Latest ArticlesHyperuricemia is not only the biochemical basis of gout, but also closely related to the development of metabolic syndrome, cardiovascular diseases, chronic kidney disease, etc. Xanthine oxidase (XOD) is the key catalytic enzyme for uric acid biosynthesis, therefore the vital target for anti-hyperuricemic drugs. In this study, compound CC18022 was designed and synthesized specifically targeting to XOD. Molecular docking analysis indicated a fairly tight binding between CC18022 and XOD. In the in vitro study, CC18022 significantly inhibited XOD activity with a half maximal inhibitory concentration (IC50) value in the order of nmol·L-1, which is relative to the XOD inhibitor febuxostat. By using both acute and chronic hyperuricemic mice model, compound CC18022 was found to have serum uric acid-lowering effect in a dose-dependent manner in vivo. The animal welfare and experimental processes were in accordance with the provisions of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. In the acute hyperuricemic mice, CC18022 significantly inhibited serum XOD activity, and also the XOD activity in intestine and liver, which were related to purine absorption and metabolism. Therefore, the novel compound CC18022 exhibited significant inhibition on XOD activity and anti-hyperuricemic effects, making it a favorable candidate for further research.
Strict regulation of human immunodeficiency virus type 1 (HIV-1) protease function is critical for efficient production of mature viral particles. During viral protein expression and viral assembly, HIV-1 protease (PR) located within Gag-Pol precursor must be inactive to prevent premature cytoplasmic processing of the viral Gag and Gag-Pol precursors. Premature activation of HIV-1 precursors leads to major defects in viral assembly and production of viral particles. Specifically activating the protease in the precursor protein can directly inhibit the replication of the virus. In addition, HIV-1 PR is able to induce cell apoptosis. In this study, we identified 6 small molecule compounds using a cell-based assay for screening compounds that activate HIV-1 PR and induce premature of HIV-1 precursors. Results showed the active compounds are able to activate HIV-1 PR, inhibit HIV-1 replication, and induce cell apoptosis. This study provides ideas for the research and development of antiviral drugs.
This study was designed to explore the protective effect and underlying mechanism of catalpol on hepatocyte apoptosis in nonalcoholic fatty liver disease (NAFLD). High fat diet (HFD) was used to establish NAFLD model in the in vivo experiment, and the procedures of the experiments and animal care protocol were approved by the Animal Care and Use Committee of Jianghan University. Human liver cancer cell line HepG2 was treated with palmitate (PA) to establish a lipid toxicity model in the in vitro experiments. The results showed that catalpol significantly decreased the contents of serum total glyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), and aspartate transaminase (AST) in HFD-fed mice. Results of TUNEL staining and flow cytometry analyses revealed that catalpol significantly inhibited hepatocytes apoptosis in HFD-fed mice and PA-treated HepG2 cells. Moreover, catalpol treatment significantly reduced the endoplasmic reticulum stress-related protein expression levels of binding immunoglobulin protein (BiP), phosphorylated PKR-like endoplasmic reticulum kinase (p-PERK), inositol-requiring kinase 1α (IRE1α), and transcriptional factor activating transcription factor 6 (ATF6), and apoptosis-related protein expression levels of C/EBP homology protein (CHOP), phosphorylated c-Jun N-terminal kinase (p-JNK), and cleaved cysteinyl aspartate specific proteinases (caspases)-12, -9, and -3 in HFD-fed mice and PA-treated HepG2 cells. Furthermore, endoplasmic reticulum stress agonist tunicamycin (TM) significantly reversed the inhibitory effect of catalpol on protein expression levels of BiP, p-PERK, IRE1α, and ATF6, subsequently the inhibitory effect of catalpol on expression levels of CHOP, p-JNK, Bcl-2, Bax, and cleaved caspases (-12, -9, and -3) was also attenuated in PA-treated HepG2 cells. Taken together, these findings demonstrated that catalpol could inhibit hepatocytes apoptosis and had a significant protective effect on liver injury, and its mechanism might be related to the relief of endoplasmic reticulum stress.
