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PubMed1987

Evidence of "cross-stressor"-induced adaptive gastric cytoprotection.

Rats were given 7 days pre-treatment with either water (p.o.), 1 h immobilization or 20% ethanol (p.o.) with or without concomitant indomethacin injection. Following the pre-treatment phase, rats from each pre-treatment group were exposed to either 3 h cold-restraint stress or to 100% ethanol p.o. Results indicated that immobilization and 20% ethanol pre-treatment significantly reduced both cold-restraint stress ulcer formation and 100% ethanol-induced ulcers. Indomethacin co-treatment attenuated the reduction of ulcer formation of both pretreatments. These results suggest that "cross-stressor" adaptive cytoprotection occurs. Indomethacin abolished these effects, implicating the involvement of endogenous prostaglandins in the mediation of "cross-stressor"-induced gastric cytoprotection.

Adaptation, Physiological↗
PubMed1989

Cytoprotective value of lysine, penicillamine, and pyridoxal phosphate against the neurotoxicity of acetaldehyde.

Rats which received acetaldehyde by intraperitoneal injection on a single occasion sustained neural degeneration in the cerebral cortex detectable with both light and electron microscopy. The degeneration was more intense and included the hippocampus when acetaldehyde exposure was given on 5 consecutive days in the form of ethanol vapor inhalation and disulfiram injections. Pretreatment of animals with a combination 2.5 g lysine/kg plus 50 mg pyridoxyl phosphate/kg did not alter the degree of degeneration response to either a single injection of acetaldehyde or 5 days acetaldehyde treatment. Penicillamine injections (1.2 g/kg) did offer some (but not complete) cytoprotective value against the neurotoxicity of acetaldehyde. This cytoprotective action was effective at concentrations of acetaldehyde which are not distant from clinically observed concentrations.

Acetaldehyde↗
PubMed1981

The cytoprotective effects of (+/-)-15-deoxy-16-alpha, beta-hydroxy-16-methyl PGE1 methyl ester (sc-29333) versus aspirin-shock gastric ulcerogenesis in the dog.

SC-29333 (SC) has been reported to protect the gastric mucosa from the effects of topical aspirin. We compared SC and 16,16-dimethyl PGE2 (16-dm) in 20 chambered canine stomachs (6 controls and 7 of each PG). Prostaglandin was added to an acid solution (100 mM HCl; 54 mM NaCl) at 0, .001, .01, 0.1, and 1.0 microgram/ml (two periods each). Then aspirin (20 mM) and PG (1.0 microgram/ml) (two periods) were followed by hemorrhagic shock (near 60 mm Hg mean arterial pressure). 16-dm caused a significant efflux of fluid (-6.5 +/- 5.3 to 17.3 +/- 6.7 microliters/min), Na+ (2.1 +/- 0.5 to 6.8 +/- 1.6 muEq/min), and Cl- (-0.9 +/- 2.4 to 5.3 +/- 1.3 muEq/min), but did not affect K+ or H+. 16-dm also caused a slight drop in potential difference (PD) (67.6 +/- 1.7 to 60.3 +/- 2.0 mV). 16-dm did not significantly affect total blood flow. Percent lesion formation was more severe than controls (20.2 +/- 3.5 vs 11.6 +/- 1.7 percent) but not statistically significant. SC had no significant effect on fluid, H+, Na+, K+, or Cl-. It caused an increase in blood flow (6.85 +/- 1.46 to 26.20 +/- 2.74 ml/min, p less than .001). SC significantly reduced percent lesion formation (1.9 +/- 0.9% p less than .001). We conclude: 1) SC causes an increase in mucosal blood flow and protects from aspirin-shock ulcerogenesis. 2) 16-dm stimulates an efflux of non-parietal extracellular fluid and fails to protect against aspirin injury during mucosal ischemia. 3) SC cytoprotection may be mediated by increased mucosal blood flow. 4) The mechanism of cytoprotection with 16-dm may require sufficient mucosal blood flow for filtration of non-acid fluid from blood to gastric lumen.

