A study on human bile and some of its constituents. II. Concerning the physico-chemical characteristics of the bile salts and cholesterol solubilization.
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Bile↗
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Results for “BILE ACIDS AND SALTS”
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Lipids isolated from bone induce the migration of human breast cancer cells.
Bone is the most common site to which breast cancer cells metastasize. We found that osteoblast-like MG63 cells and human bone tissue contain the bile acid salt sodium deoxycholate (DC). MG63 cells take up and accumulate DC from the medium, suggesting that the bone-derived DC originates from serum. DC released from MG63 cells or bone tissue promotes cell survival and induces the migration of metastatic human breast cancer MDA-MB-231 cells. The bile acid receptor farnesoid X receptor (FXR) antagonist Z-guggulsterone prevents the migration of these cells and induces apoptosis. DC increases the gene expression of FXR and induces its translocation to the nucleus of MDA-MB-231 cells. Nuclear translocation of FXR is concurrent with the increase of urokinase-type plasminogen activator (uPA) and the formation of F-actin, two factors critical for the migration of breast cancer cells. Our results suggest a novel mechanism by which DC-induced increase of uPA and binding to the uPA receptor of the same breast cancer cell self-propel its migration and metastasis to the bone.
Actins↗
Regulation of bile acid synthesis. III. Correlation between biliary bile salt hydrophobicity index and the activities of enzymes regulating cholesterol and bile acid synthesis in the rat.
Hepatic bile acid synthesis is thought to be under negative feedback control by bile salts in the enterohepatic circulation, acting at the level of cholesterol 7 alpha-hydroxylase (C7 alpha H), the initial and rate-limiting step in the bile acid biosynthetic pathway. Bile salts also suppress the activity of the rate-limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-R). The mechanisms of these regulatory effects are poorly understood, and one or both may be indirect. Previous data suggest that the hydrophilic-hydrophobic balance of bile salts, a major determinant of their cholesterol solubilizing properties, also determines their potency as regulators of bile acid and cholesterol synthesis. To further evaluate the relationship between the physicochemical and regulatory properties of bile acids, we altered the composition of the bile salt pool of rats by feeding one or more of seven different bile acids (1% w/w for 14 days). We then determined the mean hydrophilic-hydrophobic balance (hydrophobicity index) of the bile salts in bile, and correlated this with the specific activities of C7 alpha H and HMG-CoA-R, and of acyl-CoA:cholesterol acyltransferase (ACAT), a third hepatic microsomal enzyme which regulates cholesterol esterification. In all instances following bile acid feeding, conjugates of the fed bile acid(s) became the predominant bile salts in bile. Highly significant negative linear correlations (each P less than 0.0001) were found between the hydrophobicity indices of biliary bile salts and the activities of C7 alpha H (r = 0.79) or HMG-CoA-R (r = 0.63). By contrast, no significant correlation could be demonstrated between ACAT activity and the hydrophobicity index of biliary bile salts. The correlation between activities of HMG-CoA-R and C7 alpha H was also highly significant (r = 0.81; P less than 0.0001). No significant correlation existed between ACAT and either HMG-CoA-R or C7 alpha H. Microsomal free cholesterol was not consistently altered by bile acid feeding. Thus, the potency of circulating bile salts as suppressors of the enzymes regulating bile acid and cholesterol synthesis increases with increasing hydrophobicity. The hydrophobic-hydrophilic balance of the bile salt pool may play an important role in the regulation of cholesterol and bile acid synthesis.
Bile Acids and Salts↗
The effect of bile acids on the growth and adherence of Helicobacter pylori.
Bile reflux gastritis occurs in the absence of Helicobacter pylori (H. pylori). The aim of this study was to see if the bile acids cheno or ursodeoxycholic acid affected the growth or adherence of H. pylori in vitro. Twenty-seven strains growth were inhibited by 0.1% chenodeoxycholic acid whereas only 11 out of the 27 were inhibited by 0.1% ursodeoxycholic acid. Growth was totally inhibited by a combination of 0.05% chenodeoxycholic acid +0.05% ursodeoxycholic acid. Chenodeoxycholic acid was a more effective inhibitor of adherence in that the number inhibited and percentage inhibition were greater than with ursodeoxycholic acid. Bile salts might be useful in the treatment of H. pylori infection.
Animals↗
The effect of short chain fatty acids on transmural electrical potential across rat small intestine in vivo.
