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The aim of this study was to characterize the clinicopathological features and prognostic factors of T1/2 size (<4 cm) gingival squamous cell carcinoma (SCC) and to verify the impact of bone invasion. This was a single-centre, retrospective cohort study involving 206 patients with gingival SCC (maxilla or mandible), treated between 2000 and 2020. The patients were divided into three subgroups based on tumour size and bone invasion. The 5-year overall survival (OS) and disease-free survival (DFS) were 80.6% and 67.6%, respectively. Histological differentiation, advanced T stage, positive resection margin, bone invasion, and postoperative adjuvant therapy were associated with a poor prognosis (P < 0.05). Multivariate Cox analysis indicated that only histological differentiation (hazard ratio (HR) 2.68, P = 0.007) and bone invasion (HR 2.08, P = 0.036) were significantly associated with DFS. Bone invasion was observed in 145 (70.4%) patients, of whom 43 (20.9%) had a T1/2 size tumour. The subgroup with bone invasion and T1/2 size showed significantly worse OS and DFS when compared to the subgroup without bone invasion and similar or worse survival when compared to the subgroup with bone invasion and T3/T4 size. Histological differentiation and bone invasion were poor prognostic factors for gingival SCC, even in cases with small-sized tumours. For suspected bone invasion in small-sized tumours, an adequate bone margin is necessary and postoperative adjunctive therapy needs to be considered. [ABSTRACT FROM AUTHOR]

Methotrexate related lymphoproliferative disorder is a lymphoma that occurs in the gingiva, buccal mucosa, and tongue as a consequence of long-term methotrexate administration, and its association with osteonecrosis of the jaws has also been reported. T-cell dominant polymorphic type is rare lymphoproliferative disorder; however, its association with peri-implantitis has not been reported. Here, we report a case of long-term methotrexate administration related T-cell dominant polymorphic lymphoproliferative disorder associated with peri-implantitis. An 80-year-old female patient with a chief complaint of swelling of the right mandibular mucosa around the implant was referred to our hospital for the treatment of intractable gingival ulcer. Intraoral view revealed bone exposure and ulcer in the lingual mucosa of mandibular implant. Biopsy was performed from gingival ulcer and polymorphic methotrexate related lymphoproliferative disorder was diagnosed. The patient recovered from the ulcer and pain after methotrexate withdrawal; however, bone exposure remained. Sequestrectomy was subsequently performed under local anesthesia. The patient showed no signs of recurrence 8 months after operation. Our report will shed light on the treatment and diagnosis of T-cell dominant polymorphic MTX-LPD. Further case studies and research may be needed to develop a better understanding of the disease. [ABSTRACT FROM AUTHOR]

[Display omitted] Mucosal surfaces serve as the primary entry points for pathogens such as SARS- CoV-2 coronavirus or HIV in the human body. Mucosal vaccination plays a crucial role to successfully induce long-lasting systemic and local immune responses to confer sterilizing immunity. However, antigen formulations and delivery methods must be properly selected since they are decisive for the quality and the magnitude of the elicited immune responses in mucosa. We investigated the significance of using particulate antigen forms for mucosal vaccination by comparing VLP- or protein- based vaccines in a mouse model. Based on a mucosal prime-boost immunization protocol combining (i) HIV- pseudotyped recombinant VLPs (HIV-VLPs) and (ii) plasmid DNA encoding HIV- VLPs (pVLPs), we demonstrated that combination of intranasal primes and intravaginal boosts is optimal to elicit both humoral and cellular memory responses in mucosa. Interestingly, our results show that in contrast to proteins, particulate antigens induce high-quality humoral responses characterized by a high breadth, long-term neutralizing activity and cross-clade reactivity, accompanying with high T follicular helper cell (T FH) response. These results underscore the potential of a VLP-based vaccine in effectively instigating long-lasting, HIV-specific immunity and point out the specific role of particulate antigen form in driving high-quality mucosal immune responses. [ABSTRACT FROM AUTHOR]

This study aims to compare the mucus permeating and mucoadhesive properties of three generations of thiolated cyclodextrins (CDs). Free thiol groups of thiolated γ-CDs (CD-SH) were S-protected with 2-mercaptonicotinic acid (MNA), leading to a second generation of thiolated CDs (CD-SS-MNA) and with 2 kDa polyethylene glycol (PEG) bearing a terminal thiol group leading to a third generation of thiolated CDs (CD-SS-PEG). The structure of these thiolated CDs was confirmed and characterized by FT-IR, 1H NMR and colorimetric assays. Thiolated CDs were evaluated regarding viscosity, mucus diffusion, and mucoadhesion. The viscosity of the mixture of CD-SH, CD-SS-MNA, or CD-SS-PEG with mucus increased up to 11-, 16-, and 14.1-fold compared to unmodified CD within 3 hours, respectively. Mucus diffusion increased in the following rank order: unprotected CD-SH < CD-SS-MNA < CD-SS-PEG. The residence time of CD-SH, CD-SS-MNA, and CD-SS-PEG on porcine intestine was up to 9.6-, 12.55-, and 11.2-fold prolonged compared to native CD, respectively. According to these results, S-protection of thiolated CDs can be a promising approach to improve their mucus permeating and mucoadhesive properties. Three generations of thiolated cyclodextrins (CDs) with different types of thiol ligands have been synthesized to improve mucus interaction. 1st generation of thiolated CDs was synthesized by converting hydroxyl groups into thiols by reaction with Thiourea. For 2nd generation, free thiol groups were S-protected by reaction with 2-mercaptonicotinic acid (MNA), resulting in high reactive disulfide bonds. For 3rd generation, terminally thiolated short PEG chains (2 kDa) were used for S-protection of thiolated CDs. Mucus penetrating properties were found to be increased as follows: 1st generation < 2nd generation < 3rd generation. Furthermore, mucoadhesive properties were improved in the following rank order: 1st generation < 3rd generation < 2nd generation. This study suggests that the S-protection of thiolated CDs can enhance mucus penetrating and mucoadhesive properties. [Display omitted] [ABSTRACT FROM AUTHOR]

Host responses to oral inflammation include a continuous and substantive response with the influx of polymorphonuclear leukocytes (PMN). PMN, referred to as first responders, migrate rapidly from the circulatory system through the connective tissue to mitigate stimuli and localize in the saliva. This study examined the relationship between the well-established clinical indices of gingivitis and dental plaque and the PMN level. This study enrolled adults aged 18–75 years, who provided voluntary informed consent. Oral rinse samples were collected from 159 participants to estimate the PMN levels prior to the full-mouth assessment for gingivitis and dental plaque using the respective clinical indices. The gingival index and dental plaque index scores were in the range of 0.098–2.71 and 0.73–4.78, respectively. Regardless of the age and gender, higher number of PMN was observed with higher gingival index and dental plaque index scores. Our analyses indicated a significant correlation between the oral PMN level and gingival index with a correlation coefficient of 0.66 (p < 0.0001). Similarly, the correlation between the PMN level and dental plaque index was statistically significant with a correlation coefficient of 0.57 (p < 0.0001). Regression analysis identified a significant relationship between the PMN level and clinical indices (p < 0.0005). Increase in the PMN levels with increasing clinical scores (gingival and dental plaque indices) reflect the oral inflammatory burden, irrespective of age or gender. These observations warrant future studies on participants stratified by health status and research directed toward examining the effects of interventions. [ABSTRACT FROM AUTHOR]

