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Results for “Cytoprotection”

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At least 883 records · Page 49Linked to original sources
PubMed2006

Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis.

Mrp4 is a member of the multidrug resistance-associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive upregulation in response to cholestatic injury or bile acid feeding. However, the relative importance of Mrp4 in a protective adaptive response to cholestatic injury is not known. To address this issue, common bile duct ligation (CBDL) was performed in wild-type and Mrp4-/- mice and animals followed for 7 days. Histological analysis and serum aminotransferase levels revealed more severe liver injury in the absence of Mrp4 expression. Western analyses revealed that Mrp4, but not Mrp3, was significantly increased after CBDL in wild-type mice. Serum bile acid levels were significantly lower in Mrp4-/- mice than in wild-type CBDL mice, whereas serum bilirubin levels were the same, suggesting that Mrp4 was required to effectively extrude bile acids from the cholestatic liver. Mrp3 and Ostalpha-Ostbeta were upregulated in Mrp4-/- mice but were unable to compensate for the loss of Mrp4. High-performance liquid chromatography analysis on liver extracts revealed that taurine tetrahydroxy bile acid/beta-muricholic acid ratios were increased twofold in Mrp4-/- mice. In conclusion, hepatic Mrp4 plays a unique and essential protective role in the adaptive response to obstructive cholestatic liver injury.

Animals↗
PubMed2002

Restoration of wild-type conformation and activity of a temperature-sensitive mutant of p53 (p53(V272M)) by the cytoprotective aminothiol WR1065 in the esophageal cancer cell line TE-1.

The aminothiol WR1065, the active metabolite of the cytoprotector amifostine, exerts its antimutagenic effects through free-radical scavenging and other unknown mechanisms. In an earlier report, we showed that WR1065 activates wild-type p53 in MCF-7 cells, leading to p53-dependent arrest in the G(1) phase of the cell cycle. To determine whether WR1065 activates p53 by modulating protein conformation, we analyzed its effects on p53 conformation and activity in the esophageal cancer cell line TE-1. This cell line contains a mutation in codon 272 of p53 (p53(V272M), with methionine instead of a valine), conferring temperature-sensitive properties to the p53 protein. At the nonpermissive temperature (37 degrees C), p53(V272M) adopts the mutant p53 conformation (nonreactive with the antibody PAb1620), does not bind specifically to DNA, and is not activated in response to DNA-damaging treatment. However, treatment with 0.5-4 mM WR1065 partially restored wild-type conformation at 37 degrees C, stimulated DNA binding activity, and increased the expression of p53 target genes WAF-1, GADD45, and MDM2, leading to cell-cycle arrest in G(1). These results suggest that WR1065 activates p53 through a mechanism distinct from DNA-damage signaling, which involves modulation of p53 protein conformation.

Cell Cycle↗
PubMed2026

Eugenol-Derived Cytoprotective Action Against Dityrosine-Induced Oxidative Stress in Mice Liver via Akt/Nrf2/ARE Signaling Pathway.

Dityrosine (Dityr), a byproduct of protein oxidation in protein-rich food, induces oxidative stress, inflammation, and apoptosis, jeopardizing human health. Eugenol (EUG), a natural compound with antioxidative and anti-inflammatory properties, was investigated for its protective effects against Dityr-induced hepatotoxicity in this work. In this study, in vivo and in vitro analyses demonstrated EUG's protective effects against Dityr-induced hepatotoxicity. EUG significantly attenuated oxidative stress markers, inflammatory infiltration, fibrotic progression, and apoptotic signaling in mice liver tissues. Mechanistically, EUG activated the Akt/NF-E2-related factor 2/antioxidant response element (Akt/Nrf2/ARE) pathway, enhancing cellular antioxidant capacity while suppressing pro-inflammatory cytokine release. In HepG2 cells, EUG treatment effectively counteracted Dityr-induced ROS overproduction and cell death through Nrf2-mediated antioxidant upregulation. In conclusion, our findings indicate that EUG effectively mitigates Dityr-induced oxidative stress via the Akt/Nrf2/ARE pathway, and this antioxidative impact further inhibits inflammation and apoptosis. These effects ultimately ameliorate liver function impairment caused by Dityr.

Animals↗
PubMed1998

Lung cancer: therapeutic modalities and cytoprotection.

