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https://www.readbyqxmd.com/read/28440708/towards-in-vitro-to-in-vivo-translation-of-monoclonal-antibody-pharmacokinetics-application-of-a-neonatal-fc-receptor-mediated-transcytosis-assay-to-understand-the-interplaying-clearance-mechanisms
#1
Claudia A Castro Jaramillo, Sara Belli, Anne-Christine Cascais, Sherri Dudal, Martin R Edelmann, Markus Haak, Marie-Elise Brun, Michael B Otteneder, Mohammed Ullah, Christoph Funk, Franz Schuler, Silke Simon
Monoclonal antibodies (mAbs) are a rapidly growing drug class for which great efforts have been made to optimize certain molecular features in order to achieve the desired pharmacokinetic (PK) properties. One approach is to engineer the interactions of the mAb with the neonatal Fc receptor (FcRn) by introducing specific amino acid sequence mutations, and to assess their effect on the PK profile with in vivo studies. Indeed, FcRn protects mAbs from intracellular degradation, thereby prolongs antibody circulation time in plasma and modulates its systemic clearance...
April 25, 2017: MAbs
https://www.readbyqxmd.com/read/28435154/broadly-neutralizing-antibodies-suppress-post-transcytosis-hiv-1-infectivity
#2
V Lorin, M Malbec, C Eden, T Bruel, F Porrot, M S Seaman, O Schwartz, H Mouquet
No abstract text is available yet for this article.
May 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28431078/effect-of-threonine-on-secretory-immune-system-using-a-chicken-intestinal-ex%C3%A2-vivo-model-with-lipopolysaccharide-challenge
#3
Q Zhang, X Chen, S D Eicher, K M Ajuwon, T J Applegate
Secretory IgA (sIgA) and its transcytosis receptor, polymeric immunoglobulin receptor (pIgR), along with mucus, form the first lines of intestinal defense. Threonine (Thr) is a major component of intestinal mucins and IgA, which are highly secreted under lipopolysaccharide (LPS) induced inflammation. In the current study, the effect of Thr on the secretory immune system was determined in an ex vivo chicken ileal explant model. Results showed that a 2-hour Thr-deprivation of culture medium induced a compensatory increase in the mRNA expression of interleukin-8 (IL-8), mucin 2 ( ), and IgA during LPS challenge, and this increase was suppressed with Thr addition to the media ( P  ≤ 0...
April 18, 2017: Poultry Science
https://www.readbyqxmd.com/read/28424331/filtering-more-than-light-in-the-developing-retina
#4
Maria K Lehtinen
Restricting transcytosis is essential for blood-retinal barrier formation.
April 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28422786/antibody-mediated-immune-exclusion-of-hiv
#5
Ruth M Ruprecht, Samir K Lakhashe
PURPOSE OF REVIEW: Although approximately 90% of all HIV transmissions in humans occur through mucosal contact, the induction of mucosal anti-HIV immune responses has remained understudied. Here we summarize data demonstrating the powerful protection that is achievable at mucosal frontlines through virus-specific mucosal IgA alone or combined with IgG. RECENT FINDINGS: Passive immunization with different monoclonal antibody subclasses but identical epitope specificity (the conserved V3-loop crown of HIV gp120) has revealed that the dimeric IgA1 (dIgA1) form with its open hinge can prevent simian-human immunodeficiency virus (SHIV) acquisition in rhesus macaques at a higher rate than dIgA2...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28416077/blood-brain-barrier-permeability-is-regulated-by-lipid-transport-dependent-suppression-of-caveolae-mediated-transcytosis
#6
Benjamin J Andreone, Brian Wai Chow, Aleksandra Tata, Baptiste Lacoste, Ayal Ben-Zvi, Kevin Bullock, Amy A Deik, David D Ginty, Clary B Clish, Chenghua Gu
The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition specifically inhibits the caveolae-mediated transcytotic route readily used in the periphery...
