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Black rice bran (BRB) is well-known for its high antioxidant activity and its pivotal role in preventing colon cancer. The present study aims to investigate the effects of BRB administration on BALB/C mice induced with azoxymethane (AOM) and dextran sodium sulphate (DSS). The 24 mice were divided into three groups: the group induced by colon cancer (C+), the group induced by cancer and given the BRB diet (C+BRB), and the normal group (C−). Both the C− and C+ groups were given a standard AIN-93 M diet containing cellulose fiber. After 16 weeks, the mice were anesthetized, and the colonic tissue was identified for nodule distribution, histopathological observation, and mRNA expression analysis of proliferating cell nuclear antigen (PCNA), caspase-3, and caspase-8 genes using qRT PCR technique. Nodule distribution in the C+BRB group showed a significant decrease compared to the C+ group, with 1.65 ± 0.71 nodule/cm2 vs. 5.73 ± 2.93 nodule/cm2. Then, the colon weight was significantly decreased in the C+BRB group, at 0.19 ± 0.04 (g) compared to 0.25 ± 0.03 (g) in the C+ group. Also, the BRB diet in the C+BRB group significantly decreased PCNA mRNA expression compared to the C+ group, with values of 0.58 ± 0.09-fold change vs. 5.22 ± 0.80-fold change. Conversely, increased the mRNA expression of caspase-3 (0.91 ± 0.20-fold change vs. 0.36 ± 0.15-fold change) and caspase-8 (0.51 ± 0.18-fold change vs. 0.13 ± 0.31-fold change). In conclusion, administration of BRB inhibited the rate of cancer development by suppressing cancer cell proliferation and inducing apoptosis.

Black rice bran (BRB) is well-known for its high antioxidant activity and its pivotal role in preventing colon cancer. The present study aims to investigate the effects of BRB administration on BALB/C mice induced with azoxymethane (AOM) and dextran sodium sulphate (DSS). The 24 mice were divided into three groups: the group induced by colon cancer (C+), the group induced by cancer and given the BRB diet (C+BRB), and the normal group (C−). Both the C− and C+ groups were given a standard AIN-93 M diet containing cellulose fiber. After 16 weeks, the mice were anesthetized, and the colonic tissue was identified for nodule distribution, histopathological observation, and mRNA expression analysis of proliferating cell nuclear antigen (PCNA), caspase-3, and caspase-8 genes using qRT PCR technique. Nodule distribution in the C+BRB group showed a significant decrease compared to the C+ group, with 1.65 ± 0.71 nodule/cm2 vs. 5.73 ± 2.93 nodule/cm2. Then, the colon weight was significantly decreased in the C+BRB group, at 0.19 ± 0.04 (g) compared to 0.25 ± 0.03 (g) in the C+ group. Also, the BRB diet in the C+BRB group significantly decreased PCNA mRNA expression compared to the C+ group, with values of 0.58 ± 0.09-fold change vs. 5.22 ± 0.80-fold change. Conversely, increased the mRNA expression of caspase-3 (0.91 ± 0.20-fold change vs. 0.36 ± 0.15-fold change) and caspase-8 (0.51 ± 0.18-fold change vs. 0.13 ± 0.31-fold change). In conclusion, administration of BRB inhibited the rate of cancer development by suppressing cancer cell proliferation and inducing apoptosis. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC), one of the most common malignancies in the world, urgently requires more treatment strategies. Although there has been much research on probiotics, limited research has been done in treating cancer. The purpose of this study was to investigate the role of Bifidobacterium longum (B. longum) in the prevention and treatment of CRC. Through Cell Counting Kit-8 and Colony Formation Assays, 8 h and a B. longum count of 1 × 108 CFU/ml were chosen as the best cocultivation conditions with CRC cells. The role of B. longum in inhibiting the progression of CRC cells was verified by a series of functional and immunofluorescence assays. For instance, in vivo assays have verified that B. longum could alleviate CRC progression. In addition, according to the results of in vivo assays and clinical statistical analysis, B. longum could reduce diarrhea symptoms. Mechanistically, by 16S and RNA sequencing, it was found that B. longum could affect the development of CRC by regulating the composition of gut microbes and enhancing immune function. The B. longum might inhibit the occurrence and development of CRC and relieve diarrhea symptoms by regulating intestinal microbes and immune function. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that Akkermansia muciniphila (AKK) may be a potential probiotic agent for ameliorating colorectal cancer (CRC). Thus, we utilized the azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced mouse model of colorectal cancer to evaluate the intervention effect of AKK PROBIO. The results showed that AKK PROBIO significantly improved mouse colon health, decreased the serum pro-inflammatory cytokines levels, as well as downregulated the mRNA levels of p50, p52, p65, and IκBβ, upregulated the expressions of Bid, Bim, and caspase-9 in the colon. In addition, AKK PROBIO modulated the gut microbiota composition, as characterized by the increased abundance of Muribaculaceae and Akkermansia and the decreased levels of Bacteroides, and Parasutterella. Notably, the high-dosage group was better than that of low-dosage. In conclusion, AKK PROBIO has the potential to modulate colorectal cancer by alleviating intestinal inflammation through the NF-κB pathway and promoting cell apoptosis, thereby intervening in the development of colorectal tumors.

BackgroundColorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for preventing and treating CRC. Fibrinogen C domain-containing 1 (FIBCD1), a chitin-binding transmembrane protein predominantly found on human intestinal epithelial cells (IECs), has garnered attention in previous research for its ability to effectively suppress inflammatory responses and promote tissue homeostasis at mucosal barriers.MethodsIn this study, we investigated the role of FIBCD1 in CRC development using transgenic mice that mimic human expression of FIBCD1 at the intestinal mucosal barrier. To model aspects of CRC, we employed the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. Additionally, we examined the expression pattern of FIBCD1 in surgical specimens obtained from human CRC patients by immunohistochemical methods. By accessing public data repositories, we further evaluated FIBCD1 expression in colon adenocarcinoma and explored survival outcomes associated with FIBCD1 expression.ResultsHere, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis in mice. Furthermore, we identify a soluble variant of FIBCD1 that is significantly increased in feces during acute inflammation. Finally, we demonstrate increased expression of FIBCD1 by immunohistochemistry in human CRC specimens at more developed tumor stages. These results are further supported by bioinformatic analyses of publicly available repositories, indicating increased FIBCD1 expression in tumor tissues, where higher expression is associated with unfavorable prognosis.ConclusionCollectively, these findings suggest that FIBCD1 influences early inflammatory responses in the AOM/DSS model, leading to a reduction in tumor size and burden. The increased expression of FIBCD1 in human CRC samples raises intriguing questions regarding its role in CRC, positioning it as a compelling candidate and novel molecular target for future research.

