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Discovery Medicine May 2019Ulcerative colitis is a life-long, chronic, relapsing and remitting inflammatory disease of the large intestine with an unpredictable course characterized by... (Review)
Review
Ulcerative colitis is a life-long, chronic, relapsing and remitting inflammatory disease of the large intestine with an unpredictable course characterized by debilitating gastrointestinal symptoms accompanied by healthcare and emotional burdens that reduce the quality of life and the ability to work, attend school, and be productive. Ulcerative colitis affects millions of people worldwide and is now considered a global disease. Although some form of primary immune abnormality is thought to underlie this illness, extensive laboratory research conducted since the mid-20th century has largely failed to definitively establish a primary antecedent immune abnormality in individuals with ulcerative colitis or their family members. An alternative approach employing a systems pathogenesis analysis has implicated a causal role for colonocyte-generated hydrogen peroxide in the pathogenesis of this illness. Significantly elevated levels of hydrogen peroxide in non-inflamed colonic mucosa have been demonstrated in individuals with ulcerative colitis, implying a build-up prior to the onset of inflammation and supporting a causal role for colonocyte hydrogen peroxide in the development of this disease. Hydrogen peroxide's unique properties of cell membrane permeability, long life, potent oxidizing potential, and the ability to attract white blood cells combine to promote oxidative disintegration of colonic epithelial tight junctional proteins while attracting white blood cells into the colonic epithelium, both of which lead to colonic inflammation and eventual ulcerative colitis.
Topics: Colitis, Ulcerative; Colon; Female; Humans; Intestinal Mucosa; Male; Tight Junction Proteins
PubMed: 31361982
DOI: No ID Found -
Biochimica Et Biophysica Acta.... Jul 2021The human colon balances water and electrolyte absorption and secretion while also forming a barrier protecting the body from the entry of harmful components.... (Review)
Review
The human colon balances water and electrolyte absorption and secretion while also forming a barrier protecting the body from the entry of harmful components. Aquaporin-3 (AQP3) is a water, glycerol and HO transporting channel expressed in colonic epithelia. Although expression of colonic epithelial AQP3 is altered in several intestinal disorders, such as inflammatory bowel disease and irritable bowel syndrome, the regulation and specific roles of AQP3 remain to be fully defined. In this mini-review, we summarize the current understanding of the expression, regulation, and biological functions of AQP3 protein in colonic epithelia concerning intestinal absorption, secretion and barrier function.
Topics: Aquaporin 3; Colon; Epithelial Cells; Gene Expression Regulation; Humans; Hydrogen Peroxide; Inflammatory Bowel Diseases; Models, Biological; Water
PubMed: 33811845
DOI: 10.1016/j.bbamem.2021.183619 -
World Journal of Gastroenterology Feb 2012Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions are well established biological events which have an important role in not just normal tissue and... (Review)
Review
Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-β and its downstream Smad signaling, the phosphatidylinositol 3'-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microRNAs in the development of colorectal cancers via epithelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeutic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting the ATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.
Topics: Colon; Colonic Diseases; Epithelial-Mesenchymal Transition; Humans; Signal Transduction
PubMed: 22363130
DOI: 10.3748/wjg.v18.i7.601 -
The Journal of Physiology Aug 2016In recent years there have been significant technical and methodological advances in our ability to record the movements of the gastrointestinal tract. This has led to... (Review)
Review
In recent years there have been significant technical and methodological advances in our ability to record the movements of the gastrointestinal tract. This has led to significant changes in our understanding of the different types of motor patterns that exist in the gastrointestinal tract (particularly the large intestine) and in our understanding of the mechanisms underlying their generation. Compared with other tubular smooth muscle organs, a rich variety of motor patterns occurs in the large intestine. This reflects a relatively autonomous nervous system in the gut wall, which has its own unique population of sensory neurons. Although the enteric nervous system can function independently of central neural inputs, under physiological conditions bowel motility is influenced by the CNS: if spinal pathways are disrupted, deficits in motility occur. The combination of high resolution manometry and video imaging has improved our knowledge of the range of motor patterns and provided some insight into the neural and mechanical factors underlying propulsion of contents. The neural circuits responsible for the generation of peristalsis and colonic migrating motor complexes have now been identified to lie within the myenteric plexus and do not require inputs from the mucosa or submucosal ganglia for their generation, but can be modified by their activity. This review will discuss the recent advances in our understanding of the different patterns of propagating motor activity in the large intestine of mammals and how latest technologies have led to major changes in our understanding of the mechanisms underlying their generation.
Topics: Animals; Colon; Gastrointestinal Motility; Humans; Motor Activity; Motor Neurons
PubMed: 26990133
DOI: 10.1113/JP271919 -
European Journal of Pharmacology Sep 2023Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1...
Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1 expression have been identified in the gastrointestinal (GI) tract. GI mucosal functions remain largely undefined for TRPV1 and TRPA1 with side-dependence and regional differences in signalling unclear. Here we investigated TRPV1- and TRPA1-induced vectorial ion transport as changes in short-circuit current (ΔI), in defined segments of mouse colon mucosa (ascending, transverse and descending) under voltage-clamp conditions in Ussing chambers. Drugs were applied basolaterally (bl) or apically (ap). Capsaicin responses were biphasic, with primary secretory and secondary anti-secretory phases, observed with bl application only, which predominated in descending colon. AITC responses were monophasic and secretory, with ΔI dependent on colonic region (ascending vs. descending) and sidedness (bl vs. ap). Aprepitant (neurokinin-1 (NK1) antagonist, bl) and tetrodotoxin (Na channel blocker, bl) significantly inhibited capsaicin primary responses in descending colon, while GW627368 (EP4 receptor antagonist, bl) and piroxicam (cyclooxygenase inhibitor, bl) inhibited AITC responses in ascending and descending colonic mucosae. Antagonism of the calcitonin gene-related peptide (CGRP) receptor had no effect on mucosal TRPV1 signalling, while tetrodotoxin and antagonists of the 5-hydroxytryptamine-3 and 4 receptors, CGRP receptor, and EP1/2/3 receptors had no effect on mucosal TRPA1 signalling. Our data demonstrates the regional-specificity and side-dependence of colonic TRPV1 and TRPA1 signalling, with involvement of submucosal neurons and mediation by epithelial NK1 receptor activation for TRPV1, and endogenous prostaglandins and EP4 receptor activation for TRPA1 mucosal responses.
Topics: Mice; Animals; Transient Receptor Potential Channels; TRPA1 Cation Channel; Capsaicin; Tetrodotoxin; Colon; Mucous Membrane; TRPV Cation Channels
PubMed: 37394028
DOI: 10.1016/j.ejphar.2023.175897 -
Cancer Prevention Research... Oct 2022Observational studies indicate that calcium supplementation may protect against colorectal cancer. Stratified analyses suggest that this protective effect may differ...
UNLABELLED
Observational studies indicate that calcium supplementation may protect against colorectal cancer. Stratified analyses suggest that this protective effect may differ based on anatomic subsite and sex, but these hypotheses have been difficult to test experimentally. Here, we exposed 36 patient-derived organoid lines derived from normal colon biopsies (21 right colons, 15 left colons) of unrelated subjects (18 female, 18 male) to moderate (1.66 mmol/L) or high (5.0 mmol/L) concentrations of calcium for 72 hours. We performed bulk RNA-sequencing to measure gene expression, and cell composition was inferred using single-cell deconvolution in CIBERSORTx. We tested for significant differences in gene expression using generalized linear models in DESeq2. Exposure to higher levels of calcium was associated with changes in cell composition (P < 0.05), most notably increased goblet and reduced stem cell populations, and differential expression of 485 genes (FDR < 0.05). We found that 40 of these differentially expressed genes mapped to genomic loci identified through colorectal cancer genome-wide association studies, suggesting a potential biologic overlap between calcium supplementation and inherited colorectal cancer risk. Stratified analyses identified more differentially expressed genes in colon organoids derived from right sided colon and male subjects than those derived from left sided colon and female subjects. We confirmed the presence of a stronger right-sided effect for one of these genes, HSD17B2 using qPCR in a subset of matched right and left colon organoids (n = 4). By relating our findings to genetic data, we provide new insights into how nutritional and genetic factors may interact to influence colorectal cancer risk.
PREVENTION RELEVANCE
A chemopreventive role for calcium in colorectal cancer is still unclear. Here, we identify mechanisms through which calcium supplementation may reduce risk. Calcium supplementation increased differentiation and altered expression of colorectal cancer-related genes in a large study of patient-derived colon organoids. These findings were influenced by colon location and sex.
Topics: Biological Products; Calcium; Colon; Colorectal Neoplasms; Female; Genome-Wide Association Study; Humans; Male; Organoids; RNA; Transcriptome
PubMed: 36095330
DOI: 10.1158/1940-6207.CAPR-22-0068 -
The British Journal of Radiology Nov 2012Colorectal cancer is often preventable if the precursor adenoma is detected and removed. Although ultrasound is clearly not one of the widely accepted screening... (Review)
Review
Colorectal cancer is often preventable if the precursor adenoma is detected and removed. Although ultrasound is clearly not one of the widely accepted screening techniques, this non-invasive and radiation-free modality is also capable of detecting colonic polyps, both benign and malignant. Such colon lesions may be encountered when not expected, usually during general abdominal sonography. The discovery of large colonic polyps is important and can potentially help reduce the incidence of a common cancer, whereas detection of a malignant polyp at an early stage may result in a curative intervention. This pictorial review highlights our experience of sonographic detection of colonic polyps in 43 adult patients encountered at our institutions over a 2-year period. 4 out of 50 discovered polyps were found to be malignant lesions, 3 polyps were hyperplastic, 1 polyp was a hamartomatous polyp and the rest were benign adenomas. The smallest of the detected polyps was 1.3 cm in diameter, the largest one was 4.0 cm (mean 1.7 cm; median 1.6 cm). In each case, polyps were discovered during a routine abdominal or pelvic examination, particularly when scanning was supplemented by a brief focused sonographic inspection of the colon with a 6-10 MHz linear transducer. In this paper, we illustrate the key sonographic features of different types of commonly encountered colonic polyps in the hope of encouraging more observers to detect these lesions, which may be subtle.
