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1.
PLoS One ; 19(6): e0304686, 2024.
Article in English | MEDLINE | ID: mdl-38837998

ABSTRACT

Microplastics, which are tiny plastic particles less than 5 mm in diameter, are widely present in the environment, have become a serious threat to aquatic life and human health, potentially causing ecosystem disorders and health problems. The present study aimed to investigate the effects of microplastics, specifically microplastics-polystyrene (MPs-PS), on the structural integrity, gene expression related to tight junctions, and gut microbiota in mice. A total of 24 Kunming mice aged 30 days were randomly assigned into four groups: control male (CM), control female (CF), PS-exposed male (PSM), and PS-exposed female (PSF)(n = 6). There were significant differences in villus height, width, intestinal surface area, and villus height to crypt depth ratio (V/C) between the PS group and the control group(C) (p <0.05). Gene expression analysis demonstrated the downregulation of Claudin-1, Claudin-2, Claudin-15, and Occludin, in both duodenum and jejunum of the PS group (p < 0.05). Analysis of microbial species using 16S rRNA sequencing indicated decreased diversity in the PSF group, as well as reduced diversity in the PSM group at various taxonomic levels. Beta diversity analysis showed a significant difference in gut microbiota distribution between the PS-exposed and C groups (R2 = 0.113, p<0.01), with this difference being more pronounced among females exposed to MPs-PS. KEGG analysis revealed enrichment of differential microbiota mainly involved in seven signaling pathways, such as nucleotide metabolism(p<0.05). The relative abundance ratio of transcriptional pathways was significantly increased for the PSF group (p<0.01), while excretory system pathways were for PSM group(p<0.05). Overall findings suggest that MPs-PS exhibit a notable sex-dependent impact on mouse gut microbiota, with a stronger effect observed among females; reduced expression of tight junction genes may be associated with dysbiosis, particularly elevated levels of Prevotellaceae.


Subject(s)
Gastrointestinal Microbiome , Microplastics , Polystyrenes , Tight Junctions , Animals , Gastrointestinal Microbiome/drug effects , Microplastics/toxicity , Polystyrenes/toxicity , Mice , Male , Female , Tight Junctions/drug effects , Tight Junctions/metabolism , RNA, Ribosomal, 16S/genetics , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Occludin/metabolism , Occludin/genetics , Claudins/genetics , Claudins/metabolism , Claudin-1/genetics , Claudin-1/metabolism , Tight Junction Proteins/metabolism , Tight Junction Proteins/genetics
2.
Food Funct ; 15(13): 6943-6954, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38855989

ABSTRACT

Growing evidence showed the capacity of (poly)phenols to exert a protective role on intestinal health. Nevertheless, the existing findings are still heterogeneous and the underlying mechanisms remain unclear. This study investigated the potential benefits of a red raspberry (Rubus idaeus) powder on the integrity of the intestinal barrier, focusing on its ability to mitigate the effects of tumor necrosis factor-α (TNF-α)-induced intestinal permeability. Human colorectal adenocarcinoma cells (i.e., Caco-2 cells) were used as a model to assess the impact of red raspberry on intestinal permeability, tight junction expression, and oxidative stress. The Caco-2 cells were differentiated into polarized monolayers and treated with interferon-γ (IFN-γ) (10 ng mL-1) for 24 hours, followed by exposure to TNF-α (10 ng mL-1) in the presence or absence of red raspberry extract (1-5 mg mL-1). The integrity of the intestinal monolayer was evaluated using transepithelial electrical resistance (TEER) and fluorescein isothiocyanate-dextran (FITC-D) efflux assay. Markers of intestinal permeability (claudin-1, occludin, and zonula occludens-1 (ZO-1)) and oxidative stress (8-hydroxy-2-deoxyguanosine (8-OHdG) and protein carbonyl) were assessed using ELISA kits. Treatment with red raspberry resulted in a significant counteraction of TEER value loss (41%; p < 0.01) and a notable reduction in the efflux of FITC-D (-2.5 times; p < 0.01). Additionally, red raspberry attenuated the levels of 8-OHdG (-48.8%; p < 0.01), mitigating the detrimental effects induced by TNF-α. Moreover, red raspberry positively influenced the expression of the integral membrane protein claudin-1 (+18%; p < 0.01), an essential component of tight junctions. These findings contribute to the growing understanding of the beneficial effects of red raspberry in the context of the intestinal barrier. The effect of red raspberry against TNF-α-induced intestinal permeability observed in our in vitro model suggests, for the first time, its potential as a dietary strategy to promote gastrointestinal health.