Lung cancer is the leading cancer killer in the United States today. The current methods of treatment, radiation and various chemotherapies, have been used with some success; however, early detection remains the key to successful therapy. Current clinical trials indicate that an improvement of available therapies is needed. Consequently, the development of new approaches to treatment is foremost in the minds of researchers. Advances in molecular medicine have produced new drugs that can protect normal cells from chemotherapy-induced toxicities, resulting in enhanced drug delivery with few dose reductions. This review will discuss some of the advances that have been made in understanding the molecular biology of lung cancer as well as the current and most promising methods of treatment used for various forms of lung cancer. The potential contribution of cytoprotectors to enhance the safety and effectiveness of these therapies will be examined.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

Attenuation of brain derived neurotrophic factor (BDNF) by ethanol and cytoprotective effect of exogenous BDNF against ethanol damage in neuronal cells.

Ethanol-induced cell damage was investigated using human neuroblastomas SH-SY5Y cells, which can be differentiated by retinoic acid. With 100 mM or more of ethanol, cytotoxicity was significantly higher in undifferentiated cells than in differentiated cells. Thus, a severer effect of ethanol was observed in undifferentiated cells. In differentiated cells it was shown that the secreted amount of brain derived neurotrophic factor (BDNF) and the cyclic AMP responsive element binding protein (CREB) activity were significantly reduced by ethanol. These effects may be involved in ethanol-induced cell damage in differentiated cells. It was reported that neurotrophic factors have protective effects and that the hippocampus exclusively was damaged by ethanol. Since SH-SY5Y cell is a cell line (a neuronal cell model) and similar cytotoxic effect of ethanol was observed in both SH-SY5Y and primary culture neuronal cells, it will be favorable to use primary culture cells to test a protective effect of BDNF. Exogenous BDNF was shown to have a protective effect against ethanol-induced damage in primary culture neurons from rat hippocampi.

Alcohol-Induced Disorders, Nervous System↗
PubMed2007

Effect of different cyclooxygenase inhibitors on gastric adaptive cytoprotection induced by 20% ethanol.

In this study, we evaluated the effect of two different dosages of therapeutically prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, diclofenac, nimesulide, meloxicam, and celecoxib (ED80 for COX-1 and COX-2) on normal gastric mucosa and mucosa, previously exposed to 20% ethanol. At COX-2-inhibiting dosages, the NSAIDs tested were nonulcerogenic, and the same response profile was observed in "adapted" stomachs. Interestingly, low doses of nimesulide and celecoxib increase the levels of Prostaglandin E(2) and COX-2, and protect against subsequent 100% ethanol exposition, suggesting that these drugs may act as "mild irritants" to gastric mucosa. The ulcerogenic response to NSAIDs was prevented by the previous 20% ethanol exposition, probably the result of nitric oxide synthesis, because PGE(2) levels in gastric mucosa were reduced by these agents and a concomitant nitric oxide blockade reversed this protection.

Animals↗
PubMed2005

Cytoprotective role of DL-alpha-lipoic acid in cyclophosphamide induced myocardial toxicity.

Cyclophosphamide (CP), a potent antitumor drug is known to cause severe cardiotoxicity. The present study is aimed at evaluating the cardioprotective role of lipoic acid in CP induced toxicity. Male albino rats of Wistar strain were divided into four groups and treated as follows: Group I served as control, Group II received a single dose of CP (200 mg/kg b.wt., i.p.), Group III received lipoic acid (25 mg/kg b.wt., orally) for 10 days, Group IV received CP immediately followed by lipoic acid for 10 days. In CP administered rats, the activities of tissue marker enzymes (creatine phosphokinase, lactate dehydrogenase, aspartate transaminase and alanine transaminase) were significantly (p<0.001) reduced, ATPases suffered loss in enzyme activity and thiols were depleted. Histopathological observations were also in agreement with the above abnormal changes. Lipoic acid effectively reverted these abnormal biochemical changes and minimized the histopathological lesions in heart. These observations highlight the protective role of lipoic acid in CP induced cardiac injury.

Animals↗
PubMed2005

Cytoprotection by amifostine during autologous stem cell transplantation for advanced refractory hematologic malignancies.

