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PubMed2002

Nipradilol inhibits apoptosis by preventing the activation of caspase-3 via S-nitrosylation and the cGMP-dependent pathway.

To study whether nipradilol, which is used as an ophthalmic solution for the treatment of glaucoma, has a cytoprotective effect, we investigated its effect on the apoptosis induced by serum withdrawal in PC12 cells. Nipradilol has alpha1- and beta-adrenoceptor-blocking and nitric oxide (NO)-donating properties. We also investigated the effects of timolol, prazosin and S-nitroso-N-acetylpenicillamine (SNAP) on PC12 cell death. Serum withdrawal from PC12 cells resulted in apoptosis, and the survival rate was decreased in a time-dependent manner. The addition of nipradilol to the medium showed a cytoprotective effect on PC12 cell death in a dose-dependent manner, but timolol and prazosin did not. We measured caspase-3 activity to clarify the mechanism of the inhibition of apoptosis in the presence or absence of dithiothreitol (DTT). The caspase-3 activity could be reactivated by DTT. In addition, to investigate the relationship of the cGMP-dependent pathway to the nipradilol-induced cytoprotective effect, we tested the effect of the protein kinase G inhibitor KT5823. KT5823 partially reversed the nipradilol-mediated cytoprotective effect. These results indicate that the cytoprotective effect of nipradilol in PC12 cell death was due to the caspase-3 inhibition mediated by NO-related S-nitrosylation and activation of protein kinase G.

Animals↗
PubMed2006

Comparative effects of curcuminoids on endothelial heme oxygenase-1 expression: ortho-methoxy groups are essential to enhance heme oxygenase activity and protection.

Recently, it has been reported that curcumin, which is known as a potent antioxidant, acts as a non- stressful and non-cytotoxic inducer of the cytoprotective heme oxygenase (HO)-1. In this study, naturally occurring curcuminoids, such as pure curcumin, demethoxycurcumin (DMC) and bis-demethoxycurcumin (BDMC), were compared for their potential ability to modulate HO-1 expression and cytoprotective activity in human endothelial cells. All three curcuminoids could induce HO-1 expression and HO activity with differential levels. The rank order of HO activity was curcumin, DMC and BDMC. In comparison with endothelial protection against H2O2-induced cellular injury, cytoprotective capacity was found to be highest with curcumin, followed by DMC and BDMC. Interestingly, cytoprotective effects afforded by curcuminoids were considerably associated with their abilities to enhance HO activity. Considering that the main difference among the three curcuminoids is the number of methoxy groups (none for BDMC, one for DMC, and two for curcumin), the presence of methoxy groups in the ortho position on the aromatic ring was suggested to be essential to enhance HO-1 expression and cytoprotection in human endothelial cells. Our results may be useful in designing more efficacious HO-1 inducers which could be considered as promising pharmacological agents in the development of therapeutic approaches for the prevention or treatment of endothelial diseases caused by oxidative damages.

Curcumin↗
PubMed2001

1Alpha,25-dihydroxyvitamin D3 protects human keratinocytes from apoptosis by the formation of sphingosine-1-phosphate.

