Статті в журналах: "Transmembrane mucins"

1

van Putten, Jos P. M., and Karin Strijbis. "Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer." Journal of Innate Immunity 9, no. 3 (2017): 281–99. http://dx.doi.org/10.1159/000453594.

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Mucosal surfaces line our body cavities and provide the interaction surface between commensal and pathogenic microbiota and the host. The barrier function of the mucosal layer is largely maintained by gel-forming mucin proteins that are secreted by goblet cells. In addition, mucosal epithelial cells express cell-bound mucins that have both barrier and signaling functions. The family of transmembrane mucins consists of diverse members that share a few characteristics. The highly glycosylated extracellular mucin domains inhibit invasion by pathogenic bacteria and can form a tight mesh structure that protects cells in harmful conditions. The intracellular tails of transmembrane mucins can be phosphorylated and connect to signaling pathways that regulate inflammation, cell-cell interactions, differentiation, and apoptosis. Transmembrane mucins play important roles in preventing infection at mucosal surfaces, but are also renowned for their contributions to the development, progression, and metastasis of adenocarcinomas. In general, transmembrane mucins seem to have evolved to monitor and repair damaged epithelia, but these functions can be highjacked by cancer cells to yield a survival advantage. This review presents an overview of the current knowledge of the functions of transmembrane mucins in inflammatory processes and carcinogenesis in order to better understand the diverse functions of these multifunctional proteins.

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2

Sun, Lingbo, Yuhan Zhang, Wenyan Li, Jing Zhang, and Yuecheng Zhang. "Mucin Glycans: A Target for Cancer Therapy." Molecules 28, no. 20 (October 11, 2023): 7033. http://dx.doi.org/10.3390/molecules28207033.

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Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the human body, which can be classified into secreted mucins and transmembrane mucins according to their distributions. The major difference between them is that secreted mucins do not have transmembrane structural domains, and the expression of each mucin is organ and cell-specific. Under physiological conditions, mucin glycans are involved in the composition of the mucus barrier and thus protect the body from infection and injury. However, abnormal expression of mucin glycans can lead to the occurrence of diseases, especially cancer, through various mechanisms. Therefore, targeting mucin glycans for the diagnosis and treatment of cancer has always been a promising research direction. Here, we first summarize the main types of glycosylation (O-GalNAc glycosylation and N-glycosylation) on mucins and the mechanisms by which abnormal mucin glycans occur. Next, how abnormal mucin glycans contribute to cancer development is described. Finally, we summarize MUC1-based antibodies, vaccines, radio-pharmaceuticals, and CAR-T therapies using the best characterized MUC1 as an example. In this section, we specifically elaborate on the recent new cancer therapy CAR-M, which may bring new hope to cancer patients.

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3

Ballester, Milara, and Cortijo. "Mucins as a New Frontier in Pulmonary Fibrosis." Journal of Clinical Medicine 8, no. 9 (September 11, 2019): 1447. http://dx.doi.org/10.3390/jcm8091447.

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Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 3–5 years after diagnosis. Recent evidence identifies mucins as key effectors in cell growth and tissue remodeling processes compatible with the processes observed in IPF. Mucins are classified in two groups depending on whether they are secreted (secreted mucins) or tethered to cell membranes (transmembrane mucins). Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6-8 and MUC19) are released to the extracellular medium and recent evidence has shown that a promoter polymorphism in the secreted mucin MUC5B is associated with IPF risk. Otherwise, transmembrane mucins (MUC1, MUC3, MUC4, MUC12-17 and MUC20) have a receptor-like structure, sensing the external environment and activating intracellular signal transduction pathways essential for mucosal maintenance and damage repair. In this context, the extracellular domain can be released to the external environment by metalloproteinase action, increased in IPF, thus activating fibrotic processes. For example, several studies have reported increased serum extracellular secreted KL6/MUC1 during IPF acute exacerbation. Moreover, MUC1 and MUC4 overexpression in the main IPF cells has been observed. In this review we summarize the current knowledge of mucins as promising druggable targets for IPF.

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4

Chatterjee, Maitrayee, Liane Z. X. Huang, Anna Z. Mykytyn, Chunyan Wang, Mart M. Lamers, Bart Westendorp, Richard W. Wubbolts, et al. "Glycosylated extracellular mucin domains protect against SARS-CoV-2 infection at the respiratory surface." PLOS Pathogens 19, no. 8 (August 10, 2023): e1011571. http://dx.doi.org/10.1371/journal.ppat.1011571.

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Mucins play an essential role in protecting the respiratory tract against microbial infections while also acting as binding sites for bacterial and viral adhesins. The heavily O-glycosylated gel-forming mucins MUC5AC and MUC5B eliminate pathogens by mucociliary clearance. Transmembrane mucins MUC1, MUC4, and MUC16 can restrict microbial invasion at the apical surface of the epithelium. In this study, we determined the impact of host mucins and mucin glycans on epithelial entry of SARS-CoV-2. Human lung epithelial Calu-3 cells express the SARS-CoV-2 entry receptor ACE2 and high levels of glycosylated MUC1, but not MUC4 and MUC16, on their cell surface. The O-glycan-specific mucinase StcE specifically removed the glycosylated part of the MUC1 extracellular domain while leaving the underlying SEA domain and cytoplasmic tail intact. StcE treatment of Calu-3 cells significantly enhanced infection with SARS-CoV-2 pseudovirus and authentic virus, while removal of sialic acid and fucose from the epithelial surface did not impact viral entry. In Calu-3 cells, the transmembrane mucin MUC1 and ACE2 are located to the apical surface in close proximity and StcE treatment results in enhanced binding of purified spike protein. Both MUC1 and MUC16 are expressed on the surface of human organoid-derived air-liquid interface (ALI) differentiated airway cultures and StcE treatment led to mucin removal and increased levels of SARS-CoV-2 replication. In these cultures, MUC1 was highly expressed in non-ciliated cells while MUC16 was enriched in goblet cells. In conclusion, the glycosylated extracellular domains of different transmembrane mucins might have similar protective functions in different respiratory cell types by restricting SARS-CoV-2 binding and entry.

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5

Hauber, Hans-Peter, Susan C. Foley, and Qutayba Hamid. "Mucin Overproduction in Chronic Inflammatory Lung Disease." Canadian Respiratory Journal 13, no. 6 (2006): 327–35. http://dx.doi.org/10.1155/2006/901417.

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Mucus overproduction and hypersecretion are commonly observed in chronic inflammatory lung disease. Mucins are gel-forming glycoproteins that can be stimulated by a variety of mediators. The present review addresses the mechanisms involved in the upregulation of secreted mucins. Mucin induction by neutrophil elastase, bacteria, cytokines, growth factors, smoke and cystic fibrosis transmembrane conductance regulator malfunction are also discussed.

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6

Constantinou, Pamela E., Brian P. Danysh, Neeraja Dharmaraj, and Daniel D. Carson. "Transmembrane mucins as novel therapeutic targets." Expert Review of Endocrinology & Metabolism 6, no. 6 (November 2011): 835–48. http://dx.doi.org/10.1586/eem.11.70.

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7

Hansson, Gunnar C. "Mucins and the Microbiome." Annual Review of Biochemistry 89, no. 1 (June 20, 2020): 769–93. http://dx.doi.org/10.1146/annurev-biochem-011520-105053.

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Generating the barriers that protect our inner surfaces from bacteria and other challenges requires large glycoproteins called mucins. These come in two types, gel-forming and transmembrane, all characterized by large, highly O-glycosylated mucin domains that are diversely decorated by Golgi glycosyltransferases to become extended rodlike structures. The general functions of mucins on internal epithelial surfaces are to wash away microorganisms and, even more importantly, to build protective barriers. The latter function is most evident in the large intestine, where the inner mucus layer separates the numerous commensal bacteria from the epithelial cells. The host's conversion of MUC2 to the outer mucus layer allows bacteria to degrade the mucin glycans and recover the energy content that is then shared with the host. The molecular nature of the mucins is complex, and how they construct the extracellular complex glycocalyx and mucus is poorly understood and a future biochemical challenge.

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8

Mall, A. S. "Analysis of mucins: role in laboratory diagnosis." Journal of Clinical Pathology 61, no. 9 (July 19, 2008): 1018–24. http://dx.doi.org/10.1136/jcp.2008.058057.

