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Cellular and Molecular Gastroenterology... 2024Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated...
BACKGROUND & AIMS
Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR antagonism on colitis-associated carcinogenesis.
METHODS
A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn's disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR agonist proteinases.
RESULTS
AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The β-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota β-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR at the thrombin cleavage site.
CONCLUSIONS
PAR antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.
Topics: Animals; Receptor, PAR-1; Humans; Mice; Caco-2 Cells; Dextran Sulfate; Azoxymethane; Disease Models, Animal; Gastrointestinal Microbiome; Male; Colitis; Carcinogenesis; STAT3 Transcription Factor; Myofibroblasts; Colitis-Associated Neoplasms; Thrombin; Mice, Inbred C57BL; Crohn Disease
PubMed: 38614455
DOI: 10.1016/j.jcmgh.2024.04.001 -
Journal of Translational Medicine Feb 2024Adenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression...
BACKGROUND
Adenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression of APs is unknown.
METHODS
Sequencing of the 16S rRNA gene was conducted to identify characteristic bacteria in AP tissues and normal mucosa. Then, the roles of inflammation-related bacteria were clarified by Spearman correlation analysis. Furthermore, colorectal HT-29 cells, normal colon NCM460 cells, and azoxymethane-treated mice were used to investigate the effects of the characteristic bacteria on progression of APs.
RESULTS
The expression levels of inflammation-related markers (diamine oxidase, D-lactate, C-reactive protein, tumor necrosis factor-α, interleukin-6 and interleukin-1β) were increased, whereas the expression levels of anti-inflammatory factors (interleukin-4 and interleukin-10) were significantly decreased in AP patients as compared to healthy controls. Solobacterium moorei (S. moorei) was enriched in AP tissues and fecal samples, and significantly positively correlated with serum inflammation-related markers. In vitro, S. moorei preferentially attached to HT-29 cells and stimulated cell proliferation and production of pro-inflammatory factors. In vivo, the incidence of intestinal dysplasia was significantly increased in the S. moorei group. Gavage of mice with S. moorei upregulated production of pro-inflammatory factors, suppressed proliferation of CD4 and CD8cells, and disrupted the integrity of the intestinal barrier, thereby accelerating progression of APs.
CONCLUSIONS
S. moorei accelerated the progression of AP in mice via activation of the NF-κB signaling pathway, chronic low-grade inflammation, and intestinal barrier disruption. Targeted reduction of S. moorei presents a potential strategy to prevent the progression of APs.
Topics: Humans; Animals; Mice; RNA, Ribosomal, 16S; Firmicutes; Inflammation; Adenomatous Polyps
PubMed: 38368407
DOI: 10.1186/s12967-024-04977-3 -
Pharmaceutics Sep 2023Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease, is known to increase the risk of colitis-associated cancer (CAC). CAC has...
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease, is known to increase the risk of colitis-associated cancer (CAC). CAC has been found to be unresponsive to standard chemotherapy regimens, and the current treatments do not utilize effective small-molecule drugs and colon-targeted delivery systems. Previous studies indicated that the M13-nano-liposome (NL) formulation can effectively target the colon and reshape the gut microbiota in ex vivo cultures, generating altered microbial metabolites that can efficiently prevent chronic UC. In this study, we tested the cancer cell uptake ability of the NL formulation and investigated the potential of the M13-NL formulation to prevent CAC in the azoxymethane (AOM)-exposed IL10 mouse model. Our findings demonstrate that oral administration of M13-NL prevents tumor development in AOM-exposed IL10 mice, suggesting that M13-NL is a promising oral drug formulation for preventing CAC.
PubMed: 37765299
DOI: 10.3390/pharmaceutics15092331 -
Biology Mar 2024Hepatic encephalopathy (HE) is a neurological condition linked to liver failure. Acute HE (Type A) occurs with acute liver failure, while chronic HE (Type C) is tied to...