Interferon-lambda receptor 1 (IFNLR1) is the key to interferon-lambda's biological activities. Rhesus macaques (Macaca mulatta) are supposedly more suitable for translational studies on interferon lambda-associated human diseases, yet little is known about their IFNLR1 (mmuIFNLR1). In this study, we cloned the coding sequence of mmu IFNLR1 , examined its variants, and determined the distribution of mmuIFNLR1 mRNA and immunoreactivity in the buccal mucosa and arm skin of normal and immunodeficiency virus (SHIV/SIV) infected rhesus macaques. It was found that mmuIFNLR1 has 93.1% amino acid sequence identity to that of humans; all the amino acid residues of mmuIFNLR1 signal peptide, transmembrane region, PxxLxF motif and those essential for ligand binding are identical to that of humans; 6 variants of mmu IFNLR1 , including the ones corresponding to that of humans were detected; IFNLR1 immunoreactivity was localized in primarily the epithelia of buccal mucosa and arm skin; SHIV/SIV infection could affect the levels of mmuIFNLR1 mRNA and immunoreactivity. These data expanded our knowledge on mmu IFNLR1 and provided a scientific basis for rational use of rhesus macaques in studies of IFN-λ associated human diseases like AIDS. Future studies testing IFNLR1-targeting therapeutics in rhesus macaques were warranted. • MmuIFNLR1 has 93.1% amino acid sequence identity to that of humans. • Key amino acid residues of mmuIFNLR1 including PxxLxF motif are identical to that of humans. • MmuIFNLR1 has 6 variants including all the ones corresponding to that of humans. • IFNLR1 immunoreactivity was localized primarily to the epithelia of buccal mucosa and skin of rhesus macaques. • Simian immunodeficiency virus infection significantly affected the expression of mmuIFNLR1. [ABSTRACT FROM AUTHOR]

• Intranasal vaccination could induce protective mucosal immunity as well as systemic immunity with easy-to-use needle-free administration. • Novel safe adjuvants are needed to help boost immunogenicity for intranasal influenza vaccines. • Intranasal administration of gram-positive enhancer matrix (GEM), a bacterium-like particle derived from Lactococcus lactis , was safe in a first-in-human trial and showed potential as adjuvant in combination with inactivated trivalent influenza vaccine. Intranasal administration of respiratory vaccines offers many advantages such as eliciting both systemic and mucosal immunity at the point of viral entry. Immunogenicity of intranasal vaccination can be improved through the use of adjuvants. Bacteria-like particles derived from Lactococcus lactis have the potential to serve as a vaccine adjuvant. This clinical study investigated the safety, reactogenicity and immunogenicity of intranasal seasonal influenza vaccine adjuvanted with gram-positive matrix particles (FluGEM®). This was a first-in-human, randomized, double-blind, controlled, dose-escalation study performed at the Centre for Human Drug Research (CHDR), the Netherlands. Participants aged 18–49 were randomized in a 3:1 ratio to receive FluGem® in ascending doses (two-dose regimens) together with a standard trivalent inactivated influenza vaccine or unadjuvanted TIV only. Primary outcomes were safety and tolerability. Secondary outcomes were serum hemagglutination inhibition (HI) antibody titers and mucosal IgA. The most immunogenic dose was used in an additional elderly cohort (>65 years). Ninty participants were included. Intranasal FluGem® was safe and well tolerated. The majority of adverse events were mild (97.4 %) with (un)solicited adverse events comparable across all dose levels and control groups. All groups showed geometric mean increases ≥ 2.5-fold. Seroconversion (≥40 % participants) was achieved at both day 21 (single-dose) and 42 (two-dose) for the 1.25 mg dose and on day 42 (two-dose only) for the 2.5 mg dose. Highest geometric mean IgA increases were observed in the 1.25 mg group on day 21. Immunogenicity was less pronounced in elderly. Intranasal vaccination of FluGEM® was safe and tolerable in healthy adult volunteers aged 18–49 years and 65 and older. Highest immunogenicity was observed for 1.25 mg and 2.5 mg doses (compared to 5 mg) suggesting a potential non-linear dose–response relationship. More research is needed to further investigate the capabilities of bacteria-like peptides as adjuvants. [ABSTRACT FROM AUTHOR]

• ILs, a potential approach for improving physico-chemical and biological properties of APIs. • Mucus membranes serves as a barrier for drug delivery. • Choline-based ILs possess mucus-modulating properties. • High viscosity of ILs prolongs drug retention on mucosal surfaces. The utilization of ionic liquids (ILs) in pharmaceutical drug delivery applications has seen significant expansion in recent years, owing to their distinctive characteristics and inherent adjustability. These innovative compounds can be used to tackle challenges associated with traditional dosage forms, such as polymorphism, inadequate solubility, permeability, and efficacy in topical drug delivery systems. Here, we provide a brief classification of ILs, and their effectiveness in augmenting transmucosal drug delivery approaches by improving the solubility and permeability of active pharmaceutical ingredients (APIs) by temporary mucus modulation aiding the paracellular transport of APIs, prolonging drug retention, and, thus, aiding controlled drug release across various mucosal surfaces. We also highlight potential advances in, and future perspectives of, IL-based formulations in mucosal drug delivery. [ABSTRACT FROM AUTHOR]

Respiratory and digestive mucosal surfaces are continually exposed to common environmental antigens, which include potential allergens. Although innocuous in healthy individuals, allergens cause allergy in predisposed subjects and do so by triggering a pathologic T H 2 cell response that induces IgE class switching and somatic hypermutation in allergen-specific B cells. The ensuing affinity maturation and plasma cell differentiation lead to the abnormal release of high-affinity IgE that binds to powerful FcεRI receptors on basophils and mast cells. When cross-linked by allergen, FcεRI-bound IgE instigates the release of prestored and de novo –induced proinflammatory mediators. Aside from causing type I hypersensitivity reactions underlying allergy, IgE affords protection against nematodes or venoms from insects and snakes, which raises questions as to the fundamental differences between protective and pathogenic IgE responses. In this review, we discuss the impact of the mucosal environment, including the epithelial and mucus barriers, on the induction of protective IgE responses against environmental antigens. We further discuss how perturbations of these barriers may contribute to the induction of pathogenic IgE production. [ABSTRACT FROM AUTHOR]

This prospective study was undertaken to evaluate the treatment outcomes of keratinized mucosa augmentation (KMA) on the buccal and palatal/lingual sides of implants in jaws reconstructed after oncological surgery. Forty-two implants in 12 patients whose jaws had been reconstructed with a fibula or iliac bone flap were included. KMA was performed at 3 months after implant placement; this included an apically displaced partial-thickness flap and a free gingival graft (FGG) around the implants to increase the keratinized mucosa width (KMW). Patients were followed up for at least 6 months post-surgery. KMW, shrinkage, and patient pain and discomfort measured on a visual analogue scale were analysed. A histological analysis was performed of tissue epithelium from two patients. The results showed that KMW was >2 mm on both the buccal and palatal/lingual sides during follow-up. Before surgery, histological analysis showed epithelium with no epithelial spikes; normal keratinized epithelial spikes were observed at 8 weeks after KMA. Greater KMW was observed around implants in reconstructed maxillae than around those in reconstructed mandibles (P < 0.001). Patients felt more pain at the donor site than at the recipient site during the first 3 days post-surgery. KMA with FGG was predictable in reconstructed jaws and may help maintain the long-term stability of implants. [ABSTRACT FROM AUTHOR]

The overall well-being of organisms is widely recognized to be closely intertwined with their intestinal health. The intestinal mucosal layer plays a pivotal role in ensuring the proper functioning of the intestine, a fact observed not only in humans but also in animals like pigs. Any alterations to the mucosal layer of a pig's intestine can potentially disrupt its functionality, thereby impacting the animal's health and productivity. Mass spectrometry-based proteome analysis serves as a valuable tool in investigating the intricate dynamics of the proteome within the intestinal mucosa. Such studies hold promise in uncovering causal relationships between mucosal changes and overall health outcomes in pigs. It is anticipated that insights gathered from proteome studies will inform future strategies aimed at enhancing the health and productivity of pigs. However, the research field lacks a standardized and detailed method to extract proteins from pig intestinal mucosa and prepare proteins for proteome analysis. In the present study, we evaluated three alternative S-Trap-based protocols for analyzing ileal mucosal scrapings from pigs. Samples were either freeze-dried and treated as solid samples or ground in liquid nitrogen, categorized as either solid or liquid samples. In our analysis, a total of 2840 proteins were identified across all samples. Through statistical analysis and gene ontology examinations, we investigated potential differences between the three approaches. Even though our findings revealed no significant differences among the three methods, we propose the use of the protocol wherein samples are freeze-dried and treated as solid for protein extraction. This protocol stands out as the most convenient and practical option, offering ease of use and ensuring consistent and reliable results. By establishing a standardized approach, we aim to advance research efforts in understanding pig intestinal health. The development of an optimized protocol for protein extraction of intestinal mucosal scrapings in pigs addresses a gap in the field and enhances future research on pig intestinal health. By use of the protocol and mass spectrometry-based proteome analysis, valuable insights for improving the health and productivity of pigs can be presented. Studying the complex dynamics of the proteome within the intestinal mucosa, potentially identifying links between mucosal changes and health outcomes, provides us with information about the critical connection between intestinal health and the overall well-being and productivity of pigs. By creating a standardized approach, consistent, reliable, and reproducible results can be obtained for this type of research. [Display omitted] • MS-based proteomics serves as a valuable tool to investigate the intricate dynamics of the proteome of the intestinal mucosa. • Currently, no standardized, detailed protocol for protein extraction of pig intestinal mucosal samples exists. • In this study, three different approaches for protein extraction were examined and compared. • We present a standardized and reliable protocol, aimed to advance research efforts to understand pig intestinal health. [ABSTRACT FROM AUTHOR]

