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Frontiers in Immunology 2023The intestinal barrier plays a crucial role in distinguishing foods from toxins. Prostaglandin D (PGD) is one of the lipid-derived autacoids synthesized from cell...
INTRODUCTION
The intestinal barrier plays a crucial role in distinguishing foods from toxins. Prostaglandin D (PGD) is one of the lipid-derived autacoids synthesized from cell membrane-derived arachidonic acid. We previously reported that pharmacological stimulation of PGD receptor, D prostanoid 1 (DP1) attenuated the symptoms of azoxymethane/dextran sodium sulfate-induced colitis and ovalbumin-induced food allergy in mouse models. These observations suggested that DP1 stimulation protects the intestinal barrier. The present study aimed to uncover the effects of DP1 stimulation on intestinal barrier function and elucidate the underlying mechanisms.
MATERIALS AND METHODS
Intestinal permeability was assessed in mice by measuring the transfer of orally administered fluorescein isothiocyanate-dextran (40 kDa) into the blood. The DP1 agonist BW245C (1 mg/kg) was administered 10 min prior to dextran administration. The intestinal permeability was confirmed using the everted sac method. Tight junction integrity was evaluated by measuring the transepithelial electrical resistance (TER) in the human intestinal epithelial cell line Caco-2. Mucus secretion was assessed by observing Alcian Blue-stained intestinal sections.
RESULTS
Pharmacological DP1 stimulation reduced intestinal permeability both and . Immunohistochemical staining showed that DP1 was strongly expressed on the apical side of the epithelial cells. DP1 stimulation did not affect TER but induced mucus secretion from goblet cells. Mucus removal by a mucolytic agent N-acetyl-l-cysteine canceled the inhibition of intestinal permeability by DP1 stimulation.
CONCLUSION
These observations suggest that pharmacological DP1 stimulation decreases intestinal permeability by stimulating mucus secretion.
Topics: Humans; Animals; Mice; Prostaglandins; Dextrans; Prostaglandin D2; Caco-2 Cells; Mucus; Permeability
PubMed: 37942331
DOI: 10.3389/fimmu.2023.1276852 -
PeerJ 2023Colorectal cancer (CRC) is the third most common cancer. It is a heterogeneous disease, including both hereditary and sporadic types of tumors. CRC results from complex... (Review)
Review
BACKGROUND
Colorectal cancer (CRC) is the third most common cancer. It is a heterogeneous disease, including both hereditary and sporadic types of tumors. CRC results from complex interactions between various genetic and environmental factors. Inflammatory bowel disease is an important risk factor for developing CRC. Despite growing understanding of the CRC biology, preclinical models are still needed to investigate the etiology and pathogenesis of the disease, as well as to find new methods of treatment and prevention.
OBJECTIVES
The purpose of this review is to describe existing murine models of CRC with a focus on the models of colitis-associated CRC. This manuscript could be relevant for experimental biologists and oncologists.
METHODOLOGY
We checked PubMed and Google from 01/2018 to 05/2023 for reviews of CRC models. In addition, we searched PubMed from 01/2022 to 01/2023 for articles using the azoxymethane (AOM)/dextran sulfate sodium (DSS) CRC model.
RESULTS
Existing murine models of CRC include spontaneous, genetically engineered, transplantation, and chemically induced models. For the study of colitis-associated cancer (CAC), the AOM/DSS model is predominantly used. This model is very similar in histological and molecular characteristics to the human CAC, and is highly reproducible, inexpensive, and easy to use. Despite its popularity, the AOM/DSS model is not standardized, which makes it difficult to analyze and compare data from different studies.
CONCLUSIONS
Each model demonstrates particular advantages and disadvantages, and allows to reproduce different subtypes or aspects of the pathogenesis of CRC.
Topics: Mice; Humans; Animals; Azoxymethane; Dextran Sulfate; Colitis-Associated Neoplasms; Colitis; Disease Models, Animal; Colorectal Neoplasms
PubMed: 37927787
DOI: 10.7717/peerj.16159 -
International Journal of Biological... Jan 2024Oat beta-glucan is one of the soluble dietary fibre fractions with a wide spectrum of biological activities such as anti-inflammatory and anti-tumour properties. In the...
