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PubMed2004

Enhanced cytoprotection and angiogenesis by bone marrow cell transplantation may contribute to improved ischemic myocardial function.

OBJECTIVES: Heat shock proteins (HSPs) are cytoprotective proteins. Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor. This study aimed to elucidate the possible role of cytoprotection and angiogenesis on cardiac function after bone marrow cell transplantation (BMT). METHODS: Myocardial infarction was induced in inbred Lewis rats by left anterior descending artery ligation. A total of 5 x 10(6) bone marrow-mononuclear cells were transplanted into the ischemic zone by direct injection. At 1, 3, 7, 14 and 28 days post-transplantation, cardiac function was evaluated by echocardiography. The expressions of HSP32, HSP70 and VEGF were assessed by immunofluorescence and RT-PCR. The number of vessels was examined by immunohistochemistry. The differentiation of the transplanted cells was determined by immunofluorescence. RESULTS: Echocardiography showed BMT led to sustained improvement in cardiac function, as assessed by left ventricle ejection fraction and fraction of shortening. Immunofluorescence revealed that the expressions of HSP32, HSP70 and VEGF were promoted in both transplanted bone marrow cells and recipient cardiomyocytes. RT-PCR showed that the mRNA expression levels of HSP32, HSP70 and VEGF in the BMT group were markedly higher in comparison with injection of peripheral blood cells or saline (P<0.01) by day 7. Seven days later, the vessel count showed that angiogenesis had been induced to a significantly greater degree in the BMT groups. Fourteen days later, specific markers for myocardial or vascular endothelial cells were detected in the transplanted bone marrow cells. CONCLUSIONS: BMT upregulated the expressions of HSP32, HSP70 and VEGF in both transplanted bone marrow cells and recipient endogenous cardiomyocytes in the early phase post-transplantation. This enhanced cytoprotection and angiogenesis, and contributed to the functional recovery following cardiac infarction. In the late phase, the transplanted bone marrow cells might differentiate into both myocardial and vascular endothelial cells that enhanced the ischemic cardiac function further.

Animals↗
PubMed2005

Oxidative stress in ARPE-19 cultures: do melanosomes confer cytoprotection?

The pigment melanin has antioxidant properties that could theoretically reduce oxidative damage to the retinal pigment epithelium (RPE), perhaps protecting against retinal diseases with an oxidative stress component like age-related macular degeneration. To determine whether melanin confers cytoprotection on RPE cells, melanosomes or control particles were introduced by phagocytosis into the human cell line ARPE-19 and oxidative stress was induced chemically (H2O2 or tert-butyl hydroperoxide) or with visible light. Since the iron-binding capacity of melanin is important for its antioxidant function, experiments were performed to confirm that the melanosomes were not iron saturated. Cytotoxicity was assessed by measures of plasma or lysosomal membrane integrity, mitochondrial function, and cell-substrate reattachment. Oxidative stress protocols were critically evaluated to produce modest cytotoxicity, which might allow detection of a small cytoprotective effect as expected for melanosomes. Particle internalization alone had no effect on baseline metabolic activity or on major RPE antioxidants. Particles were tested in multiple oxidative stress experiments in which culture conditions known to affect stress-induced cytotoxicity, notably culture density, were varied. No testing condition or outcome measure revealed a consistent protective (or cytotoxic) effect of melanosomes, indicating that measures of lysosome stability or whole cell viability do not demonstrate an antioxidant role for RPE melanosomes. If the melanosome, an insoluble particle, performs a cytoprotective function within cells, its effects may be limited to the local environment of the organelle and undetectable by conventional methods.

Animals↗
PubMed2004

Cytoprotective effects of Glycyrrhizae radix extract and its active component liquiritigenin against cadmium-induced toxicity (effects on bad translocation and cytochrome c-mediated PARP cleavage).