Hepatic encephalopathy (HE) is a neurological condition linked to liver failure. Acute HE (Type A) occurs with acute liver failure, while chronic HE (Type C) is tied to cirrhosis and portal hypertension. HE treatments lag due to gaps in understanding its development by gender and age. We studied how sex and age impact HE and its severity with combined liver toxins. Our findings indicate that drug-induced (thioacetamide, TAA) brain edema was more severe in aged males than in young males or young/aged female rats. However, adding alcohol (ethanol, EtOH) worsens TAA's brain edema in both young and aged females, with females experiencing a more severe effect than males. These patterns also apply to Type A HE induced by azoxymethane (AZO) in mice. Similarly, TAA-induced behavioral deficits in Type C HE were milder in young and aged females than in males. Conversely, EtOH and TAA in young/aged males led to severe brain edema and fatality without noticeable behavioral changes. TAA metabolism was slower in aged males than in young or middle-aged rats. When TAA-treated aged male rats received EtOH, there was a slow and sustained plasma level of thioacetamide sulfoxide (TASO). This suggests that with EtOH, TAA-induced HE is more severe in aged males. TAA metabolism was similar in young, middle-aged, and aged female rats. However, with EtOH, young and aged females experience more severe drug-induced HE as compared to middle-aged adult rats. These findings strongly suggest that gender and age play a role in the severity of HE development and that the presence of one or more liver toxins may aggravate the severity of the disease progression.
PubMed: 38666840
DOI: 10.3390/biology13040228 -
Gut Microbes 2024The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse...
The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within on CTS. Intestine cell-specific depletion of altered GM composition and contribution of depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.
Topics: Animals; Colorectal Neoplasms; Azoxymethane; Humans; Mice; Polymorphism, Single Nucleotide; Gastrointestinal Microbiome; Collaborative Cross Mice; Dual Oxidases; Genetic Predisposition to Disease; Male; Bacteria; Disease Models, Animal; Female
PubMed: 38659246
DOI: 10.1080/19490976.2024.2341647 -
Acta Pharmaceutica Sinica. B May 2024Aberrant changes in the gut microbiota are implicated in many diseases, including inflammatory bowel disease (IBD). Gut microbes produce diverse metabolites that can...
Aberrant changes in the gut microbiota are implicated in many diseases, including inflammatory bowel disease (IBD). Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity, indicating that microbe-mediated modulation may be a promising strategy for preventing and treating IBD. Although fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies, novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently needed. Herein, we report the total synthesis of heudelotinone and the discovery of 5-heudelotinone (an enantiomer) as a potent agent against experimental colitis that acts by modulating the gut microbiota. 5-Heudelotinone alters the diversity and composition of the gut microbiota and increases the concentration of short-chain fatty acids (SCFAs); thus, it regulates the intestinal immune system by reducing proinflammatory immune cell numbers, and maintains intestinal mucosal integrity by modulating tight junctions (TJs). Moreover, 5-heudelotinone () ameliorates colitis-associated colorectal cancer (CAC) in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced carcinoma model. Together, these findings reveal the potential of a novel natural product, namely, 5-heudelotinone, to control intestinal inflammation and highlight that this product is a safe and effective candidate for the treatment of IBD and CAC.
PubMed: 38799623
DOI: 10.1016/j.apsb.2024.02.020 -
Yakugaku Zasshi : Journal of the... 2024Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism...
Zinc is one of the essential trace elements, and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, then the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added diet group compared to the normal zinc intake group, and about half the number in the high-zinc-intake group compared to the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. Collectively, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and that it increases the transcription of granzyme B, one of the key molecules involved in tumor immunity. In this symposium, we would like to introduce our latest data on the relationship between zinc and tumor immunity.
Topics: Animals; Humans; Mice; Azoxymethane; Colorectal Neoplasms; Disease Models, Animal; Granzymes; Immunity, Cellular; T-Lymphocytes, Cytotoxic; Zinc
PubMed: 38692920
DOI: 10.1248/yakushi.23-00154-1 -
Heliyon Aug 2023This research aims to identify the effects of the administration of a black rice bran diet on colorectal cancer in dextran sodium sulfate and azoxymethane-induced BALB/c...
