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Designing translational antioxidative agents that could scavenge free radicals produced during reperfusion in brain ischemia stroke and alleviate neurologic damage is the main objective for ischemic stroke treatment. Herein, we explored and simply synthesized a biomimic and translational Mn3O4 nanoenzyme (HSA-Mn3O4) to constrain ischemic stroke reperfusion-induced nervous system injury. This nanosystem exhibits reduced levels of inflammation and prolonged circulation time and potent ROS scavenging activities. As expected, HSA-Mn3O4 effectively inhibits oxygen and glucose deprivation-mediated cell apoptosis and endoplasmic reticulum stress and demonstrates neuroprotective capacity against ischemic stroke and reperfusion injury of brain tissue. Furthermore, HSA-Mn3O4 effectively releases Mn ions and promotes the increase of superoxide dismutase 2 activity. Therefore, HSA-Mn3O4 inhibits brain tissue damage by restraining cell apoptosis and endoplasmic reticulum stress in vivo. Taken together, this study not only sheds light on design of biomimic and translational nanomedicine but also reveals the neuroprotective action mechanisms against ischemic stroke and reperfusion injury.

BackgroundLaboratory rats such as the Sprague-Dawley (SD) rats are an important model for biomedical studies in relation to human physiological or pathogenic processes. Here we report the first catalog of microbial genes in fecal samples from Sprague-Dawley rats.FindingsThe catalog was established using 98 fecal samples from 49 SD rats, divided in 7 experimental groups, and collected at different time points 30 days apart. The established gene catalog comprises 5,130,167 non-redundant genes with an average length of 750 bp, among which 64.6% and 26.7% were annotated to phylum and genus levels, respectively. Functionally, 53.1%, 21.8%,and 31% of the genes could be annotated to KEGG orthologous groups, modules, and pathways, respectively.ConclusionsA comparison of rat gut metagenome catalogue with human or mouse revealed a higher pairwise overlap between rats and humans (2.47%) than between mice and humans (1.19%) at the gene level. Ninety-seven percent of the functional pathways in the human catalog were present in the rat catalogue, underscoring the potential use of rats for biomedical research.

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Multidrug resistance (MDR) is the major obstacle to the successful chemotherapy treatment of many cancers. Here we found that nobiletin, a citrus methoxyflavone, significantly sensitized ABCB1 overexpressing cells A2780/T and A549/T to chemotherapeutic agents such as paclitaxel (a 433-fold reversal of MDR to PTX at 9 μM), doxorubicin (DOX), docetaxel and dounorubicin. Nobiletin profoundly inhibited ABCB1 transporter activity since it significantly increased the intracellular accumulation of DOX and Flutax-2 in A2780/T cells and decreased the efflux of ABCB1 substrates in Caco2 cells without altering the mRNA and protein expression of ABCB1. Moreover, nobiletin stimulated ATPase activity and inhibited verapamil-stimulated ATPase activity in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, molecular docking analysis also identified favorable binding of nobiletin with the transmemberane region site 1 of homology modeled human ABCB1 transporter. Moreover, the Nrf2 protein expression and phosphorylation levels of AKT/ERK were suppressed by co-treated with nobiletin and PTX at the reversal concentrations, suggesting that inhibition of the AKT/ERK/Nrf2 pathway was associated with the sensitizing effect of nobiletin. These findings encourage further animal and clinical MDR studies with the combination therapy of nobiletin and chemotherapeutic drugs.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targeted therapy currently. Recent studies imply that protein kinase C may play important roles in TNBC development and could be a specific target. In this study, we evaluated the anti-proliferative activity of PKC inhibitor chelerythrine on a panel of breast cancer cell lines. Chelerythrine selectively inhibited the growth of TNBC cell lines compared to non-TNBC cell lines as demonstrated by in vitro cell proliferation assay and colony formation assay, as well as evidenced by in vivo xenograft assay. The selective anti-proliferative effect of chelerythrine was associated with induction of apoptosis in TNBC cell lines. We further demonstrated that PKN2, one of the PKC subtypes, was highly expressed in TNBC cell lines, and knocking down PKN2 in TNBC cells inhibited colony formation and xenograft growth. This indicates that PKN2 is required for the survival of TNBC cells, and could be the target mediates the selective activity of chelerythrine. Finally, combination of chelerythrine and chemotherapy reagent taxol showed synergistic/additive effect on TNBC cell lines. Our results suggest chelerythrine or other PKC inhibitors may be promising regimens for TNBC tumors.

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Gefitinib-resistant (G-R) nonsmall-cell lung cancer (NSCLC) and rheumatoid arthritis (RA) were studied as conditions representative of malignant and proliferative diseases, respectively. Strong lipogenic activity and high expression of sterol regulatory element-binding protein 1 (SREBP1) were found in both G-R NSCLC cells and synovial fibroblasts from RA patients (RASFs). Berberine (BBR), an effective suppressor of SREBP1 and lipogenesis regulated through reactive oxygen species (ROS)/AMPK pathway, selectively inhibited the growth of G-R NSCLC cells and RASFs but not that of normal cells. It effectively caused mitochondrial dysfunction, activated ROS/AMPK pathway, and finally suppressed cellular lipogenesis and cell proliferation. Addition of ROS blocker, AMPK inhibitor, and palmitic acid significantly reduced the effect of BBR. In an in vivo study, treatment of BBR led to significant inhibition of mouse tumor xenograft growth and remarkably slowed down the development of adjuvant-induced arthritis in rats. Innovation and Conclusion: Targeting ROS/AMPK/lipogenesis signaling pathway selectively inhibited the growth of G-R NSCLC cells and the progress of RASFs in vitro and in vivo, which provides a new avenue for treating malignancies and proliferative diseases. Antioxid. Redox Signal. 28, 339-357.