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Kelly Barford, Austin Keeler, Lloyd McMahon, Kathryn McDaniel, Chan Choo Yap, Christopher D Deppmann, Bettina Winckler
The development of the peripheral nervous system relies on long-distance signaling from target organs back to the soma. In sympathetic neurons, this long-distance signaling is mediated by target derived Nerve Growth Factor (NGF) interacting with its axonal receptor, TrkA. This ligand receptor complex internalizes into what is commonly referred to as the signaling endosome which is transported retrogradely to the soma and dendrites to mediate survival signaling and synapse formation, respectively. The molecular identity of signaling endosomes in dendrites has not yet been determined...
March 16, 2018: Scientific Reports
Seav-Ly Tran, Claire Jenkins, Valérie Livrelli, Stephanie Schüller
Shiga toxin-producing Escherichia coli (STEC) are characterized by the release of potent Shiga toxins (Stx), which are associated with severe intestinal and renal disease. Although all STEC strains produce Stx, only a few serotypes cause infection in humans. To determine which virulence traits in vitro are linked to human disease in vivo, 13 Stx2a-producing STEC strains of seropathotype (SPT) A or B (associated with severe human intestinal disease and outbreaks) and 6 strains of SPT D or E (rarely or not linked to human disease) were evaluated in a microaerobic human colonic epithelial infection model...
March 13, 2018: Microbiology
Jonas Reinholz, Christopher Diesler, Susanne Schöttler, Maria Kokkinopoulou, Sandra Ritz, Katharina Landfester, Volker Mailänder
The transport of nanocarriers through barriers like the gut in a living organism involves the transcytosis of these nanocarriers through the cell layer dividing two compartments. Understanding how this process works is not only essential to further developing strategies for a more effective nanocarrier transport system but also for providing fundamental insights into the barrier function as a means of protection against micro- and nanoplastics in the food chain. We therefore set out to investigate the different uptake mechanisms, intracellular trafficking and the routes for exocytosis for small polystyrene nanoparticles (PS-NPs ca...
March 9, 2018: Acta Biomaterialia
Asim Azhar, Qamar Zia, Shakeel Ahmad Ansari, Muhammad Amjad Kamal, Athanasios Alexiou, Nagendra Sastry Yarla, Ghulam Md Ashraf
Nanotechnology exploits materials and devices with a functional organization that has been engineered at the nanometre scale. The application of nanotechnology in neuroscience involves specific interactions with neurons and glial cells. This property is used for delivering drugs and other small molecules (such as genes, oligonucleotides and contrasting agents) across the blood brain barrier (BBB), an important requirement for delivering the drug successfully to the brain. Nanotechnology based approaches (NBA) favoured transcytosis-mediated delivery of nanoparticles to the brain by crossing the BBB...
March 5, 2018: Current Drug Metabolism
Marion David, Pascaline Lécorché, Maxime Masse, Aude Faucon, Karima Abouzid, Nicolas Gaudin, Karine Varini, Fanny Gassiot, Géraldine Ferracci, Guillaume Jacquot, Patrick Vlieghe, Michel Khrestchatisky
Insufficient membrane penetration of drugs, in particular biotherapeutics and/or low target specificity remain a major drawback in their efficacy. We propose here the rational characterization and optimization of peptides to be developed as vectors that target cells expressing specific receptors involved in endocytosis or transcytosis. Among receptors involved in receptor-mediated transport is the LDL receptor. Screening complex phage-displayed peptide libraries on the human LDLR (hLDLR) stably expressed in cell lines led to the characterization of a family of cyclic and linear peptides that specifically bind the hLDLR...
2018: PloS One
George Thom, Matthew Burrell, Arsalan S Haqqani, Alvaro Yogi, Etienne Lessard, Eric Brunette, Christie Delany, Ewa Baumann, Deborah Callaghan, Natalia Rodrigo, Carl I Webster, Danica B Stanimirovic
The blood-brain barrier (BBB) is a formidable obstacle for brain delivery of therapeutic antibodies. However, antibodies against the transferrin receptor (TfR), enriched in brain endothelial cells, have been developed as delivery carriers of therapeutic cargos into the brain via a receptor-mediated transcytosis pathway. In vitro and in vivo studies demonstrated that either a low-affinity or mono-valent binding of these antibodies to the TfR improves their release on the abluminal side of the BBB and target engagement in brain parenchyma...
