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Human Keratinocyte Migration Involves Extracellular Matrix and Soluble Factors
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
David T. Woodley, John D. Chen, Elizabeth Shim, Janice P. Kim, Jean-Christophe Lapiere, Christina Peavey
The α3β1 integrin receptor is thought to be the “promiscuous” receptor, because it can bind to various ligands including laminin, fibronectin, epiligrin, kalinin, BM600/nicein, and collagen. When we took monospecific antibodies and blocked the keratinocyte α3 integrin subunit, keratinocyte motility was actually enhanced on fibronectin and both types of collagen.11 This surprising result may have several possible explanations. It is known that the α3β1 integrin is the receptor for epiligrin (also called Kalinin and BM600/nicein). Epiligrin is a major attachment factor for human keratinocytes.12–14 It may be by blocking the α3 receptor we are making the keratinocyte unable to recognize epiligrin, which it synthesizes de novo in culture. The antibody may make the keratinocyte less attached to the substratum and, therefore, able to migrate better.
The Integrin α 6β4 in Epithelial and Carcinoma Cells
Published in Yoshikazu Takada, Integrins: The Biological Problems, 2017
Vito Quaranta, Ginetta Collo, Carla Rozzo, Lisa Starr, Guido Gaietta, Richard N. Tamura
cDNAs for the β4 subunit were cloned in several laboratories at approximately the same time.5,36,37 In our laboratory, we screened a λgt11 cDNA expression library from the carcinoma cell line FG, with polyclonal antisera raised against α6β4 purified from placenta. A series of overlapping cDNAs contained an opening reading frame that, by several independent criteria, encoded the β4 protein.5 The structure of the β4 protein, however, contained a surprise. An extracellular portion homologous to that of other integrin β chains was followed by a cytoplasmic domain unique and unusually large. The β4 cytoplasmic domain encompasses more than 1000 residues, while all other integrin β chains contain cytoplasmic domains about 50 amino acids long. The function of the β4 cytoplasmic tail remains unsolved. It could represent a link protein to the cytoskeleton that has become incorporated in the sequence of the integrin receptor itself. In this regard, it is interesting to note that α6β4 is the only integrin known to be linked to the intermediate filament network, rather than to the microfilament cytoskeleton34 (see below). Another possibility is that the β4 cytoplasmic domain may have some enzymatic function, promoting the polymerization-depolymerization of the local cytoskeleton, or engaging in a signaling pathway. At this point, these are speculations that need to be investigated by appropriate experimental schemes.
Tissue Engineering of Articular Cartilage
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
A seemingly simple act, such as compressing cartilage, can result in complex changes, including matrix and cell deformation, hydrostatic pressure gradients, fluid flow, osmotic pressure changes, and fluctuations in ion concentration and fixed charge density (Urban et al. 1993). Any one of these factors can elicit a biological response from cells, most likely through mechanosensitive ion channels (Martinac 2004) or integrins (Ingber 1991) at the cellular membrane. In the former, mechanical stimulation causes an influx of ions (e.g., calcium) that activate intracellular signaling pathways. Hyperpolarization of the membrane can occur through activation of slow-conductance Ca2+-sensitive K+ channels (Wright et al. 1996). Alternatively, stretch-activated ion channels can allow an influx of Ca2+ to levels that trigger calcium-dependent signaling pathways (Pingguan-Murphy et al. 2005). Membrane-associated integrins also act as intermediaries to external mechanical forces. The integrin receptor has an extracellular domain that binds matrix molecules surrounding the cell and an intracellular region that interacts with cytoplasmic molecules and the cytoskeleton, forming a bridge across the cell membrane. This allows for the transduction of mechanical forces directly to intracellular biochemical responses (Hynes 1992; Martinac 2004; Ramage et al. 2009). See Section 1.2.3 for more detailed discussions of the signaling pathways related to mechanotransduction.