This research aims to identify the effects of the administration of a black rice bran diet on colorectal cancer in dextran sodium sulfate and azoxymethane-induced BALB/c mice. The research was conducted on three groups consisting of eight Balb/c mice: two groups were fed with carcinogens, and the third group, referred to as the normal group, was supplied with Isotonic NaCl 0.9% intraperitoneally. One group fed with carcinogens was supplied a standard AIN 1993 M diet modified with black rice bran as a substitute of fibre source, while the other two mice groups were fed the standard diet (AIN-93M) containing cellulose fibre. At the 17th week, all mice were euthanized; their colonic sections were taken for histopathological evaluation, and cecum for short-chain fatty acids concentration, total lactic acid bacteria, pH and β-glucuronidase activity evaluations. The results show an increase in the total lactic acid bacteria and short-chain fatty acids in the mice group fed with rice bran. Consequently, pH value and β-glucuronidase activity had decreased. Histopathological evaluation of mucosal tissue exhibited inhibition of the tumor growth rate in the mice groups fed rice bran compared to the group supplied with the standard diet. Furthermore, the proliferating cell nuclear antigen expression had decreased significantly, while expression of caspase-8 and caspase-3 had increased notably, in the group fed with a rice bran diet. These results suggest that black rice bran can effectively inhibit colon carcinogenesis. The potential of black rice bran as a source of fibre has not been studied in detail regarding the inhibition mechanism of colorectal cancer cells; further investigation in this field could provide valuable information about new strategies to prevent colorectal cancer. This strand of research is very important to developing preventive methods against cancer and promoting the concept of healthy products, including functional foods.
PubMed: 37576300
DOI: 10.1016/j.heliyon.2023.e18528 -
Nutrients Nov 2023Okra flowers are a good source of polysaccharides and flavonoids, with biological activities of anti-inflammatory action and modulation of the gut microbiota....
Okra flowers are a good source of polysaccharides and flavonoids, with biological activities of anti-inflammatory action and modulation of the gut microbiota. Previously, we reported that flavonoid-rich extracts from okra flowers (AFE) presented effective anti-colorectal cancer (CRC) activity in CRC cells as well as xenograft models, but their role in colitis-associated cancer (CAC) is unidentified. In this study, we aimed to evaluate the effects of AFE and APE (polysaccharides extracted from okra flowers) on the CAC symptoms of azoxymethane (AOM)/dextran sodium sulfate (DSS)-intervened mice. The results showed that APE and AFE exert potent efficacy in inhibiting colitis and colorectal tumorigenesis stimulated by AOM/DSS, characterized by decreased colonic shortening, DAI score, and tumor numbers. Compared with the control group, APE/AFE alleviated the microbiota dysbiosis driven by AOM/DSS. In addition, AFE elicited its anticancer activity through regulation of NFκB/IL-6/Stat3, JAK2/Stat3, MAPKs, PI3K/AKT, and Wnt/β-catenin signal transductions in AOM/DSS mice, which was consistent with a vitro model of CT26 cells, while APE treatment exhibited anticancer activity through regulation of Nrf2/IL-6, MAPKs, PI3K/AKT, and Wnt/β-catenin signal transductions in the AOM/DSS mouse model. Collectively, our studies revealed, for the first time, that flavonoids and polysaccharides from okra flowers possess the ability to attenuate colitis and colorectal tumorigenesis, with them having great potential to become promising candidates against CRC.
Topics: Humans; Mice; Animals; Flavonoids; Dextran Sulfate; Abelmoschus; Interleukin-6; Colitis-Associated Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; beta Catenin; Colitis; Azoxymethane; Carcinogenesis; Cell Transformation, Neoplastic; Anticarcinogenic Agents; Disease Models, Animal; Hominidae; Mice, Inbred C57BL; Colorectal Neoplasms
PubMed: 38004214
DOI: 10.3390/nu15224820 -
Frontiers in Oncology 2023The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R)...
INTRODUCTION
The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC.
METHODS
In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, ), and mice harboring a Treg cell-specific deletion of IL-23 ( ). The role of IL-23R signaling in Treg cells in sporadic CRC was examined utilizing orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. The function of macrophages was studied using clodronate. Finally, single-cell RNA-seq of a previously published dataset in human sporadic cancer was reanalyzed to corroborate these findings.
RESULTS
In CAC, mice had increased tumor size and increased dysplasia compared to WT mice that was associated with decreased tumor-infiltrating macrophages. In the sporadic cancer model, mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of mice exhibited a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4 T cells. The decreased tumor size in mice was macrophage-dependent. These data suggest that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4 T cells that in turn promotes pro-inflammatory macrophages to clear tumors. Finally, analysis of TCGA data and single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.
CONCLUSION
Inflammation in colorectal carcinogenesis differs with respect to the contribution of IL-23R signaling in regulatory T cells.
PubMed: 38375204
DOI: 10.3389/fonc.2023.1276743