Goblet Cells Research Articles

DIREN mitigates DSS-induced colitis in mice and attenuates collagen deposition via inhibiting the Wnt/β-catenin and focal adhesion pathways

BackgroundDIREN is a SHE ethnic medicine with stasis-resolving, hemostasis, clearing heat, and removing toxin effects. It is clinically used in the treatment of gastrointestinal bleeding, such as ulcerative colitis (UC). Aim of the studyFibrosis is one of the pathological changes in the progression of UC, which can make it challenging to respond to a treatment. We aimed to illuminate the role of DIREN in DSS-induced UC and tried to unveil its related mechanisms from two perspectives: intestinal inflammation and collagen deposition. Materials and methodsA 2.5% dextran sulfate sodium (DSS) water solution was used to induce colitis in mice. The therapeutic effect of DIREN was assessed using the disease activity index, histopathological score, and colon length. Masson and Sirius Red staining was used to observe the fibrosis in the colon. Apoptosis of colonic epithelial cells was observed by TUNEL immunofluorescence staining. RNA-seq observed differential genes and enrichment pathways. Immunohistochemistry and RT-qPCR were used to detect the expression of molecules related to fibrosis and focal adhesion signaling in colon tissue. ResultsThe administration of DIREN resulted in a reduction of disease activity index (DAI) in mice with UC while simultaneously promoting an increase in colon length. DIREN mitigated the loss of goblet cells in the colon of UC mice and maintained the integrity of the intestinal mucosa barrier. Masson staining revealed a reduction in colonic fibrosis with DIREN treatment, while Sirius red staining demonstrated a decrease in collagen Ⅰ deposition. DIREN reduced apoptosis of colonic epithelial cells and the expression of genes, such as CDH2, ITGA1, and TGF-β2. Additionally, the results of GSEA analysis of colon tissue transcriptome showed that the differentially expressed genes were enriched in the focal adhesion pathway. DIREN was found to downregulate the protein expression of BAX, N-cadherin, β-catenin, Integrin A1, and Vinculin while upregulating the protein expression of BCL2. Additionally, it led to the co-expression of N-cadherin and α-SMA. ConclusionDIREN exerts a protective effect against DSS-induced UC by ameliorating colonic fibrosis via regulation of focal adhesion and the WNT/β-catenin signaling pathway, thereby inhibiting fibroblast migration and reducing collagen secretion.

Clinical manifestations, diagnosis and long-term prognosis of adult autoimmune enteropathy: Experience from Peking Union Medical College Hospital

BACKGROUND Autoimmune enteropathy (AIE) is a rare disease whose diagnosis and long-term prognosis remain challenging, especially for adult AIE patients. AIM To improve overall understanding of this disease’s diagnosis and prognosis. METHODS We retrospectively analyzed the clinical, endoscopic and histopathological characteristics and prognoses of 16 adult AIE patients in our tertiary medical center between 2011 and 2023, whose diagnosis was based on the 2007 diagnostic criteria. RESULTS Diarrhea in AIE patients was characterized by secretory diarrhea. The common endoscopic manifestations were edema, villous blunting and mucosal hyperemia in the duodenum and ileum. Villous blunting (100%), deep crypt lymphocytic infiltration (67%), apoptotic bodies (50%), and mild intraepithelial lymphocytosis (69%) were observed in the duodenal biopsies. Moreover, there were other remarkable abnormalities, including reduced or absent goblet cells (duodenum 94%, ileum 62%), reduced or absent Paneth cells (duodenum 94%, ileum 69%) and neutrophil infiltration (duodenum 100%, ileum 69%). Our patients also fulfilled the 2018 diagnostic criteria but did not match the 2022 diagnostic criteria due to undetectable anti-enterocyte antibodies. All patients received glucocorticoid therapy as the initial medication, of which 14/16 patients achieved a clinical response in 5 (IQR: 3-20) days. Immunosuppressants were administered to 9 patients with indications of steroid dependence (6/9), steroid refractory status (2/9), or intensified maintenance medication (1/9). During the median of 20.5 months of follow-up, 2 patients died from multiple organ failure, and 1 was diagnosed with non-Hodgkin’s lymphoma. The cumulative relapse-free survival rates were 62.5%, 55.6% and 37.0% at 6 months, 12 months and 48 months, respectively. CONCLUSION Certain histopathological findings, including a decrease or disappearance of goblet and Paneth cells in intestinal biopsies, might be potential diagnostic criteria for adult AIE. The long-term prognosis is still unsatisfactory despite corticosteroid and immunosuppressant medications, which highlights the need for early diagnosis and novel medications.

