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PloS One 2024Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in...
Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in polymeric mucins, a major structural component of mucus, potentially acting as important physiological regulators of mucosal drug absorption, there are no reports that have systematically evaluated the interaction between mucins and drugs. In this study, we assessed the potential interaction between human polymeric mucins (MUC2, MUC5B, and MUC5AC) and various drugs with different chemical profiles by simple centrifugal method and fluorescence analysis. We found that paclitaxel, rifampicin, and theophylline likely induce the aggregation of MUC5B and/or MUC2. In addition, we showed that the binding affinity of drugs for polymeric mucins varied, not only between individual drugs but also among mucin subtypes. Furthermore, we demonstrated that deletion of MUC5AC and MUC5B in A549 cells increased the cytotoxic effects of cyclosporin A and paclitaxel, likely due to loss of mucin-drug interaction. In conclusion, our results indicate the necessity to determine the binding of drugs to mucins and their potential impact on the mucin network property.
Topics: Humans; Paclitaxel; Mucin 5AC; A549 Cells; Drug Interactions; Mucin-5B; Mucins; Mucin-2; Rifampin; Cyclosporine; Protein Binding
PubMed: 38935605
DOI: 10.1371/journal.pone.0306058 -
Frontiers in Rehabilitation Sciences 2024Cough is a powerful, protective expulsive behavior that assists in maintaining respiratory health by clearing foreign material, pathogens, and mucus from the airways.... (Review)
Review
Cough is a powerful, protective expulsive behavior that assists in maintaining respiratory health by clearing foreign material, pathogens, and mucus from the airways. Therefore, cough is critical to survival in both health and disease. Importantly, cough protects the airways and lungs from both antegrade (e.g., food, liquid, saliva) and retrograde (e.g., bile, gastric acid) aspirate contents. Aspiration is often the result of impaired swallowing (dysphagia), which allows oral and/or gastric contents to enter the lung, especially in individuals who also have cough dysfunction (dystussia). Cough hyposensitivity, downregulation, or desensitization- collectively referred to as - is common in individuals with dysphagia, and increases the likelihood that aspirated material will reach the lung. The consequence of hypotussia with reduced airway clearance can include respiratory tract infection, chronic inflammation, and long-term damage to the lung parenchyma. Despite the clear implications for health, the problem of managing hypotussia in individuals with dysphagia is frequently overlooked. Here, we provide an overview of the current interventions and treatment approaches for hypotussic cough. We synthesize the available literature to summarize research findings that advance our understanding of these interventions, as well as current gaps in knowledge. Further, we highlight pragmatic resources to increase awareness of hypotussic cough interventions and provide support for the clinical implementation of evidence-based treatments. In culmination, we discuss potential innovations and future directions for hypotussic cough research.
PubMed: 38933659
DOI: 10.3389/fresc.2024.1394110 -
Viruses Jun 2024Previous studies from our laboratory and others have established the dendritic cell (DC) as a key target of RSV that drives infection-induced pathology. Analysis of...
Previous studies from our laboratory and others have established the dendritic cell (DC) as a key target of RSV that drives infection-induced pathology. Analysis of RSV-induced transcriptomic changes in RSV-infected DC revealed metabolic gene signatures suggestive of altered cellular metabolism. Reverse phase protein array (RPPA) data showed significantly increased PARP1 phosphorylation in RSV-infected DC. Real-time cell metabolic analysis demonstrated increased glycolysis in PARP1-/- DC after RSV infection, confirming a role for PARP1 in regulating DC metabolism. Our data show that enzymatic inhibition or genomic ablation of PARP1 resulted in increased ifnb1, il12, and il27 in RSV-infected DC which, together, promote a more appropriate anti-viral environment. PARP1-/- mice and PARP1-inhibitor-treated mice were protected against RSV-induced immunopathology including airway inflammation, Th2 cytokine production, and mucus hypersecretion. However, delayed treatment with PARP1 inhibitor in RSV-infected mice provided only partial protection, suggesting that PARP1 is most important during the earlier innate immune stage of RSV infection.