Inflammation and infection of the middle ear, known as otitis media (OM), is a leading cause of hearing loss and the most frequently diagnosed disease in children worldwide. Traditionally, mouse models for OM rely on inducing acute infection through inoculation of the middle ear, e.g. with the human otopathogen non-typeable Haemophilus influenzae (NTHi), and with very few genetic models with spontaneous or chronic OM. A2ML1 variants, including loss-of-function variants, were associated with susceptibility to OM in humans, but no animal model has been reported for A2ml1- related OM. Here, we report our middle ear findings in a mouse line with a CRISPR-induced knockout (KO) of A2ml1. Mice were X-rayed prior to harvest to determine if there are craniofacial or skeletal abnormalities. Tissue from mouse middle ears, as well as other upper respiratory mucosal tissues, were harvested. The harvested middle ear bullae were examined under microscope and submitted for histologic preparation to study phenotypic indications of OM. RNA samples isolated from middle ear tissue were assayed for expression of genes correlated with A2ML1 expression in humans. Data from a total of 119 mice (35 wildtype, 40 heterozygous, 44 homozygous) are presented here, with each analyses being performed on subsets of these mice. There were no significant craniofacial differences by genotype (n = 22). Findings in mice with the A2ml1 -KO indicated an increased incidence of OM (n= 29; odds ratio = 11; CI: 1.1, 573.6; Fisher exact two-sided p = 0.02) with tympanic membrane perforations or thickening, as well as cases of middle ear effusion, inflammatory cells, or fluid from histologic sections. Dsp was upregulated in the middle ear tissues of homozygous mice (Wilcoxon test p = 0.001). Thus far, our results in this A2ml1 -KO mouse line indicate spontaneous occurrence of OM and dysregulation of Dsp in the middle ear as a potential disease mechanism for A2ml1- related OM. [ABSTRACT FROM AUTHOR]

Ciprofloxacin (CPX), is a fluoroquinolone antibiotic used to treat a number of gram-negative and gram-positive bacterial infections. Ciprofloxacin can cause severe side effects, ranging from tendon problems, nerve damage, to serious mood or behavior changes. The purpose of this study was to investigate how ciprofloxacin affects gastric cell lines in rats with a distinctive emphasis on physiological, histopathological, and bacteriological changes. Male albino rats (n = 21) were distributed into three groups; control, CPX, and CPX-withdrawal groups. The treated rats were given CPX tablets (12.5 mg/kg) dissolved in carboxymethyl cellulose (CMC) 0.5% orally once daily via gavage for sixty consecutive days. Control rats received only the vehicle. The withdrawal group was treated for 60 days and the drug was withdrawn for another sixty days. After completion of the experiment, all rats were sacrificed and gastric tissues were treated for light, immunohistochemical, and scanning electron microscopic examination. Image J software was used to measure immune-labeled gastric epithelial cells. Blood samples were also collected for H. Pylori immunoglobulins IgM, IgA, and IgG. Results showed that treated rats acquired significantly strongly positive tumor necrosis factor (TNFα) and significant reduction of serum level of H. pylori IgM, IgA, and IgG in all the study groups. It could be concluded that prolonged oral CPX administration to albino rats changes the gastric mucosal architecture and bacteriology. [ABSTRACT FROM AUTHOR]

There is significant interest in understanding the cellular mechanisms responsible for expedited healing response in various oral tissues and how they are impacted by systemic diseases. Depending upon the types of oral tissue, wound healing may occur by predominantly re-eptihelialization, by re-epithelialization with substantial new connective tissue formation, or by a a combination of both plus new bone formation. As a result, the cells involved differ and are impacted by systemic diaseses in various ways. Diabetes mellitus is a prevalent metabolic disorder that impairs barrier function and healing responses throughout the human body. In the oral cavity, diabetes is a known risk factor for exacerbated periodontal disease and delayed wound healing, which includes both soft and hard tissue components. Here, we review the mechanisms of diabetic oral wound healing, particularly on impaired keratinocyte proliferation and migration, altered level of inflammation, and reduced formation of new connective tissue and bone. In particular, diabetes inhibits the expression of mitogenic growth factors whereas that of pro-inflammatory cytokines is elevated through epigenetic mechanisms. Moreover, hyperglycemia and oxidative stress induced by diabetes prevents the expansion of mesengenic cells that are involved in both soft and hard tissue oral wounds. A better understanding of how diabetes influences the healing processes is crucial for the prevention and treatment of diabetes-associated oral complications. [ABSTRACT FROM AUTHOR]

Cutaneous changes of facial vascularized composite allotransplants (fVCAs) are extensively described in the literature. Parts of the nose, nasal, and oral cavities are included in most fVCAs. Distinctively, the nose and mouth are lined by mucosa. Little is known about the histopathology and complications of the mucosa involved in fVCA patients. The study constitutes a retrospective cohort study of nine fVCA patients. Medical records were reviewed for information about changes of oral and nasal mucous membranes. Types of mucosal lesions were recorded and analyzed. Uni- and multivariate generalized estimating equation (GEE) models were used to assess the odds of developing mucosal inflammation in the presence of clinico-pathologic variables. A total of 186 clinical encounters with examination of oral and nasal mucous membranes were included. Membranes were devoid of clinical pathology in 101 instances (53% of all clinical assessments). Ulcerations/erosions (27%), edema (18%), and erythema (14%) were the most common lesions. Oral lesions affected the lips (58%), buccal mucosa (38%), and palate (5%). Sinonasal processes predominantly affected nasal vestibules and septae. In univariate analysis, sirolimus, skin rejection, and skin Banff grade were associated with the presence of an acute inflammatory mucosal lesion (p <0.05). In multivariate analysis, skin Banff grade and sirolimus were independent predictors of mucosal inflammation. Pathologies of fVCA mucous membranes are more common than previously reported. Mucosal assessment plays an important role in the pleomorphic allograft rejection process evaluation rather than diagnosis and treatment based on cutaneous pathology. A closer look at the pathophysiology of fVCA mucosal rejection and inflammation is warranted. [ABSTRACT FROM AUTHOR]

• ILCs play a crucial role in defending against infections and maintaining mucosal homeostasis. • ILCs regulate inflammatory, immune responses and tumorigenesis. • The frequencies and cytokines expression patterns of ILCs alter in oral diseases. • ILCs-producing cytokines mediate immune responses in oral diseases. Innate lymphoid cells (ILCs), as newly discovered antigen-independent innate immune cells, respond promptly to stimuli by secreting effector cytokines to exert effector functions similar to those of T cells. ILCs predominantly reside at mucosal sites and play critical roles in defending against infections, maintaining mucosal homeostasis, regulating inflammatory and immune responses, and participating in tumorigenesis. Recently, there has been a growing interest in the role of ILCs in oral diseases. This review outlines the classifications and the major characteristics of ILCs, and then comprehensively expatiates the research on ILCs in oral cancer, primary Sjogren's syndrome, periodontal diseases, oral lichen planus, oral candidiasis, Behcet's disease, and pemphigus vulgaris, aiming at summarising the implications of ILCs in oral diseases and providing new ideas for further research. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) are crucial for establishing the resolution phase following an intestinal inflammatory episode. Because current treatments for intestinal inflammation have a high percentage of failure and lead to immunosuppression, repair GPCRs have promising therapeutic potential because they trigger resolution pathways without compromising the immune response. [ABSTRACT FROM AUTHOR]