Alterations in the tear film and ocular surface in pediatric migraine patients.

To evaluate the ocular surface (OS) parameters in the pediatric migraine patients (PMPs). This prospective case-control study consisted of 51 PMPs (PMP group) and 55 healthy pediatric patients (HPP group). In all participants, tear function was evaluated subjectively using the Ocular Surface Disease Index (OSDI) questionnaire, objectively using Schirmer tear test (STT) and tear film disintegration time (TBUT), and with clinical and laboratory examinations (conjunctival impression cytology). The PMP group was subdivided into two groups according to their aura. The mean age and gender distribution of the study groups were almost the same (P > 0.05 for both of them). In the PMP group, both the STT value and the TBUT value were significantly lower than those determined in the HPP group (P = 0.021 and P = 0.018, respectively). In the PMP group, the OSDI scores were higher than those in the HPP group (P = 0.032). In the PMP group, the goblet cell density values were lower than those in the HPP group (P = 0.01). With regard to the aura, the TBUT and STT values were nonsignificantly lower in the PMP aura-positive group than in the PMP aura-negative group (P > 0.05 for both of them). The OSDI assessment was similar in both the groups. With regard to the goblet cell count, it was observed to be less in the PMP aura-positive group than in the PMP aura-negative group (P = 0.01). Influence of OS in children with migraine was also demonstrated using the samples taken from the conjunctiva. These changes were also demonstrated by objective tests such as STT and TBUT. Both clinical objective evaluations and pathologic changes were more prominent in the migraine with aura group.

Association between the expression of epithelial-mesenchymal transition (EMT)-related markers and oncologic outcomes of colorectal cancer.

Epithelial-mesenchymal transition (EMT) is a key step in the development of colorectal cancer (CRC) that confers metastatic capabilities to cancer cells. The present study aimed to assess the immunohistochemical (IHC) expression and impact of EMT markers, including E-cadherin, Vimentin, β-catenin, and SMAD4, on the oncologic outcomes of CRC. This was a retrospective review of 118 CRC patients. Tissue slides were retrieved from the slide archive and five tissue microarray construction blocks were constructed. IHC for E-cadherin, Vimentin, β-catenin, and SMAD4 was done. The main outcome was the association between abnormal marker expression and overall survival (OS), and disease-free survival (DFS). Adenocarcinomas accounted for 71.2% of tumors, whereas 25.4% and 3.4% were mucinous and signet ring cell carcinomas. The rates of lymphovascular invasion and perineural invasion were 72.9% and 20.3%, respectively. There was a positive, significant correlation, and association between the four markers. Abnormal expression of E-cadherin was associated with significantly lower OS (p < 0.0001) and similar DFS (p = 0.06). Abnormal Vimentin expression was associated with a significantly higher rate of distant metastasis (p = 0.005) and significantly lower OS and DFS (p < 0.0001). Abnormal expression of β-catenin was associated with significantly lower OS (p < 0.0001) and similar DFS (p = 0.15). Abnormal expression of SMAD4 was associated with significantly lower OS and DFS (p < 0.0001). Abnormal expression of all four markers was associated with a higher disease recurrence, lower OS, and lower DFS. Abnormal expression of each marker was associated with lower OS, whereas abnormal expression of Vimentin and SMAD4 only was associated with lower DFS.

Taurine Alleviates Experimental Colitis by Enhancing Intestinal Barrier Function and Inhibiting Inflammatory Response through TLR4/NF-κB Signaling.

