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PubMed1978

Colonic myoelectrical activity in irritable-bowel syndrome. Effect of eating and anticholinergics.

To determine the effect of a standard meal on colonic myoelectrical and motor activity in the irritable-bowel syndrome and to determine the effect of a single dose of an oral anticholinergic drug (clidinium bromide) on this response, we studied 10 patients. These patients showed a prolonged increase in both colonic spike (P less than 0.05) and motor activity (P less than 0.05) after eating as compared to normal subjects. Clidinium did not affect the frequency of colonic slow waves or the basal colonic spike and motor activity. However, the anticholinergic reduced the prolonged postprandial colonic spike and motor response in the patients and also reduced the postprandial increase in colonic contractions at 3 cycles per minute (P less than 0.05). These studies indicate that patients with the irritable-bowel syndrome show an abnormally prolonged post-prandial increase in colonic spike and motor activity. An anticholinergic drug reduces the duration and the magnitude of this abnormal colonic response.

Administration, Oral↗

PubMed2025

MicroRNA-122 overexpression suppresses the colon cancer cell proliferation by downregulating the astrocyte elevated gene-1/metadherin oncoprotein.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that regulate essential cellular functions, such as cell adhesion, proliferation, migration, invasion, and programmed cell death, and therefore, alterations in miRNAs can contribute to carcinogenesis. Previous studies have shown that miRNA-122 is abundant in the liver and regulates cell proliferation, migration, and apoptosis. However, the expression pattern and mechanism of actions of miR-122 remain primarily unknown in colon cancer. METHODS: In this study, we analyzed The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) database to assess the clinical significance of astrocyte elevated gene-1 (AEG-1)/metadherin (MTDH) and miR-122 in colon cancer. MiR-122 overexpression studies were performed in HCT116, SW480, and SW620 cell lines. Dual-luciferase assay was carried out to confirm the interaction between AEG-1 and miR-122. In vivo-JetPEI-transfection reagent was used for in-vivo transient transfection of miR-122 in the AOM/DSS-induced colon tumor mouse model. RESULTS: Our results demonstrate that miR-122 was downregulated in colon cancer cells, and it influences the expressions of apoptotic factors and inflammatory cytokines. MiR-122 overexpression in HCT116, SW480, and SW620 cells showed upregulation of Caspase 3, Caspase 9, and BAX and decreased expression of BCL2, which are pro-apoptotic and anti-apoptotic members that maintain a ratio between cellular survival and cell death. In vivo transient transfection of miR-122 mimic in AOM/DSS induced colon tumor mouse model showed less inflammation and disease activity. The TCGA-COAD data indicated that AEG-1 expression was higher in patients with low expression of miR-122 and lower AEG-1 expression in patients with higher expression miR-122. CONCLUSION: Our findings highlight the key role of miR-122 in the high grade of colonic inflammation, and possibly in colon cancer, and the use of miR-122 mimic might be a therapeutic option.

MicroRNAs↗

PubMed1977

Gamma glutamyl transpeptidase in colon cancer induced by 1,2-dimethylhydrazine.

The study of the gamma-glutamyl transpeptidase (GTase) in colon of adult rats showed that in the sequence: duodenum, jejunum, ileum, cecum and colon, the colon has the lowest activity. There are, on the other hand, relatively small differences between GTase activities in the ascending, transverse and descending portions of the large intestine. GTase activity in the colon of neonatal rat is several times higher than in the colon of adult rats. Colon adenocarcinoma induced by 1,2-dimethylhydrazine were found to have a much higher GTase activity than the homologous normal tissue. Because these tumors resemble human colonic adenocarcinomas, it is suggested that the assay of GTase levels of human colon mucosa might be of potential value in the diagnosis of neoplastic changes.

Adenocarcinoma↗

PubMed1978

Cytomegalovirus D.N.A. and adenocarcinoma of the colon: Evidence for latent viral infection.