February 27, 2018: Molecular Pharmaceutics
Dan Yang, Dechun Liu, Mengmeng Qin, Binlong Chen, Siyang Song, Wenbing Dai, Hua Zhang, Xueqing Wang, Yiguang Wang, Bing He, Xing Tang, Qiang Zhang
Mucus, 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...
February 27, 2018: ACS Applied Materials & Interfaces
Nino Tetro, Sonia Moushaev, Miriam Rubinchik-Stern, Sara Eyal
Optimal development of the embryo and the fetus depends on placental passage of gases, nutrients, hormones, and waste products. These molecules are transferred across the placenta via passive diffusion, carrier-mediated cellular uptake and efflux, and transcytosis pathways. The same mechanisms additionally control the rate and extent of transplacental transfer of drugs taken by the pregnant mother. Essentially all drugs cross the placenta to a certain extent, and some accumulate in the placenta itself at levels that can even exceed those in maternal plasma...
February 23, 2018: Pharmaceutical Research
Aminul Islam Khan, Jin Liu, Prashanta Dutta
BACKGROUND: Transferrin and its receptors play an important role during the uptake and transcytosis of iron through blood-brain barrier (BBB) endothelial cells (ECs) to maintain iron homeostasis in BBB endothelium and brain. Any disruptions in the cell environment may change the distribution of transferrin receptors on the cell surface, which eventually alter the homeostasis and initiate neurodegenerative disorders. In this paper, we developed a comprehensive mathematical model that considers the necessary kinetics for holo-transferrin internalization and acidification, apo-transferrin recycling, and exocytosis of free iron and transferrin-bound iron through basolateral side of BBB ECs...
February 18, 2018: Biochimica et Biophysica Acta
Daniela Schmid, Annette Buntz, Thi Ngoc Hanh Phan, Klaus Mayer, Eike Hoffmann, Irmgard Thorey, Jens Niewöhner, Katrin Vasters, Ranjan Sircar, Olaf Mundigl, Roland E Kontermann, Ulrich Brinkmann
A transcellular shuttle system was generated for delivery of non-covalently linked payloads across blood-brain-barrier (BBB) endothelial cells. Transcytosis enabling shuttles are composed of bispecific antibodies (bsAbs) that simultaneously bind transferrin receptor (TfR) and haptens such as digoxigenin or biocytinamide. Haptenylated payloads are attached to these vehicles via non-covalent hapten-antibody complexation. This enables targeting to and internalization into human BBB-derived microvascular endothelial HCMEC/D3 cells...
December 20, 2017: Biological Chemistry
Bingchao Cheng, Hao Pan, Dandan Liu, Dongyang Li, Jinyu Li, Shihui Yu, Guoxin Tan, Weisan Pan
The purpose of this work was to develop a D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) decorated nanodiamond (ND) system loading water-insoluble curcumin (ND/CUR/TPGS) to improve the colloidal dispersity and oral bioavailability of the preparation. CUR was physically loaded into ND clusters, then TPGS was coated to the ND/CUR complex forming amorphous nanostructure on the interparticle nanocage of the ND substrate. The formulation of the nanocomplexes was optimized using response surface methodology, and the optimal ND/CUR/TPGS showed small particle size (196...
February 13, 2018: International Journal of Pharmaceutics
Yang Shen, Bin Cao, Noah R Snyder, Kevin M Woeppel, James R Eles, Xinyan Tracy Cui
BACKGROUND: Oxidative stress acts as a trigger in the course of neurodegenerative diseases and neural injuries. An antioxidant-based therapy can be effective to ameliorate the deleterious effects of oxidative stress. Resveratrol (RSV) has been shown to be effective at removing excess reactive oxygen species (ROS) or reactive nitrogen species generation in the central nervous system (CNS), but the delivery of RSV into the brain through systemic administration is inefficient. Here, we have developed a RSV delivery vehicle based on polylactic acid (PLA)-coated mesoporous silica nanoparticles (MSNPs), conjugated with a ligand peptide of low-density lipoprotein receptor (LDLR) to enhance their transcytosis across the blood-brain barrier (BBB)...