Owing to its ability to induce growth arrest and differentiation of keratinocytes, 1alpha,25-dihydroxyvitamin D3 and its analogs are useful for the treatment of hyperproliferative skin diseases, such as psoriasis vulgaris. It has been implicated that the 1alpha,25-dihydroxyvitamin D3-induced differentiation of keratinocytes is mediated, at least in part, by the formation of ceramides; however, ceramides have also been identified to induce apoptosis in many cells, including keratinocytes. Therefore, it was of interest to investigate the influence of 1alpha,25-dihydroxyvitamin D3 on apoptosis in keratinocytes. Most interestingly, physiological concentrations of 1alpha,25-dihydroxyvitamin D3 did not induce apoptosis in keratinocytes, despite the formation of ceramides. Moreover, 1alpha,25-dihydroxyvitamin D3 appeared cytoprotective and made keratinocytes resistant to apoptosis induced by ceramides, ultraviolet irradiation, or tumor necrosis factor-alpha. The cytoprotective effect was accompanied by the formation of the sphingolipid breakdown product sphingosine-1-phosphate, which prevented apoptosis in analogy to 1alpha,25-dihydroxyvitamin D3. The effect of 1alpha,25-dihydroxyvitamin D3 was specific as the almost inactive precursor cholecalciferol neither induced sphingosine-1-phosphate formation nor prevented cells from apoptosis. Besides this, the cytoprotective aptitude of 1alpha,25-dihydroxyvitamin D3 was completely abolished by the sphingosine kinase inhibitor N,N-dimethylsphingosine, which blocked sphingosine-1-phosphate formation. Moreover, sphingosine-1-phosphate was able to restore the cytoprotective effect of 1alpha,25-dihydroxyvitamin D3 in the presence of N,N-dimethylsphingosine. Taken together, here we report for the first time that 1alpha,25-dihydroxyvitamin D3 protects keratinocytes from apoptosis and additionally this cytoprotection is mediated via the formation of sphingosine-1-phosphate.

Apoptosis↗
PubMed2003

Corticotropin-releasing factor (CRF) rapidly suppresses apoptosis by acting upstream of the activation of caspases.

The physiological role of the corticotropin-releasing factor (CRF) family of peptides has recently been extended by emerging evidence of their cytoprotective effects. To determine whether CRF-mediated cytoprotection is linked to caspase-dependent apoptosis, the effect of CRF on the activation of caspases was investigated in detail in Y79 human retinoblastoma cells. The results presented here demonstrate that the cytoprotective effect of CRF against the actions of camptothecin (CT) was mediated by CRF receptor subtype 1, but not subtype 2. The observed CRF-mediated cytoprotection involved rapid and pronounced suppression of proteolytic processing and activation of procaspase-3, exerted even when CRF was added hours after the application of the cytotoxic agent. Surprisingly, activation of procaspase-3 preceded activation of the initiator procaspases 2, 8, 9 and 10 during CT-induced apoptosis of Y79 cells. The mechanism of the effect of CRF was examined using inhibitors of signalling pathways such as Wortmannin (Akt), cyclic AMP-dependent protein kinase (PKA), extracellular signal-regulated kinase (ERK), protein kinase c (PKC), p38 mitogen-activated protein kinase (p38 MAPK), phospholipase c (PLC), nuclear factor-kappaB (NF-kappaBeta) and c-jun N-terminal kinase (JNK). The involvement of PKA in the mediation of the anti-apoptotic effect of CRF has been established. Taken together, these results demonstrate for the first time that the cytoprotective effect of CRF involved suppression of pro-apoptotic pathways at a site upstream of activation of procaspase-3.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Pretreatment with inducers of ER molecular chaperones protects epithelial cells subjected to ATP depletion.

We have investigated the potential cytoprotective role of endoplasmic reticulum (ER) molecular chaperones in a cultured cell model of renal ischemia. Madin-Darby canine kidney (MDCK) cells were pretreated with tunicamycin (an inducer of ER but not cytosolic molecular chaperones) for 12-16 h, followed by 6 h of ATP depletion. A rapid and severe depletion of cellular ATP was noted in both control and tunicamycin-treated cells. Trypan blue exclusion assays indicated that pretreatment of MDCK cells with tunicamycin reduced ATP depletion-induced cell damage by approximately 80% compared with nonpretreated controls. This apparent cytoprotective effect was also found following pretreatment with another inducer of ER molecular chaperones (i.e., A23187). For example, A23187 was found to reduce lactate dehydrogenase release by approximately 50% compared with untreated controls, whereas E-64, a cysteine protease inhibitor which may affect degradation of some proteins in the ER, had little or no effect on cell injury. Moreover, a fluorescent assay confirmed the marked reduction in cell damage following ATP depletion (up to 80% reduction in tunicamycin-pretreated cells). Together, these findings are consistent with the notion that induction of ER molecular chaperones leads to the acquisition of cytoprotection in the face of ATP depletion. However, inhibition of protein translation by cycloheximide was found to only partially attenuate the observed cytoprotective effect, raising the possibility that other, as yet to be identified, nonprotein synthesis-dependent mechanisms may also play a role in the observed cytoprotection.