The cause of adenocarcinoma of the colon has not been proven and a viral association has not been reported with this disease. A sensitive biochemical technique for the detection of viral nucleic acid was used to determine whether one type of herpesvirus, namely a human strain of cytomegalovirus, was uniquely present in tumour tissue. 24 specimens of colon, obtained at surgery from 14 patients, were analysed by membrane CR.N.A.-D.N.A. hybridisation. 4 of 7 tumours of the colon were definitely positive for C.M.V. D.N.A. (2greater than or equal to 2 genome-equivalents/cell), or repeatedly showed more than 1 genome-equivalent/cell. Macroscopically normal colon 5 cm from the tumour, as well as histologically normal and abnormal colon from a control population with Crohn's disease were uniformly negative for C.M.V. D.N.A., except for 1 specimen which was macroscopically normal tissue from a patient with carcinoma of the colon. Among patients with conditions that predispose to adenocarcinoma of the colon, 1 of 2 patients with familial polyposis and 1 of 3 with ulcerative colitis harboured in their colon greater than or equal to 2 genome-equivalents of C.M.V. D.N.A. per cell, and another ulcerative colitis patient had 1-2 genome-equivalents/cell.

Adenocarcinoma↗

PubMed1979

Colonic myoelectrical activity in man: comparison of recording techniques and methods of analysis.

Both monopolar and bipolar recordings of human colonic myoelectrical activity have been made on 29 occasions from implanted serosal electrodes attached to either the ascending colon or transverse colon. Visual and computer analysis of the signals were made and the incidences of the two electrical rhythms present in the colon were compared for the two recording techniques, recording sites, and methods of analysis. The percentage incidence of both rhythms was similar for the mono and bipolar recording techniques in both parts of the colon. The incidence of the two rhythms in the transverse colon was approximately twice that recorded in the ascending colon, this being true for both recording techniques and methods of analysis, but neither was detected for more than 50% of the time. It is concluded that the methods of data analysis probably account for the differing incidences of electrical activity in the human colon that have been reported previously.

Adult↗

PubMed1977

Effects of saline infusion and acute metabolic acidosis and alkalosis on water and electrolyte transport in the human colon.

Both the kidney and colon secrete bicarbonate and transport water and electrolytes. The respective contributions of these two organs to acid-base and electrolyte balance in normal man has thus been studied in eight healthy male volunteers who underwent simultaneous renal clearance studies, and colonic perfusion with a 0.9% saline or 7.2% mannitol solution, during metabolic alkalosis and acidosis, extracellular volume expansion, and control conditions. There was no influence of these acid-base conditions on electrolyte transport in the colon. In the urine, preferential loss of chloride over sodium averaged 81, 143 (P less than 0.001), and 141 (P less than 0.05) muequiv./min, during control, metabolic acidosis, and extracellular volume expansion conditions, respectively. During alkalosis more sodium than chloride was lost (146 muequiv./min) (P less than 0.001). Colonic pH averaged 7.41 during saline and 6.75 (P less than 0.005) during mannitol perfusion. Titratable acid was not produced in the colon during saline perfusion, and averaged 18 muequiv./min during mannitol perfusion. Urinary titratable acid increased from 19 to 25 muequiv./min (P less than 0.01) during volume expansion. With saline perfusion, bicarbonate secretion rate in the colon rose from 249 muequiv./min during control conditions to 289 muequiv./min during metabolic alkalosis (P less than 0.05). More bicarbonate was excreted in the urine during alkalosis when mannitol was introduced in the colon (243 muequiv./min) than when saline was perfused (152 muequiv./min) (P less than 0.05). This study indicates that the response of the human colon is trivial compared with that of the kidney during acute changes in acid-base balance.

Acid-Base Equilibrium↗

PubMed1979

Comparison of proximal and distal colonic muscle of the rabbit.