Subject(s)
Intestinal Mucosa , Oxidative Stress , Permeability , Plant Extracts , Rubus , Tight Junctions , Tumor Necrosis Factor-alpha , Humans , Rubus/chemistry , Caco-2 Cells , Oxidative Stress/drug effects , Tumor Necrosis Factor-alpha/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Plant Extracts/pharmacology , Permeability/drug effects , Tight Junctions/drug effects , Tight Junctions/metabolism , Occludin/metabolism , Occludin/genetics , Claudin-1/metabolism , Claudin-1/genetics , Zonula Occludens-1 Protein/metabolism , Zonula Occludens-1 Protein/genetics , Interferon-gamma/metabolism , Fruit/chemistry
3.
Aging (Albany NY) ; 16(10): 8472-8483, 2024 05 26.
Article in English | MEDLINE | ID: mdl-38809424

ABSTRACT

OBJECTIVE: To investigate the role of the EGFR/MAPK signaling pathway in PM2.5 in promoting the MUC5AC hypersecretion in airway and exacerbating airway inflammation. METHODS: By establishing rat model exposed to PM2.5, overexpressing miR-133b-5p and Claudin1, the content of IL-1 and TNF-α in serum were detected by ELISA, the pathology of lung tissue was observed by HE staining, p-EGFR, Claudin1, MUC5AC, p-ERK1/2, p-JNK, p-p38 in rats lung tissue were detected by immunohistochemical and WB, the expression level of miR-133b-5p in rats lung tissue were detected by qPCR. RESULTS: After the rats were exposed to PM2.5, the content of inflammatory factors in serum increased, the inflammatory damage of lung tissues occurred, the expression of miR-133b-5p was down-regulated, and the expression of MUC5AC protein was increased. The ELISA test results showed that the expression of IL-1 and TNF-α in the model group was significantly higher than that in the control group, and the model +AG1478 treatment group was down-regulated compared with the model group, and the +miR-133b-5p agomir treatment group was significantly lower than that in the control group, the model group and the model +Claudin1 overexpression blank load group, and the model +Claudin1 overexpression group was down-regulated compared with the model group and the model +Claudin1 overexpression blank load group. The protein detection results showed that the expression of p-EGFR, MUC5AC, p-ERK1/2, p-JNK and p-p38 proteins was increased and the expression of Claudin1 protein was decreased in the model group compared with the control group. In the model + AG1478 treatment group, model + miR-133b-5p agomir treatment group and model + Claudin1 overexpression group, compared with the model group, p-EGFR, MUC5AC, p-ERK1/2, p-JNK, p-p38 protein expression was down-regulated, and Claudin1 protein expression was up-regulated. CONCLUSIONS: PM2.5 inhibited the expression of miR-133b-5p to activate the EGFR/MAPK signal pathway, induce the hypersecretion of MUC5AC, thus aggravating PM2.5-related airway inflammation in rats.


Subject(s)
Claudin-1 , ErbB Receptors , MicroRNAs , Mucin 5AC , Particulate Matter , Animals , MicroRNAs/metabolism , MicroRNAs/genetics , Mucin 5AC/metabolism , Mucin 5AC/genetics , Rats , ErbB Receptors/metabolism , ErbB Receptors/genetics , Particulate Matter/toxicity , Claudin-1/metabolism , Claudin-1/genetics , Male , Rats, Sprague-Dawley , Lung/metabolism , Lung/pathology , Mucus/metabolism , Signal Transduction , Tumor Necrosis Factor-alpha/metabolism , MAP Kinase Signaling System
4.
Int J Biochem Cell Biol ; 172: 106587, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38740281

ABSTRACT

Bronchopulmonary dysplasia (BPD) remains a significant challenge in neonatal care, the pathogenesis of which potentially involves altered lipid metabolism. Given the critical role of lipids in lung development and the injury response, we hypothesized that specific lipid species could serve as therapeutic agents in BPD. This study aimed to investigate the role of the lipid Phosphatidylcholine (PC) (16:0/14:0) in modulating BPD pathology and to elucidate its underlying mechanisms of action. Our approach integrated in vitro and in vivo methodologies to assess the effects of PC (16:0/14:0) on the histopathology, cellular proliferation, apoptosis, and molecular markers in lung tissue. In a hyperoxia-induced BPD rat model, we observed a reduction in alveolar number and an enlargement in alveolar size, which were ameliorated by PC (16:0/14:0) treatment. Correspondingly, in BPD cell models, PC (16:0/14:0) intervention led to increased cell viability, enhanced proliferation, reduced apoptosis, and elevated surfactant protein C (SPC) expression. RNA sequencing revealed significant gene expression differences between BPD and PC (16:0/14:0) treated groups, with a particular focus on Cldn1 (encoding claudin 1), which was significantly enriched in our analysis. Our findings suggest that PC (16:0/14:0) might protect against hyperoxia-induced alveolar type II cell damage by upregulating CLDN1 expression, potentially serving as a novel therapeutic target for BPD. This study not only advances our understanding of the role of lipids in BPD pathogenesis, but also highlights the significance of PC (16:0/14:0) in the prevention and treatment of BPD, offering new avenues for future research and therapeutic development.


