dinoprost and Necrosis

Urinary excretion of 8-iso-prostaglandin F

Topics: Acute Coronary Syndrome; Aged; China; Coronary Vessels; Diabetes Mellitus; Dinoprost; Female; Humans; Male; Middle Aged; Necrosis; Oxidative Stress; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Risk Assessment; ROC Curve; Ultrasonography, Interventional

Oxidative stress is a major factor explaining sperm dysfunction of spermatozoa surviving freezing and thawing and is also considered a major inducer of a special form of apoptosis, visible after thawing, in cryopreserved spermatozoa. To obtain further insights into the link between oxidative stress and the induction of apoptotic changes, stallion spermatozoa were induced to oxidative stress through redox cycling after exposure to 2-methyl-1,4-naphthoquinone (menadione), or hydroxyl radical formation after FeSO

Topics: Aldehydes; Animals; Apoptosis; Caspase 3; Dinoprost; Ferrous Compounds; Horses; Hydroxyl Radical; Lipid Peroxidation; Male; Membrane Potential, Mitochondrial; Necrosis; Oxidation-Reduction; Oxidative Stress; Sperm Motility; Spermatozoa; Vitamin K 3

Programmed necrosis (necroptosis) is an alternative form of programmed cell death that is regulated by receptor-interacting protein kinase (RIPK) 1 and 3-dependent, but is a caspase (CASP)-independent pathway. In the present study, to determine if necroptosis participates in bovine structural luteolysis, we investigated RIPK1 and RIPK3 expression throughout the estrous cycle, during prostaglandin F2α (PGF)-induced luteolysis in the bovine corpus luteum (CL), and in cultured luteal steroidogenic cells (LSCs) after treatment with selected luteolytic factors. In addition, effects of a RIPK1 inhibitor (necrostatin-1, Nec-1; 50 μM) on cell viability, progesterone secretion, apoptosis related factors and RIPKs expression, were evaluated. Expression of RIPK1 and RIPK3 increased in the CL tissue during both spontaneous and PGF-induced luteolysis (P < 0.05). In cultured LSCs, tumor necrosis factor α (TNF; 2.3 nM) in combination with interferon γ (IFNG; 2.5 nM) up-regulated RIPK1 mRNA and protein expression (P < 0.05). TNF + IFNG also up-regulated RIPK3 mRNA expression (P < 0.05), but not RIPK3 protein. Although Nec-1 prevented TNF + IFNG-induced cell death (P < 0.05), it did not affect CASP3 and CASP8 expression. Nec-1 decreased both RIPK1 and RIPK3 protein expression (P < 0.05). These findings suggest that RIPKs-dependent necroptosis is a potent mechanism responsible for bovine structural luteolysis induced by pro-inflammatory cytokines.

Topics: Animals; Apoptosis; Cattle; Cells, Cultured; Corpus Luteum; Dinoprost; Estrous Cycle; Female; Gene Expression; Interferon-gamma; Luteal Cells; Luteolysis; Necrosis; Receptor-Interacting Protein Serine-Threonine Kinases; Steroids; Tumor Necrosis Factor-alpha

To evaluate the effect of TEGDMA on cell cycle progression as well as alterations of cell cycle-related gene and protein expression.. Human dental pulp cells were exposed to 0-5 mmol L(-1) TEGDMA for 24 h. Cytotoxicity was evaluated by 3-(4, 5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Cell cycle progression was analysed by propidium iodide (PI) flow cytometry. Cell death pathway was surveyed by annexin V/PI dual-staining flow cytometry. The mRNA expression of cell cycle-related genes (cdc2, cyclinB1 and p21) and COX-2 was evaluated by reverse transcriptase-polymerase chain reaction, and their protein expression was evaluated by Western blotting. The production of PGE(2) and PGF(2α) in the culture medium was determined by enzyme-linked immunosorbent assay.. Triethylene glycol dimethacrylate inhibited cellular growth and induced cell cycle deregulation in dental pulp cells. High-dose exposure provoked both necrotic and apoptotic cell death. The gene and protein expression of cdc2, cyclin B1 and cdc25C declined obviously whilst cells treated with 2.5 mmol L(-1) TEGDMA concurrent with the elevated expression of p21. The mRNA and protein expression of COX-2, along with production of PGE(2) and PGF(2α), are drastically raised by 2.5-5 mmol L(-1) TEGDMA.. Triethylene glycol dimethacrylate induced cytotoxicity, cell cycle arrest and apoptosis in dental pulp cells, which was associated with the decline of cdc2, cyclin B1, cdc25C expression and elevation of p21 expression. Concomitantly, COX-2 expression, PGE(2) and PGF(2α) production increased. These effects may contribute to explain the pulpal damage and inflammation induced by TEGDMA after operative procedures.