Mechanical length-tension properties and response to neurohumoral agents were compared for proximal and distal colonic muscle. Resting tension during stretch, acetylcholine-stimulated tension, and the total tension were determined. Proximal circular muscle developed a maximum total tension of 0.96 +/- 0.18 kg/cm2 (mean +/- SE) compared to 0.86 +/- 0.06 kg/cm2 for the distal colon (P greater than 0.05). Resting tension was 0.33 +/- 0.03 kg/cm2 for the proximal colon and 0.05 +/- 0.01 kg/cm2 for the distal colon at the length of optimal acetylcholine-stimulated tension (Lo) (P less than 0.01). Longitudinal muscle showed a similar difference for the proximal and distal colon. The high resting tension in the proximal colonic muscle was reduced by nitroprusside or calcium-free Krebs with EGTA. Dose-response curves to acetylcholine, histamine, phenylephrine, and isoproterenol were similar for the muscle of either part of the colon. Gastrin or cholecystokinin had no effect on the muscle. In summary, the circular or longitudinal muscles of the proximal and distal colon have different length-tension properties but only minimal differences in response to neurohumoral agents.

Acetylcholine↗

PubMed1978

Inhibition of DNA synthesis by 1,2-dimethylhydrazine and methylazoxymethanol acetate in rabbit colon mucosa in organ culture.

When maintained in organ culture, colon mucosa from male New Zealand White rabbits showed a near-normal mucosal morphology and linear incorporation of [3H]thymidine into mucosal DNA up to 36 hours of incubation. Explants from the descending colon had a higher DNA synthetic activity than did other segments of the large bowel. Inhibition of DNA synthesis in colon explants by 1,2-dimethylhydrazine (DMH) and methylazoxymethanol (MAM) acetate was dose-dependent. When DNA synthesis was determined after an 18-hour incubation, MAM acetate inhibited DNA synthesis at concentrations of 50, 100, 150, and 200 microgram/ml. With the same concentration of DMH, little or no inhibition was observed. At the concentration of 200 microgram/ml, both carcinogens significantly inhibited DNA synthesis after 3 and 6 hours of incubation. With longer incubation, the inhibitory effect of DMH appeared to be reversible, whereas DNA synthesis was continuously inhibited by MAM acetate up to 18 hours of incubation. No altered uptake of [3H]thymidine by colon explants incubated in the presence of DMH or MAM acetate for 18 hours was observed. No morphologic changes were seen in colon explants treated with 200 microgram MAM acetate/ml for 18 hours. Physostigmine sulfate had no influence on MAM acetate-induced inhibition of DNA synthesis in colon explants. These in vitro observations reflected a direct action of DMH and MAM acetate on the colon mucosa and supported the possibilility that colon epithelial cells contain enzymes capable of activating DMH and MAM acetate to their alkylating carcinogens.

Animals↗

PubMed1979

Metastatic colonization potential of primary tumour cells in mice.

A model has been developed for studying the capability of cells from primary murine mammary tumours to establish colonies in distant organs. The model involves the i.v. inoculation of disaggregated tumour cells into autologous and syngeneic recipients. The results show that the metastatic colonization potential of cells from a given tumour is consistent within the animals of an inoculated batch. Also, the findings are uniform in the autologous host and the syngeneic recipients. Tumours vary in their colonization potential and can be classified in 2 main groups designated high and low. These findings indicate that: (i) cells from 37% of mammary tumours can heavily colonize the lungs when inoculated i.v., even though the incidence of metastatic spread of these tumours in the undisturbed animal is almost zero. Thus, the relative infrequency of spontaneous metastasis from murine mammary tumours is not due to inability of the tumour cells to survive and colonize once free in the blood stream; and (ii) the colonization potential of the tumours is an intrinsic property of the tumour cells rather than of the host, whose prior acquaintance with the cells does not seem to confer resistance to colonization. The model presents opportunities for identification of possible differences between tumours of high and low colonization potential, and is being used to study cellular properties which favour colonization of distant organs by comparison of observations in vitro with the behaviour of cells from the same tumour in vivo.