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Mucins are high molecular weight glycoproteins with complex oligosaccharide side chains attached to the apomucin protein backbone by O-glycosidic linkage; they are found in crude mucus gels that protect epithelial surfaces in the major tracts of the body and as transmembrane proteins expressed on the apical cell surface of glandular and ductal epithelia of various organs. Changes in the sequence of glycosylation of mucins in different settings generate a variety of epitopes in the oligosaccharide side chains of mucins, including newly expressed blood-group antigens, distinguishing between normal and diseased states. Tumour-associated epitopes on mucins and their antigenicity make them suitable as immunotargets on malignant epithelial cells and their secretions, creating a surge of interest in mucins as diagnostic and prognostic markers for various diseases, and even influencing the design of mucin-based vaccines. This review discusses the emerging roles of mucins such as MUC1 and MUC4 in cancer and some other diseases, and stresses how underglycosylated and truncated mucins are exploited as markers of disease and to monitor widespread metastasis, making them useful in patient management. Furthermore the type, pattern and amount of mucin secreted in some tissues have been considered in the classification and terminology of neoplasia and in specific organs such as the pancreas. These factors have been instrumental in pathological classification, diagnosis and prognostication of neoplasia.

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9

Itah, Shir, David Elad, Ariel J. Jaffa, Dan Grisaru, and Mordechai Rosner. "Transmembrane Mucin Response in Conjunctival Epithelial Cells Exposed to Wall Shear Stresses." International Journal of Molecular Sciences 24, no. 7 (April 1, 2023): 6589. http://dx.doi.org/10.3390/ijms24076589.

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Human conjunctival epithelium cells (HCEC) line the inner surface of the eyelid and cover the sclera and are continuously subjected to wall shear stresses (WSS). The effects of external forces on the conjunctival epithelium are not fully known. The conjunctival epithelium contains stratified squamous cells that synthesize the membrane-spanning mucins MUC1 and MUC16, which play important roles in protecting the ocular surface. Alterations in both gel-forming and membrane-tethered mucins occur in drying ocular surface diseases. The aim of this study was to explore the mechanobiological characteristics of transmembrane mucin secretion and cellular alterations of primary HCEC exposed to airflow-induced WSS perturbations. We exposed the HCEC to a steady WSS of 0.5 dyne/cm2 for durations of 15 and 30 min. Cytoskeletal alterations and MUC1 secretions were studied using immunohistochemically fluorescent staining with specific antibodies. We investigated for the first time an in vitro model of membrane-tethered mucin secretion by HCEC in response to WSS. The exposure of HCEC to WSS increased the polymerization of F-actin, altered the cytoskeletal shape and reduced the secretion of membrane-tethered MUC1.

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10

Kramer, Jessica R., Bibiana Onoa, Carlos Bustamante, and Carolyn R. Bertozzi. "Chemically tunable mucin chimeras assembled on living cells." Proceedings of the National Academy of Sciences 112, no. 41 (September 29, 2015): 12574–79. http://dx.doi.org/10.1073/pnas.1516127112.

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Mucins are a family of secreted and transmembrane glycoproteins characterized by a massive domain of dense O-glycosylation on serine and threonine residues. Mucins are intimately involved in immunity and cancer, yet elucidation of the biological roles of their glycodomains has been complicated by their massive size, domain polymorphisms, and variable glycosylation patterns. Here we developed a synthetic route to a library of compositionally defined, high-molecular weight, dual end-functionalized mucin glycodomain constructs via N-carboxyanhydride polymerization. These glycopolypeptides are the first synthetic analogs to our knowledge to feature the native α-GalNAc linkage to serine with molecular weights similar to native mucins, solving a nearly 50-year synthetic challenge. Physical characterization of the mimics revealed insights into the structure and properties of mucins. The synthetic glycodomains were end-functionalized with an optical probe and a tetrazine moiety, which allowed site-specific bioorthogonal conjugation to an engineered membrane protein on live mammalian cells. This strategy in protein engineering will open avenues to explore the biological roles of cell surface mucins.

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11

Kuver, Rahul, Thomas Wong, Johanne Henriette Klinkspoor, and Sum P. Lee. "Absence of CFTR is associated with pleiotropic effects on mucins in mouse gallbladder epithelial cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 6 (December 2006): G1148—G1154. http://dx.doi.org/10.1152/ajpgi.00547.2005.

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Mucus of cystic fibrosis patients exhibits altered biochemical composition and biophysical behavior, but the causal relationships between altered cystic fibrosis transmembrane conductance regulator (CFTR) function and the abnormal mucus seen in various organ systems remain unclear. We used cultured gallbladder epithelial cells (GBEC) from wild-type and Cftr(−/−) mice to investigate mucin gene and protein expression, kinetics of postexocytotic mucous granule content expansion, and biochemical and ionic compositions of secreted mucins. Muc1, Muc3, Muc4, Muc5ac, and Muc5b mRNA levels were significantly lower in Cftr(−/−) GBEC compared with wild-type cells, whereas Muc2 mRNA levels were higher in Cftr(−/−) cells. Quantitative immunoblotting demonstrated a trend toward lower MUC1, MUC2, MUC3, MUC5AC, and MUC5B mucin levels in Cftr(−/−) cells compared with cells from wild-type mice. In contrast, the levels of secreted MUC1, MUC3, MUC5B, and MUC6 mucins were significantly higher from Cftr(−/−) cells; a trend toward higher levels of secreted MUC2 and MUC5AC was also noted from Cftr(−/−) cells. Cftr(−/−) cells demonstrated slower postexocytotic mucous granule content expansion. Calcium concentration was significantly elevated in the mucous gel secreted by Cftr(−/−) cells compared with wild-type cells. Secreted mucins from Cftr(−/−) cells contained higher sulfate concentrations. Thus absence of CFTR is associated with pleiotropic effects on mucins in murine GBEC.

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12

Szabóová, R., Z. Faixová, Z. Maková, and E. Piešová. "The Difference in the Mucus Organization Between the Small and Large Intestine and Its Protection of Selected Natural Substances. A Review." Folia Veterinaria 62, no. 4 (December 1, 2018): 48–55. http://dx.doi.org/10.2478/fv-2018-0037.

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Abstract The mucus layer of the intestinal tract plays an important role of forming the front line of innate host defense. Recent studies have suggested that the involvement of feeding natural additives on protection/prevention/promotion of mucus production in the intestinal environment is beneficial. The goblet cells continually produce mucins for the retention of the mucus barrier under physiological conditions, but different factors (e. g. microorganisms, microbial toxins, viruses, cytokines, and enzymes) can have profound effects on the integrity of the intestinal epithelium covered by a protective mucus. The intestinal mucus forms enterocytes covered by transmembrane mucins and goblet cells produce by the secreted gel-forming mucins (MUC2). The mucus is organized in a single unattached mucus layer in the small intestine and in two mucus layers (inner, outer) in the colon. The main part of the review evaluates the effects of natural additives/substances supplementation to stimulate increased expression of MUC2 mucin in the intestine of animals.

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13

Patel, Nikhil Manish, Georgios Geropoulos, Pranav Harshad Patel, Ricky Harminder Bhogal, Kevin Joseph Harrington, Aran Singanayagam, and Sacheen Kumar. "The Role of Mucin Expression in the Diagnosis of Oesophago-Gastric Cancer: A Systematic Literature Review." Cancers 15, no. 21 (November 1, 2023): 5252. http://dx.doi.org/10.3390/cancers15215252.

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Survival in oesophago-gastric cancer (OGC) is poor due to early diagnostic challenges. Non-invasive risk stratification may identify susceptible patients with pre-malignant or benign disease. Following diagnostic confirmation with endoscopic biopsy, early OGC may be treated sooner. Mucins are transmembrane glycoproteins implicated in OGC with potential use as biomarkers of malignant transformation. This systematic review defines the role of mucins in OGC diagnosis. A literature search of MEDLINE, Web of Science, Embase and Cochrane databases was performed following PRISMA protocols for studies published January 1960–December 2022. Demographic data and data on mucin sampling and analysis methods were extracted. The review included 124 studies (n = 11,386 patients). Gastric adenocarcinoma (GAc) was the commonest OG malignancy (n = 101) followed by oesophageal adenocarcinoma (OAc, n = 24) and squamous cell carcinoma (OSqCc, n = 10). Mucins MUC1, MUC2, MUC5AC and MUC6 were the most frequently implicated. High MUC1 expression correlated with poorer prognosis and metastases in OSqCc. MUC2 expression decreases during progression from healthy mucosa to OAc, causing reduced protection from gastric acid. MUC5AC was upregulated, and MUC6 downregulated in GAc. Mucin expression varies in OGC; changes may be epigenetic or mutational. Profiling upper GI mucin expression in OGC, with pre-malignant, benign and healthy controls may identify potential early diagnostic biomarkers.