• Immunization with IgG2a Fc- PspA leads to AM1 and TH1 polarization and conventional DC activation. • Immunization with IgG2a Fc- PspA promotes the early production of proinflammatory cytokines. • Immunization with IgG2a Fc- PspA enhance the S. pneumoniae specific humoral response. • The reduced protection of the IgG1 Fc-PspA fusion protein is reversed in FcγRIIB knockout mice. Streptococcus pneumoniae (Spn) remains a considerable threat to public health despite the availability of antibiotics and polysaccharide conjugate vaccines. The lack of mucosal immunity in addition to capsular polysaccharide diversity, has proved to be problematic in developing a universal vaccine against Spn. Targeting antigen to Fc receptors is an attractive way to augment both innate and adaptive immunity against mucosal pathogens, by promoting interactions with activating Fcγ receptors (FcγR) that mediate diverse immunomodulatory functions. The effect of targeting FcγR is highly influenced by the IgG subclass, which bares differential affinities for activating and inhibitory FcγR. In the current study we demonstrate targeting activating FcγR with fusion proteins consisting of PspA and IgG2a Fc enhance PspA-specific immune responses, and effectively protect against mucosal Spn challenge. Specifically, targeting PspA to FcγR polarized alveolar macrophage to the AM1 phenotype and increased conventional dendritic cell subsets in the lung in addition to augmenting Th1 cytokines and PspA-specific IgG and IgA. In contrast, fusion proteins consisting of PspA fused to the IgG1 Fc provided minimal benefit over administration of PspA alone, as a result of interaction with the inhibitory FcγRIIB. Protective efficacy of the IgG1 fusion protein was significantly enhanced in animals deficient for FcγRIIB accompanied by increased B cell maturation and proliferation levels in these animals. These studies demonstrate FcγR targeting is an effective strategy for inducing potent cellular and humoral responses via mucosal immunization with Fc fusion proteins, however, careful consideration of the Fc region utilized is required since Fc isotype subclass heavily influenced immunization induced effector functions and survival against lethal Spn challenge. Fc-engineering with specific attention to FcγRIIB engagement presents a valuable vaccine strategy for protecting against Spn infection. [ABSTRACT FROM AUTHOR]

• Metabolic, anti-inflammatory and antioxidant features of alveolar macrophages support Mycobacterium tuberculosis replication. • Transmigration of infected alveolar macrophages into the interstitium associates with neutrophil and macrophage infiltration. • Lung residing myeloid and lymphoid cells may affect early clearance of Mycobacterium tuberculosis. • Dynamics of immune cells in lung compartments is fine-tuned by cytokines and chemokines networks early post exposure. • Understanding first events during tuberculosis will lead to novel interventions. Tuberculosis (TB) most frequently affects the lung, with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, promptly gaining access to lung-resident myeloid cells, notably alveolar macrophages. Historical observational case-contact surveys and recent epidemiological studies report on resistors. These individuals are likely protected against infection by defence mechanisms occurring promptly after bacterial exposure. The early events proceeding within the Mtb -infected lung are critical for the outcome of the infection. Despite the heightened relevance of the first contact between Mtb and the host, the current understanding of precise immune events occurring shortly after Mtb exposure is still limited. More recently, new information has emerged and we here summarize cellular and molecular events of innate immunity, considering the lung compartments and cellular communication over time. We discuss new concepts emerging from experimental models of pulmonary TB, highlight recent advances and summarize requirements for accurate mapping of early events in TB. A better understanding of disease pathogenesis at incipient stages will facilitate the development of novel therapeutics and more effective prophylactic measures for TB. [ABSTRACT FROM AUTHOR]

Fibrous reactive hyperplasia (FRH) is a common fibrous lesion in the oral cavity. The disease characteristics of FRH, including the expression patterns of CD34, which is a well-known fibroblast marker, have not been investigated in detail. Therefore, in this study, we aimed to investigate the characteristics of FRH compared to those of the healthy mucosa, based on CD34 expression profiles. CD34 expression was analyzed at the protein and mRNA levels using immunohistochemistry, quantitative polymerase chain reaction, and in situ hybridization (ISH). CD34 was not expressed in the lamina propria of the oral mucosa, but was commonly observed in submucosal fibroblasts. CD34-positive fibroblasts were commonly observed in FRH. A total of 17 out of 19 cases (89.5%) were CD34-positive. Furthermore, we identified a significant difference in the ratio of CD34-positive cells between the healthy and FRH tissues. Quantitative polymerase chain reaction showed that CD3 4 mRNA was expressed in all cases of FRH, and CD3 4 mRNA expression in FRH samples was found to be localized to spindle-shaped fibroblasts, as determined by ISH. A positive correlation was also found between the CD3 4 mRNA levels and the proportion of the CD34-positive cells. These findings suggest that the increase in collagen synthesis in CD34-positive fibroblasts in the submucosa leads to the development of FRH. To our knowledge, this is the first report confirming the mRNA expression patterns of CD34 in FRH. [ABSTRACT FROM AUTHOR]

HIV-1 envelope (Env)-specific antibody present at mucosal surfaces can block entry of HIV-1 into these portals and thus should be elicited by an HIV-1 preventive vaccine. Since three molecules of tumor necrosis factor superfamily (TNFSF), APRIL, BAFF, and CD40L, could promote mucosal antibody responses, we made fusion constructs of them with an HIV-1 gp140 trimer and tested the mucosal gp140-specific antibody elicited by the fusion constructs in mice using a DNA prime-protein boost vaccination regimen. The fusion constructs formed trimers and displayed both broadly neutralizing antibody epitopes and non-broadly neutralizing antibody epitopes. Compared with the control construct, trimeric gp140, trimeric gp140-APRIL and gp140-BAFF fusion proteins mildly promoted B cell proliferation in vitro , enhanced HIV-1 gp140-binding IgG responses in vaginal lavage or fecal pellets, respectively, and decreased HIV-1 gp140-binding IgA in sera. Gp140-APRIL also augmented HIV-1 gp140-binding IgG in sera. Surprisingly, gp140-CD40L did not promote B cell proliferation in vitro and inhibited mucosal and systemic HIV-1 gp140-binding IgG or IgA. These results suggest that APRIL and BAFF should be further explored as molecular adjuvants for HIV-1 vaccines to enhance mucosal antibody responses, but covalent fusion of TNFSFs to gp140 may hinder their adjuvancy due to steric interactions. [ABSTRACT FROM AUTHOR]

In intensive Atlantic salmon aquaculture, faecal score potentially serves as a generalised indicator of gut microbiome diversity and composition and as a proxy for gut transit time. There is also the possible application to detect dysbiosis. The utility of using faecal scoring for assessing commercially farmed fish populations may, however, be impacted by rapid temporal changes in digestive status following feeding that, as yet, has not been considered. To help inform sampling strategies and better understand the utility of faecal scoring for farmed fish, this study documented Atlantic salmon faecal scores and gut bacterial 16S rRNA amplicon sequence profiles over 24 h following a feeding event. Samples were collected from two marine cohorts of salmon in different seasons (summer and winter), and comparisons were also made between non-destructive stripped hindgut faeces (HS) and destructive sampling of hindgut digesta (HD) and hind gut mucosa (HM). Average hindgut faecal scores and microbiome diversity were largely consistent over a normal (6 to 8 h) sampling day in winter, but were much more variable in summer, potentially associated with faster faecal passage and dynamic gut microbial changes in the hours after feeding. HS samples were determined to be a valid non-destructive method to obtain material for assessing the diversity and composition of transient bacterial communities in the distal intestine. For an accurate representation of both the transient and resident bacterial communities, both sample types should be considered. It is recommended that studies comparing treatment cohorts, or between individuals in large sample sets, should be designed to capture temporal and seasonal effects that are associated with changes in digestive status and gut microbiome. • Temporal change in digesta may confound comparison of gut microbiome in farmed Atlantic salmon. • Hindgut faecal score and microbiome diversity were variable in summer, associated with faster faecal passage. • In winter, sampling up to 23 h post feeding ensures consistency of faecal scores and hindgut microbial composition. [ABSTRACT FROM AUTHOR]