Animals↗

PubMed1977

Pharyngeal colonization with Haemophilus influenzae type b: a longitudinal study of families with a child with meningitis or epiglottitis due to H. influenzae type b.

A longitudinal study of pharyngeal colonization with Haemophilus influenzae type b included 264 members of families that had a child with meningitis or epiglottitis due to this organism. It was found that (1) 52 of 67 such families contained at least one carrier of H. influenzae type b, who was usually a sibling; (2) H. influenzae type b spread slowly in 39 families colonized continuously during a six-month period, with only eight of 19 uncolonized siblings acquiring the organism during that time; (3) 18 of 30 initially colonized families contained one or more carriers after 12 months, including 30% of initially colonized siblings; (4) the highest carrier rate of H. influenzae type b occurred in recovered patients, 80% of whom were colonized after hospital discharge; (5) titers of antibody in serum were higher in colonized than in uncolonized individuals (P less than 0.001); (6) levels of antibody in colonized children were lower in those younger than two years than in older children (P less than 0.001); and (7) prolonged or heavy colonization with H. influenzae type b was not associated with unusually high titers of antibody.

Age Factors↗

PubMed1979

Effect of oral tetracycline, the microbial flora, and the athymic state on gastrointestinal colonization and infection of BALB/c mice with Candida albicans.

Scanning electron microscopy, light microscopy, and quantitative culture of microorganisms in intestinal contents were used to determine the effects of oral tetracycline, the bacterial flora of conventionally reared animals (conventional), and thymus-dependent immune competency on the capacity of Candida albicans to colonize and infect the gastrointestinal tract of four groups of mice: thymus-intact conventional mice, conventional athymic mice, flora-defined athymic mice, and thymus-intact bacteria-free mice. Thymus-intact conventional mice without antibiotic treatment began to shed C. albicans less than 48 h after oral yeast challenge and were devoid of detectable yeast by day 16. Tetracycline altered the bacterial flora qualitatively and quantitatively, allowing C. albicans to colonize in less than 48 h and to persist in the gut tract for 32 days. Only 2 of 72 of these conventional mice developed candidiasis (hyphal infection). Although tetracycline altered the bacterial flora of conventional athymic (nude) mice, it was not required to allow C. albicans to colonize their gut tract to levels significantly higher than those in thymus-intact conventional mice. All conventional nude mice were consistently colonized and 14 of 24 animals showed an increased yeast colonization of the keratinized stomach, but only 3 of 24 developed gastric candidiasis. Flora-defined athymic (nude) mice had significantly lower aerobic bacterial levels and significantly higher C. albicans levels in the gut contents than conventional athymic mice. The flora-defined nude mice, however, developed gastric candidiasis by day 5. Thymus-intact bacteria-free mice were uniformly colonized and infected with C. albicans less than 48 h after oral challenge regardless of tetracycline treatment. Populations of C. albicans in the gut of bacteria-free mice were significantly higher than in the gut tract of the thymus-intact conventional or athymic mice. Gastric mycelial infection was detected in 8 of 10 bacteria-free animals 2 days after oral challenge. By 32 days, 45 of 50 mice of both tetracycline-treated and control bacteria-free groups were infected with C. albicans. These data indicate that a competive bacteria flora is more effective than an intact immune system in preventing gastric candidiasis and that an immune deficiency may allow increased yeast colonization of the keratinized and glandular stomach epithelium. Tetracycline did not appear to enhance the invasiveness or pathogenicity of C. albicans in mice even though it facilitates yeast-phase gut colonization in conventionally reared mice.

Animals↗

PubMed1979

Alteration in tryptic peptide patterns of ferritins purified from human colon carcinoma.

