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PubMed2000

Role of actin cytoskeleton in prostaglandin-induced protection against ethanol in an intestinal epithelial cell line.

Prostaglandins (PGs) protect a variety of gastrointestinal cells against injury induced by ethanol and other noxious agents. This investigation attempted to discern the mechanism of cytoprotection as it relates to the relationship between actin and PGs in IEC-6 cells (a rat intestinal epithelial cell line). IEC-6 cells were incubated in Dulbecco's modified Eagle's medium +/- 16,16-dimethyl prostaglandin E(2) (dmPG, 2.6 microM) for 15 min and subsequently incubated in medium containing 1, 2.5, 5, 7.5, and 10% ethanol (EtOH). Cells were then processed for immunocytochemistry using FITC-phalloidin in order to stain the actin cytoskeleton, and cell viability was determined by trypan blue exclusion. Quantitative Western immunoblotting of fractioned G-actin (nonpolymerized; S1) and F-actin (polymerized; S2) was also carried out. EtOH concentrations equal to and greater than 5% led to the collapse of the actin cytoskeleton as depicted by extensive disorganization and fragmentation. In addition, these same EtOH concentrations significantly decreased the S2 fraction and increased the S1 pool of actin. Preincubation with dmPG prevented collapse of the actin cytoskeleton, significantly increased the S2 polymerized fraction as determined by quantitative immunoblotting, and increased cell viability in EtOH-treated cultures. Prior incubation with cytochalasin D, an actin disruptive agent, not only reduced cell viability but also prevented the cytoprotective effects of dmPG. Phalloidin, an actin stabilizing agent, had effects similar to that of dmPG as demonstrated by stability of the actin cytoskeleton and increased cellular viability. Such findings indicate that PGs are important in the organization and stability of actin under in vitro conditions. These effects on actin may play an essential role in the mechanism of PG-induced cytoprotection.

16,16-Dimethylprostaglandin E2↗
PubMed2003

Amifostine induces anaerobic metabolism and hypoxia-inducible factor 1 alpha.

PURPOSE: The cytoprotective mechanism of amifostine (WR-2721) implies free radical scavenging and DNA repair activities. We investigated additional cytoprotective pathways involving intracellular hypoxia and the activation of the hypoxia-inducible factor (HIF) pathway, a key transcription factor regulating glycolysis, angiogenesis and apoptosis, which is also linked with radioresistance. MATERIALS AND METHODS: The glucose and oxygen levels in the peripheral blood of patients receiving 1000 mg amifostine were determined at various time-points in order to investigate the metabolic changes induced by amifostine. MDA468 breast tumor cell lines were incubated with a high amifostine concentration (10 m M) to overcome the natural resistance of cancer cells to influx of the non-hydrolyzed WR-2721, and the HIF1 alpha protein levels were determined by Western blot analysis. In vivo experiments with Wistar rats were performed in order to assess immunohistochemically changes in the intracellular accumulation of HIF1 alpha induced by amifostine (200 mg/kg). RESULTS: By 30 min following amifostine administration, the hemoglobin oxygen saturation and pO(2) levels had increased in the peripheral blood while glucose levels had reduced, providing evidence that normal tissue metabolism switches to glycolytic pathways. Incubation of cell lines with amifostine resulted in HIF1 alpha induction. In Wistar rats administration of amifostine resulted in increased HIF1 alpha accumulation in normal tissues. CONCLUSIONS: Since it is doubtful whether dephosphorylation of amifostine to the active metabolite WR-1065 occurs within tumoral tissues (an acidic environment that lacks vascular alkaline phosphatase activity), intracellular hypoxia and upregulation of HIF1 alpha represents an additional, normal tissue-specific, amifostine cytoprotective pathway.

Amifostine↗
PubMed2006

Role of heat shock proteins (molecular chaperones) in intestinal mucosal protection.

