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Epimedium brevicornu Maxim has been used as a traditional herbal drug in China. In this study, the anti-inflammatory effects of E. brevicornu Maxim ethanol extract (EBME) were investigated in RAW264.7 macrophages and mice challenged with lipopolysaccharide (LPS). Results showed that EBME attenuated inflammation by decreasing the production of several proinflammatory mediators, such as nitric oxide (NO), prostaglandin (PG) E2, inducible nitric oxide synthase, and cyclooxygenase-2, in LPS-stimulated RAW264.7 macrophages. EBME increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2. The inhibitory effects of EBME on LPS-stimulated NO and PGE2 expression were partially reversed by HO-1 inhibitor. EBME also elicited an anti-inflammatory effect by inhibiting the production of tumor necrosis factor- α , interleukin (IL)-1 β , and IL-6 in LPS-induced peritonitis. Therefore, EBME exhibited anti-inflammatory effects in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Regorafenib significantly prolongs overall survival in patients with metastatic colorectal cancer (mCRC), but the overall clinical efficacy of regorafenib remains quite limited. Combination chemotherapy is a potentially promising approach to enhance anticancer activity, overcome drug resistance, and improve disease-free and overall survival. The current study investigates the antitumor activity of regorafenib in combination with lapatinib in preclinical models of human CRC. Our results show improved antitumor efficacy when regorafenib is combined with lapatinib both in vitro and in vivo. Furthermore, pharmacokinetic analyses revealed that regorafenib and lapatinib do not influence on each plasma concentration. The finding that regorafenib in combination with lapatinib have synergistic activity warrants further clinical investigation of this beneficial combination as a potential treatment strategy for CRC patients. [ABSTRACT FROM AUTHOR]

Chemotherapeutic multidrug resistance (MDR) is a significant challenge to overcome in clinic practice. Several mechanisms contribute to MDR, one of which is the augmented drug efflux induced by the upregulation of ABCB1 in cancer cells. Regorafenib, a multikinase inhibitor targeting the RAS/RAF/MEK/ERK pathway, was approved by the FDA to treat metastatic colorectal cancer and gastrointestinal stromal tumors. We investigated whether and how regorafenib overcame MDR mediated by ABCB1. The results showed that regorafenib reversed the ABCB1-mediated MDR and increased the accumulation of [3H]-paclitaxel in ABCB1-overexpressing cells by suppressing efflux activity of ABCB1, but not altering expression level and localization of ABCB1. Regorafenib inhibited ATPase activity of ABCB1. In mice bearing resistant colorectal tumors, regorafenib raised the intratumoral concentration of paclitaxel and suppressed the growth of resistant colorectal tumors. But regorafenib did not induce cardiotoxicity/myelosuppression of paclitaxel in mice. Strategy to reposition one FDA-approved anticancer drug regorafenib to overcome the resistance of another FDA-approved, widely used chemotherapeutic paclitaxel, may be a promising direction for the field of adjuvant chemotherapy. This study provides clinical rationale for combination of conventional chemotherapy and targeted anticancer agents. [ABSTRACT FROM AUTHOR]

Background Induction immunosuppression strategies using a CD52 monoclonal antibody (mAb) have been introduced for small bowel transplantation, resulting in improved outcomes. However, little information is known about the effects of the antibody on the microstructure of the intestinal barrier, which functions to prevent bacterial translocation. In this study, we used a murine orthotopic small bowel transplantation model to investigate the impact of a CD52 mAb on tight junctions (TJs), which are considered a central part of the intestinal barrier, of the transplanted intestine. Materials and methods C57BL/6 mice were used as recipients. The grafts were harvested from BALB/c mice in allogeneic groups and C57BL/6 mice in syngeneic groups. The anti-mouse CD52 mAb was applied as a surrogate antibody. Transmission electron microscopy was used to evaluate the TJ ultrastructure. The expression of the TJ proteins occludin and ZO-1 was analyzed by Western blot. The distribution of TJ proteins was observed by immunofluorescence, and the permeability of the transplanted intestine was assessed in vivo using FITC-dextran. Results After CD52 mAb application, a compromised TJ ultrastructure was observed. In addition, TJ protein expression (occludin and ZO-1) decreased and the intestinal permeability increased. Conclusions The anti-mouse CD52 mAb impaired the transplanted intestinal TJ and barrier. [ABSTRACT FROM AUTHOR]