February 13, 2018: Journal of Nanobiotechnology
Chanettee Chanthick, Aroonroong Suttitheptumrong, Nantapon Rawarak, Sa-Nga Pattanakitsakul
The major role of endothelial cells is to maintain homeostasis of vascular permeability and to preserve the integrity of vascular vessels to prevent fluid leakage. Properly functioning endothelial cells promote physiological balance and stability for blood circulation and fluid components. A monolayer of endothelial cells has the ability to regulate paracellular and transcellular pathways for transport proteins, solutes, and fluid. In addition to the paracellular pathway, the transcellular pathway is another route of endothelial permeability that mediates vascular permeability under physiologic conditions...
February 8, 2018: Viruses
Sahrish Rehmani, James E Dixon
Oral delivery of insulin and other anti-diabetic peptides is inhibited by low intestinal absorption caused by the poor permeability across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules by electrostatic or covalent conjugation on in conjunction with nanotechnology. Endogenous cellular uptake mechanisms present in the intestine can be exploited by engineering peptide conjugates that transcytose; entering cells by endocytosis and leaving by exocytosis...
February 2018: Peptides
Donghui Zhu, Yingchao Su, Bingmei Fu, Huaxi Xu
Poor Mg status is a risk factor for Alzheimer's disease (AD), and the underlying mechanisms remain elusive. Here, we provided the first evidence that elevated Mg levels significantly reduced the blood-brain barrier (BBB) permeability and regulated its function in vitro. Transient receptor potential melastatin 7 (TRPM7) and magnesium transporter subtype 1 (MagT1) were two major cellular receptors mediating entry of extracellular Mg2+ into the cells. Elevated Mg levels also induced an accelerated clearance of amyloid-β peptide (Aβ) from the brain to the blood side via BBB transcytosis through low-density lipoprotein receptor-related protein (LRP) and phosphatidylinositol binding clathrin assembly protein (PICALM), while reduced the influx of Aβ from the blood to the brain side involving receptor for advanced glycation end products (RAGE) and caveolae...
January 30, 2018: Molecular Neurobiology
Maria Ribecco-Lutkiewicz, Caroline Sodja, Julie Haukenfrers, Arsalan S Haqqani, Dao Ly, Peter Zachar, Ewa Baumann, Marguerite Ball, Jez Huang, Marina Rukhlova, Marzia Martina, Qing Liu, Danica Stanimirovic, Anna Jezierski, Mahmud Bani-Yaghoub
We have developed a renewable, scalable and transgene free human blood-brain barrier model, composed of brain endothelial cells (BECs), generated from human amniotic fluid derived induced pluripotent stem cells (AF-iPSC), which can also give rise to syngeneic neural cells of the neurovascular unit. These AF-iPSC-derived BECs (i-BEC) exhibited high transendothelial electrical resistance (up to 1500 Ω cm2) inducible by astrocyte-derived molecular cues and retinoic acid treatment, polarized expression of functional efflux transporters and receptor mediated transcytosis triggered by antibodies against specific receptors...
January 30, 2018: Scientific Reports
Srividya Velagapudi, Antonio Piemontese, Lucia Rohrer, Arnold von Eckardstein
No abstract text is available yet for this article.
August 2017: Atherosclerosis
Yuxiang Ma, Yasumasa Okazaki, Jonathan Glass
Iron transport across the intestinal epithelium is facilitated by the divalent metal transporter 1 (DMT1) on the brush border membrane (BBM). The fluorescent metal sensor calcein, which is hydrophilic, membrane-impermeable and quenched by chelation with iron, was used to test our hypothesis that intestinal iron absorption is through the endocytic processes and is involved in a pathway where BBM-derived vesicles fuse with basolateral membrane (BLM)-derived vesicles. To monitor the flux of iron via transcytosis, Caco-2 cells were employed as a polarized cell layer in Transwell chambers...
January 2018: Journal of Clinical Biochemistry and Nutrition
Guillaume Alain Castillon, Patricia Burriat-Couleru, Daniel Abegg, Nina Criado Santos, Reika Watanabe
Recently studies in animal models demonstrate potential roles for clathrin and AP1 in apical protein sorting in epithelial tissue. However, the precise functions of these proteins in apical protein transport remain unclear. Here, we reveal mis-targeting of endogenous GPI-APs and soluble secretory proteins in MDCK cells upon clathrin heavy chain or AP1 subunit knockdown (KD). Using a novel directional endocytosis and recycling assay, we found that these KD cells are not only affected for apical sorting of GPI-APs in biosynthetic pathway but also for their apical recycling and basal to apical transcytosis routes...
January 20, 2018: Traffic
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
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