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PubMed1983

Cysteamine and prostaglandin F2 beta stimulate rat gastric mucin release.

Gastric mucin glycoproteins form an adherent gel over the surface epithelium that is thought to protect the stomach against chemical and physical damage. The purpose of this study was to measure the release of mucin glycoproteins from rat stomach after treatment with cysteamine and prostaglandin F2 beta, two structurally unrelated drugs that have been shown to protect the stomach against the noxious effects of alcohol and other damaging agents. Gastric mucin was separated into soluble (washout) and insoluble (adherent) phases before colorimetric quantitation of total mucin, protein-bound hexose, and sialic acid. Cysteamine produced a dose-dependent increase in release of soluble and gel mucin. Prostaglandin F2 beta caused a dose-dependent release of hexose-containing mucin but had no effect on sialic acid-containing glycoproteins. Sepharose 4B chromatography of both the soluble and adherent mucus revealed that greater than 90% was a high molecular weight glycoprotein fraction. N-Ethylmaleimide, a known inhibitor of cytoprotection by cysteamine, had no effect on mucin secretion. Similarly, indomethacin inhibited mucin secretion by cysteamine but did not significantly influence cytoprotection. Thus the secretion of mucin by cytoprotective agents is unlikely by itself to explain the ability of the stomach to resist chemical or physical damage.

Animals↗
PubMed1984

Prostaglandins: effects on the gastrointestinal tract.

Several prostaglandins have been shown to exert five major gastrointestinal actions. Inhibition of gastric acid secretion, orally and parenterally. Antiulcer activity (they prevent gastric and duodenal ulcers produced experimentally in animals, and they accelerate the rate of healing of duodenal ulcers in humans). Cytoprotection for the stomach, the small and the large intestine. Cytoprotection is defined as the property of many prostaglandins to protect the mucosa of the stomach and intestine from becoming inflamed and necrotic when this mucosa is exposed to noxious agents. Cytoprotection is separate from, and unrelated to, inhibition of gastric secretion. In humans, certain prostaglandins of the E type given at very low doses prevent gastric bleeding produced by aspirin and indomethacin. Stimulation of intestinal secretion, through increase of cyclic AMP formation. Stimulation of smooth muscle contraction. Certain prostaglandins are likely to be beneficial in the treatment of gastric ulcers, stress ulcers, duodenal ulcers, and perhaps gastritis and certain forms of inflammatory bowel disease.

Animals↗
PubMed1984

The effect of different prostaglandins on cysteamine-induced duodenal ulcer in the rat.

Most of the experiments have verified the cytoprotective effect of prostaglandins on the gastric mucosa and only few observations are known to deal with "cytoprotection" exerted on the duodenal or intestinal mucosa. Duodenal ulcers were produced by cysteamine (CEA). The treatment with different prostaglandins (PGI2, PGF2 alpha, PGE2) was carried out every six hours during the 48-hour experimental period. The obtained results indicate that neither prostacyclin nor prostaglandin-F2 alpha has any significant effect on CEA-induced duodenal ulceration, while prostaglandin-E2 exerts a slight anti-ulcerogenic effect. It is possible that cytoprotection is not the result of the same process in the duodenal and gastric mucosa: alternatively, three prostaglandins are not involved in the pathomechanism of CEA-induced duodenal ulceration.

Animals↗
PubMed1982

Prostaglandin and protection of the gastroduodenal mucosa.