Subject(s)
Alveolar Epithelial Cells , Bronchopulmonary Dysplasia , Claudin-1 , Hyperoxia , Phosphatidylcholines , Up-Regulation , Animals , Bronchopulmonary Dysplasia/metabolism , Bronchopulmonary Dysplasia/pathology , Bronchopulmonary Dysplasia/etiology , Hyperoxia/metabolism , Hyperoxia/complications , Hyperoxia/pathology , Rats , Claudin-1/metabolism , Claudin-1/genetics , Phosphatidylcholines/metabolism , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Rats, Sprague-Dawley , Apoptosis , Cell Proliferation , Humans , Pulmonary Alveoli/pathology , Pulmonary Alveoli/metabolism , Animals, Newborn , Disease Models, Animal
5.
Zhen Ci Yan Jiu ; 49(5): 472-479, 2024 May 25.
Article in English, Chinese | MEDLINE | ID: mdl-38764118

ABSTRACT

OBJECTIVES: To investigate the effect of Peitu Yimu(strengthening spleen and soothing liver) acupuncture on intestinal mucosal barrier function and corticotropin-releasing factor (CRF)/CRF receptor 1 (CRFR1) pathway in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), so as to explore its underlying mechanism in alleviating IBS-D. METHODS: Forty female SD rats were randomly divided into blank, model, electroacupuncture (EA), and agonist groups, with 10 rats in each group. Except for the blank group, rats in the other groups were given folium sennae infusion by gavage combined with chronic unpredictable mild stress to establish IBS-D model. Rats in the EA group received acupuncture at "Tianshu"(ST25) and EA at "Zusanli"(ST36) and "Taichong"(LR3) (2 Hz/15 Hz) on one side for 20 min, with the side chosen alternately every other day, for 14 days after modeling. Rats in the agonist group received acupuncture 30 min after intravenous injection of CRFR1 agonist urocortin, with the same manipulation method and time as the EA group. Before and after intervention, visceral pain threshold and stool Bristol scores were measured. Elevated plus maze test and open field test were used to detect anxiety and depression like behavior of rats. ELISA was used to detect the contents of CRF and CRFR1 in rats serum. Immunohistochemistry was used to detect the positive expressions of CRF, CRFR1, zonula occludens protein 1(ZO-1), occlusal protein(Occludin), and closure protein 1 (Claudin-1) in colon tissue. RESULTS: Compared with the blank group, the visceral pain threshold, open arm time percentage (OT%), total distance of movement in the open field test, and positive expression of ZO-1, Occludin, and Claudin-1 in colon were decreased (P<0.01, P<0.05), while Bristol stool scores, serum CRF and CRFR1 contents, and positive expressions of CRF and CRFR1 in colon were increased (P<0.01) in the model group. After intervention and compared with the model group, the visceral pain threshold, OT%, total distance of movement in the open field test, and positive expressions of ZO-1, Occludin, and Claudin-1 in colon were increased (P<0.05, P<0.01), while Bristol stool scores, serum CRF and CRFR1 contents, and positive expressions of CRF and CRFR1 in colon were decreased (P<0.01) in the EA group;the Bristol stool scores, serum CRF content, and CRF positive expression in colon were significantly decreased in the agonist group (P<0.01). CONCLUSIONS: Peitu Yimu acupuncture can significantly improve visceral hypersensitivity and anxiety-depression state in IBS-D rats. Its mechanism may be related to the inhibition of CRF/CRFR1 pathway and restoration of intestinal tight junction protein expressions.


Subject(s)
Acupuncture Therapy , Diarrhea , Intestinal Mucosa , Irritable Bowel Syndrome , Receptors, Corticotropin-Releasing Hormone , Animals , Female , Humans , Rats , Acupuncture Points , Claudin-1/metabolism , Claudin-1/genetics , Corticotropin-Releasing Hormone/metabolism , Corticotropin-Releasing Hormone/genetics , Diarrhea/therapy , Diarrhea/metabolism , Diarrhea/genetics , Disease Models, Animal , Intestinal Mucosa/metabolism , Irritable Bowel Syndrome/therapy , Irritable Bowel Syndrome/metabolism , Irritable Bowel Syndrome/genetics , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/metabolism , Receptors, Corticotropin-Releasing Hormone/genetics , Zonula Occludens-1 Protein/metabolism , Zonula Occludens-1 Protein/genetics
6.
Exp Dermatol ; 33(5): e15084, 2024 May.
Article in English | MEDLINE | ID: mdl-38711223

ABSTRACT

The transmembrane protein claudin-1 is critical for formation of the epidermal barrier structure called tight junctions (TJ) and has been shown to be important in multiple disease states. These include neonatal ichthyosis and sclerosing cholangitis syndrome, atopic dermatitis and various viral infections. To develop a model to investigate the role of claudin-1 in different disease settings, we used CRISPR/Cas9 to generate human immortalized keratinocyte (KC) lines lacking claudin-1 (CLDN1 KO). We then determined whether loss of claudin-1 expression affects epidermal barrier formation/function and KC differentiation/stratification. The absence of claudin-1 resulted in significantly reduced barrier function in both monolayer and organotypic cultures. CLDN1 KO cells demonstrated decreases in gene transcripts encoding the barrier protein filaggrin and the differentiation marker cytokeratin-10. Marked morphological differences were also observed in CLDN1 KO organotypic cultures including diminished stratification and reduced formation of the stratum granulosum. We also detected increased proliferative KC in the basale layer of CLDN1 KO organotypic cultures. These results further support the role of claudin-1 in epidermal barrier and suggest an additional role of this protein in appropriate stratification of the epidermis.


