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PubMed1991

Cytoprotective effects of calcium channel blockers. Mechanisms and potential applications in hepatocellular injury.

Deregulation of calcium homeostasis is strongly implicated in the development of cellular injury, including in hepatocytes, and is thought to be the limiting step in transition to an irreversible stage. Calcium channel blockers appear to exert their cytoprotective effects through several mechanisms. These may involve blockade of L-(long-lasting)-type calcium channels, reduction of oxidative stress, antagonism at inflammatory mediator receptor sites and interaction at other intracellular sites. Studies relating to the liver are few but suggest that calcium channel blockers may have a role to play in limiting hepatocellular damage, especially those arising from exposure to a variety of toxic agents.

Animals↗
PubMed1983

Interrelationships between membrane-bound ATP-dependent energy systems, gastric mucosal damage produced by NaOH, hypertonic NaCl, HCl, and alcohol, and prostacyclin-induced gastric cytoprotection in rats.

Rat gastric mucosal lesions (ulcers) were produced by topical application of 0.2 M NaOH, 25% NaCl, 0.6 M HCl and 96% ethanol. The animals were sacrificed 1 hr after administration of the different necrotizing agents. The number of gastric lesions (ulcers) was noted and their severities scored. Different doses (5 and 50 micrograms.kg-1) of prostacyclin (PGI2) were given intraperitoneally at 30 minutes before administration of necrotizing agents, and their effects were studied on the number and severity of gastric lesions (ulcers). At the time of killing of animals, the rat gastric fundic mucosa was removed for biochemical examinations. Tissue levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactate were determined enzymatically, while the tissue content of cyclic adenosine monophosphate (cAMP) was measured by radioimmunoassay. The values of the adenylate pool (ATP + ADP + AMP), the ratio of ATP X ADP-1 and the energy charge (ATP + 0.5 ADP X ATP + ADP + AMP-1) were calculated. All biochemical results were calculated in relation to one mg mucosal protein. It was found that:1. the tissue levels of ATP, cAMP, AMP decreased significantly, while the tissue level of ADP increased (without statistical significance) in all models, during the development of gastric mucosal damage; 2. the tissue level of lactate increased only in the model produced by 0.6 M HCl, while its level was unchanged in the other models during the development of gastric mucosal damage; 3. PGI2 decreased dose-dependently the number and severity of gastric lesions (ulcers); 4. the tissue level of ATP, ratio of ATP X ADP-1 and energy charge were decreased significantly, while the tissue level of ADP was increased significantly by PGI2 in all models; 5. the tissue level of lactate and the adenylate pool remained unchanged during the PGI2 effects. It was concluded that: 1. the development of gastric mucosal damage, produced by topical application of 0.2 M NaOH, 25% NaCl, 0.6 M HCl and 96% ethanol, is associated with an active metabolic adaptation of the gastric fundic mucosa; 2. the metabolic adaptation of the rat gastric fundic mucosa is further increased by PGI2, without resulting in hypoxaemic damage of the gastric mucosa; 3. the feed-back mechanism system - between the membrane-bound ATP-dependent energy systems - is broken during the development of gastric mucosal damage produced by different necrotizing agents, which is modified further by PGI2 at the time of gastric cytoprotection.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Diphosphate↗
PubMed1986

Gastric antisecretory, gastric and duodenal anti-ulcer and cytoprotective properties of Ro 22-6923, a synthetic trimethyl prostanoid in rats.

Ro 22-6923, a synthetic trimethyl prostanoid, has been studied for its ability to inhibit gastric secretion and to protect the gastroduodenal mucosa against the injuries caused by pyloric ligation, hypothermic restraint stress, nonsteroidal anti-inflammatory drugs (NSAIDs), reserpine, dimaprit, cysteamine and the cytodestructing agents--80% ethanol, 0.6 M HCl, 0.2 M NaOH, 25% NaCl, aspirin 30 mg in 0.35 M HCl and 100 mM sodium taurocholate in 0.2 M HCl. The results of this study demonstrate that Ro 22-6923 has both prophylactic and curative effects on various experimental models. It produces a dose dependent inhibition of the gastric mucosal damage induced by pyloric ligation, hypothermic restraint stress, NSAIDs, reserpine, dimaprit and cytodestructing agents and that of duodenal ulcers induced by cysteamine. It also produces a dose dependent healing of the acetic acid induced chronic gastric ulcers. These observations suggest that Ro 22-6923 exerts its anti-ulcer effects by its antisecretory, gastric mucosal resistance increasing and cytoprotective activities and that it may be a useful therapeutic agent for the treatment of peptic ulcer disease in humans.

