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PubMed1986

Gastric blood flow in ethanol injury and prostaglandin cytoprotection.

Studies performed in the author's laboratory concerning the role of gastric mucosal blood flow in ethanol-induced gastric mucosal injury and prostaglandin cytoprotection are reviewed. Fluorescent in vivo microscopic and hydrogen gas clearance studies revealed total absence of blood flow in the gross ethanol-induced lesions. Prostaglandin pretreatment not only prevented gross lesion formation but flow was present throughout the mucosa. A cytoprotective dose of the prostaglandin analogue did not increase blood flow. Transmitted light in vivo microscopy revealed rapid cessation of blood flow through mucosal microvessels within 1 min of ethanol application. The microvessels remained filled with red blood cells, suggesting an intravascular coagulation phenomenon. Histologic studies revealed no necrotic lesion formation 1 min after ethanol, but increasing necrosis from 10 to 60 min. These findings suggest that the rapid ethanol-induced cessation of blood flow renders the gastric mucosa more susceptible to ethanol injury and prostaglandin acts by preventing this blood flow change.

16,16-Dimethylprostaglandin E2↗
PubMed1988

Alternatives to the acid-oriented approach to ulcer disease: does 'cytoprotection' exist in man? A new classification of antiulcer agents.

This review summarizes the historical contradictions and inconsistencies that form the labile arguments advocating neutralization or inhibition of secretion of gastric acid for the prevention or treatment of gastroduodenal ulcers. Re-evaluation of old concepts is needed in the wake of recognition that even the most potent antisecretory agents do not change the natural history of ulcer disease; that is, the recurrence is high after termination of treatment. New biochemical, functional, and structural targets are listed for pharmacologic intervention in ulcer disease. As a supplement or alternative to the antisecretory agents, we should now consider prosecretory agents (for example, for bicarbonate and mucus secretion) and antioxidants (for example, free radical scavengers). Gastroduodenal motility, smooth muscle, the vascular endothelial cell, and the basement membrane seem to represent additional pharmacologic targets toward which new gastroprotective drugs can be directed even though the biochemical mechanism of action of these new agents may not be fully understood. New results suggest that these elements have a role in the pathogenesis of ulcer disease, and their modulations seem to exert a beneficial effect without inhibiting gastric secretion in rodents. In man, the acid antisecretory and cytoprotective doses seem to overlap, but arguments are presented to shift defining gastric 'cytoprotection' by the dose of drugs to the characterization of the phenomenon (for example, events such as the ethanol-induced hemorrhagic erosions which cannot be decreased by antisecretory agents). Furthermore, non-prostaglandin and non-H2-receptor antagonist drugs are available that exert acid-independent gastroprotection both in animals and humans. The future is thus bright for the development of new antiulcer agents.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Preparation and performance evaluation of plain proliposomal systems for cytoprotection.

Plain liposomal systems composed of soyabean lecithin, cholesterol and stearylamine were formulated using various approaches. The prepared products were characterized and evaluated for their cytoprotective performance against the necrotizing NSAID's (i.e. aspirin and phenylbutazone). Liposomes derived from proliposomes (effervescent granules based) demonstrated the best cytoprotective activity and physical and stability characteristics. This system was shown to be superior. An increased availability of regular and small sized liposome born phospholipids to the damaged mucosal systems accounted for its better and enhanced performance.

Animals↗
PubMed2006

Neuregulin 1-Beta cytoprotective role in AML 12 mouse hepatocytes exposed to pentachlorophenol.