Subject(s)
Cell Differentiation , Claudin-1 , Epidermis , Filaggrin Proteins , Keratinocytes , Keratinocytes/metabolism , Claudin-1/metabolism , Claudin-1/genetics , Humans , Filaggrin Proteins/metabolism , Epidermis/metabolism , Epidermis/pathology , Skin Diseases/genetics , Skin Diseases/metabolism , Tight Junctions/metabolism , Keratin-10/metabolism , Keratin-10/genetics , Gene Knockout Techniques , Cell Proliferation , CRISPR-Cas Systems
7.
Food Res Int ; 187: 114343, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38763636

ABSTRACT

Human breast milk promotes maturation of the infant gastrointestinal barrier, including the promotion of mucus production. In the quest to produce next generation infant milk formula (IMF), we have produced IMF by membrane filtration (MEM-IMF). With a higher quantity of native whey protein, MEM-IMF more closely mimics human breast milk than IMF produced using conventional heat treatment (HT-IMF). After a 4-week dietary intervention in young pigs, animals fed a MEM-IMF diet had a higher number of goblet cells, acidic mucus and mucin-2 in the jejunum compared to pigs fed HT-IMF (P < 0.05). In the duodenum, MEM-IMF fed pigs had increased trypsin activity in the gut lumen, increased mRNA transcript levels of claudin 1 in the mucosal scrapings and increased lactase activity in brush border membrane vesicles than those pigs fed HT-IMF (P < 0.05). In conclusion, MEM-IMF is superior to HT-IMF in the promotion of mucus production in the young gut.


Subject(s)
Filtration , Infant Formula , Mucus , Animals , Infant Formula/chemistry , Mucus/metabolism , Swine , Whey Proteins/metabolism , Intestine, Small/metabolism , Trypsin/metabolism , Humans , Goblet Cells/metabolism , Claudin-1/metabolism , Claudin-1/genetics , Lactase/metabolism , Lactase/genetics , Mucin-2/metabolism , Mucin-2/genetics , Intestinal Mucosa/metabolism , Duodenum/metabolism , Jejunum/metabolism , RNA, Messenger/metabolism , RNA, Messenger/genetics , Milk Proteins/metabolism , Milk Proteins/analysis
8.
Clin Exp Nephrol ; 28(7): 599-607, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38587753

ABSTRACT

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.


Subject(s)
Albuminuria , Claudin-1 , Diabetic Nephropathies , Epigenesis, Genetic , NAD , Sirtuin 1 , Tissue Inhibitor of Metalloproteinase-1 , Animals , Humans , Albuminuria/genetics , Claudin-1/genetics , Claudin-1/metabolism , Cytokines/metabolism , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Fibrosis , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/drug effects , Mice, Inbred C57BL , Mice, Knockout , NAD/metabolism , Nicotinamide Mononucleotide/pharmacology , Nicotinamide Phosphoribosyltransferase/genetics , Nicotinamide Phosphoribosyltransferase/metabolism , Podocytes/metabolism , Sirtuin 1/metabolism , Sirtuin 1/genetics , Sirtuins/genetics , Sirtuins/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolism , Tissue Inhibitor of Metalloproteinase-1/genetics
9.
Int J Mol Sci ; 25(8)2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38674155

ABSTRACT

Different levels of EspP2 expression are seen in strains of Glaesserella parasuis with high and low pathogenicity. As a potential virulence factor for G. parasuis, the pathogenic mechanism of EspP2 in infection of host cells is not clear. To begin to elucidate the effect of EspP2 on virulence, we used G. parasuis SC1401 in its wild-type form and SC1401, which was made EspP2-deficient. We demonstrated that EspP2 causes up-regulation of claudin-1 and occludin expression, thereby promoting the adhesion of G. parasuis to host cells; EspP2-deficiency resulted in significantly reduced adhesion of G. parasuis to cells. Transcriptome sequencing analysis of EspP2-treated PK15 cells revealed that the Rap1 signaling pathway is stimulated by EspP2. Blocking this pathway diminished occludin expression and adhesion. These results indicated that EspP2 regulates the adhesion of Glaesserella parasuis via Rap1 signaling pathway.


Subject(s)
Haemophilus parasuis , Signal Transduction , rap1 GTP-Binding Proteins , Animals , Haemophilus parasuis/pathogenicity , Haemophilus parasuis/genetics , rap1 GTP-Binding Proteins/metabolism , rap1 GTP-Binding Proteins/genetics , Bacterial Adhesion , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Occludin/metabolism , Occludin/genetics , Claudin-1/metabolism , Claudin-1/genetics , Cell Line , Swine
10.
J Sci Food Agric ; 104(10): 6262-6275, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-38466088