Taurine (Tau) is a semiessential amino acid in mammals with preventive and therapeutic effects on several intestinal disorders. However, the exact function of taurine in ulcerative colitis (UC) is still largely unclear. In this study, we used two taurine-deficient mouse models (CSAD-/- and TauT-/- mice) to explore the influence of taurine on the progression of UC in both dextran sulfate sodium (DSS)-induced colitis and LPS-stimulated Caco-2 cells. We found that cysteine sulfinic acid decarboxylase (CSAD) and taurine transporter (TauT) expressions and taurine levels were markedly reduced in colonic tissues of mice treated with DSS. The CSAD and TauT knockouts exacerbated DSS-induced clinical symptoms and pathological damage and aggravated the intestinal barrier dysfunction and the colonic mucosal inflammatory response. Conversely, taurine pretreatment enhanced the intestinal barrier functions by increasing goblet cells and upregulating tight junction protein expression. Importantly, taurine bound with TLR4 and inhibited the TLR4/NF-κB pathway, ultimately reducing proinflammatory factors (TNF-α and IL-6) and oxidative stress. Our findings highlight the essential role of taurine in maintaining the intestinal barrier integrity and inhibiting intestinal inflammation, indicating that taurine is a promising supplement for colitis treatment.

Effects of Hibernation on Colonic Epithelial Tissue and Gut Microbiota in Wild Chipmunks (Tamias sibiricus)

The gut microbiota plays a crucial role in the host’s metabolic processes. Many studies have shown significant changes in the gut microbiota of mammals during hibernation to adapt to the changes in the external environment, but there is limited research on the colonic epithelial tissue and gut microbiota of the wild chipmunks during hibernation. This study analyzed the diversity, composition, and function of the gut microbiota of the wild chipmunk during hibernation using 16S rRNA gene high-throughput sequencing technology, and further conducted histological analysis of the colon. Histological analysis of the colon showed an increase in goblet cells in the hibernation group, which was an adaptive change to long-term fasting during hibernation. The dominant gut microbial phyla were Bacteroidetes, Firmicutes, and Proteobacteria, and the relative abundance of them changed significantly. The analysis of gut microbiota structural differences indicated that the relative abundance of Helicobacter typhlonius and Mucispirillum schaedleri increased significantly, while unclassified Prevotella-9, unclassified Prevotellaceae-UCG-001, unclassified Prevotellaceae-UCG-003 and other species of Prevotella decreased significantly at the species level. Alpha diversity analysis showed that hibernation increased the diversity and richness of the gut microbiota. Beta diversity analysis revealed significant differences in gut microbiota diversity between the hibernation group and the control group. PICRUSt2 functional prediction analysis of the gut microbiota showed that 15 pathways, such as lipid metabolism, xenobiotics biodegradation and metabolism, amino acid metabolism, environmental adaptation, and neurodegenerative diseases, were significantly enriched in the hibernation group, while 12 pathways, including carbohydrate metabolism, replication and repair, translation, and transcription, were significantly enriched in the control group. It can be seen that during hibernation, the gut microbiota of the wild chipmunk changes towards taxa that are beneficial for reducing carbohydrate consumption, increasing fat consumption, and adapting more strongly to environmental changes in order to better provide energy for the body and ensure normal life activities during hibernation.

Wuliangye strong aroma baijiu promotes intestinal homeostasis by improving gut microbiota and regulating intestinal stem cell proliferation and differentiation.

Wuliangye strong aroma baijiu (hereafter, Wuliangye baijiu) is a traditional Chinese grain liquor containing short-chain fatty acids, ethyl caproate, ethyl lactate, other trace components, and a large proportion of ethanol. The effects of Wuliangye baijiu on intestinal stem cells and intestinal epithelial development have not been elucidated. Here, the role of Wuliangye baijiu in intestinal epithelial regeneration and gut microbiota modulation was investigated by administering a Lieber-DeCarli chronic ethanol liquid diet in a mouse model to mimic long-term (8 weeks') light/moderate alcohol consumption (1.6 g kg-1 day-1) in healthy human adults. Wuliangye baijiu promoted colonic crypt proliferation in mice. According to immunofluorescence and reverse transcription-quantitative polymerase chain reaction analyses, compared with the ethanol-only treatment, Wuliangye baijiu increased the number of intestinal stem cells and goblet cells and the expression of enteroendocrine cell differentiation markers in the mouse colon. Furthermore, gut microbiota analysis showed an increase in the relative abundance of microbiota related to intestinal homeostasis following Wuliangye baijiu administration. Notably, increased abundance of Bacteroidota, Faecalibaculum, Lachnospiraceae, and Blautia may play an essential role in promoting stem-cell-mediated intestinal epithelial development and maintaining intestinal homeostasis. In summary, these findings suggest that Wuliangye baijiu can be used to regulate intestinal stem cell proliferation and differentiation in mice and to alter gut microbiota distributions, thereby promoting intestinal homeostasis. This research elucidates the mechanism by which Wuliangye baijiu promotes intestinal health. © 2024 Society of Chemical Industry.