• High levels of ER stress were found in mast cells obtained from subjects with allergic disorders. • The levels of ER stress were positively correlated with mast cell mediator release. • To regulate the signal cascade of ER stress efficiently suppressed mast cell mediator release. Degranulation of mast cells leads to direct allergic symptoms. The underlying mechanism needs to be explored further. Endoplasmic reticulum (ER) stress is involved in the pathogenesis of allergic conditions. The objective of this study is to gain a better understanding of the mechanism of mast cell degranulation. Bone marrow derived mast cells and mast cells isolated from the airway tissues were prepared. The role of ER stress in mediating the release of mast cells was tested. RNA sequencing (RNAseq) was used to investigate the genetic activities of mast cells. Our observation showed that sensitization increased ER stress in mast cells. X-box-1 binding protein (XBP1) activity was linked to mast cell degranulation. Modulation of ER stress or XBP1 expression regulates the release of the mast cell mediator. XBP1 promoted the mediator release of mast cells by activating spleen tyrosine kinase (Syk). Activation of eukaryotic initiation factor 2a (eIF2a) inhibited XBP1 in mast cells. Semaphorin 3A was effective in preventing experimental allergic rhinitis (AR) due to its ability to suppress the release of mast cell mediators. ER stress is associated with the mast cell degranulation. By inhibiting XBP1, the crucial molecule of ER stress, mast cell degranulation can be suppressed and experimental AR can be mitigated. [ABSTRACT FROM AUTHOR]

[Display omitted] It is estimated that nearly a half of the world's population over 30 years old suffer from some kind of periodontal disease (PD). Although preventable, PD can pose a significant health burden to patients, causing from pain and discomfort to disfigurement and death. The management of PD often requires surgical procedures accompanied of systemic antibiotic and anti-inflammatory treatments. Curcumin (CUR), a potent anti-inflammatory and antimicrobial active, has shown great promise in the management of PD; however, its effects are often limited by its low bioavailability. In this work, we report the development of electrospun nanofibres (NFs) loaded with CUR nanocrystals (NCs) for the management of PD. NCs of 100 nm were obtained by media milling and loaded into dissolving polyvinyl alcohol NFs using electrospinning. The resultant NCs-in-NFs dissolved in water spontaneously, releasing NCs with a particle size of ∼120 nm. The physiochemical characterisation of the systems indicated the absence of chemical interactions between drug and polymer, and nanofibres with an amorphous nature. In vitro release profiles demonstrated that the NCs had a significantly higher dissolution rate (∼100 % at day 40) than the control group (approximately 6 % at day 40), which consisted of NFs containing a physical mixture of the drug and stabiliser. Finally, mucosal deposition studies demonstrated a 10-fold higher capacity of the novel NCs-in-NFs system to deposit CUR ex vivo using excised neonatal porcine mucosal tissue, when compared to the control group. [ABSTRACT FROM AUTHOR]

Background: Enteric serotonin may function as a mucosal growth factor. Previous work demonstrated increased crypt cell proliferation and intestinal mucosal surface area with potentiation of serotonin. While an indirect mechanism was postulated to explain these effects, the presence of 5-HT4 receptors on enterocytes raises the possibility of a direct action of serotonin. We hypothesized that a 5-HT4 specific agonist, prucalopride, would stimulate intestinal mucosal growth and enhance absorptive function in the murine small intestine.Methods: Adult wild-type mice were treated parenterally with prucalopride for 14 days via surgically implanted osmotic pumps. In vivo D-xylose absorption was assessed by oral gavage and serum D-xylose measurements. On day 14, glucose absorption was assessed by instilling a glucose solution into isolated segments of small intestine. The bowel was harvested and examined for morphologic parameters and crypt cell proliferation.Results: Villus height, crypt depth, and crypt proliferation were significantly increased in the distal small bowel of prucalopride-treated mice compared with control animals. Crypt depth was also increased in the proximal and middle small intestine in treated mice. There was no difference in D-xylose absorption throughout the study period; however, glucose absorption was significantly increased in the distal small intestine of prucalopride-treated mice.Conclusion: Parenteral administration of the 5-HT4 receptor specific agonist, prucalopride, results in morphologic and functional changes in the murine small intestine that are most prominent in the distal small bowel. While further studies are necessary to delineate the mechanism, it is plausible that the effects are mediated by 5-HT4 receptors on enterocytes. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Multiple W/O/W emulsion for topical application of clotrimazole has been developed. • Sphericalspherical droplets with negative charge and optimal pH were obtained. • Formulation showed pseudoplastic behavior with hysteresis areas and low viscosities. • Improved release and permeation profiles than commercial references were shown. • Higher antimycotic efficacy than commercial references were also achieved. Abstract Clotrimazole (CLT) was formulated in a multiple W/O/W emulsion (ME) with the aim of evaluating its potential as topical anticandidal agent and comparing with marketed products. A previously evaluated CLT-ME was selected and physicochemically characterized. The in vitro release behavior and the ex vivo permeation profiles were assessed using Franz diffusion cells using three different types of biological membranes: human skin and porcine buccal, sublingual and vaginal mucosae. The antifungal activity against Candida strains was also tested. Results showed CLT-MEs sizes of 29.206 and 47.678 μm with skin compatible pH values of 6.47 and 6.42 exhibiting high zeta potential values of -55.13 and -55.59 mV with dependence on the pH variation. The physicochemical stability was kept for a period of 180 days of storage at room temperature. CLT-MEs exhibited pseudoplastic behavior with hysteresis areas and viscosities of 286 and 331 mPa⋅s showing higher spreadability properties than commercial counterparts. An improved CLT release pattern was supplied by the ME system following a hyperbolic model. Likewise, ME system gave higher skin permeation flux of CLT than commercial reference. CLT amounts retained in the skin and mucosae were also higher than commercial references, which coupled with the higher antimycotic efficacy make CLT-MEs a great tool for clinical investigation of topical candidiasis treatments. [ABSTRACT FROM AUTHOR]

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The intestinal mucosa serves as a highly selective barrier that allows the absorption of nutrients and water while restricting microbiota access to tissues. This barrier is compromised in inflammatory conditions such as infectious colitis and inflammatory bowel disease (IBD). In response to mucosal injury, there is a temporal recruitment of leukocytes that crosstalk with epithelial cells to orchestrate repair. Specialized pro-resolving mediators (SPMs) play an important role in the resolution of inflammation and epithelial repair. SPMs actively promote resolution of inflammation by contributing to the clearance of neutrophils, stimulating efferocytosis, and promoting epithelial repair. SPMs have potential to serve as targeted therapeutic agents to be used in adjuvant therapy to promote resolution of inflammation and epithelial repair in chronic inflammatory diseases. Highlights SPMs are endogenously synthesized lipid mediators derived from polyunsaturated ω-3 and ω-6 fatty acids. SPMs decrease inflammation, promote resolution, and trigger repair. Resolvins are the best-studied SPMs, thus this review focuses largely on this group. Resolution and repair are active processes that are initiated by the inflammatory response. SPMs in the intestine provide spatiotemporal control of inflammation by controlling potential threats in a timely and localized manner. SPMs have potential to be used as biomarkers for different inflammatory conditions that could have signature SPM profiles as well as immunoresolvants to promote resolution of inflammation. [ABSTRACT FROM AUTHOR]