Topics: Animals; Poly (ADP-Ribose) Polymerase-1; Mice; Dendritic Cells; Respiratory Syncytial Virus Infections; Lung; Respiratory Syncytial Viruses; Mice, Knockout; Cytokines; Immunity, Innate; Female
PubMed: 38932202
DOI: 10.3390/v16060910 -
Viruses May 2024Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract disease worldwide, and a pediatric vaccine is not available. We generated a filamentous...
Intranasal Vaccination with a Respiratory-Syncytial-Virus-Based Virus-like Particle Displaying the G Protein Conserved Region Induces Severe Weight Loss and Pathology upon Challenge with Wildtype Respiratory Syncytial Virus.
Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract disease worldwide, and a pediatric vaccine is not available. We generated a filamentous RSV-based virus-like particle (VLP) that presents the central conserved region of the attachment protein G. This was achieved by co-expressing the matrix protein, phosphoprotein, nucleoprotein, and a hybrid fusion protein in which the F ectodomain was replaced with the G central region (GCR). The latter is relatively conserved and contains a receptor binding site and hence is a logical vaccine target. The immunogenicity and efficacy of the resulting VLP, termed VLP-GCR, were examined in mice using intranasal application without adjuvant. VLP-GCR induced substantial anti-N antibody levels but very low anti-G antibody levels, even after three vaccinations. In contrast, a VLP presenting prefusion-stabilized fusion (preF) protein instead of GCR induced both high anti-F and anti-nucleoprotein antibody levels, suggesting that our GCR antigen was poorly immunogenic. Challenge of VLP-GCR-vaccinated mice caused increased weight loss and lung pathology, and both VLPs induced mucus in the lungs. Thus, neither VLP is suitable as a vaccine for RSV-naive individuals. However, VLP-preF enhanced the proportion of preF antibodies and could serve as a multi-antigen mucosal booster vaccine in the RSV-experienced population.
Topics: Animals; Female; Humans; Mice; Administration, Intranasal; Antibodies, Viral; Lung; Mice, Inbred BALB C; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Vaccination; Vaccines, Virus-Like Particle; Viral Envelope Proteins; Viral Fusion Proteins; Weight Loss
PubMed: 38932136
DOI: 10.3390/v16060843 -
Polymers Jun 2024MUC2 mucin, the primary gel-forming component of intestinal mucus, is well researched and a model of polymerisation and post-secretory organisation has been published... (Review)
Review
MUC2 mucin, the primary gel-forming component of intestinal mucus, is well researched and a model of polymerisation and post-secretory organisation has been published previously. Recently, several significant developments have been made which either introduce new ideas or challenge previous theories. New ideas include an overhaul of the MUC2 C-terminal globular structure which is proposed to harbour several previously unobserved domains, and include a site for an extra intermolecular disulphide bridge dimer between the cysteine 4379 of adjacent MUC2 C-termini. MUC2 polymers are also now thought to be secreted attached to the epithelial surface of goblet cells in the small intestine and removed following secretion via a metalloprotease meprin β-mediated cleavage of the von Willebrand D2 domain of the N-terminus. It remains unclear whether MUC2 forms intermolecular dimers, trimers, or both, at the N-termini during polymerisation, with several articles supporting either trimer or dimer formation. The presence of a firm inner mucus layer in the small intestine is similarly unclear. Considering this recent research, this review proposes an update to the previous model of MUC2 polymerisation and secretion, considers conflicting theories and data, and highlights the importance of this research to the understanding of MUC2 mucus layers in health and disease.
PubMed: 38932019
DOI: 10.3390/polym16121663 -
Molecules (Basel, Switzerland) Jun 2024The discovery and investigation of new natural compounds with antimicrobial activity are new potential strategies to reduce the spread of antimicrobial resistance. The...