Topics: Annexin A5; Apoptosis; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Culture Techniques; Cell Cycle; Cell Death; Cell Proliferation; Cell Shape; Coloring Agents; Cyclin B; Cyclin B1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclooxygenase 2; Dental Materials; Dental Pulp; Dinoprost; Dinoprostone; Enzyme Inhibitors; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Humans; Necrosis; Polyethylene Glycols; Polymethacrylic Acids; Propidium; Prostaglandins; Tetrazolium Salts; Thiazoles; Time Factors

The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca(2+), coupled to oxidative stress with increased H(2)O(2) production and 8-isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal.

Topics: Animals; Cachexia; Calcium; Cardiomegaly; Dinoprost; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Hydrogen Peroxide; Hyperaldosteronism; Male; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Muscle, Skeletal; Muscular Atrophy; Myocardium; Myocytes, Cardiac; Necrosis; Rats; Rats, Sprague-Dawley; Recovery of Function; Time Factors; Ventricular Remodeling

This study investigated the cardioprotective effect of N-acetylcysteine (NAC) on isoproterenol (ISO)-induced cardiotoxicity in rats. Male Sprague-Dawley rats were divided into control, NAC alone (100 mg/kg BW orally for 14 days), ISO-control (85 mg/kg BW), and ISO with NAC (for 14 days). Serum creatine kinase-MB and Lactate dehydrogenase were measured. From the heart homogenate lipid hydroperoxides (LPO), superoxide dismutase (SOD), total glutathione (GSH), and 8-isoprostane (IP) were measured. Histopathological examination of the heart was also carried out. There was a significant increase (P < 0.05) in LPO and IP levels in ISO-control group and NAC treatment reduced these changes. Antioxidant enzyme, SOD and GSH, level decreased significantly (P < 0.05) in ISO-control group, and treatment with NAC was able to reverse these changes significantly (P < 0.05). Histopathologically, ISO-control group showed morphological changes suggestive of cardiotoxicity with large areas of coagulative necrosis, with diffused interstitial edema. NAC treatment successfully reduced these histopathological changes. In conclusion, the study proves that NAC has a strong cardioprotective effect against isoproterenol-induced cardiac changes. NAC decreases isoproterenol-induced LPO and IP levels in the heart tissue and prevented free radicals-induced damage to the myocardium.

Topics: Acetylcysteine; Animals; Body Weight; Cardiotonic Agents; Creatine Kinase, MB Form; Dinoprost; Drug Therapy, Combination; Edema; Free Radical Scavengers; Glutathione; Heart; Isoproterenol; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Myocardium; Necrosis; Organ Size; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Intracellular Ca(2+) overloading, coupled to induction of oxidative stress, is present at 4-wk aldosterone/salt treatment (ALDOST). This prooxidant reaction in cardiac myocytes and mitochondria accounts for necrotic cell death and subsequent myocardial scarring. It is intrinsically linked to increased intracellular zinc concentration ([Zn(2+)](i)) serving as an antioxidant. Herein, we addressed the temporal responses in coupled Ca(2+) and Zn(2+) dyshomeostasis, reflecting the prooxidant-antioxidant equilibrium, by examining preclinical (week 1) and pathological (week 4) stages of ALDOST to determine whether endogenous antioxidant defenses would be ultimately overwhelmed to account for this delay in cardiac remodeling. We compared responses in cardiomyocyte free [Ca(2+)](i) and [Zn(2+)](i) and mitochondrial total [Ca(2+)](m) and [Zn(2+)](m), together with biomarkers of oxidative stress and antioxidant defenses, during 1- and 4-wk ALDOST. At week 1 and compared with controls, we found: 1) elevations in [Ca(2+)](i) and [Ca(2+)](m) were coupled with [Zn(2+)](i) and [Zn(2+)](m); 2) increased mitochondrial H(2)O(2) production, cardiomyocyte xanthine oxidase activity, and cardiac and mitochondrial 8-isoprostane levels, counterbalanced by increased activity of antioxidant proteins, enzymes, and the nonenzymatic antioxidants that can be considered as cumulative antioxidant capacity; some of these enzymes and proteins (e.g., metallothionein-1, Cu/Zn-superoxide, glutathione synthase) are regulated by metal-responsive transcription factor-1; and 3) although these augmented antioxidant defenses were sustained at week 4, they fell short in combating the persistent intracellular Ca(2+) overloading and marked rise in cardiac tissue 8-isoprostane and mitochondrial transition pore opening. Thus a coupled Ca(2+) and Zn(2+) dyshomeostasis occurs early during ALDOST in cardiac myocytes and mitochondria that regulate redox equilibrium until week 4 when ongoing intracellular Ca(2+) overloading and prooxidants overwhelm antioxidant defenses.

