deoxycholic-acid and Stomach-Neoplasms

Recent evidence points to the gut microbiome's involvement in postoperative outcomes, including after gastrectomy. Here, we investigated the influence of gastrectomy for gastric cancer on the gut microbiome and metabolome, and how it related to postgastrectomy conditions.. We performed shotgun metagenomics sequencing and capillary electrophoresis time-of-flight mass spectrometry-based metabolomics analyses on faecal samples collected from participants with a history of gastrectomy for gastric cancer (n=50) and compared them with control participants (n=56).. The gut microbiota in the gastrectomy group showed higher species diversity and richness (p<0.05), together with greater abundance of aerobes, facultative anaerobes and oral microbes. Moreover, bile acids such as genotoxic deoxycholic acid and branched-chain amino acids were differentially abundant between the two groups (linear discriminant analysis (LDA) effect size (LEfSe): p<0.05, q<0.1, LDA>2.0), as were also Kyoto Encyclopedia of Genes and Genomes modules involved in nutrient transport and organic compounds biosynthesis (LEfSe: p<0.05, q<0.1, LDA>2.0).. Our results reveal alterations of gut microbiota after gastrectomy, suggesting its association with postoperative comorbidities. The multi-omic approach applied in this study could complement the follow-up of patients after gastrectomy.

Topics: Actinobacteria; Aged; Amino Acids, Branched-Chain; Bacillus; Bacteroidetes; Bifidobacterium; Bile Acids and Salts; Case-Control Studies; Clostridiales; Deoxycholic Acid; Feces; Female; Firmicutes; Gastrectomy; Gastrointestinal Microbiome; Humans; Lactobacillus; Male; Metabolome; Metagenomics; Middle Aged; Prevotella; Sequence Analysis, DNA; Stomach Neoplasms; Streptococcus; Veillonella

A gastric cancer angiogenesis marker peptide, GX1, is promising to be a desirable ligand for anti-angiogenesis targeted drug of gastric cancer treatment. In this study, GX1 was utilized to fabricate a multifunctional vascular targeting docetaxel (DCT)-loaded nanoparticle with N-deoxycholic acid glycol chitosan (DGC) as the carrier and GX1-PEG-deoxycholic acid (GPD) conjugate as the targeting ligand. The mean size of obtained GX1-DGC-DCT was 150.9 nm with a narrow size distribution and their shape was spherical with smooth surface texture. The in vitro drug release test revealed a sustained release manner and an acid pH could accelerate the release compared with the neutral pH. Furthermore, GX1-DGC-DCT showed stronger cytotoxicity against co-cultured gastric cancer cells and human umbilical vein endothelial cells (co-HUVEC) than DCT within 100 μM. In addition, GX1 efficiently enhanced the cellular uptake of nanoparticles in co-HUVEC cells as confirmed by confocal fluorescence scanning microscopy. Moreover, in vivo delivery of GX1-DGC-DCT was demonstrated to inhibit tumor growth in SGC791 tumor-bearing mice with tumor inhibition rate (TIR) of 67.05% and no weight loss of mice was observed. The anti-tumor effects were further confirmed by H&E and TUNEL analysis. Therefore, this new drug delivery system represents a potential strategy for gastric cancer therapy.

Topics: Animals; Antineoplastic Agents; Blood Vessels; Cell Death; Chitosan; Deoxycholic Acid; Docetaxel; Drug Carriers; Drug Delivery Systems; Drug Liberation; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Mice; Mice, Inbred BALB C; Nanoparticles; Polyethylene Glycols; Spectroscopy, Fourier Transform Infrared; Stomach Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Deoxycholic acid (DOA) is one of the secondary bile acids used as a mild detergent for the isolation of membrane associated proteins. This study examined whether the secondary bile acid, DOA, altered Ca(2+) movement, cell viability and apoptosis in SCM1 human gastric cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)]i. DOA-evoked [Ca(2+)]i rises concentration dependently. The response was reduced by removing extracellular Ca(2+). DOA-evoked Ca(2+) entry was inhibited by store-operated Ca(2+) channel inhibitors (nifedipine, econazole and SKF96365), the protein kinase C (PKC) activator phorbol 12-myristate 13 acetate (PMA) and the PKC inhibitor GF109203X. In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) abolished DOA-evoked [Ca(2+)]i rises. Conversely, treatment with DOA abolished TG-evoked [Ca(2+)]i rises. Inhibition of phospholipase C with U73122 abolished DOA-evoked [Ca(2+)]i rises. At 100-500 μM, DOA decreased cell viability, which was not changed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). DOA between 100 and 300 μM also induced apoptosis. Collectively, in SCM1 cells, DOA-induced [Ca(2+)]i rises by evoking phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via store-operated Ca(2+) channels. DOA also caused Ca(2+)-independent apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Calcium; Calcium Channel Blockers; Calcium Chelating Agents; Calcium Signaling; Cell Line, Tumor; Cell Survival; Deoxycholic Acid; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Fura-2; Humans; Microscopy, Fluorescence; Protein Kinase C; Protein Kinase Inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stomach Neoplasms; Time Factors

