Diseases Including Colon Cancer Research Articles

Understanding the Gastrointestinal Protective Effects of Polyphenols using Foodomics-Based Approaches.

Plant polyphenols are rich sources of natural anti-oxidants and prebiotics. After ingestion, most polyphenols are absorbed in the intestine and interact with the gut microbiota and modulated metabolites produced by bacterial fermentation, such as short-chain fatty acids (SCFAs). Dietary polyphenols immunomodulatory role by regulating intestinal microorganisms, inhibiting the etiology and pathogenesis of various diseases including colon cancer, colorectal cancer, inflammatory bowel disease (IBD) and colitis. Foodomics is a novel high-throughput analysis approach widely applied in food and nutrition studies, incorporating genomics, transcriptomics, proteomics, metabolomics, and integrating multi-omics technologies. In this review, we present an overview of foodomics technologies for identifying active polyphenol components from natural foods, as well as a summary of the gastrointestinal protective effects of polyphenols based on foodomics approaches. Furthermore, we critically assess the limitations in applying foodomics technologies to investigate the protective effect of polyphenols on the gastrointestinal (GI) system. Finally, we outline future directions of foodomics techniques to investigate GI protective effects of polyphenols. Foodomics based on the combination of several analytical platforms and data processing for genomics, transcriptomics, proteomics and metabolomics studies, provides abundant data and a more comprehensive understanding of the interactions between polyphenols and the GI tract at the molecular level. This contribution provides a basis for further exploring the protective mechanisms of polyphenols on the GI system.

Bcl9 Depletion Modulates Endothelial Cell in Tumor Immune Microenvironment in Colorectal Cancer Tumor.

Tumor endothelial cells are an important part of the tumor microenvironment, and angiogenesis inhibitory therapy has shown potential in tumor treatment. However, which subtypes of tumor endothelial cells are distributed in tumors, what are the differences between tumor endothelial cells and normal endothelial cells, and what is the mechanism of angiogenesis inhibitory therapy at the histological level, are all need to be resolved urgently. Using single-cell mRNA sequencing, we analyzed 12 CT26 colon cancer samples from mice, and found that knockdown of the downstream factor BCL9 in the Wnt signaling pathway or inhibitor-mediated functional inhibition can modulate tumor endothelial cells at a relatively primitive stage, inhibiting their differentiation into further extracellular matrix construction and angiogenesis functions. Furthermore, we propose a BCL9-endo-Score based on the differential expression of cells related to different states of BCL9 functions. Using published data sets with normal endothelial cells, we found that this score can characterize endothelial cells at different stages of differentiation. Finally, in the The Cancer Genome Atlas (TCGA) pan-cancer database, we found that BCL9-endo-Score can well predict the prognosis of diseases including colon cancer, kidney cancer and breast cancer, and identified the markers of these tumor subtypes, provide a basis for the prognosis prediction of patients with such types of tumor. Our data also contributed knowledge for tumor precision treatment with angiogenesis inhibitory therapy by targeting the Wnt signaling pathway.

<i>β</i>-Glucuronidase inhibitory activity of bromophenol isolated from red alga <i>Grateloupia lancifolia</i>

The human gastrointestinal (GI) tract plays an important role in disease and health. The overexpression of β -glucuronidase, an enzyme produced in the gastrointestinal tract, has been found to cause the retoxification of potentially damaging substances already detoxified by liver glucuronidation. Thus, β -glucuronidase has been implicated in a number of diseases including colon cancer, liver disease and Crohn's disease. This study investigated β -glucuronidase inhibitory activity of a bromophenol purified from the red alga Grateloupia lancifolia . Using an assay-guided fractionation technique, a bromophenol, bis(2, 3-dibromo-4, 5-dihydroxybenzyl) ether, a bromophenol, was isolated from the red alga G. lancifolia . Its structure was elucidated on the basis of extensive 1D- and 2D-NMR studies, high resolution EI-MS analysis and comparisons with literature data. Bis(2, 3-dibromo-4, 5-dihydroxybenzyl) ether showed potent β -glucuronidase inhibitory activity. The IC50 and KI values of bromophenol against E. coli β -glucuronidase were 0.54 and 0.53 mM, respectively. This bromophenol inhibited β -glucuronidase competitively and was stable at pH 2 up to 40 min at 37 ℃.