Topics: Aldosterone; Animals; Calcium; Dinoprost; Disease Models, Animal; Glutathione Peroxidase; Homeostasis; Hyperaldosteronism; Male; Mitochondria, Heart; Myocytes, Cardiac; Necrosis; Nephrectomy; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sodium Chloride; Zinc

Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in combination to protect cells against necrosis. Maitotoxin (MTX), which induces a massive influx of calcium, was used to provoke neuronal cell death. This toxin increased, in a concentration-dependent manner, both calpain activity and ROS formation. Calpain inhibitors or antioxidants inhibited MTX-induced necrosis only marginally (below 20%), whereas their association protected against cell death by 40-66% in a synergistic manner. BN 82204, which possesses both calpain-cathepsin L inhibitory and antioxidant properties, and its acetylated pro-drug BN 82270, totally protected cells at 100 microm. The pro-drug BN 82270, which had better cell penetration, was twice as effective as the active principle BN 82204 in protecting glioma C6 or neuroblastoma SHSY5Y cells against death. These results suggest the potential therapeutic relevance of using a single molecule with multiple activities (cysteine protease inhibitor/antioxidant), and warrant further in vivo investigations in models of neuronal disorders.

Topics: Animals; Antioxidants; Calpain; Cell Death; Cell Line, Tumor; Cell Survival; Cysteine Proteinase Inhibitors; Dinoprost; Drug Synergism; Humans; Lipid Peroxidation; Methotrexate; Necrosis; Nucleic Acid Synthesis Inhibitors; Phenothiazines; Proteasome Endopeptidase Complex; Rats; Rats, Sprague-Dawley; Serine Endopeptidases

A single dose of valproic acid (VPA), which is a widely used antiepileptic drug, is associated with oxidative stress in rats, as recently demonstrated by elevated levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP). To determine whether there was a temporal relationship between VPA-associated oxidative stress and hepatotoxicity, adult male Sprague-Dawley rats were treated ip with VPA (500 mg/kg) or 0.9% saline (vehicle) once daily for 2, 4, 7, 10, or 14 days. Oxidative stress was assessed by determining plasma and liver levels of 15-F(2t)-IsoP, lipid hydroperoxides (LPO), and thiobarbituric acid reactive substances (TBARs). Plasma and liver 15-F(2t)-IsoP were elevated and reached a plateau after day 2 of VPA treatment compared to control. Liver LPO levels were not elevated until day 7 of treatment (1.8-fold versus control, p < 0.05). Liver and plasma TBARs were not increased until 14 days (2-fold vs. control, p < 0.05). Liver toxicity was evaluated based on serum levels of alpha-glutathione S-transferase (alpha-GST) and by histology. Serum alpha-GST levels were significantly elevated by day 4, which corresponded to hepatotoxicity as shown by the increasing incidence of inflammation of the liver capsule, necrosis, and steatosis throughout the study. The liver levels of beta-oxidation metabolites of VPA were decreased by day 14, while the levels of 4-ene-VPA and (E)-2,4-diene-VPA were not elevated throughout the study. Overall, these findings indicate that VPA treatment results in oxidative stress, as measured by levels of 15-F(2t)-IsoP, which precedes the onset of necrosis, steatosis, and elevated levels of serum alpha-GST.

