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ABSTRACT: Carbonate aggregates in Late Cretaceous lamprophyre dikes of the northeastern Transdanubian Central Range (TCR) in Northwest
Hungary have been classified into three genetic groups. Type-I dolomite + calcite ± magnesite aggregates have petrographic
and geochemical features similar to ocelli described by other workers. Fluid inclusions in Type-I aggregates homogenize between
77 and 204 °C and are of hydrothermal origin. Type-II aggregates are characterized by a polygonal shape and are mostly dolomite.
Based on their shape and primary fluid inclusions which homogenize between 95 and 172 °C, these carbonate aggregates are interpreted
to fill vugs produced by the dissolution of olivine phenocrysts. Type-III carbonate aggregates show an irregular to polygonal
shape and distinct compositional zonation and contain secondary aqueous fluid inclusions. Homogenization temperatures of fluid
inclusions are below 104 °C, and zonation patterns suggest partial recrystallization. These carbonate aggregates are most
likely xenoliths and xenocrysts from the wall rocks of the lamprophyre melt conduits.
Mineralogy and Petrology 04/2012; 88(3):479-497. · 1.28 Impact Factor
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ABSTRACT: An algebra A has finite degree if its term functions are determined by some finite set of finitary relations onA. We study this concept for finite algebras in general and for finite semigroups in particular. For example, we show that
every finite nilpotent semigroup has finite degree (more generally, every finite algebra with bounded p
n
-sequence), and every finite commutative semigroup has finite degree. We give an example of a five-element unary semigroup
that has infinite degree. We also give examples to show that finite degree is not preserved in general under taking subalgebras,
homomorphic images, direct products or subdirect factors.
KeywordsSemigroup–Term functions–Clone–Finite degree–Finitely related
Agronomy Journal 04/2012; 83(1):89-110. · 0.73 Impact Factor
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ABSTRACT: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding protein, which is primarily activated by nicks in the DNA molecule.
It regulates the activity of various enzymes, including itself, and those involved in the control of DNA metabolism. Upon
binding to DNA breaks, activated PARP cleaves NAD
+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins including histones, transcription
factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. Evidence
obtained with pharmacological PARP inhibitors of various structural classes, as well as animals lacking the PARP-1 enzyme
indicate that PARP plays an important role in cerebral ischemia/reperfusion, stroke, neurotrauma, neuroinjury, and neurodegeneration.
Overactivation of PARP consumes NAD
+ and ATP culminating in cell dysfunction and necrosis. PARP activation can also act as a signal that initiates cell death
programs, for instance through apoptosis-inducing factor (AIF) translocation. PARP has also been shown to associate with and
regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor (NF)-κB-mediated
transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and
inflammatory mediators. Via this mechanism, PARP is involved in the upregulation of numerous proinflammatory genes that play
a pathogenetic role in the later stage of central nervous system (CNS) diseases. Here, we review the roles of PARP in DNA
damage signaling and cell death and summarize the pathogenetic role of PARP in neuroinflammation and neuroinjury.
12/2007: pages 427-466;
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ABSTRACT: We present a detailed textural and compositional study of two orthopyroxene-rich olivine websterites. One occurs as a vein
in a harzburgite xenolith and the other is an individual xenolith, both found at Szentbékkálla in the Bakony–Balaton Highland
Volcanic Field (central Pannonian Basin, western Hungary). The textural features of these orthopyroxene-rich rocks suggest
that they crystallized from silicate melts to form veins in peridotite mantle rock. Their geochemical features, such as the
presence of Al2O3-poor orthopyroxenes, Cr-rich spinels, and clinopyroxenes with U-shaped chondrite-normalized REE-patterns, indicate that the
vein material formed from Mg-rich silicic (boninitic) melts at mantle depths. The olivine fabric investigation of both the
veins and the wall-rock suggest that the development of the veins was followed by subsequent recrystallization during the
Cenozoic evolution of the Carpathian–Pannonian region.
