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Xiaoyou Qu, Yang Zou, Chuyu He, Yuanhang Zhou, Yao Jin, Yunqiang Deng, Ziqi Wang, Xinru Li, Yanxia Zhou, Yan Liu
To ensure that antitumor drugs can be effectively transported across intestinal barrier and then quickly released in tumor cells, mixed polymeric micelles (Mix-PMs) were designed and fabricated by combining poly(2-ethyl-2-oxazoline)-vitamin E succinate (PEOz-VES) with TPGS1000 for enhancing intestinal absorption of paclitaxel. PEOz-VES exhibited an extremely low critical micelle concentration and negligible cytotoxicity. The Mix-PMs were characterized to have about 20 nm in diameter, uniform spherical morphology, high drug-loading content and sustained drug release profile with a retained pH-sensitivity...
November 2018: Drug Delivery
Yi Cui, Wei Shan, Rui Zhou, Min Liu, Lei Wu, Quan Guo, Yaxian Zheng, Jiawei Wu, Yuan Huang
Ligand-modified nanoparticles (NPs) are an effective tool to increase the endocytosis efficiency of drugs, but these functionalized NPs face the drawback of "easy uptake hard transcytosis" in the oral delivery of proteins and peptides. Adversely, the resulting deficiency in transcytosis has not attracted much attention. Herein, NPs modified with the low-density lipoprotein receptor (LDLR) ligand NH2-C6-[cMPRLRGC]c-NH2, i.e., peptide-22 (P22NPs) were fabricated to investigate strategies related to the enhancement of transcytosis...
January 5, 2018: Nanoscale
Sophie Nguyen, Kristi Baker, Benjamin S Padman, Ruzeen Patwa, Rhys A Dunstan, Thomas A Weston, Kyle Schlosser, Barbara Bailey, Trevor Lithgow, Michael Lazarou, Antoni Luque, Forest Rohwer, Richard S Blumberg, Jeremy J Barr
No abstract text is available yet for this article.
January 2, 2018: MBio
Bo Wang, Bo Li
Antioxidant casein peptides were separated by SP-Sephadex C-25 and C 18 columns. The transepithelial transport and bioavailability including the transport ratio and the remaining ratios of antioxidant activity (RRAA) of these peptide absorbates, were then investigated using a Caco-2 cell monolayer. The results indicate that both the negatively charged peptide fractions (CF1, CF2 and CF3) and the more hydrophilic fraction (HF1) were mainly transported via PepT1 and paracellular routes. The positively charged fractions (CF4 and CF5) and hydrophobic fractions (HF2, HF3 and HF4) were transported via PepT1 and transcytosis...
April 15, 2018: Food Chemistry
Roberto Villaseñor, Ludovic Collin
The blood-brain barrier (BBB) is a dynamic multicellular interface that regulates the transport of molecules between the circulation and the brain. Transcytosis across the BBB regulates the delivery of hormones, metabolites, and therapeutic antibodies to the brain parenchyma. Here, we present a protocol that combines immunofluorescence of free-floating sections with laser scanning confocal microscopy and image analysis to visualize subcellular organelles within endothelial cells at the BBB. Combining this data-set with 3D image analysis software allows for the semi-automated segmentation and quantification of capillary volume and surface area, as well as the number and intensity of intracellular organelles at the BBB...
November 16, 2017: Journal of Visualized Experiments: JoVE
Sachiko Ono, Gyohei Egawa, Kenji Kabashima
Regulation of blood vessel permeability is essential for the homeostasis of peripheral tissues. This regulation controls the trafficking of plasma contents, including water, vitamins, ions, hormones, cytokines, amyloids, lipoproteins, carrier proteins, and immunoglobulins. The properties of blood vessels vary among tissues based on their structural differences: continuous, fenestrated, or sinusoidal. These three types of blood vessels have different charge and size barrier properties. The anionic luminal glycocalyx layer on endothelial cells establishes the "charge barrier" that repels the attachment of negatively charged blood cells and plasma molecules...
2017: Inflammation and Regeneration
Roberto Villaseñor, Michael Schilling, Janani Sundaresan, Yves Lutz, Ludovic Collin
Transcytosis across the blood-brain barrier (BBB) regulates key processes of the brain, but the intracellular sorting mechanisms that determine successful receptor-mediated transcytosis in brain endothelial cells (BECs) remain unidentified. Here, we used Transferrin receptor-based Brain Shuttle constructs to investigate intracellular transport in BECs, and we uncovered a pathway for the regulation of receptor-mediated transcytosis. By combining live-cell imaging and mathematical modeling in vitro with super-resolution microscopy of the BBB, we show that intracellular tubules promote transcytosis across the BBB...