Chronic inflammation-induced oxidative stress is an important driving force for developing colitis-associated cancer (CAC). 4-hydroxynonenal (4-HNE) is a highly reactive aldehyde derived from lipid peroxidation of ω-6 polyunsaturated fatty acids that contributes to colorectal carcinogenesis. Glutathione S-transferase alpha 4 (Gsta4) specifically conjugates glutathione to 4-HNE and thereby detoxifies 4-HNE. The correlation of these oxidative biomarkers with the pathological changes in CAC is, however, unclear. In this study, we investigated the expression of Gsta4 and 4-HNE adducts in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced murine CAC, and analyzed the correlations of 4-HNE and Gsta4 with inflammatory cytokines and the pathological scores in the colon biopsies. Real-time quantitative PCR showed that expression of IL6, TNFα, and Gsta4 sequentially increased in colon tissues for mice treated with DSS for 1, 2, and 3 cycles, respectively. Moreover, immunohistochemical staining showed remarkably increased expression of 4-HNE adducts, Gsta4, TNFα, and IL6 in the colon biopsies after 3 cycles of DSS treatment. Correlation analysis demonstrated that 4-HNE adducts in the colon biopsies were positively correlated with Gsta4 expression. Additionally, the expression of Gsta4 and 4-HNE adducts were strongly correlated with the pathological changes of colon, as well as the expression of TNFα and IL6 in colon tissues. These results provide evidence for the association of oxidative biomarkers Gsta4 and 4-HNE with the pathological changes of CAC and may help developing novel histopathological biomarkers and prevention targets for CAC.

In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water – intermittently with DSS induction – revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities. [ABSTRACT FROM AUTHOR]

Xiao-Min Liu1 *, Wen-Ting Zhu1 *, Meng-Lei Jia,1 Yu-Ting Li,1 Ye Hong,1 Zhong-Qiu Liu,2 Peng-Ke Yan1 1Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Qiu Liu, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China, Email liuzq@gzucm.edu.cn Peng-Ke Yan, Department of Pharmacy, Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Email gysyypk@126.comBackground: Transgenic C57BL/6-APC(Min/+) spontaneous cancer mouse model and the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) chemically induced orthotopic colorectal cancer mouse model represented distinct pathogenesis of colorectal cancers. Our previous study revealed that the combination of Rapamycin liposomes (Rapa/Lps) and 5-Fluorouracil (5-FU) has anti-colorectal cancer effects. However, the therapeutic efficacy of Rapa/Lps and 5-FU in other colorectal cancer mice models is yet to be thoroughly explored. The purpose of this study was to investigate the anti-tumor effect of Rapa/Lps combined with 5-FU in vivo and in vitro.Methods: In this study, we evaluated the effect of Rapa/Lps and 5-FU on APC (Min/+) mice and AOM/DSS-induced colorectal cancer mice. The small intestine, colorectum, serum, and plasma of mice in each group were collected following sacrifice to record the number of tumors. HE staining was utilized for observing pathological damage to intestine tissues. Tube formation assay, Transwell assay, wound healing assay, Western Blot were used to explore the anti-angiogenesis effect of drugs in HUVECs.Results: As expected, Rapa/Lps and 5-FU significantly suppressed tumor formation, decreased the number of tumors, and tumor load both in two mouse models, and had no influence on mouse weight. Mechanically, the anti-tumor effect of the drug also was associated in inhibiting angiogenesis and proliferation. Furthermore, we found that Rapa/Lps obviously inhibited HUVECs tube formation and migration.Conclusion: Altogether, we revealed the Rapa/Lps synergism with 5-FU decreased colon and small intestinal tumorigenesis in AOM/DSS-treated and APC (Min/+) mice, respectively, and correlated with anti-angiogenesis.Keywords: rapamycin liposomes, 5-fluorouracil, angiogenesis, APC (Min/+) mice, AOM/DSS, colorectal cancer

Simple Summary: Heat-stabilized rice bran is a nutrient-dense food ingredient that has shown colorectal cancer control and prevention properties in a suite of carcinogen-induced animal models. This study identified colon cancer protective properties associated with rice bran metabolism in feces that relate to the previously reported findings in gastrointestinal tissue. A longitudinal analysis of fecal microbiota and metabolite changes between diet treatments identified novel mechanisms for rice bran-mediated anti-cancer activity. Fecal metabolites in response to dietary rice bran intake in mice showed overlap with results from adult colorectal cancer survivors after eating rice bran. These molecules may serve as translational dietary biomarkers for colorectal cancer prevention. Dietary rice bran-mediated inhibition of colon carcinogenesis was demonstrated previously for carcinogen-induced rodent models via multiple anti-cancer mechanisms. This study investigated the role of dietary rice bran-mediated changes to fecal microbiota and metabolites over the time course of colon carcinogenesis and compared murine fecal metabolites to human stool metabolic profiles following rice bran consumption by colorectal cancer survivors (NCT01929122). Forty adult male BALB/c mice were subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colon carcinogenesis and randomized to control AIN93M (n = 20) or diets containing 10% w/w heat-stabilized rice bran (n = 20). Feces were serially collected for 16S rRNA amplicon sequencing and non-targeted metabolomics. Fecal microbiota richness and diversity was increased in mice and humans with dietary rice bran treatment. Key drivers of differential bacterial abundances from rice bran intake in mice included Akkermansia, Lactococcus, Lachnospiraceae, and Eubacterium xylanophilum. Murine fecal metabolomics revealed 592 biochemical identities with notable changes to fatty acids, phenolics, and vitamins. Monoacylglycerols, dihydroferulate, 2-hydroxyhippurate (salicylurate), ferulic acid 4-sulfate, and vitamin B6 and E isomers significantly differed between rice bran- and control-fed mice. The kinetics of murine metabolic changes by the host and gut microbiome following rice bran consumption complemented changes observed in humans for apigenin, N-acetylhistamine, and ethylmalonate in feces. Increased enterolactone abundance is a novel diet-driven microbial metabolite fecal biomarker following rice bran consumption in mice and humans from this study. Dietary rice bran bioactivity via gut microbiome metabolism in mice and humans contributes to protection against colorectal cancer. The findings from this study provide compelling support for rice bran in clinical and public health guidelines for colorectal cancer prevention and control. [ABSTRACT FROM AUTHOR]

In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water – intermittently with DSS induction – revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities.