Ferritin from malignant tissue differs electrophoretically from normal ferritin. The molecular basis of this difference has not yet been defined. Malignant tissue contains a mixture of ferritins from normal cells, inflammatory cells as well as cancer cells. GW-39 is a pure colon carcinoma cell system that synthesizes human carcinoembryonic antigen. Therefore, ferritin was isolated from normal colon mucosa and colon cancer tissues, as well as from the colon carcinoma cell line, to clarify the molecular relationship between normal and malignant ferritins. Colon carcinoma ferritin differs in primary structure from normal colon mucosal ferritin and contains at least six additional different tryptic peptides. These six peptides were also found in the ferritin from the colon carcinoma cell line. These data suggest that the alteration in ferritin structure occurs at the cellular level and is associated with the malignant state.

Amino Acids↗

PubMed2026

Aldosterone suppresses Na+/H+ exchanger-3 expression through miR-204-5P-mediated posttranscriptional regulation in distal colon.

Na+/H+ exchanger-3 (NHE3) is a major mediator of electroneutral NaCl absorption in the intestine and colon. In the distal colon, chronic aldosterone exposure suppresses NHE3 expression, but the molecular mechanism responsible for this regulation remains unclear. Here, we tested whether aldosterone represses NHE3 through microRNA-dependent posttranscriptional regulation. Transcriptomic analysis of distal colon from dietary Na+-depleted rats identified miR-204-5P (miR-204-5P) as markedly upregulated. Aldosterone increased miR-204-5P abundance and concomitantly reduced NHE3 mRNA, protein expression, and transport activity in rat and human distal colonic epithelium and in SK-CO15 cells. Bioinformatic and reporter analyses identified a conserved miR-204-5P binding site within the NHE3 3'-untranslated region, and miR-204-5P mimic transfection markedly suppressed NHE3 expression and transport activity without affecting other Na+/H+ exchanger isoforms. These findings identify a previously unrecognized aldosterone-microRNA signaling pathway that mediates chronic repression of NHE3 and provide new insight into hormonal regulation of colonic Na+ absorption.NEW & NOTEWORTHY This study identifies a previously unrecognized aldosterone-microRNA signaling mechanism regulating colonic Na+ absorption. We demonstrate that aldosterone induces miR-204-5P, which directly targets the NHE3 3'-untranslated region and suppresses NHE3 expression and transport activity in distal colonic epithelium. These findings reveal a microRNA-mediated pathway linking mineralocorticoid signaling to long-term inhibition of electroneutral NaCl absorption, providing new insight into hormonal regulation of intestinal electrolyte transport.

Animals↗

PubMed1979

Epithelial cell kinetics in the descending colon of the rat. II. The effect of experimental bypass.

The influence of experimental bypass on the epithelial cell kinetics in the rat descending colon was studied. It was found that the number of cells per crypt was markedly reduced at 6 weeks after bypass. The percentage of labelled crypt cells, 1 h after 3HTdR, and the distribution of labelled cells in the crypt was normal. Also the life span of the epithelial cells was the same in control and bypassed colon. The response of crypt cell proliferation to ischaemia-induced cell loss in the bypassed descending colon was similar to the one previously described for normal descending colon. This indicates that the absence of the normal luminal contents does not result in a different response of colonic crypts to induced cell loss. Furthermore, it was found that the number of cells per crypt and the proliferative activity did not change in the transverse colon after temporary ischaemia of the bypassed descending colon. This indicates that the increase in crypt cell proliferation after ischaemia-induced cell loss is a local response.

Animals↗

PubMed1979

Dietary cholesterol, fat, and fibre, and colon-cancer mortality. An analysis of international data.

