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PubMed1999

Thiol redox modulation of doxorubicin mediated cytotoxicity in cultured AIDS-related Kaposi's sarcoma cells.

The chemotherapeutic, doxorubicin, is currently used empirically in the treatment of AIDS- related Kaposi's sarcoma (AIDS-KS). Although often employed in a chemotherapeutic cocktail (doxorubicin, bleomycin, vincristine) single-agent therapy has recently been attempted with liposome encapsulated doxorubicin. Although doxorubicin's mechanism of action against AIDS-KS is unknown, we hypothesized that doxorubicin's ability to undergo redox cycling is associated with its clinical efficacy. The current study was conducted to investigate the effects of doxorubicin on selected xenobiotic-associated biochemical responses of three cellular populations: KS lesional cells, nonlesional cells from the KS donors, and fibroblasts obtained from HIV- aged matched men. Our results show that during doxorubicin challenge, there are strong positive correlations between cellular glutathione (GSH) levels and viability (r = 0.94), NADPH levels and viability (r = 0.93), and GSH and NADPH levels (r = 0.93), and demonstrate that as a consequence of their abilities to maintain cellular thiol redox pools HIV- donor cells are significantly less susceptible to doxorubicin's cytotoxic effects relative to AIDS-KS cells. Additional studies further supported the contribution of reduced thiols in mediating doxorubicin tolerance. While pretreatment with the GSH precursor, N-acetylcysteine was cytoprotective for all cell groups during doxorubicin challenge, GSH depletion markedly enhanced doxorubicin's cytotoxic effects. Studies to investigate the effects of a hydroxyl scavenger and iron chelator during doxorubicin challenge showed moderate cytoprotection in the AIDS-KS cells but deleterious effects in the HIV control cells. Inactivation of the longer lived membrane generated ROI in the cytoprotective deficient AIDS-KS cells, as well as an impairment of endogenous defenses in the HIV- donor control cells, may account for these scavenger and chelator associated findings. In summary, our findings show that doxorubicin mediates, at least in part, its AIDS-KS cellular cytotoxic effects by a redox related mechanism, and provides a biochemical rationale for doxorubicin's clinical efficacy in AIDS-KS treatment.

AIDS-Related Opportunistic Infections↗
PubMed1999

Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis.

Silymarin is a polyphenolic flavonoid derived from milk thistle (Silybum marianum) that has anti-inflammatory, cytoprotective, and anticarcinogenic effects. How silymarin produces these effects is not understood, but it may involve suppression of NF-kappa B, a nuclear transcription factor, which regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this report, we investigated the effect of silymarin on NF-kappa B activation induced by various inflammatory agents. Silymarin blocked TNF-induced activation of NF-kappa B in a dose- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of Iota kappa B alpha, an inhibitor of NF-kappa B. Silymarin blocked the translocation of p65 to the nucleus without affecting its ability to bind to the DNA. NF-kappa B-dependent reporter gene transcription was also suppressed by silymarin. Silymarin also blocked NF-kappa B activation induced by phorbol ester, LPS, okadaic acid, and ceramide, whereas H2O2-induced NF-kappa B activation was not significantly affected. The effects of silymarin on NF-kappa B activation were specific, as AP-1 activation was unaffected. Silymarin also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Silymarin suppressed the TNF-induced production of reactive oxygen intermediates and lipid peroxidation. Overall, the inhibition of activation of NF-kappa B and the kinases may provide in part the molecular basis for the anticarcinogenic and anti-inflammatory effects of silymarin, and its effects on caspases may explain its role in cytoprotection.

Apoptosis↗
PubMed2000

Scatter factor/hepatocyte growth factor protects against cytotoxic death in human glioblastoma via phosphatidylinositol 3-kinase- and AKT-dependent pathways.