In this study, in vitro experiments were conducted to investigate that sinomenine inhibits the macrophage classic activation by up-regulating the expression of paired immunoglobulin-like receptor B (PIR-B). A macrophage model with classic activation was established by lipopolysaccharide and interferon-gamma co-stimulation. Real-time fluorescence reverse transcription-polymerase chain reaction was executed for evaluating the PIR-B gene expression, and Western blot for PIR-B protein expression, in macrophages, respectively. The tumor necrosis factor α and interleukin 8 in cell culture supernatant were measured by enzyme-linked immunosorbent assay. The flow cytometry was utilized to detect M1 macrophages. The PIR-B expression in situ was observed by laser scanning confocal microscope. The results showed that sinomenine significantly increased the expression of PIR-B, markedly reduced the percentage of M1 macrophages, and decreased the levels of tumor necrosis factor α and interleukin 8 in the culture supernatant. The above results indicated that sinomenine can significantly inhibit the macrophage classic activation, and its mechanism may be related to the increase of PIR-B expression in macrophages. This pharmacological effect helps explain the pharmacodynamic mechanism of sinomenine in treating rheumatoid arthritis.
We explored the pharmacodynamic material basis and network regulatory mechanism of Fufang Yuxingcao Mixture (FYM) for the treatment of fever and inflammation. Targets of the 25 compounds in FYM were predicted according to the reverse pharmacophore method and TCMSP, UniProt database. Gene ontology (GO) function enrichment and pathway analysis of the targets was analyzed by Omicsbean software and the Kyoto Gene and Genome Encyclopedia (KEGG) database. A "compound-target-pathway-pharmacological action-effect" network was established with Cytoscape 3.6.1 software. The lipopolysaccharide (LPS)-induced RAW264.7 cell inflammation model was used to verify the anti-inflammatory effects of FYM and its 10 important components. The network pharmacology experiment showed that 25 compounds affected 97 pathways through 211 targets, of which 15 key targets [including RAC-alpha serine/threonine-protein kinase (AKT1), insulin (INS), vascular endothelial growth factor A (VEGFA), interleukin-6 (IL-6), cellular tumor antigen p53 (TP53), tumor necrosis factor (TNF), transcription factor AP-1 (JUN), caspase-3 (CASP3), matrix metalloproteinase-9 (MMP9), interleukin-8 (IL-8), prostaglandin G/H synthase 2 (PTGS2), proto-oncogene c-Fos (FOS), tyrosine-protein kinase SRC (SRC), c-Jun N-terminal kinase 1 (MAPK8), estrogen receptor 1 (ESR1)] and 46 pathways (including NF-kappa B signaling pathway, Toll-like receptor signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, arachidonic acid metabolism, cAMP signaling pathway, T cell receptor signaling pathway, calcium signaling pathway, inflammatory mediator regulation of TRP channels, chemokine signaling pathway, Th1 and Th2 cell differentiation, natural killer cell mediated cytotoxicity, etc.) were related to anti-inflammatory, antipyretic, immune regulation, and analgesia. In vitro cell experiments showed that FYM and the 10 components (including isoquercitrin, luteoloside, baicalein, wogonin, wogonoside, phillyrin, forsythoside A, chlorogenic acid, isochlorogenic acid A, and sweroside) could significantly reduce the expression of nitric oxide (NO), TNF-α and IL-6 in cell supernatants, indicating that the above 10 components may be the key pharmacodynamic material basis of FYM.
There is no specific drug against COVID-19, but berberine (BBR) has moderate anti-SARS-CoV-2 pseudovirus activity. Taking BBR as the lead, 18 novel N-cycloberberine derivatives were synthesized and evaluated for their anti-SARS-CoV-2 pseudovirus activities in vitro. Structure-activity relationship analysis revealed that introducing an appropriate heterocyclic group at position 9 might be beneficial for potency. Among the tested compounds, compound 3m showed the most potent activity against SARS-CoV-2, with EC50 value of 1.61 μmol·L-1 and SI value of 22.2, much better than that of BBR. Additional experiment indicated that 3m had inhibitory activity on multiple processes in viral invasion, including adsorption and membrane fusion, suggesting a multi-target synergistic mechanism of action. These results provide a novel family of lead compounds for the discovery of anti-SARS-CoV-2 candidates.