Adenosine Triphosphate↗
PubMed2003

Nuclear factor-kappaB protects the adult cardiac myocyte against ischemia-induced apoptosis in a murine model of acute myocardial infarction.

BACKGROUND: Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor kappaB (NF-kappaB) and given that NF-kappaB mediates cytoprotective responses, we asked whether NF-kappaB activation conferred cytoprotective responses in acute myocardial ischemia/infarction. METHODS AND RESULTS: We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated IkappaBalpha protein (IkappaBalphaDeltaN) that prevents nuclear translocation of NF-kappaB in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was approximately 50% greater (P<0.02) in the IkappaBalphaDeltaN mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P<0.008) in the IkappaBalphaDeltaN mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the IkappaBalphaDeltaN mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity. CONCLUSIONS: Transgenic mice with a defect in activation of NF-kappaB have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-kappaB are mediated, at least in part, by Bcl-2 or c-IAP1.

Animals↗
PubMed2001

Effects of heat shock, stannous chloride, and gallium nitrate on the rat inflammatory response.

Heat and a variety of other stressors cause mammalian cells and tissues to acquire cytoprotection. This transient state of altered cellular physiology is nonproliferative and antiapoptotic. In this study, male Wistar rats were stress conditioned with either stannous chloride or gallium nitrate, which have immunosuppressive effects in vivo and in vitro, or heat shock, the most intensively studied inducer of cytoprotection. The early stages of inflammation in response to topical suffusion of mesentery tissue with formyl-methionyl-leucyl-phenylalanine (FMLP) were monitored using intravital microscopy. Microvascular hemodynamics (venular diameter, red blood cell velocity [Vrbc], white blood cell [WBC] flux, and leukocyte-endothelial adhesion [LEA]) were used as indicators of inflammation, and tissue levels of inducible Hsp70, determined using immunoblot assays, provided a marker of cytoprotection. None of the experimental treatments blocked decreases in WBC flux during FMLP suffusion, an indicator of increased low-affinity interactions between leukocytes and vascular endothelium known as rolling adhesion. During FMLP suffusion LEA, an indicator of firm attachment between leukocytes and vascular endothelial cells increased in placebo and gallium nitrate-treated animals but not in heat- and stannous chloride-treated animals, an anti-inflammatory effect. Hsp70 was not detected in aortic tissue from placebo and gallium nitrate-treated animals, indicating that Hsp70-dependent cytoprotection was not present. In contrast, Hsp70 was detected in aortic tissues from heat- and stannous chloride-treated animals, indicating that these tissues were in a cytoprotected state that was also an anti-inflammatory state.

Animals↗
PubMed1983

The effect of centrally administered neuropeptides on the development of stress-induced gastric ulcers in rats.

Neurotensin (NT) and bombesin, which are heterogeneously distributed in both brain and gastrointestinal tissue of several mammalian species, inhibit the formation of stress-induced gastric ulcers in rats. Many other endogeneous neuropeptides have also been reported to be present in brain and gastrointestinal tissue. The present study was conducted to evaluate the effect of some of these peptides on the development of cold-restraint stress (CRS)-induced gastric ulcers in rats. In addition, the effect of thyrotropin-releasing hormone (TRH), which antagonizes many of the CNS effects of NT, was investigated to determine whether this tripeptide antagonizes the cytoprotective effect of NT in this CRS model. All peptides were initially administered intracisternally (ic) in doses equimolar to 30 micrograms NT. As previously reported, NT (30 micrograms, ic) completely prevented the development of gastric ulcers in rats exposed to three hours of CRS. Bombesin, beta-endorphin, substance P, and somatostatin also exhibited cytoprotective activity. Several other peptides studied in the CRS model exerted no significant effects on the development of gastric ulcers; these included cholecystokinin octapeptide, gastrin, leu-enkephalin, met-enkephalin, and bradykinin. Two peptides, vasoactive intestinal polypeptide and TRH, significantly increased the severity of gastric ulcerations. The cytoprotective effect of NT was dose dependent. In contrast, lower doses of beta-endorphin, substance P, and somatostatin were cytoprotective whereas higher doses were not. Finally, concomitant ic injections of TRH antagonized the cytoprotective effects of NT and bombesin, but not that of beta-endorphin. The present results suggest that certain brain peptides may participate in modulating the gastric mucosal barrier, thereby increasing or decreasing its vulnerability to stress-induced lesions.

