Gambogenic acid alleviates kidney fibrosis via epigenetic inhibition of EZH2 to regulate Smad7-dependent mechanism.

BACKGROUND: Epigenetics regulating gene expression plays important role in kidney fibrosis. Natural products originating from diverse sources including plants and microorganisms are capable to influence epigenetic modifications. Gambogenic acid (GNA) is a caged xanthone extracted from gamboge resin, exudation of Garcinia hanburyi Hook.f., and the effect of GNA on kidney fibrosis with its underlying mechanism on epigenetics remains unknown. PURPOSE: This study aimed to explore the role of GNA against kidney fibrogenesis by histone methylation mediating gene expression. METHODS: Two experimental mice of unilateral ureteral obstruction (UUO) and folic acid (FA) were given two dosages of GNA (3 and 6 mg/kg/d). TGF-ß1 was used to stimulate mouse tubular epithelial (TCMK-1) cells and siRNAs were transfected to verify the underlying mechanisms of GNA. Histological changes were evaluated by HE, MASSON stainings, immunohistochemistry and immunofluorescence. Western blot and qPCR were used to measure protein/gene transcription levels. RESULTS: GNA dose-dependently alleviated UUO-induced kidney fibrosis and FA-induced kidney early fibrosis, indicated by the pathology and fibrotic factor changes (α-SMA, collagen I, collagen VI, and fibronectin). Mechanically, GNA reduced enhancer of zeste homolog 2 (EZH2) and H3K27me3, promoted Smad7 transcription, and inhibited TGF-ß/Smad3 fibrotic signaling in injured kidneys. Moreover, with TGF-ß1-induced EZH2 increasing, GNA suppressed α-SMA, fibronectin and collagen levels in tubular epithelial TCMK-1 cells. Although partially decreasing EZH2, GNA did not influence fibrotic signaling in Smad7 siRNA-transfected TCMK-1 cells. CONCLUSION: Epigenetic inhibition of EZH2 by GNA ameliorated kidney fibrogenesis via regulating Smad7-meidated TGF-ß/Smad3 signaling.

Near-infrared light-responsive hybrid hydrogels for the synergistic chemo-photothermal therapy of oral cancer.

Light-stimulus-responsive therapies have been recognized as a promising strategy for the efficient and safe treatment of oral squamous cell carcinoma (OSCC). Hydrogels have emerged as a promising multifunctional platform combining localized drug delivery and sustained drug release with multimodal properties for combined OSCC therapy. However, inaccurate drug release and limited light-absorption efficiency have hindered their on-demand chemo-photothermal applications. To tackle these problems, an injectable and near-infrared (NIR) light-responsive hybrid system was developed by incorporating light-responsive mesoporous silica nanoparticles (MSNs) as doxorubicin (DOX) carriers into the IR820/methylcellulose hydrogel networks for chemophotothermal therapy. Under NIR radiation, the incorporated IR820, a new green cyanine dye, was excited to induce photothermal effects against tumor cells. Meanwhile, MSNs achieved self-degradation-controlled DOX release via the cleavage of diselenide bonds induced by reactive oxygen species. Through the combination of chemotherapy and phototherapy, a long-lasting synergistic anti-tumor effect was achieved in vitro and in vivo with less toxicity. These findings demonstrate the potential of light-responsive hydrogels as a multifunctional platform for accurate synergistic chemophotothermal treatment of OSCC.