Anti-inflammatory activities of natural cyclopeptide RA-XII in colitis-associated colon cancer mouse model and its effect on gut microbiome.

Colorectal cancer (CRC), the third most common cancer globally, is associated with intestinal inflammation that leads to poor prognosis. RA-XII, a natural cyclopeptide, has previously been reported to possess anti-tumor activities. Here, the anti-inflammatory activities of RA-XII were investigated in colitis-associated colon cancer mice and a co-culture in vitro model, in which colon cancer cells HCT116 and macrophages RAW264.7 were grown together to mimic the inflammatory microenvironment of CRC. Changes of inflammatory-related molecules and protein expressions in cells were evaluated after RA-XII incubation. Besides, azoxymethane and dextran sulfate sodium-induced colitis-associated colon cancer mice were treated with RA-XII for 24 days, inflammatory parameters and gut microbiome alterations were studied. Our results showed that RA-XII reversed the inflammatory responses of RAW264.7 cells induced by LPS and modulated the protein expressions of AKT, STAT3/p-STAT3, P70S6K, NF-κB and GSK3ß and suppressed the expression of LC3A/B in HCT116 cells in co-culture system. RA-XII treatment restored the colitis damage in colon, reduced colon tumors numbers and decreased inflammatory factors (IL-6, IL-10 and TNF-α). The role of RA-XII on regulating gut microbiome was also demonstrated for the first time. In conclusion, our findings provided new scientific evidence for developing RA-XII as a potent anti-inflammatory agent for CRC.

Network pharmacology reveals potential functional components and underlying molecular mechanisms of Andrographis paniculata in esophageal cancer treatment.

Antitumor and antimetastatic effects of the medicinal herb Andrographis paniculata (AP) in esophageal cancer (EC) have been previously reported. In this study, we aimed to uncover the potential functional components and the underlying molecular mechanisms of AP in EC treatment using network pharmacology and experimental validation. Twenty-two potential active AP compounds against EC were revealed, including the antitumor/antiinflammatory compounds panicolin, moslosooflavone, and deoxyandrographiside. Epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), RAC-alpha serine/threonine-protein kinase (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), chemokine (C-X-C motif) ligand 8 (CXCL8), phosphatidylinositol 4,5-bisphosphate 3-kinase subunit alpha (PIK3CA), and toll-like receptor 4 (TLR4) were most highly ranked among the predicted targets of AP in EC treatment and may play important roles in the anti-EC effects of AP. KEGG pathway analysis revealed the enrichment of multiple cancer-related pathways and signaling pathways. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting validation showed that overnight treatment with 850.3 µg/ml of AP water extract significantly reduced the mRNA expressions of EGFR and AKT in human EC-109 cells. The presence of panicolin and moslosooflavone in the AP water extract samples were confirmed using LC-MS against reference standards. This study has comprehensively revealed for the first time the potential functional components of AP in EC and explored the underlying molecular mechanisms. Future studies should characterize the potential pharmacological properties of the other highly ranked yet understudied compounds in AP detected.

Functional roles of eriocalyxin B in zebrafish revealed by transcriptome analysis.

BACKGROUND: Eriocalyxin B (EriB) is a natural ent-kaurane diterpenoid obtained from Isodon eriocalyx var. laxiflora (family Lamiaceae), which has multiple biological activities (e.g. anti-tumor and anti-inflammatory) via the alteration of gene expression and signaling transduction. Recently, RNA sequencing (RNA-seq) has been developed as a dynamic transcriptome approach to analyze the transcriptional profile and in addition use such gene expression profiles to identify novel candidate genes in a zebrafish model. In the present study, a transcriptome analysis was performed to identify differentially expressed genes (DEGs) in an EriB-exposed zebrafish model. RESULTS: RNA sequencing was conducted on zebrafish embryos after EriB (10 µM and 15 µM) treatment for 72 h. A total of 1570 (405 up-regulated and 1165 down-regulated) and 2511 genes (543 up-regulated and 1968 down-regulated) were identified in the 10 µM and 15 µM groups, respectively. Gene ontology analysis was then performed to elucidate the mechanism of action and effects of EriB. We found that 4 pathways were significantly enriched, which include glutathione metabolism, the metabolism of xenobiotics by cytochrome P450, tight junctions, and phototransduction. The critical transcriptional regulators for the DEGs were also identified by Ingenuity Pathway Analysis after the construction of a protein-protein network, which involves p53, c-myc, binding transcription factor 2, sterol regulatory element binding transcription factor 2, nuclear factor erythroid 2 like 2, and interferon regulatory factor 3. CONCLUSION: In summary, this is the first study to comprehensively explore the effects of EriB in a zebrafish model using a transcriptome analysis approach. Several important genes with substantial changes in expression levels were discovered. The results of this study will provide insights for the future investigation on the biological activities or toxic effects of EriB.