Abstract Purpose In this prospective, randomized, double-blind, controlled study, we evaluated the effects of leukocyte- and platelet-rich fibrin (L-PRF) alone and combined with hyaluronic acid (HA) sponge on early healing of soft tissue after mandibular third molar (M3) surgery. Patients and methods In total, 60 patients aged 18–30 (mean 22.3), 22 male and 38 female, were included in this study. After surgical extraction of the impacted M3, L-PRF was applied to the socket in the L-PRF group (n = 20), and a combination of L-PRF and HA was applied in the L-PRF + HA group (n = 20). Nothing was applied in the control group (n = 20). The primary outcome variable was healing score for the mucosa over the extraction socket on the 7th, 14th, and 21st days. Secondary outcome variables were frequencies of postoperative complications: hemorrhagic complications, alveolar osteitis (AO), and postoperative wound infection. Results Mean healing scores for the mucosa on the 7th, 14th, and 21st days for both the L-PRF group and the L-PRF + HA group were significantly better than those for the control group. The ratio of alveolar osteitis for the control group was 1:20 and the ratio of postoperative wound infection for the control group was 1:20. There were no cases of alveolar osteitis or postoperative wound infection in the L-PRF and L-PRF + HA groups. No hemorrhagic complications were observed in this study. Conclusion The results of this study suggest that L-PRF alone and when combined with HA can be an effective way to improve soft tissue healing, and could be used to prevent postoperative alveolar osteitis and infection after M3 surgery. Further studies with larger study groups are necessary. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Clotrimazole (CLT) was formulated in a nanoemulsion (NE) for the topical treatment of candidiasis consisting of 10% labrafac® lipophile, 60% labrasol®:capryol® 90 mixture (ratio 4:1) and 30% propylene glycol. Physicochemical properties, stability, rheology , in vitro drug release, ex vivo drug permeation through human skin and porcine buccal, sublingual and vaginal mucosae, antifungal efficacy, as well as in vivo skin tolerance were evaluated. 1% CLT-NE (CLT-NE1) and 2% CLT-NE (CLT-NE2) exhibited 153 ± 17.25 and 186 ± 15.38 nm droplet sizes, low polydispersity indexes, negative zeta potentials and biocompatible pH values. The CLT-NEs exhibited typical Newtonian profiles with viscosities of 42.14 ± 0.037 mPa·s and 41.35 ± 0.041 mPa·s, respectively and higher extensibility properties than commercial counterparts retaining their physicochemical properties for 180 days. NEs provided a sustained release of drug according to the first order model. Similar skin permeation properties were observed between CLT-NE1 and commercial reference. However, significant higher CLT amounts retained in mucosae were provided by CLT-NE2 when compared with references. Antifungal efficacies were also higher than commercial references, and the in vivo tolerance study confirmed the suitability for topical application, making CLT-NEs a great tool for clinical investigation of topical candidiasis treatments. [ABSTRACT FROM AUTHOR]

Abstract Identification of the association between tissue biomarkers, their surrogates in blood and clinical features, could provide new diagnostic tools and facilitate adequate choices of therapeutic interventions for selected patients suffering from CRS. The aim of present study was the assessment of macrophages in the polyp tissue and monocytes in the peripheral blood in the course of CRSwNP, and their functional immunophenotype. We analyzed 31 patients with CRSwNP. Nasal mucosa tissue was obtained via functional endoscopic sinus surgery (FESS). The control group included 10 patients with deviated nasal septum (DNS). Fluorochrome stained cells were proceed to acquisition using FACS Canto flow cytometer, and the results were analyzed using the software FACS Diva. In our study, we observed a significantly higher level of CD80, CD274, CD273 and TLR1 in nasal polyps compared to blood samples from patients with CRSwNP. This finding may suggest the importance of the PD-1 pathway as a therapeutic target in CRS and an important role for TLR1 in nasal polyp formation and maintenance. Our results may provide some insight into potential future targets of recurrent nasal polyp treatment and contribute to a better understanding of the inflammatory process in Chronic Rhinosinusitis. [ABSTRACT FROM AUTHOR]

Abstract This review analyzed the published studies on the effects of thermal injury on gastrointestinal motility and mucosal damage. Our strategy was to integrate all available evidence to provide a complete review on the prokinetic properties of variable reagents and the potential clinical treatment of mucosal damage and gastrointestinal dysmotility after thermal injury. We classified the studies into two major groups: studies on gastrointestinal dysmotility and studies on mucosal damage. We also subclassified the studies into 3 parts: stomach, small intestine, and colon. This review shows evidence that ghrelin can recover burn-induced delay in gastric emptying and small intestinal transit, and can protect the gastric mucosa from burn-induced injury. Oxytocin and β-glucan reduced the serum inflammatory mediators, and histological change and mucosal damage indicators, but did not show evidence of having the ability to recover gastrointestinal motility. Using a combination of different reagents to protect the gastrointestinal mucosa against damage and to recover gastrointestinal motility is an alternative treatment for thermal injury. Highlights • Ghrelin recovered gastric and small intestinal dysmotility after thermal injury. • Only ghrelin was documented to recover the burn-induced delayed small intestinal transit. • Oxytocin and β-Glucans reduced burn-induced mucosal damage. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of fish protein hydrolysate (FPH) on intestinal microbiota and health of turbot Scophthalmus maximus (average initial body weight 25.5 g). Two control diets were formulated to contain 360 g kg −1 (high fish meal, HFM) and 240 g kg−1 (low fish meal, LFM) of fish meal. Two experimental diets were derived from the HFM diet by replacing fish meal with FPH at levels of 100 g kg−1 (appropriate level, FPH10) or 300 g kg−1 (excessive level, FPH30). The supplementation of FPH at an appropriate level showed a positive effect on growth performance. According to chyme amino acid concentrations, moderate FPH in diets can alleviate the rate of amino acid absorption in middle intestine than excessive one (FPH30), and more thoroughly absorbed in distal intestine than fish meal (HFM) and plant protein (LFM). Histology of distal intestine showed that an appropriate level of FPH in diets could serve to alleviate the symptoms of structural damage (villi height and wall thickness) to the intestine caused by plant protein. The expressions of tight junction proteins and mucin 2 in the FPH10 and FPH30 diets was up-regulated in middle intestine compared to the LFM diet. FPH at a moderate level reduced the levels of pro-inflammatory factors (IL-1 β and TNF- α) but didn't increased anti-inflammatory factors (IL-10 and TGF- β) in middle intestine compared with the LFM diet. To turbot, mucosa and chyme-associated microbiota from middle and distal intestine mainly belonged to Proteobacteria and Firmicutes. The bacterial richness, diversity and/or evenness decreased in middle intestine chyme, distal intestine mucosa and/or chyme when fish were fed diets containing FPH. Fish fed an appropriate level of FPH showed an increase of genera Bacillus in middle intestine mucosa and a decrease of genera Vibrio in distal intestine mucosa, while there was an inverse trend in fish fed an excessive level of FPH. Overall, FPH at an appropriate level showed a positive effect on intestinal health by improving middle or distal intestinal structure integrity and barrier function, as well as regulating immune-related inflammatory factors. Meanwhile, moderate FPH in diets may modulate the abundance of potentially probiotic (Bacillus) and pathogenic (Vibrio) in the intestine. • FPH at an appropriate level regulated amino acid absorption based on amino acid concentrations of intestinal chyme. • FPHimproved structure integrity and barrier function, as well as regulating immune-related inflammatory factors. • FPH increased the abundance of Bacillus and decreased abundance of Vibrio in intestinal mucosa and chyme. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Different types of biodegradable nanoparticles (NP) have been studied as nasal mucosa cell delivery systems. These nanoparticles need to strongly interact with mucosa cells to deliver their payload. However, only a few simultaneous comparisons have been made and it is therefore difficult to determine the best candidate. Here we compared 5 types of nanoparticles with different surface charge (anionic or cationic) and various inner compositions as potential vectors: cationic and anionic liposomes, cationic and anionic PLGA (Poly Lactic co-Glycolic Acid) NP and porous and cationic maltodextrin NP (cationic surface with an anionic lipid core: NPL). We first quantified their nasal residence time after nasal administration in mice using in vivo live imaging and NPL showed the longest residence time. In vitro endocytosis on mucosal cells (airway epithelial cells, macrophages and dendritic cells) using labeled nanoparticles were performed by flow cytometry and confocal microscopy. Among the 5 nanoparticles, NPL were taken up to the greatest extent by the 3 different cell lines and the endocytosis mechanisms were characterized. Taken together, we observed that the nanoparticles' cationic surface charge is insufficient to improve mucosal residence time and cellular uptake and that the NPL are the best candidates to interact with airway mucosal cells. [ABSTRACT FROM AUTHOR]

