Autophagy, an evolutionarily conserved process by which components of the cell are degraded in lysosomes, may facilitate survival of cancer cells under stress conditions. 8-Azaguanine (8-AG), an inhibitor of purine nucleotide biosynthesis, shows antineoplastic activity in multiple tumor cells. However, chemoresistance has restricted its development as an anticancer agent, and the mechanism of 8-AG resistance is not fully understood. We report here that 8-AG induces a protective autophagy to eliminate its cytotoxicity, and inhibition of autophagy increases cellular sensitivity of cancer cells to 8-AG treatment. Using HepG2 or SMMC-7721 hepatic cancer cell lines, we found that 8-AG inhibited cell viability and induced intrinsic apoptosis, accompanied by the up-regulation of the pro-apoptotic protein BimS, one of Bim (also known as BCL-2-like protein 11, BCL2L11) isoforms. Furthermore, 8-AG treatment enhanced the autophagy flux by promoting the dephosphorylation and activation of Unc-51-like autophagy activating kinase 1 (ULK1) via Akt/mTORC1 (mammalian target of rapamycin complex 1) signaling inhibition. Depletion of autophagy-related gene 7 (ATG7) markedly enhanced the level of BimS, and promoted cell death in response to 8-AG. 8-AG in combination with autophagy inhibitor chloroquine (CQ) or bafilomycin A1 (Baf A1) promoted the 8-AG-induced apoptosis in hepatic cancer cells. Altogether, these findings suggest that autophagy promotes chemoresistance of cancer cells for 8-AG, and blocking autophagy increases cellular sensitivity of cancer cells to 8-AG treatment.

Multi-template molecularly imprinted solid phase extraction not only has the advantages of high selectivity, large adsorption capacity, easy preparation, reuse and low environmental pollution, but also can realize the enrichment and separation of many kinds of compounds. It has attracted wide attention in the extraction and separation of traditional Chinese medicine components. This study summarizes the latest development of multi-template molecularly imprinted solid phase extraction. At the same time, based on the classification of active components of traditional Chinese medicine (flavonoids, alkaloids, phenylpropanol, terpenes, etc.), the latest application of multi-template molecular imprinting solid phase extraction in multi-component separation of traditional Chinese medicine was reviewed, with a view to better application of multi-template molecularly imprinted polymer in active multi-component extraction and separation of traditional Chinese medicine and provide reference for the material basic research of the efficacy of traditional Chinese medicine.

This study investigated the mechanism by which icaritin (ICT) inhibits exosomes-induced lung metastasis of B16BL6 mouse melanoma cells. The culture supernatant of B16BL6 cells was collected for extraction of exosomes by ultracentrifugation and their characterization by transmission electron microscopy and Western blotting. Exosomal protein was quantified by BCA. A wound-healing assay was used to determine the effect of ICT on the migratory ability of B16BL6 cells induced by exosomes. After establishing an experimental melanoma lung metastasis model in C57BL/6 mice, we used H & E staining to study the ability of ICT to inhibit exosomes-induced melanoma metastasis. Animal experiments were approved by the Ethics Committee of Nanjing University of Chinese Medicine. ELISA and immunofluorescence were used to detect pro-inflammatory factors interleukin 6 (IL-6), S100 calcium-binding protein A8/A9 complex (S100A8/A9), serum amyloid A (SAA) and fibronectin in metastatic tumors. The expression of metastatic tissue-related proteins stimulator of interferon gene (STING), phospho-STING (p-STING), TANK-binding kinase 1 (TBK1) and phospho-TBK1 (p-TBK1) was detected by immunohistochemistry or Western blotting. The results showed that the particle size of exosomes was 149.33±2.68 nm, the polydispersity index (PDI) was 0.192±0.02, the zeta potential was -32.22±0.50 mV, and the particles had classic tea tray-like membrane structure under TEM. The protein concentration of exosomes was measured to be 838.66±62.14 μg·mL^-1. The results of the cell scratch test showed that ICT can inhibit exosomes-induced migration of B16BL6 cells at a concentration of 5, 10, and 20 μmol·L^-1. In vivo experimental results also showed that ICT can inhibit exosomes-induced metastasis of melanoma to the lungs and can significantly inhibit the expression of pro-inflammatory factors S100A8/A9, SAA and IL-6 in lung tissue, and inhibit the expression of p-STING and p-TBK1 in metastatic lung tissue. Taken together, these results indicated that ICT can significantly inhibit exosomes-induced tumor metastasis, and the inhibition is related to the inactivation of STING in metastatic foci.