Mineralogy and Petrology 01/2007; 90(1):51-72. · 1.28 Impact Factor
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ABSTRACT: Two, 42-day feeding experiments were carried out in aquaria working in a recirculation system, to determine the influence of the different dietary fat levels and fat sources on the growth and body composition of pikeperch fingerlings. In the first experiment three levels of dietary fat (F0: 60; F1: 120; F2: 180 g kg−1) were tested, compared with a commercial diet (Trouvit, 240 g kg−1 fat content). F1 and F2 were formulated by adding fish oil. Best growing and feed conversion ratio was obtained with the commercial control diet, which produced also the highest total body fat (117 g kg−1) while respective values of fish fed on the other three diets varied between 74.1 and 85.1 g kg−1. Different feeds had no significant differences in crude protein content of the fish body. In the second test, besides feeds F0, F1 and F2, two additional feeds were formulated containing 127 g kg−1 (L1) and 178 g kg−1 (L2) crude fat (from linseed oil). Dietary fat levels and fat sources had significant effect neither on growth nor on feed conversion ratio. Chemical composition of the whole body did not change significantly due to the different feeds. Linseed oil had a decreasing effect on the sum of saturated fatty acids and increased the oleic and the α-linoleic acid proportions in fillet. However, total polyunsaturated fatty acid (PUFA) proportion remained constant.
Aquaculture Nutrition 05/2006; 12(3):173 - 182. · 2.18 Impact Factor
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ABSTRACT: Abundant upper mantle and rare lower crustal xenoliths have been found in the Plio-Pleistocene alkali basalts of the Nógrád-Gömör
Volcanic Field, situated in the northern Pannonian Basin, on the border between northern Hungary and southern Slovakia. A
few lower crustal granulite xenoliths have been found in a small basaltic pyroclastic cone at Baglyaskő. The mafic granulite
xenoliths are plagioclase-bearing hornblende clinopyroxenites, plagioclase-bearing clinopyroxene hornblendites and plagioclase-bearing
clinopyroxenites. They contain unusual symplectites, composed of spinel feldspar and clinopyroxene. These symplectites are
interpreted as the product of garnet breakdown. Following the breakdown reaction, the symplectite underwent in situ partial melting. Mineral constituents of these granulite xenoliths have chemical compositions similar to those of other granulite
xenoliths worldwide. However, a distinctive positive Pb and Ce anomaly in mineral constituents of these granulites is characteristic.
Granulite xenoliths from the Nógrád-Gömör Volcanic Field must have experienced granulite facies metamorphism at pressures
that correspond to the ‘original’ thickness of the crust (>1.1 GPa; >∼30 km), whereas the breakdown reaction of garnet and
subsequent melting and recrystallization of clinopyroxenes in the symplectites happened at shallower depths close to the present-day
MOHO (0.6–0.7 GPa; ∼16–19 km).
Mineralogy and Petrology 11/2005; 85(3):269-290. · 1.28 Impact Factor
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ABSTRACT: PARP-1 is a nuclear enzyme activated by DNA breaks. Activated PARP-1 cleaves NAD into nicotinamide and ADP-ribose and polymerizes the latter covalently coupled to nuclear acceptor proteins. Poly(ADP-ribosyl)ation has been implicated in the regulation of a diverse array of cellular processes ranging from DNA repair, chromatin organization, transcription, replication to protein degradation. On the 'dark side' of poly(ADP-ribosyl)ation, PARP-1 activation has been shown to contribute to tissue injury in shock, diabetes, myocardial or cerebral ischemia reperfusion and various forms of inflammation, as proven by pharmacological studies as well as experiments utilizing PARP-1 knockout animals. To our current knowledge, two mechanisms are responsible for the beneficial effects of PARP inhibitors in inflammatory, neurodegenerative and ischemia-reperfusion-based diseases: (i) inhibition of cell death caused by over-activation of PARP-1; (ii) inhibition of inflammatory signal transduction and production of inflammatory mediators. Here we review the possible regulatory mechanisms (e.g. calcium signaling, metabolism, density-dependent signaling, kinase cascades) of the PARP-1-mediated cell death pathway and discuss recent developments shedding new light on the complex role of PARP-1 in the regulation of the expression of inflammatory mediators.
Cellular and Molecular Life Sciences CMLS 05/2005; 62(7-8):751-9. · 6.57 Impact Factor
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ABSTRACT: The stimulation of epithelial cells by cytokines or lipopolysaccharide results in a marked increase in cellular mRNA and protein levels of inducible nitric oxide synthase (iNOS) disproportionate to the small upregulation in transcriptional activity. The molecular mechanisms by which cytokines increase iNOS expression are not well characterized.
DLD-1 cells were treated with cytokines and we studied the expression patterns of various genes by using western blot analysis and RT-PCR assay method.
Expression levels of iNOS protein were detected after 4 h of incubation with cytokines and reached a peak at 10 h. After cytokine treatment, iNOS mRNA molecules received longer poly(A) tails (200-500 adenosine residues) and total iNOS mRNA levels also increased significantly. Western blot analysis revealed that poly(A) polymerase (PAP) undergoes a significant dephosphorylation process. At the same time, cytokines have no significant effect on the expression pattern of other factors involved in polyadenylation.