Animals↗
PubMed2006

Bioassay-guided isolation of antiatherosclerotic phytochemicals from Artocarpus altilis.

The cytoprotective effects of various solvent extracts of Artocarpus altilis (Parkinson) Fosberg were evaluated. The cytoprotective effects were determined in human U937 cells incubated with oxidized LDL (OxLDL) using the 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1, 3-benzene disulfonate (WST-1) assay. The results demonstrated that the ethyl acetate extract showed cytoprotective activities. To identify the main cytoprotective components, a bioassay guided isolation of the ethyl acetate extract afforded b-sitosterol (1) and six flavonoids (2-7). Their chemical structures were established on the basis of spectroscopic evidence and comparison with literature data. Of these compounds, compound 6 was obtained from A. altilis for the first time. The cytoprotective effect offers good prospects for the medicinal applications of A. altilis.

Artocarpus↗
PubMed1988

Abrogation of etoposide-mediated cytotoxicity by cycloheximide.

The antitumor agent etoposide interacts with DNA topoisomerase II to produce a unique form of DNA-enzyme intermediate referred to as a "cleavable complex". These drug-induced DNA strand breaks initiate poorly defined cell processes which result in lethality. To explore the mechanism of etoposide cytotoxicity, we studied the effect of protein synthesis inhibitor on Balb/C 3T3 fibroblasts and CCRF-CEM and L1210 leukemia cells by exposing these cell lines to cycloheximide for various periods of time prior to etoposide challenge. Cycloheximide alone during these periods of exposure was not cytotoxic; however, it conferred increasing cytoprotection from etoposide in a time-dependent fashion when it preceded etoposide. Although cycloheximide did cause a decrease in enzyme content and in etoposide-induced DNA cleavage of Balb/C 3T3 and the CCRF-CEM cell lines, cytoprotection by cycloheximide could not be accounted for completely by these phenomena since, in L1210 cells, cytoprotection was observed without significant change in DNA cleavage or enzyme content. Cycloheximide diminished DNA synthesis as well as protein synthesis. However, DNA synthesis resumed within 6 hr after removal of cycloheximide, in spite of the fact that cytoprotection persisted. Cycloheximide did not alter cell cycle distribution as measured by flow cytometry. Our data, therefore, clearly demonstrate that cycloheximide can diminish the cytotoxic potential of etoposide-mediated topoisomerase-DNA complexes. Elucidation of the mechanism by which cytoprotection occurs should shed light on the basis for the cytotoxic effect of topoisomerase II-active drugs.

Animals↗
PubMed1984

Evidence for biological activity of two N-terminal fragments of neurotensin, neurotensin1-8 and neurotensin1-10.