Neuregulins are a family of growth factor domain proteins that are structurally related to the epidermal growth factor. Accumulating evidence has shown that neuregulins have cyto- and neuroprotective properties in various cell types. In particular, the neuregulin-1 Beta (NRG1-Beta) isoform is well documented for its antiinflammatory properties in rat brain after acute stroke episodes. Pentachlorophenol (PCP) is an organochlorine compound that has been widely used as a biocide in several industrial, agricultural, and domestic applications. Previous investigations from our laboratory have demonstrated that PCP exerts both cytotoxic and mitogenic effects in human liver carcinoma (HepG2) cells, primary catfish hepatocytes and AML 12 mouse hepatocytes. We have also shown that in HepG2 cells, PCP has the ability to induce stress genes that may play a role in the molecular events leading to toxicity and tumorigenesis. In the present study, we hypothesize that NRG1-Beta will exert its cytoprotective effects in PCP-treated AML 12 mouse hepatocytes by its ability to suppress the toxic effects of PCP. To test this hypothesis, we performed the MTT-cell respiration assay to assess cell viability, and Western-blot analysis to assess stress-related proteins as a consequence of PCP exposure. Data obtained from 48 h-viability studies demonstrated a biphasic response; showing a dose-dependent increase in cell viability within the range of 0 to 3.87 microg/mL, and a gradual decrease within the concentration range of 7.75 to 31.0 microg/mL in concomitant treatments of NRG1-Beta+PCP and PCP. Cell viability percentages indicated that NRG1-Beta+PCPtreated cells were not significantly impaired, while PCP-treated cells were appreciably affected; suggesting that NRG1-Beta has the ability to suppress the toxic effects of PCP. Western Blot analysis demonstrated the potential of PCP to induce oxidative stress and inflammatory response (c-fos), growth arrest and DNA damage (GADD153), proteotoxic effects (HSP70), cell cycle arrest as consequence of DNA damage (p53), mitogenic response (cyclin- D1), and apoptosis (caspase-3). NRG1-Beta exposure attenuated stress-related protein expression in PCP-treated AML 12 mouse hepatocytes. Here we provide clear evidence that NRG1-Beta exerts cytoprotective effects in AML 12 mouse hepatocytes exposed to PCP.

Animals↗
PubMed2004

Adaptive cytoprotection through modulation of nitric oxide in ethanol-evoked gastritis.

AIM: To assess the mechanisms of protective action by different mild irritants through maintenance of gastric mucosal integrity and modulation of mucosal nitric oxide (NO) in experimental gastritis rats. METHODS: Either 200 mL/L ethanol, 50 g/L NaCl or 0.3 mol/L HCl was pretreated to normal or 800 mL/L ethanol-induced acute gastritis Sprague-Dawley rats before a subsequent challenge with 500 mL/L ethanol. Both macroscopic lesion areas and histological damage scores were determined in the gastric mucosa of each group of animals. Besides, gastric mucosal activities of NO synthase isoforms and of superoxide dismutase, along with mucosal level of leukotriene (LT)C4 were measured. RESULTS: Macroscopic mucosal damages were protected by 200 mL/L ethanol and 50 g/L NaCl in gastritis rats. However, although 200 mL/L ethanol could protect the surface layers of mucosal cells in normal animals (protection attenuated by NG-nitro-L-arginine methyl ester), no cytoprotection against deeper histological damages was found in gastritis rats. Besides, inducible NO synthase activity was increased in the mucosa of gastritis animals and unaltered by mild irritants. Nevertheless, the elevation in mucosal LTC4 level following 500 mL/L ethanol administration and under gastritis condition was significantly reduced by pretreatment of all three mild irritants in both normal and gastritis animals. CONCLUSION: These findings suggest that the aggravated 500 mL/L ethanol-evoked mucosal damages under gastritis condition could be due to increased inducible NO and LTC4 production in the gastric mucosa. Only 200 mL/L ethanol is truly "cytoprotective" at the surface glandular level of non-gastritis mucosa. Furthermore, the macroscopic protection of the three mild irritants involves reduction of LTC4 level in both normal and gastritis mucosa, implicating preservation of the vasculature.

Animals↗
PubMed2004

Autocrine expression of hepatocyte growth factor and its cytoprotective effect on hepatocyte poisoning.

AIM: To construct pEGFP-hepatocyte growth factor (HGF) expression vector, the to detect its expression in transfected human hepatocytes, and to investigate the influence of autocrine HGF expression on the proliferative potential and cytoprotective effects in human hepatocytes. METHODS: Human HGF cDNA was ligated to the pEGFP vector. Recombinant plasmid was transfected into human hepatocyte line QZG with liposome. Expression of HGF protein was observed by fluorescence microscopy and immunohistochemistry. Hepatic cells were collected 24, 48, and 72 h after transfection to detect the number of ((3)H)-TdR uptake in DNA. DNA synthesis was observed by using PCNA stain immunohistochemistry. Acute liver cell damage was induced by carbon tetrachloride. Cytoprotective effect was observed by examining the survival rate of hepatocytes and leakage of intracellular alanine transaminase (ALT) and potassium ions. RESULTS: HGF identification of pEGFP-HGF by enzyme digestion showed that HGF fragment was cloned into BamH I and Sal I sites of pEGFP-N3. Expression of GFP in transfected hepatocytes was observed with fluorescence microscopy. The ((3)H)-TdR uptake became 7 times as many as in the control group 96 h after transfection. After HGF transfection, the survival rate of hepatocytes poisoned by CCl(4) significantly increased (83% vs 61%, P<0.05), and the leakage of intracellular alanine transaminase and potassium ions decreased (586 nkat/L vs 1 089 nkat/L, P<0.01; and 5.59 mmol/L vs 6.02 mmol/L, P<0.01 respectively). Culture of transfected hepatic cells promoted the proliferation of other non-transfected cells. CONCLUSION: Transfected HGF is expressed in hepatic cells and has the activity of promoting cell division and protecting hepatic cells against poisoning.