We have shown recently that the multifunctional growth factor, scatter factor/hepatocyte growth factor (SF/HGF), and its receptor c-met enhance the malignancy of human glioblastoma through an autocrine stimulatory loop (R. Abounader et al., J. Natl. Cancer Inst., 91: 1548-1556, 1999). This report examines the effects of SF/HGF:c-met signaling on human glioma cell responses to DNA-damaging agents. Pretreating U373 human glioblastoma cells with recombinant SF/HGF partially abrogated their cytotoxic responses to gamma irradiation, cisplatin, camptothecin, Adriamycin, and Taxol in vitro. This cytoprotective effect of SF/HGF occurred at least in part through an inhibition of apoptosis, as evidenced by diminished terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling index and reduced DNA laddering. Anti-c-met U1/ribozyme gene transfer inhibited the ability of SF/HGF to protect against single-strand DNA breakage, DNA fragmentation, and glioblastoma cell death caused by DNA-damaging agents, demonstrating a requirement for c-met receptor function. Phosphorylation of the cell survival-promoting kinase Akt (protein kinase B) resulted from SF/HGF treatment of U373 cells, and both Akt phosphorylation and cell survival induced by SF/HGF were inhibited by phosphatidylinositol 3-kinase inhibitors but not by inhibitors of mitogen-activated protein kinase kinase or protein kinase C. Cytoprotection by SF/HGF in vitro was also inhibited by transient expression of dominant-negative Akt. Transgenic SF/HGF expression by intracranial 9L gliosarcomas reduced tumor cell sensitivity to gamma irradiation, confirming the cytoprotective effect of SF/HGF in vivo. These findings demonstrate that c-met receptor activation by SF/HGF protects certain glioblastoma cells from DNA-damaging agents by activating phosphoinositol 3-kinase-dependent and Akt-dependent antiapoptotic pathways.

Animals↗
PubMed2000

[Effect of fructose-1,6-diphosphate on myocardial purin and pyrimidin metabolism during coronary artery bypass grafting surgery].

During ischaemia, the glycolytic pathway (Embden-Meyerhof) is up regulated in an attempt to produce ATP anaerobically. However, this is short-lived due to negative feedback on the key glycolytic enzyme phosphofructokinase by accumulating lactate. Fructose-1,6-diphosphate (FDP), a high energy intermediary metabolite of this pathway, is unique in that is enters glycolysis distal to this inhibitory site. Exogenously administered FDP should therefore theoretically yield ATP independent of lactate accumulation and thereby ameliorate ischaemic injury. Clinical benefit has been shown in coronary artery bypass grafting (CABG) surgery, congestive cardiac failure and adult respiratory distress syndrome. Ischaemia-reperfusion injury induced by cardiopulmonary bypass (CPB) presents clinically as an impairment of myocardial function in the postoperative period. At a cellular level this reflects myocardial metabolic changes and nucleotide degradation (directly linked to high energy phosphate turnover). Quantification of myocardial nucleotide catabolite release therefore provides useful information regarding intermediary metabolism and cytoprotection conferred to myocardial (inosine, uridine) and endothelial (hypoxanthine) tissue. The authors investigated the myocardial cytoprotective effects of FDP in 16 patients scheduled for elective CABG surgery. Aortic and coronary sinus blood were collected directly into liquid nitrogen and analysed by high performance liquid chromatography prior to CPB and at different time points after reperfusion. FDP was administered intravenously in 8 patients and 5% dextrose was administered in 8 other patients. Analysis of transmyocardial (coronary sinus-aortic) nucleotide metabolite levels showed increased release of inosine, hypoxanthine and uridine in both the FDP and the control groups following reperfusion. However, compared to baseline (pre-aortic clamping) values, hypoxanthine and inosine concentrations were significantly elevated at 0, 1, 5 and 10 minutes following reperfusion in the control group. This was in contrast to earlier recovery to baseline levels (after 5 minutes of reperfusion) in the FDP group. Furthermore, when compared to control group, the hypoxanthine and inosine concentrations were significantly decreased by FDP treatment. Uridine concentrations were significantly elevated at 1 and 5 minutes in the control group and no significant change was observed in the FDP group. In conclusion, these data suggest that FDP, through an intermediary metabolic effect, may contribute to myocardial and endothelial cytoprotection during the ischaemic insult of cardiac surgery.

Adult↗
PubMed2003

Role of mast cells in gastrointestinal mucosal defense.