Oat beta-glucan is one of the soluble dietary fibre fractions with a wide spectrum of biological activities such as anti-inflammatory and anti-tumour properties. In the present study, the effect of low-molar-mass oat beta-glucan isolate (OβGl) on the level of autophagy and apoptosis in the colorectum of rats with induced early stages of colorectal cancer was investigated. Forty-five male Sprague-Dawley rats were divided into two main groups: control and azoxymethane-induced early-stage colorectal carcinogenesis (CRC). Both groups were divided into three dietary subgroups fed standard feed without OβGl (OβGl-), with 1 % of OβGl (OβGl+1 %) or with 3 % of OβGl (OβGl+3 %). The expression of autophagy (LC3B, beclin-1) and apoptosis (caspase-3, cleaved caspase-3, BAX, BCL-2 and PARP-1) markers was determined by immunohistochemistry, Western blot and PCR analysis. The obtained results showed that the expression of LC3B, caspase-3 and cleaved caspase-3 in the CRC mucosa, and LC3B-II expression in the CRC wall were higher in the OβGl+3 % compared to the OβGl- rats. A higher BAX/BCL-2 ratio was also observed in the CRC OβGl+1 % rats compared to the other CRC animals. In summary, OβGl+3 % has a modulatory effect, stimulating autophagy and the extrinsic apoptosis pathway, while OβGl+1 % has a stimulatory effect on the intrinsic apoptosis pathway.
Topics: Rats; Male; Animals; Caspase 3; Rats, Sprague-Dawley; bcl-2-Associated X Protein; Autophagy; Proto-Oncogene Proteins c-bcl-2; Apoptosis; Colorectal Neoplasms; Carcinogenesis
PubMed: 37924897
DOI: 10.1016/j.ijbiomac.2023.127832 -
Cancers Oct 2023GPR4 is a proton-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and has been shown to potentiate intestinal inflammation in murine...
GPR4 is a proton-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and has been shown to potentiate intestinal inflammation in murine colitis models. Herein, we evaluated the proinflammatory role of GPR4 in the development of colitis-associated colorectal cancer (CAC) using the dextran sulfate sodium (DSS) and azoxymethane (AOM) mouse models in wild-type and GPR4 knockout mice. We found that GPR4 contributed to chronic intestinal inflammation and heightened DSS/AOM-induced intestinal tumor burden. Tumor blood vessel density was markedly reduced in mice deficient in GPR4, which correlated with increased tumor necrosis and reduced tumor cell proliferation. These data demonstrate that GPR4 ablation alleviates intestinal inflammation and reduces tumor angiogenesis, development, and progression in the AOM/DSS mouse model.
PubMed: 37894341
DOI: 10.3390/cancers15204974 -
Acta Cirurgica Brasileira 2023The aim of this study was to assess the effects of resistance and aerobic exercise on colorectal cancer (CRC) development in mice induced by azoxymethane (AOM) coupled...
PURPOSE
The aim of this study was to assess the effects of resistance and aerobic exercise on colorectal cancer (CRC) development in mice induced by azoxymethane (AOM) coupled with colitis.
METHODS
Forty animals induced with CRC were used, divided into five groups of eight animals each: sedentary; continuous aerobics; continuous anaerobic; aerobic PI; and anaerobic PI. AOM was administered to the animals in two doses of 10 mg/kg each over the course of two weeks, the first dose administered in the third week and the second administered in the fourth. For the colitis, three cycles of dextran sodium sulfate were administered for five days, separated by two weeks of water. The 14th week of the experiment saw the euthanasia, the removal of their colons, and the creation of microscopy slides for histological analysis.
RESULTS
Preneoplastic lesions developed in all five groups; there were no significant differences between them. However, in terms of inflammatory symptoms, mucosal ulceration was much more frequently in the exercise groups than in the sedentary group (p = 0.016). The number of polyps overall (p = 0.002), the distal region's polyp development (p = 0.003), and the proximal region's polyp development (p = 0.04) were all statistically different than sedentary group.
CONCLUSIONS
The study discovered no significant difference in disease activity index scores between groups, but there was a significant difference in the number of polyps and the presence of mucosal ulceration in the colon.
Topics: Humans; Animals; Mice; Colorectal Neoplasms; Resistance Training; Disease Models, Animal; Colitis; Azoxymethane; Mice, Inbred C57BL; Dextran Sulfate
PubMed: 37878986
DOI: 10.1590/acb384923 -
Frontiers in Immunology 2023Crohn's disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the gene confer an increased susceptibility...
BACKGROUND
Crohn's disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the gene confer an increased susceptibility to ileal CD. While Nod2 in myeloid cells may confer protection against T-cell mediated ileopathy, it remains unclear whether it may promote resolution of the inflamed colon. In this study, we evaluated the function of Nod2 in myeloid cells in a model of acute colitis and colitis-associated colon cancer (CAC).