December 12, 2017: Cell Reports
Angela Ivask, Emily H Pilkington, Thomas Blin, Aleksandr Käkinen, Heiki Vija, Meeri Visnapuu, John F Quinn, Michael R Whittaker, Ruirui Qiao, Thomas P Davis, Pu Chun Ke, Nicolas H Voelcker
Two major hurdles in nanomedicine are the limited strategies for synthesizing stealth nanoparticles and the poor efficacy of the nanoparticles in translocating across the blood brain barrier (BBB). Here we examined the uptake and transcytosis of iron oxide nanoparticles (IONPs) grafted with biomimetic phosphorylcholine (PC) brushes in an in vitro BBB model system, and compared them with bare, PEG or PC-PEG mixture grafted IONPs. Hyperspectral imaging indicated IONP co-localization with cells. Quantitative analysis with total reflection X-ray fluorescence spectrometry showed that after 24 h, 78% of PC grafted, 68-69% of PEG or PC-PEG grafted, and 30% of bare IONPs were taken up by the BBB...
December 14, 2017: Biomaterials Science
Bryan K Cole, Edgar Scott, Marko Ilikj, David Bard, Darrin R Akins, David W Dyer, Susana Chavez-Bueno
Escherichia coli is the leading cause of Gram-negative neonatal septicemia in the United States. Invasion and passage across the neonatal gut after ingestion of maternal E. coli strains produce bacteremia. In this study, we compared the virulence properties of the neonatal E. coli bacteremia clinical isolate SCB34 with the archetypal neonatal E. coli meningitis strain RS218. Whole-genome sequencing data was used to compare the protein coding sequences among these clinical isolates and 33 other representative E...
2017: PloS One
Muge Yemisci, Secil Caban, Eduardo Fernandez-Megia, Yilmaz Capan, Patrick Couvreur, Turgay Dalkara
Here, we describe a nanocarrier system that can transfer chitosan nanoparticles loaded with either small peptides such as the caspase inhibitor Z-DEVD-FMK or a large peptide like basic fibroblast growth factor across the blood-brain barrier. The nanoparticles are selectively directed to the brain and are not measurably taken up by the liver and spleen. Intravital fluorescent microscopy provides an opportunity to study the penetration kinetics of nanoparticles loaded with fluorescent agents such as Nile red...
2018: Methods in Molecular Biology
Dag Sehlin, Xiaotian T Fang, Silvio R Meier, Malin Jansson, Stina Syvänen
Monoclonal antibodies (mAbs) have not been used as positron emission tomography (PET) ligands for in vivo imaging of the brain because of their limited passage across the blood-brain barrier (BBB). However, due to their high affinity and specificity, mAbs may be an attractive option for brain PET if their brain distribution can be facilitated. In the present study, a F(ab')2 fragment of the amyloid-beta (Aβ) protofibril selective mAb158 was chemically conjugated to the transferrin receptor (TfR) antibody 8D3 to enable TfR mediated transcytosis across the BBB...
December 8, 2017: Scientific Reports
Mark McCully, Macarena Sanchez-Navarro, Meritxell Teixido, Ernest Giralt
The brain is a complex, regulated organ with a highly controlled access mechanism: The blood-brain barrier (BBB). The selectivity of this barrier is a double-edged sword, being both its greatest strength and weakness. This weakness is made abundantly clear when trying to target therapeutics against diseases within the brain. Diseases such as metastatic brain cancer have extremely poor prognosis due to the poor permeability of many therapeutics across the BBB. Peptides can be designed to target BBB receptors and gain access to the brain by transcytosis...
November 30, 2017: Current Pharmaceutical Design
Keiji Tanigaki, Anastasia Sacharidou, Jun Peng, Ken L Chambliss, Ivan S Yuhanna, Debabrata Ghosh, Mohamed Ahmed, Alexander J Szalai, Wanpen Vongpatanasin, Robert F Mattrey, Qiushi Chen, Parastoo Azadi, Ildiko Lingvay, Marina Botto, William L Holland, Jennifer J Kohler, Shashank R Sirsi, Kenneth Hoyt, Philip W Shaul, Chieko Mineo
Type 2 diabetes mellitus (T2DM) is a common complication of obesity. Here, we have shown that activation of the IgG receptor FcγRIIB in endothelium by hyposialylated IgG plays an important role in obesity-induced insulin resistance. Despite becoming obese on a high-fat diet (HFD), mice lacking FcγRIIB globally or selectively in endothelium were protected from insulin resistance as a result of the preservation of insulin delivery to skeletal muscle and resulting maintenance of muscle glucose disposal. IgG transfer in IgG-deficient mice implicated IgG as the pathogenetic ligand for endothelial FcγRIIB in obesity-induced insulin resistance...
