scholarly journals Grape Pomace Inhibits Colon Carcinogenesis by Suppressing Cell Proliferation and Inducing Epigenetic Modifications in an AOM/DSS Mouse Model

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 358-358
Author(s):  
Qiyu Tian ◽  
Xhixin Xu ◽  
Xiaofei Sun ◽  
Jeanene Deavila ◽  
Min Du ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Wnt Signaling ◽  
Activity Index ◽  
Control Diet ◽  
Disease Activity Index ◽  
Experimental Period ◽  
Dna Demethylation ◽  
Grape Pomace ◽  
Protective Effects

Abstract Objectives Grape pomace (GP), a by-product of the wine and juice industry, is rich in bioflavonoids and dietary fibers. We hypothesized that grape pomace has protective effects against colitis-associated colorectal cancer (CRC). Methods Nine-week-old female mice were fed a control diet (CON) or CON with 5% grape pomace (GP) for 2 weeks, when mice were subjected to azoxymethane (AOM)/dextran sulfate sodium (DSS) for colorectal cancer (CRC) induction. All animals were received 1% DSS in drinking water for 7 days followed by a 21-day recovery in a 3-cycle experimental period, while receiving their respective diet. Results GP supplementation ameliorated the disease activity index (DAI) score, reduced tumor number, tumor size and pathological scores in AOM/DSS treated mice. Furthermore, dietary GP suppressed colonic expression of inflammatory cytokines, IL-1β and TNF-α, and inhibited NF-κB inflammatory signaling. Colorectal inflammation is known to enhance Wnt signaling and cell proliferation. In agreement, the content of β-catenin, a key downstream mediator of Wnt signaling, was reduced so for the expression of Cyclin D1 phosphorylation and content of p53 and PCNA level in GP-fed mice.  In addition, GP reduced the expression of ALDH1, a marker of cell stemness, and increased the expression of Cdx2, a key transcription factor initiating epithelial cell differentiation. Consistently, DNA methylation of the promoter region of Cdx2 gene and hypermethylation of GpG island methylator phenotype (CIMP), which commonly occurs during CRC carcinogenesis, was alleviated in GP group. Conclusions GP supplementation suppressed colitis-associated CRC carcinogenesis associated with the suppression of inflammation and cell proliferation and the enhancement of DNA demethylation in Cdx2 and CIMP genes in the colon. Funding Sources USDA-NIFA 2018–67,017-27,517.

scholarly journals Deficiency in STAT1 Signaling Predisposes Gut Inflammation and Prompts Colorectal Cancer Development

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 341 ◽  
Author(s):  
Sonia Leon-Cabrera ◽  
Armando Vázquez-Sandoval ◽  
Emmanuel Molina-Guzman ◽  
Yael Delgado-Ramirez ◽  
Norma Delgado-Buenrostro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Activity Index ◽  
Tumor Development ◽  
Disease Activity Index ◽  
Tumor Stroma ◽  
Tumor Formation ◽  
Janus Kinase ◽  
Early Stages

Signal transducer and activator of transcription 1 (STAT1) is part of the Janus kinase (JAK/STAT) signaling pathway that controls critical events in intestinal immune function related to innate and adaptive immunity. Recent studies have implicated STAT1 in tumor–stroma interactions, and its expression and activity are perturbed during colon cancer. However, the role of STAT1 during the initiation of inflammation-associated cancer is not clearly understood. To determine the role of STAT1 in colitis-associated colorectal cancer (CAC), we analyzed the tumor development and kinetics of cell recruitment in wild-type WT or STAT1−/− mice treated with azoxymethane (AOM) and dextran sodium sulfate (DSS). Following CAC induction, STAT1−/− mice displayed an accelerated appearance of inflammation and tumor formation, and increased damage and scores on the disease activity index (DAI) as early as 20 days after AOM-DSS exposure compared to their WT counterparts. STAT1−/− mice showed elevated colonic epithelial cell proliferation in early stages of injury-induced tumor formation and decreased apoptosis in advanced tumors with over-expression of the anti-apoptotic protein Bcl2 at the colon. STAT1−/− mice showed increased accumulation of Ly6G+Ly6C−CD11b+ cells in the spleen at 20 days of CAC development with concomitant increases in the production of IL-17A, IL-17F, and IL-22 cytokines compared to WT mice. Our findings suggest that STAT1 plays a role as a tumor suppressor molecule in inflammation-associated carcinogenesis, particularly during the very early stages of CAC initiation, modulating immune responses as well as controlling mechanisms such as apoptosis and cell proliferation.