Most studies into the pathogenesis of inflammatory bowel diseases (IBD) have primarily focused on the cytotoxic agents and processes involved in producing mucosal injury, including the immune system. However, less consideration has been given to the inherent mechanisms of cytoprotection and cellular repair in the intestinal mucosa. This review will focus on intestinal mucosal protection against cytotoxic agents and cellular stress mainly from the viewpoint of expression and function of heat shock proteins, in their role of "molecular chaperones," as internal cytoprotectants. Elucidation of such stress-responses in the intestinal mucosa may provide a better understanding of the mechanisms of cytoprotection and cellular repair, and present new strategies for IBD therapy.

Animals↗
PubMed2001

Mechanisms of action of retinoids in gastrointestinal mucosal protection in animals, human healthy subjects and patients.

UNLABELLED: Retinoids prevent chemically induced gastric mucosal damage without inhibiting gastric acid secretion ("nutritional gastric cytoprotection"). The gastroprotective effects of retinoids do not depend on 1) vitamin A activity; 2) number of unsaturated double bonds; 3) the presence of a characteristic chemical structure of their terminal components; however, they depend on 1) intact vagal nerve and 2) adrenals in experimental animals. The gastric cytoprotective effect of retinoids produces a dose-dependent inhibition of ATP-transformation into ADP. It also increases the transformation of ATP into cAMP. Other features of these gastric cytoprotective effects of retinoids include: 1) The retinoid-induced gastric mucosal protection differs from that of PGs; 2) The cAMP is an intracellular signal in the development of gastric mucosal damage produced by chemicals (e.g., ethanol, HCl, indomethacin) and in the protection of gastric mucosa induced by retinoids (but not by PGs); 3) The gastric mucosal protection induced by retinoids and gastric mucosal permeability can be separated in time. The existence of gastric mucosal protection can be demonstrated in healthy persons (against indomethacin treatment), in patients with gastric ulcer (GU) and duodenal ulcer (DU) without any inhibition of gastric acid secretion. The serum levels of vitamin A and zeaxanthin were significantly decreased in patients with chronic gastrointestinal (GI) inflammatory diseases (e.g., terminal ileitis, ulcerative colitis), colorectal polyposis, and different (e.g., esophageal, gastric, pancreatic, hepatocellular and colorectal) malignant diseases. The serum levels of vitamin A provitamins were unchanged and their GI mucosal protective effects do not depend on vitamin A activity. CONCLUSIONS: 1) Abundant experimental and human observations clearly proved the defensive role of retinoids in the GI tract; 2) There is a correlation between the a) scavenger properties of retinoids vs. intact vagal nerve; b) scavenging properties vs. intact adrenals. 3) The GI mucosal protective effect of retinoids is correlated with biochemical changes in the GI mucosa.

Adenosine Diphosphate↗
PubMed2003

Selective protection of renal tubular epithelial cells by heme oxygenase (HO)-1 during stress-induced injury.

BACKGROUND: The renal pathology of human heme oxygenase (HO)-1 deficiency is characterized by advanced tubulointerstitial injury, whereas the glomerular structures are affected little. These facts suggest that the renal tubuli are dependent on intrinsic HO-1 production for their survival under oxidative stresses. METHODS: We compared the patterns of HO-1 expression by primary cultured human mesangial cells (HMCs) and renal proximal tubular epithelial cells (HRPTECs) in vitro. Furthermore, the cytoprotective roles of HO-1 induced in these cells were evaluated by stress-induced cytotoxicity assays. HO-1 expressions in HRPTECs and HMCs were evaluated by immunoblotting, and by reverse transcriptase (RT) and/or real time polymerase chain reaction (PCR). RESULTS: In HRPTECs, both HO-1 mRNA expression and protein production peaked at around 12 h and persisted until 24 h after hemin stimulation. In contrast, HO-1 mRNA expression and protein production by HMCs peaked at 4 h and 6 h respectively, and the levels declined rapidly, being undetectable at 24 h. The peak level of HO-1 expression was significantly higher in HRPTECs than in HMCs. Oxidative stress-induced cell injury in HRPTECs was significantly reduced when HO-1 production had been induced prior to the culture. In contrast, HO-1 induction had little cytoprotective effect on HMCs. Tin protoporphyrin (SnPP), an inhibitor of HO function, significantly reversed the cytoprotection by HO-1. CONCLUSION: These data suggest that HRPTECs are more susceptible to oxidative stress and are significantly more dependent on HO-1 for protection against noxious stimuli than HMCs. Collectively, these results indicate that HO-1 is an important protective factor for kidney tissue, in particular, renal tubular epithelial cells.