There are significant sex differences in colorectal cancer (CRC), including in incidence, onset, and molecular characteristics. Further, while inflammatory bowel disease (IBD) is a risk factor for CRC in both sexes, men with IBD have a 60% higher risk of developing CRC compared to women. In this study, we investigated sex differences during colitis-associated CRC (CAC) using a chemically induced CAC mouse model. The mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) and followed for 9 and 15 weeks. We performed RNA-sequencing of colon samples from males (n = 15) and females (n = 15) to study different stages of inflammation and identify corresponding transcriptomic sex differences in non-tumor colon tissue. We found a significant transcriptome response to AOM/DSS treatment in both sexes, including in pathways related to inflammation and cell proliferation. Notably, we found a stronger response in males and that male-specific differentially expressed genes were involved in NFκB signaling and circadian rhythm. Further, an overrepresented proportion of male-specific gene regulations were predicted to be targets of Stat3, whereas for females, targets of the glucocorticoid receptor (Gr/Nr3c1) were overrepresented. At 15 weeks, the most apparent sex difference involved genes with functions in T cell proliferation, followed by the regulation of demethylases. The majority of sex differences were thus related to inflammation and the immune system. Our novel data, profiling the transcriptomic response to chemically induced colitis and CAC, indicate clear sex differences in CRC initiation and progression. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide and thus mouse models of CRC are of significant value to study the pathogenesis. The Azoxymethane/Dextran sulfate sodium (AOM/DSS) model is a widely used, robust initiation-promotion model for chemical induction of colitis-associated CRC in rodents. However, the dosage of chemicals, treatment regimens and outcome measures vary greatly among studies employing this model. Thus, the aim of this study was to examine an AOM/DSS model involving a reduced (1%) dose of DSS for induction of carcinogenesis in A/J and C57BL/6J (B6) mice. Results We show that colonic preneoplastic lesions can be reliably detected in A/J and B6 mice by use of a AOM/DSS model involving a single injection of 10 mg/kg AOM followed by three 7-day cycles of a low-dose (1%) DSS administration. Supporting existing evidence of A/J mice exhibiting higher susceptibility to AOM than B6 mice, our AOM/DSS-treated A/J mice developed the highest number of large colonic lesions. Clinical symptoms in both strains subjected to the AOM/DSS treatment did not persist in-between treatment cycles, demonstrating that the animals tolerated the treatment well. Conclusions Our findings suggest that a reduced dose of DSS in the AOM/DSS model can be considered in future studies of early phase colorectal carcinogenesis in the A/J and B6 mouse strains using preneoplastic lesions as an outcome measure, and that such regimen may reduce the risk of early trial terminations to accommodate human endpoints. Overall, our data emphasize the importance of devoting attention towards choice of protocol, outcome measures and mouse strain in studies of CRC in mice according to the study purpose.

Sodium butyrate (NaB) is a by-product of dietary fiber that has an anti-tumor effect on colorectal cancer (CRC). The aim of this study was to explore the effect of NaB on tumor and colitis using a colitis-associated colorectal cancer (CAC) model. CAC model was induced in mice by administration of azoxymethane (AOM) and dextran sulfate sodium salt (DSS). 0.1 M NaB in drinking water, or intraperitoneal injection of NaB (1 g/kg body weight) was given during the study period. NLRP3 inflammasome-related molecules were detected. The composition and taxonomy of colorectal microbiota were analyzed. NaB increased spleen index decreased by AOM/DSS. NaB attenuated tumors by reducing tumor load and tumor size in AOM/DSS-induced mice. NaB protected mice from CAC by improving colitis and inhibiting expression of NLRP3 and IL-1β. NaB regulated gut microbiota dysbiosis induced by AOM/DSS. In conclusion, NaB inhibited CAC by ameliorating the gut microbiota dysbiosis and inhibiting colitis.

ObjectiveTo screen and identify molecular targets and bacteria genus leading to adenomatous polyps in mouse induced by high-fat diet (HFD) +AOM/DSS using omics technology.MethodsThe molecular targets of colorectal adenoma disease were obtained from the GeneCards and OMIM database. The SPF C57BL mice were randomly divided into blank (Control) and AOM/DSS+HFD colorectal adenoma model (ADH) groups. The ADH model group was intraperitoneally injected with AOM reagent. Then, mice were given with 2.5% DSS (in free drinking water) and high-fat diet to establish the mouse model. During this period, the changes of physical signs of mice in each group were observed. After the end of modeling, HE staining was used to evaluate the histopathological change of mice. The differentially expressed genes and proteins in the Control group and ADH group were detected by RNA-seq transcriptome sequencing and Tandem Mass Tags (TMT) quantitative proteomics. The histological results were analyzed by intersection with the intestinal adenoma molecular targets obtained from the database. Moreover, the changes of intestinal flora in the two groups were examined. The correlation between targets and differential bacteria was analyzed and verified by Parallel Reaction Monitoring (PRM) to comprehensively evaluate the mouse model of adenomatous polyp induced by AOM/DSS+HFD.ResultsThe general condition and histopathological results of mice confirmed that the ADH mouse model was successfully established and tubular adenoma was formed. A total of 604 genes and 42 proteins related to intestinal adenoma were obtained by histological analysis and database intersection analysis. The intestinal microflora of ADH mice was different from that of normal mice, and the constituents and abundance of intestinal flora were similar to those of human intestinal adenoma. GATA4 and LHPP were selected as potential pathological markers of the model mice by correlation analysis of targets and intestinal flora. The results of PRM verification were highly consistent with the results of RNA-Seq transcriptome sequencing and TMT analysis.ConclusionThe pathological results, molecular pathological markers and the changes of intestinal flora suggest that the mouse ADH model is ideal for studying the transformation of inflammatory cancer. The ADH model will be helpful for understanding the occurrence and development of human colorectal cancer at the transcriptomic and proteomic level.