Cytokines appear to induce elongation of iNOS mRNA poly(A) tail length by activating PAP. These results indicate a novel link between mRNA 3' end formation and iNOS gene expression.
Inflammation Research 12/2004; 53(11):604-8. · 2.11 Impact Factor
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ABSTRACT: Xenoliths from the upper mantle and lower crust are abundant in Plio–Pleistocene alkali basalts of the Nó grád-Gfmfr Volcanic Field (NGVF; northern Pannonian Basin, northern Hungary/southern Slovakia), representing a valuable dprobe' of lithospheric structures and processes. Ultramafic xenoliths have been divided into two groups: (1) Type-I, composed mostly of olivine with subsidiary orthopyroxene, clinopyroxene and spinel, and (2) Type-II, containing mostly Al-and Ti-rich clinopyroxene with subordinate olivine, spinel and plagioclase. Both types often contain amphibole and, to a lesser extent, mica. The refractory character of Type-I xenoliths suggests they represent mantle depleted by prior episodes of partial melting. In contrast, Type-II series (wehrlites, olivine clinopyroxenites, clinopyroxenites and plagioclase-bearing ultramafic lithologies), on the basis of their textural features, thermobarometric histories and major and trace element variation, appear to have formed as magmatic cumulates. Petrologic and geochemical studies of Type-II xenoliths from Nó grád-Gfmfr suggest they crystallized from basaltic melts emplaced within the lithospheric mantle and lower crust, prior to the onset of Plio–Pleistocene volcanic activity. After their consolidation, metasomatic agents reacted with the anhydrous cumulate phases producing amphiboles and micas at the expense of olivine and clinopyroxene. The metasomatic agents appear to have been adakitic rather than basaltic in composition, possibly linked to a retreating arc–forearc system. Large-scale contamination of the lithospheric mantle can therefore be attributed to fluid and melt fractions related to subduction beneath the outer Carpathian arc. D 2004 Elsevier B.V. All rights reserved.
10/2004;
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ABSTRACT: Poly(ADP-ribose) polymerase activation depletes NAD+ and high-energy phosphates, activates protein kinase C, and affects gene expression in various tissues. This study was designed to characterise the effects of the potent, orally active poly(ADP-ribose) polymerase inhibitor PJ34 in the Wistar rat model of early diabetic neuropathy.
Control and streptozotocin-diabetic rats were maintained with or without PJ34 treatment (30 mg x kg(-1) x day(-1)) for two weeks, after two weeks without treatment. Endoneurial blood flow was assessed by hydrogen clearance; metabolites and high-energy phosphates were assayed by enzymatic spectrofluorometric methods; and poly(ADP-ribose) was detected by immunohistochemistry.
Blood glucose concentrations were increased to a similar extent in untreated and PJ34-treated diabetic rats compared with controls. Intense poly(ADP-ribose) immunostaining was observed in the sciatic nerve of diabetic rats, but not in other groups. Final sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced by 24% and 22% respectively in diabetic rats compared with controls (p<0.01 for both), and both were 98% corrected by PJ34 (p<0.01 vs diabetic group for both). In contrast, with PJ34 treatment, nerve blood flow showed a modest (17%) increase, and vascular conductance showed a tendency to increase. Free mitochondrial and cytosolic NAD+:NADH ratios, assessed from the glutamate and lactate dehydrogenase systems, phosphocreatine concentrations, and phosphocreatine:creatine ratios were decreased in diabetic rats and essentially normalised by PJ34. In both untreated and PJ34-treated diabetic rats, nerve glucose, sorbitol and fructose were increased to a similar extent. PJ34 did not affect any variables in control rats.
Short-term poly(ADP-ribose) polymerase inhibitor treatment reverses functional and metabolic abnormalities of early diabetic neuropathy. Complete normalisation of nerve blood flow is not required for correction of motor or sensory nerve conduction velocities, provided that a therapeutic agent can restore nerve energy state via direct action on Schwann cells.