Langerhans cells (LCs) are classically viewed as unique antigen-presenting cells (APCs) that originate from embryonic precursors and maintain themselves independently in the epidermis. However, recent studies have demonstrated that murine LCs in mucosal epithelia arise and are continuously replenished from circulating bone marrow (BM) precursors. This has led to the emergence of a novel perspective proposing that LCs can evolve from various origins. Because both embryonic and BM precursors differentiate into LCs only after entering the epithelium, this highlights its crucial role in nurturing LC development to perfectly comply with the physiological functions of the tissue. Thus, current evidence suggests plasticity of LC differentiation, revealing novel developmental mechanisms that are controlled by environmental cues. Highlights Whereas mouse skin LCs originate from embryonic macrophages and fetal liver monocytes, mucosal LCs arise from adult bone marrow precursors – pre-dendritic cells and monocytes. Despite their distinct ontogeny, mouse mucosal and skin LCs share a similar anatomic location, phenotype, transcriptomic signature, and function, which highlights the plasticity of the mononuclear phagocytic system. Indeed, under some conditions skin LCs can also develop from bone marrow precursors. The epithelium holds the cues to instruct LC differentiation. Nevertheless, the mouse epithelium of the skin and the various mucosae (e.g., oral, vaginal, and corneal mucosa), can fine-tune LC differentiation to adjust their phenotype and frequencies to the physiological function and architecture of the tissue. Differentiation of mouse mucosal LCs, unlike skin LCs, can be controlled by the microbiota via regulation of epithelial differentiation signals. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) frequently affects the oral mucosa and is generally responsive to topical immunomodulatory therapies. Clinicians may benefit from guidance in choosing the most appropriate therapy with respect to practicality and cost. To assess the economic considerations related to topical immunomodulatory treatments for management of oral mucosal cGVHD and their practical implications. Topical treatments used for management of oral cGVHD were obtained from the National Institutes of Health Consensus document for ancillary and supportive care. Cost data for a standard 1-month prescription was obtained from national databases for commercially available formulations and from compounding pharmacies for formulations requiring compounding. There are numerous topical preparations used for the management of oral cGVHD, many of which require compounding. The average wholesale price of the commercially available agents ranges from $5 to $277/month, and the cost of the compounded preparations ranges from $43 to $499/month. Costs can be influenced by drug-, patient-, and pharmacy-related factors. The costs associated with topical treatment of oral cGVHD are substantial, particularly because the disease is chronic and expenses accumulate over time. Rational prescribing according to a proposed algorithm, including de-escalation of therapy when indicated, can help to minimize associated costs. This has practical implications for patients, physicians, pharmacies, and insurance providers. [ABSTRACT FROM AUTHOR]

Background Mycobacterial infections greatly affect human and animal health worldwide, and vaccines are effective, sustainable and economic interventions for the prevention and control of these infectious diseases. Recent results support the use of zebrafish as a model for studying the pathophysiology of mycobacterial infection and for the development of novel interventions for tuberculosis (TB) control. Recently, we showed that oral immunization with the heat-inactivated M. bovis vaccine ( M. bovis IV) protect wild boar against TB, and suggested that this vaccine may controls mycobacterial infection in other species. Methods In this study we evaluated the effect of M. bovis IV on the control of mycobacteriosis in zebrafish mucosally vaccinated by immersion and challenged intraperitoneally with Mycobacterium marinum . Results The results showed that the M. bovis IV administered by immersion protected zebrafish against mycobacteriosis caused by M. marinum by reduction in mycobacterial infection, the number of mycobacteria per granuloma and the number of granulomas per fish. An IgM antibody response against M. bovis antigens was developed in vaccinated fish. Evidences suggested that the protective mechanism elicited by mucosal vaccination with M. bovis IV in zebrafish was based on the activation of the innate immune response through the C3 pathway. Conclusions These results support the use of the M. bovis IV administered by immersion for the control of mycobacteriosis in fish. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate whether or not the use of a prebiotic yeast cell wall (YCW) affects threonine requirements in starter broilers. Two hundred and forty 1-d-old Ross 308 broiler chickens were distributed among 2 Petersime battery brooder units (48 pens; 5 birds per pen). Different threonine to lysine ratios (0.60, 0.65, and 0.70 to 1.0) with 1.22% available lysine with and without YCW at 250 ppm was fed to the chickens in order to evaluate performance and intestinal morphology over a 21-d trial. A basal diet with 22% protein and 2,980 kcal/kg ME was prepared to create the 6 dietary treatments. The calculated lysine concentration was 1.34%, whereas threonine was 0.81, 0.88, and 0.94%, respectively. Pen weights and feed consumption were recorded at d 1, 7, 14, and 21 of the experiment. Jejunal and ileal samples were collected on d 21 for histology analysis to evaluate villi height (VH), crypt depth, villi width (VW), and muscularis thickness. A threonine to lysine ratio of 0.7:1.0 resulted in significant improvement of performance variables with increased jejunum VW and ileum VH compared with the other threonine to lysine ratios. Adding YCW to starter broiler did not affect the requirement for threonine. [ABSTRACT FROM AUTHOR]

On June 24, 2017, the 22nd annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite conference during the annual Research Society on Alcoholism (RSA) Scientific Meeting in Denver, Colorado. The 2017 meeting focused broadly on mechanisms that link alcohol to tissue injury and inflammation, and how this research can be translated to improve human health. Two plenary sessions composed the meeting, which first explored the association between alcohol and trauma/tissue injury, and finished with a discussion of alcohol and mucosal inflammation. The presentations encompassed diverse areas of alcohol research, from effects on the brain, to airway and pulmonary systems, to gut barrier disruption. The discussions also thoughtfully highlighted how current laboratory and clinical research can be used to prevent or treat alcohol-related morbidity and mortality. [ABSTRACT FROM AUTHOR]

During sexual intercourse, HIV-1 crosses epithelial barriers composing the genital mucosa, a poorly understood feature that requires an HIV-1-infected cell vectoring efficient mucosal HIV-1 entry. Therefore, urethral mucosa comprising a polarized epithelium and a stroma composed of fibroblasts and macrophages were reconstructed in vitro. Using this system, we demonstrate by live imaging that efficient HIV-1 transmission to stromal macrophages depends on cell-mediated transfer of the virus through virological synapses formed between HIV-1-infected CD4+ T cells and the epithelial cell mucosal surface. We visualized HIV-1 translocation through mucosal epithelial cells via transcytosis in regions where virological synapses occurred. In turn, interleukin-13 is secreted and HIV-1 targets macrophages, which develop a latent state of infection reversed by lipopolysaccharide (LPS) activation. The live observation of virological synapse formation reported herein is key in the design of vaccines and antiretroviral therapies aimed at blocking HIV-1 access to cellular reservoirs in genital mucosa. • HIV-1-infected T cells form viral synapse with the epithelium in reconstructed mucosa • These viral synapse dynamics were recorded by live imaging for the first time • HIV-1 formed at the viral synapse crosses the epithelium by transcytosis • Transcytosed HIV-1 targets stromal macrophages, resulting in their latent infection Real et al. established by live imaging the dynamics of virological synapses formed between HIV-1-infected T cells and the epithelium at the surface of a human reconstructed mucosa. HIV-1 virions formed at the viral synapse cross the epithelium and reach the mucosal stroma, where the virus establishes a latent infection in macrophages. [ABSTRACT FROM AUTHOR]

Mucosal but not parenteral vaccination with whole Leishmania amazonensis promastigotes antigens (LaAg) is known to increase host resistance to infection by an as yet unknown immune mechanism. Since early immune responses are critical for infection establishment, in the present study the differential responses elicited by subcutaneous (s.c.) and intranasal (i.n.) vaccination with LaAg were investigated during the initial stages of infection. For that, BALB/c mice were given two LaAg doses by i.n. or s.c. route prior to L. amazonensis infection in the footpad. It was found that mucosal vaccination prevented both T helper (Th) 2-associated cutaneous hypersensitivity and local interleukin (IL)-4 production in the first days after parasite challenge in the footpad. That was accompanied by increased Th1 (T-bet and IL-12) and T reg (Foxp3 and IL-10) transcription factor and cytokine expression in the lesion draining lymph nodes. In contrast, s.c. LaAg predominantly led to higher Th2 (GATA3) and transforming growth factor (TGF)-β expression. Prior i.n. vaccination was able to prevent the disease-exacerbating effect of s.c. vaccination. Although both CD4 + and CD8 + T cells were transiently increased in the cervical lymph nodes (cLN), the numbers of CD4 + Foxp3 + regulatory T (T reg ) cells decreased within 48 h of i.n. vaccination as compared to non-vaccinated mice. Adoptive transfer of such cLN cells conferred increased resistance to infected mice, mimicking the effect of i.n. vaccination. Altogether, these data indicate that i.n. vaccination with LaAg may prevent early peripheral expansion of detrimental cells normally elicited by active infection or s.c. vaccination, thus allowing full expansion of protective responses. [ABSTRACT FROM AUTHOR]