Animals↗
PubMed1992

The cytoprotective properties of prostaglandin E2 against the toxic effects of actinomycin C on embryonic neural retina cells.

Prostaglandins (PGs) have been shown to cytoprotect various tissue types against the toxic effects of many chemicals. The mechanism of this protection is poorly understood, but the involvement of cAMP is often implied. Only one previous study examined nervous tissue and PG protection. The present study was designed to determine if PGE2 affords cytoprotection to a more specific nervous tissue (embryonic neural retina) from the toxicity of actinomycin C (AMC) using a trypan blue exclusion assay. The lowest concentration of PGE2 (2 x 10(-5)M) had no effect, but as the concentration increased (3 x 10(-5)M and 5 x 10(-5)M), PGE2 did afford protection against AMC in a dose dependent fashion. Theophylline treated cells were not protected, suggesting that cAMP may not be the primary mechanism of protection.

Animals↗
PubMed1992

Cytoprotective effect of copper(II) complexes against ethanol-induced damage to rat gastric mucosa.

The cytoprotective effect of various copper(II) complexes on the gastric mucosa damage induced by acute intragastric administration of ethanol was investigated. For in vitro experiments, the following copper(II) complexes were tested: Cu(II)(L-Trp)(L-Phe), Cu(II)(L-Leu)Cu(II)(L-Leu-Leu)(L-Leu), Cu(II)(L-Phe-L-Leu), Cu(II)(Gly-His-Lys), and Cu(II)(cyHis)2(ClO4)2. Inorganic copper such as CuSO4 was also tested. The free radical generating system, acting for 2 hr on cardial and fundic mucosa scrapings or mucosal microsomes, was Fe++ (20 microM)/ascorbate (0.25 mM). We found a marked inhibition to 75% of lipid peroxidation in the range 10-100 mM, regardless of whether copper was given in complexed or inorganic form. The results suggest that nontoxic copper(II)-amino acid complexes are able to neutralize oxygen-derived free radicals. In addition, copper(II) complexes suppressed membrane lipid peroxidation when mucosa homogenates were exposed to t-butyl hydroperoxide (1-20 microM) plus Fe++ (50 microM). In vivo experiments on rat stomachs, pretreated p.o. by gavage either with Cu(II)(L-Trp)(L-Phe) as paradigmatic agent or with copper sulphate at equivalent doses in the range 3-30 mg/kg body weight showed a significant decrease (30 min after 95% ethanol administration) in the number and severity of mucosal hemorrhagic lesions. In the gastric mucosa scrapings of copper-treated rats after ethanol exposure, we found that malondialdehyde and conjugated diene levels were unchanged compared to those of untreated controls; five enzyme activities released from lysosomes were near control values. In isolated mucosal cells, whether or not pretreated with 200 microM solution of either Cu(II)(L-Trp)(L-Phe) or CuSO4, the release of cathepsin D activity was also unmodified. The results suggest that the cytoprotective effect of Cu(II) complexes against ethanol-induced mucosal lesions was not associated in vivo to lipid peroxidation.

Amino Acid Sequence↗
PubMed1993

Liver cytoprotection by prostaglandins.

During the last decade intensive work on the relationships between the liver and the arachidonic acid cascade has greatly expanded our knowledge of this area of research. The liver has emerged as the major organ participating in the degradation and elimination of arachidonate products of systemic origin. The synthesis in the liver of arachidonate products derived from the cyclooxygenase, lipoxygenase and cytochrome P450 system pathways has been demonstrated. The participation of leukotriene B4 and cysteinyl-leukotrienes as mediators of liver damage and the possible therapeutic usefulness of prostaglandins (PGs) in acute liver injury has attracted the interest of clinicians. This article reviews the essential features regarding the role of arachidonate metabolites in liver disease and specially focuses on the cytoprotective effects on the liver displayed by PGE2, PGE1, PGI2 and synthetic PG analogs in experimental models of liver damage induced by ischemia-reperfusion injury, carbon tetrachloride, bacterial lipopolysaccharide and viral hepatitis and on the possible mechanisms underlying liver cytoprotection in these experimental models. The therapeutic usefulness of PGs in clinical practice is critically analyzed on the basis of available evidence in patients with fulminant hepatic failure and primary graft nonfunction following liver transplantation.