Glycyrrhizae radix has been popularly used as one of the oldest and most frequently employed botanicals in herbal medicine in Asian countries, and currently occupies an important place in food products. Cadmium (Cd) induces both apoptotic and non-apoptotic cell death, in which alterations in cellular sulfhydryls participate. In the present study, we determined the effects of G. radix extract (GRE) and its representative active components on cell death induced by Cd and explored the mechanistic basis of cytoprotective effects of G. radix. Incubation of H4IIE cells with GRE inhibited cell death induced by 10 microM Cd. Also, GRE effectively blocked Cd (1 microM)-induced cell death potentiated by buthionine sulfoximine (BSO) without restoration of cellular GSH. GRE prevented both apoptotic and non-apoptotic cell injury induced by Cd (10 microM) or Cd (0.3-1 microM) + BSO. Inhibition of Cd-induced cell injury by pretreatment of cells with GRE suggested that the cytoprotective effect result from alterations in the levels of the protein(s) responsible for cell viability. GRE inhibited mitochondrial Bad translocation by Cd or CD+BSO, and caused restoration of mitochondrial Bcl(xL) and cytochrome c levels. Cd-induced poly(ADP-ribose)polymerase cleavage in control cells or in cells deprived of sulfhydryls was prevented by GRE treatment. Among the major components present in GRE, liquiritigenin, but not liquiritin, isoliquiritigenin or glycyrrhizin, exerted cytoprotective effect. These results demonstrated that GRE blocked Cd-induced cell death by inhibiting the apoptotic processes involving translocation of Bad into mitochondria, decreases in mitochondrial Bcl(xL) and cytochrome c, and poly(ADP-ribose)polymerase cleavage.

Animals↗
PubMed2001

Protection of ATP-depleted cells by impermeant strychnine derivatives: implications for glycine cytoprotection.

Glycine and structurally related amino acids with activities at chloride channel receptors in the central nervous system also have robust protective effects against cell injury by ATP depletion. The glycine receptor antagonist strychnine shares this protective activity. An essential step toward identification of the molecular targets for these compounds is to determine whether they protect cells through interactions with intracellular targets or with molecules on the outer surface of plasma membranes. Here we report cytoprotection by a cell-impermeant derivative of strychnine. A strychnine-fluorescein conjugate (SF) was synthesized, and impermeability of plasma membranes to this compound was verified by fluorescence confocal microscopy. In an injury model of Madin-Darby canine kidney cells, ATP depletion led to lactate dehydrogenase release. SF prevented lactate dehydrogenase leakage without ameliorating ATP depletion. This was accompanied by preservation of cellular ultrastructure and exclusion of vital dyes. SF protection was also shown for ATP-depleted rat hepatocytes. On the other hand, when a key structural motif in the active site of strychnine was chemically blocked, the SF lost its protective effect, establishing strychnine-related specificity for SF protection. Cytoprotective effects of the cell-impermeant strychnine derivative provide compelling evidence suggesting that molecular targets on the outer surface of plasma membranes may mediate cytoprotection by strychnine and glycine.

Adenosine Triphosphate↗
PubMed2002

Cytoprotective role of taurine in a renal epithelial cell culture model.

Taurine (TAU) is a sulfur-containing amino acid that has been shown to decrease during aging and is believed to be important for cytoprotection. A decrease in TAU could exacerbate the accumulation of free radical-induced damage that may lead to cell death during the aging process. We have shown previously that TAU directly inhibits dopamine (DA) and (-)-3-(3,4-dihydroxyphenyl)-L-alanine (L-dopa) oxidation. Experiments were conducted to establish a cytoprotective role for TAU. Porcine renal epithelial cells were treated for 1 hr with iron and catecholamines (L-dopa and DA) to produce cytotoxicity by a free radical and quinone mechanism in the absence and presence of 10 or 20mM TAU. Viability assays, protein, and DNA measurements were performed after a 24hr recovery period. In some experiments, cells were extracted immediately after the insult for DA and TAU content measurements using high performance liquid chromatography with electrochemical detection. Catecholamine-induced cytotoxicity caused a 50% loss in cell viability, and 10 or 20mM TAU provided significant protection from cytotoxicity and maintained the functional integrity of the cells. Photomicrographs showed attenuation in cell loss and swelling in the presence of TAU. Pretreatment with 1mM TAU followed by exposure to iron and L-dopa in the presence of 1mM TAU caused a moderate but non-significant increase in cell survival. These data conclusively show that TAU can play a cytoprotective role in the LLC-PK(1) cell culture model.