The prostaglandins, PGs, are formed mainly from arachidonic acid by all nucleated cell populations in the human body. The biosynthesis is easily initiated by unspecific stimulation and is influenced by hormonal, neural and local factors. Human gastroduodenal tissue produces mainly PGE2 and PGF2; an atraumatic approach to follow local production is to identify luminal PGs and their metabolites. In the gastrointestinal tract, the most studied biological action of exogenous PGs is inhibition of the basal and stimulated gastric acid secretion. In addition, PGs stimulate the gastric and duodenal bicarbonate secretion and the production and release of mucus glycoproteins and may have trophic effects on the gastric mucosa. Thus, PGs seem capable of mobilizing all recognized mucosal defense factors. The ability of small amounts of orally administered PGs to protect the gastric mucosa against the gross damage produced by necrotizing agents in experimental animals and to prevent and heal gastroduodenal lesions in man is called "cytoprotection" and is independent of acid inhibition. Cytoprotection may be connected to stimulation of the defensive bicarbonate-mucus barrier or result from yet unidentified mechanisms. --Evidence suggesting a role for the locally biosynthesized PGs in the regulation of the gastric parietal and nonparietal secretions is indirect and based on studies with blocking of the PG-biosynthesis by antiphlogistic compounds. The possible importance of endogenous PGs in the pathophysiology of gastroduodenal disease has been insufficiently examined. --Analogues of PGE2, produced by total synthesis, combine acid antisecretory and cytoprotective properties at dose levels without side effects or systemic actions and are now being tested in clinical trials to confirm effectiveness in the prevention and treatment of peptic ulcer and other gastroduodenal lesions.

Animals↗
PubMed1980

Effect of 16-16-dimethyl-prostaglandin E2 on ulceration of isolated amphibian gastric mucosa.

In order to investigate the cytoprotective action of 16-16-dimethyl-prostaglandin E2 (16-16D), we studied its effect on sacs of isolated amphibian gastric mucosa known to ulcerate with high frequency in the absence of nutrient HCO3-. The actions of 16-16D, 2.85 X 10(-6) M, were also studied in an in vitro chamber. The incidence of ulceration in HCO3- -free nutrient media containing 10(-4) M histamine was significantly reduced by 16-16D. When artificial gastric juice (AGJ) was instilled into the lumen of the sac, protection occurred only after a pretreatment period of 60 min. Cytoprotection was not observed when active secretion of H+ was inhibited with 10(-3) M metiamide, and AGJ was placed in the lumen of the sac. In open sheets of fundus stimulated with 10(-4) M histamine, 16-16D did not influence H+ secretion. Isc was significantly higher than in control tissues. We conclude that 16-16D is cytoprotective in amphibian gastric mucosa by an action independent of changes in acid secretion or in blood flow. In addition, our studies suggest that 16-16D may increase the availability to the surface cells of nutrient HCO3- produced by actively secreting oxyntic cells.

16,16-Dimethylprostaglandin E2↗
PubMed1994

Capsaicin-induced gastric mucosal hyperemia and protection: the role of calcitonin gene-related peptide.

BACKGROUND: Topical capsaicin augments gastric mucosal blood flow and is cytoprotective. This phenomenon is blocked by nitric oxide (NO) synthase and cyclooxygenase inhibition. Capsaicin-sensitive neurons store and release calcitonin gene-related peptide (CGRP). The purpose of this investigation was to study the effects of a CGRP antagonist on capsaicin-induced hyperemia and protection and to determine the role of NO and the cytoprotective prostaglandin PGE2 in this process. METHODS: The glandular stomachs in male Sprague-Dawley rats (280 to 350 gm) were chambered with the blood supply intact. Animals were divided into four groups. Normal saline solution (group 1) or the CGRP antagonists hCGRP8-37 (groups 2 through 4, 0.047 mg/ml) were continuously infused intraarterially via a retrograde splenic artery catheter at a rate of 0.034 ml/min after rats were given an intravenous bolus of either NSS (groups 1 and 2), L-arginine (group 3), or D-arginine (group 4) (200 mg/kg). The gastric mucosa was then topically exposed to normal saline solution (pH 7.4), followed by 160 mumol/L capsaicin and then 100 mmol/L acidified taurocholate (pH 1.2), each for 15 minutes. Gastric mucosal blood flow (ml/min/100 gm tissue) was continuously measured (laser Doppler) and mucosal injury was assessed. Luminal PGE2 production was measured during the bile acid injury period by radioimmunoassay. RESULTS: The CGRP antagonist hCGRP8-37 significantly inhibits capsaicin-induced hyperemia and its associated mucosal cytoprotection and also significantly decreases luminal mucosal PGE2 production. Pretreatment with L-arginine, but not D-arginine, reverses these effects of CGRP antagonism. CONCLUSIONS: CGRP is a mediator of capsaicin-induced hyperemia and protection. This effect may be dependent on both NO and PGE2 production.