Cells, Cultured↗
PubMed2006

Ceramide attenuates hypoxic cell death via reactive oxygen species signaling.

We have previously demonstrated that tumor necrosis factor alpha (TNFalpha), a cytokine known to be induced by ischemia, independently promotes preconditioning in part via ceramide generation. As reactive oxygen species (ROS) signaling is evoked by ischemic preconditioning, by TNFalpha and by ceramide we reasoned that ceramide-induced preconditioning is ROS-mediated. Fibroblastic L-cells were subjected to 8 hours simulated ischemia and were preconditioned by pretreatment with cell permeable c2 ceramide (1 microM) with or without the antioxidant N-mercaptopropionyl glycine (MPG; 1 mM). Pretreatment with ceramide reduced lactate dehydrogenase release at the end of the simulated ischemia but this cytoprotective effect was lost in the presence of MPG. Concurrent temporal ROS generation was measured using confocal microscopy on cells stained with dichlorofluorescein diacetate (DCF-DA). Ceramide increased ROS production after 30 minutes and this induction was decreased by MPG. Incubation of ceramide with cyclooxygenase-2 inhibitor, NS 398 (10 microM), or with a mitochondrial respiratory chain inhibitor, rotenone (10 microM) reduced the cytoprotective effect of ceramide in parallel with a partial diminution in ROS generation. In contrast, inhibition of other ROS-producing systems including nitric oxide synthase, xanthine oxidase, or NADPH oxidase failed to modulate ceramide-induced cytoprotection. Collectively, these data demonstrate that ceramide induces a cell survival program through ROS signaling activated, in part, via cyclooxygenase and the mitochondrial respiratory chain.

Animals↗
PubMed2004

Role and regulation of intestinal epithelial heat shock proteins in health and disease.

Mucosal injury and inflammation are cardinal manifestations of inflammatory bowel diseases (IBD), arising when the effects of cytotoxic factors and conditions overwhelm the cell's capacity for defense (i.e. cytoprotection) or repair. To date, most research in this area has focused primarily on agents and processes involved in producing tissue injury, with less consideration given to inherent mechanisms of cytoprotection and cellular repair. Therapeutic approaches to IBD reflect this bias, being largely directed towards down-regulating the inflammatory process by inhibiting the production of immune and inflammatory mediators. This review will focus on the cell's inherent ability to defend itself against cellular stress and injury through the production of evolutionarily conserved stress proteins called heat shock proteins (HSP). The physiological role of these proteins in maintaining intestinal epithelial cell structure and function will be reviewed, with emphasis on studies that examine the role of HSP in IBD. A clearer understanding of the innate cytoprotective mechanisms inherent in intestinal epithelial cells will foster the development of new insights into basic epithelial cell biology, which ultimately can be used to establish target-specific therapies directed at reducing or alleviating mucosal injury, thereby promoting tissue healing and repair.

Animals↗
PubMed2002

Blockade of maitotoxin-induced endothelial cell lysis by glycine and L-alanine.

The maitotoxin (MTX)-induced cell death cascade in bovine aortic endothelial cells (BAECs) is a model for oncotic/necrotic cell death. The cascade is initiated by an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)), which is followed by the biphasic uptake of vital dyes. The initial phase of dye entry reflects activation of large pores and correlates with surface membrane bleb formation; the second phase reflects cell lysis. In the present study, the effect of the cytoprotective amino acid glycine was examined. Glycine had no effect on MTX-induced change in [Ca(2+)](i) or on the first phase of vital dye uptake but produced a concentration-dependent (EC(50) approximately 1 mM) inhibition of the second phase of dye uptake. No cytoprotective effect was observed with l-valine, l-proline, or d-alanine, whereas l-alanine was equieffective to glycine. Furthermore, glycine had no effect on MTX-induced bleb formation. To test the hypothesis that glycine specifically blocks formation of a lytic "pore," the loss of fluorescence from BAECs transiently expressing GFP and concatemers of GFP ranging in size from 27 to 162 kDa was examined using time-lapse videomicroscopy. MTX-induced loss of GFP was rapid, correlated with the second phase of dye uptake, and was relatively independent of molecular size. The MTX-induced loss of GFP from BAECs was completely blocked by glycine. The data suggest that the second "lytic" phase of MTX-induced endothelial cell death reflects formation of a novel permeability pathway that allows macromolecules such as GFP or LDH to escape, yet can be prevented by the cytoprotective agents glycine and l-alanine.