Topics: Animals; Anticonvulsants; Biomarkers; Dinoprost; Fatty Liver; Glutathione Transferase; Lipid Peroxidation; Liver; Necrosis; Oxidative Stress; Rats; Thiobarbituric Acid Reactive Substances; Valproic Acid

This study investigated the mechanisms involved in the protective actions exerted by lansoprazole against experimental gastric injury. Following the intraluminal injection of ethanol-HCl, the histomorphometric analysis of rat gastric sections demonstrated a pattern of mucosal lesions associated with a significant increase in the mucosal contents of malondialdehyde and 8-iso-prostaglandin F(2alpha) (indices of lipid peroxidation), as well as a decrease in the levels of mucosal sulfhydryl compounds, assayed as reduced glutathione (GSH). Pretreatment with lansoprazole 90 micromol/kg, given intraduodenally as single dose or once daily by intragastric route for 8 days, significantly prevented ethanol-HCl-induced gastric damage. The concomitant changes in the mucosal levels of malondialdehyde, 8-iso-prostaglandin F(2alpha) and GSH elicited by ethanol-HCl were also counteracted by lansoprazole. In separate experiments, performed on animals undergoing 2-h pylorus ligation, lansoprazole did not enhance the concentration of prostaglandin E(2), bicyclo-prostaglandin E(2), or nitric oxide (NO) metabolites into gastric juice. Western blot analysis revealed the expression of both type 1 and 2 cyclooxygenase (COX) isoforms in the gastric mucosa of pylorus-ligated rats. These expression patterns were not significantly modified by single-dose or repeated treatment with lansoprazole. Lansoprazole also exhibited direct antioxidant properties by reducing 8-iso-prostaglandin F(2alpha) generation in an in vitro system where human native low-density lipoproteins were subjected to oxidation upon exposure to CuSO(4). The present results suggest that the protective effects of lansoprazole can be ascribed to a reduction of gastric oxidative injury, resulting in an increased bioavailability of mucosal sulfhydryl compounds. It is also proposed that lansoprazole does not exert modulator effects on the gastric expression of COX isoforms as well as on the activity of NO pathways.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Anti-Ulcer Agents; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprost; Ethanol; Gastric Juice; Gastric Mucosa; Hydrochloric Acid; Isoenzymes; Lansoprazole; Male; Malondialdehyde; Membrane Proteins; Necrosis; Omeprazole; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Stomach Ulcer; Sulfhydryl Compounds

Free radical-induced peroxidation is an important factor in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm infant. Isoprostanes are major peroxidation products. Since microvascular dysfunction seems to contribute to ischemic encephalopathies, we studied the cytotoxicity of 8-iso-prostaglandin F2alpha (PGF2alpha) on cerebral microvascular cells.. Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF2alpha on these cells was determined by MTT assays and lactate dehydrogenase (LDH) release, propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of intraventricular injections of 8-iso-PGF2alpha and possible involvement of thromboxane in 8-iso-PGF2alpha-induced cytotoxicity were determined.. 8-Iso-PGF2alpha induced time- and concentration-dependent endothelial cell death (EC50=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide incorporation and LDH release). Cell death was associated with increased endothelial thromboxane A2 (TXA2) formation and was prevented by TXA2 synthase inhibitors (CGS12970 and U63557A); TXA2 mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF2alpha induced periventricular damage, which was attenuated by CGS12970 pretreatment.. These data disclose a novel action of 8-iso-PGF2alpha involving TXA2 in oxidant stress-induced cerebral microvascular injury and brain damage.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Cell Death; Cell Survival; Cells, Cultured; Dinoprost; Dinoprostone; DNA Fragmentation; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; F2-Isoprostanes; In Vitro Techniques; Injections, Intraventricular; Isoprostanes; L-Lactate Dehydrogenase; Microcirculation; Muscle, Smooth, Vascular; Necrosis; Rats; Rats, Sprague-Dawley; Swine; Thromboxane A2; Thromboxane-A Synthase