Emerging drugs for the treatment of diabetic retinopathy
Published in Expert Opinion on Emerging Drugs, 2020
Elio Striglia, Andrea Caccioppo, Niccolò Castellino, Michele Reibaldi, Massimo Porta
ALG-1001 (Luminate®, Allegro Ophthalmics) is an integrin receptor antagonist. Integrins play a key role in the proliferation of new vessels. There are about 27 known integrin receptors. This drug targets four different integrin receptor sites and acts with two different mechanism: anti-angiogenesis and vitreolysis. ALG-1001 can be administered monthly intravitreally in monotherapy or with bevacizumab [61]. In 2014 Allegro Ophthalmics reported that ALG-1001 inhibits growth and leakage of new vessels and then started a phase 2 clinical trial (NCT 02348918) to compare safety and efficacy of Luminate vs bevacizumab in the treatment of DME. The trial showed that BCVA increased by 7.1 letters in the group treated with Luminate and bevacizumab compared to + 6.1 letters in the control group with bevacizumab alone. Although a small improvement, the authors suggested that Luminate may be an interesting option to treat patients, particularly those who don’t respond to anti-VEGF.
Tetrac-decorated chitosan-coated PLGA nanoparticles as a new platform for targeted delivery of SN38
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Mona Alibolandi, Sara Amel Farzad, Marzieh Mohammadi, Khalil Abnous, Seyed Mohammad Taghdisi, Fatemeh Kalalinia, Mohammad Ramezani
Many studies have been evaluated the integrin receptor-mediated uptake of chemotherapeutics. In this regard, we previously confirmed the higher uptake of tetrac-conjugated campthotecin-loaded polymersomes in comparison with non-targeted polymersomes in HT29 and C26 cells. We verified that using tetrac ligand and targeting integrin increases camtothecin uptake by the target cells that overexpress integrin protein on their surfaces [4]. Moreover, the enhanced cellular uptake level of tetrac-conjugated formulation may be attributed to the reduced exocytosis of tet-CS-PLGA-SN38 formulation in comparison with CS-PLGA-SN38 NPs [15].
Long-term delivery of protein and peptide therapeutics for cancer therapies
Published in Expert Opinion on Drug Delivery, 2019
Sadia Sikder, Vrinda Gote, Meshal Alshamrani, Jeff Sicotte, Dhananjay Pal
In the past two decades, cell-surface targeting peptides were developed by molecular docking and by screening combinatorial peptide libraries for known molecular targets. Screening of peptide libraries for a known target can be achieved by biological method like Phage-display and chemical approach like one-bead one-compound (OBOC) [83,84]. Integrin receptor α3β1 is overexpressed in various cancer types like ovarian cancer, breast cancer, glioblastoma multiform, melanoma, and lung cancer. It is associated with tumorigenesis, poor prognosis, and resistance to chemotherapeutic treatment and can serve as a cancer-specific therapeutic target and as a bio-marker. Lam et al. screened random OBOC libraries and discovered a cyclic peptide cDGXGXXc, which binds to α3 sub-unit of α3β1 integrin receptor expressed on ovarian adenocarcinoma cell lines. Subsequently, the researchers designed, synthesized, and screened two specific OBOC cyclic peptide libraries against triple negative breast cancer cell line MDA-MB-231 in the hope to find peptides specific and selective for α3β1 integrin receptor-mediated delivery. They identified a cyclic peptide LXY3 (cyclic cdG-Tyr (3-NO2)-G-Hyp-Nc), which has higher binding affinity to α3β1 integrin receptor. The tumor targeting ability of LXY3 was further established in vivo in a mouse xenograft model of breast adenocarcinoma by fluoresce optical imaging [85]. Lam et al. also designed a second cyclic nano-peptide ligand LXY30 (cyclic cdG-Phe(3,5-diF)-G-Hyp-GcR), which had higher targeting ability. The ligand was evaluated in-vitro and in-vivo for tumor targeting. The in-vitro tumor targeting ability of LXY30 was evaluated in ovarian adenocarcinoma cell line SKOV3 (Figure 4(a)) and clinical ovarian tumor tissue (Figure 4(b)). For studying the in vivo uptake of NP-peptide ligand LXY30, a SKOV3 xenograft mouse model was established. The in vivo and ex vivo targetability of ligand LXY30 for α3β1 integrin receptor are illustrated in Figure 4(c,d), respectively. This study demonstrated improved and enhanced tumor-targeting property of peptide ligand LXY30, which can be harnessed for the targeted delivery of imaging agents and chemotherapeutics [86].