The purpose of this review, based on studies from our laboratory as well as from others, is to summarize salient features of mast cell immunobiology and to describe their associations with gastrointestinal mucosal defense. Gastrointestinal mast cells are involved in many pathologic effects, such as food hypersensitivity. On the other hand, they also play a protective role in defense against parasitic and microbial infections. Thus, they have both positive and negative effects, but presently the mechanisms that control the balance of these various effects are poorly known. It has been suggested that stabilization of mast cells may be a key mechanism to protect the gastrointestinal tract from injury. Few molecules are known to possess both mast cell stabilizing and gastrointestinal cytoprotective activity. These include zinc compounds, sodium cromoglycate, FPL 52694, ketotifen, aloe vera, certain flavonoids such as quercetin, some sulfated proteoglycans such as chondroitin sulfate and dehydroleucodine. Dehydroleucodine, a sesquiterpene lactone isolated from Artemisia douglasiana Besser, exhibits anti-inflammatory and gastrointestinal cytoprotective action. The lactone stimulates mucus production, and inhibits histamine and serotonin release from intestinal mast cells. The lactone could act as a selective mast cell stabilizer by releasing cytoprotective factors and inhibiting pro-inflammatory mast cell mediators.

Animals↗
PubMed2004

Heme oxygenase system in ischemia and reperfusion injury.

Ischemia/reperfusion injury (IRI) is a multifactorial antigen-independent process that affects both early and late graft function after transplantation. The complex mechanism of IRI can be attributed to neutrophil accumulation at the site of tissue injury, release of pro-inflammatory mediators such as oxygen free radicals (OFRs), and cytokines, which lead to cellular injury that culminates in the ultimate graft failure. The heme oxygenase-1 (HO-1) system is among the most critical of cytoprotective mechanisms activated during the cellular stress. The cytoprotection often seen in the transplanted organ following local HO-1 overexpression may include several factors, such as: a) antioxidant function, b) maintenance of microcirculation, c) anti-apoptotic function, and d) anti-inflammatory function. The role of enhanced endogenous HO-1 overexpression, and HO-1 downstream mediators (bilirubin, ferritin, CO), which protect against the IRI sequel, remain currently one of the most active areas of investigation. Indeed, HO-1, which functions to amplify multiple intracellular cytoprotective pathways, may serve as a novel therapeutic concept in transplantation to maximize organ donor pool through their safer use despite prolonged periods of cold ischemia.

Animals↗
PubMed2004

Thiamine attenuates hypoxia-induced cell death in cultured neonatal rat cardiomyocytes.

Previous studies have demonstrated that thiamine (vitamin B1) has a cytoprotective effect against ischemic damage to the heart, and that heat shock protein 70 (Hsp70) is capable of protecting cardiac cells from lethal ischemia/hypoxia. We show here that thiamine has a cytoprotective effect on cultured neonatal rat cardiomyocytes under hypoxic insult, and also protects the cardiomyocytes against hypoxia-induced apoptosis; caspase-3 activation, PARP cleavage and DNA fragmentation are all inhibited. Moreover, it increases the level of Hsp70 protein in the cardiomyocytes even under prolonged hypoxic stress and its effects on hypoxia-induced cardiac cell death are antagonized by an Hsp70 inhibitor. These results suggest that the cytoprotective effect of thiamine in cardiomyocytes under hypoxic stress is due to its ability to induce Hsp70.

Animals↗
PubMed2006

Cyclooxygenase-2 inhibitor, nimesulide, improves radiation treatment against non-small cell lung cancer both in vitro and in vivo.