Selenium and vitamin E deficiencies were studied as part of an evaluation of oxidant defenses in guinea pigs. Male guinea pigs (100-120 g) were fed a control diet (C) or the diet without selenium (0 Se), without vitamin E (0 E), or without either selenium or vitamin E (0 Se-0 E). Between d 30 and 35, 7 of 13 guinea pigs fed the 0 Se-0 E diet were euthanized because of severe weakness of their extremities. No guinea pigs in the other diet groups developed weakness. Guinea pigs from each group were killed on d 37. Selenium deficiency and vitamin E deficiency were verified by measurement of glutathione peroxidase and alpha-tocopherol. Creatine phophokinase (CPK) activity was greater than controls in both groups fed vitamin E-deficient diets, but the increase was greater in the 0 Se-0 E group than in the 0 E group. Muscle F(2)-isoprostanes were greater than controls in both groups fed vitamin E-deficient diets with the level in the 0 Se-0 E group greater than that in the 0 E group. Histologic muscle necrosis was severe in the 0 Se-0 E group, minimal in the 0 E group and absent from other groups. The diets used in this study induced selenium and vitamin E deficiencies in guinea pigs. The study demonstrates that combined selenium and vitamin E deficiency results in a fatal myopathy in guinea pigs that is associated with lipid peroxidation in the affected muscle. This nutritional myopathy is much more severe than the myopathy that occurs with vitamin E deficiency alone.

Topics: Animals; Body Weight; Creatine Kinase; Diet; Dinoprost; F2-Isoprostanes; Guinea Pigs; Liver; Male; Muscle, Skeletal; Muscular Diseases; Necrosis; Selenium; Survival Analysis; Vitamin E; Vitamin E Deficiency

Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothesized to cause defective actin cytoskeletal function. This resultant dysfunction of the actin cytoskeleton has been implicated in the pathogenesis of Wiskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated actin polymerization is kinetically normal in the hematopoietic lineages affected in WAS. It was also found that the actin cytoskeleton in WAS platelets is capable of producing the hallmark cytoarchitectural features associated with activation. Further analysis revealed accelerated cell death in WAS lymphocytes as evidenced by increased caspase-3 activity. This increased activity resulted in accelerated apoptosis of these cells. CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS pathway in WAS lymphocytes. Additionally, inhibition of actin polymerization in lymphocytes using cytochalasin B did not accelerate apoptosis in these cells. This suggests that the accelerated apoptosis observed in WAS lymphocytes was not secondary to an underlying defect in actin polymerization caused by mutation of the WAS gene. These data indicate that WASP does not play a universal role in signaling actin polymerization, but does play a role in delaying cell death. Therefore, the principal consequence of mutations in the WAS gene is to accelerate lymphocyte apoptosis, potentially through up-regulation of the FAS-mediated cell death pathway. This accelerated apoptosis may ultimately give rise to the clinical manifestations observed in WAS. (Blood. 2000;95:1283-1292)

Topics: Actins; Adenosine Diphosphate; Apoptosis; Blood Platelets; Cell Survival; Cytochalasin B; Cytoskeleton; Dinoprost; fas Receptor; Humans; In Vitro Techniques; Kinetics; Leukocytes; Lymphocytes; Mutation, Missense; N-Formylmethionine Leucyl-Phenylalanine; Necrosis; Point Mutation; Proteins; Reference Values; src Homology Domains; Tetradecanoylphorbol Acetate; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein

Acute exposure to acetylcholinesterase (AChE) inhibitors such as organophosphates and carbamates induces functional changes at the neuromuscular junctions, leading to fasciculations that ultimately cause muscle fiber necrosis. There is recent evidence that oxygen free radical formation may be a factor in the toxicity of these insecticides. One of the targets of free radical-induced injury is lipid peroxidation. The role of lipid peroxidation in diisopropylphosphorofluoridate (DFP)-induced muscle necrosis was investigated by quantifying two products resulting from the oxidation of lipids in muscle tissue-the thiobarbituric acid-malondialdehyde complex (TBA-MDA) and F2-isoprostanes, the latter being a novel and extremely accurate marker of lipid peroxidation in vivo. When compared with control animals, significant increases in MDA of 96% and in F2-isoprostanes of 56% were found in the diaphragms of rats treated with 2.0 mg/kg DFP after 60 min (P < 0.01). In rats pretreated with the neuromuscular blocking agent d-tubocurarine or the lazaroid U-78517F, an antioxidant, no DFP-induced increases in either MDA or F2-isoprostanes were observed. It is suggested that the AChE inhibitor-induced cholinergic hyperactivity initiates that accumulation of free radicals leading to lipid peroxidation, which may be the initiator of the AChE inhibitor-induced cell injury.