Earthworm, Perionyx excavatus as an alternate protein source for Nile tilapia: Effects on growth performance, blood biochemistry, erythrocyte morphology and intestinal health

AbstractRecently, an increasing disparity has emerged in the need for raw fish meal (FM) and its supply, along with the environmental and financial obstacles associated with its use. Therefore, increasing and elevating the diversity of alternative protein sources for aquaculture nutrition is imperative. The study investigated the impact of substituting FM protein with EW meal on the growth, haemato-biochemical response and intestinal histomorphology of Nile tilapia. Up to 20% fishmeal replacement with EW meal had no adverse effects on fish growth performance. A quadratic analysis of the final body weight and EW meal level indicated the best growth performance at 17.5% replacement. Fish fed the 40% replacement level had significantly decreased height and width of intestinal folds and number of mucosal goblet cells compared to the control. Although red and white blood cell counts were found unchanged between the control, the 10% and 20% replacement groups, a significantly higher number of white blood cells and a lower number of red blood cells were found in the 40% group compared to the control. Blood glucose level was the highest, while haemoglobin level was the lowest in the 40% group. In the same group, significantly higher frequencies of erythrocyte cellular and nuclear abnormalities were noted. Lipid droplet accumulation in the liver was significantly higher in the 40% group, whilst the 10% and 20% groups showed no significant difference compared to the control.

Integrated Mechanism of Immune Response Modulation by Arctium Lappa L. Fructans Based on Microbiome and Metabolomics Technologies.

Arctium lappa L. is widely consumed for its various biological effects, and polysaccharides are its main functional components. The present study aimed to evaluate the immunoregulatory effects of the main polysaccharides from burdock (ALP-1) and reveal the underlying mechanisms. ALP-1 consisted of fructose and glucose (14.57:1) and had a molecular weight of 2757 Da, with typical characteristics of (1 → 2)-linked linear fructans. Oral intake of ALP-1 significantly increased the number of colonic goblet cells, serum immunoglobulin A and immunoglobulin G levels, and fecal secretory immunoglobulin A content as well as up-regulated antioxidant enzymes and increased short chain fatty acid production. In addition, ALP-1 administration regulated pro/anti-inflammatory cytokines (i.e., interleukin (IL)-1β, IL-6, tumor necrosis factor-α, interferon-γ, and IL-10), intestinal microbiota structure, and the spatial information on key metabolites. Some gut-microbiota-mediated metabolic processes were also significantly altered. These results indicated that ALP-1 could exert beneficial effects on immune responses and intestinal health in healthy mice.

Combination of PEGylation and Cationization on Phospholipid-Coated Cyclosporine Nanosuspensions for Enhanced Ocular Drug Delivery.

Strong precorneal clearance mechanisms including reflex blink, constant tear drainage, and rapid mucus turnover constitute great challenges for eye drops for effective drug delivery to the ocular epithelium. In this study, cyclosporine A (CsA) for the treatment of dry eye disease (DED) was selected as the model drug. Two strategies, PEGylation for mucus penetration and cationization for potent cellular uptake, were combined to construct a novel CsA nanosuspension (NS@lipid-PEG/CKC) by coating nanoscale drug particles with a mixture of lipids, DSPE-PEG2000, and a cationic surfactant, cetalkonium chloride (CKC). NS@lipid-PEG/CKC with the mean size ∼173 nm and positive zeta potential ∼+40 mV showed promoted mucus penetration, good cytocompatibility, more cellular uptake, and prolonged precorneal retention without obvious ocular irritation. More importantly, NS@lipid-PEG/CKC recovered tear production and goblet cell density more efficiently than the commercial cationic nanoemulsion on a dry eye disease rat model. All results indicated that a combination of PEGylation and cationization might provide a promising strategy to coordinate mucus penetration and cellular uptake for enhanced drug delivery to the ocular epithelium for nanomedicine-based eye drops.