This study evaluated whether amifostine protects against mucositis and other toxicities in patients with advanced, refractory, or recurrent hematologic malignancies undergoing high-dose chemotherapy and total body irradiation. Thirty-five patients (20 with non-Hodgkin lymphoma, 12 with Hodgkin disease, and 3 with acute myelogenous leukemia) who underwent autologous stem cell transplantation were conditioned with total body irradiation 2 Gy twice daily on days -8 through -6; cyclophosphamide 6 g/m(2), etoposide 1.8 g/m(2), and carboplatin 1 g/m(2) on days -5 through -3; and amifostine 500 mg/m(2) on days -8 through -2. Prior institutional experience in patients treated without amifostine was used as a historical comparison (no-amifostine group). Severe mucositis occurred in 14 (40%) of 35 patients in the amifostine group, compared with 33 (94%) of 35 in the no-amifostine group (P < .0001). Total parenteral nutrition was used by 4 (11%) of 35 amifostine-treated patients and 34 (97%) of 35 no-amifostine patients (P < .0001). The median duration of narcotic use decreased from 15.5 days with no amifostine to 11 days with amifostine (P = .002). Granulocyte and platelet engraftment times were similar. Prospective trials with innovative designs and clearly defined stopping rules are warranted to confirm whether amifostine reduces the toxicities of a myelosuppressive conditioning regimen before autologous stem cell transplantation without compromising therapeutic response.

Acute Disease↗
PubMed2004

The arachidonate-dependent cytoprotective signaling evoked by peroxynitrite is a general response of the monocyte/macrophage lineage.

U937, THP-1, and J774 cells or human monocytes and macrophages display similar levels of sensitivity to peroxynitrite and exposure to an otherwise non-toxic concentration of the oxidant in the presence of a phospholipase A(2) inhibitor was invariably associated with the onset of mitochondrial permeability transition (MPT)-dependent toxicity. These events were prevented by exogenous arachidonic acid (AA). In general, the protective concentrations of AA were greater in those cell types releasing more AA. Thus, non-toxic concentrations of peroxynitrite commit cells belonging to the monocyte/macrophage lineage to MPT-dependent toxicity that is however prevented by endogenous AA.

Animals↗
PubMed2005

Antioxidant activity and cytoprotective effect of kappa-carrageenan oligosaccharides and their different derivatives.

Antioxidant activity of kappa-carrageenan oligosaccharides (OM) and their chemical modification derivatives was investigated employing various established in vitro systems, such as reducing power, iron ion chelation, and total antioxidant activity using beta-carotene-linoleic acid system. The oversulfated (SD), lowly (LAD), and highly acetylated derivatives (HAD) in reducing power assay, the phosphorylated derivative (PD) in metal chelating assay, and oversulfated and phosphorylated derivatives in total antioxidant activity assay exhibited antioxidant activity higher than that of carrageenan oligosaccharides. The results indicated that the chemical modification of carrageenan oligosaccharides can enhance their antioxidant activity in vitro. The protective effects of the carrageenan oligosaccharides and their chemically modified derivatives against H(2)O(2) and UVA (long-wave ultraviolet radiation) induced oxidative damage on rat thymic lymphocyte were investigated by measuring cell viability via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Thymic lymphocyte exposure to H(2)O(2) and UVA, a marked reduction in cell survival was observed, which was significantly prevented by carrageenan oligosaccharides and their derivatives (preincubated for 2h) at 66.7-2000 microg/mL. But both the carrageenan oligosaccharides and their different derivatives showed the similar protective effects on intracellular level. Taken together, these results suggest that carrageenan oligosaccharides and their derivatives show relevant antioxidant activity both in vitro and in a cell system.

Animals↗
PubMed2004

A putative mitochondrial mechanism for antioxidative cytoprotection by 17beta-estradiol.