Intracisternal (i.c.) administration of the endogenous tridecapeptide neurotensin (NT) has been previously shown to significantly reduce the incidence of cold-restraint stress (CRS)-induced gastric ulcers in rats. In this study we confirm the cytoprotective activity of central NT, and document structure-activity relationships for this effect of NT. When tested in a dose equimolar to 17.9 nmol of NT the NT analogs [Gln4]NT, D-Trp11-NT, and D-Arg8-NT were cytoprotective, whereas D-Arg9-NT was not. Gonadotropin-releasing hormone (Gn-RH) and melanocyte-stimulating hormone-release inhibiting factor (MIF-1), two oligopeptides structurally unrelated to NT exhibited no cytoprotective efficacy in this paradigm. The C-terminal fragments of NT, xenopsin and NT8-13, and the N-terminal fragment NT1-6 were completely ineffective. Finally, NT1-8 and NT1-10, two N-terminal fragments of NT produced significant cytoprotective activity at this dose level. The cytoprotection afforded by NT1-8 and NT1-10, like that of NT, was dose-dependent with ED50's similar to that of NT (NT = 16.2 nmol, NT1-8 = 17.8 nmol and NT1-10 = 19.9 nmol). In conclusion, we demonstrate that smaller molecular weight forms of NT thought to be degradation products of NT can effectively exert biological effects.

Animals↗
PubMed1987

Inhibition of galactosamine cytotoxicity in an in vivo/in vitro hepatocellular toxicity model.

A combined in vivo/in vitro model of galactosamine hepatotoxicity was employed to test whether previously reported cytoprotective actions of cystamine administration on galactosamine-induced hepatic injury in vivo could be attributed to a direct action of cystamine on toxicant-challenged hepatocytes. In this model, male Sprague-Dawley rats received a 400 mg/kg galactosamine challenge via intraperitoneal injection 1 hr prior to portal vein cannulation for hepatocyte isolation. Isolated cells are established in monolayer culture and galactosamine-induced cellular injury is then expressed over the ensuing 24-48 hr in culture. Consistent with the biochemical basis of galactosamine-induced hepatocellular injury in vivo, cytotoxicity could be prevented by in vitro uridine treatments within 3 hr of the in vivo galactosamine challenge, but not when added 12 hr later. Cystamine, in contrast, exhibited a cytoprotective effect even when added to cultures 12 hr after the in vivo toxicant challenge. Post-toxicant cytoprotection by cystamine in vitro was concentration dependent and did not produce an alteration of hepatocyte nonprotein sulfhydryl content. Post-toxicant cytoprotection by uridine and cystamine in this in vivo/in vitro model of toxicity were fully consistent with in vivo protection from galactosamine-induced necrosis by these agents. This model eliminates potential "extrahepatic" mechanisms for cystamine's hepatoprotective effect and demonstrates a direct cytoprotective action on galactosamine-challenged hepatocytes.

Animals↗
PubMedDate not supplied

Direct cellular effects of some mediators, hormones and growth factor-like agents on denervated (isolated) rat gastric mucosal cells.

The brain-gut axis has an important role in the mechanism of gastric cytoprotection in vivo. The aim of this study was to evaluate the in vitro effect of protective agents without any central and peripheral innervation. A mixed population of rat gastric mucosal cells was isolated by the method of Nagy et al (Gastroenterology (1994) 77, 433-443). Cells were incubated for 60 min with cytoprotective drugs such as prostacyclin, histamine, pentagastrin and PL-10 substances (synthesized parts of BPC). At the end of this incubation cells were treated by 15% ethanol for 5 min. Cell viability was tested by trypan blue exclusion test and succinic dehydrogenase activity. The following results were obtained: 1) prostacyclin, histamine and pentagastrin had no direct cytoprotective effect on isolated cells; and 2) PL-10 substances significantly protected the cells against ethanol-induced cellular damage. This led to the following conclusions: 1) in the phenomenon of gastric cytoprotection only the growth factor-like agents have a direct cellular effect; and 2) the intact peripheral innervation is basically necessary for the development of mediators and hormone-induced gastric cytoprotection.

Animals↗
PubMed2003

Agonist-specific transactivation of phosphoinositide 3-kinase signaling pathway mediated by the dopamine D2 receptor.