Animals↗
PubMedDate not supplied

The key-role of vagal nerve and adrenals in the cytoprotection and general gastric mucosal integrity.

BACKGROUND: Our laboratory group observed earlier that the gastric mucosal cytoprotective effect of prostacyclin (PGI(2)) disappeared after surgical vagotomy in rats. Similarly to this, the beta-carotene induced gastric cytoprotection disappeared in adrenalectomized rats too. AIMS: In these studies we aimed to investigate the possible role of vagal nerve and adrenals in the development of gastric mucosal lesions induced by exogenously administered chemicals (ethanol, HCl, NaOH, NaCl and indomethacin), and on the effects of cytoprotective and antisecretory drugs (atropine, cimetidine), and scavengers (vitamin A and beta-carotene). METHODS: The observations were carried out in fasted CFY strain rats. The gastric mucosal lesions were produced by intragastric (i.g.) administration of narcotising agents (96% ethanol; 0.6 M HCl; 0.2 M NaOH; 25% NaCl) or subcutaneously (s.c.) administered indomethacin (20 mg/kg) in intact, surgically bilaterally vagatomized, and adrenalectomized rats without or with glucocorticoid supplementation (Oradexon, 0.6 mg/kg given i.m. for 1 week). The gastric mucosal protective effect of antisecretory doses of atropine (0.1-0.5-1.0 mg/kg i.g.) and cimetidine (10-25-50 mg/kg i.g.), and vitamin A and beta-carotene (0.01-0.1-1.0-10 mg/kg i.g.) was studied. The number and severity of mucosal gastric lesions was numerically or semiquantitatively measured. In other series of observations the gastric acid secretion and mucosal damage were studied in 24 h pylorus-ligated rats without and with acute bilateral surgical vagotomy. RESULTS: It was found that: (1) the chemical-induced gastric mucosal damage was enhanced in vagotomized and adrenalectomized rats, meanwhile the endogenous secretion of gastric acid, and the development of mucosal damage can be prevented by surgical vagotomy; (2) the gastric cyto- and general protection produced by the drugs and scavengers disappeared in vagotomized and adrenalectomized rats; (3) the gastric mucosal protective effects of drugs and of scavengers returned after sufficient glucocorticoid supplementation of the rats. CONCLUSION: It has been concluded that the intact vagal nerve and adrenals have a key role in the gastric mucosal integrity, and in drugs- and scavengers-induced gastric cyto- and general mucosal protection.

Adrenal Glands↗
PubMed2003

Incomplete assessment of experimental cytoprotectants in rodent ischemia studies.

BACKGROUND: Inadequate preclinical testing (e.g., rodent studies) has been partly blamed for the failure of many cytoprotectants to effectively treat stroke in humans. For example, some drugs went to clinical trial without rigorous functional and histological assessment over long survival times. In this study, we characterized recent experimental practices in rodent cytoprotection experiments to determine whether the limitations of early studies have been rectified. METHODS: We identified 138 rodent cytoprotection studies published in several leading journals (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism and Experimental Neurology) for 2000-2002 and compared these to those published in 1990. From each study we determined the ischemia model, age and sex of the animal, the histological and functional endpoints used, and the methodology used to assess intra- and postischemic temperature. RESULTS: Ninety-eight percent of recent studies used young adult rodents and most used males. Most studies (60%) did not assess functional outcome and survival times were often < or = 48 hr (66%) for focal ischemia and < or = 7 days (80%) for global ischemia. Over 60% of the experiments relied solely upon rectal temperature during ischemia and only 32.6% of ischemia studies measured temperature after surgery. The 1990 data were similar. CONCLUSIONS: Many investigators ignore the need to assess long-term functional and histological outcome and do not accurately represent clinical conditions of ischemia (e.g., use of aged animals). In addition, intra- and postischemic temperature measurement and control is frequently neglected or inadequately performed. Further clinical failures are likely.