Diabetologia 04/2004; 47(4):710-7. · 6.81 Impact Factor
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ABSTRACT: The aim of the present study was to test the effects of a topical administration of a novel nitric oxide donor, linear polyethylenimine-nitric oxide/nucleophile adduct (DS1), on vaginal blood flow and hemodynamics in rats. Laser Doppler flowmetry was used to measure blood flow changes following topical application of DS1 (0.3 or 1.5 mg in 0.15 ml saline) into the vagina of anesthetized Wistar rats. In vivo hemodynamic parameters were measured with Millar-tip-catheter placed in the left ventricle. DS1 (1.5 mg) increased vaginal blood flow by 191+/-24, 226+/-22 and 166+/-23% of the baseline value (at 5, 15 and 30 min, respectively, after application) without affecting systemic blood pressure, heart rate and cardiac function. The increased vaginal blood flow following DS1 application returned to baseline between 45 and 60 min. Thus, topical application of nitric oxide donors such as DS1 may be useful for the treatment of female sexual dysfunction that develops due to an impairment of local blood flow supply to the vaginal tissue.
International Journal of Impotence Research 01/2004; 15(6):461-4. · 1.71 Impact Factor
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ABSTRACT: We have investigated the role of the activation of nuclear poly(ADP-ribose) polymerase (PARP) enzyme, a mediator of downstream nitric oxide toxicity, using a combined approach of pharmacological inhibition and genetic disruption in a ligature-induced-periodontitis model in rats and mice. Immunohistochemical analysis revealed significantly increased poly(ADP-ribose) nuclear staining (indicative of PARP activation) in the subepithelial connective tissue of the ligated side compared with the non-ligated side. Ligation-induced periodontitis resulted in marked plasma extravasation in the gingivomucosal tissue and led to alveolar bone destruction compared with the non-ligated side, as measured by the Evans blue technique and by videomicroscopy, respectively. PARP inhibition with PJ34, as well as genetic PARP-1 deficiency, significantly reduced the extravasation and the alveolar bone resorption of the ligated side compared with controls. Thus, PARP activation contributes to the development of periodontal injury. Inhibition of PARP may represent a novel host response modulatory approach for the therapy of periodontitis.
Journal of Dental Research 01/2004; 82(12):987-92. · 3.49 Impact Factor
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ABSTRACT: Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic beta-cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NFkappaB. Inhibition of the entire NFkappaB family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NFkappaB subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NFkappaB subunit, p50, in the development of IDDM, mice with gene disruption for NFkappaB (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NFkappaB (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NFkappaB (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NFkappaB (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.
Journal of Endocrinology 07/2002; 173(3):457-64. · 3.55 Impact Factor
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ABSTRACT: Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury in conditions associated with oxidative stress. Increased oxidative stress is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), a widely used antitumor anthracycline antibiotic. Thus, we hypothesized that the activation of PARP may contribute to the DOX-induced cardiotoxicity. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ34, we now demonstrate the role of PARP in the development of cardiac dysfunction induced by DOX. PARP-1+/+ and PARP-1-/- mice received a single injection of DOX (25 mg/kg i.p). Five days after DOX administration, left ventricular performance was significantly depressed in PARP-1+/+ mice, but only to a smaller extent in PARP-1-/- ones. Similar experiments were conducted in BALB/c mice treated with PJ34 or vehicle. Treatment with a PJ34 significantly improved cardiac dysfunction and increased the survival of the animals. In addition PJ34 significantly reduced the DOX-induced increase in the serum lactate dehydrogenase and creatine kinase activities but not metalloproteinase activation in the heart. Thus, PARP activation contributes to the cardiotoxicity of DOX. PARP inhibitors may exert protective effects against the development of severe cardiac complications associated with the DOX treatment.
Journal of Pharmacology and Experimental Therapeutics 04/2002; 300(3):862-7. · 3.83 Impact Factor
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ABSTRACT: Nicotine has been previously shown to have immunosuppressive actions. Type I diabetes is an autoimmune disease resulting from the specific destruction of the insulin-producing pancreatic beta-cells. Thus, we hypothesized that nicotine may exert protective effects against type I diabetes. The multiple low-dose streptozotocin (MLDS)-induced model and spontaneous nonobese diabetic (NOD) mouse model of type I diabetes were used to assess whether nicotine could prevent this autoimmune disease. Blood glucose levels, diabetes incidence, pancreas insulin content, and cytokine levels were measured in both models of diabetes, both to asses the level of protection exerted by nicotine and to further investigate its mechanism of action. Nicotine treatment reduced the hyperglycemia and incidence of disease in both the MLDS and NOD mouse models of diabetes. Nicotine also protected against the diabetes-induced decrease in pancreatic insulin content observed in both animal models. The pancreatic levels of the Th1 cytokines interleukin (IL)-12, IL-1, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were increased in both MLDS-induced and spontaneous NOD diabetes, an effect prevented by nicotine treatment. Nicotine treatment increased the pancreatic levels of the Th2 cytokines IL-4 and IL-10. Nicotine treatment reduces the incidence of type I diabetes in two animal models by changing the profile of pancreatic cytokine expression from Th1 to Th2.