April 11, 2017: Neuron
https://www.readbyqxmd.com/read/28414297/tumor-penetrating-peptide-enhances-transcytosis-of-silicasome-based-chemotherapy-for-pancreatic-cancer
#7
Xiangsheng Liu, Paulina Lin, Ian Perrett, Joshua Lin, Yu-Pei Liao, Chong Hyun Chang, Jinhong Jiang, Nanping Wu, Timothy Donahue, Zev Wainberg, Andre E Nel, Huan Meng
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1-mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD...
April 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28402948/c-type-natriuretic-peptide-modified-lipid-vesicles-fabrication-and-use-for-the-treatment-of-brain-glioma
#8
Jia-Shuan Wu, Li-Min Mu, Ying-Zi Bu, Lei Liu, Yan Yan, Ying-Jie Hu, Jing Bai, Jing-Ying Zhang, Weiyue Lu, Wan-Liang Lu
Chemotherapy of brain glioma faces a major obstacle owing to the inability of drug transport across the blood-brain barrier (BBB). Besides, neovasculatures in brain glioma site result in a rapid infiltration, making complete surgical removal virtually impossible. Herein, we reported a novel kind of C-type natriuretic peptide (CNP) modified vinorelbine lipid vesicles for transferring drug across the BBB, and for treating brain glioma along with disrupting neovasculatures. The studies were performed on brain glioma U87-MG cells in vitro and on glioma-bearing nude mice in vivo...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28390677/calibrated-flux-measurements-reveal-a-nanostructure-stimulated-transcytotic-pathway
#9
Tarianna Stewart, William T Koval, Samuel A Molina, Suzanne M Bock, James W Lillard, Russell F Ross, Tejal A Desai, Michael Koval
Transport of therapeutic agents across epithelial barriers is an important element in drug delivery. Transepithelial flux is widely used as a measure of transit across an epithelium, however it is most typically employed as a relative as opposed to absolute measure of molecular movement. Here, we have used the calcium switch approach to measure the maximum rate of paracellular flux through unencumbered intercellular junctions as a method to calibrate the flux rates for a series of tracers ranging in 0.6-900kDa in size across barriers composed of human colon epithelial (Caco-2) cells...
April 5, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28389376/botulinum-neurotoxin-type-a-cleaved-snap25-is-confined-to-primary-motor-neurons-and-localized-on-the-plasma-membrane-following-intramuscular-toxin-injection
#10
Brian B Cai, Joseph Francis, Mitchell F Brin, Ron S Broide
The mechanism of action of botulinum neurotoxin type A (BoNT/A) is well characterized, but some published evidence suggests the potential for neuronal retrograde transport and cell-to-cell transfer (transcytosis) under certain experimental conditions. The present study evaluated the potential for these processes using a highly selective antibody for the BoNT/A-cleaved substrate (SNAP25197) combined with 3-dimensional imaging. SNAP25197 was characterized in a rat motor neuron (MN) pathway following toxin intramuscular injections at various doses to determine whether SNAP25197 is confined to MNs or also found in neighboring cells or nerve fibers within spinal cord (SC)...
April 5, 2017: Neuroscience
https://www.readbyqxmd.com/read/28361904/ige-binds-asymmetrically-to-its-b-cell-receptor-cd23
#11
Balvinder Dhaliwal, Marie O Y Pang, Anthony H Keeble, Louisa K James, Hannah J Gould, James M McDonnell, Brian J Sutton, Andrew J Beavil
The antibody IgE plays a central role in allergic disease mechanisms. Its effector functions are controlled through interactions between the Fc region and two principal cell surface receptors FcεRI and CD23. The interaction with FcεRI is primarily responsible for allergic sensitization and the inflammatory response, while IgE binding to CD23 is involved in the regulation of IgE synthesis and allergen transcytosis. Here we present the crystal structure of a CD23/IgE-Fc complex and conduct isothermal titration calorimetric binding studies...