Topics: Adult; Colon; Colonic Polyps; Humans; Ultrasonography
PubMed: 22806624
DOI: 10.1259/bjr/60593124 -
Digestive Surgery 2013Databases of information on surgical treatment for colorectal cancer have been created in various countries and data have started to be released. The most important... (Review)
Review
INTRODUCTION
Databases of information on surgical treatment for colorectal cancer have been created in various countries and data have started to be released. The most important facets of research for statistical processing include the methodology and firm definitions of content. However, for trials involving colorectal cancer, the applicable terminology has not been defined, and much bias is frequently encountered. Starting from definitions of the colon and vascular system of the colon, we propose definitions of surgical procedures for colorectal cancer.
METHODOLOGY
This paper reviews the colon segments and vascular anatomy of the colon. If surgical treatment of colon cancer is considered from this perspective, we can see that definitions for these surgical procedures are lacking. The definition of surgical treatment would also allow clarification of the range of lymph node dissection. In general, surgical procedures and the area of surgical lymph node dissection are both defined according to the basic structure of the associated arteries. However, the existing descriptions are not based on a definition of the arteries. We therefore tried to establish the most useful nomenclature for the arterial system of the large intestine for colorectal surgeons and reviewed the frequency of important arterial variations. Using the resulting definitions, we provided consistent definitions for colon cancer surgery.
CONCLUSION
The segments of the colon need to be defined. In surgery, procedures are performed using the arteries as indicators, so vessels originating from the superior and inferior mesenteric arteries are referred to as arteries, with others are referred to as branches. Surgical treatment of colon cancer can be defined from the relationship between these arteries. For the first time, this may allow proper application of statistics for the treatment of colon cancer.
Topics: Arteries; Colon; Colorectal Neoplasms; Humans; Terminology as Topic
PubMed: 24135859
DOI: 10.1159/000343156 -
International Journal of Molecular... Jun 2019E-cadherin is the core component of epithelial adherens junctions, essential for tissue development, differentiation, and maintenance. It is also fundamental for tissue... (Review)
Review
E-cadherin is the core component of epithelial adherens junctions, essential for tissue development, differentiation, and maintenance. It is also fundamental for tissue barrier formation, a critical function of epithelial tissues. The colon or large intestine is lined by an epithelial monolayer that encompasses an E-cadherin-dependent barrier, critical for the homeostasis of the organ. Compromised barriers of the colonic epithelium lead to inflammation, fibrosis, and are commonly observed in colorectal cancer. In addition to its architectural role, E-cadherin is also considered a tumor suppressor in the colon, primarily a result of its opposing function to Wnt signaling, the predominant driver of colon tumorigenesis. Beyond these well-established traditional roles, several studies have portrayed an evolving role of E-cadherin as a signaling epicenter that regulates cell behavior in response to intra- and extra-cellular cues. Intriguingly, these recent findings also reveal tumor-promoting functions of E-cadherin in colon tumorigenesis and new interacting partners, opening future avenues of investigation. In this Review, we focus on these emerging aspects of E-cadherin signaling, and we discuss their implications in colon biology and disease.
Topics: Animals; Cadherins; Colon; Colonic Diseases; Gastrointestinal Microbiome; Homeostasis; Humans; Signal Transduction
PubMed: 31195621
DOI: 10.3390/ijms20112756 -
World Journal of Gastroenterology Jul 2008Deposition of pigment in the intestinal mucosa is commonly observed by the endoscopist, especially within the colon, and particularly during investigations for... (Review)
Review
Deposition of pigment in the intestinal mucosa is commonly observed by the endoscopist, especially within the colon, and particularly during investigations for constipation. Pigment may also be detected in the small intestine. Although labeled as melanosis, electron microscopy and X-ray analytical methods have provided evidence that this pigment is not melanin at all, but lipofuscin. Often, herbal remedies or anthracene containing laxatives are often historically implicated, and experimental studies in both humans and animal models have also confirmed the intimate relationship with these pharmacological or pseudo-pharmacological remedies. The appearance of melanosis coli during colonoscopy is largely due to pigment granule deposition in macrophages located in the colonic mucosa. The pigment intensity is not uniform, being more intense in the cecum and proximal colon compared to the distal colon. Possibly, this reflects higher luminal concentrations of an offending agent in the proximal compared to distal colon, differential absorption along the length of the colon, or finally, differences in macrophage distribution within the colon. Mucosal lymphoid aggregates normally display a distinct absence of pigment producing a "starry sky" appearance, especially in the rectosigmoid region. Interestingly, some focal, usually sessile, colonic mucosal neoplastic lesions, rather than submucosal lesions, may be better appreciated as pigment deposition may be absent or limited. If detected, removal and further histopathologic analysis of the polyp may be facilitated.
Topics: Animals; Colon; Gastroenterology; Humans; Intestinal Mucosa; Intestine, Large; Intestine, Small; Melanosis; Microscopy, Electron; Pigmentation
PubMed: 18666316
DOI: 10.3748/wjg.14.4296