Objective: To screen and identify molecular targets and bacteria genus leading to adenomatous polyps in mouse induced by high-fat diet (HFD) +AOM/DSS using omics technology. Methods: The molecular targets of colorectal adenoma disease were obtained from the GeneCards and OMIM database. The SPF C57BL mice were randomly divided into blank (Control) and AOM/DSS+HFD colorectal adenoma model (ADH) groups. The ADH model group was intraperitoneally injected with AOM reagent. Then, mice were given with 2.5% DSS (in free drinking water) and high-fat diet to establish the mouse model. During this period, the changes of physical signs of mice in each group were observed. After the end of modeling, HE staining was used to evaluate the histopathological change of mice. The differentially expressed genes and proteins in the Control group and ADH group were detected by RNA-seq transcriptome sequencing and Tandem Mass Tags (TMT) quantitative proteomics. The histological results were analyzed by intersection with the intestinal adenoma molecular targets obtained from the database. Moreover, the changes of intestinal flora in the two groups were examined. The correlation between targets and differential bacteria was analyzed and verified by Parallel Reaction Monitoring (PRM) to comprehensively evaluate the mouse model of adenomatous polyp induced by AOM/DSS+HFD. Results: The general condition and histopathological results of mice confirmed that the ADH mouse model was successfully established and tubular adenoma was formed. A total of 604 genes and 42 proteins related to intestinal adenoma were obtained by histological analysis and database intersection analysis. The intestinal microflora of ADH mice was different from that of normal mice, and the constituents and abundance of intestinal flora were similar to those of human intestinal adenoma. GATA4 and LHPP were selected as potential pathological markers of the model mice by correlation analysis of targets and intestinal flora. The results of PRM verification were highly consistent with the results of RNA-Seq transcriptome sequencing and TMT analysis. Conclusion: The pathological results, molecular pathological markers and the changes of intestinal flora suggest that the mouse ADH model is ideal for studying the transformation of inflammatory cancer. The ADH model will be helpful for understanding the occurrence and development of human colorectal cancer at the transcriptomic and proteomic level. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study explored the intervention effect of Akkermansia muciniphila (AKK PROBIO) on a mouse model of colorectal cancer. • AKK PROBIO intervention improved weight loss, colon symptoms, and tumor cell accumulation in colorectal cancer mice. • AKK PROBIO exerted its effects through modulating the NF-κB pathway, cell apoptosis, and the gut microbiota composition. Emerging evidence indicates that Akkermansia muciniphila (AKK) may be a potential probiotic agent for ameliorating colorectal cancer (CRC). Thus, we utilized the azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced mouse model of colorectal cancer to evaluate the intervention effect of AKK PROBIO. The results showed that AKK PROBIO significantly improved mouse colon health, decreased the serum pro-inflammatory cytokines levels, as well as downregulated the mRNA levels of p50 , p52 , p65 , and IκBβ , upregulated the expressions of Bid , Bim , and caspase-9 in the colon. In addition, AKK PROBIO modulated the gut microbiota composition, as characterized by the increased abundance of Muribaculaceae and Akkermansia and the decreased levels of Bacteroides , and Parasutterella. Notably, the high-dosage group was better than that of low-dosage. In conclusion, AKK PROBIO has the potential to modulate colorectal cancer by alleviating intestinal inflammation through the NF-κB pathway and promoting cell apoptosis, thereby intervening in the development of colorectal tumors. [ABSTRACT FROM AUTHOR]

Treatment with exogenous GLP-2 has been shown to accelerate the growth of intestinal adenomas and adenocarcinomas in experimental models of colonic neoplasia, however, the role of endogenous GLP-2 in tumor promotion is less well known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) display an increase in circulating GLP-1 and GLP-2. Due to the intestinotrophic nature of GLP-2, we hypothesized that Gcgr-/- mice would be more susceptible to colonic dysplasia in a model of inflammation-induced colonic carcinogenesis. Female Gcgr-/- mice were first characterized for GLP-2 secretion and in a subsequent study they were given a single injection with the carcinogen azoxymethane (7.5 mg/kg) and treated with dextran sodium sulfate (DSS) (3%) for six days (n=19 and 9). A cohort of animals (n=4) received a colonoscopy 12 days following DSS treatment and all animals were sacrificed after six weeks. Disruption of glucagon receptor signaling led to increased GLP-2 secretion (p

Treatment with exogenous GLP-2 has been shown to accelerate the growth of intestinal adenomas and adenocarcinomas in experimental models of colonic neoplasia, however, the role of endogenous GLP-2 in tumor promotion is less well known. Mice with a global deletion of the glucagon receptor (Gcgr-/-) display an increase in circulating GLP-1 and GLP-2. Due to the intestinotrophic nature of GLP-2, we hypothesized that Gcgr-/- mice would be more susceptible to colonic dysplasia in a model of inflammation-induced colonic carcinogenesis. Female Gcgr-/- mice were first characterized for GLP-2 secretion and in a subsequent study they were given a single injection with the carcinogen azoxymethane (7.5 mg/kg) and treated with dextran sodium sulfate (DSS) (3%) for six days (n=19 and 9). A cohort of animals (n=4) received a colonoscopy 12 days following DSS treatment and all animals were sacrificed after six weeks. Disruption of glucagon receptor signaling led to increased GLP-2 secretion (p<0.0001) and an increased concentration of GLP-2 in the pancreas of Gcgr-/- mice, coinciding with an increase in small intestinal (p<0.0001) and colonic (p<0.05) weight. Increased villus height was recorded in the duodenum (p<0.001) and crypt depth was increased in the duodenum and jejunum (p<0.05 and p<0.05). Disruption of glucagon receptor signaling did not affect body weight during AOM/DSS treatment, neither did it affect the inflammatory score assessed during colonoscopy or the number of large and small adenomas present at the end of the study period. In conclusion, despite the increased endogenous GLP-2 secretion Gcgr-/- mice were not more susceptible to AOM/DSS-induced tumors. [ABSTRACT FROM AUTHOR]

Inonotus obliquus polysaccharide (IOP), the primary constituent of the parasitic fungus Inonotus obliquus, has anti-tumor, anti-inflammatory, anti-oxidation effects. However, the roles of IOP on colitis-associated cancer (CAC) are still unclear. Herein, we tested the efficacy of IOP using a mouse model of CAC induced by azoxymethane and dextran sulfate sodium (AOM/DSS). We confirmed that intragastric administration of IOP decreased CAC-induced body weight loss, colon tissue damage, colon shortening, and expression of proinflammatory mediators. Meanwhile, IOP treatment increased in expression of the NLRP3 inflammasome, IL-1β, and IL-18 in the colon of CAC mice. Moreover, in vitro, IOP inhibited the proliferation of SW620 colorectal cancer cells. Finally, overexpression of NLRP3 with plasmid transfection could further enhance the activation of NLRP3 inflammasome by IOP. Taken together, these results suggest that IOP suppresses the development of CAC, possibly by activation of the NLRP3 inflammasome, and reveal that IOP may be a therapeutic drug candidate for CAC.

Colorectal cancer (CRC) is a common malignant tumor that occurs in the colon. Gut microbiota is a complex ecosystem that plays an important role in the pathogenesis of CRC. Our previous studies showed that the soluble dietary fiber of foxtail millet (FMB-SDF) exhibited significant antitumor activity in vitro. The present study evaluated the anticancer potential of FMB-SDF in the azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced mouse CRC models. The results showed that FMB-SDF could significantly alleviate colon cancer symptoms in mice. Further, we found that FMB-SDF consumption significantly altered gut microbiota diversity and the overall structure and regulated the abundance of some microorganisms in CRC mice. Meanwhile, KEGG pathway enrichment showed that FMB-SDF can also alleviate the occurrence of colon cancer in mice by regulating certain cancer-related signaling pathways. In conclusion, our findings may provide a novel approach for the prevention and biotherapy of CRC.