Short chain fatty acids suddenly produce a phasic increase in transmural electrical potential difference (PD) when placed in the lumen of rat small intestine in vivo. With concentrations of propionate ranging from 50 muM to 1000 muM the amplitude of the response in jejunum is about 5.5 mV. The concentration giving half this effect is about 20 muM. With 10 mM propionate the duration of the response is 3-5 min; after this, PD again equals the control value and the gut is refractory to further additions. Removing propionate from the mucosal surface produces no change in PD, but does restore responsiveness to subsequent exposure to short chain fatty acids. This effect is independent of a variety of other alterations in PD such as those caused by sugars, amino acids, bile salts, theophylline, prostaglandins, and ATP. Mechanism and significance of this surprisingly sensitive response remain obscure.
Animals↗
Measurement of subnanomolar retinoic acid binding affinities for cellular retinoic acid binding proteins by fluorometric titration.
Cellular retinoic acid binding protein I (CRABP-I) and cellular retinoic acid binding protein II (CRABP-II) are small, cytoplasmic proteins which bind all-trans-retinoic acid with high affinity. Both of these proteins belong to a family of intracellular proteins which bind amphiphilic lipids, including fatty acids, bile salts, and retinoids. Because CRABP-I and -II exhibit different tissue distributions and differential transcriptional regulation, they are proposed to serve different functions. The binding properties of mouse CRABP-I and -II purified from Escherichia coli were examined to further understand their role in intracellular retinoic acid processing. Fluorescence titrations were performed using nanomolar protein concentrations, near the obtained dissociation constants, and analyzed by direct mathematical fitting to raw data, in order to extend the range and accuracy of binding constant determination. The apparent dissociation constants, K'd, of mouse CRABP-I and CRABP-II binding all-trans-retinoic acid were determined to be 0.4 +/- 0.3 nM and 2 +/- 1 nM respectively, stronger binding than previously reported. The K'd of mCRABP-I and mCRABP-II complexing with acitretin, a pharmacologically active synthetic retinoid used in the treatment of psoriasis, was 3 +/- 1 nM and 15 +/- 11 nM. Both CRABPs bound 9-cis-retinoic acid with a K'd of roughly 200 nM, and neither exhibited significant binding of 13-cis-retinoic acid.
Acitretin↗
Differentiation of isomeric conjugated bile acids using positive-ion B/E linked scans.
The main objective of this work was to use positive-ion fast atom bombardment mass spectrometry (FAB-MS) B/E linked scan spectra to investigate the possibility of differentiating positional isomers of various authentic glycine- and taurine-conjugated bile acids. Sodium salts of 14 conjugated bile acids were individually ionized by FAB-MS and characterized by scanning simultaneously the magnetic field B and the electric sector field E such that B/E remained constant throughout the scan. The dominant fragment ions could be related to cleavage of the aliphatic side chain with charge retention on the conjugated end of the bile acids. However, fragment ions arising from ring cleavages were also observed and could be used to distinguish the positions of substituent hydroxyl groups. For example, ring cleavage of conjugated dihydroxy bile acids at C-7/C-8 and C-9/C-10 permitted the differentiation of chenodeoxycholyltaurine (3 alpha,7 alpha-substitution pattern) from deoxycholyltaurine (3 alpha,12 alpha-substitution pattern) based on the presence of fragment ions at m/z 388 or m/z 404, which were indicative of hydroxyl group substitutions at either the 7- or 12-positions, respectively. It was concluded that B/E linked scans can be used to discriminate positional isomers of conjugated bile acids.
Bile Acids and Salts↗
Substrate-directed modulation of elastin oxidation by lysyl oxidase.
The oxidation of an elastin substrate by highly purified bovine aortic lysyl oxidase (LO) is markedly influenced by amphiphilic molecules known to bind to elastin. Negatively charged elastin ligands, including fatty acids, bile salts or sodium dodecyl sulfate can completely inhibit the oxidation of lysine in elastin, the cationic amphiphilic ligands stimulate the enzymatic reaction five-fold, while small hydrophilic molecules of either charge or neutral detergents have no effect. In addition, evidence has been obtained that changes in the conformation of a synthetic polypeptide substrate markedly alter its susceptibility to LO. The coacervated state of the substrate is most readily oxidized and crosslinked by the enzyme. These results point to the importance of small ligands, electrostatic charge, and conformation as substrate-directed influences which can control the expression of LO activity.
Amino Acid Oxidoreductases↗
The ecology and immunology of the gastrointestinal tract in health and critical illness.