It has been demonstrated that estrogens are potent antioxidants and protect against H2O2-mediated depletion of intracellular ATP in human lens epithelial cells (HLE-B3) [Invest. Ophthalmol. Vis. Sci. 44 (2003) 2067]. To investigate the mechanism by which 17beta-estradiol (17beta-E2) protects against oxidative stress, HLE-B3 cells were exposed to insult with H2O2 at physiological (50 microm) and moderately supra- physiological (100 microm) levels over a time course of several hours, with and without pretreatment with 17beta-E2. The ability of 17beta-E2 to prevent H2O2-induced injury to several oxidant susceptible components of the cellular ATP generating machinery, including abundances of mitochondrial gene transcripts encoding respiratory chain subunits and cytochrome c, the glycolytic pathway enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the energy-shuttling creatine kinase (CK) system, and mitochondrial membrane potential (deltapsi(m)) a measure of mitochondrial membrane integrity, were determined 3 hr after oxidative insult. Northern blot analysis revealed H2O2-induced reductions in mitochondrial transcripts for nicotinamide adenine dinucleotide dehydrogenase (NADH) subunits 4 and 5 and cytochrome c. H2O2 also inactivated GAPDH but did not alter CK activity. Pretreatment and simultaneous addition of 17beta-E2 with H2O2 did not prevent the reductions in mitochondrial transcript levels and GAPDH activity. 17beta-Estradiol did moderate the collapse of mitochondrial membrane potential (deltapsi(m)) in response to H2O2 as demonstrated by JC-1 staining and fluorescence microscopy. Although the precise mode of action responsible for protection by estradiols against oxidative stress remains to be determined, these results indicate that the hormone stabilizes the mitochondrial membrane, thereby preserving the driving force for oxidative ATP synthesis.

Adenosine Triphosphate↗
PubMed2005

Catalytically inactive heme oxygenase-2 mutant is cytoprotective.

Heme oxygenase (HO) catalyzes the rate-limiting step in heme degradation, producing iron, carbon monoxide, and bilirubin/biliverdin. HO consists of two isozymes: HO-1, which is an oxidative stress-response protein, and HO-2, which is constitutively expressed. HO-2 accounts for most HO activity within the nervous system. Its posttranslational modifications and/or interactions with other proteins make HO-2 a unique regulator of cellular homeostasis. Our previous results revealed that brain infarct volume was enlarged in HO-2 knockout mice. A similar neuroprotective role of HO-2 was shown using primary cortical neurons. To better understand the neuroprotective mechanism of HO-2, we used a catalytically inactive mutant, HO-2H45A, and investigated its cellular effects in response to hemin and hydrogen peroxide-induced cytotoxicity. We observed that HO-2WT overexpression in the HEK293 cell lines became less sensitive to hemin, whereas the inactive mutant HO-2H45A was more sensitive to hemin as compared to control. Interestingly, HO-2WT- and HO-2H45A-overexpressing cells were both protected against H2O2-induced oxidative stress and had less oxidatively modified proteins as compared to control cells. These data indicate that when HO-2 cannot metabolize the prooxidant heme, more cytotoxicity is found, whereas, interestingly, the catalytically inactive HO-2H45A was also able to protect cells against oxidative stress injury. These results suggest the multiplicity of action of the HO-2 protein itself.

Amino Acid Substitution↗
PubMed2005

Biliverdin reductase, a major physiologic cytoprotectant, suppresses experimental autoimmune encephalomyelitis.

Oxidative stress plays an important role in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Bilirubin is regarded today as a potent antioxidant. Recent studies show that the potent antioxidant actions of bilirubin reflect an amplification mechanism whereby biliverdin reductase (BVR) physiologically regenerates bilirubin in a catalytic cycle. We hypothesized that BVR might prove to be a new effective target for the treatment of free radical-mediated diseases. In this study, we demonstrated that treatment with BVR ameliorated both clinical and pathological signs of EAE more efficiently than treatments with traditional antioxidant enzymes. In vitro, interference with cellular BVR activity by siRNA elicited greater increases in reactive oxygen species and cell death than interference with the activities of other antioxidant enzymes. Further studies showed that BVR surpasses other enzymes by the multifactorial functions of its only end product, bilirubin, including anti-complement activity, and an activity that inhibits antibody-dependent cell-mediated cytotoxicity of lymphocytes. Since BVR regenerates bilirubin in a redox cycle without significantly increasing the concentration of bilirubin, our results suggest that BVR may represent a novel strategy for the treatment of multiple sclerosis and other oxidative stress-mediated diseases.

Animals↗
PubMed2004

The cytoprotective effect of inulin-type hexasaccharide extracted from Morinda officinalis on PC12 cells against the lesion induced by corticosterone.