Background: Colorectal cancer (CRC) ranks third in terms of cancer incidence and fourth in terms of cancer-related deaths worldwide. Identifying potential biomarkers of CRC is crucial for treatment and drug development. Methods: In this study, we established a C57B/6N mouse model of colon carcinogenesis using azoxymethane-dextran sodium sulfate (AOM-DSS) treatment for 14 weeks to identify proteins associated with colon cancer. An isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis was conducted on the cell membrane components enriched in the colonic mucosa. Additionally, tumor tissues and adjacent normal colon tissues were collected from patients with colon cancer for comparative protein and metabolite analyses. Results: In total, 74 differentially expressed proteins were identified in the tumor tissue samples from AOM/DSS-treated mice compared to both the adjacent tissue samples from AOM/DSS-treated mice and tissue samples from saline-treated control mice. Bioinformatics analysis revealed eight downregulated proteins enriched in the branched-chain amino acids pathway (valine, leucine, and isoleucine degradation). Moreover, these proteins are already known to be associated with the survival rate of patients with cancer. Targeted metabolomics showed increased levels of valine, leucine, and isoleucine in tumor tissues compared to those in adjacent normal tissues in patients with colon cancer. Furthermore, a real-time PCR experiment demonstrated that Aldehyde dehydrogenase, mitochondrial (short protein name ALDH2, gene name Aldh2 ) and Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial (short protein name HCDH, gene name Hadh ) (two genes) in the pathway of branched-chain amino acids) were downregulated in patients with colon cancer (colon tumor tissues vs. their adjacent colon tissues). ALDH2 expression was further validated by western blotting in AOM/DSS-treated mouse model and in clinical samples. Conclusion: This study highlighted the inactivation of the branched-chain amino acid degradation pathway in colon cancer and identified ALDH2 and HCDH as potential biomarkers for diagnosing colon cancer and developing new therapeutic strategies., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Colorectal cancer (CRC), one of the most common malignancies in the world, urgently requires more treatment strategies. Although there has been much research on probiotics, limited research has been done in treating cancer. The purpose of this study was to investigate the role of Bifidobacterium longum ( B. longum ) in the prevention and treatment of CRC. Through Cell Counting Kit-8 and Colony Formation Assays, 8 h and a B. longum count of 1 × 10 8 CFU/ml were chosen as the best cocultivation conditions with CRC cells. The role of B. longum in inhibiting the progression of CRC cells was verified by a series of functional and immunofluorescence assays. For instance, in vivo assays have verified that B. longum could alleviate CRC progression. In addition, according to the results of in vivo assays and clinical statistical analysis, B. longum could reduce diarrhea symptoms. Mechanistically, by 16S and RNA sequencing, it was found that B. longum could affect the development of CRC by regulating the composition of gut microbes and enhancing immune function. The B. longum might inhibit the occurrence and development of CRC and relieve diarrhea symptoms by regulating intestinal microbes and immune function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shang, Jiang, Wang, Guo, Kang, Xu, Wang, Chen, Li, Liu and Zhao.)

Estrogen hormones protect against colorectal cancer (CRC) and a preventative role of estrogen receptor beta (ERβ) on CRC has been supported using full knockout animals. However, it is unclear through which cells or organ ERβ mediates this effect. To investigate the functional role of intestinal ERβ during colitis-associated CRC we used intestine-specific ERβ knockout mice treated with azoxymethane and dextran sodium sulfate, followed by ex vivo organoid culture to corroborate intrinsic effects. We explored genome-wide impact on TNFα signaling using human CRC cell lines and chromatin immunoprecipitation assay to mechanistically characterize the regulation of ERβ. Increased tumor formation in males and tumor size in females was noted upon intestine-specific ERβ knockout, accompanied by enhanced local expression of TNFα, deregulation of key NFκB targets, and increased colon ulceration. Unexpectedly, we noted especially strong effects in males. We corroborated that intestinal ERβ protects against TNFα-induced damage intrinsically, and characterized an underlying genome-wide signaling mechanism in CRC cell lines whereby ERβ binds to cis-regulatory chromatin areas of key NFκB regulators. Our results support a protective role of intestinal ERβ against colitis-associated CRC, proposing new therapeutic strategies. [ABSTRACT FROM AUTHOR]

The gut microbiota, including pathogenic microorganisms and probiotics, has been involved in tumor initiation and progression by regulating the components of intestinal flora. Canmei formula (CMF), a traditional Chinese medicine, chronicled in the Chuang Yang Jing Yan Quan Shu, has been clinically used as an adjuvant therapy to treat patients with colorectal carcinoma (CRC) in China. In this study, we investigate the treatment effect of CMF in the azoxymethane (AOM) and dextran sodium sulfate (DSS) induced and high-fat diet augmented colitis-associated colorectal cancer in vivo, and explore its mechanism of action. We found that CMF treatment relieved the inflammation and alteration of the gut microbiota and significantly inhibited the development of intestinal adenoma. Linear discriminant analysis showed that the flora diversity in the normal mice, model mice and CMF treatment mice was different. At the family level, the relative abundance of Desulfovibrionaceae decreased in CMF groups. The relative abundance of Desulfovibrionaceae were lower in the CMF groups than in model group, whereas Rikenellaceae and Alistipes were increased. Altogether our results indicate that CMF treatment ameliorate colitis-associated colorectal carcinogenesis by modulating the composition of the gut microbiota in vivo.