METHODS
To ablate Nod2 specifically within the myeloid compartment, we generated mice. The role of NOD2 was studied in a setting of Dextran Sodium Sulfate (DSS)-induced colitis and in azoxymethane (AOM)/DSS model. Clinical parameters were quantified by colonoscopy, histological, flow cytometry, and qRT-PCR analysis.
RESULTS
Upon DSS colitis model, mice lost less weight than control littermates and had less severe damage to the colonic epithelium. In the AOM/DSS model, endoscopic monitoring of tumor progression revealed a lowered number of adenomas within the colon of mice, associated with less expression of . Mechanistically, lysozyme M was required for the improved disease severity in mice with a defect of NOD2 in myeloid cells.
CONCLUSION
Our results indicate that loss of Nod2 signaling in myeloid cells aids in the tissue repair of the inflamed large intestine through lysozyme secretion by myeloid cells. These results may pave the way to design new therapeutics to limit the inflammatory and tumorigenic functions of NOD2.
Topics: Animals; Mice; Azoxymethane; Colitis; Crohn Disease; Macrophages; Muramidase; Nod2 Signaling Adaptor Protein
PubMed: 37876927
DOI: 10.3389/fimmu.2023.1252979 -
European Neuropsychopharmacology : the... Jan 2024Social and cognitive dysfunctions are the most persistent symptoms of schizophrenia. Since oxytocin (OXT) is known to play a role in social functions and modulates...
Social and cognitive dysfunctions are the most persistent symptoms of schizophrenia. Since oxytocin (OXT) is known to play a role in social functions and modulates cognitive processes, we investigated the effects of a novel, nonpeptide, selective OXT receptor agonist, LIT-001, in a neurodevelopmental model of schizophrenia. Administration of methylazoxymethanol acetate (MAM; 22 mg/kg) on the 17th day of rat pregnancy is known to cause developmental disturbances of the brain, which lead to schizophrenia-like symptomatology in the offspring. Here, we examined the effects of acutely administered LIT-001 (1, 3, and 10 mg/kg) in MAM-exposed males and females on social behaviour, communication and cognition. We report that MAM-treated adult male and female rats displayed reduced social behaviour, ultrasonic communication and novel object recognition test performance. LIT-001 partially reversed these deficits, increasing the total social interaction time and the number of 'positive', highly-modulated 50 kHz ultrasonic calls in male rats. The compound ameliorated MAM-induced deficits in object discrimination in both sexes. Present results confirm the pro-social activity of LIT-001 and demonstrate its pro-cognitive effects following acute administration.
Topics: Pregnancy; Rats; Female; Male; Animals; Schizophrenia; Oxytocin; Receptors, Oxytocin; Cognition; Methylazoxymethanol Acetate; Disease Models, Animal; Pyrazoles; Pyrrolidines
PubMed: 37866191
DOI: 10.1016/j.euroneuro.2023.09.005 -
Gastroenterology Feb 2024Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of...
BACKGROUND & AIMS
Dietary fibers are mainly fermented by the gut microbiota, but their roles in colorectal cancer (CRC) are largely unclear. Here, we investigated the associations of different fibers with colorectal tumorigenesis in mice.
METHODS
Apc mice and C57BL/6 mice with azoxymethane (AOM) injection were used as CRC mouse models. Mice were fed with mixed high-fiber diet (20% soluble fiber and 20% insoluble fiber), high-inulin diet, high-guar gum diet, high-cellulose diet, or diets with different inulin dose. Germ-free mice were used for validation. Fecal microbiota and metabolites were profiled by shotgun metagenomic sequencing and liquid chromatography-mass spectrometry, respectively.
RESULTS
Mixed high-fiber diet promoted colorectal tumorigenesis with increased tumor number and tumor load in AOM-treated and Apc mice. Antibiotics use abolished the pro-tumorigenic effect of mixed high-fiber diet, while transplanting stools from mice fed with mixed high-fiber diet accelerated tumor growth in AOM-treated germ-free mice. We therefore characterized the contribution of soluble and insoluble fiber in CRC separately. Our results revealed that soluble fiber inulin or guar gum, but not insoluble fiber cellulose, promoted colorectal tumorigenesis in AOM-treated and Apc mice. Soluble fiber induced gut dysbiosis with Bacteroides uniformis enrichment and Bifidobacterium pseudolongum depletion, accompanied by increased fecal butyrate and serum bile acids and decreased inosine. We also identified a positive correlation between inulin dosage and colorectal tumorigenesis. Moreover, transplanting stools from mice fed with high-inulin diet increased colonic cell proliferation and oncogene expressions in germ-free mice.