scholarly journals Sulforaphane Protects Against DSS-Induced Acute Colitis

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 481-481
Author(s):  
Qiyu Tian ◽  
Min Du ◽  
Xhixin Xu ◽  
Mei-Jun Zhu
Keyword(s):  
Activity Index ◽  
Inflammatory Marker ◽  
Control Diet ◽  
Body Weight Loss ◽  
Disease Activity Index ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Ampk Signaling ◽  
Epithelial Regeneration ◽  
Epithelial Structure

Abstract Objectives This study tested the hypothesis that sulforaphane (SFN) enhances intestinal integrity and epithelial regeneration via AMPK/Nrf2 activation. Methods Male mice at 8-wk-old were subjected to control diet (CON) or CON with 600 ppm SFN for 4 weeks, and then half of mice within each dietary group were subjected to colitis induction (9-day-2.5% DSS treatment in drinking plus 9-day-recovery), while remaining their respective diet. Results SFN administration alleviated acute DSS-induced body weight loss and reduced disease activity index (DAI) score, as well as colon shortening in DSS-treated mice. Additionally, SFN supplementation decreased the mRNA expression of inflammatory markers, interleukin (IL)-1β, while increased anti-inflammatory marker IL-10 in DSS-challenged mice. Furthermore, SFN protected colonic epithelial structure, which was associated with activated AMPK signaling, increased Nrf2 and heme oxygenase-1 content in DSS-induced colitis mice. The roles of AMPK/Nrf2 signaling in mediating the improvement of gut epithelial regeneration following DSS-induced injury will be further studied. Conclusions SFN supplementation had protective effects against DSSinduced colitis and improved gut epithelial structure, which was associated with activation of AMPK/NrF2 signaling. Dietary SFN is a promising approach for the management and prevention of colitis. Funding Sources USDA-NIFA 2018-67,017-27,517.

scholarly journals Protective Effects of Zerumbone on Colonic Tumorigenesis in Enterotoxigenic Bacteroides fragilis (ETBF)-Colonized AOM/DSS BALB/c Mice

2020 ◽  
Vol 21 (3) ◽  
pp. 857 ◽  
Author(s):  
Soonjae Hwang ◽  
Minjeong Jo ◽  
Ju Eun Hong ◽  
Chan Oh Park ◽  
Chang Gun Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Activity Index ◽  
Oral Treatment ◽  
Bacteroides Fragilis ◽  
Disease Activity Index ◽  
Colonic Polyp ◽  
Spleen Weight ◽  
Protective Agent ◽  
Protective Effects ◽  
Murine Models

Chronic inflammation has been linked to colitis-associated colorectal cancer in humans. The human symbiont enterotoxigenic Bacteroides fragilis (ETBF), a pro-carcinogenic bacterium, has the potential to initiate and/or promote colorectal cancer. Antibiotic treatment of ETBF has shown promise in decreasing colonic polyp formation in murine models of colon cancer. However, there are no reported natural products that have shown efficacy in decreasing polyp burden. In this study, we investigated the chemopreventive effects of oral administration of zerumbone in ETBF-colonized mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. Zerumbone significantly reduced the severity of disease activity index (DAI) scores as well as several parameters of colonic inflammation (i.e., colon weight, colon length, cecum weight and spleen weight). In addition, inflammation of the colon and cecum as well as hyperplasia was reduced. Zerumbone treatment significantly inhibited colonic polyp numbers and prevented macroadenoma progression. Taken together, these findings suggest that oral treatment with zerumbone inhibited ETBF-promoted colon carcinogenesis in mice indicating that zerumbone could be employed as a promising protective agent against ETBF-mediated colorectal cancer.

scholarly journals The Protection of Crocin Against Ulcerative Colitis and Colorectal Cancer via Suppression of NF-κB-Mediated Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Shanshan Teng ◽  
Jie Hao ◽  
Hui Bi ◽  
Congcong Li ◽  
Yongfeng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ulcerative Colitis ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Activity Index ◽  
Disease Activity Index ◽  
Protective Effects ◽  
Protein Protein Interactions ◽  
Anti Inflammatory ◽  
Factor Α