Topics: Animals; Cholinesterase Inhibitors; Chromans; Dinoprost; Fasciculation; Isoflurophate; Lipid Peroxidation; Male; Malondialdehyde; Muscles; Necrosis; Piperazines; Rats; Rats, Sprague-Dawley; Tubocurarine

Selenium and glutathione have interrelated oxidant defense roles in vivo. Experiments were carried out to determine the effect of glutathione depletion in selenium-deficient rats.. Selenium-deficient and control rats were injected with phorone to deplete glutathione. Histologic assessment of liver and kidney injury was performed at 24 hours. In another experiment, glutathione depletion, lipid peroxidation, and liver injury were measured for 12 hours after phorone administration to determine their relationships with one another. In a final experiment, selenoproteins were correlated with protection against lipid peroxidation and liver necrosis. Selenium-deficient rats were injected with vehicle alone and with 5, 10, or 25 micrograms of selenium/kg. Twelve hours later, selenoproteins were measured in some of the rats, and phorone was injected into others. Liver injury and lipid peroxidation were assessed 6 hours after the phorone injection.. Twenty-four hours after phorone administration (125 mg/kg), centrilobular hepatic necrosis and renal tubular necrosis were evident in selenium-deficient rats but not in controls. The time-course experiment revealed that phorone (250 mg/kg) caused sharp decreases in liver and kidney glutathione levels in both groups within 2 to 4 hours. Lipid peroxidation, as assessed by F2 isoprostane concentrations, in selenium-deficient animals. Liver necrosis, indicated by a rise in plasma ALT, took place in selenium-deficient rats but not in controls. Selenium injections into selenium-deficient rats increased selenoprotein P concentrations from 4% of control to as high as 39% but had little effect on glutathione peroxidase activities. Six hours after phorone administration, rats that had received selenium had no rise in ALT, and the rises in F2 isoprostanes were abolished or attenuated.. We conclude that depletion of glutathione in selenium-deficient liver and kidney leads to necrosis in those organs associated with evidence of lipid peroxidation. Protection against this injury by selenium correlates with selenoprotein P concentration in plasma but not with glutathione peroxidase activity in tissues or in plasma. These findings raise the possibility that selenoprotein P protects cell membranes against oxidant injury and that glutathione is involved in that protection.

Topics: Animals; Buthionine Sulfoximine; Dinoprost; Glutathione; Ketones; Kidney; Lipid Peroxides; Liver; Male; Maleates; Methionine Sulfoximine; Necrosis; Osmolar Concentration; Proteins; Rats; Rats, Sprague-Dawley; Selenium; Selenoprotein P; Selenoproteins

A dose of diquat below the amount injurious to selenium-replete animals causes lipid peroxidation and massive liver necrosis in selenium-deficient rats. The current study was undertaken to characterize the lipid peroxidation with respect to the liver injury and to correlate the presence of several selenoproteins with the protective effect of selenium. Lipid peroxidation was assessed by measurement of F2 isoprostanes. Diquat caused an increase in liver and plasma F2 isoprotanes. A gradient of these compounds was detected across the liver in some animals, indicating that this organ was a source of some of the plasma F2 isoprostanes. A time-course experiment showed that liver F2 isoprostane concentration increased before plasma alanine transaminase (ALT) levels rose. Selenium-deficient rats were injected with selenium doses from 2 to 50 micrograms/kg and studied 12 hours later. A dose of 10 micrograms/kg or more prevented diquat-induced lipid peroxidation and liver injury. This dose increased plasma selenoprotein P substantially, and a dose-response was present. Liver cellular and plasma glutathione peroxidase activities remained below 2% of their values in control rats for all selenium doses. In selenium-deficient rats given diquat, hepatic lipid peroxidation precedes hepatic necrosis and could therefore be an important mechanism of the necrosis. Selenoprotein P levels were increased by selenium injections, which protected against diquat injury, but glutathione peroxidase activity was not increased. This is consistent with selenoprotein P being the mediator of the selenium effect.