The discovery and investigation of new natural compounds with antimicrobial activity are new potential strategies to reduce the spread of antimicrobial resistance. The presented study reveals, for the first time, the promising antibacterial potential of two fractions from mucus with an MW < 20 kDa and an MW > 20 kDa against five bacterial pathogens- 1085, 1897, 8691, 3915, and 8754. Using de novo sequencing, 16 novel peptides with potential antibacterial activity were identified in a fraction with an MW < 20 kDa. Some bioactive compounds in a mucus fraction with an MW > 20 kDa were determined via a proteomic analysis on 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and bioinformatics. High homology with proteins and glycoproteins was found, with potential antibacterial activity in mucus proteins named aspernin, hemocyanins, H-lectins, and L-amino acid oxidase-like protein, as well as mucins (mucin-5AC, mucin-5B, mucin-2, and mucin-17). We hypothesize that the synergy between the bioactive components determined in the composition of the fraction > 20 kDa are responsible for the high antibacterial activity against the tested pathogens in concentrations between 32 and 128 µg/mL, which is comparable to vancomycin, but without cytotoxic effects on model eukaryotic cells of . Additionally, a positive effect, by reducing the levels of intracellular oxidative damage and increasing antioxidant capacity, on cells was found for both mucus extract fractions of . These findings may serve as a basis for further studies to develop a new antibacterial agent preventing the development of antibiotic resistance.
Topics: Anti-Bacterial Agents; Mucus; Microbial Sensitivity Tests; Peptides; Enterococcus faecalis; Enterococcus faecium; Bacillus cereus; Animals; Propionibacterium acnes; Salmonella enterica
PubMed: 38930951
DOI: 10.3390/molecules29122886 -
Microorganisms Jun 2024CRL1505 possesses immunomodulatory activities in the gastrointestinal and respiratory tracts when administered orally. Its adhesion to the intestinal mucosa does not...
CRL1505 possesses immunomodulatory activities in the gastrointestinal and respiratory tracts when administered orally. Its adhesion to the intestinal mucosa does not condition its beneficial effects. The intranasal administration of CRL1505 is more effective than the oral route at modulating immunity in the respiratory tract. Nonetheless, it has not yet been established whether the adherence of the CRL1505 strain to the respiratory mucosa is needed to provide the immune benefits to the host. In this study, we evaluated the role of adhesion to the respiratory mucosa of the mucus-binding factor (mbf) knock-out CRL1505 mutant ( CRL1505) in the context of a Toll-like receptor 3 (TLR3)-triggered innate immunity response. In vitro adhesion studies in porcine bronchial epitheliocytes (PBE cells) indicated that CRL1505 adhered weakly compared to the wild-type strain. However, in vivo studies in mice demonstrated that the CRL1505 also reduced lung damage and modulated cytokine production in the respiratory tract after the activation of TLR3 to a similar extent as the wild-type strain. In addition, the mutant and the wild-type strains modulated the production of cytokines and antiviral factors by alveolar macrophages in the same way. These results suggest that the Mbf protein is partially involved in the ability of CRL1505 to adhere to the respiratory epithelium, but the protein is not necessary for the CRL1505 strain to exert its immunomodulatory beneficial effects. These findings are a step forward in the understanding of molecular interactions that mediate the beneficial effects of nasally administered probiotics.
PubMed: 38930591
DOI: 10.3390/microorganisms12061209 -
Animals : An Open Access Journal From... Jun 2024This study offers a comprehensive morpho-histological analysis of the gastrointestinal tract (GIT) of the Malabar red snapper. A comparison of its GIT morphology with...
