A metal ions-mediated natural small molecules carrier-free injectable hydrogel achieving laser-mediated photo-Fenton-like anticancer therapy by synergy apoptosis/cuproptosis/anti-inflammation.

Tumor microenvironment (TME) plays an important role in the tumorigenesis, proliferation, invasion and metastasis. Thereby developing synergistic anticancer strategies with multiple mechanisms are urgent. Copper is widely used in the treatment of tumor chemodynamic therapy (CDT) due to its excellent laser-mediated photo-Fenton-like reaction. Additionally, copper can induce cell death through cuproptosis, which is a new modality different from the known death mechanisms and has great promise in tumor treatment. Herein, we report a natural small molecules carrier-free injectable hydrogel (NCTD Gel) consisted of Cu2+-mediated self-assembled glycyrrhizic acid (GA) and norcantharidin (NCTD), which are mainly governed by coordination and hydrogen bonds. Under 808 nm laser irradiation, NCTD Gel can produce reactive oxygen species (ROS), consume glutathione (GSH) and overcome hypoxia in TME, leading to synergistically regulate TME via apoptosis, cuproptosis and anti-inflammation. In addition, NCTD Gel's CDT display high selectivity and good biocompatibility as it relies on the weak acidity and H2O2 overexpression of TME. Notably, NCTD Gel's components are originated from clinical agents and its preparation process is easy, green and economical, without any excipients. This study provides a new carrier-free hydrogel synergistic antitumor strategy, which has a good prospect in industrial production and clinical transformation.

Strip intercropping with local crops increased Aconitum carmichaeli yield and soil quality.

Aconitum carmichaeli Debx. is a traditional Chinese medicine that is cultivated in China and Japan. However, the monoculturing of this herb substantially decreases soil quality. Therefore, scientific planting management is crucial for resolving the current problems in the cultivation of A. carmichaeli. In this study, we conducted a comparative study on the soil environmental characteristics, herb growth and quality of A. carmichaeli intercropping with five local crops in two different areas. Herb growth and quality, including biomass and secondary metabolites, and rhizosphere soil environmental characteristics were measured. The results showed that the intercropping with the five local crops substantially improved the A. carmichaeli biomass and polysaccharide content, decreased the disease index, and altered three monoester diterpenoid alkaloids and three diester diterpenoid alkaloids accumulations. The intercrops also increased the soil pH, nitrogen-cycling-gene abundances, and potentially beneficial microorganism abundances, and it also changed the soil nutrient levels. Moreover, these intercropping patterns could alleviate the continuous cropping obstacles of A. carmichaeli. According to a comprehensive evaluation of the A. carmichaeli growth and quality, as well as the soil quality, the best intercropping systems were the A. carmichaeli intercropping with rice, maize, and peanut. In summary, the strip-intercropping systems could improve the A. carmichaeli growth and soil quality, and be beneficial to the sustainable ecological planting of A. carmichaeli.

Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium chrysotoxum Lindl, a well-known traditional Chinese medicinal herb used in the treatment of gastric disease, is distinguished as the first of the "nine immortal grasses". Dendrobium chrysotoxum Lindl and the traditional Chinese medicine prescriptions containing Dendrobium chrysotoxum Lindl are often prescribed clinically to treat chronic gastritis and precancerous lesions of gastric cancer (PLGC), showing favorable clinical effects and medicinal value in the prevention of gastric cancer. However, the effective ingredients and pharmacological mechanisms through which Dendrobium chrysotoxum Lindl prevents and treats PLGC have not been adequately identified or interpreted. AIM OF THE STUDY: The present study aimed to evaluate the effective ingredients and pharmacological mechanisms of Dendrobium chrysotoxum Lindl in the prevention and treatment of PLGC using network pharmacology. In addition, in vitro verification was performed to evaluate the mechanism of action of Erianin, the main active ingredient in Dendrobium chrysotoxum Lindl, providing experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl in the treatment of PLGC. MATERIALS AND METHODS: Using network pharmacology methods, the main ingredients in Dendrobium chrysotoxum Lindl were screened from the ETCM, BATMAN-TCM, and TCMID databases, and their potential targets were predicted using the Swiss Target Prediction platform. The targets related to PLGC were retrieved through the GeneCard database, and the targets common to the main ingredients of Dendrobium chrysotoxum Lindl and PLGC were analyzed. The protein-protein interaction (PPI) network was obtained via the STRING database and analyzed visually using Cytoscape 3.7.2. The underlying mechanisms of the common targets identified through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were analyzed using DAVID online. The "component-target-pathway" networks of Dendrobium chrysotoxum Lindl and Erianin were visually constructed by Cytoscape 3.7.2. The biological activity evaluation of Erianin's effect on PLGC was carried out using MC cell lines, the PLGC cell model established using MNNG to induce damage in normal gastric mucosal epithelial cell (GES-1). After the intervention of different concentrations of Erianin, MC cell viability was explored using the MTT assays, cell migration was determined by wound healing assays, the cell cycle and apoptosis were analyzed using flow cytometry, and the expression levels of related proteins and their phosphorylation in the HRAS-PI3K-AKT signaling pathway were detected by Western blot. RESULTS: The "component-target-pathway" network constructed in this study showed 37 active ingredients from Dendrobium chrysotoxum Lindl and 142 overlapping targets related to both Dendrobium chrysotoxum Lindl and PLGC. The targets were associated with a variety of cancer-related signaling pathways, including Pathways in cancer, PI3K-Akt signaling pathway, Rap1 signaling pathway, Focal adhesion, Ras signaling pathway, and MAPK signaling pathway. Notably, the network showed that Erianin, the primary active ingredient from Dendrobium chrysotoxum Lindl and the component associated with the most targets, could regulate Pathways in cancer, PI3K-AKT signaling pathway, Focal adhesion, Rap1 signaling pathway, cell cycle, and RAS signaling pathway in the treatment of PLGC. Verification through in vitro experiments found that Erianin can significantly inhibit MC cell viability, inhibit cell migration, block the cell cycle in the G2/M phase, and induce cell apoptosis in a dose-dependent manner. The results of the Western blot experiment further showed that Erianin can significantly decrease the protein expression levels of HRAS, AKT, p-AKT, MDM2, Cyclin D1, and p-Gsk3ß, and increase the protein expression level of p21, which suggests that Erianin can treat PLGC by regulating the HRAS-PI3K-AKT signaling pathway. CONCLUSION: This study explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with Dendrobium chrysotoxum Lindl in the treatment of PLGC. Our results suggest that Erianin may be a promising candidate in the development of prevention and treatment methods for PLGC. This study provided experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl to treat PLGC and prevent gastric cancer.

SERPINE2 promotes esophageal squamous cell carcinoma metastasis by activating BMP4.

Metastasis is a major lethal cause of esophageal squamous cell carcinoma (ESCC) and confers a poor prognosis. Previous studies demonstrated that serpin family E member 2 (SERPINE2) is involved in tumor metastasis. However, the function and mechanism of SERPINE2 in ESCC metastasis remains unclear. In this study, we found that SERPINE2 was increased in ESCC and associated with tumor metastasis. SERPINE2 knockdown inhibited tumor cell invasion and lymph node and lung metastasis by inducing epithelial-mesenchymal transition (EMT). We identified a total of 410 differentially expressed genes in SERPINE2-knockdown cells by RNA-Seq analysis. Among them, bone morphogenetic protein 4 (BMP4) was significantly downregulated. Conversely, BMP4 was increased in SERPINE2-overexpressing cells. Inhibiting BMP4 could attenuate SERPINE2-induced migration and invasion. Moreover, SERPINE2 was positively correlated with clinical stage, tumor invasion depth and lymph node metastasis in ESCC patients. These findings suggest that SERPINE2 promotes tumor metastasis by activating BMP4 and could serve as a potential therapeutic target for clinical intervention in ESCC.

ATP-P2Y2-ß-catenin axis promotes cell invasion in breast cancer cells.

Extracellular adenosine 5'-triphosphate (ATP), secreted by living cancer cells or released by necrotic tumor cells, plays an important role in tumor invasion and metastasis. Our previous study demonstrated that ATP treatment in vitro could promote invasion in human prostate cancer cells via P2Y2, a preferred receptor for ATP, by enhancing EMT process. However, the pro-invasion mechanisms of ATP and P2Y2 are still poorly studied in breast cancer. In this study, we found that P2Y2 was highly expressed in breast cancer cells and associated with human breast cancer metastasis. ATP could promote the in vitro invasion of breast cancer cells and enhance the expression of ß-catenin as well as its downstream target genes CD44, c-Myc and cyclin D1, while P2Y2 knockdown attenuated above ATP-driven events in vitro and in vivo. Furthermore, iCRT14, a ß-catenin/TCF complex inhibitor, could also suppress ATP-driven migration and invasion in vitro. These results suggest that ATP promoted breast cancer cell invasion via P2Y2-ß-catenin axis. Thus blockade of the ATP-P2Y2-ß-catenin axis could suppress the invasive and metastatic potential of breast cancer cells and may serve as potential targets for therapeutic interventions of breast cancer.