ABSTRACT

BACKGROUND: Early weaning is prone to damage intestinal barrier function, resulting in diarrhea, whereas rutin, as a natural flavonoid with multiple biological functions, shows potential in piglets. Therefore, the effects of dietary rutin on growth, antidiarrheal, barrier function, antioxidant status and cecal microbiota of weaned piglets were investigated with the control group (CON) (basal diet) and Rutin (basal diet+500 mg kg-1 rutin) groups fed for 14 days. RESULTS: The results showed that dietary 500 mg kg-1 rutin significantly decreased diarrhea index, serum diamine oxidase activity and total aerobic bacterial population in mesenteric lymph nodes, whereas it significantly increased the gain-to-feed ratio (G:F) and serum growth hormone content, jejunal villus height and villus height to crypt depth ratio, and also enhanced jejunal claudin-1 and zonula occludens-1 mRNA and protein expression. Meanwhile, dietary rutin significantly decreased inflammation-associated mRNA expression, malondialdehyde (MDA) content, swollen mitochondrial number and mitochondrial area in the jejunum, whereas it increased the total superoxide dismutase (T-SOD) and glutathione peroxidase activities and activated the Nrf2 signaling pathway. Moreover, dietary rutin significantly increased Firmicutes abundance and decreased Campylobacterota abundance, which were closely associated with the decreased diarrhea index and MDA content or increased Claudin-1 expression and T-SOD activity. CONCLUSION: Dietary 500 mg kg-1 rutin increased G:F by improving intestinal morphology, and alleviated diarrhea by enhancing intestinal barrier, which might be associated with the enhanced antioxidant capacity via activating the Nrf2/Keap1 signaling pathway and the improved cecal microbial composition in weaned piglets. © 2024 Society of Chemical Industry.


Subject(s)
Antidiarrheals , Antioxidants , Cecum , Diarrhea , Gastrointestinal Microbiome , Intestinal Mucosa , Rutin , Weaning , Animals , Swine/metabolism , Swine/growth & development , Gastrointestinal Microbiome/drug effects , Antioxidants/metabolism , Cecum/microbiology , Cecum/metabolism , Intestinal Mucosa/metabolism , Diarrhea/microbiology , Diarrhea/diet therapy , Diarrhea/veterinary , Antidiarrheals/administration & dosage , Bacteria/classification , Bacteria/isolation & purification , Bacteria/genetics , Bacteria/metabolism , Swine Diseases/microbiology , Swine Diseases/metabolism , Claudin-1/metabolism , Claudin-1/genetics , Animal Feed/analysis , Jejunum/metabolism , Jejunum/microbiology , Dietary Supplements/analysis , Male , Superoxide Dismutase/metabolism , Malondialdehyde/metabolism , Intestinal Barrier Function
11.
Biomolecules ; 14(3)2024 Feb 24.
Article in English | MEDLINE | ID: mdl-38540693

ABSTRACT

Claudins (CLDN1-CLDN24) are a family of tight junction proteins whose dysregulation has been implicated in tumorigeneses of many cancer types. In colorectal cancer (CRC), CLDN1, CLDN2, CLDN4, and CLDN18 have been shown to either be upregulated or aberrantly expressed. In the normal colon, CLDN1 and CLDN3-7 are expressed. Although a few claudins, such as CLDN6 and CLDN7, are expressed in CRC their levels are reduced compared to the normal colon. The present review outlines the expression profiles of claudin proteins in CRC and those that are potential biomarkers for prognostication.


Subject(s)
Claudins , Colorectal Neoplasms , Humans , Claudin-1/genetics , Claudins/genetics , Tight Junction Proteins , Colorectal Neoplasms/genetics
12.
Molecules ; 29(3)2024 Feb 05.
Article in English | MEDLINE | ID: mdl-38338475

ABSTRACT

The global increase in antibiotic consumption is related to increased adverse effects, such as antibiotic-associated diarrhea (AAD). This study investigated the chemical properties of Zingiber officinale Rosc (ZO) extract and its ameliorative effects using a lincomycin-induced AAD mouse model. Intestinal tissues were evaluated for the expression of lysozyme, claudin-1, and α-defensin-1, which are associated with intestinal homeostasis. The cecum was analyzed to assess the concentration of short-chain fatty acids (SCFAs). The chemical properties analysis of ZO extracts revealed the levels of total neutral sugars, acidic sugars, proteins, and polyphenols to be 86.4%, 8.8%, 4.0%, and 0.8%, respectively. Furthermore, the monosaccharide composition of ZO was determined to include glucose (97.3%) and galactose (2.7%). ZO extract administration ameliorated the impact of AAD and associated weight loss, and water intake also returned to normal. Moreover, treatment with ZO extract restored the expression levels of lysozyme, α-defensin-1, and claudin-1 to normal levels. The decreased SCFA levels due to induced AAD showed a return to normal levels. The results indicate that ZO extract improved AAD, strengthened the intestinal barrier, and normalized SCFA levels, showing that ZO extract possesses intestinal-function strengthening effects.