March 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28359811/delivery-of-doxorubicin-loaded-plga-nanoparticles-into-u87-human-glioblastoma-cells
#12
Yulia Malinovskaya, Pavel Melnikov, Vladimir Baklaushev, Anna Gabashvili, Nadezhda Osipova, Sergey Mantrov, Yulia Ermolenko, Olga Maksimenko, Marina Gorshkova, Vadim Balabanyan, Jörg Kreuter, Svetlana Gelperina
The paramount problem in the therapy of brain tumors is the inability of most drugs to cross the blood-brain barrier. PLGA nanoparticles overcoated with poloxamer 188 could overcome this problem and enabled a high anti-tumoral effect against the very aggressive intracranial 101.8 glioblastoma in rats that closely resembles human grade IV glioblastomas. The basis for the transport of these particles across the blood-brain barrier appears to be adsorption of blood apolipoproteins (ApoE or ApoA-I) on the nanoparticle surface caused by the poloxamer 188-coating, followed by receptor-mediated transcytosis of the nanoparticles...
March 27, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28350088/reactive-oxygen-species-mediate-angiotensin-ii-induced-transcytosis-of-low-density-lipoprotein-across-endothelial-cells
#13
Fang Bian, Jun Cui, Tao Zheng, Si Jin
The retention of plasma low-density lipoprotein (LDL) particles to subendothelial spaces through transcytosis across the endothelium is the initial step of atherosclerosis (AS). Angiotensin II (Ang II), as the principal effector molecule of the renin-angiotensin system (RAS), is implicated in several important steps of AS development. However, whether or not Ang II can directly exert a pro‑atherogenic effect by promoting LDL transcytosis across endothelial barriers, has not been defined. In the present study, we found that Ang II upregulated intracellular reactive oxygen species (ROS) levels in endothelial cells (ECs) by measuring fluorescence of 2',7'-dichlorofluorescein (DCF‑DA)...
February 13, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28347688/effects-of-diabetic-retinopathy-on-the-barrier-functions-of-the-retinal-pigment-epithelium
#14
Tina Xia, Lawrence J Rizzolo
Diabetic retinopathy is a debilitating microvascular complication of diabetes mellitus. A rich literature describes the breakdown of retinal endothelial cells and the inner blood-retinal barrier, but the effects of diabetes on the retinal pigment epithelium (RPE) has received much less attention. RPE lies between the choroid and neurosensory retina to form the outer blood-retinal barrier. RPE's specialized and dynamic barrier functions are crucial for maintaining retinal health. RPE barrier functions include a collection of interrelated structures and activities that regulate the transepithelial movement of solutes, including: diffusion through the paracellular spaces, facilitated diffusion through the cells, active transport, receptor-mediated and bulk phase transcytosis, and metabolic processing of solutes in transit...
March 29, 2017: Vision Research
https://www.readbyqxmd.com/read/28337939/bidirectional-apical-basal-traffic-of-the-cation-independent-mannose-6-phosphate-receptor-in-brain-endothelial-cells
#15
Piotr Siupka, Maria Ns Hersom, Karin Lykke-Hartmann, Kasper B Johnsen, Louiza B Thomsen, Thomas L Andresen, Torben Moos, N Joan Abbott, Birger Brodin, Morten S Nielsen
Brain capillary endothelium mediates the exchange of nutrients between blood and brain parenchyma. This barrier function of the brain capillaries also limits passage of pharmaceuticals from blood to brain, which hinders treatment of several neurological disorders. Receptor-mediated transport has been suggested as a potential pharmaceutical delivery route across the brain endothelium, e.g. reports have shown that the transferrin receptor (TfR) facilitates transcytosis of TfR antibodies, but it is not known whether this recycling receptor itself traffics from apical to basal membrane in the process...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28334606/gradual-suppression-of-transcytosis-governs-functional-blood-retinal-barrier-formation
#16
Brian Wai Chow, Chenghua Gu
Blood-central nervous system (CNS) barriers partition neural tissues from the blood, providing a homeostatic environment for proper neural function. The endothelial cells that form blood-CNS barriers have specialized tight junctions and low rates of transcytosis to limit the flux of substances between blood and CNS. However, the relative contributions of these properties to CNS barrier permeability are unknown. Here, by studying functional blood-retinal barrier (BRB) formation in mice, we found that immature vessel leakage occurs entirely through transcytosis, as specialized tight junctions are functional as early as vessel entry into the CNS...