Animals↗
PubMed1991

Cadmium toxicity: unique cytoprotective properties of alpha tocopheryl succinate in hepatocytes.

Rat hepatocyte suspensions were exposed to toxic concentrations of cadmium (Cd) in the presence and absence of unesterified alpha-tocopherol (T) or alpha-tocopheryl succinate (TS). The exogenous administration of TS completely protected hepatocytes from Cd-induced injury and lipid peroxidation. However, hepatocytes exposed to T were not protected from the toxic manifestations of cadmium even though this treatment resulted in a rapid marked accumulation of cellular T. The rate of cadmium uptake by hepatocytes was not significantly altered by exogenous TS or T treatment. These studies indicate that TS cytoprotection against Cd toxicity results not from alterations in Cd uptake or the accumulation of T but rather from the cellular presence of the intact TS molecule. The data also indicate that the depletion of cellular T is not the critical cellular event that is responsible for Cd-induced injury. Instead it appears that TS possess unique cytoprotective properties that intervene in the critical cellular events that lead to Cd toxicity. Thus, TS administration represents a promising new strategy for the mechanistic study and prevention of tissue damage resulting from Cd exposure.

Animals↗
PubMed1990

Oxygen toxicity: unique cytoprotective properties of vitamin E succinate in hepatocytes.

Freshly isolated rat hepatocytes suspensions were incubated under an atmosphere of 95% O2/5% CO2 or 95% air/5% CO2 for 10 h. Cell injury and death were observed between the 6th and 10th hour of incubation, only in 95% O2-treated hepatocytes. Oxygen-induced injury was preceded by marked lipid peroxidation and rapid depletion of cellular alpha tocopherol content. The exogenous administration of unesterified alpha tocopherol (T, 25 microM) resulted in a 20-fold increase in cellular T levels (4.2 nmol/10(6) cells) but failed to protect these hepatocytes from the toxic effects of oxygen. In contrast, hepatocytes incubated with 25 microM of the succinate ester of alpha tocopherol (TS) contained both TS (3.0 nmol/10(6) cells) and T (1.4 nmol/10(6) cells) and were completely protected from the toxic effects of oxygen, including the induction of lipid peroxidation. These findings suggest that TS cytoprotection results not from the cellular accumulation of T but rather, from cellular TS accumulation. The data also indicate that the depletion of cellular T is not the critical cellular event that is responsible for hyperoxia (reactive oxygen intermediate)-induced injury. Instead, it appears that TS possesses unique cytoprotective properties that intervene in the critical cellular events that lead to oxygen toxicity. Thus, vitamin E succinate and our hyperoxic hepatocyte preparation provide a promising new model system for the study and prevention of tissue damage resulting from the toxic effects of hyperoxia and reactive oxygen intermediates.

Animals↗
PubMed1990

Cytoprotective effect of iloprost on isolated cortical brain tissue grafts in rats.

The cytoprotective effect of iloprost was studied on isolated embryonic cortical brain tissue grafts of rats, using light and transmission electronmicroscopy. The brain tissue pieces were stored either in saline or 50 ng/ml iloprost solution for 30 minutes, 3, 6, 24 hours at +4 degrees C. It was demonstrated that iloprost significantly protected the neuronal integration of the tissue pieces compared with saline preserved pieces. Tissues preserved in iloprost showed only minimal dissolution of the tissue with minimal extracellular edema only in the later stages of preservation. The mechanism of action of the cytoprotective effect of iloprost is discussed.

Animals↗
PubMed2005

Gastric cytoprotective activity of ilicic aldehyde: structure-activity relationships.