Lung cancer is the leading cause of cancer-related deaths in the United States. Despite improvements in radiation, surgery and chemotherapy the 5 year survival statistics of non-small cell lung cancer (NSCLC) have improved little over the past two decades. It has been proposed that NF-kappaB is a participant in the cytoprotection against several redox-mediated therapeutic agents including ionizing radiation. Cyclooxygenase-2 (COX-2) inhibition has become an attractive target for enhancing the efficacy of radiation and chemotherapy. Numerous mechanistic pathways have been proposed as the means through which COX-2 inhibition enhances the efficacy of radiation. We hypothesize that the COX-2 inhibitor, nimesulide, will improve the efficacy of radiation therapy (RT), at least in part, via the suppression of NF-kappaB mediated cytoprotective pathways. In this study we used the COX-2 inhibitor nimesulide to improve the efficacy of RT when measured by tumor regrowth assays in vivo and clonegenic survival in vitro. For the in vivo assay, A549 tumor cells representing NSCLC were subcutaneously injected into the right flanks of female athymic nude mice (n=10/group). Mice were given nimesulide via drinking water at a concentration of 5 microg/g body weight (b.w.) and the water was replenished daily. Tumors were treated with 30 Gy fractionated radiation and measured bi-weekly. For our in vitro study, clonogenic survival assays were evaluated to determine the effect of nimesulide, radiation, and the combination. The NF-kappaB mediated mechanism of nimesulide was measured by Western blot analysis of NF-kappaB target genes, MnSOD and survivin. In vivo, mice that received combined treatments of 5 microg/g b.w. nimesulide and 30 Gy radiation (3 Gy/fraction, 10 daily fractions) had significant reduction in tumor size in comparison to the 30 Gy radiation control group (p<0.05). In vitro, nimesulide alone produced a significant decrease in clonogenic survival at doses from 0-300 microM. Nimesulide demonstrated an additive effect in combination with radiation. Nimesulide alone reduced MnSOD and survivin protein levels in a dose-dependent manner. 6 Gy radiation caused an initial elevation of MnSOD protein levels which was inhibited by prior treatment of nimesulide suggesting an inhibition of radiation induced NF-kappaB target genes. These results support the hypothesis that COX-2 inhibitors such as nimesulide can increase the efficacy of radiation therapy. In vitro, our results suggest that the radiosensitization of A549 tumor cells by nimesulide is mediated by the suppression of NF-kappaB-mediated, radiation-induced cytoprotective genes.

Animals↗
PubMedDate not supplied

[Role of hemeoxygenase-1 in the neurodegenerative disorders].

AIM: To review some evidences about the role of hemeoxygenase-1 (HO-1) in neurodegenerative disorders. DEVELOPMENT: HO is the rate-limiting enzyme that catalyzes the conversion of heme into biliverdin, carbon monoxide, and free iron. They are the inducible HO-1 and the constitutive HO-2. A large body of evidence suggests that HO-1 confers cytoprotection against oxidative stress. Postmortem studies conducted in humans have revealed increase in HO-1 protein in association with Alzheimer disease, Parkinson disease and Huntington disease. It is unknown the meaning of that increase. Nevertheless, there are evidences indicating that the overexpression of HO-1 contributes to the pathological iron deposition suggesting a detrimental role of HO-1. In contrast, there are evidences indicating that the overexpression of HO-1 decreases the neurotoxin-induced cell death in transgenic mice and neuronal cultures suggesting a cytoprotective role of HO-1. CONCLUSION: It is controversial if the overexpression of HO-1 has a detrimental or cytoprotective role. Therefore, it is necessary to continue the study about the role of the HO-1 in neurodegenerative diseases.

Heme Oxygenase-1↗
PubMed2006

Apoptosis and autophagy in mammary gland remodeling and breast cancer chemotherapy.

Apoptosis - programmed cell death (PCD) type I is physiological process responsible for cell loss during mammary gland involution after natural weaning or litter removal in rodents, after weaning in sow and during drying off in goat and cow. The regulation of mammary epithelial cell (MEC) apoptosis in bovine mammary gland occurs at three levels. The first level comprises intracellular regulatory proteins, e.g. Bcl-2 family death promoters and inhibitors. The second level is represented by intramammary inductors of apoptosis, e.g. FIL, IGFBPs, Fas ligand, TGF-betas. The expression and activity of these auto/paracrine inductors of apoptosis is controlled and modulated by the third level factors, e.g. systemic galactopoetic hormones, nutrition, reproductive status and milking management. Our recent study proved that apoptosis in involuting bovine mammary gland is accompanied by increased intensity of autophagy, regarded as a cytoprotective process but in advanced stage as a PCD type II. Moreover, we have reported for the first time the ability of TGF-beta(1) to induce both apoptosis and autophagy in bovine BME-UV1 MEC. Much more pronounced heterogeneity of PCD was observed when breast cancer cells were exposed to anticancer drugs. The primary responses of breast cancer MCF-7 cells to camptothecin (CPT) are apoptosis and autophagy (as a cytoprotective process). In this case autophagy occurs in cells which are resistant to apoptosis as a tool of cancer cell survival. The fail-safe responses of breast cancer cells to persisting CPT-induced stress are apoptosis accompanied by morphological and biochemical features of autophagy or type II PCD with advanced subcellular degradation. The threshold between autophagy as a cytoprotective process (reversible) or PCD (irreversible) is difficult to establish and probably depends on the extent of degradation of cellular components. Proapoptotic protein Bid may serve as a molecular switch between apoptosis and autophagy. Bid knock down in MCF-7 cells exposed to CPT leads to a shift of cell death from apoptosis to autophagy. Since bid and other proapoptotic genes undergo mutations in malignant cells, the ability of cancer cells commitment to autophagy may have important therapeutic implications.

