotemporal specificity, no drug resistance and broad-spectrum antimicrobial ability. However, extremely high temperature (55-65 ℃) is needed to achieve highly efficient bactericidal effect during PTT treatment process. Thus, this procedure will inevitably cause collateral damage to normal tissues. Silver nanoparticles (AgNPs) are one of the most commonly used broad-spectrum antimicrobial agents. Its antimicrobial activity is mainly derived from the release of silver ions (Ag⁺). However, excessive AgNPs not only would cause toxic to the body, but also waste precious metals. In this study, oxidized mesoporous carbon nanospheres (OMCN) were used as photothermal materials to prepare OMCN-Ag⁺ composites. The composite material can improve the antibacterial activity, reduce the waste of metal Ag and decrease the toxic and side effects. Moreover, the precisely controlled mild heat can overcome the shortcoming such as the damage to normal tissue caused by the excessive temperature during traditional photothermal antimicrobial process. The antimicrobial treatment system exhibits a good biocompatibility both in vitro and in vivo. Specially, the designed nanosytem can effectively eliminate the bacteria from the infected wound, subsequently promoting the process of wound healing. All animal experiments were carried out with approval of the Animal Experiment Ethics Committee of Henan University.

Invasive fungal infections are a tricky problem with high morbidity and mortality. The emerging of drug resistance worsens this problem. Therefore, developing novel antifungal agents is an urgent need to break these hurdles. Although protein kinase inhibitors have been extensively investigated in various fields such as cancer, diabetes, rheumatosis and so on, they are less explored in fungal infection. Previously, we found 12 protein kinase inhibitors with different antifungal activities, among them 5-iodotubercidin (5-Itu) was found to be the most potent antifungal agent with minimal inhibitory concentrations ranging from 2 to 4 μg·mL^-1. Moreover, 5-Itu displayed potent fungicidal effect, inhibition of hyphal formation and anti-biofilm activity. The mechanistic studies indicated that 5-Itu changed membrane sterol compositions and ultrastructures, increased the cell membrane permeability and induced apoptosis. Therefore, it needs to further study 5-Itu for the discovery of promising antifungal lead compounds.

This study aimed to research the antitumor activity and mechanisms of caffeic acid phenethyl ester derivative PEC01 in mouse G422 glioma. MTT assay, flow cytometry (FCM) and Transwell migration assay were used to detect the effects of PEC01 on proliferation, apoptosis, and migration of G422 cells respectively. Mouse subcutaneously transplanted G422 tumor model was used to analyse the effect of PEC01 on the growth of glioma in vivo. Animal welfare and experimental procedure are in accordance with the regulations of the Animal Ethics Committee of institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. Western blot was used to detect the protein levels of epidermal growth factor receptor (EGFR), Src and their downstream signaling pathways in G422 cells and tumor issue. The results showed that PEC01 inhibited proliferation of G422 cells in a time- and dose-dependent manner, with IC₅₀ of (9.02 ± 0.36) μmol·L^-1 at 96 h. PEC01 significantly induced early apoptosis and late apoptosis of G422 cells at 10.0 and 20.0 μmol·L^-1 concentrations for 96 h. Scratch healing rate of G422 cells reduced after treated with different concentrations (0.625-5.0 μmol·L^-1) of PEC01 for 12-48 h in scratch healing assay. The number of transmembrane G422 cells decreased in groups treated with PEC01 for 8 h compared with DMSO group. The average tumor weight of groups treated with 30.0 and 60.0 mg·kg^-1 PEC01 was significantly reduced in G422 insubcutaneously transplanted tumor model, and the inhibition rate of tumor weight was 72.29% and 59.44%, respectively. Protein levels of EGFR, Src, c-myc and hypoxia-inducible factor 1-alpha (HIF-1α) decreased significantly in G422 cells and tumor tissue. The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway related proteins were down-regulated. Related proteins of invasion, metastasis and cell cyclin were significantly down-regulated. PEC01 can suppress the growth of G422 glioma in vitro and in vivo. The antitumor activity of PEC01 in mouse subcutaneously transplanted G422 tumor model might be related to the blockcade of PI3K/Akt/mTOR and MAPK/ERK signaling pathways.