A Novel Protein Sourced from Chinese Medicine Residue for Golden Pompano Feed: Endothelium Corneum Gigeriae Galli Residue (ECGGR)

Fishmeal is an important protein source in aquafeed. However, due to the limited natural resources, fishmeal is in short supply, resulting in a price surge for fishmeal. Here, we reported a kind of Chinese medicine residue, endothelium corneum gigeriae galli residue (ECGGR), as a fishmeal substitute in the diets of Trachinotus ovatus. Six isonitrogenous and isolipidic diets were formulated, substituting fishmeal at 0%, 6.25%, 12.5%, 18.75%, 25%, and 31.25%. There was no significant difference in the growth performance when the fishmeal substitution level was no more than 25%. The smallest FCR was obtained at the 18.75% substitution level. Furthermore, substituting ECGGR for fishmeal had no effect on whole-body and muscle proximate compositions, except when the replacement level exceeded 25%, which led to a decrease in whole-body moisture and an increase in whole-body crude protein. The contents of Gly, Cys, Ile, Tyr, Pro, and EAAs/TAAs were altered as the substitution level varied. However, dietary replacement of fishmeal with ECGGR did not degrade muscle protein quality, according to a nutritional evaluation of muscle essential amino acid composition. In terms of hepatic antioxidant capacity, neither the overall antioxidant status nor the expression of genes in the Nrf2-ARE pathway was altered by dietary ECGGR. Moreover, the expressions of p65, TNF-α, and IL-8 in the intestine were upregulated at the 31.25% substitution level. Also, more goblet cells were observed in the intestine at substitution levels of 25% and 31.25%. In conclusion, ECGGR can substitute for fishmeal at the optimal level of 18.75% without adversely affecting the growth performance, protein quality, or hepatic and intestinal health of golden pompano.

Histological features of the gastrointestinal tract of elongate tigerfish, Hydrocynus forskahlii (Cuvier, 1819), from Lake Albert

BackgroundThe tigerfish (Hydrocynus forskahlii) is an important food fish in different regions of Africa. As such, interest in its performance and nutritional requirements as a potential candidate for aquaculture is increasing. Characterization of the morpho-histological features and functions of the gut provides valuable insights into the feeding physiology and digestive system of fish species.ResultAn investigation of the morpho-histological features of the gastrointestinal tract of H. forskahlii captured from Lake Albert was conducted over an eight-month period. The digestive tract of H. forskahlii is characterised by a short oesophagus, well-developed and distensible stomach and moderately long intestine. The oesophagus had a higher abundance of mucous-secreting goblet cells compared to other digestive tract tissues. The stomach had a bag-like shape for swallowing large prey and was distinguishable into the cardiac, fundic and pyloric regions. Both the cardiac and fundic regions of the stomach had numerous gastric glands, whereas the pyloric region had large compound folds consisting of pseudo-stratified columnar epithelium. Many goblet cells were also observed in the mid and posterior regions of the intestine. The relative length of the gut of the H. forskahlii was 1.27 ± 0.03 cm, and it had a total of 20–22 pyloric caeca. The liver was observed to be divided in lobules by a central vein contained within connective sheets. Irregular cords of hepatocytes were also visible throughout the parenchyma.ConclusionsThe histological features of the H. forskahlii gut observed in the present study are consistent with those of carnivorous and omnivorous fish.

Developmental events in the mandibular salivary gland of Indian sheep (Ovis aries): Morphological and histochemical studies.

At 22nd day of fetal development, the primordial anlage of mandibular gland was first noticed as a solid epithelial bud from oral epithelium. The terminal buds were arranged in the form of clusters with undifferentiated epithelial cells and terminated in a bulb like structure in 28-day-old fetus. The lumenization and branching of the main cord was noticed at 35th day. The primary septa, which divide the glandular mass into lobes was observed from 53rd day onwards which resulted in the formation of distinct lobulation at 58th day. At 61st day, the capsule formation was initiated by the aggregation of mesenchymal tissue. The terminal tubules differentiated to form the secretory end pieces and the tubular portion leads to the formation of intercalated and striated ducts at 98th day. Predominantly mucous types of acinar cells were seen from 108th day onwards. The number of lobules increased with steep increase in parenchyma from 128th day onwards. Micrometrical studies revealed that the mean diameter of acinar cells and all ducts was increased with the advancement of age and the significant differences were observed between groups. Localization of acidic and neutral mucopolysaccharides was observed in mucous cells and goblet cells. RESEARCH HIGHLIGHTS: The primordial anlage of mandibular salivary gland was seen at 22nd day. Lobulation of gland was appeared at 53rd day of development, however; it was completed at 58th day. At 98th day, the terminal tubules differentiated to form the secretory end pieces. The parenchyma of the gland showed predominantly mucous type of cells from 108th day onwards. Myoepithelial cells were first appeared as flattened basal cells initially around the developing acinar cells at 132nd day. Localization of acidic as well as neutral mucopolysaccharides was observed in mucous cells and goblet cells. Fine lipid droplets were observed in intralobular as well as interlobular connective tissue, however; phospholipids were observed in the cell membrane of secretory cells and ducts.