A series of sesquiterpene compounds possessing both eudesmane and eremophilane skeletons were tested as gastric cytoprotective agents on male Wistar rats. The presence of an alpha,beta-unsaturated aldehyde on the C-7 side chain together with a hydroxyl group at C-4 is the requirement for the observed antiulcerogenic activity. In an attempt to establish new molecular structural requirements for this gastric cytoprotective activity, a structure-activity study was performed.

Animals↗
PubMed2005

Combined use of a cytoprotectant and rehabilitation therapy after severe intracerebral hemorrhage in rats.

After moderate intracerebral hemorrhage (ICH), both hypothermia (HYPO) and constraint-induced movement therapy (CIMT) improve recovery and reduce the volume of brain injury. We tested the hypothesis that more severe ICH requires both cytoprotection and rehabilitation to significantly improve recovery. Rats were subjected to a unilateral striatal ICH via collagenase infusion. Rats remained normothermic or were subjected to mild HYPO ( approximately 2 days) starting 12 h later. Fourteen days after ICH, half of the rats received CIMT (7 days of restraint of the less affected limb plus daily exercises); the remainder were untreated. Walking, limb use and skilled reaching were assessed up to 60 days, at which time animals were euthanized and the volume of tissue lost was determined. The HYPO treatment alone did not improve outcome, whereas CIMT alone provided significant benefit on the limb use asymmetry test. In the staircase test, the greatest benefit was achieved with the combination of HYPO and CIMT treatments. The volume of tissue lost after ICH was similar among groups arguing against cytoprotection as a mechanism of functional recovery. Finally, these findings suggest that, at least under the present circumstances (e.g., severe striatal ICH), CIMT provides superior benefit to HYPO and that combination therapy will sometimes further improve recovery.

Analysis of Variance↗
PubMed2003

Involvement of calcitonin gene-related peptide and capsaicin-sensitive afferents in central thyrotropin-releasing hormone-induced hepatic cytoprotection.

The involvement of capsaicin-sensitive afferent neurons and calcitonin gene-related peptide (CGRP) in central thyrotropin-releasing hormone (TRH)-induced hepatic cytoprotection was investigated in rats. Both systemic capsaicin pretreatment and intravenous administration of CGRP receptor antagonist, human CGRP-(8-37), completely abolished the protective effect of intracisternal TRH analog (RX-77368; p-Glu-His-(3,3'-dimethyl)-Pro-NH2, 5 ng) against carbon tetrachloride (CCl4)-induced acute liver injury, assessed by serum alanin aminotransferase levels and histological changes. These data demonstrate the involvement of capsaicin-sensitive afferent neurons and CGRP in central TRH-induced hepatic cytoprotection.

Animals↗
PubMed2006

Cytoprotective effect against UV-induced DNA damage and oxidative stress: role of new biological UV filter.

The majority of chemical solar filters are cytotoxic, particularly on sensitive ocular cells (corneal and conjunctival cells). Consequently, a non-cytotoxic UV filter would be interesting in dermatology, but more especially in ophthalmology. In fact, light damage to the eye can be avoided thanks to a very efficient ocular antioxidant system; indeed, the chromophores absorb light and dissipate its energy. After middle age, a decrease in the production of antioxidants and antioxidative enzymes appears with accumulation of endogenous molecules that are phototoxic. UV radiations can induce reactive oxygen species formation, leading to various ocular diseases. Because most UV filters are cytotoxic for the eye, we investigated the anti-UV properties of Calophyllum inophyllum oil in order to propose it as a potential vehicle, free of toxicity, with a natural UV filter action in ophthalmic formulation. Calophyllum inophyllum oil, even at low concentration (1/10,000, v/v), exhibited significant UV absorption properties (maximum at 300nm) and was associated with an important sun protection factor (18-22). Oil concentrations up to 1% were not cytotoxic on human conjunctival epithelial cells, and Calophyllum inophyllum oil appeared to act as a cytoprotective agent against oxidative stress and DNA damage (85% of the DNA damage induced by UV radiations were inhibited with 1% Calophyllum oil) and did not induce in vivo ocular irritation (Draize test on New Zealand rabbits). Calophyllum inophyllum oil thus exhibited antioxidant and cytoprotective properties, and therefore might serve, for the first time, as a natural UV filter in ophthalmic preparations.