Background: In China, the incidence of ulcerative colitis (UC) is increasing every year, but the etiology of UC remains unclear. UC is known to increase the risk of colorectal cancer (CRC). The aim of this study was to investigate the protective effects of crocin against UC and CRC in mouse models.Methods: Crocin was used to treat the dextran sodium sulfate (DSS)-induced UC mice for 3 weeks, and ApcMinC/Gpt mice with colorectal cancer for 8 weeks. Proteomics screening was used to detect changes in the protein profiles of colon tissues of UC mice. Enzyme-linked immunosorbent assays and western blot were used to verify these changes.Results: Crocin strongly reduced the disease activity index scores of UC mice, and improved the pathological symptoms of the colonic epithelium. The anti-inflammatory effects of crocin were indicated by its regulation of the activity of various cytokines, such as interleukins, via the modulation of nuclear factor kappa-B (NF-κB) signaling. Crocin significantly suppressed tumor growth in ApcMinC/Gpt mice and ameliorated pathological alterations in the colon and liver, but had no effects on spleen and kidney. Additionally, crocin significantly decreased the concentrations of interleukins and tumor necrosis factor-α in the sera and colon tissues, suggesting its anti-inflammatory effects related to NF-κB signaling. Finally, 12-h incubation of SW480 cells with crocin caused cell cycle arrest, enhanced the apoptotic rate, promoted the dissipation of mitochondrial membrane potential, and the over-accumulation of reactive oxygen species. From the theoretical analyses, phosphorylated residues on S536 may enhance the protein-protein interactions which may influence the conformational changes in the secondary structure of NF-κB.Conclusion: The protective effects of crocin on UC and CRC were due to its suppression of NF-κB-mediated inflammation.

scholarly journals Supplementation of the diet with Salecan attenuates the symptoms of colitis induced by dextran sulphate sodium in mice

2014 ◽  
Vol 111 (10) ◽  
pp. 1822-1829 ◽  
Author(s):  
Mengyi Zhou ◽  
Zhongqiu Wang ◽  
Jinping Chen ◽  
Yibei Zhan ◽  
Tao Wang ◽  
...  
Keyword(s):  
Activity Index ◽  
Disease Activity Index ◽  
Experimental Period ◽  
Water Soluble ◽  
Myeloperoxidase Activity ◽  
Mrna Levels ◽  
Protective Effects ◽  
Dextran Sulphate ◽  
Dextran Sulphate Sodium ◽  
Tnf Α

As a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, Salecan has an excellent toxicological profile and exerts multiple physiological effects. The aims of the present study were to investigate the protective effects of a Salecan diet in the well-defined dextran sulphate sodium (DSS) model of experimental murine colitis and to elucidate the mechanism involved in its effects with special attention being paid to its effect on the production of TNF-α, a primary mediator involved in the inflammatory response. Male C57BL/6J mice were fed a diet supplemented with either 4 or 8 % Salecan for 26 d and DSS was administered to induce acute colitis during the last 5 d of the experimental period. Several clinical and inflammatory parameters as well as mRNA expression of TNF-α and Dectin-1 were evaluated. The results indicated that the dietary incorporation of Salecan attenuated the severity of DSS colitis as evidenced by the decreased disease activity index, reduced severity of anaemia, attenuated changes in colon architecture and reduced colonic myeloperoxidase activity. This protection was associated with the down-regulation of TNF-α mRNA levels, which might derive from its ability to increase Dectin-1 mRNA levels. In conclusion, the present study suggests that Salecan contributes to the reduction of colonic damage and inflammation in mice with DSS-induced colitis and holds promise as a new, effective nutritional supplement in the management of inflammatory bowel disease.