Animals↗
PubMed1998

Adaptive cytoprotection against deoxycholate-induced injury in human gastric cells in vitro: is there a role for endogenous prostaglandins?

The majority of previous work investigating adaptive cytoprotection has involved in vivo studies, which have suggested that this protective response is in large part mediated by endogenous prostaglandins (PGs). The aim of this study was to investigate adaptive cytoprotection under in vitro conditions in human gastric cells and to better delineate the role of endogenous PGs in this protective response. AGS cells (a human gastric carcinoma cell line) were characterized morphologically and subsequently used for all experiments. Sodium deoxycholate was used as both the mild irritant and the damaging agent, and cell injury was quantified using both a commercial viability/cytotoxicity kit as well as transepithelial permeability studies. Finally, endogenous PG synthesis in response to varying concentrations of deoxycholate was determined. AGS cells were determined to be morphologically similar to gastric mucous cells. Pretreatment of cells with low-dose deoxycholate significantly attenuated injury upon subsequent exposure to damaging concentrations of deoxycholate, and this protection was determined to be dependent upon both concentration and duration of mild irritant exposure. Preincubation of AGS cells with indomethacin reversed protection induced by mild irritant pretreatment and also significantly increased cellular susceptibility to injury. Results of the permeability studies closely paralleled those assessing cell mortality. While deoxycholate exposure increased PG synthesis, the concentrations required were much higher than those needed to initiate protection. Adaptive cytoprotection exists in AGS cells under in vitro conditions independent of intact blood flow, neural innervation, or circulating humoral mediators. While this protection is reversed by indomethacin, it appears that this reversal results from increased cellular injury secondary to diminished basal PGs, rather than inhibition of endogenous PG synthesis.

Cell Membrane Permeability↗
PubMed2004

Adaptive cytoprotection induced by pretreatment with ethanol protects against gastric cell damage by NSAIDs.

In this study, we examined adaptive cytoprotection against NSAIDs in human gastric carcinoma cells in culture. Pretreatment of cells with low (nontoxic) concentrations of ethanol protected cells from cell death induced by subsequent exposure to NSAIDs. The adaptive cytoprotection against NSAIDs induced by ethanol was not attenuated by pretreatment of cells with inhibitors of protein synthesis or prostaglandin synthesis, thus inferring that neither newly synthesized proteins nor prostaglandins are involved in this process. Furthermore, treatment of cells with the low concentration of ethanol did not affect the synthesis and secretion of mucin. In in vivo experiments on rats, oral preadministration of a low dose of ethanol protected the gastric mucosa from gastric lesions induced by subsequent oral administration of NSAIDs. One possible explanation for this in vivo phenomenon is that the adaptive cytoprotection induced by ethanol protects the gastric mucosa from the direct cytotoxic effect of NSAIDs.

Adaptation, Physiological↗
PubMed2002

Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans.