A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma

By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Advantages of pulsed electric field ablation for COPD: Excellent killing effect on goblet cells

Mucus hypersecretion resulting from excessive proliferation and metaplasia of goblet cells in the airways is the pathological foundation for Chronic obstructive pulmonary disease (COPD). Clinical trials have confirmed the clinical efficacy of pulsed electric field ablation (PFA) for COPD, but its underlying mechanisms is poorly understood. Cellular and animal models of COPD (rich in goblet cells) were established in this study to detect goblet cells’ sensitivity to PFA. Schwan’s equation was adopted to calculate the cells’ transmembrane potential and the electroporation areas in the cell membrane. We found that goblet cells are more sensitive to low-intensity PFA (250 V/cm-500 V/cm) than BEAS-2B cells. It is attributed to the larger size of goblet cells, which allows a stronger transmembrane potential formation under the same electric field strength. Additionally, the transmembrane potential of larger-sized cells can reach the cell membrane electroporation threshold in more areas. Trypan blue staining confirmed that the cells underwent IRE rate was higher in goblet cells than in BEAS-2B cells. Animal experiments also confirmed that the airway epithelium of COPD is more sensitive to PFA. We conclude that lower-intensity PFA can selectively kill goblet cells in the COPD airway epithelium, ultimately achieving the therapeutic effect of treating COPD.

Salivary Gland Tissue Recombination Can Modify Cell Fate.

Although mesenchyme is essential for inducing the epithelium of ectodermal organs, its precise role in organ-specific epithelial fate determination remains poorly understood. To elucidate the roles of tissue interactions in cellular differentiation, we performed single-cell RNA sequencing and imaging analyses on recombined tissues, where mesenchyme and epithelium were switched ex vivo between two types of embryonic mouse salivary glands: the parotid gland (a serous gland) and the submandibular gland (a predominantly mucous gland). We found partial induction of molecules that define gland-specific acinar and myoepithelial cells in recombined salivary epithelium. The parotid epithelium recombined with submandibular mesenchyme began to express mucous acinar genes not intrinsic to the parotid gland. While myoepithelial cells do not normally line parotid acini, newly induced myoepithelial cells densely populated recombined parotid acini. However, mucous acinar and myoepithelial markers continued to be expressed in submandibular epithelial cells recombined with parotid mesenchyme. Consequently, some epithelial cells appeared to be plastic, such that their fate could still be modified in response to mesenchymal signaling, whereas other epithelial cells appeared to be already committed to a specific fate. We also discovered evidence for bidirectional induction: transcriptional changes were observed not only in the epithelium but also in the mesenchyme after heterotypic tissue recombination. For example, parotid epithelium induced the expression of muscle-related genes in submandibular fibroblasts that began to mimic parotid fibroblast gene expression. These studies provide the first comprehensive unbiased molecular characterization of tissue recombination approaches exploring the regulation of cell fate.

Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function.

Numerous biological interventions and small molecules are used to treat Crohn's disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn's disease. The aim of this study was to elucidate the expression of precursor and mature IL-18 in patients with Crohn's disease who exhibited varied responses to cytokine-targeted treatments and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expression of precursor and mature IL-18 was analyzed in patients with Crohn's disease. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in an acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. Precursor and mature IL-18 expression was upregulated and goblet cell function was impaired in patients with Crohn's disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. The newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn's disease.

The immune interactions of gut glycans and microbiota in health and disease.