Alanine↗
PubMed2003

HSP70 induced by hyperosmotic stress partially protects LLC-PK1 cells against nephrotoxic drugs.

Accumulation of HSP70 is related to the cytoprotection. It was evaluated whether hyperosmotic stress induces HSP70 accumulation in LLC-PK1 cells, and protects cells against toxicity provoked by cisplatin (Cis) and cyclosporine A (CyA). Cells were maintained in isosmotic (Iso) or hyperosmotic (H) culture medium for 24 h and then exposed to Cis or CyA for an additional period of 12 or 24 h (groups H+Cis and H+CyA). The H medium did not induce cell death and increased both HSP70 mRNA and protein levels, suggesting a role in cell adaptation to H condition. H medium produced partial cytoprotection against Cis and CyA compared with control cells. Despite the cytoprotection, there was a reduction in HSP70 mRNA and protein levels in H+Cis group. In contrast, the H+CyA group presented high levels of HSP70 mRNA and protein. The induction of HSP70 by H medium was associated with tolerance of LLC-PK1 cells against Cis and CyA cytotoxicity but this protection was induced by different mechanisms and depended on the characteristics of the drug used.

Animals↗
PubMed2003

Aspirin protects endothelial cells from oxidant damage via the nitric oxide-cGMP pathway.

OBJECTIVE: Aspirin is known to exert cytoprotection by presently unidentified mechanisms. This study investigates the involvement of nitric oxide (NO) in antioxidant cellular protection induced by aspirin. METHODS AND RESULTS: A 24-hour incubation with hydrogen peroxide markedly reduced viability of cultured endothelial cells. Preincubation with aspirin (3 to 30 micromol/L) protected endothelial cells from hydrogen peroxide-mediated toxicity and increased viability in a concentration-dependent fashion by up to 95% of control. This effect was specific in that other nonsteroidal anti-inflammatory drugs, such as salicylate or indomethacin, did not alter hydrogen peroxide toxicity. Aspirin-induced endothelial protection was abrogated in the presence of the NO scavenger PTIO (30 micromol/L) and the inhibitor of soluble guanylyl cyclase ODQ (1 micromol/L). Moreover, the l-arginine antagonist L-NMMA (25 micromol/L), but not its D-enantiomer, led to complete inhibition of aspirin-dependent cytoprotection. Correspondingly, aspirin enhanced NO synthase activity (citrulline formation) and intracellular cyclic GMP accumulation in endothelial cells. Protein expression of endothelial NO synthase remained unaffected in the presence of aspirin. CONCLUSIONS: Our data suggest that endothelial NO synthase is a site of action of aspirin and that the NO/cyclic GMP system assumes a crucial function in mediating the cytoprotective action of aspirin.

Animals↗
PubMed2006

Protection of human vascular smooth muscle cells from H2O2-induced apoptosis through functional codependence between HO-1 and AKT.