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Pelaseyed, Thaher, Jenny K. Gustafsson, Ida J. Gustafsson, Anna Ermund, and Gunnar C. Hansson. "Carbachol-induced MUC17 endocytosis is concomitant with NHE3 internalization and CFTR membrane recruitment in enterocytes." American Journal of Physiology-Cell Physiology 305, no. 4 (August 15, 2013): C457—C467. http://dx.doi.org/10.1152/ajpcell.00141.2013.

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We have reported that transmembrane mucin MUC17 binds PDZ protein PDZK1, which retains MUC17 apically in enterocytes. MUC17 and transmembrane mucins MUC3 and MUC12 are suggested to build the enterocyte apical glycocalyx. Carbachol (CCh) stimulation of the small intestine results in gel-forming mucin secretion from goblet cells, something that requires adjacent enterocytes to secrete chloride and bicarbonate for proper mucin formation. Surface labeling and confocal imaging demonstrated that apically expressed MUC17 in Caco-2 cells and Muc3(17) in murine enterocytes were endocytosed upon stimulation with CCh. Relocation of MUC17 in response to CCh was specific as MUC3 and MUC12 did not relocate following CCh stimulation. MUC17 colocalized with PDZK1 under basal conditions, while MUC17 relocated to the terminal web and into early endosomes after CCh stimulation. CCh stimulation concomitantly internalized the Na+/H+exchanger 3 (NHE3) and recruited cystic fibrosis transmembrane conductance regulator (CFTR) to the apical membranes, a process that was important for CFTR-mediated bicarbonate secretion necessary for proper gel-forming mucin unfolding. The reason for the specific internalization of MUC17 is not understood, but it could limit the diffusion barrier for ion secretion caused by the apical enterocyte glycocalyx or alternatively act to sample luminal bacteria. Our results reveal well-orchestrated mucus secretion and trafficking of ion channels and the MUC17 mucin.

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15

Kosmerl, Erica, Celeste Miller, and Rafael Jiménez-Flores. "Preventative Effects of Milk Fat Globule Membrane Ingredients on DSS-Induced Mucosal Injury in Intestinal Epithelial Cells." Nutrients 16, no. 7 (March 26, 2024): 954. http://dx.doi.org/10.3390/nu16070954.

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The goblet cells of the gastrointestinal tract (GIT) produce glycoproteins called mucins that form a protective barrier from digestive contents and external stimuli. Recent evidence suggests that the milk fat globule membrane (MFGM) and its milk phospholipid component (MPL) can benefit the GIT through improving barrier function. Our objective was to compare the effects of two digested MFGM ingredients with or without dextran sodium sulfate (DSS)-induced barrier stress on mucin proteins. Co-cultured Caco-2/HT29-MTX intestinal cells were treated with in vitro digests of 2%, 5%, and 10% (w/v) MFGM or MPL alone for 6 h or followed by challenge with 2.5% DSS (6 h). Transepithelial electrical resistance and fluorescein isothiocyanate (FITC)-dextran (FD4) permeability measurements were used to measure changes in barrier integrity. Mucin characterization was performed using a combination of slot blotting techniques for secreted (MUC5AC, MUC2) and transmembrane (MUC3A, MUC1) mucins, scanning electron microscopy (SEM), and periodic acid Schiff (PAS)/Alcian blue staining. Digested MFGM and MPL prevented a DSS-induced reduction in secreted mucins, which corresponded to the prevention of DSS-induced increases in FD4 permeability. SEM and PAS/Alcian blue staining showed similar visual trends for secreted mucin production. A predictive bioinformatic approach was also used to identify potential KEGG pathways involved in MFGM-mediated mucosal maintenance under colitis conditions. This preliminary in silico evidence, combined with our in vitro findings, suggests the role of MFGM in inducing repair and maintenance of the mucosal barrier.

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Lee, Dong-Hee, Seunghyun Choi, Yoon Park, and Hyung-seung Jin. "Mucin1 and Mucin16: Therapeutic Targets for Cancer Therapy." Pharmaceuticals 14, no. 10 (October 17, 2021): 1053. http://dx.doi.org/10.3390/ph14101053.

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The mucin (MUC) family is a group of highly glycosylated macromolecules that are abundantly expressed in mammalian epithelial cells. MUC proteins contribute to the formation of the mucus barrier and thus have protective functions against infection. Interestingly, some MUC proteins are aberrantly expressed in cancer cells and are involved in cancer development and progression, including cell growth, proliferation, the inhibition of apoptosis, chemoresistance, metabolic reprogramming, and immune evasion. With their unique biological and structural features, MUC proteins have been considered promising therapeutic targets and also biomarkers for human cancer. In this review, we discuss the biological roles of the transmembrane mucins MUC1 and MUC16 in the context of hallmarks of cancer and current efforts to develop MUC1- and MUC16-targeted therapies.

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Brossard-Barbosa, Natalie, Matias Agoglia, Maria Elena Vergara, Monique Costa, Ernesto Cairoli, and Teresa Freire. "Possible Correlation between Mucin Gene Expression and Symptoms of Dry Eye Syndrome Secondary to Sjogren’s Disease." Journal of Clinical & Translational Ophthalmology 2, no. 3 (August 28, 2024): 87–98. http://dx.doi.org/10.3390/jcto2030008.

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(1) Background: It is estimated that 10% of dry eye disease (DED) occurs in patients with Sjogren’s syndrome (SS-DED) and represents a challenge when it comes to treatment. Both innate and adaptive immunity participate in the pathogenesis of SS-DED. Previous studies suggest that Th1 and Th17 cell immune responses are the main actors associated with the pathogenesis of this disease. Ocular surface mucins play a fundamental role in ocular surface homeostasis. In particular, the main transmembrane mucins, MUC1, MUC4 and MUC16, are dysregulated in DED and could be involved in the activation of pro-inflammatory cytokines at the ocular interface. Thus, the objective of this work was to analyze mucin and cytokine expression in ocular surface (OS) damage and correlate it with clinical symptoms.; (2) Methods: 18 patients with SS-DED and 15 healthy controls were included in the study. Samples of conjunctival cells were obtained through cytology impression. RNA was extracted from the collected samples and used to determine the expression of MUC1, 4 and 16 by qRT-PCR. Pro-inflammatory cytokines associated with DED pathogenesis (IL17 and IL-22) were also evaluated. The results were contrasted with the clinical findings on examination of the patients. (3) Results: We observed a significant increase in the expression of MUC1 and MUC4 in patients with SS-DED. MUC4 significantly correlated with both lower production and stability of the tear film, as well as greater superficial keratopathy. On the other hand, MUC1 and MUC16 were positively correlated with the presence of more severe DED symptoms. However, we could not reproduce an increase in IL-17 and IL-22 in DED patients as previously reported; (4) Conclusions: This work constitutes an approach to understanding how the gene expression of transmembrane mucins associates with SS-DED symptoms and clinical signs.

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Okuda, Kenichi, Kendall M. Shaffer, and Camille Ehre. "Mucins and CFTR: Their Close Relationship." International Journal of Molecular Sciences 23, no. 18 (September 6, 2022): 10232. http://dx.doi.org/10.3390/ijms231810232.

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Mucociliary clearance is a critical defense mechanism for the lungs governed by regionally coordinated epithelial cellular activities, including mucin secretion, cilia beating, and transepithelial ion transport. Cystic fibrosis (CF), an autosomal genetic disorder caused by the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, is characterized by failed mucociliary clearance due to abnormal mucus biophysical properties. In recent years, with the development of highly effective modulator therapies, the quality of life of a significant number of people living with CF has greatly improved; however, further understanding the cellular biology relevant to CFTR and airway mucus biochemical interactions are necessary to develop novel therapies aimed at restoring CFTR gene expression in the lungs. In this article, we discuss recent advances of transcriptome analysis at single-cell levels that revealed a heretofore unanticipated close relationship between secretory MUC5AC and MUC5B mucins and CFTR in the lungs. In addition, we review recent findings on airway mucus biochemical and biophysical properties, focusing on how mucin secretion and CFTR-mediated ion transport are integrated to maintain airway mucus homeostasis in health and how CFTR dysfunction and restoration of function affect mucus properties.