Evaluation of MACF1-regulatory non-coding RNA as a potential therapeutic target in Colorectal Cancer

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Rowaida Mohammed Reda M. M Aboushahba ◽  
Fayda Ibrahim Abdel Motaleb ◽  
Ahmed Abdel Aziz Abou-Zeid ◽  
Enas Samir Nabil ◽  
Dalia Abdel-Wahab Mohamed ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Wnt Signaling ◽  
Cell Line ◽  
Signaling Pathway ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Control Group ◽  
Potential Therapeutic Target

ABSTRACT Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths world-wide. There is an increasing need for the identification of novel biomarkers/targets for early diagnosis and for the development of novel chemopreventive and therapeutic agents for CRC. Recently, MACF1 gene has emerged as a potential therapeutic target in cancer as it involved in processes critical for tumor cell proliferation, invasion and metastasis. It is suggested that MACF1 may function in cancers through Wnt signaling. MiR-34a is a well-known tumor suppressor miRNA.miR-34a targets MACF1 gene as a part of the wnt signaling pathway. In this study, 40 colonic tissues were collected from CRC patients (20) and control subjects (20). miR-34a-5p was assessed by real time PCR in all study groups. The results showed highly significant decrease (P < 0.01) in miR-34a relative expression in the CRC group (median RQ 0.13) when compared to the benign group (median RQ 5.3) and the healthy control group (median RQ 19.63). miR-34a mimic and inhibitor were transfected in CaCo-2 cell line and proliferation was assessed. The transfection of the cell line with miR-34a mimic decreased cell proliferation. Our study suggests that miR-34a-5p targets MACF1 gene as a part of the wnt signaling pathway leading to the involvement in the molecular mechanisms of CRC development and progression.

scholarly journals Brusatol-Enriched Brucea javanica Oil Ameliorated Dextran Sulfate Sodium-Induced Colitis in Mice: Involvement of NF-κB and RhoA/ROCK Signaling Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Xinghan Zheng ◽  
Liting Mai ◽  
Tongtong Wang ◽  
Ying Xu ◽  
Zireng Su ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Activity Index ◽  
Disease Activity Index ◽  
Protective Effects ◽  
Intestinal Epithelial ◽  
Colon Tissue ◽  
Epithelial Barrier Function ◽  
Brucea Javanica ◽  
Tnf Α ◽  
Brucea Javanica Oil

Brucea javanica oil (BJO) is beneficial for the treatment of ulcerative colitis (UC), and that quassinoids in particular brusatol are bioactive components. However, it is still uncertain whether or not other components in BJO, such as oleic acid and fatty acids, have an anti-UC effect. The present study is aimed at comparing the anti-UC effects between brusatol-enriched BJO (BE-BJO) and brusatol-free BJO (BF-BJO) and at exploring the effects and mechanisms of BE-BJO on colon inflammation and intestinal epithelial barrier function. Balb/C mice received 3% (wt/vol) DSS for one week to establish the UC model. Different doses of BE-BJO, BF-BJO, or BJO were treated. The result illustrated that BE-BJO alleviated DSS-induced loss of body weight, an increase of disease activity index (DAI), and a shortening of colon, whereas BF-BJO did not have these protective effects. BE-BJO treatment improved the morphology of colon tissue, inhibited the production and release of TNF-α, IFN-γ, IL-6, and IL-1β in the colon tissue, and reversed the decreased expressions of ZO-1, occludin, claudin-1, and E-cadherin induced by DSS but augmented claudin-2 expression. Mechanistically, BE-BJO repressed phosphorylation of NF-κB subunit p65, suppressed RhoA activation, downregulated ROCK, and prevented phosphorylation of myosin light chain (MLC) in DSS-treated mice, indicating that the protective effect of BE-BJO is attributed to suppression of NF-κB and RhoA/ROCK signaling pathways. These findings confirm that brusatol is an active component from BJO in the treatment of UC.

scholarly journals l-Isoleucine Administration Alleviates DSS-Induced Colitis by Regulating TLR4/MyD88/NF-κB Pathway in Rats

2022 ◽  
Vol 12 ◽  
Author(s):  
Xiangbing Mao ◽  
Rui Sun ◽  
Qingxiang Wang ◽  
Daiwen Chen ◽  
Bing Yu ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Activity Index ◽  
Control Diet ◽  
Average Daily Gain ◽  
Disease Activity Index ◽  
Inflammatory Cells ◽  
Feed Conversion ◽  
Enterocyte Apoptosis

