Piceatannol Prevents Colon Cancer Progression via Dual-Targeting to M2-Polarized Tumor-Associated Macrophages and the TGF-ß1 Positive Feedback Signaling Pathway.

SCOPE: M2 phenotype tumor-associated macrophages (M2-TAMs) play a key role in distant metastasis and poor clinical outcomes. Herein, a specific molecular mechanism that contributes to malignant progression is illuminated and investigates whether piceatannol (PIC) can target the crosstalk between M2-TAMs and cancer cells for potential colorectal cancer (CRC) therapy. METHODS AND RESULTS: To mimic the tumor microenvironment (TME), direct and indirect coculture systems in vitro and in vivo mouse xenograft models are established. The results demonstrate that post-treatment with PIC in TME more effectively prevented the aggressive features and stemness of SW480 cells by restricting the polarization of M2-like macrophages and blocking the transforming growth factor ß1 (TGF-ß1) positive feedback autocrine/paracrine loop that exists between M2-like polarized macrophages and cancer cells. Furthermore, xenograft assays also observe significant repression in tumor growth and lung metastases with the administration of PIC. The key mechanism underlying the antimetastasis effects of PIC may include its directly inhibitory activity against TGF-ß receptor type-1 (TGF-ßR1) in the M2-like TAMs-created TME. CONCLUSION: These novel findings demonstrate that PIC is a potent TGF-ß1/TGF-ßR1 pathway inhibitor and TME modulator for preventing tumor progression and metastasis in CRC by reeducating TAMs.

Drought stress induces biosynthesis of flavonoids in leaves and saikosaponins in roots of Bupleurum chinense DC.

Drought stress affects vegetative and reproductive growth processes and synthesis of secondary metabolites in plants. We assessed relevant indicators of vegetative and reproductive growth in Bupleurum chinense DC. during drought stress. Samples were collected on days 4, 8, 12, 20, and 24 of a drought treatment according to drought stress severity in order to elucidate potential effects on synthesis of flavonoids in leaves and saikosaponins in roots of B. chinense. The results showed that B. chinense can adapt to drought stress mainly by increasing concentrations of osmoregulatory substances (soluble protein and proline) and increasing activity of protective enzymes (superoxide dismutase and catalase), as observed on days 12 and 20 of the treatment. Secondary metabolite concentrations in B. chinense roots and leaves showed significant differences-drought stress increased saikosaponin concentrations in roots by 9.85% and 6.41% during vegetative and reproductive growth, respectively, on day 20, and saikosaponin concentrations in roots were higher during vegetative growth than during reproductive growth. In leaves, large amounts of antioxidants were consumed owing to drought stress, which decreased leaf rutin concentrations by 38.79% and 30.11% during vegetative and reproductive growth, respectively, as observed on day 20; overall, leaf rutin concentrations were lower during vegetative growth than during reproductive growth. Changes in soil water content are known to affect synthesis of secondary metabolites in medicinal plants by altering gene transcription, and affected genes may synergistically respond to soil water changes and alter concentrations of flavonoid in leaves and of saikosaponin in roots. The gene F3H down-regulates flavonoid production in leaves. Squalene epoxidase and ß-amyrin synthase genes may be key genes regulating saikosaponin accumulation, and changes in their expression corresponded to accumulation of saikosaponins. Our results provide insights in B. chinense adaptation to drought stress through physiological changes and regulation of secondary metabolite production in different plant tissues.