Bromocriptine, acting through the dopamine D2 receptor, provides robust protection against apoptosis induced by oxidative stress in PC12-D2R and immortalized nigral dopamine cells. We now report the characterization of the D2 receptor signaling pathways mediating the cytoprotection. Bromocriptine caused protein kinase B (Akt) activation in PC12-D2R cells and the inhibition of either phosphoinositide (PI) 3-kinase, epidermal growth factor receptor (EGFR), or c-Src eliminated the Akt activation and the cytoprotective effects of bromocriptine against oxidative stress. Co-immunoprecipitation studies showed that the D2 receptor forms a complex with the EGFR and c-Src that was augmented by bromocriptine, suggesting a cross-talk between these proteins in mediating the activation of Akt. EGFR repression by inhibitor or by RNA interference eliminated the activation of Akt by bromocriptine. D2 receptor stimulation by bromocriptine induced c-Src tyrosine 418 phosphorylation and EGFR phosphorylation specifically at tyrosine 845, a known substrate of Src kinase. Furthermore, Src tyrosine kinase inhibitor or dominant negative Src interfered with Akt translocation and phosphorylation. Thus, the predominant signaling cascade mediating cytoprotection by the D2 receptor involves c-Src/EGFR transactivation by D2 receptor, activating PI 3-kinase and Akt. We also found that the agonist pramipexole failed to stimulate activation of Akt in PC12-D2R cells, providing an explanation for our previous observations that, despite efficiently activating G-protein signaling, this agonist had little cytoprotective activity in this experimental system. These results support the hypothesis that specific dopamine agonists stabilize distinct conformations of the D2 receptor that differ in their coupling to G-proteins and to a cytoprotective c-Src/EGFR-mediated PI-3 kinase/Akt pathway.

Animals↗
PubMed2005

Pivotal role of Akt activation in mitochondrial protection and cell survival by poly(ADP-ribose)polymerase-1 inhibition in oxidative stress.

According to the classical view, the cytoprotective effect of inhibitors of poly(ADP-ribose)polymerase (PARP) in oxidative stress was based on the prevention of NAD+ and ATP depletion, thus the attenuation of necrosis. Our previous data on PARP inhibitors in an inflammatory model suggested that PARP-catalyzed ADP-ribosylations may affect signaling pathways, which can play a significant role in cell survival. To clarify the molecular mechanism of cytoprotection, PARP activity was inhibited pharmacologically by suppressing PARP-1 expression by a small interfering RNA (siRNA) technique or by transdominantly expressing the N-terminal DNA-binding domain of PARP-1 (PARP-DBD) in cultured cells. Cell survival, activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt system, and the preservation of mitochondrial membrane potential were studied in hydrogen peroxide-treated WRL-68 cells. Our data showed that suppression of the single-stranded DNA break-induced PARP-1 activation by pharmacological inhibitor, siRNA, or by the transdominant expression of PARP-DBD protected cells from oxidative stress and induced the phosphorylation and activation of Akt. Furthermore, prevention of Akt activation by inhibiting PI3-kinase counteracted the cytoprotective effect of PARP inhibition. Microscopy data showed that PARP inhibition-induced Akt activation was responsible for protection of mitochondria in oxidative stress because PI3-kinase inhibitors diminished the protective effect of PARP inhibition. Similarly, Src kinase inhibitors, which decrease Akt phosphorylation, also counteracted the protection of mitochondrial membrane potential supporting the pivotal role of Akt in cytoprotection. These data together with the finding that PARP inhibition in the absence of oxidative stress induced the phosphorylation and activation of Akt indicate that PARP inhibition-induced Akt activation is dominantly responsible for the cytoprotection in oxidative stress.

Acetylcysteine↗
PubMedDate not supplied

16,16-dimethyl prostaglandin E2 modulates aflatoxin B1-induced injury of rat hepatocytes in primary culture: possible role of cAMP.