Animals↗
PubMed1992

Paracetamol toxicity and its prevention by cytoprotection with iloprost.

In a well-established two phase model of paracetamol toxicity in hamster hepatocytes cell death was accompanied, but not preceded, by a rise in cytosolic free calcium [Ca2+]i. Cell death appears to involve reversible oxidative damage, possibly to the cytoskeleton or mitochondria. In this model low concentrations (10(-8) to 10(-14) M) of iloprost, a stable analogue of prostacyclin, offered protection against the toxic effects of paracetamol. In preliminary studies with a rat liver epithelial cell line transduced with murine P4501A2 the toxicity of paracetamol was attenuated by iloprost. Inhibition of protein synthesis with cycloheximide had no effect on paracetamol toxicity but abolished the cytoprotective effect of iloprost.

Acetaminophen↗
PubMed1991

Cytoprotective activity of pectic polysaccharides from the root of panax ginseng.

An acidic polysaccharide fraction, GRA-4, of the root extract of Panax ginseng, when administered from 50 to 200 mg/kg orally, inhibited gastric lesions induced by HCl-ethanol or absolute ethanol, in a dose-dependent manner. The cytoprotective activity of GRA-4 decreased after its treatment with periodate but not after protein digestion, indicating that the carbohydrate moiety of this acidic polysaccharide contributes to this activity.

Administration, Oral↗
PubMed1993

Selenoperoxidase-mediated cytoprotection against the damaging effects of tert-butyl hydroperoxide on leukemia cells.

Murine leukemia L1210 cells grown for 5-7 d in the presence of 1% serum without added selenium [Se(-) cells] expressed < 5% of the glutathione peroxidase (GPX) activity of selenium-supplemented controls [Se(+) cells]. Clonogenic survival assays indicated that t-butyl hydroperoxide (t-BuOOH) is much more toxic to Se(-) cells (LC50 approximately 10 microM) than to Se(+) or selenium-repleted [Se(-/+)] cells (LC50 approximately 250 microM). Hypersensitivity of Se(-) cells to t-BuOOH was partially reversed by treating them with Ebselen, a selenoperoxidase mimetic; thus, selenoperoxidase insufficiency was probably the most serious defect of Se deprivation. Cytotoxicity of t-BuOOH was inhibited by desferrioxamine and by alpha-tocopherol, indicating that redox iron and free radical intermediates are involved. Elevated sensitivity of Se(-) cells to t-BuOOH was accompanied by an increased susceptibility to free radical lipid peroxidation, which became even more pronounced in cells that had been grown in arachidonate (20:4, n-6) supplemented media. That glutathione (GSH) is required for cytoprotection was established by showing that Se(+) cells are less resistant to t-BuOOH after exposure to buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. Coupled enzymatic assays indicated that Se(+) or Se(-/+) cells metabolize t-BuOOH 20-25 times more rapidly than Se(-), consistent with the measured difference in GPX activities of these cells. Correspondingly, when challenged with t-BuOOH, Se(+) cells showed an initial loss of GSH and elevation of GSSG that exceeded that of Se(-) cells. It was further shown that like Se(-) cells, BSO- or BCNU-treated Se(+) cells metabolize t-BuOOH more slowly than nontreated controls. These results clearly indicate that selenoperoxidase action in the glutathione cycle is a vital element in cellular defense against toxic hydroperoxides.

Animals↗
PubMed1990

Prostacyclin does not play any cytoprotective role in endothelial cell injury induced by 15-hydroperoxy-eicosatetraenoic acid, an arachidonate lipoxygenase product.