The aim of the present study was to investigate the effects of deoxycholic acid (DCA) on BGC‑823 human gastric carcinoma cells and to explore the possible mechanisms underlying any such effects. Cell proliferation was detected using a 3‑(4,5‑Dimethylthiazol‑2‑yl)‑2,5‑diphenyl tetrazolium bromide assay, cell morphology was observed by inverted microscopy, and cell cycle progression and the mitochondrial membrane potential were analyzed using flow cytometry. The expression of Bcl‑2, Bax, p53, Cyclin D1 and cyclin‑dependent kinase (CDK)2 proteins in BGC‑823 cells was analyzed with western blotting. The results demonstrated that DCA significantly inhibited cell growth, and that the cell cycle was arrested at the G1 phase. DCA was also shown to induce BGC‑823 cell apoptosis, which was associated with the collapse of the mitochondrial membrane potential. The mitochondria‑dependent pathway was activated via an increase in the ratio of Bax:Bcl‑2 in BGC‑823 cells. In addition, the expression of p53, cyclin D1 and CDK2 was altered following DCA treatment. These results suggest that DCA induces apoptosis in gastric carcinoma cells through activation of an intrinsic mitochondrial‑dependent pathway, in which p53 is involved.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Deoxycholic Acid; Humans; Membrane Potential, Mitochondrial; Signal Transduction; Stomach Neoplasms; Tumor Suppressor Protein p53

Bile acids might induce mucin expression and regulate tumor behavior in esophageal and colon cancers. However, little is known about the effect of bile acids on tumor invasiveness of gastric carcinoma (GC). The aim of the current study was to elucidate the mechanisms by which bile acids regulate tumor invasion in GC.. We investigated bile acid-induced MUC2 expression and cell invasion and migration in the cultured GC cell lines, SNU-216, and MKN45. In addition, immunohistochemical analysis of MUC2 and Snail was performed on 389 archival paraffin-embedded tissues of GC to evaluate the correlation of their expression with prognosis.. Deoxycholic acid (DCA), a secondary bile acid, had no effect on the viability of SNU-216 and MKN45 GC cells at low concentrations (0-100 μM), but decreased viability at a higher concentration (200 μM). MKN45 cells showed higher MUC2 expression than SNU-216 cells under basal conditions. DCA treatment upregulated MUC2 mRNA expression in both SNU-216 and MKN45 cells. Expression of Snail and MMP9 was markedly decreased by DCA treatment, and E-cadherin expression was subsequently increased. DCA significantly inhibited invasion and migration of SNU-216 and MKN45 cells. In human GC, MUC2 expression showed a negative correlation with Snail expression (P = 0.021) and a significantly positive correlation with better prognosis (P = 0.023).. Taken together, our data suggest that DCA induced MUC2 expression in GC cells and inhibited tumor invasion and migration. Additionally, MUC2-expressing GCs showed low rates of Snail expression and were associated with a favorable prognosis.

