Anti-angiogenesis targeting VEGFR-2 has been considered as an important strategy for cancer therapy. Ellagic acid is a naturally existing polyphenol widely found in fruits and vegetables. It was reported that ellagic acid interfered with some angiogenesis-dependent pathologies. Yet the mechanisms involved were not fully understood. Thus, we analyzed its anti-angiogenesis effects and mechanisms on human breast cancer utilizing in-vitro and in-vivo methodologies. The in-silico analysis was also carried out to further analyze the structure-based interaction between ellagic acid and VEGFR-2. We found that ellagic acid significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR-2 tyrosine kinase activity and its downstream signaling pathways including MAPK and PI3K/Akt in endothelial cells. Ellagic acid also obviously inhibited neo-vessel formation in chick chorioallantoic membrane and sprouts formation of chicken aorta. Breast cancer xenografts study also revealed that ellagic acid significantly inhibited MDA-MB-231 cancer growth and P-VEGFR2 expression. Molecular docking simulation indicated that ellagic acid could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR-2 kinase unit. Taken together, ellagic acid could exert anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer.
The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the T1 and T17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9), is associated with several autoimmune diseases. However, the function of CARD9 has remained unknown. Here we generated CARD9 knock-in mice and found that CARD9 facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9 mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive T2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9 can turn alveolar macrophages into IL-5-producing cells and facilitates T2 cell-mediated pathologic responses.
By feeding various amino acids to the marine fungus Scedosporium apiospermum F41-1, 22 diverse alkaloids, including 14 new compounds, were obtained. Scedapins A-E (1-5) possess a rare skeleton of a pyrazinoquinazolinedione and an imidazoindolone/indolone linked by a tetrahydrofuran ring. Scedapin C (3) is the first example of fumiquinazoline that contains an aminosulfonyl group. Their structures were determined by HRMS, NMR, ECD calculations and X-ray single-crystal diffraction analysis. The biosynthetic pathways of fumiquinazolines 1-18 were proposed. Scedapin C (3) and scequinadoline D (8) displayed significant antiviral activity against hepatitis C.
Mucus, which is secreted by the goblet cells of enterocytes, constitutes the first obstacle encountered for the intestinal absorption of nanomedicines. For decades, mucus has simply been regarded as a physical barrier that hinders the permeation and absorption of drugs, because of its high viscosity and reticular structure, whereas the interaction of mucus ingredients with nanomedicines is usually neglected. It is unclear whether glycoproteins, as the main components of mucus, interact with nanomedicines. We also do not know how the potential interaction affects the subsequent transportation of nanomedicines through the intestinal epithelium. In this study, mucin as the key element of mucus was investigated to characterize the interaction of nanomedicines with mucus. PEG-modified gold nanoparticles (PGNPs) were fabricated as model nanoparticles. Mucin was found to adhere to the nanoparticle surface to form a corona structure and induce the clustering of PGNPs by joining particles together, demonstrating the interaction between mucin and PGNPs. In addition, two intestinal epithelia, Caco-2 (non- mucus secretion) and HT-29 (high mucus secretion), were compared to evaluate the influence of mucin on the cellular interaction of PGNPs. Amazingly, mucin altered the trafficking characteristic of PGNPs in intestinal epithelium. Both in vitro and in vivo investigations demonstrated more nanoparticles being internalized by cells due to the mucin coverage. However, mucin induced a significant reduction in the transcytosis of PGNPs across epithelial monolayers. The mechanism exploration further revealed that the "more endocytosis but less transcytosis (MELT)" effect was mainly attributed to the strengthened retrograde pathway in which more PGNPs were transported to Golgi apparatus and exocytosed back to the apical but not the basolateral side of the epithelial monolayers. The "MELT" effect endowed mucin with duality in the nanoparticle transportation. Therefore, the rational regulation based on the "MELT" effect will provide new insight into overcoming the mucus obstacle as a barrier and enhancing the oral absorption rate of nanomedicines.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.