Dammarane-type triterpenoid saponins are regarded as the main active constituents of Gynostemma longipes C.Y.Wu. By using MCI and silica gel column chromatography, as well as preparative HPLC, we isolated four new dammarane-type triterpenoid saponins from the polar saponin fraction of G. longipes C.Y.Wu. Their structures were determined by comprehensive analyses of NMR and MS data and identified as (20S)-3β, 20, 21-trihydroxydammar-19-oxo-24-ene-3-O-{[α-L-rhamnopyranosyl(1→2)]-[β-D-xylopyranosyl(1→3)]-α-L-arabinopyranosyl}-21-O-β-D-glucopyranosyl(1→6)-β-D-glucopyranoside (1), (20S)-3β, 20, 21-trihydroxydammar-24-ene-19-oxo-3-O-[α-L-rhamnopyranosyl(1→2)]-[β-D-xylopyranosyl(1→3)]-α-L-arabinopyranosyl-21-O-α-L-rhamnopyranosyl(1→6)-β-D-glucopyranoside (2), (20S)-3β, 19, 20, 21-terahydroxydammar-24-ene-3-O-{[α-L-rhamnopyranosyl(1→2)]-[β-D-xylopyranosyl(1→3)]-α-L-arabinopyranosyl}-21-O-[β-D-glucopyranosyl(1→6)]-β-D-glucopyranoside (3), (20S)-3β, 20, 21-trihydroxydammar-24-ene-3-O-{[α-L-rhamnopyranosyl(1→2)]-[β-D-glucopyranosyl(1→3)]-β-D-glucopyranosyl}-21-O-[β-D-glucopyranosyl(1→6)]-β-D-glucopyranoside (4). Compounds 1-4 are new dammarane-type triterpenoid saponins which contain five glycosyl residues.
Research on polymer impurities has always been important in the quality control of cephalosporins. Research on polymers in cephalosporins that lack active amino groups on the C-7 side chain has not been reported. Therefore, our study used cefazolin sodium, which is widely used in the clinic, as an example. The polymer in cefazolin sodium and its product "cefazolin sodium pentahydrate for injection" was analyzed by column switching liquid chromatography-high resolution mass spectrometry. Two polymer impurity peaks were detected and the possible structures of these polymers were suggested. Through two-dimensional liquid chromatography, the chromatographic peaks following Sephadex gel chromatography and high-performance gel chromatography were compared to those obtained by reverse high-performance liquid chromatography (HPLC) for cefazolin sodium as reported in the Chinese Pharmacopoeia. The HPLC method proves more suitable for polymer detection than Sephadex gel chromatography and high-performance gel chromatography. The method of polymer detection for cefazolin sodium was established using the method of related substances HPLC as described in the Chinese Pharmacopoeia.
The compatibility of kanamycin with sodium citrate for the formulation of kanamycin sulfate injection was determined, including optimization of the amount of sodium citrate in the injection and the sterilization process. An HPLC coupled with an evaporative light scattering detector (ELSD) was used to measure the amount of sodium citrate and the impurity profiles. A validated post-column derivatization HPLC coupled with a fluorescence detector (FLD) was used to determine the correlation between specific impurities in a domestic factory and sodium citrate, and then the formulation was evaluated by HPLC coupled with mass detector (MS) characterization of degradation products. The results show that the amount of sodium citrate in kanamycin sulfate injection from a domestic factory is about 40 times higher than that of the Meiji formulation. Several specific impurities can be detected in solutions heated under simulated sterilization conditions (121 ℃), which were correlated with the amount of sodium citrate. Impurities were characterized by HPLC-MS/MS, and data showed that the identified impurities were interaction products of kanamycin and sodium citrate. These results indicate that greater attention should be directed at formula optimization in domestic factories, as it is crucial to the safety and efficacy of the preparations. Drug-excipient chemical compatibility should also be evaluated in the development of pharmaceutical dosages forms especially when the active pharmaceutical ingredients have a primary amine group.
The intestinal absorption properties of the main effective components (glycyrrhizic acid, isoliquiritigenin, 6-gingerol, ginsenoside Rb1, atractylode-Ⅰ) in Lizhong decoction (LZD) extracts were investigated with an in situ single-pass intestinal perfusion model in rats. UPLC-TQ-MS was used to determine the concentration of the five components in the intestinal perfusion. Animal welfare and experimental procedures were in accordance with the regulations of the Animal Ethics Committee of Nanjing University of Chinese Medicine. As evaluation indexes for the intestinal absorption characteristics, the absorption rate constant (Ka) and the apparent permeability coefficient (Peff) of the five main ingredients were analyzed. Results showed that the best absorption sites for glycyrrhizic acid, isoliquiritin and 6-gingerol were the ileum, colon and duodenum, respectively, and the differences between different intestinal segments were statistically significant (P < 0.05). There was no notable difference in Ka and Peff between ginsenoside Rb1 and atractylode-Ⅰ in the different intestinal segments (P > 0.05), suggesting that they were absorbed throughout. The five components were well-absorbed in the whole intestine (Peff > 1.0×10-3 cm·min-1), indicating that LZD is suitable for preparing sustained, controlled release and enteric-coated preparations.
No. 86 Xueyuan South Road, Haidian District, Beijing
010-62662699(Operation and Technical Support)
qkjq@cast.org.cn
Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House