Drug-induced liver injury and herbal preparations containing pyrrolizidine alkaloid (PA) have gained global attention. The purpose of this research was to investigate the effects and mechanisms of Alismatis Rhizoma, a traditional Chinese medicine, to protect against acute liver injury in mice induced by senecionine (SEN), a representative toxic PA compound. All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine. Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine. Acute liver injury was induced by a single intragastric administration of SEN (50 mg·kg^-1). Mice in the protection groups received intragastric administration of Alismatis Rhizoma water extract (WE, 18 g·kg^-1 per day) or ethanol extract (EE, 18 g·kg^-1 per day) 5 days before SEN treatment. The results show that Alismatis Rhizoma extracts can significantly attenuate acute liver injury in mice. Mice in the protection groups showed decreased serum activities of alanine aminotransferase and aspartate aminotransferase, as well as decreased total bile acids. In addition, the infiltration of inflammatory cells, sinusoidal hemorrhage, and hepatic necrosis in SEN-treatment mice was clearly attenuated in the protection groups. Interestingly, EE showed a better effect than WE. The content of principal bile acids in serum and the mRNA and protein expression of key factors related to bile acid metabolism were also measured. Alismatis Rhizoma up-regulated the bile acid transporters and drug metabolism enzymes, consistent with the observed bile acid homeostasis and alleviation of SEN-induced injury to hepatocytes. The present study points to the possibility of utilizing Alismatis Rhizoma for protection against liver injury caused by drugs and preparations containing PA.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the degradation of tryptophan to kynurenine. IDO1 is highly expressed in some tumor tissues. IDO1 can deplete tryptophan in tumor microenvironment, inhibit T cell function, and mediate the immune escape of tumor cells. Thus, IDO1 is considered a potential target of tumor immunotherapy. Currently, there are several IDO1 inhibitors in clinical research studies. The mechanism of IDO1-mediated tumor immune escape and the structure of IDO1 inhibitors are summarized in this review.

Nucleotide binding oligomerization domain (NOD)-like receptor protein 3, NLRP3) inflammasomes regulate the secretion of caspase-1, interleukin-18 (IL-18), IL-1β, and other cytokines, and participates in aging. In recent years, it has been found that NLRP3 inflammasomes are abnormally activated in aging heart and vessels, and inhibition of NLRP3 inflammasomes can alleviate heart aging and vascular aging. This review summarizes the research of NLRP3 inflammasome in heart and vascular aging, and the related drugs to promote the discovery of the mechanism of NLRP3 inflammasome in heart and vascular aging and the development of related drugs.

Blood-brain barrier (BBB) is the most challengeable obstacle for brain-targeted drug delivery. The combination of focused ultrasound (FUS) and microbubbles provides a new way for brain-targeted drug delivery across BBB based on the cavitation effect. This review briefly described the recent research of FUS combined with microbubbles to enhance the BBB permeability for brain-targeted drug delivery. The contents included the FUS mechanism, the types of the commercial microbubbles, shell materials, inner gas and preparation techniques of microbubbles, the opening mechanism of FUS with microbubbles, and the safety consideration. FUS combined with microbubbles may be the effective strategy to improve the BBB permeability for brain-targeted delivery, which could provide references for the clinical applications.

Five cadinane-type sesquiterpenoids were isolated from the n-hexane extract of Commiphora myrrha by using various chromatographic techniques, including silica gel, ODS and semi-preparative HPLC. Their structures were identified by physicochemical properties and spectroscopic data. These compounds were defined as (3S, 4R)-3, 9-dimethoxymyrrhone (1), 9-methoxymyrrhone (2), myrrhone (3), commiterpene B (4) and comosone Ⅱ (5). Compound 1 is a new compound, of which the absolute configuration was established by single crystal X-ray crystallographic analysis. Compound 5 is firstly isolated from the Commiphora genus.

Sempervirine, a yohimbane-type alkaloid isolated from Gelsemium elegans, was found to significantly inhibit the cellular proliferation of U251 cells in vitro and in vivo in a dose-dependent manner. U251 cells were treated with 0-16 μmol·L^-1 of sempervirine for 24, 48 or 72 h. An MTT assay and clone formation assay were used to investigate cell survival and clone formation. Hoechst staining and Annexin V-FITC/PI staining were used to measure cell apoptosis. The expression of PI3K, AKT, p-AKT, Bax, Bcl-2, caspase-3 and cleaved caspase-3 was determined by Western blot analysis. The antitumor effect of sempervirine in vivo was investigated by inoculating nude mice with U251 cells. All animal experiments were in strict accordance with the regulations of the Biomedical Ethics Committee of Fujian Medical University (Fujian, China). The results show that sempervirine significantly inhibits the proliferation and induces the apoptosis of U251 cells, promotes cleavage of caspase-3, down-regulates the protein expression of PI3K and Bcl-2/Bax, and inhibits phosphorylation of AKT in vitro. Intraperitoneal injection of 4 or 8 mg·kg^-1·day^-1 of sempervirine inhibits U251 cells tumor growth in the xenograft nude mice, and tumor weight decreased by 44.76% and 61.26%, respectively. Our study shows that sempervirine significantly inhibits the proliferation of U251 cells in vitro and in vivo, laying a foundation for further research and development of its anti-glioma effect.

Selective activation or inhibition of the angiotensin Ⅱ type 2 (AT₂) receptor can cause vasodilation, decrease cell proliferation, promote neurite outgrowth and block neuronal excitability. The AT₂ receptor can be used as a potential drug target for the treatment of cardiovascular diseases, fibrosis, inflammation, neuronal diseases and tumors. Research and development of new drugs that selectively act on the AT₂ receptor and the mechanism of intracellular signal transduction involving the AT₂ receptor is a challenging but worthy endeavor. We review research progress on the AT₂ receptor and compounds that act on the AT₂ receptor, along with structure-activity relationship analysis, to provide reference and guidance for further research in this field.