The human digestive system harbors a vast diversity of commensal bacteria and maintains a symbiotic relationship with them. However, imbalances in the gut microbiota accompany various diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancers (CRCs), which significantly impact the well-being of populations globally. Glycosylation of the mucus layer is a crucial factor that plays a critical role in maintaining the homeostatic environment in the gut. This review delves into how the gut microbiota, immune cells, and gut mucus layer work together to establish a balanced gut environment. Specifically, the role of glycosylation in regulating immune cell responses and mucus metabolism in this process is examined.

CXCR2, as a key regulatory gene of HDP-PG-1, maintains intestinal mucosal homeostasis

The intestine defends against pathogenic microbial invasion via the secretion of host defense peptides (HDPs). Nutritional immunomodulation can stimulate the expression of endogenous HDPs and enhance the body's immune defense, representing a novel non-antibiotic strategy for disease prevention. The project aims to explore the regulatory mechanism of protegrin-1 (PG-1) expression using sodium phenylbutyrate (PBA) by omics sequencing technology and further investigate the role of key regulatory genes on intestinal health. The results showed that PBA promoted PG-1 expression in intestinal epithelial cells based on cell density through epidermal growth factor receptor (EGFR) and G protein-coupled receptor (GPR43). Transcriptome sequencing and microRNA sequencing revealed that C-X-C motif chemokine receptor 2 (CXCR2) exhibited interactions with PG-1. Pre-treatment cells with a CXCR2 inhibitor (SB225002) effectively suppressed the induction of PG-1 by PBA. Furthermore, SB225002 significantly suppressed the gene expression of HDPs in the jejunum of mice without influencing on the morphology, number of goblet cells, and proliferation of the intestine. CXCR2 inhibition significantly reduced the expression of HDPs during E. coli infection, and resulted in the edema of jejunal epithelial cells. The 16S rDNA analysis of cecal contents showed that the E. coli and SB225002 treatments changed gut microbiota diversity and composition at different taxonomic levels. Correlation analysis suggested a potential regulatory relationship between gut microbiota and HDPs. To that end, a gene involved in the HDP expression, CXCR2, has been identified in the study, which contributes to improving intestinal immune function. PBA may be used as a functional additive to regulate intestinal mucosal function, thereby enhancing the health of the intestinal and host.

Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats.

Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal sensitivity. The impact of diabetes on the lacrimal functional unit (LFU) and the structures responsible for maintaining tear homeostasis, is not completely known. It has been shown that the Opioid Growth Factor Receptor (OGFr), and its ligand, Opioid Growth Factor (OGF), is dysregulated in the ocular surface of diabetic rats leading to overproduction of the inhibitory growth peptide OGF. The opioid antagonist naltrexone hydrochloride (NTX) blocks the OGF-OGFr pathway, and complete blockade following systemic or topical treatment with NTX restores the rate of re-epithelialization of corneal epithelial wounds, normalizes corneal sensitivity, and reverses dry eye in diabetic animal models. These effects occur rapidly and within days of initiating treatment. The present study was designed to understand mechanisms related to the fast reversal (<5 days) of dry eye by NTX in type 1 diabetes (T1D) by investigating dysregulation of the LFU. The approach involved examination of the morphology of the LFU before and after NTX treatment. Male and female adult Sprague-Dawley rats were rendered hyperglycemic with streptozotocin, and after 6 weeks rats were considered to be a T1D model. Rats received topical NTX twice daily to one eye for 10 days. During the period of treatment, tear production and corneal sensitivity were recorded. On day 11, animals were euthanized and orbital tissues including conjunctiva, eyelids, and lacrimal glands, were removed and processed for histologic examination including immunohistochemistry. Male and female T1D rats had significantly decreased tear production and corneal insensitivity, significantly decreased number and size of lacrimal gland acini, decreased expression of aquaporin-5 (AQP5) protein and decreased goblet cell size. Thus, 10 days of NTX treatment restored tear production and corneal sensitivity to normal values, increased AQP5 expression, and restored the surface area of goblet cells to normal. NTX had no effect on the number of lacrimal gland acini or the number of conjunctival goblet cells. In summary, blockade of the OGF-OGFr pathway with NTX reversed corneal and lacrimal gland complications and restored some components of tear homeostasis confirming the efficacy of topical NTX as a treatment for ocular defects in diabetes.