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Massey, Andrew. "Abstract PO-044: Mechanobiological analysis of human patient pancreatic cancer tissues and the effect of cellular transmembrane mucins on glycocalyx-actomyosin mechanics." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—044—PO—044. http://dx.doi.org/10.1158/1538-7445.panca21-po-044.

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Abstract Pancreatic cancer is one of the most lethal malignancies with a 5-year survival rate currently below 10%. Unfortunately, current diagnostic methods are unable to readily recognize early disease progression, and symptoms are commonly misdiagnosed. Therefore, determining novel biomarkers related to disease progression remains an important area of research. Transmembrane mucins, a major component of the cellular glycocalyx, normally play a protective role in epithelial tissues; they are also known to be overexpressed in various cancers, including pancreatic. In addition, mucins are known to increase aggressiveness, enhance drug resistance, and reduce survivability in cancers where they are upregulated. Although the biochemical effects of mucins are well understood, there is minimal research into how they affect cancer cells at a biophysical level. Recently, there has been great interest in examining the biophysical properties of cancer cells. The current consensus is that cancerous cells are softer than their normal counterparts, and that more metastatic cells become softer compared to more benign tumor cells. Measuring these physical properties could potentially give clinicians a more rapid way to diagnose tumors, determine the course of disease progression, physically determine the effect of a biomolecule when its expression is altered, or determine the efficacy of various chemotherapeutics. In this study, we will first use atomic force microscopy-based nanomechanical mapping to measure the biophysical differences between normal cells, cancerous cells, and the extracellular matrix extracted from human patient tumor tissues and track the measured changes, both before and after chemo treatments. Our preliminary in vitro results suggest that 2D-adherent human cancerous pancreatic cells are indeed softer than their normal counterparts, in agreement with the literature. In addition, modulation of the glycocalyx architecture via hyaluronidase treatment leads to considerable changes in cellular stiffness in both normal and cancerous cells, implying a link between the glycocalyx and the underlying actomyosin skeleton. Future studies will examine the in vitro effects of specific transmembrane mucins. Using overexpression and knockdown transfection models, the impact on cellular mechanics, as well as structural changes in the glycocalyx and actomyosin cortex, will be analyzed in pancreatic cancer cells to determine how these mucins effect cellular mechanics and by extension regulate tumorigenesis and metastasis. Citation Format: Andrew Massey. Mechanobiological analysis of human patient pancreatic cancer tissues and the effect of cellular transmembrane mucins on glycocalyx-actomyosin mechanics [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-044.

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20

Breugelmans, Tom, Hanne Van Spaendonk, Joris G. De Man, Heiko U. De Schepper, Aranzazu Jauregui-Amezaga, Elisabeth Macken, Sara K. Lindén, et al. "In-Depth Study of Transmembrane Mucins in Association with Intestinal Barrier Dysfunction During the Course of T Cell Transfer and DSS-Induced Colitis." Journal of Crohn's and Colitis 14, no. 7 (January 31, 2020): 974–94. http://dx.doi.org/10.1093/ecco-jcc/jjaa015.

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Abstract Background and Aims There is evidence for a disturbed intestinal barrier function in inflammatory bowel diseases [IBD] but the underlying mechanisms are unclear. Because mucins represent the major components of the mucus barrier and disturbed mucin expression is reported in the colon of IBD patients, we studied the association between mucin expression, inflammation and intestinal permeability in experimental colitis. Methods We quantified 4-kDa FITC-dextran intestinal permeability and the expression of cytokines, mucins, junctional and polarity proteins at dedicated time points in the adoptive T cell transfer and dextran sodium sulfate [DSS]-induced colitis models. Mucin expression was also validated in biopsies from IBD patients. Results In both animal models, the course of colitis was associated with increased interleukin-1β [IL-1β] and tumour necrosis factor-α [TNF-α] expression and increased Muc1 and Muc13 expression. In the T cell transfer model, a gradually increasing Muc1 expression coincided with gradually increasing 4-kDa FITC-dextran intestinal permeability and correlated with enhanced IL-1β expression. In the DSS model, Muc13 expression coincided with rapidly increased 4-kDa FITC-dextran intestinal permeability and correlated with TNF-α and Muc1 overexpression. Moreover, a significant association was observed between Muc1, Cldn1, Ocln, Par3 and aPKCζ expression in the T cell transfer model and between Muc13, Cldn1, Jam2, Tjp2, aPkcζ, Crb3 and Scrib expression in the DSS model. Additionally, MUC1 and MUC13 expression was upregulated in inflamed mucosa of IBD patients. Conclusions Aberrantly expressed MUC1 and MUC13 might be involved in intestinal barrier dysfunction upon inflammation by affecting junctional and cell polarity proteins, indicating their potential as therapeutic targets in IBD.

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Allavena, P., M. Chieppa, G. Bianchi, G. Solinas, M. Fabbri, G. Laskarin, and A. Mantovani. "Engagement of the Mannose Receptor by Tumoral Mucins Activates an Immune Suppressive Phenotype in Human Tumor-Associated Macrophages." Clinical and Developmental Immunology 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/547179.

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Tumor-Associated Macrophages (TAMs) are abundantly present in the stroma of solid tumors and modulate several important biological processes, such as neoangiogenesis, cancer cell proliferation and invasion, and suppression of adaptive immune responses. Myeloid C-type lectin receptors (CLRs) constitute a large family of transmembrane carbohydrate-binding receptors that recognize pathogens as well as endogenous glycoproteins. Several lines of evidence demonstrate that some CLRs can inhibit the immune response. In this study we investigated TAM-associated molecules potentially involved in their immune suppressive activity. We found that TAMs isolated from human ovarian carcinoma samples predominantly express the CLRs Dectin-1, MDL-1, MGL, DCIR, and most abundantly the Mannose Receptor (MR). Components of carcinomatous ascites and purified tumoral mucins (CA125 and TAG-72) bound the MR and induced its internalization. MR engagement by tumoral mucins and by an agonist anti-MR antibody modulated cytokine production by TAM toward an immune-suppressive profile: increase of IL-10, absence of IL-12, and decrease of the Th1-attracting chemokine CCL3. This study highlights that tumoral mucin-mediated ligation of the MR on infiltrating TAM may contribute to their immune suppressive phenotype.

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Almasmoum, Hussain. "The Roles of Transmembrane Mucins Located on Chromosome 7q22.1 in Colorectal Cancer." Cancer Management and Research Volume 13 (April 2021): 3271–80. http://dx.doi.org/10.2147/cmar.s299089.

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Gipson, Ilene K., Sandra Spurr-Michaud, Ann Tisdale, and Balaraj B. Menon. "Comparison of the Transmembrane Mucins MUC1 and MUC16 in Epithelial Barrier Function." PLoS ONE 9, no. 6 (June 26, 2014): e100393. http://dx.doi.org/10.1371/journal.pone.0100393.

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Singh, Ajay P., Subhash C. Chauhan, Sangeeta Bafna, Sonny L. Johansson, Lynette M. Smith, Nicolas Moniaux, Ming-Fong Lin, and Surinder K. Batra. "Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas." Prostate 66, no. 4 (March 1, 2006): 421–29. http://dx.doi.org/10.1002/pros.20372.

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Lang, T. "Bioinformatic identification of polymerizing and transmembrane mucins in the puffer fish Fugu rubripes." Glycobiology 14, no. 6 (January 22, 2004): 521–27. http://dx.doi.org/10.1093/glycob/cwh066.

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Duraisamy, Sekhar, Selvi Ramasamy, Surender Kharbanda, and Donald Kufe. "Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 AND MUC16." Gene 373 (May 2006): 28–34. http://dx.doi.org/10.1016/j.gene.2005.12.021.

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Walters, Robert W., Joseph M. Pilewski, John A. Chiorini, and Joseph Zabner. "Secreted and Transmembrane Mucins Inhibit Gene Transfer with AAV4 More Efficiently than AAV5." Journal of Biological Chemistry 277, no. 26 (March 29, 2002): 23709–13. http://dx.doi.org/10.1074/jbc.m200292200.