Topics: Animals; Carbon Tetrachloride; Dinoprost; Diquat; Dose-Response Relationship, Drug; Lipid Peroxidation; Liver; Male; Necrosis; Proteins; Rats; Rats, Sprague-Dawley; Selenium; Selenoprotein P; Selenoproteins

The purpose of the study was to evaluate the effects of drug therapy on the throphoblast and on the tubal wall when protaglandin F2 alpha (PGF2 alpha) was administered in cases of tubal pregnancies. 42 patients were divided into two groups: women of group I (n = 30) were secondarily treated by surgery because of raising serum HCG levels. Group II (n = 12) consisted of patients who were operated on because of acute symptoms (abdominal pains, intraabdominal haemorrhage), despite already failing HCG values. In group I in 66% (n = 20) of the histological specimens an intact (vital) trophoblast was found. Five cases (17%) showed partly necrotic gestational tissue, whereas in another five cases (17%) the whole trophoblast was necrotic. In patients of group II all ectopic pregnancies showed histological signs of necrosis. In the histopathology of the Fallopian tubes no signs of trophic regression could be found. However, ten out of 22 cases showed ruptured tubal pregnancies. In this analysis we could show that the instillation of PGF2a electively destroys the ectopic trophoblast and does not exercise any necrotic action on the tubal wall.

Topics: Abortifacient Agents, Nonsteroidal; Adult; Combined Modality Therapy; Dinoprost; Fallopian Tubes; Female; Humans; Injections, Intralesional; Laparoscopy; Necrosis; Pregnancy; Pregnancy, Tubal; Rupture, Spontaneous; Trophoblasts

Changes in endogenous pancreas production of prostaglandins D2, F2 alpha, E2, and E1 in early stages of acute necrotizing pancreatitis induced by intraductal administration of 3.5% sodium taurocholate have been determined by radioimmunoassay of chromatographically purified tissue extracts. For this purpose 18 male Wistar rats were randomized in three groups: control, pancreatitis, and pancreatitis plus indomethacin. Pancreas tissue samples were obtained 5 min after pancreatitis induction. In the pancreatitis-induced group, prostaglandins D2, F2 alpha, and E2 show significantly increased tissue levels relative to the controls whereas prostaglandin E1 remains unmodified. These results suggest a role for series 2 prostaglandins in the earlier stages of pancreatitis.

Topics: Acute Disease; Alprostadil; Amylases; Animals; Dinoprost; Dinoprostone; Hemorrhage; Indomethacin; Lipase; Male; Necrosis; Pancreas; Pancreatitis; Prostaglandin D2; Prostaglandins; Rats; Rats, Wistar; Taurocholic Acid

Cytoprotective effects of the prostaglandins 16,16-dimethyl PGE2 (dmPGE2) and PGF2 alpha tromethamine (PGF2 alpha) were evaluated in the rat model of acute hepatocellular necrosis induced by thioacetamide (TAA). dmPGE2 (100 micrograms/kg SC 8 hourly) did not induce a significant increase in survival when started after the onset of TAA-induced fulminant hepatic failure. However, priming with dmPGE2 (100 micrograms/kg SC 30 min before TAA) reduced TAA-induced elevations in serum ALT (684 +/- 68 (SEM) vs 274 +/- 135 IU/1, p less than 0.01). This phenomenon did not occur if dmPGE2 was administered after TAA or by the IP route. Modulation of TAA-induced centrizonal hepatocellular necrosis by dmPGE2 was associated with a striking increase in centrizonal ballooning of hepatocytes (p less than 0.01), and, as assessed by stereology, less hepatocellular necrosis and degenerative changes. PGF2 alpha, which in contrast to dmPGE2 does not act via cAMP, had no effect on TAA-induced changes in serum ALT or hepatic histology. These findings suggest that dmPGE2 decreases hepatocellular necrosis by activating surface membrane adenylate cyclase and consequently stimulating cAMP. Ballooning of hepatocytes could occur secondary to these membrane events and appears to be a marker of dmPGE2-induced cytoprotection in this model.