CONCLUSION
High-dose soluble but not insoluble fiber potentiates colorectal tumorigenesis in a dose-dependent manner by dysregulating gut microbiota and metabolites in mice.
Topics: Mice; Animals; Gastrointestinal Microbiome; Inulin; Mice, Inbred C57BL; Carcinogenesis; Dietary Fiber; Cellulose; Azoxymethane; Colorectal Neoplasms
PubMed: 37858797
DOI: 10.1053/j.gastro.2023.10.012 -
International Journal of Molecular... Sep 2023Cholangiocarcinoma is the second most common primary cancer of the liver and has a poor prognosis. Various animal models, including carcinogen-induced and genetically...
Cholangiocarcinoma is the second most common primary cancer of the liver and has a poor prognosis. Various animal models, including carcinogen-induced and genetically engineered rodent models, have been established to clarify the mechanisms underlying cholangiocarcinoma development. In the present study, we developed a novel mouse model of malignant lesions in the biliary ducts induced by the administration of the carcinogen azoxymethane to obese C57BLKS/J-db/db mice. A histopathological analysis revealed that the biliary tract lesions in the liver appeared to be an intrahepatic cholangiocarcinoma with higher tumor incidence, shorter experimental duration, and a markedly increased incidence in obese mice. Molecular markers analyzed using a microarray and a qPCR indicated that the cancerous lesions originated from the cholangiocytes and developed in the inflamed livers. These findings indicated that this is a novel mouse model of intrahepatic cholangiocarcinoma in the context of steatohepatitis. This model can be used to provide a better understanding of the pathogenic mechanisms of cholangiocarcinoma and to develop novel therapeutic strategies for this malignancy.
Topics: Mice; Animals; Bile Ducts, Intrahepatic; Azoxymethane; Bile Duct Neoplasms; Cholangiocarcinoma; Carcinogens
PubMed: 37834032
DOI: 10.3390/ijms241914581 -
Cancer Letters Dec 2023Metastasis is the primary cause of death in colorectal cancer (CRC). Thyroid hormone receptor interacting protein 6 (TRIP6) is an adaptor protein that regulates cell...
Metastasis is the primary cause of death in colorectal cancer (CRC). Thyroid hormone receptor interacting protein 6 (TRIP6) is an adaptor protein that regulates cell motility. Here, we aim to elucidate the role of TRIP6 in driving CRC tumorigenesis and metastasis and evaluate its potential as a therapeutic target. TRIP6 mRNA is up-regulated in CRC compared to adjacent normal tissues in three independent cohorts (all P < 0.0001), especially in liver metastases (P < 0.001). High TRIP6 expression predicts poor prognosis of CRC patients in our cohort (P = 0.01) and TCGA cohort (P = 0.02). Colon-specific TRIP6 overexpression (Trip6Villin-Cre) in mice accelerated azoxymethane (AOM)-induced CRC (P < 0.05) and submucosal invasion (P < 0.0001). In contrast, TRIP6 knockout (Trip6 mice) slowed tumorigenesis (P < 0.05). Consistently, TRIP6 overexpression in CRC cells promoted epithelial-mesenchymal transition (EMT), cell migration/invasion in vitro, and metastases in vivo (all P < 0.05), whereas knockdown of TRIP6 exerted opposite phenotypes. Mechanistically, TRIP6 interacted PDZ domain-containing proteins such as PARD3 to impair tight junctions, evidenced by decreased tight junction markers and gut permeability dysfunction, inhibit PTEN, and activate oncogenic Akt signaling. TRIP6-induced pro-metastatic phenotypes and Akt activation depends on PARD3. Targeting TRIP6 by VNP-encapsulated TRIP6-siRNA synergized with Oxaliplatin and 5-Fluorouracil to suppress CRC liver metastases. In conclusion, TRIP6 promotes CRC metastasis by directly interacting with PARD3 to disrupt tight junctions and activating Akt signaling. Targeting of TRIP6 in combination with chemotherapy is a promising strategy for the treatment of metastatic CRC.
Topics: Animals; Humans; Mice; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Colorectal Neoplasms; Drug Resistance; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Tight Junctions; Transcription Factors
PubMed: 37827326
DOI: 10.1016/j.canlet.2023.216438