Inflammatory bowel disease (namely, colitis) severely impairs human health. Isoleucine is reported to regulate immune function (such as the production of immunoreactive substances). The aim of this study was to investigate whether l-isoleucine administration might alleviate dextran sulfate sodium (DSS)-induced colitis in rats. In the in vitro trial, IEC-18 cells were treated by 4 mmol/L l-isoleucine for 12 h, which relieved the decrease of cell viability that was induced by TNF-α (10 ng/ml) challenge for 24 h (P <0.05). Then, in the in vivo experiment, a total of 44 Wistar rats were allotted into 2 groups that were fed l-isoleucine-supplemented diet and control diet for 35 d. From 15 to 35 d, half of the rats in the 2 groups drank the 4% DSS-adding water. Average daily gain, average daily feed intake and feed conversion of rats were impaired by DSS challenge (P <0.05). Drinking the DSS-supplementing water also increased disease activity index (DAI) and serum urea nitrogen level (P <0.05), shortened colonic length (P <0.05), impaired colonic enterocyte apoptosis, cell cycle, and the ZO-1 mRNA expression (P <0.05), increased the ratio of CD11c-, CD64-, and CD169-positive cells in colon (P <0.05), and induced extensive ulcer, infiltration of inflammatory cells, and collagenous fiber hyperplasia in colon. However, dietary l-isoleucine supplementation attenuated the negative effect of DSS challenge on growth performance (P <0.05), DAI (P <0.05), colonic length and enterocyte apoptosis (P <0.05), and dysfunction of colonic histology, and downregulated the ratio of CD11c-, CD64-, and CD169-positive cells, pro-inflammation cytokines and the mRNA expression of TLR4, MyD88, and NF-κB in the colon of rats (P <0.05). These results suggest that supplementing l-isoleucine in diet improved the DSS-induced growth stunting and colonic damage in rats, which could be associated with the downregulation of inflammation via regulating TLR4/MyD88/NF-κB pathway in colon.

The Adipokine Metrnl Ameliorates Chronic Colitis in Il-10–/– Mice by Attenuating Mesenteric Adipose Tissue Lesions During Spontaneous Colitis

2019 ◽  
Vol 13 (7) ◽  
pp. 931-941 ◽  
Author(s):  
Lugen Zuo ◽  
Sitang Ge ◽  
Yuanyuan Ge ◽  
Jingjing Li ◽  
Bing Zhu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Activity Index ◽  
Disease Activity Index ◽  
Experimental Colitis ◽  
Protective Effects ◽  
Systemic Delivery ◽  
Chronic Colitis ◽  
Mesenteric Adipose Tissue ◽  
Proinflammatory Mediators ◽  
Ppar Γ

Abstract Background Crosstalk between mesenteric adipose tissue [MAT] and the intestines affects the progression of Crohn’s disease [CD]. The adipokine metrnl regulates adipocyte function and has anti-inflammatory activity. We aimed to explore metrnl expression in CD MAT, investigate the influence of metrnl on the experimental colitis disease course and determine the mechanism underlying this effect. Methods Metrnl expression in MAT specimens obtained from patients with and without CD was tested by immunohistochemistry. Male Il-10–/– mice with spontaneous enteritis were divided into positive control and metrnl-treated [Metrnl-Fc, 10 mg/kg/d, intraperitoneally, 8 weeks] groups. Age-matched male wild-type [WT] mice were used as negative controls. The effects of metrnl on enteritis and mesenteric lesions and the potential controlling mechanisms were evaluated. Results Metrnl expression was higher in human CD MAT than in control MAT. Systemic delivery of metrnl significantly ameliorated chronic colitis in Il-10–/– mice, as demonstrated by decreases in the disease activity index, inflammatory score and proinflammatory mediators. The protective effects of metrnl on MAT included reduced mesenteric hypertrophy, increased adipocyte size, improved adipocyte intrinsic function and ameliorated inflammation. Metrnl treatment activated STAT5/PPAR-γ signaling and promoted adipocyte differentiation in the MAT. Conclusions Metrnl expression was increased in the MAT of CD patients. Metrnl administration attenuated mesenteric lesions by promoting adipocyte function and differentiation partly through STAT5/PPAR-γ signaling pathway activation, thereby ameliorating CD-like colitis in mice.

scholarly journals Indigo Naturalis Suppresses Colonic Oxidative Stress and Th1/Th17 Responses of DSS-Induced Colitis in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Hai-tao Xiao ◽  
Jiao Peng ◽  
Bo Wen ◽  
Dong-dong Hu ◽  
Xiao-peng Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chinese Medicine ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Activity Index ◽  
Disease Activity Index ◽  
Protective Effects ◽  
Mesenteric Lymph Nodes ◽  
Indigo Naturalis

Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An in vitro assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD.

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