OBJECTIVE: Obesity, defined as a body mass index (BMI) greater than 30 kg/m(2), is now recognised as a risk factor for diabetes mellitus, hyperlipidaemia, colon cancer, sudden death and other cardiovascular diseases. In this study, it is hypothesized that obesity is an independent risk factor for lipid peroxidation and decreased activities of cytoprotective enzymes in humans. SUBJECTS: Fifty normal healthy subjects with healthy BMI (19-25 kg/m(2)) and 250 subjects with different grades of obesity (30-50 kg/m(2)) with no history of smoking or biochemical evidence of diabetes mellitus, hypertension, hyperlipidaemia, renal or liver disease or cancer. MEASUREMENTS: To test this hypothesis, we assessed lipid peroxidation and cytoprotection by measuring the concentrations of plasma malondialdehyde (P-MDA) and the activities of erythrocyte copper zinc-superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GPX). RESULTS: The concentration of P-MDA was significantly lower (P<0.001) in subjects with healthy BMI (2.53+/-0.04 micro mol/l) than in those with BMI above 40 kg/m(2) (4.75+0.05 micro mol/l). Furthermore, there was a significantly positive association (r=0.342, P=0.013) between BMI and P-MDA. On the other hand, subjects with healthy BMI had significantly higher (P<0.001) erythrocyte CUZn-SOD (1464+/-23 units/g Hb) and GPX (98.4+/-3.3 units/g Hb) than those with BMI above 40 kg/m(2) (1005+/-26 units/g Hb) and (84.3+/-6.7 units/g Hb) respectively. Furthermore, erythrocyte CuZn-SOD and GPX activities were negatively associated with BMI (r=-0.566, P=0.005 and r=-0.436, P=0.018) respectively. CONCLUSION: It is concluded from these results that obesity in the absence of smoking, diabetes mellitus, hyperlipidaemia, renal or liver disease causes lipid peroxidation and decreased activities of cytoprotective enzymes, and should therefore receive the same attention as obesity with complications.

Adult↗
PubMed2004

Inhibition of mitochondrial respiration by nitric oxide rapidly stimulates cytoprotective GLUT3-mediated glucose uptake through 5'-AMP-activated protein kinase.

Recently, we have reported that the inhibition of mitochondrial respiration by nitric oxide (NO) leads to an up-regulation of glycolysis and affords cytoprotection against energy failure through the stimulation of AMPK (5'-AMP-activated protein kinase) [Almeida, Moncada and Bolanos (2004) Nat. Cell Biol. 6, 45-51]. To determine whether glucose transport contributes specifically to this effect, we have now investigated the possible role of NO in modulating glucose uptake through GLUT3, a facilitative high-affinity glucose carrier that has been suggested to afford cytoprotection against hypoglycaemic episodes. To do so, GLUT3-lacking HEK-293T cells (human embryonic kidney 293T cells) were transformed to express a plasmid construction encoding green fluorescent protein-tagged GLUT3 cDNA. This carrier was preferentially localized to the plasma membrane, was seen to be functionally active and afforded cytoprotection against low glucose-induced apoptotic death. Inhibition of mitochondrial respiration by NO triggered a rapid, cGMP-independent enhancement of GLUT3-mediated glucose uptake through a mechanism that did not involve transporter translocation. Furthermore, the functional disruption of AMPK by the RNA interference strategy rendered cells unable to respond to NO by activating GLUT3-mediated glucose uptake. These results suggest that the inhibition of mitochondrial respiration by NO activates AMPK to stimulate glucose uptake, thereby representing a novel survival pathway during pathophysiological conditions involving transient reductions in the supply of cellular glucose.

AMP-Activated Protein Kinases↗
PubMed2000

Cytoprotective influence of ZVAD-fmk and glycine on gel-entrapped rat hepatocytes in a bioartificial liver.