Subject(s)
Zingiber officinale , alpha-Defensins , Mice , Animals , Muramidase , Claudin-1/genetics , Diarrhea/chemically induced , Diarrhea/drug therapy , Anti-Bacterial Agents/adverse effects , Sugars
13.
Cancer Lett ; 586: 216611, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38309617

ABSTRACT

Pancreatic cancer (PC) is one of the most malignant and deadly tumors of digestive system with complex etiology and pathogenesis. Dysregulations of oncogenes and tumor suppressors due to epigenetic modifications causally affect tumorogenesis; however the key tumor suppressors and their regulations in PC are only partially defined. In this study, we found that Claudin-1 (encoded by CLDN1 gene) was significantly suppressed in PC that correlated with a poor clinical prognosis. Claudin-1 knockdown enhanced PC cell proliferation, migration, and stemness. Pancreatic specific Cldn1 knockout in KPC (LSLKrasG12D/Pdx1-Cre/Trp53R172H+) and KC (LSLKrasG12D/Pdx1-Cre) mice reduced mouse survival, promoted acinar-to-ductal metaplasia (ADM) process, and accelerated the development of pancreatic intraepithelial neoplasia (PanIN) and PC. Further investigation revealed that Claudin-1 suppression was mainly caused by aberrant DNA methylatransferase 1 (DNMT1) and DNMT3A elevations and the resultant CLDN1 promoter hypermethylation, as a DNMT specific inhibitor SGI-1027 effectively reversed the Claudin-1 suppression and inhibited PC progression both in vitro and in vivo in a Claudin-1 preservation-dependent manner. Together, our data suggest that Claudin-1 functions as a tumor suppressor in PC and its epigenetic suppression due to DNMT aberrations is a crucial event that promotes PC development and progression.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Animals , Mice , Carcinoma, Pancreatic Ductal/pathology , Claudin-1/genetics , Disease Progression , Pancreas/pathology , Pancreatic Neoplasms/pathology
14.
EMBO Rep ; 25(1): 144-167, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38177906

ABSTRACT

The tight junction (TJ) in epithelial cells is formed by integral membrane proteins and cytoplasmic scaffolding proteins. The former contains the claudin family proteins with four transmembrane segments, while the latter includes Par3, a PDZ domain-containing adaptor that organizes TJ formation. Here we show the single membrane-spanning protein TMEM25 localizes to TJs in epithelial cells and binds to Par3 via a PDZ-mediated interaction with its C-terminal cytoplasmic tail. TJ development during epithelial cell polarization is accelerated by depletion of TMEM25, and delayed by overexpression of TMEM25 but not by that of a C-terminally deleted protein, indicating a regulatory role of TMEM25. TMEM25 associates via its N-terminal extracellular domain with claudin-1 and claudin-2 to suppress their cis- and trans-oligomerizations, both of which participate in TJ strand formation. Furthermore, Par3 attenuates TMEM25-claudin association via binding to TMEM25, implying its ability to affect claudin oligomerization. Thus, the TJ protein TMEM25 appears to negatively regulate claudin assembly in TJ formation, which regulation is modulated by its interaction with Par3.


Subject(s)
Claudins , Tight Junctions , Tight Junctions/metabolism , Claudins/genetics , Claudins/metabolism , Carrier Proteins/metabolism , Epithelial Cells , Claudin-1/genetics , Claudin-1/metabolism
15.
Arch Biochem Biophys ; 751: 109824, 2024 01.
Article in English | MEDLINE | ID: mdl-37984759

ABSTRACT

Small-cell lung cancer (SCLC), which accounts for about 15 % of all lung cancers, progresses more rapidly than other histologic types and is rarely detected at an operable early stage. Therefore, chemotherapy, radiation therapy, or their combination are the primary treatments for this type of lung cancer. However, the tendency to acquire resistance to anticancer drugs is a severe problem. Recently, we found that an intercellular adhesion molecule, claudin (CLDN) 1, known to be involved in the migration and invasion of lung cancer cells, is involved in the acquisition of anticancer drug resistance. In the present study, we investigated the effect of CLDN1 on the anticancer-drug sensitivity of SCLC SBC-3 cells. Since epithelial-mesenchymal transition (EMT), which is involved in cancer cell migration and invasion, is well known for its involvement in anticancer-drug sensitivity via inhibition of apoptosis, we also examined EMT involvement in decreased anticancer-drug sensitivity by CLDN1. Sensitivity to doxorubicin (DOX) in SBC-3 cells was significantly decreased by CLDN1 overexpression. CLDN1 overexpression resulted in increased TGF-ß1 levels, enhanced EMT induction, and increased migratory potency of SBC-3 cells. The decreased sensitivity of SBC-3 cells to anticancer drugs upon TGF-ß1 treatment suggested that activation of the TGF-ß1/EMT signaling pathway by CLDN1 causes the decreased sensitivity to anticancer drugs and increased migratory potency. Furthermore, treatments with antiallergic agents tranilast and zoledronic acid, known EMT inhibitors, significantly mitigated the decreased sensitivity of CLDN1-overexpressing SBC-3 cells to DOX. These results suggest that EMT inhibitors might effectively overcome reduced sensitivity to anticancer drugs in CLDN1-overexpressing SCLC cells.