Topics: Adenocarcinoma; Bile Acids and Salts; Biomarkers, Tumor; Cell Survival; Deoxycholic Acid; Gene Expression Regulation, Neoplastic; Humans; Mucin-2; Neoplasm Invasiveness; Prognosis; Stomach Neoplasms; Tissue Array Analysis; Tumor Cells, Cultured

Human telomerase reverse transcriptase (hTERT) is upregulated in most cancer cell types as well in immortalized cells. The underlying mechanism for such upregulation, however, remains largely unknown. We report here that bile acids under acidified media increase hTERT expression via c-myc activation in primary human gastric cancer cell lines. Human gastric cancer MKN28, MGC803 and SGC7901 cells were treated with 100 µM deoxycholic acid (DCA) or chenodeoxycholic acid (CDCA) with or without acidified media in the presence or absence of the c-myc inhibitor 10058-F4 for 24 h. hTERT and c-myc protein levels were determined by western blot analysis. hTERT and c-myc mRNA levels were determined by RT-PCR. The promoter activities of hTERT and c-myc transcription were determined using promoter reporter luciferase assays for both. Telomerase enzyme activity was analyzed by stretch PCR. hTERT mRNA and protein levels were significantly increased by bile acids in acidified media and were accompanied with enhanced telomerase activity. No changes were found at a pH of 7.0 or with acidified media alone. Similarly, the mRNA and protein levels of c-myc were also increased by bile acids in acidified media but not at a pH of 7.0 or with acidified media alone. Importantly, pharmacologic inhibition of c-myc using 10058-F4 prevented hTERT induction by DCA or CDCA in gastric cancer cells under acidic conditions. Bile acids (DCA and CDCA) under acidic conditions increased hTERT expression in human gastric cancer cells by activation of c-myc transcription. This suggests that acidified bile acids may promote tumorigenesis and affect cell ageing via telomerase activation.

Topics: Bile Acids and Salts; Cell Line, Tumor; Chenodeoxycholic Acid; Deoxycholic Acid; Gene Expression Regulation, Neoplastic; Humans; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc; RNA, Messenger; Stomach Neoplasms; Telomerase; Thiazoles; Transcriptional Activation

The study aimed to evaluate the effects of deoxycholic acid (DCA) on human gastric carcinoma cell lines and to explore its mechanisms. In the present study, effects of DCA on SGC-7901 cell growth, cell cycle, and apoptosis were investigated by MTT assay, inverted microscopy, fluorescence microscopy, PI single- and FITC/PI double-staining flow cytometry, and western blotting. The study have revealed that DCA significantly inhibited the growth of SGC-7901 cells in a dose- and time-dependent manner and arrested cell cycle at G0/G1 phase. SGC-7901 cells showed typical apoptotic morphological changes after treated with DCA for 48 h. The intensity of typical apoptosis pattern- "ladders" formed by DNA in fragments of multiples of 200 base pairs was also observed. Apoptosis of SGC-7901 cells induced by DCA were associated with collapse of the mitochondrial membrane potential. DCA treatment could also increase the ratio of Bax to Bcl-2 in SGC-7901 cells. Meanwhile, the expression of p53, cyclinD1, and c-Myc were changed after DCA treatment. These results suggest that DCA induces apoptosis of gastric carcinoma cells through an intrinsic mitochondrial-dependent pathway, and the increase in the Bax/Bcl-2 ratio and collapse of the mitochondrial membrane potential may play important roles in DCA-induced apoptosis of gastric carcinoma cells.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Deoxycholic Acid; Humans; Mitochondria; Stomach Neoplasms