Among various arachidonic acid metabolites examined, only 15(S)-hydroxperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE), a lipoxygenase product, caused a time- and dose-dependent injury to bovine endothelial cells in culture. There also occurred a significant inhibition of endothelial prostacyclin (PGI2) production due to 15-HPETE. But there were obvious dissociations in time course and dose dependence between 15-HPETE-induced cellular injury and 15-HPETE-induced inhibition of PGI2 synthesis. In addition, the cytotoxicity of 15-HPETE was not aggravated even when the endothelial monolayers were pretreated with several inhibitors of PGI2 synthesis. Also, some stable analogues of PGI2 had no protective effect on the injury. These results suggest that the reduced production of PGI2 caused by 15-HPETE is not directly associated with the onset of cellular injury, and that PGI2 does not play any cytoprotective role in endothelial cell injury induced by at least such lipid peroxides as 15-HPETE.

Animals↗
PubMed1995

Cytoprotective and antisecretory activity of a ranitidine-zinc complex.

The effects of a ranitidine-zinc complex and ranitidine alone were compared in three different experimental models (pyloric ligation, ethanol and indomethacin) of gastric ulceration in the rat. In the pyloric ligation model, the ranitidine-zinc complex (50, 100 and 150 mg/kg p.o.) showed antiulcerogenic activity similar to that observed with equimolar doses of ranitidine (35, 70 and 105 mg/kg p.o.). Both the ranitidine-zinc complex and ranitidine significantly reduced (p < 0.05) gastric acid secretion in a dose-dependent manner. The protective effect of the ranitidine-zinc complex (100 and 150 mg/kg p.o.) against gastric damage developing after p.o. administration of absolute ethanol or indomethacin was enhanced (p < 0.05) with respect to that obtained with equimolar doses of ranitidine (70 and 105 mg/kg p.o.). The presence of zinc in the ranitidine-zinc complex does not interfere with the antisecretory effects of ranitidine on the gastric mucosa, while it confers an additional cytoprotective action to the final compound.

Animals↗
PubMed2005

Comparative cytoprotective activity of vitamin C, E and beta-carotene against chromium induced oxidative stress in murine macrophages.

The present study reports the cytoprotective efficacy of vitamin C, E and beta-carotene against chromium (VI) induced oxidative stress in murine macrophages. Addition of chromium (VI) resulted in enhanced cytotoxicity as revealed by fall in neutral red uptake and increase in LDH release compared to control cells. Further there was an appreciable increase in apoptosis, ROS production and fall in reduced glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities. Chromium also inhibited macrophage proliferation and phagocytic activity. Addition of vitamin C but not vitamin E and beta-carotene inhibited chromium induced cytotoxicity, ROS generation and apoptosis. Vitamin C significantly inhibited NO production, enhanced macrophage proliferation and phagocytic activity while vitamin E and beta-carotene had marginal effect.

Animals↗
PubMed2005

Cytoprotection by nipradilol, an anti-glaucomatous agent, via down-regulation of apoptosis related gene expression and activation of NF-kappaB.

It has been reported that nipradilol, a nonselective beta- and selective alpha1-receptor antagonist, has cytoprotective effects. We attempted to clarify the effects of nipradilol on the expression of apoptosis associated genes and the activity of nuclear factor-kappaB, a transcription factor, in PC12 cells during serum deprivation induced apoptosis. PC12 cells were cultured in serum free RPMI1640 medium with or without 0.01, 0.1, 1, or 10 microM of nipradilol, or in serum-added medium as a control. The gene expressions of Bax, Bcl-2, Fas, FasL, Caspase-1, 2, 3, and 9, p53, and Smac/DIABLO were examined using a quantitative real time polymerase chain reaction method, while nuclear factor-kappaB activity was examined using an electrophoresis mobility shift assay with a nuclear factor-kappaB consensus sequenced DNA probe. The effects of denitronipradilol were also examined to clarify the effect of nitric oxide donative action. Nipradilol down-regulated Bax gene expression 12 hr after serum deprivation, and that of the capase-9 and Smac/DIABLO genes at 24 hr, compared to the serum-free sample, while it also increased cell viability and decreased DNA ladder formation at 48 hr. However, the expressions of other examined genes were not affected by the agent. In addition, nuclear factor-kappaB activity was increased 2 hr after the addition of 0.1 or 1 microM of nipradilol. In contrast, denitronipradilol did not show any effects toward PC12 cells. Our results suggest that nipradilol may have an effect on apoptosis associated gene expression and nuclear factor-kappaB activity during the prevention of apoptosis via nitric oxide donative action.