Interactions between the indigenous flora of the gastrointestinal tract and immunologically competent cells in the gut mucosa, gut-associated lymphoid tissues and liver play an important role in normal immune homeostasis. The microbial flora of the normal gut is complex, yet remarkably constant over time. The relative sterility of the upper gut is maintained by multiple factors including gastric acid, bile salts, normal motility and mucosal IgA, while the lower gut is densely colonized with a complex flora. An intact Gram-negative flora is a prerequisite for normal immunological maturation. On the other hand, overgrowth of the gut, particularly by Gram-negative bacteria or fungi, facilitates the translocation of bacteria into the host, and results in suppression of T-cell responses and altered hepatic Kupffer cell function. Bacterial overgrowth and the consequences of the interactions of this potentially pathogenic flora with the gut immune system may contribute to the septic state in critical illness, and to the syndrome of multiple organ failure.
Critical Illness↗
Identification of sodium-dependent and sodium-independent dicarboxylate transport systems in rat liver basolateral membrane vesicles.
The mechanisms involved in the hepatocellular uptake of Krebs-cycle intermediates were investigated in isolated basolateral (sinusoidal and lateral) rat liver plasma membrane (blLPM) vesicles. An inwardly directed Na+ gradient markedly stimulated uptake of 2-oxoglutarate and succinate into voltage- and pH-clamped blLPM vesicles. This Na(+)-dependent portion of the dicarboxylate uptake was characterized by (a) saturability with increasing substrate concentrations (Km = 6.4-10 mM; Vmax approximately 0.2 nmol min-1 mg protein-1), (b) cis-inhibition by lithium (10 mM), other Krebs-cycle dicarboxylates (1 mM) and DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid; 1 mM) but not by sulphate, monocarboxylates, oxalate, acidic amino acids, bile salts and probenecid, (c) stimulation by an intravesicular negative K(+)-diffusion potential indicating electrogenic [(Na+)n greater than 2-succinate] cotransport, and (d) a pH optimum for transport between 7.0 and 7.5. In the absence of Na+, an inside alkaline pH gradient also markedly stimulated 2-oxoglutarate uptake. This pH-gradient-driven 2-oxoglutarate uptake was insensitive to lithium, but could also be inhibited by DIDS and succinate. Furthermore, saturation kinetics demonstrated Km (approximately 34 mM) and Vmax (approximately 0.8 nmol min-1 mg protein-1) values that were clearly different from those of the Na(+)-dependent uptake system. These results indicate the occurrence of two separate dicarboxylate transport systems along the sinusoidal border of hepatocytes, one being a Na(+)-dicarboxylate symporter and the other representing an anion-exchange system.
Animals↗
Serum creatine kinase isoenzymes behavior in hepatic failure with encephalopathy.
Serum creatine kinase isoenzymes were determined in 24 patients with hepatic failure. Hepatic failure was due to severe acute and chronic liver disease. The 24 patients presented different degrees of coma. Nineteen cases (seven hepatitis and 12 cirrhosis) in coma grades III and IV showed the presence in serum of BB, brain and MB, myocardial isoenzymes. Follow up in six of these cases demonstrated that worsening or improvement was accompanied by an increase or decrease of this brain isoenzyme concentration. The leakage from their respective tissues of the brain and myocardial creatine kinase isoenzymes is probably due to the toxic and surface activity properties of serum free fatty acids, bile salts, and bilirrubin, which increase, among other factors, in these pathological entities.
Adult↗
Cyclooxygenase-2 and its role in colorectal cancer development.
Cyclooxygenase 2 (COX-2), also called prostaglandin endoperoxide synthase 2, is involved in colorectal tumor development. This review deals with particular questions raised in this field such as the mechanisms of COX-2 related tumor promotion, the role of the different types of cells (epithelial and interstitial) expressing COX-2, the factors that trigger COX-2 induction, and the clinical potential of selective COX-2 inhibitors to treat or prevent colorectal tumors. Several mechanisms of COX-2 related tumor promotion have been identified. Some are dependent on prostaglandin E(2) production (such as induction of cell proliferation, angiogenenis or local immunosuppression, inhibition of apoptosis, increase in cell motility) and others are not (such as carcinogen activation or malondialdehyde production). COX-2 expression has been demonstrated in epithelial cells of colorectal cancers and adenomas and also in interstitial cells. These cells correspond to macrophages and/or fibroblasts and endothelial cells. COX-2 expression in these interstitial cells participates in tumor development. Factors or events that trigger COX-2 expression include oncogene activation, antioncogene inactivation, cytokines, growth factors, some fatty acids, bile salts, and mucins. Finally, selective COX-2 inhibitors may be effective in preventing or treating colorectal adenomas or carcinomas. However, their real efficiency and the cost/benefit balance are currently evaluated, and no definite conclusion can be made at the moment.