The heat shock protein 90 (HSP90) plays a crucial role in the stability of several proteins that are essential for cell survival and for malignant transformation. The binding of HSP90 with pro-survival kinase Akt prevents proteosomal degradation of Akt and contributes to the functional stabilization of PI3K/Akt signaling and cell survival. Akt kinase and HSP90 are therefore highly over-expressed in a large panel of cancer cell lines and are present in multi-chaperoning complexes. In this paper, we investigated whether targeting both Akt and HSP90 would inhibit the survival pathway in AGS cells (human gastric mucosal cells), and how Akt/HSP90 inhibition modulates the deoxycholate (DC)-induced apoptosis.. AGS cells in the presence of Akt inhibitors (LY294002 and wortmannin), or HSP90 inhibitor (geldanamycin, GA) for 30 min or 18 h, respectively, were treated with DC (50 µM). Activation of PI3K/Akt signaling was evaluated by measuring the Akt and PTEN phosphorylation. HSP90, caspase-3 and caspase-9 were detected in whole lysates by Western blot analysis. AGS cells, transiently transfected with Akt siRNA, were treated with DC, and apoptosis was measured by caspase-3 activation. Apoptotic-positive cells were counted according to changes of cell morphology by Hoechst staining and fluorescence microscopy.. The intrinsic level of phospho-Akt (pAkt; active form), phospho-PTEN (pPTEN; inactive enzyme) and HSP90 were highly expressed in AGS cells indicating the active PI3K/Akt/HSP90 signaling. Although, deoxycholate at low concentration (50 µM) slightly inhibited the expression of pAkt and cleaved HSP90 to 55 KDa fragment, no significant effect on apoptosis induction, up to 4 h (as assessed by caspase-3 activation) was observed. The higher concentrations of DC (100 µM-300 µM) resulted in progressive inhibition of pAkt, activation of PTEN, and specific cleavage of HSP90 to approximately 45 KDa fragments with significant induction of apoptosis. Although DC (50 µM) had no profound effect on Akt/HSP90 and did not induce apoptosis, it became an inducer of apoptosis when cells were pretreated with LY294002, wortmannin, or geldanamycin. Consistent with these findings, significant activation of apoptosis in response to DC (50 µM) was observed in cells with depleted Akt protein.. These results demonstrate that down-regulation of PI3K/Akt pathway with specific cleavage of HSP90 to 45 KDa modulates the pro-apoptotic effects of DC in gastric cells. They further indicate the importance of stable Akt/HSP90 complex in regulation of survival/death responses.

Topics: Androstadienes; Apoptosis; Benzoquinones; Caspase 3; Caspase 9; Cell Line, Tumor; Chromones; Deoxycholic Acid; Drug Delivery Systems; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Morpholines; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms; Wortmannin

As a prospective vaccine carrier, nanoparticles can protect antigens from degradation and enhance immune response. This study prepared nanovaccines with MAGE-3-derived CD4+-CD8+T cell epitope peptides, and investigated its character and antitumor effects on transplanted gastric cancer in mice.. We adopted the self-assembly method to prepare peptide/chitosan conjugated with deoxycholic acid (chitosan-deoxycholic acid) nanoparticles. We observed the appearance of the chitosan-deoxycholic acidnanoparticles through a transmission electron microscope (TEM) and analyzed the peptide content and its release pattern by fluorescence spectrophotometry. We observed tumor-suppression efficacy in vivo through animal experiments.. We successfully prepared nanoparticles with MAGE-3 peptide antigen, and its encapsulation efficiency and loading level were about 37% and 17.0%, respectively. These nanoparticles presented a delayed release pattern in phosphate buffered saline (PBS) at pH 7.4, and the full release time was about 48 h. In 2 mg/mL lysozyme, the nanoparticles showed a sudden release, and the full release time was about 24 h. ELISPOT and cytotoxic experiments showed that the MAGE-3 peptide loaded nanoparticles could stimulate immune response in vivo and could generate MAGE-3-targeted cytotoxic T lymphocytes (CTLs), and kill MAGE-3-specific tumor cells. Tumor suppression experiments showed that the regression ratio of the peptide-loaded nanoparticles group was 37.81%.. MAGE-3 peptide/chitosan-deoxycholic acidvaccine-loaded nanoparticles can stimulate antitumor immune response in vivo and can regress the growth of mouse forestomach carcinoma cell line MFC.

Topics: Animals; Antigens, Neoplasm; Cancer Vaccines; Cell Line, Tumor; Chitosan; Dendritic Cells; Deoxycholic Acid; Drug Carriers; Epitopes, T-Lymphocyte; Male; Mice; Nanoparticles; Neoplasm Proteins; Neoplasm Transplantation; Stomach Neoplasms; T-Lymphocytes, Cytotoxic; Tumor Burden

While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue-specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto-oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine-specific cascade in which NF-kappaB transactivated the tissue-specific transcription factor CDX2. In turn, CDX2 orchestrated a lineage-specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage-specific differentiation program involving suppression of EGFR and AKT, activating the NF-kappaB-CDX2 axis. Induction of this axis provides the context for lineage-addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF-kappaB signaling, amplifying tumorigenic programs.