The gut microbiota, including pathogenic microorganisms and probiotics, has been involved in tumor initiation and progression by regulating the components of intestinal flora. Canmei formula (CMF), a traditional Chinese medicine, chronicled in the Chuang Yang Jing Yan Quan Shu, has been clinically used as an adjuvant therapy to treat patients with colorectal carcinoma (CRC) in China. In this study, we investigate the treatment effect of CMF in the azoxymethane (AOM) and dextran sodium sulfate (DSS) induced and high-fat diet augmented colitis-associated colorectal cancer in vivo , and explore its mechanism of action. We found that CMF treatment relieved the inflammation and alteration of the gut microbiota and significantly inhibited the development of intestinal adenoma. Linear discriminant analysis showed that the flora diversity in the normal mice, model mice and CMF treatment mice was different. At the family level, the relative abundance of Desulfovibrionaceae decreased in CMF groups. The relative abundance of Desulfovibrionaceae were lower in the CMF groups than in model group, whereas Rikenellaceae and Alistipes were increased. Altogether our results indicate that CMF treatment ameliorate colitis-associated colorectal carcinogenesis by modulating the composition of the gut microbiota in vivo. [ABSTRACT FROM AUTHOR]

Allicin is the major biologically active compounds of freshly crushed garlic. It has been reported to inhibit the proliferation and promote the apoptosis of multiple colorectal cancer cells. However, the anti-colorectal cancer effect of Allicin has not been verified by in vivo studies. In the present study, we investigated the effect of Allicin on azoxymethane/dextran sodium sulfate (AOM/DSS) colorectal cancer mouse model and explore the underlying possible mechanism. Our result showed that Allicin could inhibit colonic tumorigenesis of AOM/DSS mice in vivo. In vitro study showed that Allicin promoted the apoptosis and suppressed the survival and proliferation of HCT116 cells. The molecular mechanism is related to the suppression of STAT3 signaling activation. Thus, our data provide further support for Allicin as a potential favorable supplement for human colorectal cancer. [ABSTRACT FROM AUTHOR]

Summary: Chronic inflammation may drive development of cancer as observed in inflammation‐induced colorectal cancer (CRC). Though immune cells can infiltrate the tumour microenvironment, cancer cells seem to evade anti‐tumour responses, which is one of the established hallmarks of cancer. Targeting the programmed cell death protein‐1 (PD‐1)/PD‐L1 signalling pathway is currently at the forefront in the development of anti‐tumour immunity‐based therapies for multiple malignancies. By blocking the immune‐checkpoint of activated T‐cells, it is possible to rewire the adaptive resistance induced by the PD‐1 ligands expressed in the tumour microenvironment. However, adverse immunotherapy‐modulated events could complicate the treatment of individuals with preexisting chronic inflammatory conditions. In this study, we investigated the expression of different systemic and mucosal T‐cell subsets during the course of azoxymethane (AOM)/dextran sulphate sodium (DSS)‐induced colitis and colitis‐associated CRC. In addition, we examined the expression of PD‐1 and its ligands PD‐L1 and PD‐L2 as well as other molecular targets related to T‐cell exhaustion. We found a significant increase in PD‐1 expression on all examined mucosal T‐cell subsets of the colon and the ileum, which correlated with disease progression. We also observed an upregulation of PD‐L1 and PD‐L2 mRNA expression throughout the AOM/DSS regime. Blocking PD‐1 signalling with an anti‐PD1 antibody did not affect the tumour burden in the AOM/DSS‐treated mice, but did potentiate the weight loss in the third DSS cycle, indicating possible immune‐mediated toxicity. This raises a concern for patients with colitis‐associated CRCs and should be further investigated. [ABSTRACT FROM AUTHOR]

Background and Aims Epithelial expression of the insulin receptor in the colon has previously been reported to correlate with extent of colonic inflammation. However, the impact of insulin signalling in the intestinal mucosa is still unknown. Here, we investigated the effects of inactivating the epithelial insulin receptor in the intestinal tract, in an experimental model of inflammation-induced colorectal cancer. Methods The mice were generated by utilizing the intestinal- and epithelial-specific villin promoter and the Cre-Lox technology. All mice included in the cohorts were generated by crossing [ vil-Cre-INSR +/–] × [ INSRfl/fl ] to obtain [ vil-Cre-INSR –/–], and their floxed littermates [ INSRfl/fl ] served as the control group. For the intervention study, phosphate-buffered saline with or without insulin was instilled rectally in anaesthetized wild-type mice with chemically induced colitis. Results We found higher endoscopic colitis scores together with potentiated colonic tumorigenesis in the knockout mice. Furthermore, we showed that topically administered insulin in inflamed colons of wild-type mice reduced inflammation-induced weight loss and improved remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores and reduced cyclooxygenase 2 mRNA expression, and developed significantly fewer and smaller tumours compared with the control group receiving phosphate-buffered saline only. Conclusions Rectal insulin therapy could potentially be a novel treatment, targeting the epithelial layer to enhance mucosal healing in ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

The oral bioavailability and efficacy of citrus polymethoxyflavone, tangeretin, was attenuated by its poor aqueous solubility. An emulsion-based delivery system was utilized to enhance the anti-tumourigenesis activity of tangeretin. The in vitro anti-proliferative activity of tangeretin was first evaluated using methyl thiazol tetrazolium bromide (MTT) test on colonic carcinoma cell lines, HCT116 and HT29. The utilization of emulsion system significantly improved the efficacy of tangeretin at dosing concentrations at 12.5 and 25 µM. The effectiveness of the emulsion system in enhancing the in vivo oral efficacy of tangeretin against colorectal cancer development was also evaluated by azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis related colon tumourigenesis model. The tumour incidence, multiplicity, and pathological signs of colorectal adenoma were significantly reduced when tangeretin emulsion was applied. The regulation on tumourigenesis related protein expression was more effective in mice treated with tangeretin emulsion than unformulated suspension. Our finding indicated that emulsion-based delivery system was an effective means to increase the oral efficacy of tangeretin. This study is the first successful demonstration of the effect of delivery system on the oral efficacy of nutraceutical using long-term animal model.

Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, highlighting the pressing need to address its development. Inflammation plays a crucial role in augmenting the risk of CRC and actively contributes to all stages of tumorigenesis. Consequently, targeting early inflammatory responses in the intestinal tract to restore homeostasis holds significant potential for preventing and treating CRC. Fibrinogen C domain-containing 1 (FIBCD1), a chitin-binding transmembrane protein predominantly found on human intestinal epithelial cells (IECs), has garnered attention in previous research for its ability to effectively suppress inflammatory responses and promote tissue homeostasis at mucosal barriers., Methods: In this study, we investigated the role of FIBCD1 in CRC development using transgenic mice that mimic human expression of FIBCD1 at the intestinal mucosal barrier. To model aspects of CRC, we employed the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. Additionally, we examined the expression pattern of FIBCD1 in surgical specimens obtained from human CRC patients by immunohistochemical methods. By accessing public data repositories, we further evaluated FIBCD1 expression in colon adenocarcinoma and explored survival outcomes associated with FIBCD1 expression., Results: Here, we demonstrate that FIBCD1 substantially impacts CRC development by significantly reducing intestinal inflammation and suppressing colorectal tumorigenesis in mice. Furthermore, we identify a soluble variant of FIBCD1 that is significantly increased in feces during acute inflammation. Finally, we demonstrate increased expression of FIBCD1 by immunohistochemistry in human CRC specimens at more developed tumor stages. These results are further supported by bioinformatic analyses of publicly available repositories, indicating increased FIBCD1 expression in tumor tissues, where higher expression is associated with unfavorable prognosis., Conclusion: Collectively, these findings suggest that FIBCD1 influences early inflammatory responses in the AOM/DSS model, leading to a reduction in tumor size and burden. The increased expression of FIBCD1 in human CRC samples raises intriguing questions regarding its role in CRC, positioning it as a compelling candidate and novel molecular target for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shahgoli, Dubik, Pilecki, Skallerup, Schmidt, Detlefsen, Sorensen, Holmskov, Baradaran and Moeller.)