Immunoglobulin receptors expression in indian colon cancer patients and healthy subjects using a noninvasive approach and flowcytometry

Background:Isolation of viable colonocytes from human stool is a noninvasive and convenient approach that can be used for diagnostic, screening, management, and research on various gastrointestinal (GI) diseases including colon cancer. Limited studies are available globally and for the first time in this article, we have reported the immunoglobulin (Ig) (IgA and IgG) receptors concentration on viable colonocytes for Indian colon cancer patients using this noninvasive approach.Materials and Methods:Viable colonocytes from stool were isolated by the Somatic Cell Sampling and Recovery method (Noninvasive Technology, USA) and processed for the assessment of Igs (IgA and IgG) receptors expression using standard immunophenotyping and flow cytometry.Results:IgA and IgG receptor expression was measured and reported on these viable colonocytes. There was a significant difference in the expression of IgA and IgG receptors on viable colonocytes between colon cancer patients and healthy individuals.Conclusion:This noninvasive technique is a promising approach for the detection of molecular and immunological markers that will help clinicians in the diagnosis, screening, monitoring, and management of different GI diseases including colon cancer.

PH-sensitive polymeric nanoparticles of quercetin as a potential colon cancer-targeted nanomedicine

Quercetin (QCT) is an abundant plant polyphenol with demonstrated efficacy in several diseases including colon cancer. Herein we have developed polymeric nanoparticles (NPs) of QCT based on the pH-sensitive polymer Eudragit® S100 to achieve colon pH-specific drug release following oral administration. NPs were prepared by the nanoprecipitation technique and showed a mean diameter of 66.8 nm and a partially negative surface charge of −5.2 mV. NPs contained on average 2.2% w/w QCT at an encapsulation efficiency of 41.8%. IR spectroscopy and differential scanning calorimetry (DSC) both revealed the presence of intermolecular interactions, most likely H-bonding, between QCT and Eudragit® S100, which likely contributed to drug loading. DSC also indicated that the drug was present in the NPs in an amorphous state, which was further confirmed by X-ray diffraction. In vitro release testing showed a delay in drug release in acidic pH, but complete release within 24 h at pH 7.2. A cytotoxicity assay was performed on CT26 murine colon carcinoma cells, where QCT-loaded NPs displayed significantly higher potency (IC50 = 0.8 μM) than free QCT (IC50 = 65.1 μM). Our findings present a promising nanomedicine for colon-targeted delivery of QCT in diseases such as colon cancer.

Role of hypoxia-inducible factors (HIF) in the maintenance of stemness and malignancy of colorectal cancer

Hypoxia is a condition of insufficient tissue oxygenation, which is observed during normal development as well as tumorigenesis and its response at the cellular level is primarily mediated through hypoxia inducible factors (HIFs). HIFs have a significant role in the maintenance of stemness in both stem cells as well as in cancer stem cells (CSC) by acting as transcription factors. The CSCs are proposed to be the driving force of colon tumorigenesis and malignancy. These HIFs play a significant role in a wide range of diseases including colon cancer. HIF's signaling functions with stemness, and maintaining Wnt/β-catenin signaling pathways. Due to HIFs functional significance in stemness maintenance in malignancy, targeting HIFs might provide a new approach for development of new therapy for colon cancer. In this review, we will be briefing on the colon and its stem cells, various molecular signaling pathways involved in stemness preservation, and the role hypoxia and its HIFs in the maintenance of stemness in colon stem cells and colon cancer stem cells.

N-3 PUFAs: an Elixir in Prevention of Colorectal Cancer

Dietary fats especially essential unsaturated fatty acids have been proven to be major determinants in cancer progression and propagation. Epidemiological and experimental data indicates that consumption of higher amounts of n-6 PUFAs with respect to n-3 PUFAs increases the predisposition to various diseases including colon cancer. The chemopreventive effect of n-3 PUFAs has been ascribed to the replacement of n-6 PUFAs in cell membrane-associated lipid rafts. The change in architecture of their lipid rafts influences the behavior of membrane-bound proteins and receptors, and thereby, modulation of various signalling cascades regulating cell proliferation, apoptosis, and other pathways involved in carcinogenesis. Altered signalling pathways can maintain the intestinal homeostasis by hampering the expression of the genes involved in inflammation, angiogenesis, and metastasis of colon cancer. These properties of n-3 PUFAs make them a potential candidate for cancer chemoprevention. In this review, we discuss the molecular mechanism of action of n-3 PUFAs on the chemoprevention of colon cancer.

The Gβ5 protein regulates sensitivity to TRAIL-induced cell death in colon carcinoma.