Subject(s)
Antineoplastic Agents , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , Claudin-1/genetics , Transforming Growth Factor beta1/metabolism , Cell Line, Tumor , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Signal Transduction , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Epithelial-Mesenchymal Transition
16.
Mol Nutr Food Res ; 68(4): e2300615, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38152983

ABSTRACT

SCOPE: Torreya grandis kernel has traditionally been used to remove intestinal parasites and increases intestinal motility. However, the effect of Torreya grandis kernel oil (TKO) on constipation has not yet been investigated. Therefore, mouse model is used to investigate the effect of TKO on slow transit constipation (STC) and its possible mechanism. METHODS AND RESULTS: The effects of TKO on intestinal motility of STC mice are evaluated by fecal weight, fecal water content, colon length, defecation test, and intestinal propulsion test. The mechanism of TKO alleviating STC is explored by detecting biochemical analysis, histological analysis, western blot, qRT-PCR, immunohistochemistry, and gut microbiota analysis. The results reveal that TKO effectively promotes defecation and intestinal motility, increases the level of endothelin-1, and restores the histopathological morphology of the colon under LOP pretreatment. The expression levels of occludin, claudin-1, and zonula occludens-1 (ZO-1) mRNA and protein are up-regulated in mice receiving TKO treatment. The colonic 5-hydroxytryptamine 3R/4R (5-HT3R/5-HT4R) expressions are also increased by TKO supplementation. Additionally, TKO rescues LOP-caused disorders of the gut microbiota. CONCLUSION: Consumption of TKO is beneficial to STC recovery, and it can alleviate LOP-induced STC by up-regulating the colonic expressions of Occludin/Claudin-1/ZO-1 and 5-HT3R/5-HT4R.


Subject(s)
Loperamide , Tight Junctions , Mice , Animals , Loperamide/adverse effects , Loperamide/metabolism , Claudin-1/genetics , Claudin-1/metabolism , Occludin/genetics , Occludin/metabolism , Mice, Inbred BALB C , Constipation/chemically induced , Constipation/drug therapy , Constipation/metabolism
17.
Clin Genet ; 105(1): 44-51, 2024 01.
Article in English | MEDLINE | ID: mdl-37814412

ABSTRACT

Neonatal ichthyosis and sclerosing cholangitis syndrome (NISCH), also known as ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC), is an extremely rare disease of autosomal recessive inheritance, resulting from loss of function of the tight junction protein claudin-1. Its clinical presentation is highly variable, and is characterized by liver and ectodermal involvement. Although most ILVASC cases described to date were attributed to homozygous truncating variants in CLDN1, a single missense variant CLDN1 p.Arg81His, associated with isolated skin ichthyosis phenotype, has been recently reported in a family of Moroccan Jewish descent. We now describe seven patients with ILVASC, originating from four non consanguineous families of North African Jewish ancestry (including one previously reported family), harboring CLDN1 p.Arg81His variant, and broaden the phenotypic spectrum attributed to this variant to include teeth, hair, and liver/bile duct involvement, characteristic of ILVASC. Furthermore, we provide additional evidence for pathogenicity of the CLDN1 p.Arg81His variant by transmission electron microscopy of the affected skin, revealing distorted tight junction architecture, and show through haplotype analysis in the vicinity of the CLDN1 gene, that this variant represents a founder variant in Jews of Moroccan descent with an estimated carrier frequency of 1:220.


Subject(s)
Cholangitis, Sclerosing , Ichthyosis , Leukocyte Disorders , Humans , Infant, Newborn , Alopecia/genetics , Cholangitis, Sclerosing/genetics , Claudin-1/genetics , Ichthyosis/genetics , Jews/genetics , Leukocyte Disorders/complications , Leukocyte Disorders/genetics , Syndrome
18.
Toxicol Lett ; 392: 46-55, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38142011

ABSTRACT

Tobacco smoke contains various carcinogenic ingredients such as nicotine, acrolein, and benzopyrene; however, their effects on cancer treatment are not fully understood. Claudin-1 (CLDN1), a component of tight junctions, is involved in the increased resistance to anticancer drugs. In this study, we found that acrolein increases the mRNA and protein levels of CLDN1 in RERF-LC-AI cells derived from human lung squamous cell carcinoma (SCC). Acrolein increased the p-extracellular signal-regulated kinase (ERK) 1/2 levels without affecting the p-Akt level. The acrolein-induced elevation of CLDN1 expression was attenuated by U0126, a mitogen-activated protein kinase kinas (MEK) inhibitor. These results indicate that the activation of MEK/ERK pathway is involved in the acrolein-induced elevation of CLDN1 expression. In a spheroid model, acrolein suppressed the accumulation and toxicity of doxorubicin (DXR), which were rescued by CLDN1 silencing. The acrolein-induced effects were also observed in lung SCC-derived EBC-1 and LK-2 cells. Acrolein also increased the expression level of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and detoxifying genes, which were inhibited by CLDN1 silencing. In spheroid cells, the levels of reactive oxygen species were enhanced by acrolein, which was inhibited by CLDN1 silencing. Taken together, acrolein may reduce the anticancer drug-induced toxicity in human lung SCC cells mediated by high CLDN1 expression followed by the upregulation of Nrf2 signaling pathway.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Humans , Claudin-1/genetics , Claudin-1/metabolism , NF-E2-Related Factor 2/genetics , Acrolein/toxicity , Carcinoma, Non-Small-Cell Lung/genetics , Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/pathology , Lung/pathology , Mitogen-Activated Protein Kinase Kinases
19.
PLoS Negl Trop Dis ; 17(12): e0011816, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38048314