Topics: Adenocarcinoma; Bile Acids and Salts; Biopsy; Cell Line, Tumor; Cell Lineage; Deoxycholic Acid; ErbB Receptors; Esophageal Neoplasms; Guanylate Cyclase; Humans; Ligands; NF-kappa B; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins c-akt; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Stomach Neoplasms

Apoptosis is a major mechanism of gastric cell death induced by deoxycholate (DC) and aspirin (ASA), and the caspase cascade and protein kinase C (PKC) signaling play key roles in this process. The transcription factor kappa B (NF-kappaB) has been shown to modulate apoptosis by regulating the transcription of numerous pro- and anti-apoptotic genes. The aim of this study was to investigate the effect of DC and ASA on NF-kappaB signaling, and determine its role in programmed cell death in a human gastric carcinoma cell line.. Cells were incubated with DC in the presence or absence of ASA or proteasome inhibitors (PI- I, lactacystin, and MG-132). Cell lysates were evaluated by Western blotting. NF-kappaB (p65) was measured in the cytosol and nuclear fractions.. DC induced a translocation of NF-kappaB into the nuclear compartment that was completely blocked by proteasome inhibitors. Although, ASA itself had no effect on the NF-kappaB pathway, nor did it reduce DC-induced NF-kappaB translocation, it did prevent DC-induced caspase-3, -6 and -9 activation, poly (ADP-ribose) polymerase and lamin A processing, DNA degradation, and PKC signaling, all indices of apoptosis. In contrast, proteasome inhibitors had no effect on DC-induced apoptosis.. Deoxycholate activates NF-kappaB at the same time that it induces apoptosis in gastric epithelial cells. Prevention of NF-kappaB activation does not alter DC-induced apoptosis, indicating that in our experimental conditions, NF-kappaB is not essential for apoptosis to proceed. In contrast, the ability of aspirin to restore the alterations in PKC isoforms induced by DC and at the same time prevent caspase cascade activation suggests the importance of the PKC signaling system in this process.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Aspirin; Caspase Inhibitors; Cell Line, Tumor; Cholagogues and Choleretics; Collagen Type XI; Cysteine Proteinase Inhibitors; Deoxycholic Acid; Humans; NF-kappa B; Protein Kinase C; Signal Transduction; Stomach Neoplasms

Increases in fecal bile acids may play a role in colorectal carcinogenesis. The authors tested the hypothesis that high concentrations of primary and secondary bile acids are more common in patients with colon cancer than in patients with other gastrointestinal diseases.. In this retrospective study the secondary bile acid deoxycholic acid and the primary bile acid cholic acid were measured in the feces by enzyme-linked immunoabsorbent assay in 63 patients with colorectal cancer, 24 patients with gastric cancer, 11 patients with biliary disorders, and 47 healthy volunteers.. Preoperatively, the mean deoxycholic acid values tended to be higher and the cholic acid values were significantly lower in patients with colorectal cancer than in healthy subjects. Patients with other gastrointestinal diseases had lower deoxycholic acid and cholic acid values than healthy subjects. In healthy subjects the deoxycholic acid to cholic acid ratio ranged from 0.10 to 2.86 (mean, 0.88), but in almost two-thirds, the ratio did not exceed 1. In contrast, the mean preoperative ratio in patients with colorectal cancer was 2.26 (range, 0.06-7.17; P < 0.0001) and tended to be higher in patients with advanced cancer and in those with sigmoid and rectal tumors. If 1.1 is taken as the upper limit of normal for deoxycholic acid to cholic acid ratio, 67 percent of patients with colorectal cancer had an abnormal value preoperatively.. A high deoxycholic acid concentration and deoxycholic acid to cholic acid ratio may be indicators of colorectal cancer. Further study is needed to improve sensitivity and specificity, perhaps by combining fecal bile acid measurements with other tests, and a large prospective trial may be warranted to determine whether these measurements have value in screening for this common cancer.

