No abstract

No abstract

Background & AimsRifampicin (RFP)‐induced cholestatic liver injury is characterized by impaired hepatic bile acid (BA) transport. Bile salt efflux pump (BSEP) and Na+/taurocholate cotransporter (NTCP) are the major BA transporters. However, little is known about the mechanisms underlying these transporters.MethodsThe role of tanshinone IIA (TAN IIA) in preventing RFP‐induced liver injury was evaluated in vitro and in vivo, based on the regulatory mechanism of nuclear factor erythroid 2‐related factor 2 (NRF2)‐BSEP/NTCP signalling. The epigenetic induction of NRF2 by TAN IIA was investigated as well as the influence on BSEP and NTCP transcriptional activation and NRF2 DNA‐binding ability.ResultsTAN IIA strongly induced BSEP and NTCP expression in hepatocytes. NRF2 knockdown abrogated the induction. We found two NRF2 binding sites on the human BSEP promoter, called musculoaponeurotic fibrosarcoma recognition elements (MAREs), and one MARE on the NTCP promoter. Human BSEP and NTCP promoter luciferase reporter gene plasmids were stimulated by NRF2. Mutations of the predicted MAREs abolished NRF2 transcriptional activation. TAN IIA induced the expression of ten‐eleven translocation 2 (TET2) to mediate the demethylation of NRF2, which promoted NRF2 DNA‐binding on the BSEP and NTCP promoters and their transcriptional activation. Finally, in vivo, Nrf2 played an important role in RFP‐induced liver injury (more serious liver injury in Nrf2‐/‐ mice), and TAN IIA prevented it.ConclusionsThese results indicate that NRF2 regulates the target transporters BSEP and NTCP, depending on the DNA demethylation by TET2. Pharmacological activation of NRF2 by TAN IIA may be beneficial for RFP‐induced liver injury.

In the studies of chemoprevention, the Nrf2-ARE signaling pathway has received widespread attention due to its anti-inflammatory and anti-oxidation effects. Our previous study indicated that atractylenolide II, which is an active component of Atractylodes macrocephala Koidz, is a potential activator of Nrf2-ARE signaling pathway. In this study, we observed that atractylenolide II significantly increased Nrf2 expressing, nuclear translocation and the expression of its downstream detoxifying enzymes, thus decreasing 17β-Estradiol induced malignant transformation in MCF 10A cells, and we found that atractylenolide II acted through JNK/ERK-Nrf2-ARE pathway. Furthermore, atractylenolide II significantly reduced N-Nitroso-N-methylurea induced tumor incidence, multiplicity and volume, with activation of Nrf2-ARE pathway and decreased inflammation and oxidative stress in rat mammary tissue. Collectively, our results suggested that atractylenolide II could protect against mammary tumorigenesis both in vivo and in vitro via activating Nrf2-ARE signaling pathway, which supported atractylenolide II as a novel chemopreventive agent of breast cancer.

No abstract

No abstract

Poor penetration of mAbs in solid tumors is explained, in part, by the binding site barrier hypothesis. Following extravasation, mAbs rapidly bind cellular antigens, leading to the observation that, at subsaturating doses, therapeutic antibody in solid tumors localizes around tumor vasculature. Here we report a unique strategy to overcome the binding site barrier through transient competitive inhibition of antibody–antigen binding. The anti-trastuzumab single domain antibody 1HE was identified through in vitro binding assays as a model inhibitor. Coadministration of 1HE did not alter the plasma pharmacokinetics of trastuzumab or ado-trastuzumab emtansine (T-DM1) in vivo. Administration of 1HE alone was rapidly eliminated with a terminal plasma half-life of 1.2 hours, while coadministrations of 1HE with trastuzumab had a terminal half-life of 56 hours. In mice harboring SKOV3 xenografts, coadministration of 1HE with trastuzumab led to significant increases in both penetration of trastuzumab from vasculature and the percentage of tumor area that stained positive for trastuzumab. 1HE coadministered with a single dose of T-DM1 to NCI-N87 xenograft–bearing mice significantly enhanced T-DM1 efficacy, increasing median survival. These results support the hypothesis that transient competitive inhibition can improve therapeutic antibody distribution in solid tumors and enhance antibody efficacy. Significance: This study describes the development of a transient competitive inhibition strategy that enhances the tumor penetration and efficacy of anticancer antibodies. See related commentary by van Dongen, p. 3956

Berberine treatment ameliorates RIF in a UUO rat model by inhibition of oxidative stress, inflammatory responses, and TGF-β1/pSmad3 signalling.