Latest ArticlesThe traditional cigarette smoke-induced chronic obstructive pulmonary disease (COPD) mouse model has a long period and its stability is not easily guaranteed. Based on the intratracheal instillation of cigarette smoke extract (CSE), this study aims to establish a CSE-induced COPD mouse model. C57BL/6J mice were used as model animals, except for the normal control group, animals in each group received intratracheal instillation of CSE. The airway reactivity and pulmonary function of the mice were measured using a small animal respiratory pulmonary function testing system, the leukocyte classification count in the bronchoalveolar lavage fluid (BALF) of the mice was determined using a blood and body fluid analyzer, the levels of inflammatory factors and neutrophil extracellular traps (NETs) in BALF were measured using enzyme-linked immunosorbent assay (ELISA), and the histopathological changes in the mouse lung tissue were detected using H&E staining method. The experiments were approved by the animal care and welfare committee of Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (approval No. 00006301). The results of the study showed that after intratracheal instillation of CSE, the model group mice exhibited significant COPD-like pathological and functional changes, characterized by tachypnea, slow weight gain. H&E staining showed pathologic changes such as massive inflammatory infiltration of lung tissue, alveolar wall collapse and alveolar lumen dilatation. The leukocyte classification count (total leukocytes, neutrophils, eosinophils), the levels of inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NETs levels in the BALF were significantly increased compared to the normal control group (P < 0.01, P < 0.001). The index of airway reactivity, specific resistance, airway (sRaw) was significantly increased (P < 0.05), pulmonary function indicators such as peak expiratory flow (PEF), forced expiratory flow at 75% of forced vital capacity (FEF75), dynamic lung compliance (Cdyn), forced expiratory volume in the first 100 ms (FEV100), and the ratio of forced expiratory volume in the first 100 ms to forced vital capacity (FEV100/FVC) were significantly reduced (P < 0.01), while the respiratory index (RI) was significantly increased (P < 0.05). Compared to the model group, roflumilast can significantly improve the inflammatory pathological changes and pulmonary function damage in model animals. In summary, the intratracheal instillation of CSE can rapidly establish a COPD mouse model, replicating the airway inflammation and decreased pulmonary function of COPD to a certain extent, and provides a new candidate animal model for the study of the pathological mechanism and drug screening evaluation of COPD.
The objective of this study was to explore the therapeutic effects and underlying mechanisms of Guizhi Fuling Wan (GZFLW) in the treatment of hepatocellular carcinoma (HCC). Firstly, the therapeutic effect of GZFLW on HCC was evaluated by constructing a subcutaneous xenograft mouse model of H22 hepatoma cell line and combining with cell experiments. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to analyze the drug components of GZFLW, and network pharmacology and transcriptomics methods were combined to screen out the potential core targets and signaling pathways of GZFLW in the treatment of HCC, and the core targets were verified by molecular experiments. Bioinformatics analysis results showed that, GZFLW may regulate p53, vascular endothelial growth factor A (VEGF-A) and hypoxia inducible factor-1α (HIF-1α), which may play an important role in the regulation of GZFLW. HIF-1α and other key targets, which have a certain impact on angiogenesis and ferroptosis in HCC. The results of in vitro and in vivo experiments showed that GZFLW could significantly inhibit the growth of subcutaneous transplanted tumor, and the serum containing GZFLW could inhibit the proliferation of H22 cells in vitro. The results of immunofluorescence and immunohistochemistry showed that GZFLW could down-regulate the expression of vascular endothelial markers cluster designation 31 (CD31) and cluster designation 34 (CD34). It also reduced the levels of VEGF-A and HIF-1α. Western blot analysis further showed that after GZFLW treatment, the expression of ferroptosis-related proteins solute carrier family 7 member 11 (SCL7A11) and glutathione peroxidase 4 (GPX4) was significantly decreased. However, the expression of p53 was significantly increased. The comprehensive analysis results suggest that GZFLW may induce ferroptosis in HCC by regulating the p53/SLC7A11/GPX4 signaling pathway, and inhibit tumor angiogenesis by inhibiting the expression of HIF-1α and VEGF-A, thereby effectively inhibiting the occurrence and development of HCC. This experiment has been approved by the Animal Experiment Ethics Committee of Shaanxi University of Chinese Medicine (ethics approval number: SUCMDL20230915001).
