Gastritis or peptic ulcer is believed to affect about half of people worldwide. Traditional medications can lead to adverse effects, therefore, alternative nutritional strategies are needed to prevent the development of gastric mucosal damage. A novel combination of two food-grade ingredients, wheat peptides and fucoidan (WPF), was prepared to treat male Sprague Dawley rats for 30 days before gastric mucosal damage was induced by oral administration of ethanol. The serum levels of biomarkers were determined by enzyme-linked immunosorbent assay. Biomarkers in stomach tissue were analyzed using immunohistochemistry. In addition, human gastric epithelial cell line (GES-1) was used to investigate protein expression by Western blot. WPF could attenuate ethanol-induced gastric mucosal damage in an inverse dose-dependent manner, with both ulcer index and pathological index improved. WPF increased superoxide dismutase level and decreased malondialdehyde level. WPF also decreased the levels of interleukin-8, platelet-activating factor, and Caspase 3, while increasing the levels of prostaglandin E-2, epidermal growth factor (EGF), and EGF receptor (EGFR). Furthermore, phosphorylation of EGFR and extracellular signal–regulated kinases was induced by WPF in GES-1 cells. In conclusion, the novel combination of wheat peptides and fucoidan attenuated ethanol-induced gastric mucosal damage in rats through anti-oxidant, anti-inflammatory, and pro-survival mechanisms.
Glycosylated natural products are reliable platforms for the development of anticancer drugs, simply due to the important features added by sugar appendages to the shape and the stereoelectronic properties of natural scaffolds. Herein, we indentified D11, a novel diphyllin glycoside with acetylated D-quinovose sugar moiety, as a potent topoisomerase IIα (Topo IIα) inhibitior. This peculiar sugar moiety endows D11 an optimal conformation with a high binding affinity for Topo IIα via hydrogen bonding to the entrance of ATPase pocket, thereby helping achieve more potent Topo II inhibition activity compared to the aglycon diphyllin. Further biochemical insights manifested that D11 significantly inhibited Topo IIα ATPase-catalyzed ATP hydrolysis in an ATP-dependent, but a DNA-independent manner. All these underlie the consequent superiority of D11 in the in vitro proliferation inhibition, apoptosis induction and the in vivo remarkable antitumor potency in xenograft mouse model. Moreover, D11 treatment also displayed no obvious body weight loss and other apparent toxicities, indicative of the restricted side effects by the virtue of sugar attachment. Taken together, a defined glycosylated manipulation of diphyllin may be a promising alternative approach in the development of novel Topo II inhibitors.
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