Human TFF2-Fc fusion protein alleviates DSS-induced ulcerative colitis in C57BL/6 mice by promoting intestinal epithelial cells repair and inhibiting macrophage inflammation.

The clinical drugs for ulcerative colitis mainly affect the inflammatory symposiums with limited outcomes and various side effects. Repairing the damaged intestinal mucosa is a promising and alternative strategy to treat ulcerative colitis. Trefoil factor family 2 (TFF2) could repair the intestinal mucosa, however, it has a short half-life in vivo. To improve the stability of TFF2, we have prepared a new fusion protein TFF2-Fc with much stability, investigated the therapeutic effect of TFF2-Fc on ulcerative colitis, and further illustrated the related mechanisms. We found that intrarectally administered TFF2-Fc alleviated the weight loss, the colon shortening, the disease activity index, the intestinal tissue injury, and the lymphocyte infiltration in dextran sulfate sodium (DSS)-induced colitis mice. In vitro, TFF2-Fc inhibited Caco2 cells injury and apoptosis, promoted cellular migration, and increased the expression of Occludin and ZO-1 by activating P-ERK in the presence of H2O2 or inflammatory conditioned medium (LPS-RAW264.7/CM). Moreover, TFF2-Fc could reduce lipopolysaccharide (LPS)-induced production of inflammation cytokines and reactive oxygen species in RAW264.7 cells, and also inhibits the polarization of RAW264.7 cells to M1 phenotype by reducing glucose consumption and lactate production. Taken together, in this work, we have prepared a novel fusion protein TFF2-Fc, which could alleviate ulcerative colitis in vivo via promoting intestinal epithelial cells repair and inhibiting macrophage inflammation, and TFF2-Fc might serve as a promising ulcerative colitis therapeutic agent.

A novel alginate from Sargassum seaweed promotes diabetic wound healing by regulating oxidative stress and angiogenesis.

Diabetic skin ulcer is one of the most severe complications in diabetes, however, current therapeutic approaches are not effective enough. Agents modulating oxidative stress, inflammation, and angiogenesis are quite promising for alleviation of diabetic skin ulcers. In this study, a novel Sargassum kjellmanianum-derived polysaccharide (SARP) was prepared. SARP was an alginate with Mw of 45.4 kDa, consisting of 76.56% mannuronic acid, 18.89% guluronic acid, and 4.55% glucuronic acid. SARP could attenuate oxidative stress-induced cell damage via activating nuclear factor erythroid 2-related factor 2 (Nrf2). SARP also promoted the migration and tube formation of HUVECs, which was related to the increased vascular endothelial growth factor (VEGF) expression. In diabetic wound model, SARP (iv, 200 mg/kg) administration increased angiogenesis, alleviated oxidative stress, ameliorated diabetes-related aberrations, and thereby accelerated diabetic wound healing. These findings identified SARP had potential to be developed as a drug candidate for diabetic skin ulcers.

Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common primary hepatic malignancy. Herein, a series of semisynthesized derivatives (2-30) of the natural product (+)-sclerotiorin (1) was prepared and evaluated the cytotoxic activities against six cancer cell lines. Among them, 3 and 5 were the most effective compounds against human hepatocellular carcinoma Bel-7402 cell line with IC50 values of 1.45 and 1.15 µM, respectively. Molecular mechanism study showed that 5 disrupted the mitochondrial membrane potential and induced apoptosis in a caspase-dependent manner. In addition, 5 affected AKT and ERK signaling pathways and induced AKT and ERK proteins degradation through ubiquitin-proteasome system. Furthermore, 5 displayed significant in vivo anticancer effects in the xenograft models with decreasing the tumor mass by 52.5%. The safety evaluation was confirmed by acute toxicity subchronic toxicity tests, paraffin sections of mice organ and blood routine examination. Taken together, 5 can be developed as a potential therapeutic agent for hepatocellular carcinoma.

Xanthohumol, a Prenylated Flavonoid from Hops, Induces Caspase-Dependent Degradation of Oncoprotein BCR-ABL in K562 Cells.

BCR-ABL oncoprotein drives the initiation, promotion, and progression of chronic myelogenous leukemia (CML). Tyrosine kinase inhibitors are the first choice for CML therapy, however, BCR-ABL mediated drug resistance limits its clinical application and prognosis. A novel promising therapeutic strategy for CML therapy is to degrade BCR-ABL using small molecules. Antioxidant xanthohumol (XN) is a hop-derived prenylated flavonoid with multiple bioactivities. In this study, we showed XN could inhibit the proliferation, induce S phase cell cycle arrest, and stimulate apoptosis in K562 cells. XN degraded BCR-ABL in a concentration- and time-dependent manner, and the involved degradation pathway was caspase activation, while not autophagy induction or ubiquitin proteasome system (UPS) activation. Moreover, we revealed for the first time that XN could inhibit the UPS and autophagy in K562 cells, and the inhibitory effect of XN on autophagy could attenuate imatinib-induced autophagy and enhance the therapeutic efficiency of imatinib in K562 cells. Our present findings identified XN act as a degrader of BCR-ABL in K562 cells, and XN had potential to be developed as an alternate agent for CML therapy.