Animals↗
PubMed2003

Evolutionarily conserved cytoprotection provided by Bax Inhibitor-1 homologs from animals, plants, and yeast.

Programmed cell death (PCD) plays important roles in the development and physiology of both animals and plants, but it is unclear whether similar mechanisms are employed. Bax Inhibitor-1 (BI-1) is an intracellular multi-membrane-spanning protein and cell death inhibitor, originally identified by a function-based screen for mammalian cDNAs capable of suppressing cell death in yeast engineered to ectopically express the pro-apoptotic protein Bax. Using this yeast assay, we screened expression libraries for cDNAs from the plant, Lycopersicon esculentum (tomato), and the invertebrate animal Drosophila melanogaster (fruit fly), identifying close homologs of BI-1 as Bax-suppressors. We studied the fly and tomato homologs of BI-1, as well as BI-1 homologs identified in Arabidopsis thaliana, Oryza sativa (rice), and Saccharomyces cerevisiae (budding yeast). All eukaryotic homologs of BI-1 blocked Bax-induced cell death when expressed in yeast. Eukaryotic BI-1 homologs also partially rescued yeast from cell death induced by oxidative stress (H(2)O(2)) and heat shock. Deletion of a C-terminal domain from BI-1 homologs abrogated their cytoprotective function in yeast, demonstrating conserved structure-function relations among these proteins. Expression of tomato BI-1 by agroinfiltration of intact plant leaves provided protection from damage induced by heat-shock and cold-shock stress. Altogether, these findings indicate that BI-1 homologs exist in multiple eukaryotic species, providing cytoprotection against diverse stimuli, thus implying that BI-1 regulates evolutionary conserved mechanisms of stress resistance that are germane to both plants and animals.

Amino Acid Sequence↗
PubMed2005

Increased cytoprotective function in the liver of transgenic mice expressing osteopontin in hepatocytes.

Osteopontin is a crucial factor for initiation of Th1 immune reaction. Previously, we established transgenic mice expressing osteopontin in hepatocytes, in which lymphocyte infiltration occurred spontaneously at 12 weeks of age and liver necrosis at 24 weeks of age. This liver necrosis may develop through provocation by excessive Th1 immune reaction, but it is also possible that hepatocytes become fragile under abundant osteopontin in the cytoplasm. Thus, gene expression profiles in the liver were evaluated to seek such contributing factors in the transgenic mice. On DNA microarray analysis of 3774 mouse genes, 16 genes were selected as hepatic genes significantly up-regulated in the transgenic mice aged 8 weeks than in the negative littermate, which included mRNAs of cytoprotective metallothionein and glutathione S-transferase (GST). Hepatic up-regulations of both genes were also seen by Western blotting. Liver necrosis in the centrilobular areas developed after carbon tetrachloride treatment, but its histological extent and plasma ALT activities were significantly smaller in the transgenic mice aged 8 weeks than in the wild-type C57BL/6 control mice. We conclude that cytoprotective function of the liver is increased through up-regulated expressions of metallothionein and GST, and thereby susceptibility of hepatocytes to the stress may be less possible, if any, in the development of spontaneous liver necrosis in transgenic mice expressing osteopontin in hepatocytes.

Journal Article↗
PubMed2004

Impact on cytoprotective efficacy of intermediate interval between amifostine administration and radiotherapy: a retrospective analysis.

