• Gut and Liver
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• v.12 no.6
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• pp.682-693
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• 2018

Background/Aims: Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model. Methods: The effects of $17{\beta}$-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions. Results: The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p<0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-${\kappa}B$, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2. Conclusions: E2 acts through the estrogen receptor ${\beta}$ signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines.

• Journal of Life Science
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• v.29 no.9
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• pp.941-948
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• 2019

Colorectal cancer is a major health problem in industrialized countries. Ziyuglycoside II ($3{\beta}-3-{\alpha}$-1- arabinopyranosyloxy-19-hydroxyurs-12-en-28-oicacid), a triterpenoid saponin isolated from the roots of Sanguisorba officinalis L., possesses antioxidant, antiangiogenic, and anticancer properties. However, the therapeutic function of ziyuglycoside II in colitis-associated colorectal carcinogenesis is undefined. In the present study, the effect of ziyuglycoside II on colitis-associated colon cancer induced in mice using azoxymethane (AOM)/dextran sulfate sodium (DSS) was explored. The AOM model recapitulates many features of human colon cancer, but it lacks an inflammatory component. DSS induces colitis and promotes AOM-induced colon cancer in mice. BALB/c mice were injected with AOM and administered 2% DSS in drinking water. The mice were given ziyuglycoside II (1 or 5 mg/kg) orally three times per week, and colonic tissue was collected at 64 days. Administration of ziyuglycoside II markedly diminished the formation of colonic tumors. Western blot and immunohistological analyses showed that ziyuglycoside II noticeably decreased nuclear factor kappa-B-positive cells and levels of inflammation-related proteins, such as inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-${\alpha}$, and interleukin-6 in colon tissue. It also prompted apoptosis. Ziyuglycoside II treatment augmented cleaved forms of caspase-3, caspase-7, and poly (ADP-ribose) polymerase in colonic tissues. In conclusion, ziyuglycoside II could defend against colitis-associated tumorigenesis in mice by inhibiting inflammation and inducing apoptosis. This shows a promising chemopreventive potential for its use in colitis-associated colon cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2827-2832
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• 2015

Oxidative stress is associated with colon carcinogenesis including aberrant crypt foci (ACF) formation and it plays an important role in pathophysiological changes in cancer cells. The aims of this study were to investigate the effects of dietary unpolished Thai rice (UTR) on ACF formation and dysplastic progression in azoxymethane (AOM)-treated rats. Anti-cancer efficacy of UTR regarding apoptotic induction and oxidative redox status in human colon cancer (CaCo-2) cells was also investigated. Rats given 20% and 70% of UTR in the diet showed significantly and dose-dependently decreased total number of ACF. UTR treatment also was strongly associated with the low percentage of dysplastic progression and mucin depletion. In addition, we found that UTR significantly induced cancer cell apoptosis, increased cellular oxidants, and decreased the level of GSH/GSSG ratio in CaCo-2 cells. Our study suggests that UTR supplementation may be a useful strategy for CRC prevention with the inhibition of precancerous progression, with induction of cancer cell apoptosis through redox alteration.

• Journal of the Korean Society of Food Science and Nutrition
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• v.30 no.3
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• pp.535-539
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• 2001

The modulating effect of feeding sea mustard (Undarina pinnatifida), a fiber-rich seaweed, during initiation and post-initiation phases of colon carcinogenesis was investigated in Sprague Dawley rats. Four groups of animals were exposed to the two weekly injections of a chemical carcinogen, azoxymethane (AOM). Animals were placed on diet containing 15% sea mustard during initiation. post-initiation or initiation+post-initiation phase of carcinogenesis for 10 weeks, and colonic aberrant crypt formation and cell proliferation were compared to those of rats fed semi-synthetic control diet. Results showed that sea mustard feeding significantly reduced the numbers of both aberrant crypts and aberrant crypt foci. Also, labeling indices and proliferation zones were significantly reduced in the colon of the rats fed sea mustard diets. These results indicate that the diet containing sea mustard may decrease the risk of colon cancer development, and a part of such effect may be mediated through both the blocking of initiation and the suppression of cell proliferation in the colonic crypts, although precise mechanisms should be further examined.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.1929-1933
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• 2012

Oxidative stress has been proposed to be involved in colorectal cancer development. Many dark pigments of plants have potent oxidative stress preventive properties. In this study, unpolished Thai rice was assessed for antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) methods. Red strain unpolished Thai rice was also administered to rats exposed to azoxymethane (AOM) for induction of aberrant crypt foci (ACF). Serum malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) were investigated for cellular oxidative stress and serum antioxidants, respectively. Red pigment unpolished Thai rice demonstrated high antioxidant activity and was found to significantly and dose dependently decrease the total density and crypt multiplicity of ACF. Consumption of Thai rice further resulted in high serum antioxidant activity and low MDA cellular oxidative stress. Interestingly, the density of ACF was strongly related to MDA at r = 0.964, while it was inversely related with FRAP antioxidants (r = -0.915, p < 0.001). The results of this study suggest that the consumption of red strain of unpolished Thai rice may exert potentially beneficial effects on colorectal cancer through decrease in the level of oxidative stress.