Adrenergic alpha-Antagonists↗
PubMed2005

Cytoprotectivity of Prunella vulgaris on doxorubicin-treated rat cardiomyocytes.

The cardioprotective effect of Prunella vulgaris ethylacetate fraction (PVEF) and its constituent rosmarinic acid (RA) was evaluated on isolated rat cardiomyocytes subjected to doxorubicin-induced oxidative stress. The cytoprotectivities of PVEF and RA were concentration-dependent in the range of 0.005 to 0.05 mg/ml and the effect of PVEF correlated with the RA content. Dexrazoxan (DE), used as positive control, was less effective than PVEF or RA.

Animals↗
PubMed2003

Red blood cells upregulate cytoprotective proteins and the labile iron pool in dividing human T cells despite a reduction in oxidative stress.

We have recently reported that red blood cells (RBC) promote T cell growth and survival by inhibiting activation-induced T cell death. In the present study, we have examined parameters of oxidative stress and intracellular iron in activated T cells and correlated these data with the expression of ferritin, heme oxygenase-1 (HO-1), and the transferrin receptor CD71. T cells growing in the presence of RBC had reduced levels of reactive oxygen species (ROS) and oxidatively modified proteins, suggesting that RBC efficiently counteracted ROS production on the activated T cells. Flow cytometry and immunodetection demonstrated that T cells dividing in the presence of RBC had increased levels of intracellular ferritin rich in L-subunits and HO-1 along with a downmodulation in CD71 expression. Finally, using the fluorescent iron indicator calcein and flow cytometry analysis, we were able to show that a relative amount of the labile iron pool (LIP) was upregulated in T cells growing in the presence of RBC. These findings are consistent with a typical response to iron overload. However, neither heme compounds nor ferric iron reproduced the levels of expansion and survival of T cells induced by intact RBC. Altogether, these data suggest that RBC inhibit apoptosis of activated T cells by a combination of ROS scavenging and upregulation of cytoprotective proteins such as ferritin and HO-1, which may counteract a possible toxic effect of the increased intracellular free iron.

Antigens, CD↗
PubMed2004

An endogenous metabolite of dopamine, 3,4-dihydroxyphenylethanol, acts as a unique cytoprotective agent against oxidative stress-induced injury.

A natural compound contained in olive oil, 3,4-dihydroxyphenylethanol (DOPE), is also known as an endogenous metabolite of dopamine. The role of DOPE in oxidative stress-induced cell damage was investigated using differentiated PC12 cells. Superoxide (O(2)(-)) and H(2)O(2) induced a dose-dependent leakage of lactate dehydrogenase (LDH) and decreased cell viability denoted by MTT assay. While O(2)(-) -induced cell damage was not affected by DOPE, pretreatment of the cells with DOPE dose-dependently prevented the leakage of LDH induced by H(2)O(2). In these cells, augmented activity of catalase was demonstrated, while the levels of glutathione and glutathione peroxidase activity remained unchanged. The effect of DOPE was abolished when an inhibitor of catalase 3-amino-l, 2,4-triazole, was included in the medium. DOPE also protected against cell damage induced by H(2)O(2), and Fe(2+). In the hydroxyl radical ((.-)OH) assay using p-nitroso-N, N-dimethylaniline (PNDA), oxidation of PNDA by (.-)OH generated by the Fenton reaction was significantly attenuated in the presence of DOPE. By an electron spin resonance spin trapping study that represents the direct activity of DOPE to scavenge (.-)OH, however, limited scavenging activity was demonstrated for DOPE. Taken together, DOPE may act as a unique cytoprotective compound in nerve tissue subjected to oxidative stress.