OBJECTIVE: Oxidative stress (OS) induces smooth muscle cell apoptosis in the atherosclerotic plaque, leading to plaque instability and rupture. Heme oxygenase-1 (HO-1) exerts cytoprotective effects in the vessel wall. Recent evidence suggests that PKB/Akt may modulate HO-1 activity. This study examined the role of Akt in mediating the cytoprotective effects of HO-1 in OS-induced apoptosis of human aortic smooth muscle cells (HASMCs). METHODS AND RESULTS: HASMCs were transduced with retroviral vectors expressing HO-1, Akt, or GFP and exposed to H2O2. Cell viability was assessed by MTT assay. OS was determined by CM-H2DCFDA fluorescence, and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), caspase-3 activity, and Bcl-2/Bad levels. Mitochondrial membrane potential (delta psi(m)) was assessed by fluorescence-activated cell sorter (FACS) using JC-1. HO-1 reduced H2O2-induced OS and apoptosis. Akt knockdown removed the protective effect of HO-1 on delta psi(m) during exposure to H2O2. Conversely, HO-1 knockdown removed the protective effect of Akt on delta psi(m). Inhibition of PI3K-Akt reduced induction of HO-1 protein expression by H2O2 and blocked its anti-apoptotic effects. The Akt-mediated upregulation of HO-1 was dependent on activation of HO-1 promoter by Nrf2. CONCLUSIONS: HO-1 and Akt exert codependent cytoprotective effects against OS-induced apoptosis in HASMCs. These findings may have implications for the design of novel therapeutic strategies for plaque stabilization.

Apoptosis↗
PubMed2004

Silymarin protects pancreatic beta-cells against cytokine-mediated toxicity: implication of c-Jun NH2-terminal kinase and janus kinase/signal transducer and activator of transcription pathways.

Silymarin is a polyphenolic flavonoid that has a strong antioxidant activity and exhibits anticarcinogenic, antiinflammatory, and cytoprotective effects. Although its hepatoprotective effect has been well documented, the effect of silymarin on pancreatic beta-cells is largely unknown. In this study, the effect of silymarin on IL-1beta and/or interferon (IFN)-gamma-induced beta-cell damage was investigated using RINm5F cells and human islets. IL-1beta and/or IFN-gamma induced cell death in a time-dependent manner in RINm5F cells. The time-dependent increase in cytokine-induced cell death appeared to correlate with the time-dependent nitric oxide (NO) production. Silymarin dose-dependently inhibited both cytokine-induced NO production and cell death in RINm5F cells. Treatment of human islets with a combination of IL-1beta and IFN-gamma (IL-1beta+IFN-gamma), for 48 h and 5 d, resulted in an increase of NO production and the impairment of glucose-stimulated insulin secretion, respectively. Silymarin prevented IL-1beta+IFN-gamma-induced NO production and beta-cell dysfunction in human islets. These cytoprotective effects of silymarin appeared to be mediated through the suppression of c-Jun NH2-terminal kinase and Janus kinase/signal transducer and activator of transcription pathways. Our data show a direct cytoprotective effect of silymarin in pancreatic beta-cells and suggest that silymarin may be therapeutically beneficial for type 1 diabetes.

Animals↗
PubMed2006

Increased expression of heat shock protein 72 protects renal proximal tubular cells from gentamicin-induced injury.

The nephrotoxicity of gentamicin (GM) has been widely recognized. Heat shock protein 72 (HSP72) has been reported to be a cytoprotectant. However, its cytoprotective effect against GM induced kidney injury has not yet been studied. In this study, we investigated the cytoprotective effect of HSP72 on GM-induced nephrotoxicity in vitro. Human Kidney tubular cell line, HK-2 cells were divided into four groups: control group, GM group (cells incubated with GM only), heat shock (HS) group (cells incubated at 43 degrees C for 30 min), and GM plus HS group, respectively. Lactate dehydrogenase (LDH) release increased time-dependently from 24 hr to 96 hr compared to the data of cells treated with GM only. Results of NAG activities, superoxide dismutase (SOD) activities and malondialdehyde (MDA) content were similar to that of the LDH release. The amount of HSP72 positive cells increased significantly at 72 hr after cells were treated with GM only. Both HSP72 protein and gene expression increased significantly at 72 hr when cells were treated with GM. On the other hand, HS induced HSP72 expression markedly. Pretreatment of HS inhibited HK-2 cells from GM-induced injury. It could reduce LDH release and NAG activity. HS also increased SOD activity, and decreased MDA content when cells were damaged by GM. These findings suggested that HS may protect kidney cells from GM-induced injury. Pre-induction of HSP72 may provide therapeutic strategies for nephrotoxicity induced by GM.

Cells, Cultured↗
PubMed2005

A group randomized trial to improve safe use of nonsteroidal anti-inflammatory drugs.