Animals↗
PubMed1993

Inhibition of doxorubicin-induced apoptosis in vivo by 2-deoxy-D-glucose.

Previous studies have shown that DNA cleavage by mammalian topoisomerase II is ATP dependent and can be inhibited by metabolic inhibitors. Furthermore, it has been shown that metabolic inhibitors also have a cytoprotective effect in vitro against topoisomerase II-targeting antitumor drugs. However, the nature of the ATP-dependent process is not known. We have previously shown that doxorubicin induces apoptosis (programmed cell death) in the murine small intestine which can be inhibited by the protein synthesis inhibitor cycloheximide. In the present study, we have demonstrated that 2-deoxy-D-glucose reduces the incidence of doxorubicin-induced apoptosis in vivo if administered within 45 min of the doxorubicin. Maximum reduction was observed at 2 h after treatment (approximately 66%); however, significant reduction was still observable at 9 h after treatment (approximately 33%). Significant positive correlation was observed between protein synthesis inhibition and apoptosis inhibition. Other possible mechanisms of action of the inhibitor do not appear to be important in cytoprotection. The inhibitor did not reduce the uptake of doxorubicin into the intestinal epithelium; however, it caused a significant increase in retention of the drug. The kinetics of inhibition suggest that alteration of cell cycle kinetics, inhibition of formation of doxorubicin-topoisomerase II complex or induction of glucose-regulated proteins are not significant factors in cytoprotection. These studies indicate that at least in the mouse small intestinal epithelium, the ATP-dependent process in cell killing by doxorubicin may involve protein synthesis.

Adenosine Triphosphate↗
PubMed1996

Extracellular acidosis and chloride channel inhibitors act in the late phase of cellular injury to prevent death.

Extracellular acidosis is cytoprotective in several models against anoxia/hypoxia and a variety of toxicants. The goal of this study was to determine the temporal relationships among toxicant exposure, the initiation of extracellular acidosis, Cl. Influx, Cl- channel inhibition and the onset of cellular death in rabbit renal proximal tubule suspensions. Extracellular acidosis was produced by adding HCl or H2SO4 to renal proximal tubule suspensions to decrease the extracellular buffer pH to 6.4 or by resuspending renal proximal tubules in a pH 6.4 buffer. The initiation of extracellular acidosis 15 min after the mitochondrial inhibitors antimycin A or carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone addition, a time point in which adenosine triphosphate levels are depleted and intracellular K+ is decreased, ameliorated lactate dehydrogenase release, a marker of necrotic cellular death. The initiation of extracellular acidosis 120 min after the addition of the toxicants tetrafluoroethyl-L-cysteine or t-butyl hydroperoxide decreased lactate dehydrogenase release 120 min later. Increased Cl- influx is an important step during the late phase of toxicant-induced cellular injury. Therefore, we determined if extracellular acidosis cytoprotection was associated with inhibition of Cl- influx and whether the Cl- channel inhibitors indanyloxyacetic acid (1.0 mM). niflumic acid (100 microM) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (100 microM) decreased Cl- influx and cellular death in renal proximal tubules exposed to antimycin A. Indeed, all three Cl- channel inhibitors significantly decreased 38Cl- influx and cellular death. In contrast, extracellular acidosis did not decrease 38Cl- influx but did prevent lactate dehydrogenase release. These results demonstrate that extracellular acidosis cytoprotection occurs during the late phase of cellular injury at a site distal to Cl- influx. Furthermore, the Cl- influx that occurs during the late phase of cellular injury and is critical for cellular swelling and lysis is sensitive to 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid, niflumic acid and indanyloxyacetic acid.

Acidosis↗
PubMed1996

The Fanconi anemia complementation group C protein corrects DNA interstrand cross-link-specific apoptosis in HSC536N cells.