Amitrole↗
PubMed2005

Cytotoxicity and cytoprotective activity in naphthalenediols depends on their tendency to form naphthoquinones.

We consider the cytotoxicity and the protection against oxidative stress for members of the naphthalenediol family and the known antioxidant epigallocatechin gallate (EGCG). Compounds include the 1,2-naphthalenediol (1,2-ND), 1,4-ND, 2,3-ND, 1,8-ND, and 1,4-dipropyl-2,3-naphthalenediol (DPND). The cell line is an adherent clone of rat pheochromocytoma (PC12-AC). Oxidative stress was induced by the peroxyl radical generator AAPH. The relative order of cytotoxicity was 1,4-ND > 1,2-ND > DPND > 2,3-ND > 1,8-ND > EGCG, with EC(50)'s of 15, 40, 160, >250, >250, >>250 muM, respectively. Despite their high toxicity, both 1,4-ND and 1,2-ND showed narrow zones of protective behavior whereas DPND, 2,3-ND and 1,8-ND and especially EGCG showed an extended protective range. The total protection obtained for the combination of cells/oxidative stressor/protective compounds (PC12-AC/AAPH/naphthalenediols) was defined by an integrated measure, the cytoprotective area (CPA). We relate the observed cytotoxicity and CPA to the different electronic structures of the naphthalenediols, characterized by the first and second bond dissociation enthalpies and the pK(a)'s for parent (diol) and semiquinone. Since the 2,3- and 1,8-naphthalenediols do not form quinones, their cytotoxicity is much lower than for the compounds which do. Thus selected members of the naphthalenediol family show promise as antioxidants.

Animals↗
PubMed2006

Heme oxygenase-1 contributes to the cytoprotection of alpha-lipoic acid via activation of p44/42 mitogen-activated protein kinase in vascular smooth muscle cells.

Alpha-lipoic acid (ALA) is a natural antioxidant that scavenges reactive oxygen species (ROS) and regenerates or recycles endogenous antioxidants. ALA has recently been reported to protect against oxidative injury in various disease processes. The aim of this study was to investigate whether the antioxidant effect of ALA is mediated by the induction of heme oxygenase (HO)-1 in rat aortic smooth muscle cells (A10 cells). ALA significantly induced HO-1 expression accompanied by an increase in HO activity in A10 cells. Pretreatment with ALA increased the resistance of A10 cells to hydrogen-peroxide-induced oxidant stress. This protection of ALA was abrogated in the presence of the HO inhibitor zinc protoporphyrin IX. ALA significantly increased ROS, and this effect was blocked by N-acetyl-cysteine, which also inhibited ALA-induced activation of p44/42 mitogen-activated protein kinase (MAPK) and AP-1, HO-1 expression, and HO activity. These results suggest that ALA induces HO-1 expression through the production of ROS and subsequent activation of the p44/42 MAPK pathway and AP-1 in vascular smooth muscle cells. This study demonstrated that ALA increases the expression of HO-1, a critical cytoprotective molecule, and identified a novel pleiotropic effect of ALA on cardiovascular protection.

Animals↗
PubMed2006

Antioxidant and cytoprotective properties of high-density lipoproteins in vascular cells.

Beside their key role in the regulation of cholesterol homeostasis, HDL exhibit antioxidant and anti-inflammatory properties that participate to their general antiatherogenic effect. The purpose of this review is to summarize the recent findings on antioxidant activity and cytoprotective cell signalling elicited by HDL against oxidized LDL and proatherogenic agents in vascular cells. HDL exhibit an antioxidant activity efficient to prevent LDL oxidation, or to inactivate newly formed lipid oxidation products. The antioxidant ability of HDL is due to the apoprotein moiety and to the presence of associated enzymes, paraoxonase and PAF-Acetyl Hydrolase. HDL prevent the intracellular oxidative stress and the inflammatory response elicited by oxidized LDL (ox-LDL), by inhibiting the NFkappaB signalling pathway, and the subsequent inflammatory events (expression of adhesion molecules, recruitment and proliferation of mononuclear cells within the vascular wall). HDL prevent ox-LDL-mediated cell activation and proliferation, this being also attributed to the presence in HDL of sphingosine-1 phosphate which modulates the migration and survival of vascular cells. Lastly, HDL inhibit apoptosis elicited by ox-LDL in vascular cells. Recent evidences indicate that, beside their strong antiatherogenic properties, HDL could exert their protective effect in diseases generally associated to inflammatory events.