Animals↗
PubMed1991

Calcium and acidosis in renal hypoxia.

The effects of lowering extracellular calcium concentration on hypoxic injury in the thick ascending limb of Henle (TAL) were studied in the isolated perfused rat kidney. At standard conditions of pH 7.4 and total perfusate calcium 1.9 mM, widespread TAL necrosis results from the combined effects of low medullary O2 delivery and the demands of solute transport activity. Reducing calcium to 0.5 or 0.1 mM, effectively prevented TAL membrane fragmentation. This cytoprotection was not accompanied by improved O2 delivery or by any consistent effects on renal physiology (glomerular filtration rate, sodium reabsorption, free water clearance or O2 consumption) that might have suggested that the mechanism was reduced O2 demand. In addition, the medullary ATP depletion which characteristically precedes TAL necrosis was not reversed. Finally, reduced perfusate calcium also markedly decreased TAL damage in an alternative model of hypoxia-like injury caused by a respiratory uncoupler. In aggregate, these findings indicate that reducing extracellular calcium does not prevent hypoxia itself, but rather disrupts the mechanism of its effects on cell integrity. The relationship of H+ and Ca2+ in the pathogenesis of hypoxic TAL injury was also studied. Lowering media pH to 7.0 reduced TAL damage but this cytoprotection was overcome by increasing media calcium concentration. Furthermore, with more severe acidosis (media pH 6.5 or 6.0), progressively greater perfusate calcium concentrations were required to reproduce severe TAL damage. These results indicate that extracellular calcium promotes the development of hypoxic TAL necrosis and that the cytoprotective effect of acidosis in hypoxia may be to counteract the calcium-dependent mechanism of injury.

Acidosis↗
PubMed1990

Alcohol and gastrointestinal bleeding.

Ethanol has experimentally been shown to be "ulcerogenic," independent of gastric intraluminal pH. Ethanol remains ulcerogenic despite antisecretory doses of H2-receptor antagonists. Low-dose alcohol stimulates acid secretion in man, an effect possibly mediated by histamine or gastrin. High-dose alcohol reduces intraluminal acid by damaging mucosa, thereby enhancing back diffusion of hydrogen ion, and also by direct damage to oxyntic (parietal) cells. Ethanol is capable of increasing gastric mucosal permeability as evidenced by the increase in back diffusion (increases intraluminal pH) and by the characteristic fall in transmucosal potential difference which reflects surface cell layer exfoliation. This exfoliation may offer an explanation for the potentiating effect of alcohol on gastric mucosal injury when it is ingested simultaneously with other gastric irritants. Ethanol of greater than 20% concentration can rapidly destroy the gastric mucus-bicarbonate layer, which may be a defense layer for both the inhibition of back diffusion and bicarbonate neutralization of existing acid. Ethanol depletes sulfhydryl compounds in gastric mucosa. These sulfhydryls may be necessary for stabilization of cell membranes as well as for binding free radicals. Ethanol is damaging to the mucosal microcirculation. The rapidity of ethanol-induced damage makes it unlikely that the process is purely ischemic. The cytoprotective phenomenon, as this brief literature review suggests, is a multifactorial, dynamic process. The complex interplay of mucosal defense factors, endogenous and exogenous stimuli, induction of humoral responses, and ultimately the success or failure of cellular repair, is unlikely to be solely mediated by endogenous prostaglandins. Although prostaglandins are unquestionably significant to cytoprotection, the supporting and, perhaps, major roles of leukotrienes, sulfhydryls, histamines, and like substances cannot be ignored. Several innovative therapeutic agents directly derived from these research efforts have already entered the clinician's formulary. The significance of the concept of cytoprotection is only now being realized in clinical applications. Alcoholic hemorrhagic gastritis, although a significant clinical entity, remains a rather elusive diagnosis for the emergency physician. As a diagnosis of suspicion, therapeutic trials of antacids, sucralfate, or perhaps synthetic prostaglandin analogues are acceptable, pending endoscopic verification or short-term resolution of symptoms. All patients presenting with true hemorrhage or with persistent symptoms should undergo gastroenterologic referral and endoscopic evaluation. The Mallory-Weiss syndrome has long been associated with acute and chronic alcohol abuse.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcoholism↗
PubMed1989

Gastric antisecretory and antiulcer/cytoprotective effects of 2-cyano-3-(ethylthio-3-methylthio)-2-propenoic acid methyl ester.