This study offers a comprehensive morpho-histological analysis of the gastrointestinal tract (GIT) of the Malabar red snapper. A comparison of its GIT morphology with that of the Asian seabass reveals similarities and differences between the two species. Additionally, the moisture content, crude protein, and ash in the fillets of Malabar red snapper and Asian seabass were slightly different, with Malabar red snapper exhibiting higher levels of essential fatty acids. Furthermore, higher levels of the polyunsaturated fatty acid (PUFA)/saturated fatty acid (SFA) ratio and docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) ratio, and a lower omega-6/omega-3 ratio, were observed in Malabar red snapper compared to Asian seabass. The Malabar red snapper's esophagus featured protective mechanisms such as simple columnar epithelial cells, mucous-secreting glands, and goblet cells that were predominantly stained for acid and neutral mucosubstances. Furthermore, its stomach, with mucus cells that were weakly stained for acid mucosubstances, exhibited distinct regions with varying glandular densities, with the pyloric region featuring few glands. The pyloric caeca of the fish were composed of five finger-like structures and few goblet cells. Several goblet cells gradually increased from the anterior to the posterior region of the intestine. These findings provide useful insights for the aquaculture sector, focusing on Malabar red snapper.
PubMed: 38929422
DOI: 10.3390/ani14121803 -
Animals : An Open Access Journal From... Jun 2024This research aimed to compare the conception rates among AI at 12, 24, and 36 h after estrus in cattle living in tie-stall barns in a tropical environment. The second...
This research aimed to compare the conception rates among AI at 12, 24, and 36 h after estrus in cattle living in tie-stall barns in a tropical environment. The second study was to determine factors at insemination at 24 h after estrus, including secondary signs of estrus behavior, reproductive tract characteristics, and heat-stress factors, in relation to conception. The study was conducted on 22 tie-stall dairy farms in Chiang Mai, Thailand. After secondary signs of estrus were observed, all farmers were informed for data collection at the insemination time. Repeated logistic regression models were used to determine factors associated with conception. The results revealed that cattle inseminated 24 h after estrus detection had the highest conception rate (67.5%). The study also found that cattle with three or two secondary estrus signs before insemination had a higher risk of conception than those with only one sign. Interestingly, there was an increased risk of conception when sticky or no cervical mucus was observed during insemination (OR = 6.85 and OR = 5.96, respectively). Moreover, increases in body temperature and ambient relative humidity were related to a decrease in the chances of conception. This study recommends delaying insemination to 24 h after the initiation of secondary estrus signs. Multiple signs of estrus, sticky cervical mucus, and lower body temperature increased conception risk in dairy cattle living in tie-stall barns in a heat-stress environment.
PubMed: 38929382
DOI: 10.3390/ani14121763 -
International Journal of Molecular... Jun 2024Cystic fibrosis (CF), also known as mucoviscidosis, is the most common autosomal recessive genetic disease in the Caucasian population, with an estimated frequency of... (Review)
Review
Cystic fibrosis (CF), also known as mucoviscidosis, is the most common autosomal recessive genetic disease in the Caucasian population, with an estimated frequency of 1:2000-3000 live births. CF results from the mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene localized in the long arm of chromosome 7. The product of CFTR gene expression is CFTR protein, an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that regulates the transport of chloride ions (Cl) across the apical cell membrane. Primary manifestations of CF include chronic lung and pancreas function impairment secondary to the production of thick, sticky mucus resulting from dehydrated secretions. It is well known that CF can cause both anterior and posterior ocular abnormalities. Conjunctival and corneal xerosis and dry eye disease symptoms are the most characteristic manifestations in the anterior segment. In contrast, the most typical anatomical and functional changes relating to the posterior segment of the eye include defects in the retinal nerve fiber layer (RNFL), vascular abnormalities, and visual disturbances, such as reduced contrast sensitivity and abnormal dark adaptation. However, the complete background of ophthalmic manifestations in the course of CF has yet to be discovered. This review summarizes the current knowledge regarding ocular changes in cystic fibrosis.
Topics: Humans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Eye Diseases; Mutation; Animals
PubMed: 38928397
DOI: 10.3390/ijms25126692