Adenomatous Polyposis Coli↗
Quantitative determination of 3,7,12-triketocholanic acid in biological fluids by gas-liquid chromatography.
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Bile Acids and Salts↗
Determination of deoxycholic and cholic acids in bile.
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Bile↗
Stress-induced gastric lesions and the synthesis of prostaglandins and leukotrienes.
Prostaglandin E2 renders the mucosa of the GI tract more resistant to acute injury by aspirin, acid, bile salts, and stress, whereas leukotrienes promote inflammation and retard healing of ulcers. The relationship of stress ulcer formation to changes in the activities of prostaglandin synthetase and lipoxygenase was evaluated in this study. After a 24 hr fast, 10 rats were stressed by the cold-restraint method for 4 hr and 10 rats were not stressed. Rats were terminated, stomachs were excised, the number of lesions were counted, and the nonulcerated mucosa was assayed for prostaglandin E2 and leukotriene synthesis. The mucosa was minced, washed in buffered saline, and then incubated for 10 min in a 1.3 mM sodium arachidonate solution containing a nonionic detergent (poloxamer 188), NaCl, KCl, KPO4, glutathione, hemin, MgSO4 and Hepes at pH 8.0. An ANOVA was used to compare the groups. Following stress the number of gastric lesions increased from 0.7 +/- 0.6 to 13.5 +/- 2.6, while leukotriene synthesis increased from 173 +/- 20 to 2170 +/- 187 pg/mg/min. A shift in synthesis from prostaglandins to leukotrienes in the mucosa appears to be detrimental to cytoprotection.
Animals↗
Innate host defense mechanisms of fish against viruses and bacteria.
The integumental defenses provide a physical and chemical barrier to the attachment and penetration of microbes. Besides the entrapping and sloughing of microbes in the mucus, the latter contains many antibacterial substances including anti-bacterial peptides, lysozyme, lectins and proteases. The gastro-intestinal tract is a hostile environment of acids, bile salts and enzymes able to inactivate and digest many viruses and bacteria. In most cases the integumental defenses are sufficient to protect against even quite virulent organisms which often only produce disease when the integument has been physically damaged. If a microbe gains access to the tissues of the fish, it is met with an array of soluble and cellular defenses. The complement system, present in the blood plasma, plays a central role in recognising bacteria and its activated products may lyse the bacterial cells, initiate inflammation, induce the influx of phagocytes and enhance their phagocytic activity. Complement can be activated directly by bacterial products and constituents and also indirectly by other factors, principally C-reactive protein and lectins, which can also bind to the bacterial surface. Plasma also contains a number of factors which inhibit bacterial growth(e.g. transferrin and anti-proteases) or which are bactericidal e.g. lysozyme. Following the infection of fish with virus pathogens, infected cells produce interferon. This induces antiviral defenses in neighbouring cells which are then protected from becoming infected. Anti-viral cytotoxic cells are able to lyse virally infected cells and thus reduce the rate of multiplication of virus within them. Innate defenses thus provide a pre-existing and fast-acting system of protection which is non-specific and relatively temperature-independent and thus has several advantages over the slow-acting and temperature-dependent specific immune responses.
Animals↗
Apoptosis and gastrointestinal pharmacology.
Apoptosis is a fundamental biological process that regulates cell number and removes cells that are neoplastic or infected by viruses. This review summarises present knowledge of the mechanisms and genetic regulation of apoptosis in the gastrointestinal tract and highlights areas of pharmacological relevance. In the intestine, apoptosis occurs in the crypt and possibly at the villus tip. Abnormal apoptosis plays a role in a number of gastrointestinal disease including colorectal cancer. The effects of cytotoxic drugs, chemical carcinogens, nonsteroidal anti-inflammatory drugs, short-chain fatty acids, bile salts and anthraquinolones on apoptosis in the gastrointestinal tract are reviewed.
Animals↗
Partial synthesis of the two 3alpha:7alpha:12alpha-trihydroxycoprostanic acids and of similar bile acids with extended chains.
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Bile Acids and Salts↗