BACKGROUND: This study was designed to determine if an anti-necrotic compound, glycine, and/or an anti-apoptotic agent, ZVAD-fmk, improved the viability and function of hepatocytes in a bioartificial liver. METHODS: Isolated rat hepatocytes were entrapped in collagen gel (1.0-10.0 x 10(6) cells/mL) and cultured in serum-free medium (1:10 ratio of gel:media) supplemented with glycine alone, ZVAD-fmk alone, or glycine and ZVAD-fmk. The cytoprotective effects of glycine and ZVAD-fmk on gel-entrapped rat hepatocytes (GERH) were determined after anoxic exposure (0-20 hours). Cell functionality (measured by urea production), cell viability (quantitated by vital staining with fluorescein diacetate:ethidium bromide [FDA:EB]), and the mechanism of cell death (verified by electron microscopy and DNA fragmentation studies) were determined for each condition. RESULTS: The viability of GERH declined gradually and then stabilized 12 hours after hepatocyte isolation. The rate of urea production by GERH was directly proportional to the number of viable hepatocytes. Apoptotic death predominated at low cell density, and necrotic cell death became significant at high cell density. Hepatocyte necrosis became more significant after exposure to longer periods of anoxia (4, 8, 12, and 20 hours). ZVAD-fmk provided dose-dependent cytoprotection to GERH with an optimum benefit at a concentration of 60 mumol/L. After anoxic exposure or under high cell density culture, glycine demonstrated a maximum benefit of inhibiting necrosis at a concentration of 3 mmol/L. The beneficial effects of glycine and ZVAD-fmk were additive. CONCLUSIONS: The metabolic activity of a hepatocyte bioartificial liver may benefit from the use of cytoprotective agents such as ZVAD-fmk and glycine.

Amino Acid Chloromethyl Ketones↗
PubMed2002

Coenzyme Q cytoprotective mechanisms for mitochondrial complex I cytopathies involves NAD(P)H: quinone oxidoreductase 1(NQO1).

The commonest mitochondrial diseases are probably those impairing the function of complex I of the respiratory electron transport chain. Such complex I impairment may contribute to various neurodegenerative disorders e.g. Parkinson's disease. In the following, using hepatocytes as a model cell, we have shown for the first time that the cytotoxicity caused by complex I inhibition by rotenone but not that caused by complex III inhibition by antimycin can be prevented by coenzyme Q (CoQ1) or menadione. Furthermore, complex I inhibitor cytotoxicity was associated with the collapse of the mitochondrial membrane potential and reactive oxygen species (ROS) formation. ROS scavengers or inhibitors of the mitochondrial permeability transition prevented cytotoxicity. The CoQ1 cytoprotective mechanism required CoQ1 reduction by DT-diaphorase (NQO1). Furthermore, the mitochondrial membrane potential and ATP levels were restored at low CoQ1 concentrations (5 microM). This suggests that the CoQ1H2 formed by NQO1 reduced complex III and acted as an electron bypass of the rotenone block. However cytoprotection still occurred at higher CoQ1 concentrations (>10 microM), which were less effective at restoring ATP levels but readily restored the cellular cytosolic redox potential (i.e. lactate: pyruvate ratio) and prevented ROS formation. This suggests that CoQ1 or menadione cytoprotection also involves the NQO1 catalysed reoxidation of NADH that accumulates as a result of complex I inhibition. The CoQ1H2 formed would then also act as a ROS scavenger.

Animals↗
PubMed1999

Characterization of distinct heat shock- and thapsigargin-induced cytoprotective proteins in FRTL-5 thyroid cells.

Heat shock induces the expression of proteins with molecular weights of 70-72 kd and 90 kd, whereas thapsigargin induces the expression of a glucose-regulated protein 78 kd (GRP-78) in certain cells. In this study we examined the induction and cytoprotective effects of heat shock- and thapsigargin-induced proteins in FRTL-5 rat thyroid cells. New protein synthesis was assessed in [35S]methionine-labeled cells and quantitated densitometrically. The expression of specific stress proteins was identified using Western blots, whereas cytoprotection provided by these proteins was evaluated by trypan blue exclusion. Exposure to heat shock (45 degrees C, 15 minutes) induced the expression of proteins with molecular weights at the range of low 70 kD and low 90 kD that peaked between 2-6 hours and returned to baseline within 24 hours. Treatment of cells with thapsigargin (200 nM, 15 minutes) induced the expression of different molecular weight proteins, most likely GRP-78 and -94, that peaked at 4-6 hours and lasted for 24 hours. Neither the removal of growth factors (thyroid-stimulating hormone and insulin) for 5 days nor the elimination of extracellular Ca2+ with EGTA or clamping of the intracellular Ca2+ with BAPTA for 15 minutes affected expression of the heat shock- and the thapsigargin-induced stress proteins. In contrast, protein kinase C inhibitors H7 and GF109203X abolished the expression of all three groups of stress proteins. Both heat shock- and thapsigargin-inuced proteins completely protected cells from subsequent thermal injury (47 degrees C, 35 minutes). The induction of cytoprotective proteins by heat shock and thapsigargin requires the presence of protein kinase C but is Ca(2+)- and growth factor-independent.