• Journal of Nutrition and Health
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• v.33 no.7
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• pp.717-724
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• 2000

A number of epidemiological studies has indicated lifestyles including dietary habits are closely related to the development of certain forms of cancer. These findings have led several investigators to identify the ways in which these factors mdulate the risk of cancer. Seaweeds are rich sources of non-digestible polysaccharides which possibly posses physiological functions. In vitro studies showed several components in seaweeds inhibit tumor cell growth and mutagenicity of known food mutagens. On the other hand non-digestible polysaccharides of different food sources negatively affect mineral nutrition by decreasing mineral absorption. The objectives of this study was to investigate the effect of major seaweed intake on azoxymethane(AOM) - induced DNA damage a known cancer initiation step and on apparent absorption of calcium and iron. To accomplish these objectives twenty five ICR mice were divided into five groups and fed one of the following diets for 10 days : control diet d, diet containing 10% water-soluble fraction of seamustard or seatangle diet containing 10% water-insoluble fraction of seamustard or seatangle. AOM was injected 6 hours before sacrifice and N7-methylated guanines from the colonic DNA were quantified using a gas chromatography -mass spectroscopy. Fecal samples were collected on days 4 and 8. Caclium and iron contents of the diets and feces were analyzed using an atomic absorption spectrophotometry to determine the apparent absorption of these minerals. Results are as follows. AOM-induced guanine methylation of colon was decreased in animals fed diets containing water-soluble fractions of seamustard or seatangle compared to those in animals fed control diet although only the seatnagle fed group showed statistically significant effect. Apparent calcium absorption was significantly reduced in animals fed diets containing water-insoluble fractions of seaweeds. Iron absorption was significantly decreased and negatively balanced in animals fed diets containing water-insoluble fractions of both seaweeds, and water-soluble fraction of seatangle. In conclusion, seamustard and seatangle intakes may effectively prevent colon tumorigenesis by reducing a carcinogen-induced DNA damages, and more mechanistic studies on possible role of seaweeds on carcinogenesis are required. Also, adverse effects of seaweed diets cintaming a large amount of polysaccharides on mineral nutrition should be carefully monitored.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.947-952
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• 2015

The aim of this study was to evaluate the effects of grape juice on colon carcinogenesis induced by azoxymethane (AOM) and expression of NF-kB, iNOS and TNF-${\alpha}$. Methods: Forty male Wistar rats were divided into 7 groups: G1, control; G2, 15 mg/kg AOM; G3, 1% grape juice 2 weeks before AOM; G4, 2% grape juice 2 weeks before AOM; G5, 1% grape juice 4 weeks after AOM; G6, 2% grape juice 4 weeks after AOM; G7, 2% grape juice without AOM. Histological changes and aberrant crypt foci (ACF) were studied, while RNA expression of NF-kB, TNF- and iNOS was evaluated by qPCR. Results: The number of ACF was higher in G2, and G4 presented a smaller number of crypts per focus than G5 (p=0.009) and G6. Small ACF (1-3) were more frequent in G4 compared to G2, G5 and G6 (p=0.009, p=0.009 and p=0.041, respectively). RNA expression of NF-kB was lower in G3 and G4 compared to G2 (p=0.004 and p=0.002, respectively). A positive correlation was observed between TNF-${\alpha}$ and NF-kB gene expression (p=0.002). In conclusion, the administration of 2% grape juice before AOM reduced the crypt multiplicity, attenuating carcinogenesis. Lower expression of NF-kB was observed in animals exposed to grape juice for a longer period of time, regardless of concentration.