The hepatocellular cytoprotective effects of 16,16-dimethyl prostaglandin E2 (dmPGE2), an analogue of PGE2, were investigated using primary cultures of rat hepatocytes and aflatoxin B1 as the hepatotoxin. Lactic dehydrogenase (LDH) release by hepatocytes was used as an index of hepatotoxicity. When aflatoxin-treated hepatocytes were co-cultured with 16,16-dmPGE2 (0.01-0.5 micrograms/mL) LDH release was significantly reduced and ultrastructural changes of hepatocellular injury were markedly diminished. The magnitude of the cytoprotective effect was not dependent on the concentration of the prostaglandin over the range tested. A significant cytoprotective effect was also induced when hepatocellular cyclic AMP (cAMP) levels were increased by the addition of dibutyl-cAMP. In contrast to 16,16-dmPGE2, PGF2 alpha Tromethamine, an analogue of PGF2 alpha, which does not stimulate cAMP, induced insignificant changes in cytoprotection. These findings indicate that only a low concentration of 16,16-dmPGE2 (> or = 0.01 micrograms/mL) is necessary to induce a maximal hepatocellular cytoprotective effect and suggest that this effect may be dependent on activation of cAMP.

16,16-Dimethylprostaglandin E2↗
PubMed2005

Corticosteroids inhibit cell death induced by doxorubicin in cardiomyocytes: induction of antiapoptosis, antioxidant, and detoxification genes.

Psychological or physical stress induces an elevation of corticosteroids in the circulating system. We report here that corticosterone (CT) protects cardiomyocytes from apoptotic cell death induced by doxorubicin (Dox), an antineoplastic drug known to induce cardiomyopathy possibly through reactive oxygen species production. The cytoprotection induced by CT is within the range of physiologically relevant doses. The lowest dose tested, 0.1 microM (or 3.5 microg/dl), inhibited apoptosis by approximately 25% as determined by caspase activity. With 1 microM CT, cardiomyocytes gain a cytoprotective effect after 8 h of incubation and remain protected for at least 72 h. Hydrocortisone, cortisone, dexamethasone, and aldosterone but not androstenedione or cholesterol also induced cytoprotection. Analyses of 20,000 gene expression sequences using Affymetrix high-density oligonucleotide array found that CT caused up-regulation of 140 genes and down-regulation of 108 genes over 1.5-fold. Among the up-regulated genes are bcl-xL, metallothioneins, glutathione peroxidase-3, and glutathione S-transferases. Western blot analyses revealed that CT induced an elevation of bcl-xL but not bcl-2 or proapoptotic factors bax, bak, and bad. Inhibiting the expression of bcl-xL reduced the cytoprotective effect of CT. Our data suggest that CT induces a cytoprotective effect on cardiomyocytes in association with reprogramming gene expression and induction of bcl-xL gene.

Adrenal Cortex Hormones↗
PubMed1983

Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms.

Recent evidence indicates that prostaglandins (PGs) possess potent gastric antiulcer properties independent of their known inhibitory effects on acid secretion. The mechanism underlying this cytoprotective property, as it has been called, has remained elusive. Although exogenously administered PGs can prevent disruption of the gastric mucosal barrier, enhance gastric mucosal blood flow, and stimulate mucus and bicarbonate secretion, as well as a number of cellular transport processes, evidence for and against each of these proposed mechanisms for cytoprotection has been demonstrated. Thus, it is doubtful whether any of these effects of PGs on gastric epithelium is the mechanism responsible for cytoprotection, if indeed a single, common mechanism exists. In addition, an association between alterations in endogenous PGs and gastric mucosal injury induced by a variety of damaging agents has also been observed, but the importance of this association in terms of mediating gastric damage needs further clarification. Finally, the phenomenon of adaptive cytoprotection in which mild irritants protect the gastric mucosa against the damaging effects of various necrotizing agents may also be PG mediated since it can be blocked by indomethacin, an inhibitor of PG synthesis, but a clear association between changes in endogenous PGs and adaptive cytoprotection remains to be demonstrated. Despite being inconclusive, these findings suggest that PGs may play a significant role in the pathogenesis of gastric ulceration and may serve an important function in maintaining normal gastric mucosal integrity.

Animals↗