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Indian Journal of Ophthalmology Apr 2023Dry eye disease (DED) is a multi-factorial ocular surface condition driven by compromised ocular lubrication and inflammation which leads to itching, dryness, and vision... (Review)
Review
Dry eye disease (DED) is a multi-factorial ocular surface condition driven by compromised ocular lubrication and inflammation which leads to itching, dryness, and vision impairment. The available treatment modalities primarily target the acquired symptoms of DED including tear film supplements, anti-inflammatory drugs, mucin secretagogues, etc., However, the underlying etiology is still an area of active research, especially in regard to the diverse etiology and symptoms. Proteomics is a robust approach that has been playing major role in understanding the causative mechanism and biochemical changes in DED by identifying the changes in protein expression profile in tears. Tears are a complex fluid composed of several biomolecules such as proteins, peptides, lipids, mucins, and metabolites secreted from lacrimal gland, meibomian gland, cornea, and vascular sources. Over the past two decades, tears have emerged as a bona-fide source for biomarker identification in many ocular conditions because of the minimally invasive and simple sample collection procedure. However, the tear proteome can be altered by several factors, which increases the complexity of the approach. The recent advancements in untargeted mass spectrometry-based proteomics could overcome such shortcomings. Also, these technological advancements help to distinguish the DED profiles based on its association with other complications such as Sjogren's syndrome, rheumatoid arthritis, diabetes, and meibomian gland dysfunction. This review summarizes the important molecular profiles found in proteomics studies to be altered in DED which have added to the understanding of its pathogenesis.
Topics: Humans; Proteomics; Dry Eye Syndromes; Tears; Sjogren's Syndrome; Lacrimal Apparatus; Mucins
PubMed: 37026251
DOI: 10.4103/IJO.IJO_2851_22 -
PLoS Genetics Jun 2023Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD)....
Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822-1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10-1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02-1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB.
Topics: Humans; Mucins; Sputum; Pulmonary Disease, Chronic Obstructive; Mucus; Phenotype
PubMed: 37352370
DOI: 10.1371/journal.pgen.1010445 -
Science Advances Oct 2023Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the...
Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the intestinal epithelium is well appreciated, the direct effect of BMP on intestinal stromal cells is poorly understood. Here, we show that disruption of BMP signaling by genetic ablation of or expands the stromal cell pool, the mucosa tumefaction, and colonic polyposis in the large intestine. Interleukin (IL) secretion by stromal cells is notably increased, including IL-1, IL-11, and IL-17. Specifically, IL-1 and IL-17a hyperactivate the mucin production by goblet cells through nuclear factor κB signaling, and abnormal mucin accumulation results in the morphological changes, epithelial barrier destruction, and polyposis development. Together, our results provide an insight into the role of BMP signaling in intestinal stromal cells to regulate epithelium function. This study further highlights the role of mucin-producing goblet cells in intestinal homeostasis and colitis development.
Topics: Humans; Mucins; Interleukin-17; Signal Transduction; Colorectal Neoplasms; Interleukin-1
PubMed: 37889976
DOI: 10.1126/sciadv.adi1827 -
Biomolecules Jul 2022Breast cancer (BRCA) is the leading cause of death from malignant tumors among women. Fortunately, however, immunotherapy has recently become a prospective BRCA... (Review)
Review
Breast cancer (BRCA) is the leading cause of death from malignant tumors among women. Fortunately, however, immunotherapy has recently become a prospective BRCA treatment with encouraging achievements and mild safety profiles. Since the overexpression and aberrant glycosylation of MUC1 (human mucin) are closely associated with BRCA, it has become an ideal target for BRCA immunotherapies. In this review, the structure and function of MUC1 are briefly introduced, and the main research achievements in different kinds of MUC1-mediated BRCA immunotherapy are highlighted, from the laboratory to the clinic. Afterward, the future directions of MUC1-mediated BRCA immunotherapy are predicted, addressing, for example, urgent issues in regard to how efficient immunotherapeutic strategies can be generated.
Topics: Breast Neoplasms; Female; Glycosylation; Humans; Immunologic Factors; Immunotherapy; Mucin-1; Mucins; Prospective Studies
PubMed: 35883508
DOI: 10.3390/biom12070952 -
Pediatric Pulmonology Nov 2019Cystic fibrosis (CF) is both the most common and most lethal genetic disease in the Caucasian population. CF is caused by mutations in the cystic fibrosis transmembrane... (Review)
Review
Cystic fibrosis (CF) is both the most common and most lethal genetic disease in the Caucasian population. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is characterized by the accumulation of thick, adherent mucus plaques in multiple organs, of which the lungs, gastrointestinal tract and pancreatic ducts are the most commonly affected. A similar pathogenesis cascade is observed in all of these organs: loss of CFTR function leads to altered ion transport, consisting of decreased chloride and bicarbonate secretion via the CFTR channel and increased sodium absorption via epithelial sodium channel upregulation. Mucosa exposed to changes in ionic concentrations sustain severe pathophysiological consequences. Altered mucus biophysical properties and weakened innate defense mechanisms ensue, furthering the progression of the disease. Mucins, the high-molecular-weight glycoproteins responsible for the viscoelastic properties of the mucus, play a key role in the disease but the actual mechanism of mucus accumulation is still undetermined. Multiple hypotheses regarding the impact of CFTR malfunction on mucus have been proposed and are reviewed here. (a) Dehydration increases mucin monomer entanglement, (b) defective Ca chelation compromises mucin expansion, (c) ionic changes alter mucin interactions, and (d) reactive oxygen species increase mucin crosslinking. Although one biochemical change may dominate, it is likely that all of these mechanisms play some role in the progression of CF disease. This article discusses recent findings on the initial cause(s) of aberrant mucus properties in CF and examines therapeutic approaches aimed at correcting mucus properties.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mucins; Mucus
PubMed: 31715083
DOI: 10.1002/ppul.24530 -
Nature Communications Oct 2023Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and...
Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome.
Topics: Hepatitis A Virus Cellular Receptor 2; Mucins; Polysaccharide-Lyases; Polysaccharides
PubMed: 37794035
DOI: 10.1038/s41467-023-41756-y -
Nature Mar 2022Membrane fusion triggered by Ca is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic...
Membrane fusion triggered by Ca is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes. For neurotransmitter release, the Ca sensitivity is introduced by interactions between the Ca sensor synaptotagmin and the SNARE complex, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion. Disruption of Ca-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we designed a hydrocarbon-stapled peptide that specifically disrupts Ca-triggered membrane fusion by interfering with the so-called primary interface between the neuronal SNARE complex and the Ca-binding C2B domain of synaptotagmin-1. In reconstituted systems with these neuronal synaptic proteins or with their airway homologues syntaxin-3, SNAP-23, VAMP8, synaptotagmin-2, along with Munc13-2 and Munc18-2, the stapled peptide strongly suppressed Ca-triggered fusion at physiological Ca concentrations. Conjugation of cell-penetrating peptides to the stapled peptide resulted in efficient delivery into cultured human airway epithelial cells and mouse airway epithelium, where it markedly and specifically reduced stimulated mucin secretion in both systems, and substantially attenuated mucus occlusion of mouse airways. Taken together, peptides that disrupt Ca-triggered membrane fusion may enable the therapeutic modulation of mucin secretory pathways.
Topics: Animals; Calcium; Hydrocarbons; Membrane Fusion; Mice; Mucins; Neurotransmitter Agents; Peptides; Respiratory Mucosa; SNARE Proteins
PubMed: 35322233
DOI: 10.1038/s41586-022-04543-1 -
Advanced Drug Delivery Reviews Dec 2022Mucin glycoproteins are the major component of mucus and coat epithelial cell surfaces forming the glycocalyx. The glycocalyx and mucus are involved in the transport of... (Review)
Review
Mucin glycoproteins are the major component of mucus and coat epithelial cell surfaces forming the glycocalyx. The glycocalyx and mucus are involved in the transport of nutrients, drugs, gases, and pathogens toward the cell surface. Mucins are also involved in diverse diseases such as cystic fibrosis and cancer. Due to inherent heterogeneity in native mucin structure, many synthetic materials have been designed to probe mucin chemistry, biology, and physics. Such materials include various glycopolymers, low molecular weight glycopeptides, glycopolypeptides, polysaccharides, and polysaccharide-protein conjugates. This review highlights advances in the area of design and synthesis of mucin mimic materials, and their biomedical applications in glycan binding, epithelial models of infection, therapeutic delivery, vaccine formulation, and beyond.
Topics: Humans; Mucins; Mucus; Cystic Fibrosis; Polysaccharides; Glycopeptides
PubMed: 36228896
DOI: 10.1016/j.addr.2022.114540 -
International Journal of Molecular... Nov 2020Preterm births are a global health priority that affects 15 million babies every year worldwide. There are no effective prognostic and therapeutic strategies relating to... (Review)
Review
Preterm births are a global health priority that affects 15 million babies every year worldwide. There are no effective prognostic and therapeutic strategies relating to preterm delivery, but uterine infections appear to be a major cause. The vaginal epithelium is covered by the cervicovaginal mucus, which is essential to health because of its direct involvement in reproduction and functions as a selective barrier by sheltering the beneficial lactobacilli while helping to clear pathogens. During pregnancy, the cervical canal is sealed with a cervical mucus plug that prevents the vaginal flora from ascending toward the uterine compartment, which protects the fetus from pathogens. Abnormalities of the cervical mucus plug and bacterial vaginosis are associated with a higher risk of preterm delivery. This review addresses the current understanding of the cervicovaginal mucus and the cervical mucus plug and their interactions with the microbial communities in both the physiological state and bacterial vaginosis, with a focus on gel-forming mucins. We also review the current state of knowledge of gel-forming mucins contained in mouse cervicovaginal mucus and the mouse models used to study bacterial vaginosis.
Topics: Animals; Cervix Uteri; Female; Humans; Infectious Disease Transmission, Vertical; Mice; Microbiota; Mucins; Mucus; Pregnancy; Pregnancy Complications, Infectious; Vagina; Vaginosis, Bacterial
PubMed: 33158227
DOI: 10.3390/ijms21218266 -
The Journal of Clinical Investigation Oct 2023The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the...
The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and noninflamed samples from patients with inflammatory bowel disease (IBD) undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF/CFTR signaling axis in the adult intestine and identify epithelial cell-derived TNF as an upstream regulator of mucin homeostasis.
Topics: Humans; Animals; Mice; Mucins; Cystic Fibrosis Transmembrane Conductance Regulator; Tumor Necrosis Factor Inhibitors; Epithelial Cells; Cell Differentiation; Tumor Necrosis Factors; Homeostasis
PubMed: 37643009
DOI: 10.1172/JCI163591