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THOMSSON, Kristina A., Marina HINOJOSA-KURTZBERG, Karin A. AXELSSON, Steven E. DOMINO, John B. LOWE, Sandra J. GENDLER та Gunnar C. HANSSON. "Intestinal mucins from cystic fibrosis mice show increased fucosylation due to an induced Fucα1-2 glycosyltransferase". Biochemical Journal 367, № 3 (1 листопада 2002): 609–16. http://dx.doi.org/10.1042/bj20020371.

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In gene-targeted mouse models for cystic fibrosis (CF), the disease is mainly manifested by mucus obstruction in the intestine. To explore the mucus composition, mucins insoluble and soluble in 6M guanidinium chloride were purified by three rounds of isopycnic ultracentrifugation from the small and large intestines of CF mice (Cftrm1UNC/Cftrm1UNC) and compared with wild-type mice. The amino acid composition was typical of that for mucins and showed increased amounts of the insoluble (2.5-fold increase) and soluble (7-fold increase) mucins in the small intestine of the CF mice compared with wild-type mice. Mucins from the large intestine of both wild-type and CF mice showed a high but constant level of fucosylation. In contrast, the insoluble and soluble mucins of the small intestine in CF mice revealed a large increase in fucose, whereas those of wild-type mice contained only small amounts of fucose. This increased fucosylation was analysed by releasing the O-linked oligosaccharides followed by GC-MS. NMR spectroscopy revealed that the increased fucosylation was due to an increased expression of blood group H epitopes (Fucα1-2Gal-). Northern-blot analysis, using a probe for the murine Fucα1-2 fucosyltransferase (Fut2), showed an up-regulation of this mRNA in the small intestine of the CF mice, suggesting that this enzyme is responsible for the observed increase in blood group H-type glycosylation. The reason for this up-regulation could be a direct or indirect effect of a non-functional CF transmembrane conductance regulator (CFTR) caused by the absence of CFTR channel.

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Malmberg, Emily K., Thaher Pelaseyed, Åsa C. Petersson, Ursula E. Seidler, Hugo De Jonge, John R. Riordan, and Gunnar C. Hansson. "The C-terminus of the transmembrane mucin MUC17 binds to the scaffold protein PDZK1 that stably localizes it to the enterocyte apical membrane in the small intestine." Biochemical Journal 410, no. 2 (February 12, 2008): 283–89. http://dx.doi.org/10.1042/bj20071068.

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The membrane-bound mucins have a heavily O-glycosylated extracellular domain, a single-pass membrane domain and a short cytoplasmic tail. Three of the membrane-bound mucins, MUC3, MUC12 and MUC17, are clustered on chromosome 7 and found in the gastrointestinal tract. These mucins have C-terminal sequences typical of PDZ-domain-binding proteins. To identify PDZ proteins that are able to interact with the mucins, we screened PDZ domain arrays using YFP (yellow fluorescent protein)-tagged proteins. MUC17 exhibited a strong binding to PDZK1 (PDZ domain containing 1), whereas the binding to NHERF1 (Na+/H+-exchanger regulatory factor 1) was weak. Furthermore, we showed weak binding of MUC12 to PDZK1, NHERF1 and NHERF2. GST (glutathione transferase) pull-down experiments confirmed that the C-terminal tail of MUC17 co-precipitates with the scaffold protein PDZK1 as identified by MS. This was mediated through the C-terminal PDZ-interaction site in MUC17, which was capable of binding to three of the four PDZ domains in PDZK1. Immunostaining of wild-type or Pdzk1−/− mouse jejunum with an antiserum against Muc3(17), the mouse orthologue of human MUC17, revealed strong brush-border membrane staining in the wild-type mice compared with an intracellular Muc3(17) staining in the Pdzk1−/− mice. This suggests that Pdzk1 plays a specific role in stabilizing Muc3(17) in the apical membrane of small intestinal enterocytes.

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Stremmel, Wolfgang, Simone Staffer, and Ralf Weiskirchen. "Phosphatidylcholine Passes by Paracellular Transport to the Apical Side of the Polarized Biliary Tumor Cell Line Mz-ChA-1." International Journal of Molecular Sciences 20, no. 16 (August 19, 2019): 4034. http://dx.doi.org/10.3390/ijms20164034.

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Phosphatidylcholine (PC) translocation into mucus of the intestine was shown to occur via a paracellular transport across the apical/lateral tight junction (TJ) barrier. In case this could also be operative in biliary epithelial cells, this may have implication for the pathogenesis of primary sclerosing cholangitis (PSC). We here evaluated the transport of PC across polarized cholangiocytes. Therefore, the biliary tumor cell line Mz-ChA-1 was grown to confluency. In transwell culture systems the translocation of PC to the apical compartment was analyzed. After 21 days in culture, polarized Mz-ChA-1 cells revealed a predominant apical translocation of choline containing phospholipids including PC with minimal intracellular accumulation. Transport was suppressed by TJ destruction employing chemical inhibitors and pretreatment with siRNA to TJ forming proteins as well as the apical transmembrane mucin 3 as PC acceptor. Apical translocation was dependent on a negative apical electrical potential created by the cystic fibrosis transmembrane conductance regulator (CFTR) and the anion exchange protein 2 (AE2). It was stimulated by apical application of secretory mucins. The results indicated the existence of a paracellular PC passage across apical/lateral TJ of the polarized biliary epithelial tumor cell line Mz-ChA-1. This has implication for the generation of a protective mucus barrier in the biliary tree.

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Mallya, Kavita, Dhanya Haridas, Parthasarathy Seshacharyulu, Ramesh Pothuraju, Wade M. Junker, Shiv Ram Krishn, Sakthivel Muniyan, Raghupathy Vengoji, Surinder K. Batra, and Satyanarayana Rachagani. "Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model." Biology Open 9, no. 9 (July 24, 2020): bio052878. http://dx.doi.org/10.1242/bio.052878.

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ABSTRACTPancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KrasG12D; Ptf1a-CreER™ (iKC) mouse model, in which Kras is activated postnatally at week 16 upon tamoxifen (TAM) administration. Upon TAM treatment, iKC mice develop pancreatic intraepithelial neoplasia (PanIN) lesions and PC with metastasis at the fourth and fortieth weeks, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation upregulated the transcription factors Ncoa3, p-cJun and FoxM1, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4 and Muc16) and secretory mucin (Muc5Ac). Interestingly, knockdown of KrasG12D in multiple PC cell lines resulted in downregulation of MUC1, MUC4, MUC5AC and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show that the iKC mouse more closely mimics human PC development and can be used to investigate pancreatic ductal adenocarcinoma (PDAC) biomarkers, early onset of PDAC, and ADM. The iKC model can also be used for preclinical strategies such as targeting mucin axis alone or in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.

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Schneider, Hannah, Evelin Berger, Brendan Dolan, Beatriz Martinez-Abad, Liisa Arike, Thaher Pelaseyed та Gunnar C. Hansson. "The human transmembrane mucin MUC17 responds to TNFα by increased presentation at the plasma membrane". Biochemical Journal 476, № 16 (22 серпня 2019): 2281–95. http://dx.doi.org/10.1042/bcj20190180.

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Abstract Transmembrane mucin MUC17 is an integral part of the glycocalyx as it covers the brush border membrane of small intestinal enterocytes and presents an extended O-glycosylated mucin domain to the intestinal lumen. Here, we identified two unknown phosphorylated serine residues, S4428 and S4492, in the cytoplasmic tail of human MUC17. We have previously demonstrated that MUC17 is anchored to the apical membrane domain via an interaction with the scaffolding protein PDZK1. S4492, localized in the C-terminal PDZ binding motif of MUC17, was mutated to generate phosphomimetic and phosphodeficient variants of MUC17. Using Caco-2 cells as a model system, we found that induction of an inflammatory state by long-term stimulation with the proinflammatory cytokine TNFα resulted in an increase of MUC17 protein levels and enhanced insertion of MUC17 and its two phospho-variants into apical membranes. Up-regulation and apical insertion of MUC17 was followed by shedding of MUC17-containing vesicles. Transmembrane mucins have previously been shown to play a role in the prevention of bacterial colonization by acting as sheddable decoys for encroaching bacteria. Overexpression and increased presentation at the plasma membrane of wild-type MUC17 and its phosphodeficient variant MUC17 S-4492A protected Caco-2 cells against adhesion of enteropathogenic Escherichia coli, indicating that C-terminal phosphorylation of MUC17 may play a functional role in epithelial cell protection. We propose a new function for MUC17 in inflammation, where MUC17 acts as a second line of defense by preventing attachment of bacteria to the epithelial cell glycocalyx in the small intestine.

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Kootiswaran S, P. D. Balamurali, V. Ramesh, Karthikshree V. Prashad, D. Mounika, and Dhanalakshmi. "Mucin1 utterance in oral squamous cell carcinoma: A cancer maker and target for nanotheranostics." Journal of Oral Medicine, Oral Surgery, Oral Pathology and Oral Radiology 9, no. 3 (September 15, 2023): 138–43. http://dx.doi.org/10.18231/j.jooo.2023.031.

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Mucins are cell bound high molecular weight glycoproteins which are secreted by epithelial cells. Total 21 mucin variants are identified till date. Mucin1 (MUC1) is a transmembrane glycoprotein, which when reacts with beta-catenin, can able to enter the nucleus to activate T-cell factor/leukocyte enhancing factor 1 transcription factors and gene expression, after which it may inhibit cell-cell and cell-stroma interactions and function as a signal transducer, leading to tumor progression.To compare and correlate the expression and positive intensity of MUC1 in oral squamous cell carcinoma, oral epithelial dysplasia and normal oral mucosa using Immunohistochemistry. This study included a total of 45 cases in which the study groups are oral squamous cell carcinoma (n=15), oral epithelial dysplasia (n=15) and control of normal oral mucosa (n=15), which are analysed for the expression of anti MUC1 rabbit monoclonal antibody using immunohistochemical technique.The mucin1 positive cells in the study groups were as follows, 53.3% cases in OSCC, 13.3% cases in OED and none showed positivity in normal oral mucosa. The results obtained were statistically analysed using Kruskal-Wallis test and there was a statistically significant difference in score between the different tissue groups, Kruskal – Wallis H score = 13.034, p = 0.001.There is progressive increase in the MUC1 expression from oral epithelial dysplasia to OSCC. This utterance might be due to suppression of inhibitory proteins for MUC1 immunoexpression in mature atypical squamous cells as well as proposed to act both as an anti-adhesive and adhesive molecule.

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Groux-Degroote, Sophie, Marie-Ange Krzewinski-Recchi, Aurélie Cazet, Audrey Vincent, Sylvain Lehoux, Jean-Jacques Lafitte, Isabelle van Seuningen, and Philippe Delannoy. "IL-6 and IL-8 increase the expression of glycosyltransferases and sulfotransferases involved in the biosynthesis of sialylated and/or sulfated Lewisx epitopes in the human bronchial mucosa." Biochemical Journal 410, no. 1 (January 29, 2008): 213–23. http://dx.doi.org/10.1042/bj20070958.

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Bronchial mucins from patients suffering from CF (cystic fibrosis) exhibit glycosylation alterations, especially increased amounts of the sialyl-Lewisx (NeuAcα2-3Galβ1-4[Fucα1-3]GlcNAc-R) and 6-sulfo-sialyl-Lewisx (NeuAcα2-3Galβ1-4[Fucα1-3][SO3H-6]GlcNAc-R) terminal structures. These epitopes are preferential receptors for Pseudomonas aeruginosa, the bacteria responsible for the chronicity of airway infection and involved in the morbidity and early death of CF patients. However, these glycosylation changes cannot be directly linked to defects in CFTR (CF transmembrane conductance regulator) gene expression since cells that secrete airway mucins express no or very low amounts of the protein. Several studies have shown that inflammation may affect glycosylation and sulfation of various glycoproteins, including mucins. In the present study, we show that incubation of macroscopically healthy fragments of human bronchial mucosa with IL-6 (interleukin-6) or IL-8 results in a significant increase in the expression of α1,3/4-fucosyltransferases [FUT11 (fucosyltransferase 11 gene) and FUT3], α2-6- and α2,3-sialyltransferases [ST3GAL6 (α2,3-sialyltransferase 6 gene) and ST6GAL2 (α2,6-sialyltransferase 2 gene)] and GlcNAc-6-O-sulfotransferases [CHST4 (carbohydrate sulfotransferase 4 gene) and CHST6] mRNA. In parallel, the amounts of sialyl-Lewisx and 6-sulfo-sialyl-Lewisx epitopes at the periphery of high-molecular-mass proteins, including MUC4, were also increased. In conclusion, our results indicate that IL-6 and -8 may contribute to the increased levels of sialyl-Lewisx and 6-sulfo-sialyl-Lewisx epitopes on human airway mucins from patients with CF.

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Dharmaraj, N., P. J. Chapela, M. Morgado, S. M. Hawkins, B. A. Lessey, S. L. Young, and D. D. Carson. "Expression of the transmembrane mucins, MUC1, MUC4 and MUC16, in normal endometrium and in endometriosis." Human Reproduction 29, no. 8 (June 17, 2014): 1730–38. http://dx.doi.org/10.1093/humrep/deu146.

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Woodward, A. M., J. Mauris, and P. Argueso. "Binding of Transmembrane Mucins to Galectin-3 Limits Herpesvirus 1 Infection of Human Corneal Keratinocytes." Journal of Virology 87, no. 10 (March 13, 2013): 5841–47. http://dx.doi.org/10.1128/jvi.00166-13.

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37

Kaur, Sukhwinder, Navneet Momi, Subhankar Chakraborty, David G. Wagner, Adam J. Horn, Subodh M. Lele, Dan Theodorescu, and Surinder K. Batra. "Altered Expression of Transmembrane Mucins, MUC1 and MUC4, in Bladder Cancer: Pathological Implications in Diagnosis." PLoS ONE 9, no. 3 (March 26, 2014): e92742. http://dx.doi.org/10.1371/journal.pone.0092742.

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Tatebayashi, Kazuo, Keiichiro Tanaka, Hui-Yu Yang, Katsuyoshi Yamamoto, Yusaku Matsushita, Taichiro Tomida, Midori Imai, and Haruo Saito. "Transmembrane mucins Hkr1 and Msb2 are putative osmosensors in the SHO1 branch of yeast HOG pathway." EMBO Journal 26, no. 15 (July 12, 2007): 3521–33. http://dx.doi.org/10.1038/sj.emboj.7601796.

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Bravo-Osuna, I., M. Noiray, E. Briand, A. M. Woodward, P. Argüeso, I. T. Molina Martínez, R. Herrero-Vanrell, and G. Ponchel. "Interfacial Interaction between Transmembrane Ocular Mucins and Adhesive Polymers and Dendrimers Analyzed by Surface Plasmon Resonance." Pharmaceutical Research 29, no. 8 (May 8, 2012): 2329–40. http://dx.doi.org/10.1007/s11095-012-0761-1.

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Plaisancié, Pascale, Rachel Boutrou, Monique Estienne, Gwénaële Henry, Julien Jardin, Armelle Paquet та Joëlle Léonil. "β-Casein(94-123)-derived peptides differently modulate production of mucins in intestinal goblet cells". Journal of Dairy Research 82, № 1 (22 жовтня 2014): 36–46. http://dx.doi.org/10.1017/s0022029914000533.

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We recently reported the identification of a peptide from yoghurts with promising potential for intestinal health: the sequence (94-123) of bovine β-casein. This peptide, composed of 30 amino acid residues, maintains intestinal homoeostasis through production of the secreted mucin MUC2 and of the transmembrane-associated mucin MUC4. Our study aimed to search for the minimal sequence responsible for the biological activity of β-CN(94-123) by using several strategies based on (i) known bioactive peptides encrypted in β-CN(94-123), (ii) in silico prediction of peptides reactivity and (iii) digestion of β-CN(94-123) by enzymes of intestinal brush border membranes. The revealed sequences were tested in vitro on human intestinal mucus-producing HT29-MTX cells. We demonstrated that β-CN(108-113) (an ACE-inhibitory peptide) and β-CN(114-119) (an opioid peptide named neocasomorphin-6) up-regulated MUC4 expression whereas levels of the secreted mucins MUC2 and MUC5AC remained unchanged. The digestion of β-CN(94-123) by intestinal enzymes showed that the peptides β-CN(94-108) and β-CN(117-123) were present throughout 1·5 to 3 h of digestion, respectively. These two peptides raised MUC5AC expression while β-CN(117-123) also induced a decrease in the level of MUC2 mRNA and protein. In addition, this inhibitory effect was reproduced in airway epithelial cells. In conclusion, β-CN(94-123) is a multifunctional molecule but only the sequence of 30 amino acids has a stimulating effect on the production of MUC2, a crucial factor of intestinal protection.