Topics: 16,16-Dimethylprostaglandin E2; Alanine Transaminase; Animals; Dinoprost; Hepatic Encephalopathy; Liver; Male; Necrosis; Rats; Rats, Sprague-Dawley; Thioacetamide

Exogenous thiol compounds have been reported to protect the stomach from ethanol-induced necrotic lesions. The gastric mucosa contains high levels of an endogenous thiol, glutathion (GSH). Because of the known role of glutathione in protecting against hepatic injury, its role in gastric mucosal cytoprotection was of interest. By use of an animal model for acute gastric injury from ethanol, a close parallel relation between depletion of endogenous mucosal GSH and induction of mucosal protection was demonstrated. Surprisingly, mucosal protection varied inversely with the level of mucosal GSH obtained after treatment with specific GSH-depleting agents (diethyl maleate and cyclohexene-1-one). Depletion of gastric mucosal GSH was associated with an increase in the mucosal content of prostaglandins 6-keto F1 alpha and F2 alpha but not E2. The protective effect induced by GSH-depleting agents was partially reversed by indomethacin in some but not all studies. Although GSH depletors increased gastric juice volume, protection with these agents persisted after the volume and mucosal GSH had returned to control levels and also was not reversed by increasing the dose of ethanol threefold to overcome a possible dilutional effect. We conclude that, contrary to apparent predictions, depletion of endogenous gastric GSH protects the stomach from acute ethanol-induced injury. Although the mechanism of this protection is unknown, a mediation by endogenous release of prostaglandins seems to play a minor role since diethyl maleate was protective even in indomethacin-treated animals.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclohexanones; Dinoprost; Dinoprostone; Ethanol; Gastric Mucosa; Glutathione; Indomethacin; Male; Maleates; Necrosis; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains

Placentae from 23 patients whose midtrimester therapeutic abortions were induced by the prostaglandin (PG) F2 alpha were examined microscopically. In a majority of the cases, the predominant finding was severe decidual necrosis. Different quantities of edematous villi, with or without congestion, containing swollen stromal Hofbauer cells, were found along with trophoblastic necrosis and subchorionic intervillous thrombosis. The amniotic epithelium, however, had usually not degenerated in spite of the intraamniotic injection of PGF2 alpha. These findings were compared with the histological findings described in placentae from 18 cases of midtrimester spontaneous abortions with normal fetuses. It seems that prostaglandins used in midtrimester abortion affect the placental membranes to a lesser degree than do hypertonic solutions. These findings might explain the fewer maternal complications in PGF2 alpha midtrimester abortions. The significance of decidual changes and their role in the production of maternal complications is unknown.

Topics: Abortion, Induced; Dinoprost; Female; Humans; Necrosis; Placenta; Pregnancy; Pregnancy Trimester, Second; Prostaglandins F

To examine the role of prostaglandins and the kallikrein system in the recovery from acute renal failure, we studied the sequential changes in urinary prostaglandins and kallikrein after the onset of oliguria. The six patients studied had acute tubular necrosis of the vasomotor type. Urinary PGE2, PGF2 alpha, the PGF2 alpha-main urinary metabolite, 6-keto-PGF1 alpha and TXB2 were all measured by radioimmunoassay. Urinary kallikrein was assayed by means of hydrolytic activity using a chromogenic tripeptide substrate. Following onset of diuresis, urinary PGE2 excretion was increased to normal, parallel to the increase in urine volume. In contrast, the ratio of urinary PGF2 alpha/PGE2 peaked at the onset of diuresis, indicating a relative increase in PGF2 alpha production at this time. Prior to this peak, urinary kallikrein concentrations reached the highest levels, suggesting a close connection with renal prostaglandin metabolism. On the other hand, changes in PGF2 alpha-MUM, 6-keto-PGF1 alpha and TXB2 were not found. These results indicate that there may be an interlocking acute alteration of the kallikrein-prostaglandin system occurring immediately before the resolution of oliguria, although the role of the acute shift to PGF2 alpha production observed needs further study.

Topics: Acute Kidney Injury; Adult; Aged; Dinoprost; Dinoprostone; Diuresis; Humans; Kallikreins; Kidney Tubules; Middle Aged; Necrosis; Prostaglandins; Prostaglandins E; Prostaglandins F