Antibacterial activities of anthraquinones: structure-activity relationships and action mechanisms.

With the increasing prevalence of untreatable infections caused by antibiotic-resistant bacteria, the discovery of new drugs from natural products has become a hot research topic. The antibacterial activity of anthraquinones widely distributed in traditional Chinese medicine has attracted much attention. Herein, the structure and activity relationships (SARs) of anthraquinones as bacteriostatic agents are reviewed and elucidated. The substituents of anthraquinone and its derivatives are closely related to their antibacterial activities. The stronger the polarity of anthraquinone substituents is, the more potent the antibacterial effects appear. The presence of hydroxyl groups is not necessary for the antibacterial activity of hydroxyanthraquinone derivatives. Substitution of di-isopentenyl groups can improve the antibacterial activity of anthraquinone derivatives. The rigid plane structure of anthraquinone lowers its water solubility and results in the reduced activity. Meanwhile, the antibacterial mechanisms of anthraquinone and its analogs are explored, mainly including biofilm formation inhibition, destruction of the cell wall, endotoxin inhibition, inhibition of nucleic acid and protein synthesis, and blockage of energy metabolism and other substances.

Casticin and chrysosplenol D from Artemisia annua L. induce apoptosis by inhibiting topoisomerase IIα in human non-small-cell lung cancer cells.

BACKGROUND: Artemisia annua L. (A. annua) and its active components exhibit antitumour effects in many cancer cells. However, the biological processes and mechanisms involved are not well understood, especially for the treatment of non-small-cell lung cancer (NSCLC). PURPOSE: This study aimed to comprehensively explore the biological processes of A. annua and its active components in NSCLC cells and to identify the mechanism by which these compounds induce apoptosis. STUDY DESIGNS/METHODS: Cell viability and flow cytometry assays were used to evaluate the cytotoxicity of A. annua active components casticin (CAS) and chrysosplenol D (CHD) in A. annua in NSCLC cells. After treatment with CAS and CHD, A549 cells were subjected to RNA sequencing (RNA-seq) analysis, differentially expressed genes (DEGs) were screened and subjected to functional enrichment analysis (KEGG and GO analysis) as well as protein interaction network analysis. The key targets associated with apoptosis induction in A549 cells were screened by Cytoscape, and the screened DEGs were validated by qRT-PCR. Immunoblotting, immunofluorescence, and molecular docking assays were used to determine whether CAS and/or CHD could induce apoptosis in NSCLC cells by inducing DNA damage through down-regulation of topoisomerase IIα (topo IIα) expression. The same experiments were verified again in the H1299 lung cancer cell line. RESULTS: CAS and CHD inhibited NSCLC cells proliferation in a time- and dose-dependent manner, and significantly induced apoptosis. A total of 115 co-upregulated DEGs and 277 co-downregulated DEGs were identified in A549 cells following treatment with CAS and CHD. Comprehensive and systematic data about biological processes and mechanisms were obtained. DNA damage pathways and topo IIα targets were screened to study the apoptosis effects of CAS and CHD on NSCLC cells. CAS and CHD may be able to induce DNA damage by binding to topo IIα-DNA and reducing topo IIα activity. CONCLUSION: This study suggested that CAS and CHD may reduce topo IIα activity by binding to topo IIα-DNA, affecting the replication of DNA, triggering DNA damage, and inducing apoptosis. It described a novel mechanism associated with topo IIα inhibition to reveal a novel role for CAS and CHD in A. annua as potential anticancer agents and/or adjuvants in NSCLC cells.

[Research advances of biosynthesis, in vivo analysis and pharmacokinetics of chemical constituents in Artemisiae Annuae Herba].

Artemisiae Annuae Herba is a traditional Chinese medicine for clearing deficiency and heat. It is the only natural source of artemisinin, which is a specific antimalarial drug, and has been widely concerned all over the world. In addition to artemisinin, Artemisiae Annuae Herba also contains many sesquiterpenes, coumarins, flavonoids, volatile oils, polysaccharides and other chemical components, which show antipyretic, anti-inflammatory, antiviral microorganisms, anti-asthma, anti-oxidation, anti-tumor and other pharmacological activities. In addition to their own pharmacological activities, some components could enhance the antimalarial activity of artemisinin through different mechanisms at absorption and metabolism in vivo. In order to understand the pharmacokinetic characte-ristics of the chemical constituents contained in Artemisiae Annuae Herba and provide reference for the full development and clinical utilization of Artemisiae Annuae Herba resources in China, this present paper systematically collated the modern research literatures, and summarized the biosynthesis, in vivo analysis and pharmacokinetics of the chemical constituents in Artemisiae Annuae Herba.

Acute and subchronic toxicity of arprinocid in Sprague-Dawley rats.

We subjected Sprague-Dawley rats to an acute and 13-week subchronic oral toxicity of arprinocid, a nucleoside analogue used as a coccidiostat, according to toxicological guidelines as part of its safety assessment. In the acute study, arprinocid was administered once by oral gavage to rats at doses ranging from 292.4 to 506.0mg/kgb.w. The calculated LD50 was 442.9mg/kgb.w. in males and 378.7mg/kgb.w. in females. In the subchronic study, male and female rats were fed with diets supplemented with 0, 25, 187.5 or 500ppm arprinocid for 13weeks. Significantly lower body weights were noted in the 500ppm group females. The mean body weights of the 500ppm group females were 12.9% lower than that of the controls. Significant differences in haematological and biochemical parameters as well as organ weights were detected between the 500 and 187.5ppm groups. Histopathological observations revealed that 500 and 187.5ppm arprinocid could induce hepatic steatosis and focal hepatocellular necrosis. Slight protein cast in some renal tubules and tubular regeneration were observed in the high dose group of both genders. The dietary no-observed-adverse-effect level (NOAEL) of arprinocid in rats for 13weeks is 25ppm (approximately 1.7mg/kgb.w./day).

Nitazoxanide inhibits the replication of Japanese encephalitis virus in cultured cells and in a mouse model.

BACKGROUND: Japanese encephalitis virus (JEV) has a significant impact on public health. An estimated three billion people in 'at-risk' regions remain unvaccinated and the number of unvaccinated individuals in certain Asian countries is increasing. Consequently, there is an urgent need for the development of novel therapeutic agents against Japanese encephalitis. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. Recently, NTZ has been demonstrated to have antiviral properties. In this study, the anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model. METHODS: JEV-infected cells were treated with NTZ at different concentrations. The replication of JEV in the mock- and NTZ-treated cells was examined by virus titration. NTZ was administered at different time points of JEV infection to determine the stage at which NTZ affected JEV replication. Mice were infected with a lethal dose of JEV and intragastrically administered with NTZ from 1 day post-infection. The protective effect of NTZ on the JEV-infected mice was evaluated. FINDINGS: NTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 µg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 µg/ml). The chemotherapeutic index calculated was 154.92. The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells. NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection. The anti-JEV effect of NTZ was also demonstrated in vivo, where 90% of mice that were treated by daily intragastric administration of 100 mg/kg/day of NTZ were protected from a lethal challenge dose of JEV. CONCLUSIONS: Both in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis.