The purpose of the study was to investigate the thermal expansion characteristics of brivaracetam form Ⅰ, and explore the influence mechanism of the crystal structure on its thermal expansion behavior. The crystal structure of brivaracetam form Ⅰ was characterized by X-ray single crystal diffraction and variable temperature X-ray powder diffraction at different temperatures. The interaction energy of brivaracetam molecule calculated by B3LYP/6-31G(d, p) wave function with the aid of CrystalExplorer 21.5 software. The results show that brivaracetam form Ⅰ exhibits significant reversible anisotropic thermal expansion under the temperature range of 123-323 K. The principal expansion X₁, X₂, X₃ axes are approximately aligned with the a, b and c axes of the unit cell, and the thermal expansion coefficients of the principal expansion axes are -127.61×10^-6, 95.96×10^-6, 233.80×10^-6 K^-1, respectively. The a-axis exhibits negative expansion characteristics. The volumetric thermal expansion coefficient is 202.17×10^-6 K^-1. The energy framework of the crystal is obvious layered, and the interaction energy between layers is weak, which leads to a significant linear positive expansion in the c-axis direction of the unit cell. Through a combination of experimental and theoretical methods, the thermal expansion characteristics of brivaracetam form Ⅰ are systematically analyzed, and the influence mechanism of the crystal structure on its thermal expansion behavior is explored, which has certain guiding significance for the production process of tablet preparations in practice.

Lornoxicam (LOR) is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory and antipyretic effects. As a biopharmaceutics classification system (BCS) class Ⅱ drug, it has poor aqueous solubility and then low bioavailability after oral administration. In addition, the tabletability of LOR itself is also poor and could not form the tablet after compression, which seriously limits the development of its oral solid dosage. The current study aims to improve dissolution and tabletability of LOR by cocrystallization technique with small molecule puerarin (PUE). LOR cocrystal with the co-former PUE was prepared via the solvent-evaporation method and characterized by powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and thermo-gravimetric analyzer. The dissolution behavior, tabletability and stability of the prepared cocrystal were also further investigated. In comparison to pure LOR, LOR-PUE cocrystal showed higher apparent and intrinsic dissolution rate. Moreover, after cocrystallization, the solubility of LOR and PUE showed 4.0-fold and 1.5-fold increase compared to the raw ones in water, respectively. LOR-PUE cocrystal showed significantly improved tabletability compared to LOR alone under a wide compression range of 75-375 MPa. In addition, such cocrystal exhibited superior chemical stability with no change of drug contents for at least 60 days under the conditions of 40 ℃ and 25 ℃/75% RH.

To expand the structural diversity of Matijin-Su (MTS) derivatives and explore novel anti-HBV activity compounds, a series of fluorinated dipeptidomimetics of MTS were designed and synthesized by using trifluoromethyl substituted methylamine unit as bioisostere to replace the amide bond of the MTS derivatives. The structures of all target compounds were confirmed by ¹H NMR, ¹³C NMR, ¹⁹F NMR, HRMS, or ESI-MS, and the crystal structure of 10' was determined by X-ray single crystal diffraction. Their inhibitory activity against hepatitis B virus (HBV) in vitro were evaluated using HepG2 2.2.15 cell model. The results showed that all target compounds had inhibitory effect on HBV DNA replication, the IC₅₀ of 14e, 14f, and 14k were 0.37, 0.29, and 0.79 μmol·L^-1, respectively.

α3β4 nicotinic acetylcholine receptors (nAChRs) are potential therapeutic targets in diseases such as addiction, cancer, and obesity. In this study, by replacing three amino acids of the α3 subunit with the corresponding positions of the rα6 subunit simultaneously, an α3[K152E, E184D, Q195T] subunit mutant was constructed by PCR-mediated site-directed mutagenesis and its cRNA was obtained by in vitro transcription. The cRNA of mutant subunits mixed in equal molar ratios with β4 subunits were microinjected into Xenopus oocytes. The pharmacological activity and function of α3[K152E, E184D, Q195T]β4 nAChR was evaluated by a two-electrode voltage clamp electrophysiological technique. Acetylcholine, nicotine, and cytisine were used as agonists to evaluate the magnitude of ligand-gated currents and gating characteristics of wild-type and mutant α3β4 nAChRs. The half-maximal effective concentrations (EC₅₀) of acetylcholine, nicotine, and cytisine on wild-type α3β4 nAChRs were 277.5, 34.02 and 23.05 µmol·L^-1, respectively, while their EC₅₀ values with α3[K152E, E184D, Q195T]β4 nAChR were 170.5, 26.6, and 98.45 µmol·L^-1, respectively. Thus these EC₅₀ values for the three agonists towards the mutant receptor were changed 0.6-fold, 0.8-fold, and 4.3-fold, respectively, compared with the wild-type receptor; cytisine was most strongly affected, with a 77% decrease in potency. However, the maximum agonistic efficiency (E_max) of cytisine on wild-type and mutant α3β4 nAChRs was increased from 94.12% to 155.08% relative to the peak current amplitude induced by 1 mmol·L^-1 acetylcholine. Thus, although the α3[K152E, E184D, Q195T]β4 nAChR had significantly reduced sensitivity to cytisine, the maximum current amplitude induced by cytisine was clearly increased. This mutant had slightly increased sensitivity to acetylcholine and nicotine. The results indicate that these three amino acids of the α3 subunit have important and varying effects on ligand binding to the α3β4 nAChR, providing a basis for further structure-functional research on α3β4 nAChR, as well as the pathology of related diseases.