Aberrant signaling via G protein-coupled receptors (GPCRs) is implicated in numerous diseases including colon cancer. The heterotrimeric G proteins transduce signals from GPCRs to various effectors. So far, the G protein subunit Gβ5 has not been studied in the context of cancer. Here we demonstrate that Gβ5 protects colon carcinoma cells from apoptosis induced by the death ligand TRAIL via different routes. The Gβ5 protein (i) causes a decrease in the cell surface expression of the TRAIL-R2 death receptor, (ii) induces the expression of the anti-apoptotic protein XIAP and (iii) activates the NF-κB signaling pathway. The intrinsic resistance to TRAIL-triggered apoptosis of colon cancer cells is overcome by antagonization of Gβ5. Based on these results, targeting of G proteins emerges as a novel therapeutic approach in the experimental treatment of colon cancer.

Wnt5a promotes human colon cancer cell migration and invasion but does not augment intestinal tumorigenesis in Apc 1638N mice

Whereas aberrant activation of canonical Wnt/β-catenin signaling underlies the majority of colorectal cancer cases, the contribution of non-canonical Wnt signaling is unclear. As enhanced expression of the most extensively studied non-canonical Wnt ligand WNT5A is observed in various diseases including colon cancer, WNT5A is gaining attention nowadays. Numerous in vitro studies suggest modulating capacities of WNT5A on proliferation, differentiation, migration and invasion, affecting tumor and non-mutant cells. However, a possible contribution of WNT5A to colorectal cancer remains to be elucidated. We have analyzed WNT5A expression in colorectal cancer profiling data sets, altered WNT5A expression in colon cancer cells and used our inducible Wnt5a transgenic mouse model to gain more insight into the role of WNT5A in intestinal cancer. We observed that increased WNT5A expression is associated with poor prognosis of colorectal cancer patients. WNT5A knockdown in human colon cancer cells caused reduced directional migration, deregulated focal adhesion site formation and reduced invasion, whereas Wnt5a administration promoted the directional migration of colon cancer cells. Despite these observed protumorigenic activities of WNT5A, the induction of Wnt5a expression in intestinal tumors of Apc1638N mice was not sufficient to augment malignancy or metastasis by itself. In conclusion, WNT5A promotes adhesion sites to form in a focal fashion and promotes the directional migration and invasion of colon cancer cells. Although these activities appear insufficient by themselves to augment malignancy or metastasis in Apc1638N mice, they might explain the poor colon cancer prognosis associated with enhanced WNT5A expression.

Elevated incidence of polyp formation in APC(Min/⁺)Msh2⁻/⁻ mice is independent of nitric oxide-induced DNA mutations.

Gut microbiota has been linked to a number of human diseases including colon cancer. However, the mechanism through which gut bacteria influence colon cancer development and progression remains unclear. Perturbation of the homeostasis between the host immune system and microbiota leads to inflammation and activation of macrophages which produce large amounts of nitric oxide that acts as a genotoxic effector molecule to suppress bacterial growth. However, nitric oxide also has genotoxic effects to host cells by producing mutations that can predispose to colon cancer development. The major DNA lesions caused by nitric oxide are 8oxoG and deamination of deoxycytosine bases. Cellular glycosylases that belong to the base excision repair pathway have been demonstrated to repair these mutations. Recent evidence suggests that the mismatch repair pathway (MMR) might also repair nitric oxide-induced DNA damage. Since deficiency in MMR predisposes to colon cancer, we hypothesized that MMR-deficient colon epithelial cells are incapable of repairing nitric-oxide induced genetic lesions that can promote colon cancer. Indeed, we found that the MMR pathway repairs nitric oxide-induced DNA mutations in cell lines. To test whether nitric oxide promotes colon cancer, we genetically ablated the inducible nitric oxide synthase (iNOS) or inhibited iNOS activity in the APCMin/+Msh2−/− mouse model of colon cancer. However, despite the fact that nitric oxide production was strongly reduced in the colon using both approaches, colon cancer incidence was not affected. These data show that nitric oxide and iNOS do not promote colon cancer in APCMin/+Msh2−/− mice.