High concentration of corticosterone (Cort) 0.2 mM was incubated with PC12 cells to simulate the lesion state of brain neurons in depressive illness, it was found that the inulin-type oligosaccharides extracted from Morinda officinalis, inulin-type hexasaccharide (IHS) at the doses of 0.625, 1.25 microM or desipramine (DIM) 0.25, 1 microM protected the PC12 cells from the lesion induced by Cort. With Fura-2/AM labeling assay, DIM 0.25, 1 microM or IHS 2.5, 10 microM attenuated the intracellular Ca2+ overloading induced by Cort 0.1 mM for 48 h in PC12 cells. Using RT-PCR, treatment with Cort 0.1 mM for 48 h decreased the nerve growth factor (NGF) mRNA level in PC12 cells, IHS 5, 10 microM reversed this change. In summary, IHS attenuate the intracellular Ca2+ overloading and thereby up-regulate the NGF mRNA expression in Cort-treated PC12 cells, which may be consisted at least part of the cytopretective effect of IHS. These results also extend evidence for our hypothesis that neuroprotective action is one of the common mechanisms for antidepressants.

Analysis of Variance↗
PubMed2005

Low dose (-)deprenyl is cytoprotective: it maintains mitochondrial membrane potential and eliminates oxygen radicals.

Hypoxia leads to a collapse in mitochondrial transmembrane potential (Deltapsi(M)), a fall in the ATP/ADP ratio, and finally cell death. Since (-)deprenyl directly modulates Deltapsi(M) and production of reactive oxygen species (ROS) by altering the respiratory function of mitochondria, we were interested in the dose-response relations of these effects. The changes in JC-1 red/green signal ratios {mitochondrial transmembrane potential}, and the changes in the cerium staining (intracellular ROS) in hypoxic and normoxic PC12 cell cultures were measured following 1 h of Argon hypoxia and 24 h of re-oxygenation in the absence and in the presence of various concentrations of (-)deprenyl. Deltapsi(M) shifted to lower values following hypoxia/re-oxygenation and all cells had decreased and uniform Deltapsi(M) levels. The amount of ROS increased. Following 24 h of treatment with various concentrations of (-)deprenyl during the re-oxygenation period, survival increased, the Deltapsi(M) shift caused by oxygen deprivation was reversed and the peroxy radical levels decreased except for at 10(-3) M.

Animals↗
PubMed2006

Cortisol can be pro- or anti-apoptotic in sea bream cells: potential role of HSP70 induction for cytoprotection.

Cortisol, and heat shock protein 70 (HSP70) are known to perform key roles as part of the fish stress response. In the present study, two in vitro systems were used to investigate a possible cortisol-HSP70-apoptosis regulatory relationship. Using a developed silver sea bream fibroblast cell line (SSF), cortisol was found to induce HSP70 synthesis with a concomitant protection against camptothecin induced apoptosis. The induction of HSP70 synthesis using azetidine was also found to protect SSF against apoptosis. A primary culture of silver sea bream macrophages (SSM) displayed reduced HSP70, underwent apoptosis and displayed reduced phagocytic activity upon exposure to cortisol. The effect of cortisol on HSP70 expression in both SSF and SSM were blocked by the glucocorticoid antagonist, RU486. Treatment of SSM with azetidine protected against apoptosis and also enhanced phagocytic activity. The data from this study demonstrates for the first time that cortisol can be either anti- apoptotic or pro-apoptotic in different fish cells and such actions can be mediated via HSP70 induction or suppression respectively.

Animals↗
PubMed2005

Different cytoprotective effect of antioxidants and change in the iron regulatory system in rodent cells exposed to paraquat or formaldehyde.

To study the mechanism of toxicity of paraquat and formaldehyde, the response of oxidant-exposed cultured NIH3T3 cells to antioxidants or an iron chelator was investigated. Paraquat-induced cell death was reduced by treatment with 10 microM pyrrolidine dithiocarbamate (PDTC) and 10 microM desferrioxamine (DFO), but not with N-acetyl-L-cysteine (NAC). Cells were protected from formaldehyde-induced cytotoxicity by 1 mM NAC, but not by PDTC or DFO. Moreover, paraquat modulated the cellular iron regulatory system. Paraquat induced a time-dependent increase in the binding of iron regulatory protein 1 (IRP1) to iron-responsive element (IRE), and the enhanced IRP1 activity continued over 24 h. On the other hand, no induction of increased IRP1 binding to IRE was observed in rodent cells exposed to formaldehyde. Previously, we observed stimulation of EpRE-mediated ferritin mRNA expression in the cells exposed to hydrogen peroxide. However, paraquat did not induce any transcriptional activation of ferritin genes. These results suggest that intracellular iron may be involved in paraquat-mediated cytotoxicity and the influence of paraquat on iron metabolism differs from that of hydrogen peroxide.

Animals↗