Chronic inflammation-induced oxidative stress is an important driving force for developing colitis-associated cancer (CAC). 4-hydroxynonenal (4-HNE) is a highly reactive aldehyde derived from lipid peroxidation of ω-6 polyunsaturated fatty acids that contributes to colorectal carcinogenesis. Glutathione S -transferase alpha 4 (Gsta4) specifically conjugates glutathione to 4-HNE and thereby detoxifies 4-HNE. The correlation of these oxidative biomarkers with the pathological changes in CAC is, however, unclear. In this study, we investigated the expression of Gsta4 and 4-HNE adducts in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced murine CAC, and analyzed the correlations of 4-HNE and Gsta4 with inflammatory cytokines and the pathological scores in the colon biopsies. Real-time quantitative PCR showed that expression of IL6, TNFα, and Gsta4 sequentially increased in colon tissues for mice treated with DSS for 1, 2, and 3 cycles, respectively. Moreover, immunohistochemical staining showed remarkably increased expression of 4-HNE adducts, Gsta4, TNFα, and IL6 in the colon biopsies after 3 cycles of DSS treatment. Correlation analysis demonstrated that 4-HNE adducts in the colon biopsies were positively correlated with Gsta4 expression. Additionally, the expression of Gsta4 and 4-HNE adducts were strongly correlated with the pathological changes of colon, as well as the expression of TNFα and IL6 in colon tissues. These results provide evidence for the association of oxidative biomarkers Gsta4 and 4-HNE with the pathological changes of CAC and may help developing novel histopathological biomarkers and prevention targets for CAC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: An azoxymethane/dextran sulfate sodium (AOM/DSS) protocol has been developed for the induction in an animal model of the precancerous stages of colitis-associated carcinogenesis, by modification of the established (AOM/DSS protocol for carcinogenesis.Methods: Female C57BL6 mice were treated with a single intraperitoneal dose (10 mg/kg of body weight) of AOM followed by three, 5-day, cycles of oral DSS, at different dosages, with each cycle interrupted by a 2-week rest period.Results: The 3 mice in the group that were given three, 5-day, cycles of oral 2.5 % DSS all developed colonic adenomas with dysplastic lesions, but none had developed adenocarcinoma at 60 days. In contrast, of 6 mice treated with AOM administration along with either three, 5-day, cycles of 3.0% DSS or three, 7-day, cycles of 2.5% DSS, 5 had developed cancer at day 84 of the experiment. These results suggest that the administration of three, 5-day, cycles of 2.5% DSS following an initial dose of AOM may successfully induce adenoma formation in female C57BL6 mice at day 60, without the concurrent presence of carcinoma.Conclusion: This modification of the widely used AOM/DSS protocol for induction of colonic carcinoma may constitute a novel approach for investigating colitis-related colonic adenomas. [ABSTRACT FROM AUTHOR]

Objective: Chronic intestinal inflammation is a risk factor for colorectal cancer (CRC) initiation and development. Diets that are rich in Western style fats have been shown to promote CRC. This study was conducted to investigate the role of intestinal microbiome in American ginseng-mediated CRC chemoprevention in a mouse model. The population and diversity of enteric microbiome were evaluated after the ginseng treatment.Methods: Using an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced gut inflammation and tumorigenesis mouse model, the effects of oral American ginseng on high fat diet-associated enteric pathology were determined. After establishment of a 16S rRNA illumina library from fecal samples, MiSeq sequencing was carried out to reveal the microbial population. The alpha and beta diversities of microbiome were analyzed.Results: American ginseng significantly attenuated AOM/DSS-induced colon inflammation and tumorigenesis by reducing the colitis score and colon tumor multiplicity. The MiSeq results showed that the majority of sequences fell into three phyla: Firmicutes, Bacteroidetes and Verrucomicrobia. Further, two significant abundance shifts at the family level, Bacteroidaceae and Porphyromonadaceae, were identified to support ginseng’s anti-colitis and anti-tumor effects. In addition, alpha and beta diversity data demonstrated that ginseng led to a profound recovery from the AOM/DSS-induced dysbiosis in the microbial community.Conclusion: Our results suggest that the CRC chemopreventive effects of American ginseng are mediated through enteric microbiome population-shift recovery and dysbiosis restoration. Ginseng’s regulation of the microbiome balance contributes to the maintenance of enteric homeostasis. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, occurring in the colon or rectum portion of large intestine. With marked antioxidant, anti-inflammation and anti-tumor activities, Camellia nitidissima Chi has been used as an effective treatment of cancer. The azoxymethane/dextran sodium sulfate (AOM/DSS) induced CRC mice model was established and the prevention effect of C. nitidissima Chi extracts on the evolving of CRC was evaluated by examination of neoplastic lesions, histopathological inspection, serum biochemistry analysis, combined with nuclear magnetic resonance (NMR)-based metabolomics and correlation network analysis. C. nitidissima Chi extracts could significantly inhibit AOM/DSS induced CRC, relieve the colonic pathology of inflammation and ameliorate the serum biochemistry, and could significantly reverse the disturbed metabolic profiling toward the normal state. Moreover, the butanol fraction showed a better efficacy than the water-soluble fraction of C. nitidissima Chi. Further development of C. nitidissima Chi extracts as a potent CRC inhibitor was warranted.

Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood. To investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-phenyloxazol-5-one, Citrobacter rodentium , Fusobacterium nucleatum , and doxorubicin) with respect to their ability to lead to colonic tumorigenesis. We attempted to correlate the severity of colitis and inflammatory profile with the risk of tumorigenesis in both azoxymethane-dependent and Dclk1/APC fl/fl murine models of colitis-associated cancer. DSS colitis reproducibly led to colonic tumors in both mouse models of colitis-associated cancer. In contrast, all other forms of colitis did not lead to cancer. When compared with the colitis not associated with tumorigenesis, DSS colitis was characterized by significantly increased CD11b+F4/80+Ly6Chigh macrophages and CD11b+Ly6G+ neutrophils. Interestingly, depletion of the CD11b+F4/80+Ly6Chigh macrophages inhibited tumorigenesis, whereas depletion of CD11b+Ly6G+ neutrophils had no effect on tumorigenesis. Furthermore, the macrophage-derived cytokines interleukin-1β, tumor necrosis factor–α, and interleukin-6 were significantly increased in DSS colitis and promoted stemness of Dclk1+ tuft cells that serve as the cellular origin of cancer. We have identified CD11b+F4/80+Ly6Chigh macrophages as key mediators of cancer initiation in colitis-associated cancer. Development of new therapies that target these cells may provide an effective preventative strategy for colitis-associated cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Background & Aims: Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood., Methods: To investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-phenyloxazol-5-one, Citrobacter rodentium, Fusobacterium nucleatum, and doxorubicin) with respect to their ability to lead to colonic tumorigenesis. We attempted to correlate the severity of colitis and inflammatory profile with the risk of tumorigenesis in both azoxymethane-dependent and Dclk1/APC fl/fl murine models of colitis-associated cancer., Results: DSS colitis reproducibly led to colonic tumors in both mouse models of colitis-associated cancer. In contrast, all other forms of colitis did not lead to cancer. When compared with the colitis not associated with tumorigenesis, DSS colitis was characterized by significantly increased CD11b + F4/80 + Ly6C high macrophages and CD11b + Ly6G + neutrophils. Interestingly, depletion of the CD11b + F4/80 + Ly6C high macrophages inhibited tumorigenesis, whereas depletion of CD11b + Ly6G + neutrophils had no effect on tumorigenesis. Furthermore, the macrophage-derived cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 were significantly increased in DSS colitis and promoted stemness of Dclk1 + tuft cells that serve as the cellular origin of cancer., Conclusions: We have identified CD11b + F4/80 + Ly6C high macrophages as key mediators of cancer initiation in colitis-associated cancer. Development of new therapies that target these cells may provide an effective preventative strategy for colitis-associated cancer., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim of the study In this study, we examined the effect of different fractions and components of Chaga mushroom (Inonotus Obliquus) on viability and apoptosis of colon cancer cells. Among them, one component showed the most effective growth inhibition and was identified as ergosterol peroxide by NMR analysis. We investigated the anti-proliferative and apoptosis mechanisms of ergosterol peroxide associated with its anti-cancer activities in human colorectal cancer (CRC) cell lines and tested its anti-tumor effect on colitis-induced CRC developed by Azoxymethane (AOM)/Dextran sulfate sodium (DSS) in a mouse model. Materials and methods We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, Western blot analysis, colony formation assays, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and AOM/DSS mouse models to study the molecular mechanism of metastatic activities in CRC cells. Results Ergosterol peroxide inhibited cell proliferation and also suppressed clonogenic colony formation in HCT116, HT-29, SW620 and DLD-1 CRC cell lines. The growth inhibition observed in these CRC cell lines was the result of apoptosis, which was confirmed by FACS analysis and Western blotting. Ergosterol peroxide inhibited the nuclear levels of β-catenin, which ultimately resulted in reduced transcription of c-Myc, cyclin D1, and CDK-8. Ergosterol peroxide administration showed a tendency to suppress tumor growth in the colon of AOM/DSS-treated mice, and quantification of the IHC staining showed a dramatic decrease in the Ki67-positive staining and an increase in the TUNEL staining of colonic epithelial cells in AOM/DSS-treated mice by ergosterol peroxide for both prevention and therapy. Conclusion Our data suggest that ergosterol peroxide suppresses the proliferation of CRC cell lines and effectively inhibits colitis-associated colon cancer in AOM/DSS-treated mice. Ergosterol peroxide down-regulated β-catenin signaling, which exerted anti-proliferative and pro-apoptotic activities in CRC cells. These properties of ergosterol peroxide advocate its use as a supplement in colon cancer chemoprevention. [ABSTRACT FROM AUTHOR]

The oral bioavailability and efficacy of citrus polymethoxyflavone, tangeretin, was attenuated by its poor aqueous solubility. An emulsion-based delivery system was utilized to enhance the anti-tumourigenesis activity of tangeretin. The in vitro anti-proliferative activity of tangeretin was first evaluated using methyl thiazol tetrazolium bromide (MTT) test on colonic carcinoma cell lines, HCT116 and HT29. The utilization of emulsion system significantly improved the efficacy of tangeretin at dosing concentrations at 12.5 and 25 µM. The effectiveness of the emulsion system in enhancing the in vivo oral efficacy of tangeretin against colorectal cancer development was also evaluated by azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis related colon tumourigenesis model. The tumour incidence, multiplicity, and pathological signs of colorectal adenoma were significantly reduced when tangeretin emulsion was applied. The regulation on tumourigenesis related protein expression was more effective in mice treated with tangeretin emulsion than unformulated suspension. Our finding indicated that emulsion-based delivery system was an effective means to increase the oral efficacy of tangeretin. This study is the first successful demonstration of the effect of delivery system on the oral efficacy of nutraceutical using long-term animal model. [ABSTRACT FROM AUTHOR]

• LEP inhibits colorectal cancer mouse colon shortening and weight loss. • LEP can decrease tumor incidence, restored intestinal barrier integrity. • LEP can reduce excessive inflammation. • LEP consumption significantly alter microbiota overall structure and community. • LEP may be used to treat and prevent colorectal cancer. It is still uncertain whether the consumption of Lachnum sp. polysaccharides (LEP) alleviates colorectal cancer (CRC) through the gut microbiota. In this study, our efforts are focused on the influence of LEP on CRC, intestinal barrier and inflammation, and fecal microbiota and the metabolites, in azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC mice. Results showed that LEP inhibited CRC mouse colon shortening and weight loss, decreased tumor incidence, restored intestinal barrier integrity, and reduced excessive inflammation. LEP consumption significantly altered microbiota overall structure and community, with reduced pernicious bacteria (such as Parabacteroides , Escherichia_Shigella , Desulfovibrio and Helicobacter), and increased beneficial bacterium (such as Alistipes , Alloprevotella and Ruminiclostridium). Fecal-metabolome profile indicated that a total of 43 metabolites were clearly changed, with 10 down-regulated and 33 up-regulated metabolites. In addition, short-chain fatty acids (SCFAs), including acetic acid, propionic acid and n-butyric acid, were significantly increased after LEP administration. Moreover, a strong correlation between the fluctuant gut microbiota and metabolites was found. These findings provided not only deeper insights into the responsibility of LEP for CRC alleviation, and but also the potential of LEP as a promising candidate for CRC prevention and treatment. [ABSTRACT FROM AUTHOR]