Cell Division↗
PubMed2004

Effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer.

AIM: To investigate the effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham operation without ginkgo, sham operation with ginkgo, duodenal ulcer without ginkgo, and duodenal ulcer with ginkgo. Rats with duodenal ulcer were induced by 500 mL/L acetic acid. Rats with ginkgo were intravenously injected with Ginkgo biloba extract from the tail at a dose of 0.5 mg/(kg/d) for 7 and 14 days. RESULTS: Pathological result showed that duodenal ulcer rats with ginkgo improved mucosal healing and inflammation compared with those without ginkgo after 7 d treatment. After 14 d treatment, duodenal ulcer rats with ginkgo significantly increased weight gain (34.0+/-4.5 g versus 24.5+/-9.5 g, P<0.05) compared with those without ginkgo. Duodenal ulcer rats significantly increased cell proliferation (27.4+/-4.0 and 27.8+/-2.3 BrdU-labeled cells in duodenal ulcer rats with and without ginkgo versus 22.4+/-3.5 and 20.8+/-0.5 BrdU-labeled cells in sham operation rats with and without ginkgo, P<0.05) compared with sham operation rats. Mucosal prostaglandin E(2) concentration significantly increased by 129% (P<0.05) in duodenal ulcer rats with ginkgo compared with that in those without ginkgo. Duodenal ulcer rats without ginkgo significantly decreased superoxide dismutase activity in the duodenal mucosa and erythrocytes (19.4+/-6.7 U/mg protein versus 38.1+/-18.9 U/mg protein in the duodenal mucosa, and 4.87+/-1.49 U/mg protein versus 7.78+/-2.16 U/mg protein in erythrocytes, P<0.05) compared with sham operation rats without ginkgo. However, duodenal ulcer rats with ginkgo significantly increased erythrocyte superoxide dismutase activity (8.22+/-1.92 U/mg protein versus 4.87+/-1.49 U/mg protein, P<0.05) compared with those without ginkgo. Duodenal ulcer rats without ginkgo significantly increased plasma lipid peroxides (4.18+/-1.12 micromol/mL versus 1.60+/-1.10 micromol/mL and 1.80+/-0.73 micromol/mL, P<0.05) compared with sham operation rats without ginkgo and duodenal ulcer rats with ginkgo during the experimental period. CONCLUSION: Ginkgo biloba extract can improve weight gain and mucosal healing in duodenal ulcer rats by the actions of cytoprotection and antioxidation.

Acetic Acid↗
PubMed1999

Complications of nonsteroidal antiiflammatory drug gastropathy and use of gastric cytoprotection: experience at a tertiary care health center.

OBJECTIVE: To determine what proportion of patients admitted to an academic medical center with complications of nonsteroidal antiinflammatory drug (NSAID) gastropathy had true indications for NSAID use, and whether patients with risk factors for NSAID gastropathy were receiving appropriate cytoprotection. METHODS: A retrospective chart review was carried out of all patients admitted with upper gastrointestinal (GI) bleeding, ulcer perforation, or gastric outlet obstruction during 1990-91 and 1995-96. NSAID or acetylsalicylic acid (ASA) use and medical indications were determined. Risk factors for NSAID gastropathy were documented and included concomitant steroid use, history of peptic ulcer disease or GI bleeding, history of cardiovascular disease, age > 60 years, and use of more than one NSAID. GI medication coprescription for patients with risk factors for gastropathy was evaluated. RESULTS: A total of 296 cases were identified. Use of NSAID was a contributing factor in 24% of patients admitted with upper GI bleeding, ulcer perforation, or gastric outlet obstruction. Use of ASA was a contributing factor in 25%. A true indication for NSAID/ASA use was identified in only 55% of cases. Fifty-nine patients had a single risk factor for NSAID gastropathy. Of these, 24% were receiving a coprescription for any GI medication at the time of admission to hospital and 8% were receiving misoprostol. In the 64 patients with 2 or more risk factors for NSAID gastropathy, 23% were concurrently receiving and GI medication and 2% were receiving misoprostol. In the 46 patients identified with a history of peptic ulcer disease or GI bleeding 28% were coprescribed a GI medication and 2% were taking misoprostol. There were no significant differences in the proportion of patients in any of the high risk groups who were receiving GI medications between 1990-91 and 1995-96. CONCLUSION: Inappropriate use of NSAID/ASA and failure to adequately cytoprotect patients at risk of NSAID gastropathy may account for a significant proportion of patients who develop life threatening complications.