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Anton, Friederike, Ina Leverkoehne, Lars Mundhenk, Wallace B. Thoreson, and Achim D. Gruber. "Overexpression of eCLCA1 in Small Airways of Horses with Recurrent Airway Obstruction." Journal of Histochemistry & Cytochemistry 53, no. 8 (August 2005): 1011–21. http://dx.doi.org/10.1369/jhc.4a6599.2005.

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The human hCLCA1 and murine mCLCA3 (chloride channels, calcium-activated) have recently been identified as promising therapeutic targets in asthma. Recurrent airway obstruction in horses is an important animal model of human asthma. Here, we have cloned and characterized the first equine CLCA family member, eCLCA1. The 913 amino acids eCLCA1 polypeptide forms a 120-kDa transmembrane glycoprotein that is processed to an 80-kDa protein in vivo. Three single nucleotide polymorphisms were detected in the eCLCA1 coding region in 14 horses, resulting in two amino acid changes (485H/R and 490V/L). However, no functional differences were recorded between the channel properties of the two variants in transfected HEK293 cells. The eCLCA1 protein was detected immunohistochemically in mucin-producing cells in the respiratory and intestinal tracts, cutaneous sweat glands, and renal mucous glands. Strong overexpression of eCLCA1 was observed in the airways of horses with recurrent airway obstruction using Northern blot hybridization, Western blotting, immunohistochemistry, and real-time quantitative RT-PCR. The results suggest that spontaneous or experimental recurrent airway obstruction in horses may serve as a model to study the role of CLCA homologs in chronic airway disease with overproduction of mucins.

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Kumar, Pardeep, F. Matthew Kuhlmann, Kirandeep Bhullar, Hyungjun Yang, Bruce A. Vallance, Lijun Xia, Qingwei Luo, and James M. Fleckenstein. "Dynamic Interactions of a Conserved Enterotoxigenic Escherichia coli Adhesin with Intestinal Mucins Govern Epithelium Engagement and Toxin Delivery." Infection and Immunity 84, no. 12 (October 10, 2016): 3608–17. http://dx.doi.org/10.1128/iai.00692-16.

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At present, there is no vaccine for enterotoxigenicEscherichia coli(ETEC), an important cause of diarrheal illness. Nevertheless, recent microbial pathogenesis studies have identified a number of molecules produced by ETEC that contribute to its virulence and are novel antigenic targets to complement canonical vaccine approaches. EtpA is a secreted two-partner adhesin that is conserved within the ETEC pathovar. EtpA interacts with the tips of ETEC flagella to promote bacterial adhesion, toxin delivery, and intestinal colonization by forming molecular bridges between the bacteria and the epithelial surface. However, the nature of EtpA interactions with the intestinal epithelium remains poorly defined. Here, we demonstrate that EtpA interacts with glycans presented by transmembrane and secreted intestinal mucins at epithelial surfaces to facilitate pathogen-host interactions that culminate in toxin delivery. Moreover, we found that a major effector molecule of ETEC, the heat-labile enterotoxin (LT), may enhance these interactions by stimulating the production of the gel-forming mucin MUC2. Our studies suggest, however, that EtpA participates in complex and dynamic interactions between ETEC and the gastrointestinal mucosae in which host glycoproteins promote bacterial attachment while simultaneously limiting the epithelial engagement required for effective toxin delivery. Collectively, these data provide additional insight into the intricate nature of ETEC interactions with the intestinal epithelium that have potential implications for rational approaches to vaccine design.

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Rivadeneyra, Leonardo, Melissa M. Lee-Sundlov, Simon Glabere, Heather Ashwood, Robert Burns, and Karin M. Hoffmeister. "Sialylated Glycans Regulate MUC13 and the Proto-Oncogenes Pim-1 and Myc to Control Hematopoietic Stem and Progenitor Cell Numbers." Blood 136, Supplement 1 (November 5, 2020): 8. http://dx.doi.org/10.1182/blood-2020-143365.

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Анотація:

The enzyme β-1-4 galactosyltransferase 1 (β4GalT1) plays a critical role in thrombopoiesis by modulating sialo-glycan (sialyl N-acetyl-lactosamine or LacNAc) content and function of the β1 integrin on megakaryocytes (MKs) (Nat. Commun. 2020;11(1):356). Recent data, however, point to a more complex role for β4GalT1 in hematopoiesis, as the promoter region of its conserved gene, B4galt1, is rich in enhancer sequences for transcription factors associated with cell identity and pro-oncogenic regulatory programs. Here, we investigated the homeostasis of hematopoietic stem and progenitor cells (HSPCs) in B4galt1-/- mice. We demonstrate that lack of Sialylated LacNAc synthesis perturbs HSPCs beyond the homing deficiency associated with lack of homing sialo-glycan motifs. Flow cytometry analysis showed that B4galt1-/- mouse bone marrows have increased numbers of Long-Term HSCs (LT-HSCs, defined as LineageNeg/Sca-1Pos/c-KitPos/CD150Pos/CD48Neg). The increase in HSC numbers led us to investigate their phenotypic and functional features further. While quiescence markers in B4galt1-/- LT-HSCs were indistinguishable relative to controls, LT-HSCs expressed more of the platelet marker CD41 on their surface, supporting a highly expanded CD41+ subset of LT-HSCs. Platelet-bias of LT-HSCs has been associated with inflammation and aging. However, our data do not support an increased cytokine inflammatory profile in the bone marrow. Instead, single-cell RNA sequencing (scRNA seq) of sorted β4galt1-/- LineageNeg/Sca-1Pos/c-KitPos (LSK) cells showed a significantly increased expression of the proto-oncogene Pim-1, its target, Myc, and the heavily O-glycosylated transmembrane receptor mucin 13 (MUC13), compared to control cells. Analysis of LT-HSC glycan expression using lectin microarray showed the expected decrease in N-glycosylation associated with B4galt1 deficiency, but also an increase in O-glycans, consistent with overexpression of MUC13, expression of which was enriched compared to other surface mucins. The data show that B4galt1 deletion leads to overexpression of the proto-oncogenes Pim-1, Myc, and MUC13 in HSPCs. The data suggest that MUC13-associated O-glycans and glyco-synthetic genes are potential therapeutic targets for hematologic malignancies since mucins have anti-inflammatory functions and alterations in mucin expression are with inflammation and cancer. Disclosures No relevant conflicts of interest to declare.

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44

O’Connell, Emer, Ian S. Reynolds, Deborah A. McNamara, John P. Burke, and Jochen H. M. Prehn. "Resistance to Cell Death in Mucinous Colorectal Cancer—A Review." Cancers 13, no. 6 (March 19, 2021): 1389. http://dx.doi.org/10.3390/cancers13061389.

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Mucinous colorectal cancer (CRC) is estimated to occur in approximately 10–15% of CRC cases and is characterized by abundant extracellular mucin. Mucinous CRC is frequently associated with resistance to apoptosis. Inferior prognosis is observed in mucinous CRC, particularly in rectal cancer and metastatic cases. Mucins are heavily glycosylated secretory or transmembrane proteins that participate in protection of the colonic epithelium. MUC2 overexpression is a hallmark of mucinous CRCs. Mucinous CRC is associated with KRAS and BRAF mutation, microsatellite instability and the CpG island methylator phenotype. Mutations of the APC gene and p53 mutations which are characteristic non-mucinous colorectal adenocarcinoma are less common in mucinous CRC. Both physical and anti-apoptotic properties of mucin provide mechanisms for resistance to cell death. Mucin glycoproteins are associated with decreased expression of pro-apoptotic proteins, increased expression of anti-apoptotic proteins and increased cell survival signaling. The role for BCL-2 proteins, including BCL-XL, in preventing apoptosis in mucinous CRC has been explored to a limited extent. Additional mechanisms opposing cell death include altered death receptor expression and altered mutation rates in genes responsible for chemotherapy resistance. The roles of alternate cell death programs including necroptosis and pyroptosis are not well understood in mucinous CRC. While the presence of MUC2 is associated with an immunosuppressive environment, the tumor immune environment of mucinous CRC and the role of immune-mediated tumor cell death likewise require further investigation. Improved understanding of cell death mechanisms in mucinous CRC may allow modification of currently used regimens and facilitate targeted treatment.