Animals↗
PubMed2003

Effect of beta-amyloid peptide 1-42 on the cytoprotective action mediated by alpha7 nicotinic acetylcholine receptors in growth factor-deprived differentiated PC-12 cells.

Brain deposition of beta-amyloid peptide (Abeta1-42)-containing senile plaques is a consistent finding in Alzheimer's disease (AD). However, the link between Abeta1-42 and neuronal degeneration remains unclear. It has been reported that Abeta peptides bind with selectivity to alpha7 nicotinic acetylcholine receptors (alpha7nAChRs) and that the two proteins are associated in human AD brain tissue. A potential functional interaction between alpha7nAChRs and Abeta1-42 also has been suggested through the ability of nicotine to inhibit Abeta1-42-induced cytotoxicity. Differentiated PC-12 cells share several features in common with cholinergic basal forebrain neurons. The cells express alpha7nAChRs, they require growth factor stimulation for their maintenance and survival, and nicotine protects against cytotoxicity subsequent to growth factor withdrawal. Using these cells as a model system, we designed experiments to more directly determine whether Abeta peptides (Abeta1-42 and Abeta1-40) interfere with a potential nicotinic cytoprotective action and with the ability of nicotine to increase intracellular Ca2+. Differentiated PC-12 cells were preloaded with fura 2/acetoxymethyl ester and intracellular free Ca2+ levels were determined by fluorescent imaging. Nicotine-induced Ca2+ signals were inhibited by pretreatment with the alpha7nAChR-selective antagonists alpha-bungarotoxin and methyllycaconitine, and they were completely absent in cells maintained in Ca2+-free medium. The nicotine response also was blocked by pretreatment with 100 nM Abeta1-42. Nicotine (1-1000 muM) produced a concentration-dependent increase in cell viability in differentiated PC-12 cells that underwent nerve growth factor withdrawal for 24 h. Cell viability was maintained near 100% by 100 muM nicotine. The cytoprotective action of nicotine was efficiently antagonized by cotreatment with alpha7nAChR antagonists. A concentration-dependent inhibition of the cytoprotective action of nicotine also was produced by cotreatment with Abeta1-42 (1-100 nM), but not with Abeta40 -1. It is possible, therefore, that in AD, as growth factor support to basal forebrain cholinergic neurons declines, the interaction of Abeta peptides with alpha7nAChRs may enhance toxicity by interfering with an important nicotinic signal for neuronal viability.

Amyloid beta-Peptides↗
PubMed2002

bFGF and VEGF synergistically enhance endothelial cytoprotection via decay-accelerating factor induction.