Aged↗
PubMed1999

[Pharmacologic cytoprotection of the central nervous system].

Ischaemia of the central nervous system is considered to be a phenomenon, which manifests after the ischaemic episode and has limited therapeutic possibilities. Clinical situations in which the oxygen supply may be reduced include the following: stroke and transient ischaemic attacks, subarachnoid haemorrhage before, during and after carotid artery surgery, prolonged cardiopulmonary bypass during heart surgery, head injuries, cardiac arrest: (during arrest and recirculation), aortic surgery, spinal cord ischaemia, severe hypoxia/hypoxaemia, severe hypoperfusion/shock conditions. Although these clinical conditions are markedly different, they share the major similarities of cell death and its pathophysiology and pathogenesis, to which lies the therapy of CNS ischaemia is aimed. New cytoprotective drugs for neuronal damage are lazaroids. The 21-aminosteroids are known as inhibitors of lipid membrane peroxidation which preserve post-injural Ca2+ homeostasis (after total and focal ischaemia). During the last few years evidence has been accumulated about CCAs brain protection against cerebral ischaemia by a virtue of direct neuronal action. The excitatory amino acid antagonists, barbiturates, corticosteroids, antiepileptic drugs and antioxidants complete the cytoprotective treatment possibilities in situations of reduced oxygen supply for CNS. (Ref. 17.)

Animals↗
PubMed2000

Sustained activation of p42/p44 mitogen-activated protein kinase during recovery from simulated ischaemia mediates adaptive cytoprotection in cardiomyocytes.

Delayed cytoprotection (preconditioning) occurs 24 h after sublethal simulated ischaemia and reperfusion (SI/R) in neonatal rat ventricular cardiomyocytes. SI/R was used to investigate the role of activation of mitogen-activated protein kinases (MAPKs), stress-activated protein kinases (SAPKs) and phosphoinositide 3-kinase-dependent protein kinase B (PKB)/Akt in cytoprotection. SI resulted in transient dual (Thr/Tyr) phosphorylation of p42/p44-MAPK and p38-MAPK, weak phosphorylation of p46/p54-SAPK, but no phosphorylation of PKB. 'Reperfusion' caused further transient phosphorylation of p38-MAPK, but sustained phosphorylation of p42/p44-MAPK (lasting 4 h) and of Ser(473) of PKB (lasting 2 h). Furthermore, SI/R (24 h) induced delayed protection against lethal SI, as determined by an increase in cell viability ¿bioreduction of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide]¿ and a decrease in cell injury (release of creatine kinase). Both protection and phosphorylation of p42/p44-MAPK were blocked by the MEK-1/2 (MAPK/Erk kinase-1/2) inhibitor PD98059 (50 microM) when given during SI/R, but not when given during SI alone. The p38-MAPK inhibitor SB203580 (10 microM) blocked the p38-MAPK-dependent phosphorylation of activating transcription factor 2 in vitro, and the phosphoinositide 3-kinase inhibitor wortmannin (100 nM) blocked PKB phosphorylation on Ser(473). However, neither SB203580 nor wortmannin had any effect on delayed protection. Therefore sustained activation of p42/p44-MAPK during simulated 'reperfusion' following sublethal SI mediates preconditioning in cardiomyocytes independently of transient activation of p38-MAPK or sustained activation of PKB.

Adaptation, Physiological↗
PubMedDate not supplied

Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer.