Fanconi anemia (FA) cells are hypersensitive to cytotoxicity, cell cycle arrest, and chromosomal aberrations induced by DNA cross-linking agents, such as mitomycin C (MMC) and nitrogen mustard (HN2). Although MMC hypersensitivity is complemented in a subset of FA cells (complementation group C [FA-C]) by wild-type FAC cDNA, the cytoprotective mechanism is unknown. In the current study, we tested the hypothesis that FAC protein functions in the suppression of DNA interstand cross-link (ISC)-induced cell cycle arrest and apoptosis. Comparison of HN2-induced cell cycle arrest and apoptosis with those of its non-cross-linking analogs, diethylaminoethyl chloride and 2-dimethylaminoethyl chloride, delineated the DNA ISC specificity of FAC-mediated cytoprotection. Overexpression of wild-type FAC cDNA in FA-C lymphoblasts (HSC536N cell line) prevented HN2-induced growth inhibition, G2 arrest, and DNA fragmentation that is characteristic of apoptosis. In contrast cytoprotection was not conferred against the effects of the non-cross-linking mustards. Our data show that DNA ISCs induce apoptosis more potently than do DNA monoadducts and suggest that FAC suppresses specifically DNA ISC-induced apoptosis in the G2 phase of the cell cycle.

Apoptosis↗
PubMed1996

Effects of heat shock and teprenone on ethanol-induced damage to cultured rabbit gastric mucosal cells.

We examined whether or not heat shock and teprenone (a gastric mucosal protective drug), through the induction of heat shock proteins (HSPs), protect cultured rabbit gastric mucosal cells from ethanol-induced damage. Cell viability was assessed by mitochondrial function and membrane permeability assays. Exposure of mucosal cells to 5% ethanol for 1h caused an about 50% reduction in viability. When the cells had been heated at 43 degrees C for 1 h, the cell damage caused by ethanol was significantly prevented. However, pretreatment with teprenone at 1-100 microM failed to prevent the ethanol-induced damage. Western blot analysis with an anti-HSP-72 antibody showed that HSP-72 was apparently induced by heat treatment, but not by teprenone. Both the cytoprotection and induction of HSP-72 on heat treatment were potently inhibited by cycloheximide and actinomycin D. These results demonstrate that, in rabbit gastric mucosal cells, the induction of HSPs is strongly associated with cytoprotection against ethanol-induced damage, but that teprenone has no effect on the cytoprotection or HSP induction.

Animals↗
PubMed1997

Physiological, immunohistochemical and molecular aspects of gastric adaptation to stress, aspirin and to H. pylori-derived gastrotoxins.

Gastric mucosa is continuously exposed to various aggressive factors such as stress, ulcerogenic drugs including aspirin-like agents, gastrotoxic bacteria, particularly Helicobacter pylori (Hp) and many other exogenous and endogenous irritants. The maintenance of mucosal barrier depends upon the activation of pre-epithelial (mucus-alkaline secretion), epithelial (surface active phospholipids, mucosal cell restitution and proliferation) and post-epithelial (mucosal microcirculation) lines of mucosal defence. The mucosa exposed to aggressive factors develops acute lesions, which usually heal completely within few days, but following repeated exposures to hostile environment it adapts to survive the challenge of noxious agents. This adaptation may be of short term (adaptive cytoprotection) and follows the exposure to "mild" irritants that activate local mucosal biosynthesis of protective prostaglandins (PG) and nitric oxide (NO) and stimulate sensory nerves and mucosal cell migration and proliferation through enhanced expression of growth factors such as EGF, TGF alpha and trefoil peptides. The fact that exogenous PG, NO-donor agents, growth factors and capsaicin, stimulating sensory nerves, protect the mucosa against strong necrotizing agents (direct cytoprotection), supports the notion that endogenous PG, NO, growth factors and sensory nerves are involved in the complex process of adaptive cytoprotection. With repeated insults of ulcerogens such as stress aspirin, Hp-derived gastrotoxins, especially ammonia, a long-term adaptation develops which is mediated mainly by overexpression of EGF and TGF alpha and their common receptor (EGFR) with subsequent increase of mucosal cell proliferation and enhanced healing of mucosal lesions. The failure of mucosal adaptation seems to play a pivotal role in the pathogenesis of gastric lesions and peptic ulcerations.

Analgesics, Non-Narcotic↗
PubMed1997

[New concepts in the therapy of diabetic cardiopathies].