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45

McNEER, R. Richard, Daming HUANG, L. Nevis FREGIEN, and L. Kermit CARRAWAY. "Sialomucin complex in the rat respiratory tract: a model for its role in epithelial protection." Biochemical Journal 330, no. 2 (March 1, 1998): 737–44. http://dx.doi.org/10.1042/bj3300737.

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The pulmonary epithelium has a multitude of specialized functions, which depend on regulated growth and differentiation of several cell types. One such function is the synthesis and secretion of mucins, which offer the epithelium protection from and a means for removal of noxious environmental factors. Sialomucin complex (SMC) is a heterodimeric glycoprotein consisting of a mucin subunit (ASGP-1, ascites sialoglycoprotein-1) and a transmembrane protein (ASGP-2) with two epidermal-growth-factor-like domains. SMC was originally discovered in a highly metastatic rat mammary adenocarcinoma and has been implicated in metastasis and in the protection of the tumour cells from natural killer cells. It can also act as a ligand for the receptor tyrosine kinase 185neu, suggesting that it is bifunctional as well as heterodimeric. SMC is expressed on the epithelium of rat conducting airways, with the highest levels occurring in the proximal trachea and progressively decreasing into the bronchioles. Airway SMC consists of two forms: a soluble form that lacks the C-terminal cytoplasmic and transmembrane domains and accounts for about 70% of the total, and a membrane-associated form that has the C-terminal domains. Immunocytochemical analyses show that SMC is predominantly present on the apical surfaces of the airway epithelium, but not in goblet cells. Soluble form can be removed from the trachea by rinsing, suggesting that a fraction of the protein is adsorbed to the apical surface. Based on these results, we propose a protective mechanism in which membrane and soluble forms of SMC are produced by airway luminal epithelial cells to provide a cell-associated epithelial glycoprotein barrier that also serves as an interface with flowing mucus. In support of this mechanism, we demonstrated secretion of soluble SMC by primary cultures of tracheal epithelial cells. This model suggests that SMC is a critical element in the protective barrier of the airway epithelium.

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46

KOMATSU, Masanobu, Maria E. ARANGO, and Kermit L. CARRAWAY. "Synthesis and secretion of Muc4/sialomucin complex: implication of intracellular proteolysis." Biochemical Journal 368, no. 1 (November 15, 2002): 41–48. http://dx.doi.org/10.1042/bj20020862.

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Muc4/sialomucin complex (SMC) is a heterodimeric glycoprotein complex implicated in epithelial protection and overexpressed in some tumours. It is encoded by a single gene, and the two subunits are produced by proteolytic cleavage at a time before substantial O-glycosylation, near the time of transit from the endoplasmic reticulum to the Golgi. Although Muc4/SMC is translated as a membrane protein, it is produced as a soluble form in many epithelia. Transfection experiments using Cos-7, HBL-100 human epithelial, MCF-7 human breast tumour and HC11 mouse mammary cell lines showed that soluble rat Muc4/SMC is produced by a proteolytic cleavage mechanism and released by secretion from multiple cell lines, including both human and mouse normal epithelial cells and tumour cells. Similar transfection experiments demonstrated the same mechanism for the human analogue MUC4. Gel electrophoresis analyses of deglycosylated membrane and soluble transmembrane subunits and of the membrane-associated cleavage fragment indicated a released cleavage product of 25kDa, resulting from cleavage between two epidermal growth factor-like domains. Further evidence for this site was obtained from deletion mutants removing this region of the protein, which blocked secretion. Finally, pulse—chase analyses of Muc4/SMC biosynthesis indicated no kinetic difference between the timing of the cleavage to release the soluble form and that to produce the two subunits, indicating that the soluble form is created early in transit to the cell surface. These studies provide the first clear evidence that membrane mucins can be released from cells by an intracellular proteolytic mechanism that leads to secretion of the soluble form of the mucin.

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47

Liu, Zhongyu, Justin D. Anderson, Lily Deng, Stephen Mackay, Johnathan Bailey, Latona Kersh, Steven M. Rowe, and Jennifer S. Guimbellot. "Human Nasal Epithelial Organoids for Therapeutic Development in Cystic Fibrosis." Genes 11, no. 6 (May 29, 2020): 603. http://dx.doi.org/10.3390/genes11060603.

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We describe a human nasal epithelial (HNE) organoid model derived directly from patient samples that is well-differentiated and recapitulates the airway epithelium, including the expression of cilia, mucins, tight junctions, the cystic fibrosis transmembrane conductance regulator (CFTR), and ionocytes. This model requires few cells compared to airway epithelial monolayer cultures, with multiple outcome measurements depending on the application. A novel feature of the model is the predictive capacity of lumen formation, a marker of baseline CFTR function that correlates with short-circuit current activation of CFTR in monolayers and discriminates the cystic fibrosis (CF) phenotype from non-CF. Our HNE organoid model is amenable to automated measurements of forskolin-induced swelling (FIS), which distinguishes levels of CFTR activity. While the apical side is not easily accessible, RNA- and DNA-based therapies intended for systemic administration could be evaluated in vitro, or it could be used as an ex vivo biomarker of successful repair of a mutant gene. In conclusion, this highly differentiated airway epithelial model could serve as a surrogate biomarker to assess correction of the mutant gene in CF or other diseases, recapitulating the phenotypic and genotypic diversity of the population.

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48

Ballester, Beatriz, Javier Milara, Paula Montero та Julio Cortijo. "MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway". International Journal of Molecular Sciences 22, № 12 (17 червня 2021): 6502. http://dx.doi.org/10.3390/ijms22126502.

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Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-β1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-β1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-β1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF.

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49

Harding, Stephen E. "Analytical Ultracentrifugation as a Matrix-Free Probe for the Study of Kinase Related Cellular and Bacterial Membrane Proteins and Glycans." Molecules 26, no. 19 (October 8, 2021): 6080. http://dx.doi.org/10.3390/molecules26196080.

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Analytical ultracentrifugation is a versatile approach for analysing the molecular mass, molecular integrity (degradation/aggregation), oligomeric state and association/dissociation constants for self-association, and assay of ligand binding of kinase related membrane proteins and glycans. It has the great property of being matrix free—providing separation and analysis of macromolecular species without the need of a separation matrix or membrane or immobilisation onto a surface. This short review—designed for the non-hydrodynamic expert—examines the potential of modern sedimentation velocity and sedimentation equilibrium and the challenges posed for these molecules particularly those which have significant cytoplasmic or extracellular domains in addition to the transmembrane region. These different regions can generate different optimal requirements in terms of choice of the appropriate solvent (aqueous/detergent). We compare how analytical ultracentrifugation has contributed to our understanding of two kinase related cellular or bacterial protein/glycan systems (i) the membrane erythrocyte band 3 protein system—studied in aqueous and detergent based solvent systems—and (ii) what it has contributed so far to our understanding of the enterococcal VanS, the glycan ligand vancomycin and interactions of vancomycin with mucins from the gastrointestinal tract.

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50

Bose, Mukulika, and Pinku Mukherjee. "Potential of Anti-MUC1 Antibodies as a Targeted Therapy for Gastrointestinal Cancers." Vaccines 8, no. 4 (November 5, 2020): 659. http://dx.doi.org/10.3390/vaccines8040659.

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Gastrointestinal cancers (GI) account for 26% of cancer incidences globally and 35% of all cancer-related deaths. The main challenge is to target cancer specific antigens. Mucins are heavily O-glycosylated proteins overexpressed in different cancers. The transmembrane glycoprotein MUC1 is the most likeable target for antibodies, owing to its specific overexpression and aberrant glycosylation in many types of cancers. For the past 30 years, MUC1 has remained a possible diagnostic marker and therapeutic target. Despite initiation of numerous clinical trials, a comprehensively effective therapy with clinical benefit is yet to be achieved. However, the interest in MUC1 as a therapeutic target remains unaltered. For all translational studies, it is important to incorporate updated relevant research findings into therapeutic strategies. In this review we present an overview of the antibodies targeting MUC1 in GI cancers, their potential role in immunotherapy (i.e., antibody-drug and radioimmunoconjugates, CAR-T cells), and other novel therapeutic strategies. We also present our perspectives on how the mechanisms of action of different anti-MUC1 antibodies can target specific hallmarks of cancer and therefore be utilized as a combination therapy for better clinical outcomes.

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