ABSTRACT

BACKGROUND: Cathepsin L, a lysosomal enzyme, participates in diverse physiological processes. Recombinant Trichinella spiralis cathepsin L domains (rTsCatL2) exhibited natural cysteine protease activity and hydrolyzed host immunoglobulin and extracellular matrix proteins in vitro, but its functions in larval invasion are unknown. The aim of this study was to explore its functions in T. spiralis invasion of the host's intestinal epithelial cells. METHODOLOGY/PRINCIPAL FINDINGS: RNAi significantly suppressed the expression of TsCatL mRNA and protein with TsCatL specific siRNA-302. T. spiralis larval invasion of Caco-2 cells was reduced by 39.87% and 38.36%, respectively, when anti-TsCatL2 serum and siRNA-302 were used. Mice challenged with siRNA-302-treated muscle larvae (ML) exhibited a substantial reduction in intestinal infective larvae, adult worm, and ML burden compared to the PBS group, with reductions of 44.37%, 47.57%, and 57.06%, respectively. The development and fecundity of the females from the mice infected with siRNA-302-treated ML was significantly inhibited. After incubation of rTsCatL2 with Caco-2 cells, immunofluorescence test showed that the rTsCatL2 gradually entered into the cells, altered the localization of cellular tight junction proteins (claudin 1, occludin and zo-1), adhesion junction protein (e-cadherin) and extracellular matrix protein (laminin), and intercellular junctions were lost. Western blot showed a 58.65% reduction in claudin 1 expression in Caco-2 cells treated with rTsCatL2. Co-IP showed that rTsCatL2 interacted with laminin and collagen I but not with claudin 1, e-cadherin, occludin and fibronectin in Caco-2 cells. Moreover, rTsCatL2 disrupted the intestinal epithelial barrier by inducing cellular autophagy. CONCLUSIONS: rTsCatL2 disrupts the intestinal epithelial barrier and facilitates T. spiralis larval invasion.


Subject(s)
Cathepsin L , Tight Junctions , Trichinella spiralis , Trichinellosis , Animals , Female , Humans , Mice , Caco-2 Cells , Cadherins/metabolism , Cathepsin L/genetics , Cathepsin L/metabolism , Claudin-1/genetics , Claudin-1/metabolism , Epithelial Cells/metabolism , Epithelial Cells/parasitology , Laminin/genetics , Laminin/metabolism , Larva/parasitology , Mice, Inbred BALB C , Occludin/genetics , Occludin/metabolism , RNA, Double-Stranded , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Tight Junctions/parasitology , Tight Junctions/pathology , Trichinella spiralis/genetics
20.
Sci Rep ; 13(1): 22685, 2023 12 19.
Article in English | MEDLINE | ID: mdl-38114708

ABSTRACT

Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome, which is characterized by podocyte injury. Given that the pathophysiology of nondiabetic glomerulosclerosis is poorly understood and targeted therapies to prevent glomerular disease are lacking, we decided to investigate the tight junction protein claudin-1 and the histone deacetylase sirtuin-1 (SIRT1), which are known to be involved in podocyte injury. For this purpose, we first examined SIRT1, claudin-1 and podocin expression in kidney biopsies from patients diagnosed with nondiabetic FSGS and found that upregulation of glomerular claudin-1 accompanies a significant reduction in glomerular SIRT1 and podocin levels. From this, we investigated whether a small molecule activator of SIRT1, SRT1720, could delay the onset of FSGS in an animal model of adriamycin (ADR)-induced nephropathy; 14 days of treatment with SRT1720 attenuated glomerulosclerosis progression and albuminuria, prevented transcription factor Wilms tumor 1 (WT1) downregulation and increased glomerular claudin-1 in the ADR + SRT1720 group. Thus, we evaluated the effect of ADR and/or SRT1720 in cultured mouse podocytes. The results showed that ADR [1 µM] triggered an increase in claudin-1 expression after 30 min, and this effect was attenuated by pretreatment of podocytes with SRT1720 [5 µM]. ADR [1 µM] also led to changes in the localization of SIRT1 and claudin-1 in these cells, which could be associated with podocyte injury. Although the use of specific agonists such as SRT1720 presents some benefits in glomerular function, their underlying mechanisms still need to be further explored for therapeutic use. Taken together, our data indicate that SIRT1 and claudin-1 are relevant for the pathophysiology of nondiabetic FSGS.


Subject(s)
Glomerulosclerosis, Focal Segmental , Kidney Diseases , Podocytes , Humans , Mice , Animals , Glomerulosclerosis, Focal Segmental/pathology , Claudin-1/genetics , Claudin-1/metabolism , Sirtuin 1/genetics , Sirtuin 1/metabolism , Kidney Glomerulus/pathology , Podocytes/metabolism , Kidney Diseases/pathology , Doxorubicin/pharmacology
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