Animals↗
PubMed2004

Phosphatidylinositol-3 kinase/Akt and GSK-3 mediated cytoprotective effect of epigallocatechin gallate on oxidative stress-injured neuronal-differentiated N18D3 cells.

Epigallocatechin gallate (EGCG) is one of most famous compounds of green tea. EGCG suppresses apoptosis induced by oxidative radical stress through several mechanisms. This study was designed to investigate whether EGCG plays a cytoprotective role by activating phosphatidylinositol-3 kinase (PI3K)/Akt-dependent anti-apoptotic pathway and inhibiting glycogen synthase kinase-3 (GSK-3) activity in oxidative stressed N18D3 neural cells. N18D3 cells, mouse neuroblastoma X dorsal root ganglion hybrid cell line, were pre-treated with EGCG or z-VAD-fmk, non-selective caspase inhibitor used as a control substance, for 2 h. The N18D3 cells were then exposed to low concentration of H(2)O(2) (100 microM) for 30 min, and further incubated for 24 h. MTT (3,[4,5-dimethylthiazol]-2-yl) assay and trypan blue staining were used to identify cell viability. Immunoreactivity (IR) of PI3K, Akt, and GSK-3 beta were measured by Western blotting. MTT assay and trypan blue staining showed that EGCG and z-VAD-fmk significantly increased cell viability, and IR of PI3K, phospho-Akt and phospho-GSK-3 beta was significantly increased in the cells treated with EGCG, but not in z-VAD-fmk treated. These results imply that EGCG has neuroprotective effect by increasing PI3K/Akt-dependent anti-apoptotic signals.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Cytoprotective function of tetrahydrobiopterin in rat liver ischemia/reperfusion injury.

BACKGROUND: Tetrahydrobiopterin (BH(4)) is a key coenzyme of nitric oxide synthase (NOS), which is associated with a cytoprotective function in various ischemia-reperfusion (I/R) injury models. There have been a few reports on the efficacy of BH(4) in the treatment of I/R injury in other organs; therefore, the aim of this study was to investigate the effect of BH(4) related with NOS reaction in hepatic I/R injury. METHODS: A model of 70% liver I/R injury with a 100-minute ischemic time was created in rats, and the non-ischemic lobes were then resected. The rats were given BH(4) (BH(4) group) or saline solution (saline group) before reperfusion. The specific inducible NOS blocker 1400W was used to evaluate the effect of endogenous inducible NOS in the I/R hepatic injury. Survival, nitric oxide products (nitrate and nitrite), NOS expression, and nitrotyrosine (ie, the peroxynitrite product) were measured after reperfusion. RESULTS: On day 7, the survival rate was 62.5% in the BH(4) group, as opposed to 14.3% in the saline group (P = .0004); 1400W administration to the BH(4) group decreased the survival rate to 0% (P = .003). BH(4) prevented the significant increase in total bilirubin levels (P < .01) after 12-hour reperfusion. The increases in serum alanine transaminase levels (after 3 hours and 12 hours of reperfusion) were significantly (P < .01) attenuated in the BH(4) group. BH(4) increased the nitrate/nitrite concentrations in liver tissue (P < .05) and reduced nitrotyrosine production, and the protein assay showed that BH(4) increased inducible NOS and endothelial NOS expression. Histologic examination of the liver revealed that BH(4) mitigated the damage that was caused by liver I/R. CONCLUSION: Exogenous BH(4) increased nitric oxide production, which attenuated the hepatic I/R injury.

Animals↗