The complement-regulatory protein decay-accelerating factor (DAF) can be upregulated on endothelial cells (EC) by protein kinase C (PKC)-dependent and -independent pathways. We hypothesized that basic fibroblast growth factor (bFGF) might induce EC DAF expression, providing a cytoprotective mechanism for angiogenic neovessels against complement-mediated injury. Incubation of umbilical vein, aortic, and dermal EC with bFGF or vascular endothelial growth factor (VEGF) significantly increased DAF expression. Growth factor-induced EC proliferation was inhibited by PKC antagonists. In contrast, although PKC antagonists inhibited VEGF-induced DAF expression, bFGF-induced DAF was unaffected. Investigation of mitogen-activated kinase (MAPK) pathways also revealed differences, with bFGF-induced DAF dependent on p44/42 and p38 MAPK and VEGF requiring activation of p38 MAPK alone. Upregulation of DAF by bFGF was functionally relevant, reducing C3 deposition on EC after complement activation by 60% and resulting in marked reduction in complement-mediated EC lysis. bFGF and VEGF were synergistic in terms of DAF expression, resulting in enhanced cytoprotection. These observations reveal parallel PKC-dependent and -independent pathways regulating complement activation during angiogenesis. Further elucidation of these pathways may provide important insights into innate cytoprotective mechanisms in endothelium.

Antigens, CD↗
PubMedDate not supplied

Pentoxifylline contributes to the hepatic cytoprotective process in rats undergoing hepatic ischemia and reperfusion injury.

AIM: Considerable efforts have been made to find and/or eliminate the underyling causes of hepatic ischemia-reperfusion injury, but many points are still unclear. Pentoxifylline-related cytoprotection is one of these unclear points. Our study tests the effects of pentoxifylline on the hepatic cytoprotective process in an experimental model. MATERIALS AND METHODS: The animals were divided into two groups: (1) placebo-pretreated rats and (2) pentoxifylline-pretreated rats. After pretreatment, all rats underwent the hepatic ischemia-reperfusion procedure which was performed by clamping the hepatoduodenal ligament. To evaluate the liver injury, serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), and liver tissue levels of prostaglandin E(2) (PGE(2)) were measured before ischemia, immediately after ischemia and immediately after reperfusion. RESULTS: Before ischemia and immediately after ischemia, there were no significant differences between ALT and AST levels of groups 1 and 2 (p >0.05). However, at the end of reperfusion, ALT and AST levels of group 2 were significantly decreased when compared with group 1 (p < 0.05 and p < 0.01, respectively). Additionally, tissue levels of PGE(2) that were obtained before ischemia, immediately after ischemia and immediately after reperfusion in group 2 were significantly higher than those of group 1 (p < 0.001). CONCLUSION: Pentoxifylline reduces reperfusion injury of the liver through significantly decreased transaminase levels, and contributes to hepatic cytoprotection by increasing tissue levels of PGE(2) significantly. These effects reflect the role of tissue PGE(2) in pentoxifylline-related hepatoprotection against ischemia-reperfusion injury of the liver.

Alanine Transaminase↗
PubMed2004

Heme oxygenase-1 expression in human lungs with cystic fibrosis and cytoprotective effects against Pseudomonas aeruginosa in vitro.

Inflammation and oxidative stress play important roles in cystic fibrosis (CF) lung disease. Inflammatory/oxidant-mediated induction of heme oxygenase-1 (HO-1) is believed to be a cytoprotective response. This study examined HO-1 expression in lung samples from patients with CF using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. In addition, we evaluated myeloperoxidase staining as a marker of acute inflammation and potentially an increase in oxidant stress and Prussian blue and ferritin staining to assess iron status of the lung. Macrophage HO-1 staining was increased in diseased lungs as compared with normal control subjects and correlated with myeloperoxidase staining. Quantitative reverse transcription-polymerase chain reaction further supported an increase in HO-1 expression in CF lung disease. Although iron staining was minimal, ferritin staining was increased in diseased lungs in concert with HO-1 staining. To determine whether HO-1 induction was cytoprotective, we evaluated a CF airway epithelial cell line, IB3.1, in response to Pseudomonas aeruginosa-induced injury/apoptosis in cells overexpressing HO-1 by either transient or stable transfection of pcDNA3.1/HO-1 construct. Overexpression of HO-1 resulted in protection against P. aeruginosa-induced injury/apoptosis. This suggests that the induction of HO-1 in patients with CF is a cytoprotective event and that augmenting its expression is a potential therapy against bacterial injury.

Apoptosis↗