BACKGROUND: To evaluate the use of D-methionine(D-met) as a cytoprotectant in the context of clinically relevant doses of cisplatin. MATERIALS AND METHODS: Forty five Fischer rats were injected intraperitoneally with 10(6) NuTu-19 cells and treated as follows: group 1 was the control group and received no treatment, group 2 received cisplatin 4 mg/kg and group 3 received cisplatin 4 mg/kg plus D-met. There were two groups that received high dose cisplatin. Group 4 received cisplatin 8 mg/kg and group 5 received cisplatin 8 mg/kg plus D-met. Treatment was initiated four weeks after injection of the NuTu-19 cells, and consisted of four weekly intraperitoneal injections. Serum BUN and creatinine levels in the high dose groups evaluated nephrotoxicity and clinical outcome was measured by mean survival using Kaplan Meier analysis. RESULTS: There were no significant elevations in serum BUN or creatinine levels in any of the rats treated with high dose cisplatin. In the animals given cisplatin 8 mg/kg plus D-met, death from toxicity was prevented and all animals completed four treatments. In contrast, only two animals in group 4 (cisplatin 8 mg/kg alone) completed 4 treatments. There was a significant improvement in survival for the animals given D-met. (p = .0001) In all treated groups except for group 4, there was an improvement in survival compared to the control group. When comparing groups 2 and 3 (4 mg/kg +/- D-met), there was a subjective decrease in tumor response for group 3 but mean survival was not statistically different. (91 vs. 81 days; p = 0.07) A comparison of groups 2 and 5 revealed no survival benefit using high dose cisplatin with D-met. (91 vs. 79 days; p = 0.10). CONCLUSIONS: Our results indicate that D-methionine provides cytoprotection against cisplatin toxicity without significant compromise of antitumor activity. All though D-methionine allowed for significant dose intensification of cisplatin above standard doses, there was no survival advantage noted in this group of animals. The indications for its use in the treatment of ovarian cancer remain to be determined.

Animals↗
PubMed2002

Cytoprotective antioxidant activity of serum albumin and autocrine catalase in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) cells are long lived in vivo but undergo spontaneous apoptosis when cultured in vitro. Intriguingly, CLL cells also appear to have a specific susceptibility to oxidative stress - a potent inducer of apoptosis. Here, we show that serum albumin can function as a cytoprotective antioxidant of potential relevance to circulating CLL cells, and that autocrine catalase - a hydrogen peroxide-inactivating enzyme that may be released extracellularly - can perform a similar role under the crowded conditions that prevail at sites of tissue involvement. Albumin lowered oxidative stress in cultured CLL cells and inhibited spontaneous and reactive oxidant-induced apoptosis. Maximal effects were observed at a concentration of 10 mg/ml - fourfold lower than that in plasma and twofold higher than that in standard culture medium containing 10% fetal calf serum. Oxidative stress and spontaneous apoptosis were also decreased by cell crowding and by conditioned medium (CM) from crowded CLL cells, indicating that these processes were subject to autocrine regulation. CLL cells were found to express catalase and release enzyme activity into the culture medium. Exogenous catalase decreased oxidative stress and spontaneous apoptosis, and the anti-apoptotic effect of CM from crowded CLL cells was abrogated by the specific catalase inhibitor, 3'-amino-1,2,4-triazole. Together, these data strongly implicate autocrine catalase as a cytoprotective antioxidant. Oxidative stress in CLL cells was greatly diminished by ruthenium red - an inhibitor of mitochondrial reactive oxidant production - and by the glutathione (GSH) precursor N-acetylcysteine, suggesting that the GSH peroxidase antioxidant system may be compromised by lack of available substrate. Our findings highlight the importance of endogenous reactive oxidants in regulating CLL-cell apoptosis, and help to explain why CLL cells survive for prolonged periods in vivo despite their vulnerability to oxidative stress and spontaneous apoptosis when cultured in vitro.

Acetylcysteine↗
PubMed2002

Relationships between cytoprotection and mutation prevention by WR-1065.