In this study, a series of 4-phenoxypyridine derivatives containing imidazole-4-formamido and 1,2,4-triazole were designed and synthesized as novel inhibitors of Fms-like tyrosine kinase 3 (FLT3). The results showed that the series of compounds had good antiproliferative activity. Among them, the preferred compound 10c was in two cell lines containing FLT3-ITD (internal tandem duplication, ITD) mutations, namely human myeloid core solo leukemia cells (MV4-11) and human acute myeloid leukemia cells (Molm-13), with IC50 values of 1.90 and 5.78 μmol·L-1, respectively. Apoptosis and cycle results showed that compound 10c could promote apoptosis and prevent cells in S phase. Molecular docking results showed that compound 10c formed two π-π stacking effects with PHE691 and HIS809 of FLT3, and the pyridine parent nucleus and Linker part formed important hydrogen bonds with LYS644 and CYS694 of FLT3, respectively. In summary, compound 10c exhibited good anti-proliferation activity in vitro, which is of value for further in-depth research, and also lays the foundation for the development of more novel FLT3 inhibitors with novel structures.
Microtubule-targeting drugs play a significant role in the treatment of metastatic and drug-resistant cancers. However, the emergence of resistance to microtubule-targeting drugs in clinical settings necessitates the development of molecules with novel modes of action and mechanisms to overcome drug resistance. The multi-target drug molecule strategy is an approach that has been developed in recent years to address complex diseases and drug resistance issues. A series of compounds based on tirbanibulin with increased Fsp3 have been prepared, which have been identified with 1H NMR, 13C NMR and MS. The antiproliferative activities have been evaluated against HeLa and HepG2 with MTT method. The effect on microtubule and cell cycle distribution of compound 22 has been evaluated with immunofluorescence and flow cytometry. IC50 of compound 22 against HeLa and HepG2 were 45 and 51 nmol·L-1. And it destroys microfilament and arrests cell cycle at G2/M. The SAR show that pyridine moiety in tirbanibulin cannot be replaced with 2-imidazolidinone. Compound 22 was identified as a lead in the further research.
Ischemic stroke (IS) is a disease with high mortality and disability rate worldwide, and there are few clinical treatment drugs. The natural active ingredients of traditional Chinese medicine, such as cinnamaldehyde and anisaldehyde, have antioxidant and anti-inflammatory effects, which can reduce the oxidative stress injury caused by ischemic stroke. In addition, studies have found that L-arginine is a substrate of nitric oxide synthase (NOS), which can be converted into NO in the body to dilate blood vessels and increase blood flow in the cerebral ischemic area. In this paper, 10 new L-arginine/active aldimine derivatives were designed and synthesized, and the neuroprotective effects of ischemic stroke were evaluated biologically. The results of oxygen glucose deprivation/reperfusion (OGD/R) cell model showed that the cell survival rate of the arginine imine derivative AI-2 group formed by L-arginine and 2-methoxycinnamaldehyde was higher than that of the positive drug butylphthalide (NBP) group, and it could effectively release L-arginine, significantly reduce the levels of reactive oxygen species and malondialdehyde, increase the level of superoxide dismutase, and had a high antioxidant effect. The results of in vivo experiments showed that AI-2 (5 mg·kg-1) could significantly improve the neurological function score of transient middle cerebral artery occlusion model in rats and effectively reduce cerebral infarction, which was superior to butylphthalide. In this study, a class of L-arginine/active aldimine derivatives with neuroprotective activity were found, which provided lead compounds for the treatment of ischemic stroke. All operations in the experiment were approved by the Animal Ethics Committee of China Pharmaceutical University, approval No. YSL-202503102.
A total synthesis of dehydrocurvularin (DCV) demethylated derivatives and structure modification have been completed using a Friedel-Crafts reaction and a highly olefin metathesis reaction. All compounds were identified by NMR, HRMS, etc. Their antitumor activity with high expression of ATP-citrate lyase was evaluated by CCK-8 assay in MDA-MB-231 and HepG2 cells. The structure activity relationship studies were also investigated. Among them, compound 7e showed better antitumor activity than DCV, and could significantly induce apoptosis in MDA-MB-231 cells. These results represent a step toward the development of novel and improved DCV derivatives.