• BMB Reports
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• v.39 no.6
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• pp.649-655
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• 2006

The NSAID activated gene (NAG-1), a member of the TGF-$\beta$ superfamily, is involved in tumor progression and development. The over-expression of NAG-1 in cancer cells results in growth arrest and increase in apoptosis, suggesting that NAG-1 has anti-tumorigenic activity. This conclusion is further supported by results of experiments with transgenic mice that ubiquitously express human NAG-1. These transgenic mice are resistant to the development of intestinal tumors following treatment with azoxymethane or by introduction of a mutant APC gene. In contrast, other data suggest a pro-tumorigenic role for NAG-1, for example, high expression of NAG-1 is frequently observed in tumors. NAG-1 may be like other members of the TGF-$\beta$ superfamily, acting as a tumor suppressor in the early stages, but acting pro-tumorigenic at the later stages of tumor progression. The expression of NAG-1 can be increased by treatment with drugs and chemicals documented to prevent tumor formation and development. Most notable is the increase in NAG-1 expression by the inhibitors of cyclooxygenases that prevent human colorectal cancer development. The regulation of NAG-1 is complex, but these agents act through either p53 or EGR-1 related pathways. In addition, an increase in NAG-1 is observed in inhibition of the AKT/GSK-$3{\beta}$ pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by tumor suppressor pathways and appears to modulate tumor progression.

• Journal of Microbiology and Biotechnology
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• v.30 no.11
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• pp.1640-1650
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• 2020

Colorectal cancer (CRC) is the leading cause of common malignant neoplasm worldwide. Many studies have analyzed compositions of gut microbiota associated with various diseases such as inflammatory bowel diseases (IBD) and colon cancer. One of the most representative bacteria involved in CRC is enterotoxigenic Bacteroides fragilis (ETBF), a species belonging to phylum Bacteroidetes. We used ETBF colonized mice with azoxymethane (AOM)/dextran sulphate sodium (DSS) and zerumbone, a compound with anti-bacterial effect, to determine whether zerumbone could restore intestinal microbiota composition. Four experimental groups of mice were used: sham, ETBF colonized AOM/DSS group, ETBF colonized AOM/DSS group zerumbone 60 mg kg-1 (ETBF/AOM/DSS + Z (60)), and only zerumbone (60 mg kg^-1)-treated group. We performed reversible dye terminators-based analysis of 16S rRNA gene region V3-V4 for group comparison. Microbiota compositions of ETBF/AOM/DSS + Z (60) group and ETBF colonized AOM/DSS group not given zerumbone were significantly different. There were more Bacteroides in ETBF/AOM/DSS + Z (60) group than those in ETBF colonized AOM/DSS group, suggesting that B. fragilis could be a normal flora activated by zerumbone. In addition, based on linear discriminant analysis of effect size (LEfSe) analysis, microbial diversity decreased significantly in the ETBF colonized AOM/DSS group. However, after given zerumbone, the taxonomic relative abundance was increased. These findings suggest that zerumbone not only influenced the microbial diversity and richness, but also could be helpful for enhancing the balance of gut microbial composition. In this work, we demonstrate that zerumbone could restore the composition of intestinal microbiota.

• Journal of Nutrition and Health
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• v.55 no.1
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• pp.47-58
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• 2022

Purpose: Obesity and a high-fat diet (HFD) are risk factors for colorectal cancer. We have previously shown that luteolin (LUT) supplementation in HFD-fed mice markedly inhibits tumor development in chemically induced colon carcinogenesis. In this study, we evaluated the anticancer effect of LUT in the inhibition of cell proliferation in HFD-fed obese mice and HT-29 human colorectal adenocarcinoma cells grown in an adipocyte-derived medium. Methods: C57BL/6 mice were fed a normal diet (ND, 11.69% fat out of total calories consumed, n = 10), HFD (40% fat out of total calories consumed, n = 10), HFD with 0.0025% LUT (n = 10), and HFD with 0.005% LUT (n = 10) and were subjected to azoxymethane-dextran sulfate sodium chemical colon carcinogenesis. All mice were fed the experimental diet for 11 weeks. 3T3-L1 preadipocytes and HT-29 cells were treated with various doses of LUT in an adipocyte-conditioned medium (Ad-CM). Results: The weekly body weight changes in the LUT groups were similar to those in the HFD group; however, the survival rates of the LUT group were higher than those of the HFD group. Impaired crypt integrity of the colonic mucosa in the HFD group was observed to be restored in the LUT group. The colonic expression of proliferating cell nuclear antigen and insulin-like growth factor 1 (IGF-1) receptors were suppressed by the LUT supplementation in the HFD-fed mice. The LUT treatment (10, 20, and 40 µM) inhibited the proliferation and migration of HT-29 cells cultured in Ad-CM in a dose-dependent manner, as well as the differentiation of 3T3-L1 preadipocytes. Conclusion: These results suggest that the anticancer effect of LUT is probably due to the inhibition of IGF-1 signaling and adipogenesis-related cell proliferation in colon cancer cells.