AY-28,200 (2-cyano-3-(ethylthio-3-methylthio)-2-propenoic acid methyl ester), a new gastric antisecretory/antiulcer agent, inhibited basal and pentagastrin-stimulated gastric acid secretion in the conscious rat (ED50 = 7.6 and 1.9 mg/kg i.g., respectively). For inhibition of basal secretion, peak activity was attained in 5 to 6 h after dosing and was maintained for more than 10 h, with no gastric antisecretory activity occurring at 24 h. The K+ stimulated H+-K+ ATPase activity from rabbit gastric microsomes was inhibited by AY-28,200 (IC50 = 22 mumol/l). AY-28,200 inhibited ethanol-induced gastric lesions, at 3 mg/kg p.o. AY-28,200's cytoprotective effects against ethanol lasted for more than 4 h. AY-28,200 blocked acetylsalicylic acid and stress-induced gastric ulcers but was inactive against indomethacin-induced gastric ulcers. These results suggest that AY-28,200 is a parietal cell proton pump inhibitor with cytoprotective properties, and may produce its cytoprotective effect by stimulating the formation of endogenous prostaglandins.

Adenosine Triphosphatases↗
PubMed1987

Prostaglandins for duodenal ulcer.

Studies to date indicate that certain synthetic prostaglandin E derivatives, notably misoprostol and enprostil, possess duodenal ulcer healing efficacy that is equivalent to that of the existing H2-receptor antagonists. Whether healing is achieved by virtue of their antisecretory action alone or in combination with their cytoprotective properties cannot be ascertained. Earlier reports that non-antisecretory prostaglandin E2 was effective for duodenal-ulcer healing suggested that cytoprotective mechanisms may contribute to ulcer healing, but this needs be confirmed. Chronic cigarette smoking adversely affects duodenal ulcer healing despite treatment with potent acid-reducing regimens. Evidence is available that cigarette smoking reduces luminal prostaglandins in the stomach, and that misoprostol, a prostaglandin E1 is able to overcome the adverse effect of smoking on duodenal ulcer healing, further suggesting that cytoprotective mechanisms may contribute to ulcer healing. Furthermore, misoprostol has been shown to be the first therapeutic agent capable of improving active chronic antral gastritis, which has recently been found to be almost invariably associated with active duodenal ulcer.

Anti-Ulcer Agents↗
PubMed1987

Action of famotidine and ranitidine on prostaglandin E2 (PGE2) content of fundic and duodenal mucosa in duodenal ulcer patients.

PGE2 plays an important role in gastric cytoprotection. Previous experience has shown that H2-blocker drugs may have a role in gastric cytoprotective mechanisms. The effects have been compared of ranitidine and famotidine on PGE2 content in duodenal ulcer patients. Twenty patients were treated for 4 weeks as follows: group A, ranitidine (150 mg twice daily); group B, famotidine (40 mg daily). The patients underwent EGDS before and after therapy. The results show that both famotidine and ranitidine significantly increase the PGE2 content of fundic mucosa (from 112.3 +/- 73 to 210.7 +/- 106 ng/g wet wt and from 109.6 +/- 52.4 to 230.2 +/- 104.6 ng/g wet wt, respectively) in duodenal ulcer patients (p less than 0.01). Similarly, the PGE2 content of duodenal mucosa significantly increases after famotidine treatment (from 51.9 +/- 27.5 to 105.3 +/- 55.6 ng/g wet wt) as well as ranitidine treatment (from 53.8 +/- 24 to 172.6 +/- 72.9 ng/g wet wt) (p less than 0.01). It is concluded that these drugs play an important role in gastric and duodenal cytoprotection.

Adult↗
PubMed1988

Protective effects against alcohol insult: does somatostatin play any role?