Is There True Gender Difference of Irritable Bowel Syndrome in Asia?: Author's Reply

TO THE EDITOR: We appreciate sincerely the interest of Dr. Jung on our paper on the Prevalence of irritable bowel syndrome: a community based study from Northern India.1 We do agree with the points raised by Dr. Jung. We limited the age group of participants between 18-64 years in this study. In elderly, the clinical features of colonic malignancy may mimic that of irritable bowel syndrome (IBS) and before making a diagnosis of IBS, one needs to do thorough investigations to exclude organic diseases including colon cancer especially once the symptoms are of recent origin. IBS is more common in women than in men in many Western countries. No consistent gender difference however has been observed in the community based studies from Asia.2 A clear male predominance is observed in patients with IBS in hospital based studies. In male dominant society, health seeking behavior of males is probably the best explanation for a difference in the prevalence of IBS in the studies conducted in hospital setting and those done in the community. We agree with Dr. Jung that more information should be drawn in any epidemiological study. Since we had piggy bagged this study with our main objective of finding out the community prevalence of celiac disease, we purposely kept the questionnaire related with IBS to the basic minimum.3 We thank again Dr. Jung for bringing some of her thoughts on our paper.

Chemical Analysis of the Chinese Herbal Medicine Turmeric (Curcuma longa L.)

Turmeric (Curcuma longa L., Zingiberaceae family) is a well known Chinese herbal medicine. It possesses diverse pharmacologic effects including antioxidant, anti-inflammatory, antiproliferative and antiangiogenic activities. The main bioactive constituents of C. longa include sesquiterpenes, which are responsible for its aroma, and curcuminoids, which contribute to its bright yellow color. Both sesquiterpenes and curcuminoids exhibit great potential as therapeutic agents for various diseases including colon cancer, pancreatic cancer, diabetes and Alzheimer's disease. Particularly, curcumin, one of the major curcuminoids of turmeric, has been proved to be effective in cancer treatment and prevention by recent phase I clinical trials. In order to ensure the efficacy and safety of turmeric in clinical applications, sensitive and accurate analytical methods are of significance for the comprehensive quality control of C. longa. This review summarizes recent progress in the chemical analysis of sesquiterpenes and curcuminoids in turmeric. Keywords: Curcuma longa L, Sesquiterpenes, Curcuminoids, Chemical analysis, Quality control, Chinese herbal medicine

Monocarboxylate transporter expression is associated with the absorption of benzoic acid in human intestinal epithelial cells

AbstractA diet rich in fruit and vegetables is associated with a decreased risk of developing a number of chronic diseases including colon cancer. The active components of the diet which exert these protective effects are unknown but may include small aromatic and phenolic acids. To elicit a physiological response, these acids must first be absorbed by the intestinal epithelium and the present study has focussed on one potential absorptive pathway—the monocarboxylate transporter MCT1. Using Caco‐2 cells (a human intestinal cell line) we have established that benzoic acid uptake is pH‐dependent (resulting in intracellular acidification) and is enhanced in cells expressing higher levels of MCT1 protein. A number of monohydroxybenzoic acids (including salicylic acid) also induced a decrease in intracellular pH which was of a similar magnitude to that elicited by benzoic acid itself, suggesting that they may all be substrates for the same transport pathway. The role of these small organic acids in maintaining normal cell physiology remains to be fully explored. Copyright © 2006 Society of Chemical Industry

Novel sites of cytosolic glutathione peroxidase expression in colon

Glutathione peroxidases (Gpx) are important moderators of oxidative stress that is implicated in the pathogenesis of numerous diseases including colon cancer. Previous studies report limited examinations of cytosolic glutathione peroxidase location of expression in colon tissue. This study reports evidence of both common sites of Gpx1 and Gpx2 expression in rat colon and sites that are exclusive to each isoform. Semi-quantitative PCR performed previously demonstrated RNA expression of Gpx1 and Gpx2 in proximal, transverse and distal colon. Mapping the distribution throughout the entire colon has revealed specific, novel sites of glutathione peroxidase expression in colon lymphatic tissue. In situ hybridisation and immunohistochemistry confirmed micro-anatomical location of Gpx1 within lymphatic tissue and the lamina propria, sub-mucosa, muscularis and serosa, but not the lumenal epithelium. In situ hybridisation and immunohistochemistry were consistent with reports of microanatomical location of Gpx2 in the lumenal epithelium. Novel sites of Gpx2 expression were also observed in lymphatic tissue. Immunolocalisation in the vicinity of aberrant crypt foci was also examined to further investigate the link between glutathione peroxidases and colon cancer. This did not reveal significant abnormalities, nor did measurement of cytosolic glutathione peroxidase activity or gene expression in colon tissue from rats treated with the colontropic chemical, 1,2-dimethylhydrazine. These results support the potential for Gpx1 and Gpx2 redundancy in lymphatic tissue, but not in epithelial cells of the colon crypt or in the lamina propria, sub-mucosa, muscularis or serosa.