It has been suggested that high fat, high cholesterol, and low fibre intakes play a role in the causation of colon cancer, but since they are highly intercorrelated, it is difficult to determine which (if any) variable is truly related to colon cancer. Food disappearance data for 1954--65 and mortality data for 1967--73 from 20 industrialised countries were used to assess which variables are independently related to colon cancer. Simple correlation analysis indicated that intake of total fat, saturated fat, monounsaturated fat, cholesterol, and fibres are each highly correlated with mortality-rate for colon cancer. The partial correlation of dietary cholesterol with colon cancer remains highly significant when fat or fibre is controlled. However, the partial correlations of fat or of fibre iwth colon cancer are no longer significant when cholesterol is controlled. Cross-classification showed a highly signficant main effect for cholesterol, but nor for fat or fibre. The findings support the possibility of a causal relationship between cholesterol intake and colon cancer.

Adult↗

PubMed1975

Ammonia and urea transport by the excluded human colon.

1. Ammonia and urea transport across the colonic mucosa was studied by a perfusion technique in four subjects with colonic exclusion for chronic hepatic encephalopathy. 2. Reduction of luminal pH inhibited net and unidirectional transport of ammonia from lumen to plasma, but net absorption from high luminal concentrations persisted at low pH. 3. Neither addition of urea to the perfusate nor intravenous infusion of urea produced a consistent increase in the colonic excretion of ammonia when ammonia-free solutions were perfused. 4. In one subject intravenous infusion of (15N)-ammonium chloride produced rapid labelling of colonic effluent ammonia and within 60 min the specific enrichments of ammonia in effluent and in arterial plasma were approximately equal. 5. During perfusion of nitrogen-free solutions, only small amounts of urea appeared in the effluent, suggesing limited permeability of the colonic mucosa to urea. 6. These results are discussed in relation to the equilibration of ammonia across the colonic mucosa by both ionic and non-ionic diffusion. The lack of evidence of 'juxtamucosal' (as opposed to luminal) ureolysis is in contrast to other observations on the intact colon. The possible reasons for and implications of this discrepancy are discussed.

Ammonia↗

PubMed1979

Method of preparing isolated colonic epithelial cells (colonocytes) for metabolic studies.

Suspensions of isolated colonic epithelial cells (colonocytes) have been obtained from rats by incubating everted lengths of colon with EDTA at 37 degrees C in Krebs-Henseleit saline from which calcium was omitted and containing 0.25% (w/v) bovine serum albumin. Measurements of oxygen consumption and lactate production by cell suspensions indicate that they are metabolically active for at least one hour. The method has been modified for the preparation of isolated epithelial cells from the human colon by including an enzyme digestion step and by increasing the concentration of EDTA to 10 mM. Human colonocytes have been obtained either from normal mucosa (ascending and descending colon) or from the mucosa in ulcerative colitis (descending colon). Oxygen consumption of human cell suspensions is lower than in the rat but in colonocytes from both species the rate is increased by glucose and by n-butyrate, a normal constituent of the colonic lumen. The method yields metabolically active cell suspensions from diseased colonic mucosa and promises to be of value for biochemical studies of ulcerative colitis.

Animals↗

PubMed1979

Cardiac output distribution after left colon anastomosis in the rat.

Resection and anastomosis of the left colon result in an aysmmetric breakdown of preexisting collagen in the colonic wall during the first days of healing. Suture technique influences this reaction. To study the regional blood flow in the colon after resection and anastomosis a tracer microsphere technique was used for determination of the cardiac output distribution in four groups of rats: unoperated and sham-operated controls and rats with left colon anastomosis sutured either by continuous or interrupted sutures. There were no differences in the organ distribution of caridac output between unoperated and sham-operated controls. Left colon resection and anastomosis led to an increased regional blood flow in the colon, which was most marked proximal to the anastomosis and furthermore more pronounced in animals with anastomosis made of continuous suture than in those made of interrupted sutures. Further, resection and anastomosis resulted in an increased cardiac output distribution to the visceral organs. The visceral increase was most pronounced in animals with continuous suture. This increase was predominantly observed in the kidneys and in the colon. The latter is interpreted as being due to an increased metabolic demand induced by resection and anastomosis.

Animals↗