OBJECTIVE: To determine whether audit/feedback and educational materials improve adherence to recommendations for laboratory monitoring and cytoprotective agents to detect and prevent adverse events caused by nonsteroidal anti-inflammatory agents (NSAIDs). STUDY DESIGN: Controlled, cluster-randomized trial. METHODS: Physicians commonly prescribing NSAIDs were identified within a large managed care organization and randomized to a control or an intervention group (audit/feedback with peer-derived benchmarks and continuing medical education). Medical records were examined 10 months before and after the intervention for clinical data and receipt of complete blood count (CBC), creatinine testing, and cytoprotective agents (process measures). Primary analysis compared intervention versus control physicians among those who initially performed below a peer-derived benchmark. General estimating equations accounted for patient clustering. RESULTS: Of 101 physicians initially randomized, 85 remained eligible (38 internists, 36 family physicians, 11 rheumatologists) postintervention. Mean percent change in performance between intervention and control physicians for CBC monitoring was 16% versus 10%; for creatinine monitoring, 0% versus 17%; and use of cytoprotective agents, -3% versus -1%. None of these changes were significant. Rheumatology specialty, number of NSAID prescriptions and physician visits, and patient risk factors for NSAID-related toxicity were more strongly associated with improved safety practices than the intervention. CONCLUSIONS: Audit/feedback and educational materials had no observed effect on improving NSAID-related safety practices. Potentially contributing factors include high baseline performance (ceiling effect), dilution of the intervention effect by case mix and provider factors, nonreceipt of intervention materials, and diverse indications for lab tests.

Adult↗
PubMed2005

Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2.

Efficient functioning of maintenance and repair processes seem to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, under control of several genes termed vitagenes. These include members of the heat shock protein system, and there is now evidence that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human conditions, including inflammation, neurodegenerative disorders, and aging. Among the various heat shock proteins, heme oxygenase-1 has received considerable attention; it has been recently demonstrated that heme oxygenase-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, we report here that treatment of astrocytes with acetyl-L-carnitine induces heme oxygenase-1 in a dose- and time-dependent manner and that this effect was associated with up-regulation of heat shock protein 60 as well as high expression of the redox-sensitive transcription factor Nrf2 in the nuclear fraction of treated cells. In addition, we show that addition of acetyl-L-carnitine to astrocytes, prior to proinflammatory lipopolysaccharide- and interferon-gamma-induced nitrosative stress, prevents changes in mitochondrial respiratory chain complex activity, protein nitrosation and antioxidant status induced by inflammatory cytokine insult. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases.

Acetylcarnitine↗
PubMed2004

Restoration of heat shock protein70 suppresses gastric mucosal inducible nitric oxide synthase expression induced by Helicobacter pylori.

Heat shock proteins (HSPs) are crucial for the maintenance of cell integrity during normal cellular growth as well as during pathophysiological conditions. While functioning mainly as molecular chaperones, HSPs also appear to be involved in diverse biological activities, such as apoptosis, carcinogenesis, and cytoprotection from cytotoxic damage. Infection with Helicobacter pylori causes inflammation in the gastric mucosa, leading to gastritis, gastric ulcers, duodenal ulcer disease, and even gastric cancer, but the role of HSPs in H. pylori-associated gastropathy is not known. Using two-dimensional electrophoretic analysis, we have observed significant shifts in HSP profiles after H. pylori infection in RGM-1 cells. We therefore evaluated the effect of treatments that induce HSPs on H. pylori-induced inducible nitric oxide synthase (iNOS) expression. We found that H. pylori infection significantly attenuated the expression of HSP70, whereas exposure of cells to noncytotoxic heat shock or geranylgeranylacetone restored HSP70 expression, as well as suppressing the expression of iNOS, a major cause of H. pylori-induced gastric tissue damage. Our results suggest that induction of HSP70 confers cytoprotection against H. pylori infection by inhibiting the expression of iNOS. In conclusion, these results provide important insights into the flux in HSPs profiles in response to H. pylori infection and highlight the cytoprotective role of HSP70 in H. pylori infection.

Animals↗
PubMed2000

Pituitary adenylate cyclase-activating polypeptide prevents cytokine-induced cytotoxicity via inhibition of inducible nitric oxide synthase expression in beta TC cells.