Most reasonable cause of diabetic cardiopathy might be the impaired energy fuel supply and metabolism producing inevitably a hypotic condition and needing myocardial cytoprotection. Under diabetic conditions glucose disposal of the heart muscle-decreases, but working myocardial cell remains penetrable for glucose even in the absence of insulin. Therefore, it is worth to stimulate aerobic glycolysis to protect diabetic heart from frequent ischaemic events induced by diabetic late complications, since fatty acids oxidation wastes more oxygen than glycolysis for ATP production. Trimetazidine has an original cytoprotective mode of action reducing oxygen demand without altering heart activity. Consequently, trimetazidine protects structure and functions of the ischemic myocardial cell. On the other hand, glycation and altered turnover of proteins play also an important role in the development of diabetic cardiopathy. Consequently, not only trimetazidine but aminoguanidine could also reduce the development of alterations in diabetic cardiopathy inhibiting the glycation of proteins. Finally, calcium antagonists are also very usefull in myocardial cytoprotection of the diabetic heart, according to the altered cellular calcium regulation and a calcium overload which play the main role in the development of diabetic cardiopathy.

Adenosine Triphosphate↗
PubMedDate not supplied

The efficacy of immunochemotherapy with strontium (Sr) in the 1,2-dimethylhydrazine (DMH) induced rat carcinogenetic model: ultrastructural characteristics of the mitochondria in the liver.

It is said that stable strontium (Sr), which exists naturally in living cells as a microelement, has cytoprotective effects on liver cells in mammals. We attempted to examine the cytoprotective and anticancer effects of Sr using the rat carcinogenetic model induced by DMH (1,2-dimethylhydrazine). In a comparison of animals given UFT, PSK and Sr or UFT and PSK, carcinogenes in the colon and also increases in immunosuppressive acidic protein (IAP) levels were suppressed. Electron microscopic observation in the Sr group revealed a tendency toward stabilization of the mitochondrial membrane and highly developed rough endoplasmic reticulum in both the right and left lobe. This tendency became more obvious as the duration of oral intake of Sr was prolonged. Our study suggest that the cytoprotective effect of Sr on mitochondria in the liver may suppress carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed2000

Human thioredoxin attenuates hypoxia-reoxygenation injury of murine endothelial cells in a thiol-free condition.

The adult T cell leukemia-derived factor (ADF), or human thioredoxin (hTRX), has a radical scavenging effect similar to that of N-acetyl cysteine (NAC). We have recently shown that ADF/hTRX protects the lung and the heart from ischemia-reperfusion induced injury. To elucidate mechanisms of the protective effect, a hypoxia-reoxygenation (H-R) injury model was developed using a murine endothelial cell line, cultured in a thiol-free medium. In this condition, cells became much more vulnerable to H-R injury. The viability of cells decreased significantly after 1 h of hypoxic incubation followed by 1 h of reoxygenation. The injury was reduced by ADF/hTRX (100 microM) or NAC (10 mM). These two agents also demonstrated an additive protective effect. When cells were cultured in thiol-free medium for 2 h in a normoxic condition, intracellular hydrogen peroxide production was increased, which was associated with a decrease in glutathione level. NAC (10 mM) attenuated these changes whereas ADF/hTRX (100 microM) did not. These results suggest that although both ADF/hTRX and NAC protected cells from H-R injury, the underlying mechanisms are different. Because the cytoprotective effect of ADF/hTRX occurs in the thiol-free condition, it must be mediated via a novel mechanism other than enhancing thiol uptake. The additive cytoprotective effect between ADF/hTRX and NAC suggests that we should combine these two agents clinically.

Acetylcysteine↗
PubMed2000

Protective effects of boldine against free radical-induced erythrocyte lysis.

Boldine, an aporphine alkaloid extracted from the leaves and bark of boldo (Peumus boldus Mol.), has been shown to exhibit strong free-radical scavenger and antioxidant properties. Here, we report the in vitro ability of boldine to protect intact red cells against the haemolytic damage induced by the free radical initiator 2, 2'-azobis-(2-amidinopropane) (AAPH). Boldine concentration-dependently prevented the AAPH-induced leakage of haemoglobin into the extracellular medium. Substantial and similar cyto-protective effects of boldine were observed whether the antioxidant was added 1 h prior to, or simultaneously with, the azo-compound. The delayed addition of boldine, by 1 h relative to AAPH, diminished but did not abolish its cytoprotective effect. However, negligible effects of boldine were observed after its addition to erythrocytes previously incubated with AAPH for 2 h. The data presented demonstrate that, in addition to its well-established antioxidant effects, boldine also displays time-dependently strong cytoprotective properties against chemically induced haemolytic damage.