PURPOSE: To evaluate the cytoprotective impact of the interval between amifostine administration and radiotherapy (RT). METHODS AND MATERIALS: In a nonrandomized study, we reviewed the records of 177 patients with tumors localized in the pelvis (prostate, bladder, or gynecologic cancer), upper abdomen (pancreas, stomach, kidney), thorax (lung and breast cancer), head and neck (nasopharynx), soft tissue (sarcomas), and central nervous system. The patient records were stratified according to whether the patients had undergone RT either 25-40 min (Group 1, 96 subjects) or 10-15 min (Group 2, 81 subjects) after i.v. amifostine administration. The mean toxicity score was the mean value of recorded acute radiation toxicity. The mean interruption time was the mean value of the recorded interruption time due to radiation toxicity. RESULTS: A significantly reduced severity of symptoms related to oral (p = 0.023), esophageal (p = 0.05) and rectal (p = 0.015) mucosa was noted in Group 2. A statistically significant reduction in the mean toxicity score (p <0.001) and mean interruption time (p = 0.001) was observed in Group 2 vs. Group 1. In terms of the incidence of radiation-induced dermatitis and alopecia, multivariate logistic analysis revealed only the total dose (p = 0.018) and the amifostine-RT interval (p = 0.002) as independent factors. CONCLUSION: A significantly better cytoprotective effect of amifostine against radiation-induced mucositis, dermatitis, and alopecia was noted if RT was administered no later than 15 min after i.v. amifostine infusion. The results presented here need additional investigation with randomized prospective trials.

Amifostine↗
PubMed2003

Activation of p53 by the cytoprotective aminothiol WR1065: DNA-damage-independent pathway and redox-dependent modulation of p53 DNA-binding activity.

WR1065 is an aminothiol with selective cytoprotective effects in normal compared to cancer cells, which is used to protect tissues against the damaging effect of radiation and chemotherapeutic drugs. WR1065 has been shown to induce wild-type p53 accumulation and activation in cultured cells, suggesting a role of p53 in cytoprotection. However, the molecular mechanisms by which WR1065 activates p53 remain unclear. Here, we demonstrated that p53 accumulation by WR1065 in MCF-7 cells did not result from the formation of DNA-damage as measured by DNA fragmentation and Comet assay, nor from oxidative stress as detected by measurement of glutathione levels, lipid peroxidation and reactive oxygen species production. p53 activation by WR1065 was not prevented by inhibition of PI-3 kinases, and was still detectable in MCF-7 cells stably transfected with the oncoprotein E6, which repressed p53 induction by DNA damage. These data provided evidence that WR1065 induces p53 by a pathway different than the one elicited by DNA-damage. Direct reduction by WR1065 of key cysteines in p53 may play an important role in this alternative pathway, as shown by the fact that WR1065 activated the redox-dependent, DNA-binding activity of p53 in vitro.

DNA↗
PubMed2000

Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction.

OBJECTIVES: We reported that the activation of gp130 transduced hypertrophic and cytoprotective signals via Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in cardiac myocytes. Recent in vivo experiments have demonstrated that the JAK/STAT pathway is activated in acute pressure overload hearts. The present study was designed to examine whether the JAK/STAT pathway is also activated in acute myocardial infarction (AMI) and to determine its pathophysiological roles in ischemic heart disease. METHODS AND RESULTS: AMI model was generated by the ligation of proximal left anterior descending coronary artery of male Wistar rat. They were sacrificed at various time points ranging from 1 to 24 h after coronary ligation and their hearts were examined. Tyrosine phosphorylation of STAT3 was observed in the myocardium obtained from both the ischemic area and the healthy border area adjacent to the infarcted area. The AMI rats were next randomly assigned to two groups, one with coronary ligation only (group M), and the other with coronary ligation with AG-490 treatment (1 mg/kg i.v., every 4 h), a specific JAK2 inhibitor (group A). In group A, phosphorylation of STAT3 was significantly suppressed and caspase-3 activity and Bax expression were significantly increased in the myocardium after AMI. In group M, few apoptotic myocytes were identified in the border area by means of TUNEL assay. However, a significant increase in apoptotic cells was observed in group A. CONCLUSIONS: Administration of JAK2 inhibitor resulted in deterioration of myocardial viability in AMI hearts. The JAK/STAT pathway is activated in AMI myocardium and plays a pivotal role in cytoprotective signaling.

Analysis of Variance↗