Type 1 diabetes mellitus is an autoimmune disease resulting from apoptotic destruction of pancreatic beta-cells. The activation of inducible nitric oxide synthase (iNOS) by inflammatory cytokines is considered a mediator of destruction in beta-cells. Recent findings showed that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), whose distribution was identified in pancreatic neurons, inhibited nitric oxide (NO) production in cytokine-activated macrophages. In the present study, we investigated the cytoprotective effect of PACAP in the cytokine-exposed mice beta-cell line, beta TC cells. 1 x 10(-8) M PACAP inhibited the reduction of cell viability, NO production, expression of iNOS mRNA, and iNOS promoter activity caused by the combination of three proinflammatory cytokines. Selective iNOS inhibitor also showed the cytoprotective effect in beta TC cells. These data suggested that PACAP has a cytoprotective effect in cytokine-treated beta-cells through inhibition of iNOS transcription.

Cell Line↗
PubMed2001

Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: an overview of a decade of research.

Over the past decade, an enormous number of studies (>100) have focused on the role of nitric oxide (NO) in myocardial ischemia. It is important to distinguish the function of NO in unstressed (non-preconditioned) myocardium from its function in preconditioned myocardium (i.e. myocardium that has shifted to a defensive phenotype in response to stress). Of the 92 studies that have examined the role of NO in modulating the severity of ischemia/reperfusion injury in non-preconditioned myocardium, the vast majority [67 (73%)] have concluded that NO (either endogenous or exogenous) has a protective effect and only 11 (12%) found a detrimental effect. The proportion of studies supporting a cytoprotective role of NO is similar in vivo[35 (71%) out of 49] and in vitro[32 (74%) out of 43]. With regard to the delayed acquisition of tolerance to ischemia [late preconditioning (PC)], overwhelming evidence indicates a critical role of NO in this phenomenon. Specifically, enhanced biosynthesis of NO by eNOS is essential to trigger the late phase of ischemia-induced and exercise-induced PC, and enhanced NO production by iNOS is obligatorily required to mediate the anti-stunning and anti-infarct actions of late PC elicited by five different stimuli (ischemia, adenosine A1 agonists, opioid delta1 agonists, endotoxin derivatives and exercise). Thus, NO plays a dual role in the pathophysiology of the late phase of PC, acting initially as the trigger and subsequently as the mediator of this adaptive response ("NO hypothesis of late PC"). The diversity of the PC stimuli that converge on iNOS implies that the upregulation of this enzyme is a central mechanism whereby the myocardium protects itself from ischemia. The NO hypothesis of late PC has thus revealed a cytoprotective function of iNOS in the heart, a novel paradigm which has recently been extended to other tissues, including kidney and intestine. Other corollaries of this hypothesis are that the heart responds to stress in a biphasic manner, utilizing eNOS as an immediate but short-term response and iNOS as a delayed but long-term defense, and that the fundamental difference between non-preconditioned and late preconditioned myocardium is the tissue level of iNOS-derived NO, which is tonically higher in the latter compared with the former. Hence, late PC can be viewed as a state of enhanced NO synthesis. The NO hypothesis of late PC has important therapeutic implications. In experimental animals, administration of NO donors in lieu of ischemia can faithfully reproduce the molecular and functional aspects of ischemia-induced late PC, indicating that NO is not only necessary but also sufficient to induce late PC. The recent demonstration that nitroglycerin also induces late PC in patients provides proof-of-principle for the concept that nitrates could be used as a PC-mimetic therapy for the prophylaxis of ischemic injury in the clinical arena. This novel application of nitrates could be as important as, or perhaps even more important than, their current use as antianginal and preload-reducing agents. In addition, gene transfer of either eNOS or iNOS has been shown to replicate the infarct-sparing actions of ischemic PC, suggesting that NOS gene therapy could be an effective strategy for alleviating ischemia/reperfusion injury. Ten years of research have demonstrated that NO plays a fundamental biological role in protecting the heart against ischemia/reperfusion injury. The time has come to translate this enormous body of experimental evidence into clinically useful therapies by harnessing the cytoprotective properties of NO.

Animals↗