Animals↗
PubMed2004

Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats.

The inducible isoform of heme oxygenase (HO), HO-1, has been shown to play an important role in attenuating tissue injury. Because HO-1 catalyzes the rate-limiting step in bilirubin synthesis, we examined the hypothesis that bilirubin is a key mediator of HO-1 cytoprotection, employing a rat model of endotoxemia. Bilirubin treatment resulted in improved survival and attenuated liver injury in response to lipopolysaccharide infusion. Serum levels of NO and tumor necrosis factor alpha, key mediators of endotoxemia, and hepatic inducible nitric oxide synthase (iNOS) expression were significantly lower in bilirubin-treated rodents versus control animals. Both intraperitoneal and local administration of bilirubin also was found to ameliorate hindpaw inflammation induced by the injection of lambda-carrageenan. Consistent with in vivo results, bilirubin significantly inhibited iNOS expression and suppressed NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. In contrast, bilirubin treatment induced a threefold increase in LPS-mediated prostaglandin synthesis in the absence of significant changes in cyclooxygenase expression or activity, suggesting that bilirubin enhances substrate availability for eicosanoid synthesis. Bilirubin had no effect on LPS-mediated activation of nuclear factor kappaB or p38 mitogen-activated protein kinase, consistent with a nuclear factor kappaB-independent mechanism of action. Taken together, these data support a cytoprotective role for bilirubin that is mediated, at least in part, through the inhibition of iNOS expression and, potentially, through stimulation of local prostaglandin E2 production. In conclusion, our findings suggest a role for bilirubin in mollifying tissue injury in response to inflammatory stimuli and support the possibility that the phenomenon of "jaundice of sepsis" represents an adaptive physiological response to endotoxemia. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

Animals↗
PubMed2004

Biliverdin therapy protects rat livers from ischemia and reperfusion injury.

Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1beta, tumor necrosis factor alpha, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs.

Animals↗
PubMed2005

Activation of CREB by tauroursodeoxycholic acid protects cholangiocytes from apoptosis induced by mTOR inhibition.

Tauroursodeoxycholic acid (TUDCA) is a cytoprotective bile acid frequently prescribed to patients with cholestatic diseases. Several mechanisms of action have been investigated, but the possibility that cyclic adenosine monophosphate responsive element binding protein (CREB), a transcription factor promoting cell survival, mediates TUDCA's protective effects has not been considered. We examined whether TUDCA activates CREB and whether this activation can protect biliary epithelial cells. Cholangiocytes were stressed by exposure to CCI-779, which inhibits signaling though the kinase mTOR (mammalian target of rapamycin), resulting in cell cycle arrest and apoptosis. Incubation of normal rat cholangiocytes (NRC) cells, with TUDCA resulted in phosphorylation of CREB (Western blotting analysis) and activation of CREB transcription activity (luciferase reporter assay). Inhibition of calcium signals and inhibition of protein kinase C prevented the TUDCA-induced activation of CREB. CCI-779 decreased the viability of rat cholangiocytes in a dose-dependent manner (MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay). TUDCA protected against CCI-779 cytotoxicity. A dominant negative form of CREB was stably transduced in NRC cells (NRC-M1). TUDCA protection was decreased in NRC-M1. While CCI-779 induced apoptosis in NRC cells as determined by caspase 3 activity, TUDCA attenuated CCI-779-induced apoptosis, an effect absent in NRC-M1. Finally, CCI-779 blocked proliferation of both NRC and NRC-M1 (thymidine incorporation) and this was unaffected by TUDCA. In conclusion, TUDCA activates CREB in cholangiocytes, reducing the apoptotic effect of CCI-779. These findings suggest a novel cytoprotective mechanism for this bile acid.

Animals↗