WR-2721, the leading compound that has emerged from the U.S. Army's Drug Synthesis and Development Program, has become the first clinically used cytoprotector in cancer therapy. The ability of its active thiol, WR-1065, to act as an antioxidant to scavenge free radicals, donate hydrogen atoms, and induce auto-oxidation is related to its cytoprotective effectiveness. However, at concentrations 10 to 20 times lower than those required for cytoprotection, this nonprotein thiol also affects gene expression, transcription factor binding, protein phosphorylation levels, and mutagenesis. For example, WR-1065 treatment activates binding of the redox-sensitive transcription factor NF-kappa B to DNA and affects expression of a number of genes, including thymidine kinase, c-myc, and manganese superoxide dismutase. At these lower drug concentrations, phosphorylation levels and subsequent activities on intracellular enzymes are also inhibited. These observations suggest that the mechanisms of action of WR-2721 and its metabolites to protect against cell killing are different from those that protect against mutagenesis and cancer formation. The ability to affect these postexposure processes makes WR-2721 an important agent in the reduction of the carcinogenic risks of environmental exposure to radiation or deleterious chemicals.

Amifostine↗
PubMed2002

S-adenosylmethionine and cAMP confer differential cytoprotection against bile acid-induced apoptosis in canine renal tubular cells and primary rat hepatocytes.

Cholestasis results in the accumulation of cytotoxic bile acids in the body. The cytoprotective effect of S-adenosylmethionine (SAMe) and cAMP were compared in two in vitro models of bile acid-induced apoptosis. Primary cultures of rat hepatocytes and canine renal tubular cells (Madin-Darby canine kidney [MDCK] cells stably transfected with the conjugated bile salt transporter, sodium [Na+]/taurocholate cotransporting polypeptide [Ntcp]) were treated with conjugated bile acids and monitored for apoptosis. Glycine-conjugated bile acids caused similar amounts of apoptosis, whereas taurine-conjugated bile acids were five to 10 times more toxic in MDCK-Ntcp cells than in hepatocytes. Treatment with the 1,4-butanedisulfonate salt of SAMe (500 microM) or the stable chlorophenylthio-cAMP analogue (100 microM) inhibited bile acid-induced apoptosis in hepatocytes by 70% and 40%, respectively. In MDCK-Ntcp cells, SAMe inhibited apoptosis by 20%, but cAMP was without effect. Immunoblotting for activation of putative survival kinases in cAMP-treated cells (phosphorylated protein kinase B [Akt] or mitogen-activated protein kinase [MAPK]) was done using phosphospecific antibodies. cAMP increased Akt phosphorylation threefold in hepatocytes but not in MDCK-Ntcp cells. Activation of p42/p44 MAPK was inhibited by cAMP in both cells. SAMe protects against bile acid-induced apoptosis in hepatocytes and MDCK-Ntcp cells. The cytoprotective effect of cAMP is seen only in hepatocytes and may reflect tissue-specific activation of Akt.

Animals↗
PubMed2003

[Relation between nitric oxide synthase, psychology, gastric mucosal blood flow and gastric mucosal adaptive cytoprotection under stress in rats].

OBJECTIVE: To explore the relation between nitric oxide synthase (NOS), psychology, gastric mucosal blood flow(GMBF) and gastric mucosal adaptive cytoprotection under stress in rats and its possible mechanism. METHODS: Animal model was constructed with impulsive stimulator of high voltage and stable currency, seventy-two male SD rats were randomly divided into three groups: control(C), regular(R) and irregular(I) group. NOS activity was measured by spectrophotometry and injure of gastric mucosa was measured by method of Nils Lambecht, GMBF was measured by LDF-3 flowmeter. RESULTS: In both R group and I group, NOS increased significantly, but injury index(II) was on contrary apparently decreasing. GMBF was increased gradually after stress. In R group, there was a negative proportion between II and GMBF, in I group, there was a negative proportion between II and GMBF and NOS, but there was a positive relationship between NOS and GMBF. CONCLUSION: NOS, psychology and GMBF all might participate in the course of the gastric mucosal adaptive cytoprotection under stress.

Animals↗
PubMed1992

Are all "cytoprotective" drugs gastroprotective?

The effect of three--structurally different--groups of compounds was compared against gastric mucosal damages induced by ethanol or prostaglandin (PG) synthesis inhibitors, as well as against carrageenan-induced inflammation. All the compounds studied--SH-compounds (cysteamine, 2,3-dimercaptosuccinic acid, D,L-penicillamine), SH-blocking N-ethylmaleimide (NEM) and morphine-exerted dose-dependent inhibition on carrageenan edema test and against ethanol-induced gastric damage. Mucosal lesions induced by PG synthesis inhibitors (indomethacin 20 mg/kg, naproxen 75 mg/kg, piroxicam 60 mg/kg) were inhibited by drugs studied when the compounds were given before the damaging agents. However, when the drugs were injected 1 h after the inhibitors of PG synthesis opposite actions were observed; SH-compounds exerted protective, while NEM (2 mg/kg p.o.) and morphine (5 mg/kg p.o.) aggravating action. The results suggest that: 1. SH-compounds might have therapeutic importance in the treatment of gastric damage induced by prostaglandin synthesis inhibitors. 2. Reconsideration of the use of the term "cytoprotection" is necessary, since "cytoprotective" agents may aggravate mucosal damage in other ulcer model.