March 22, 2017: Neuron
https://www.readbyqxmd.com/read/28330995/hepatic-fcrn-regulates-albumin-homeostasis-and-susceptibility-to-liver-injury
#17
Michal Pyzik, Timo Rath, Timothy T Kuo, Sanda Win, Kristi Baker, Jonathan J Hubbard, Rosa Grenha, Amit Gandhi, Thomas D Krämer, Adam R Mezo, Zachary S Taylor, Kevin McDonnell, Vicki Nienaber, Jan Terje Andersen, Atsushi Mizoguchi, Laurence Blumberg, Shalaka Purohit, Susan D Jones, Greg Christianson, Wayne I Lencer, Inger Sandlie, Neil Kaplowitz, Derry C Roopenian, Richard S Blumberg
The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28323750/humoral-responses-against-hiv-in-male-genital-tract-role-in-sexual-transmission-and-perspectives-for-preventive-strategies
#18
Amandine Gagneux-Brunon, Nicolas Rochereau, Elisabeth Botelho-Nevers, Frédéric Lucht, Bruno Pozzetto, Stéphane Paul, Thomas Bourlet
: Most new HIV infections occur via sexual routes. The induction of protective anti-HIV antibodies in genital mucosa is an important step toward reducing HIV transmission. Mucosal anti-HIV antibodies may play a dual role by either protecting against HIV transmission or facilitating it. Protective properties against HIV of mucosal IgGs and IgAs exhibiting neutralizing or antibody-dependent cell-mediated cytotoxicity activities have been described in highly exposed seronegative individuals. Conversely, some IgGs may facilitate the crossing of HIV free-particles through epithelial barriers by transcytosis...
May 15, 2017: AIDS
https://www.readbyqxmd.com/read/28315051/development-of-antibody-modified-chitosan-nanoparticles-for-the-targeted-delivery-of-sirna-across-the-blood-brain-barrier-as-a-strategy-for-inhibiting-hiv-replication-in-astrocytes
#19
Jijin Gu, Karam Al-Bayati, Emmanuel A Ho
RNA interference (RNAi)-mediated gene silencing offers a novel treatment and prevention strategy for human immunodeficiency virus (HIV) infection. HIV was found to infect and replicate in human brain cells and can cause neuroinfections and neurological deterioration. We designed dual-antibody-modified chitosan/small interfering RNA (siRNA) nanoparticles to deliver siRNA across the blood-brain barrier (BBB) targeting HIV-infected brain astrocytes as a strategy for inhibiting HIV replication. We hypothesized that transferrin antibody and bradykinin B2 antibody could specifically bind to the transferrin receptor (TfR) and bradykinin B2 receptor (B2R), respectively, and deliver siRNA across the BBB into astrocytes as potential targeting ligands...
March 17, 2017: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/28304381/tnf-%C3%AE-stimulates-endothelial-palmitic-acid-transcytosis-and-promotes-insulin-resistance
#20
Wenjing Li, Xiaoyan Yang, Tao Zheng, Shasha Xing, Yaogong Wu, Fang Bian, Guangjie Wu, Ye Li, Juyi Li, Xiangli Bai, Dan Wu, Xiong Jia, Ling Wang, Lin Zhu, Si Jin
Persistent elevation of plasma TNF-α is a marker of low grade systemic inflammation. Palmitic acid (PA) is the most abundant type of saturated fatty acid in human body. PA is bound with albumin in plasma and could not pass through endothelial barrier freely. Albumin-bound PA has to be transported across monolayer endothelial cells through intracellular transcytosis, but not intercellular diffusion. In the present study, we discovered that TNF-α might stimulate PA transcytosis across cardiac microvascular endothelial cells, which further impaired the insulin-stimulated glucose uptake by cardiomyocytes and promoted insulin resistance...
March 17, 2017: Scientific Reports
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