This study evaluated the cytoprotective properties of misoprostol, a synthetic prostaglandin E1 analogue and cimetidine, against alcohol-induced gastric mucosal injury and examined the role of increased gastric juice somatostatin in cytoprotection. Forty-give healthy adult male volunteers were enrolled in a randomized, double-blind, placebo-controlled endoscopic study. Screening endoscopy was done to exclude subjects with asymptomatic gastric mucosal abnormality. Misoprostol (200 micrograms) intragastrically, cimetidine (300 mg) orally or placebo were administered prior to ethanol challenge. Injury to the gastric mucosa was produced by spraying it with 80% ethanol solution instilled intragastrically. Endoscopic evaluation of gastric mucosa was conducted 15 and 30 minutes after ethanol by two endoscopists independently according to a seven-point scale. Thirty minutes following the instillation of ethanol, gastric contents were aspirated and analysed for immunoreactive somatostatin. The gastric mucosa of placebo-treated subjects showed marked damage with endoscopic score (mean +/- standard deviation) of 5.5 +/- 0.9. Cimetidine partially prevented gastric mucosal damage with endoscopic score of 4.5 +/- 1.7 as compared to placebo (P = 0.04). Misoprostol prevented significant gastric mucosal injury, (endoscopic score of 1 +/- 1.7) when compared to placebo (P = 0.0001) and to cimetidine (P = 0.0002). The gastric juice somatostatin concentration (pg/ml) was 75.79 +/- 13.59 in the misoprostol group, 64.71 +/- 8.06 in the cimetidine group and 34.34 +/- 5.66 in the placebo group. Both misoprostol and cimetidine showed significant (P = 0.05) increase in gastric juice somatostatin when compared to placebo treatment. The degree of gastric mucosal protection afforded by misoprostol was significantly greater than cimetidine. Since gastric juice somatostatin in the misoprostol group was not significantly different from the cimetidine group, it was concluded that gastric juice somatostatin is not solely responsible for the cytoprotective ability of misoprostol.

Adult↗
PubMed1986

Gastroprotection and lysosomal membrane stabilization by sulglicotide.

Well-known agents that induce gastric ulcers cause a decrease in lysosomal stability, with release of lytic enzymes. Some antiulcer and cytoprotective agents have lysosomal membrane stabilizing activity when tested in vitro and ex vivo. Sulglicotide (Gliptide), a polysulfated glycopeptide with antiulcer and cytoprotective activities, was able to stabilize lysosomal membranes in vitro at concentrations between 9 and 36 micrograms/ml. The ratio of potency of sulglicotide to that of carbenoxolone was 12.2. In ex vivo experiments in rats, it was found that sulglicotide stabilized lysosomes after oral treatment. The effect was dose-dependent after intravenous treatment. Carbenoxolone, injected i.v. under the same experimental conditions, was less active (potency ratio 0.65). 16,16-dimethyl-PGE2, administered at a dose of 10 micrograms/kg orally or intravenously, had an activity equivalent to that of sulglicotide at a dose of 12.5 mg/kg i.v. or 200 mg/kg p.o. Sulglicotide (200-400 mg/kg p.o.) was also able to prevent the release of acid phosphatase from stomachs challenged for 10 min or 3 h with absolute ethanol. The same result was obtained with 200 mg/kg p.o. of carbenoxolone. These data show that sulglicotide is a potent lysosomal membrane stabilizer in vitro and ex vivo, and could explain the cytoprotective activity of this compound in different experimental models of ulcer.

Animals↗
PubMed1984

Evidence for the development of tolerance to PGF2 alpha on the ethanol-induced gastric mucosal damage.

PGF2 alpha, 100 micrograms/kg intraperitoneally, applied 30 min before 1.0 ml intragastric ethanol (96%) exerts cytoprotective effect on the gastric mucosal membrane. After a week long pretreatment of the animals with 0.25; 0.5 and 1.0 mg/day PGF2 alpha resulted in a diminishing cytoprotective effect. The gastric tissue cAMP level raised simultaneously and after the PGF2 alpha pretreatment with the taming cytoprotection the cAMP level diminished parallel in a dose dependent manner. It is assumed that after PGF2 alpha pretreatment the density of the cellular PGF2 alpha receptors decreases, according to the observed phenomenon.

Animals↗