Animals↗
PubMed1992

Selenoperoxidase-mediated cytoprotection against merocyanine 540-sensitized photoperoxidation and photokilling of leukemia cells.

Photodynamic therapy with the lipophilic sensitizing dye merocyanine 540 (MC540) is a promising new approach for extracorporeal purging of neoplastic cells from autologous remission bone marrow grafts. Resistance-conferring cellular defenses against the cytotoxic effects of MC540/photodynamic therapy have not been well characterized. This study focuses on the cytoprotective effects of the glutathione-dependent selenoperoxidases GPX and PHGPX, which can detoxify a wide variety of hydroperoxides, including lipid-derived species (LOOHs). Murine leukemia L1210 cells were grown in 1% serum media without [L.Se(-)] and with [L.Se(+)] selenium supplementation. L.Se(-) cells expressed 10- to 20-fold lower GPX and PHGPX activities than L.Se(+) controls and were markedly more sensitive to MC540-mediated photoperoxidation (LOOH formation) and clonally assessed photokilling. Susceptibility of L.Se(-) cells to photoperoxidation and photokilling could be fully reversed to L.Se(+) levels by replenishing Se, and partially reversed by treating with Ebselen, a selenoperoxidase mimetic. Altered lipid composition, greater uptake of MC540, and defective catabolism of H2O2 were all ruled out as possible factors in the elevated photosensitivity of L.Se(-) cells. Human leukemia K562 cells (capable of expressing PHGPX but not GPX) exhibited 5- to 10-fold lower PHGPX activity under Se-deficient relative to Se-sufficient conditions. Although MC540 uptake (nmol/mg lipid) by K562 and L1210 cells was essentially the same, the former were more resistant to photoinactivation. However, like murine counterparts, Se-deficient cells were more susceptible to photoperoxidation and photokilling than Se-sufficient controls. These results clearly demonstrate that GPX and/or PHGPX in L1210 cells and PHGPX in K562 cells play an important cytoprotective role during photooxidative stress. Whether membrane damage due to lipid photoperoxidation is causally related to cell death is not certain; however, the parallel effects of Se deficiency on LOOH formation and cell killing are at least consistent with this possibility.

Animals↗
PubMed2003

Cytoprotective effect is one of common action pathways for antidepressants.

AIM: To explore the possible common action mechanism of antidepressants. METHODS: The cell viability was detected by MTT assay. The intracellular Ca2+ concentration ([Ca2+]i) was measured by Fura 2-AM fluorescence labeling assay. Using RT-PCR, the mRNA level of nerve growth factor (NGF) was also detected. RESULTS: High concentration of corticosterone (0.2 mmol/L) was incubated with PC12 cells to simulate the lesion state of brain neurons in depressive illness. Three main kinds of antidepressants used in clinic [(1) tricyclic antidepressants (TCAs), such as desipramine (DIM) 0.625-10 micromol/L; (2) selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (FLU) 0.625-10 micromol/L; (3) monoamine oxidase inhibitors (MAOIs), such as moclobemide (MOC) 2.5-40 micromol/L] protected cells from the lesion induced by corticosterone. While antipsychotic drug chlorpromazine or anxiolytic agent diazepam 0.4-50 micromol/L had no such effect. Moreover, DIM 1, 5 micromol/L or FLU 1, 5 micromol/L attenuated the [Ca2+]i overload induced by corticosterone 0.1 mmol/L for 48 h in PC12 cells. Furthermore, treatment with DIM or FLU 10 micromol/L for 48 h elevated the NGF mRNA expression in PC12 cells. CONCLUSION: Despite a remarkable structural diversity, the cytoprotective effect can be viewed as the common action pathway of the antidepressants. Moreover, attenuation of the intracellular Ca2+ overload and elevation of neurotrophic factor (such as NGF) expression is one of the mechanisms of cytoprotective effect of antidepressants.

Animals↗