Colorectal cancer (CRC) poses a serious threat to human life and health. The intestinal pathogenic bacteria Fusobacterium nucleatum (Fn) and enterotoxigenic Bacteroides fragilis (ETBF) are closely associated with the occurrence and progression of CRC. The development of novel compounds targeting Fn and ETBF holds significant clinical importance for the treatment of CRC. In this study, broth microdilution method was employed to screen 3 400 compounds in a compound library for in vitro antibacterial activity against the two bacteria. Using a criterion of MIC50 ≤ 64 μg·mL-1, 52 compounds with anti-Fn activity and 44 compounds with anti-ETBF activity were identified. Among them, compound G7 exhibited the best inhibitory activity against both two bacteria (Fn, MIC50 = 1 μg·mL-1; ETBF, MIC50 = 4 μg·mL-1) and could effectively inhibit the migration of colorectal cancer cells by inhibiting bacteria. Preliminary mechanistic studies revealed that G7 exerts its antibacterial effects by inhibiting biofilm formation and the expression of multiple genes related to adhesion and hyphal formation.
From an aqueous extract of the stems with hooks of Uncaria rhynchophylla, eight pairs of scalemic enantiomers of minor lignanoid (+)-/(-)-1 - (+)-/(-)-6、(+)-/(-)-9, and (+)-/(-)-10 as well as two pairs of racemic enantiomers (+)-/(-)-7 and (+)-/(-)-8 were isolated and chirally separated by column chromatographic techniques over macroporous adsorbent resin, MCI resin, Toyopearl HW-40, silica gel, and Sephadex LH-20, together with flash and chiral HPLC techniques. Their structures including the absolute configurations were determined by spectroscopic data analysis and theoretic calculations of electronic circular dichroism (ECD) spectra. Among them, chiral separation and absolute configurational determination of the optical active compounds (+)-/(-)-1 - (+)-/(-)-7 are reported for the first time, while the occurrence of scalemic enantiomers (+)-/(-)-9 and (+)-/(-)-10 in nature are discovered for the first time. Preliminary bioassay showed that (+)-8 and (-)-8 inhibited acetaminophen (APAP) induced HepG2 cell damage at a concentration of 10 μmol·L-1.
The chemical constituents of the aerial parts of Euphorbia antiquorum (family Euphorbiaceae) were investigated. From the EtOAc partition of the 90% EtOH extract of the title species, thirteen compounds were separated by silica gel, octadecylsilyl silica gel and Sephadex LH-20 column chromatographies, as well as semi-preparative HPLC. The structures of these isolates were characterized as five pimarane-type (1-5), two abietane-type (6, 7) and six atisane-type (8-13) diterpenoids on the basis of spectroscopic analyses (MS, NMR, ECD, etc.). Among them, compounds 1 and 6 were identified as two previously unreported ones. The α-glucosidase inhibitory activity of selective diterpenoids was further evaluated in the current work. Compound 1 exhibited moderate inhibition against the enzyme, with an IC50 of 150.03 ± 3.41 μmol·L-1, being lower than that of the reference drug acarbose.
This study employed plant morphology, histology, and DNA barcoding techniques to identify the species of wild Cistanche plant in Kenya, and HPLC to determine the contents of its main active components, phenylethanoid glycosides, sugar alcohols, and betaine, alongside its fingerprint. The results showed that the wild Cistanche plant collected from Kenya was taxonomically identified as Cistanche senegalensis (Reut.) Beck. Compared to cultivated C. tubulosa from China, Kenyan C. senegalensis exhibited lower levels of echinacoside, cistanoside A, acteoside, isoacteoside, and 2′-acetylacteoside, but higher concentrations than those in C. deserticola. Betaine content was comparable to C. deserticola, while glucose was undetectable. The fingerprint of Kenyan C. senegalensis showed closer similarity to C. tubulosa. This work establishes a foundation for conserving Kenyan Cistanche resources and supports further research into their potential applications.
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