Bronchi are exposed daily to irritants, microbes and allergens as well as extremes of temperature and acid. The airway mucosal epithelium plays a pivotal role as a sentinel, releasing alarmins when danger is encountered. To maintain homeostasis, an elaborate counter-regulatory network of signals and cellular effector mechanisms are needed. Specialized pro-resolving mediators (SPMs) are chemical mediators that enact resolution programs in response to injury, infection or allergy. SPMs are enzymatically derived from essential polyunsaturated fatty acids with potent cell-type specific immunoresolvent properties. SPMs signal by engaging cell-based receptors to turn off acute inflammatory responses and restore tissue homeostasis. Several common lung diseases involving the airways, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), are characterized by unresolved bronchial inflammation. In preclinical murine models of lung disease, SPMs carry potent bronchoprotective actions. Here, we review cellular and molecular effects for SPM-initiated catabasis in the lung and their human translation. [ABSTRACT FROM AUTHOR]

Mitochondria are cellular organelles that are the place of many metabolic processes and thus have a significant impact on the proper functioning of the organism. These organelles respond easily to environmental stimuli and cellular energy demands. To ensure the proper functioning of mitochondria, a high supply of specific nutrients is needed. Literature reports suggest that a favorable profile of the intestinal microbiota may improve the functioning of the mitochondria. The gut microbiota transmits a signal to the mitochondria of the mucosa cells. This signaling alters mitochondrial metabolism, activates cells of the immune system, and alters intestinal epithelial barrier functions. The aim of the study is to determine the relative number of mtDNA copies and to analyze the mitochondrial expression of genes related to respiratory chain proteins and energy metabolism in the intestinal mucosa and cecal tonsils of broiler chickens injected on the d 12 of egg incubation with various prebiotics. 300 incubated eggs of Ross 308 broiler chicken on d 12 of incubation were injected with: control group with physiological saline, prebiotics: XOS3, XOS4, MOS3, and MOS4. On d 42 after hatching, 8 individuals from each group were sacrificed. Cecal mucosa and cecal tonsils were collected postmortem for DNA and RNA isolation. Relative mitochondrial DNA copy number analysis was performed by qPCR method using 2 calculation methods. Gene expression analysis of the cecal tonsils and cecal mucosa was performed by RT-qPCR for the gene panel selected based on literature data and gene functions related to mitochondria: CS, EPX (MPO), CYCS, TFAM, NRF1, ND2, MnSOD (SOD2). As the results showed the overall mt DNA copy number is stable in both tissues. The significant change in gene expression in cecal mucosa was induced by XOS4 and MOS3. Both prebiotics caused upregulation of gene expression. In cecal tonsils all prebiotics caused downregulation of entire set of genes under the analysis. Statistically significant results of gene expression were detected for CYCS, ND2, NRF, TFAM for all experimental groups. [ABSTRACT FROM AUTHOR]

A higher concentration of melatonin (MEL) in the intestine — even more than that in the plasma and pineal gland — implies its putative important role in the gastrointestinal structural or functional regulation. However, little evidence has shown that MEL can regulate the physiological functions of the intestinal mucosa. In this study, fertilized chicken eggs were treated with MEL (0.1 to 10 μg/d) from embryonic d 12 (E12) to post-hatching d 6 (D6), and the small intestine samples were collected at D6 to determine the changes in mucosal construction and function. Results of HE staining showed that the enterocyte number was not changed after MEL treatment. Alcian blue - periodic acid Schiff reaction (AB-PAS) staining and qRT-PCR showed that the goblet cells populations and mucins gene (MUC2) expression in the small intestine were significantly increased after MEL treatment. Meanwhile, 5-ethynyl-2’-deoxyuridine staining showed that both the proliferation and migration rates of the small intestine mucosal epithelium were promoted by MEL treatment. Importantly, MEL significantly increased the activities of the digestive enzymes (maltase, sucrose, and lactase) and expression of the nutrient transporter genes such as GLUT5, BOAT, and EAAT3 mRNAs in the duodenum or jejunum. Meanwhile, the expression of Notch receptors (Notch1 and Notch2) and their ligands (Dll1 and Dll4) were remarkably decreased after MEL treatment. In conclusion, MEL treatment increased the goblet cell populations, MUC2 expression, epithelium migration, and digestive and absorptive function of the chicken small intestine involving repressed Notch signaling. [ABSTRACT FROM AUTHOR]

Research on the Gram-positive human-restricted pathogen Streptococcus pyogenes (Group A Streptococcus , GAS) has long focused on invasive illness, the most severe manifestations of GAS infection. Recent advances in descriptions of molecular mechanisms of GAS virulence, coupled with massive sequencing efforts to isolate genomes, have allowed the field to better understand the molecular and evolutionary changes leading to pandemic strains. These findings suggest that it is necessary to rethink the dogma involving GAS pathogenesis, and that the most productive avenues for research going forward may be investigations into GAS in its ‘normal’ habitat, the nasopharynx, and its ability to either live with its host in an asymptomatic lifestyle or as an agent of superficial infections. This review will consider these advances, focusing on the natural history of GAS, the evolution of pandemic strains, and novel roles for several key virulence factors that may allow the field to better understand their physiological role. [ABSTRACT FROM AUTHOR]

Objectives: Severe oral mucosal and tissue defects can lead to pain, infection, and later undesirable healing of scarring and adhesion, resulting in a poor quality of life. In vitro-engineered oral mucosal equivalents for covering such defects are an alternative to avoiding the donor site morbidity of conventional skin or tissue grafts. We examined the efficacy of our newly developed three-dimensional mucosal cell sheets in an in vivo tongue wound model mimicking the surgical extirpation of tongue cancer.Materials and Methods: Small oral mucosal and autologous fibrin samples were obtained from surgical patients and Sprague-Dawley rats. The fibrin was mixed with fibroblasts and seeded with keratinocytes that had been primarily cultured for in vitro cell expansion. The three-dimensional autologous cell sheets, cultured in air-lift interface inserts, were transplanted into deep wounds of the rat ventral tongue. Gross and microscopic findings of the postsurgical wounds were compared between wound control and cell sheet groups.Results: The cell sheets were flexible, expandable, and easy to transfer, and had histological characteristics similar to that of the normal oral mucosa, with high p63 positivity. They promoted oral wound healing with earlier re-epithelialization and less fibrosis than that in the wound control. The cell sheet-healed tongue had similar histology to that of a normal tongue.Conclusions: Our engineered cell sheets have potential applicability for the rapid healing of oral mucosal and soft tissue defects, without scarring, adhesion, and functional deficits.Condensed Abstract: The efficacy of in vitro-engineered mucosal equivalents, using completely autologous mucosa and plasma, was examined. Transplantation of the autologous cell sheets into deep wounds of the rat ventral tongue promoted oral wound healing with earlier re-epithelialization and less fibrosis than that in controls. Healed and normal tongues showed similar histology. [ABSTRACT FROM AUTHOR]

The accumulation of peripheral blood late-differentiated memory CD8 T cells with features of replicative (cellular) senescence, including inability to proliferate in vitro, has been extensively studied. Importantly, the abundance of these cells is directly correlated with increased morbidity and mortality in older persons. Of note, peripheral blood contains only 2% of the total body lymphocyte population. By contrast, the gut-associated lymphoid tissue (GALT) is the most extensive lymphoid organ, housing up to 60% of total body lymphocytes, but has never been assessed with respect to senescence profiles. We report here the development of a method for measuring and comparing proliferative capacity of peripheral blood and gut colorectal mucosa-derived CD8 T cells. The protocol involves a 5-day culture of mononuclear leukocyte populations, from blood and gut colorectal mucosa respectively, labeled with 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2′-deoxyuridine (BrdU) and stimulated with anti-CD2/3/28-linked microbeads. Variables tested and optimized as part of the protocol development include: mode of T cell stimulation, CFSE concentration, inclusion of a second proliferation marker, BrdU, culture duration, initial culture concentration, and inclusion of autologous irradiated feeder cells. Moving forward, this protocol demonstrates a significant advance in the ability of researchers to study compartment-specific differences of in vitro proliferative dynamics of CD8 T cells, as an indicator of replicative senescence and immunological aging. The study's two main novel contributions are (1) Optimization and adaptation of standard proliferative dynamics blood T cell protocols for T cells within the mucosal immune system. (2) Introduction of the novel technique of combining CFSE and BrdU staining to do so. [ABSTRACT FROM AUTHOR]