Topics: Adult; Aged; Aged, 80 and over; Biliary Tract Diseases; Biomarkers, Tumor; Cholic Acid; Colorectal Neoplasms; Deoxycholic Acid; Enzyme-Linked Immunosorbent Assay; Feces; Female; Humans; Male; Middle Aged; Retrospective Studies; Sensitivity and Specificity; Stomach Neoplasms

Bile reflux into the stomach has been considered carcinogenic. Secondary bile acids, and in particular deoxycholic acid, have been shown to act experimentally as co-carcinogens in the colon and are increased in patients with colorectal adenocarcinoma. No information is available with respect to biliary bile acid composition in patients with gastric cancer. We studied biliary bile acid composition in 11 patients with gastric cancer and 23 healthy controls. Bile acids were measured using high-performance liquid chromatography. The site of gastric cancer was the antrum in 6 patients and body in 5. There were 6 intestinal-type and 5 diffuse adenocarcinomas. Only 2 patients had Helicobacter pylori infection. Deoxycholic acid constituted 24% +/- 2% of biliary bile acid in gastric cancer patients versus 22% +/- 2% in healthy controls (NS). Similarly, no differences were found between the two groups for all other bile acids. Deoxycholic acid constituted 23% +/- 3% of biliary bile acid (NS vs. controls) in patients with antral adenocarcinoma and 25% +/- 2% (NS vs. controls) in patients with intestinal-type gastric adenocarcinoma. Gastric adenocarcinoma is not associated with an increase in the more-toxic secondary bile acids, and deoxycholic acid in particular. This reduces the importance of bile acid composition as a promotor in gastric carcinogenesis.

Topics: Adenocarcinoma; Aged; Bile Acids and Salts; Chenodeoxycholic Acid; Deoxycholic Acid; Female; Humans; Male; Stomach Neoplasms; Ursodeoxycholic Acid

We have developed an in vitro model of adaptive cytoprotection induced by deoxycholate (DC) in human gastric cells and have shown that pretreatment with a low concentration of DC (mild irritant, 50 microM) significantly attenuates injury induced by a damaging concentration of DC (250 microM). This study was undertaken to assess the effect of the mild irritant on changes in intracellular Ca2+ and to determine if these perturbations account for its protective action. Protection conferred by the mild irritant was lost when any of its effects on intracellular Ca2+ were prevented: internal Ca2+ store release via phospholipase C and inositol 1,4, 5-trisphosphate sustained Ca2+ influx through store-operated Ca2+ channels or eventual Ca2+ efflux. We also investigated the relationship between Ca2+ accumulation and cellular injury induced by damaging concentrations of DC. In cells exposed to high concentrations of DC, sustained Ca2+ accumulation as a result of extracellular Ca2+ influx, but not transient changes in intracellular Ca2+ content, appeared to precede and induce cellular injury. We propose that the mild irritant disrupts normal Ca2+ homeostasis and that this perturbation elicits a cellular response (involving active Ca2+ efflux) that subsequently provides a protective action by limiting the magnitude of intracellular Ca2+ accumulation.

Topics: Acclimatization; Calcium; Cell Membrane; Cell Survival; Deoxycholic Acid; Dose-Response Relationship, Drug; Estrenes; Gastric Mucosa; Humans; Kinetics; Lanthanum; Microscopy, Confocal; Neomycin; Nifedipine; Phosphodiesterase Inhibitors; Pyrrolidinones; Quercetin; Stomach Neoplasms; Tumor Cells, Cultured; Type C Phospholipases; Verapamil

The promoting effect of bile acids on the development of gastric carcinoma was examined in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). At the first experiment, two hundred and fifteen male Wistar rats were divided into 5 groups; after oral administration MNNG (120 micrograms/ml) for 24 weeks, group 1 received tap water, group 2 administered of chenodeoxycholic acid (CDCA) solution, group 3 had deoxycholic acid (DCA) solution for the next 12 weeks. Group 4 received CDCA solution and group 5 received DCA solution for 36 weeks without MNNG. At the second experiment, fifty one rats were divided into 3 groups; for the first 12 weeks, group 1 received tap water, group 2 CDCA and group 3 DCA. These 3 groups received MNNG for the next 24 weeks followed by tap water for 12 weeks. The incidence of gastric adenocarcinoma in MNNG-treated rats was significantly higher in group 3 (63.6%) as compared with that in group 1 (36.7%) in the first experiment. No carcinoma lesions was found in groups 4 and 5. In the second experiment, no significant changes was observed among 3 groups. Undifferentiated adenocarcinomas were identified in groups 2 and 3, especially treated with MNNG plus bile acids. The result suggested a promoting effect of bile acids, especially DCA, in stomach carcinogenesis.