November 27, 2017: Journal of Clinical Investigation
Qin Zheng, Yu Tang, Peng-Yi Hu, Dan Liu, Delin Zhang, Pengfei Yue, Yuanyuan Guo, Ming Yang
Efficient transcytosis across the blood-brain-barrier is an important strategy for accessing drug targets within the central nervous system. Ligusticum chuanxiong Hort. was used as a messenger drug to increase the distribution of drugs in brain tissue in Traditional Chinese Medicine. The present study investigates the transport of echinacoside (ECH) through MDCK-MDR1 cell and the effects of ligustilide (LIG), senkyunolide A (SENA) and senkyunolide I (SENI) in chuanxiong on its transport. The results indicated that the absorption of ECH was relatively poor in MDCK-MDR1cells, and was concentration dependent and not saturable...
November 29, 2017: Phytotherapy Research: PTR
George Thom, Jon Hatcher, Arron Hearn, Judy Paterson, Natalia Rodrigo, Arthur Beljeana Ian Gurrell, Carl Webster
The blood-brain barrier (BBB) is a formidable obstacle for delivery of biologic therapeutics to central nervous system (CNS) targets. Whilst the BBB prevents passage of the vast majority of molecules, it also selectively transports a wide variety of molecules required to maintain brain homeostasis. Receptor-mediated transcytosis is one example of a macromolecule transport system that is employed by cells of the BBB to supply essential proteins to the brain and which can be utilized to deliver biologic payloads, such as antibodies, across the BBB...
November 28, 2017: MAbs
Xiang Xiao, Ya Ni, Chenhuan Yu, Linxi Li, Baiping Mao, Yue Yang, Dongwang Zheng, Bruno Silvestrini, C Yan Cheng
Non-receptor Src family kinases (SFKs), mostly notably c-Src and c-Yes, are recently shown to be expressed by Sertoli and/or germ cells in adult rat testes. Studies have shown that SFKs are involved in modulating the cell cytoskeletal function, and involved in endocytic vesicle-mediated protein endocytosis, transcytosis and/or recycling as well as intracellular protein degradation events. Furthermore, a knockdown to SFKs, in particular c-Yes, has shown to induce defects in spermatid polarity. These findings, coupled with emerging evidence in the field, thus prompt us to critically evaluate these findings to put forth a developing concept regarding the role of SFKs and cell polarity, which will become a basis to design experiments for future investigations...
November 21, 2017: Seminars in Cell & Developmental Biology
Sarah E Lutz, Julian R Smith, Dae Hwan Kim, Carl V L Olson, Kyle Ellefsen, Jennifer M Bates, Sunil P Gandhi, Dritan Agalliu
Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs) or caveolae to induce tissue inflammation. In the CNS, Th17 lymphocytes cross the blood-brain barrier (BBB) before Th1 cells; yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial tight junctions to determine how tight junction remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis...
November 21, 2017: Cell Reports
Christopher R Wilcox, Beth Holder, Christine E Jones
At birth, neonates are particularly vulnerable to infection and transplacental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life. Transcytosis of IgG occurs via binding with the neonatal Fc receptor (FcRn) in the placental synctiotrophoblast. As maternal vaccination becomes an increasingly important strategy for the protection of young infants, improving our understanding of transplacental transfer and the factors that may affect this will become increasingly important, especially in low-income countries where the burden of morbidity and mortality is highest...
2017: Frontiers in Immunology
Karen Y Fung, Changsen Wang, Steffen Nyegaard, Bryan Heit, Gregory D Fairn, Warren L Lee
The vascular endothelium supplying the brain exhibits very low paracellular and transcellular permeability and is a major constituent of the blood-brain barrier. High-density lipoprotein (HDL) crosses the blood-brain barrier by transcytosis, but technical limitations have made it difficult to elucidate its regulation. Using a combination of spinning-disc confocal and total internal reflection fluorescence microscopy, we examined the uptake and transcytosis of HDL by human primary brain microvascular endothelial cell monolayers...
2017: Frontiers in Physiology
Xin Liu, Sidi Zheng, Yue Qin, Wenya Ding, Yabin Tu, Xingru Chen, Yunzhou Wu, Li Yanhua, Xuehui Cai
For the development of an efficient intestinal delivery system for Porcine interferon-α (PoIFN-α), the understanding of transport mechanisms of which in the intestinal cell is essential. In this study, we investigated the absorption mechanisms of PoIFN-α in intestine cells. Caco-2 cells and fluorescein isothiocyanate-labeled (FITC)-PoIFN-α were used to explore the whole transport process, including endocytosis, intracellular trafficking, exocytosis, and transcytosis. Via various techniques, the transport pathways of PoIFN-α in Caco-2 cells and the mechanisms were clarified...
2017: Frontiers in Pharmacology
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