In order to explore the genetic diversity and structure of Bupleurum chinense, we used 18 pairs of SSR molecular markers to analyze the genetic diversity of 619 individuals in 62 cultivated and wild populations of Bupleurum chinense from Shanxi and the surrounding provinces. The results show that the 62 Bupleurum chinense populations have high genetic diversity, with that of the wild Bupleurum chinense populations greater than that of cultivated populations. AMOVA analysis indicated that genetic variation within populations was greater than between populations. Principal coordinate analysis (PCoA) divided the Bupleurum chinense populations into 3 groups, the first group containing wild Bupleurum chinense populations from all parts of Shanxi, the second group consisting of cultivated Bupleurum chinense populations from Shanxi, Hebei, Shaanxi and Liaoning, and the third group consisting of cultivated Bupleurum chinense from Shanxi and Gansu. STRUCTURE software cluster genetic structure analysis grouped the 62 Bupleurum chinense into two populations: the first group composition was the same as the population classified as the third category in the PCoA analysis, while the second group includes the populations from the first and second categories of the PCoA. PCoA, cluster genetic structure analysis, and NJ tree cluster all gather wild Bupleurum chinense population into a single category, distinguishing it from the cultivated populations. This study provides a theoretical basis for the utilization of germplasm resources, genetic variation and the development of quality germplasm resources for Bupleurum chinense.

Histone deacetylases (HDACs) are a class of key enzymes that regulate epigenetics. There are 5 small-molecule HDACs inhibitors having been approved for anti-cancer therapy on the market. In recent years, there have been more and more studies on the antiviral aspects of HDACs inhibitors. This article classifies viruses into human immunodeficiency virus 1 (HIV-1), new coronavirus (SARS-CoV-2), Epstein-Barr virus (EBV) and other viruses, systematically summarizes the recent advances of antiviral effects of the HDACs inhibitors from the perspective of medicinal chemistry. This review aims to provide the researchers the convenience of accessing the latest advances of the antiviral effects of HDACs inhibitors, and to analyze the challenges and prospects of this field in future drug discovery.

To profile and characterize the ingredients absorbed into blood and their metabolites of the Eucommiae Cortex (EC) extracts in rats with renal fibrosis induced by adenine, and so as to provide a reference for investigation of the pharmacodynamic substances of EC. SD rats with renal fibrosis induced by adenine were intragastrically administered with the EC extracts, and the rat plasma samples were collected and analyzed by UHPLC-Q-TOF-MS/MS to identify the prototype ingredients absorbed into blood and their metabolites. The experiment was approved by the experimental Animal Ethics Committee from Nanjing University of Chinese Medicine (No. 202103A008). The results showed that a total of 24 prototype compounds were identified, including 9 lignans, 4 iridoids, 8 phenylpropanoids, and 3 organic acids. Furthermore, 30 metabolites were obtained by further analysis, including 9 lignans, 19 iridoids, and 2 organic acids. The results of this study can provide the valuable reference for further elucidation of the pharmacodynamic substantial basis and mechanism of EC in the treatment of renal fibrosis.

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.

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.

Based on the chemical structure of known compound, 12 isatin derivatives palmitoyl transferase inhibitors are designed and synthesized using bioisosterism and molecular docking, while their anti-tumor activities in vitro are determined. The structures of the target compounds are confirmed by ¹H NMR, ¹³C NMR and HR-MS. In vitro anti-tumor assay illustrates that compound 5b exhibits similar anti-tumor activity to the control (IC₅₀ = 8.4 μmol·L^-1), with IC₅₀ value of 12.0 μmol·L^-1 against MCF-7 in which palmitoyl transferase is highly expressed. Compound 4b shows higher inhibitory activity against HeLa (IC₅₀ = 8.1 μmol·L^-1) than cisplatin (IC₅₀ = 40.1 μmol·L^-1). The molecular docking demonstrates that all compounds could completely enter the site of 3'-adenosine monophosphate-5'-diphosphate (PAP). Taken together, isatin derivatives represent promising compounds for the discovery of novel anti-tumor agents.