Topics: Adenocarcinoma; Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Deoxycholic Acid; Drug Synergism; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms

Bile acids may damage the gastric mucosa, and they are cocarcinogenic in experimental colonic and gastric cancer. Chronic atrophic gastritis (CAG) and chronic atrophic gastritis with intestinal metaplasia (CAGIM) are associated with gastric carcinoma. We, therefore, analysed bile acids in the antral mucosa in controls (n = 10), in patients with CAG (n = 12) and CAGIM (n = 20). In both forms of chronic antral gastritis, total mucosal bile acid concentrations drop, caused mainly by lower primary bile acids. The proportions of secondary bile acids rise, in particular of toxic lithocholic acid. This is probably caused by bacterial activity in the stomach. Whether secondary bile acids, especially lithocholic acid, alone or in combination with other bacterial degradation products, influence gastric carcinogenesis remains to be elucidated in further studies.

Topics: Adult; Aged; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acid; Cholic Acids; Deoxycholic Acid; Female; Gastric Mucosa; Gastritis; Gastritis, Atrophic; Humans; Intestines; Lithocholic Acid; Male; Metaplasia; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Ursodeoxycholic Acid

Bile acids are thought to be involved in both the aetiology and development of colorectal cancer. In this study the existence of specific bile acid receptor proteins has been postulated. A receptor assay which involved labelling with 14C-deoxycholic acid was performed as well as autoradiography using 3H-deoxycholic acid. In an initial study resected colorectal cancer and adjacent histologically normal colorectal mucosa from 39 patients were studied, as were samples of normal gastric mucosa, cancers and benign colorectal tumours. Specific receptors to deoxycholic acid were detected in 12 (30.8 per cent) of the colorectal cancers, but in only 1 (2.6 per cent) of the samples from normal colorectal mucosa (X2 = 11.16, P less than 0.005). No deoxycholic acid receptors were detected in any other tissue studied. Autoradiographs of colorectal cancers showed binding of 3H-deoxycholic acid in receptor-positive tumour tissue. These findings might provide some explanation for the evidence linking bile acids with the disease.

Topics: Autoradiography; Colonic Neoplasms; Deoxycholic Acid; Gastric Mucosa; Humans; Intestinal Polyps; Receptors, Cell Surface; Receptors, Steroid; Rectal Neoplasms; Stomach Neoplasms

It has been postulated that reflux of bile into the stomach promotes gastric carcinogenesis. Bile-stained aspirates from 50 asymptomatic patients, partially gastrectomized more than 10 years earlier, were examined bacteriologically and with regard to conjugated and deconjugated bile acids. Endoscopic biopsies showed atrophic gastritis in all patients, cancer in two and severe dysplasia in another two. pH in the reflux aspirates was 7.3 +/- 0.4 (mean +/- standard deviation). Bacterial cultures were positive in all patients studied. Fecal type flora, mostly E. coli, klebsiella and Clostridium perfringens, was found in 85% of the patients. Total bile acids were found to be 2.6 +/- 2.0 mg/ml, 23% of which were deconjugated. Deoxycholic acid, known to promote carcinogenesis in animals, amounted to 27% of total bile acids and deconjugated deoxycholic acid was 5% of total bile acids. The mostly anaerobic microflora and the presence of mainly free secondary and primary bile acids may contribute to the high incidence of cancer in the gastric remnant observed after Billroth I or II operations.

Topics: Bile; Bile Acids and Salts; Deoxycholic Acid; Endoscopy; Female; Gastric Juice; Gastritis; Humans; Male; Postgastrectomy Syndromes; Stomach Neoplasms

Topics: Adult; Aged; Bile; Bile Acids and Salts; Cholesterol; Deoxycholic Acid; Duodenal Ulcer; Female; Gallbladder; Humans; Male; Middle Aged; Stomach Neoplasms; Stomach Ulcer

Topics: ABO Blood-Group System; Adult; Anemia, Pernicious; Bacteria; Bile Acids and Salts; Carcinogens; Colonic Neoplasms; Deoxycholic Acid; Diet; Feces; Female; Gastritis; Gastrointestinal Neoplasms; Humans; Male; Middle Aged; Sex Factors; Stomach Neoplasms; United States