Journal of Pharmacology and Experimental Therapeutics 04/2002; 300(3):876-81. · 3.83 Impact Factor
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ABSTRACT: Inosine is an endogenous purine, which has been recently shown to exert immunomodulatory, anti-inflammatory and anti-shock effects in rodent experimental systems. Some of these actions may be related to partial adenosine receptor agonistic effects. It has not been investigated previously whether inosine exerts similar immunomodulatory or anti-inflammatory effects in human cells or enzymes. Here we investigated the effects of inosine on the activation of human monocytes, neutrophils and epithelial cells in vitro. Furthermore, using a human inosine-5'-monophosphate dehydrogenase (IMPDH) enzyme, we examined the potential effects of inosine on the activity of IMPDH, an enzyme involved in the regulation of certain inflammatory/immune processes. Tumor necrosis factor alpha (TNF-alpha) production of bacterial lipopolysaccharide (LPS) stimulated whole blood was used as an indicator of human monocyte activation. The response was dose-dependently, partially suppressed in the presence of inosine. Inosine exerted a dose-dependent and, at the highest dose (3 mM), complete inhibition of the ability of human neutrophils activated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) to induce cytochrome C reduction in vitro. In the human colon cancer cell line HT-29, inosine dose-dependently attenuated the production of IL-8. Inosine failed to affect the activity of IMPDH. Taken together, we conclude that inosine exerts anti-inflammatory effects in many human cell types. Further studies need to establish whether inosine supplementation exerts anti-inflammatory effects in human beings.
International Journal of Molecular Medicine 01/2002; 8(6):617-21. · 1.98 Impact Factor
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ABSTRACT: The proinflammatory cytokines, interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and interferon gamma (IFNgamma), are cytotoxic to pancreatic islet beta cells, possibly by inducing nitric oxide and/or oxygen radical production in the beta cells. Peroxynitrite, the reaction product of nitric oxide and the superoxide radical, is a strong oxidant and cytotoxic mediator; therefore, we hypothesized that peroxynitrite might be a mediator of cytokine-induced islet beta-cell destruction. To test this hypothesis we incubated islets isolated from human pancreata with the cytokine combination of IL-1beta, TNFalpha, and IFNgamma. We found that these cytokines induced significant increases in nitrotyrosine, a marker of peroxynitrite, in islet beta cells, and the increase in nitrotyrosine preceded islet-cell destruction. Peroxynitrite mimicked the effects of cytokines on nitrotyrosine formation and islet beta-cell destruction. L-N(G)-monomethyl arginine, an inhibitor of nitric oxide synthase, prevented cytokine-induced nitric oxide production but not hydrogen peroxide production, nitrotyrosine formation, or islet beta-cell destruction. In contrast, guanidinoethyldisulphide, an inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite, prevented cytokine-induced nitric oxide and hydrogen peroxide production, nitrotyrosine formation, and islet beta-cell destruction. These results suggest that cytokine-induced peroxynitrite formation is dependent upon increased generation of superoxide (measured as hydrogen peroxide) and that peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells.
Laboratory Investigation 01/2002; 81(12):1683-92. · 3.64 Impact Factor
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ABSTRACT: We investigated the role of the inducible isoform of cyclooxygenase (COX-2) in a rat model of periodontitis using a selective COX-2 inhibitor NS-398. Periodontitis was produced by a silk ligature placed around the lower left 1st molar. Animals were treated with NS-398 (3 mg kg(-1) i.p., 2 times per day for 7 days) or vehicle. At Day 8, the gingivomucosal tissues encircling the mandibular 1st molars were removed on both sides for COX-2 immunohistochemistry, measurement of plasma extravasation by the Evans blue technique, and alveolar bone loss by videomicroscopy. Immunohistochemical analysis revealed numerous strongly COX-2-positive cells in the subepithelial tissues in the ligated side and only a few COX-2-reactive cells in the contralateral (control) side. Ligation significantly increased Evans blue extravasation in the gingivomucosal tissue and alveolar bone destruction compared to the control side. NS-398 treatment significantly reduced the plasma extravasation and alveolar bone resorption of the ligated side compared to vehicle administration. The present results suggest that COX-2 is induced by periodontitis, and plays an important role in gingival inflammation and alveolar bone destruction. In a previous study (Br J Pharmacol 1998;123:353-60) we found the expression of the inducible isoform of nitric oxide synthase in this model. Therefore, based on our own data and the literature, we propose that selective inhibition of these inducible enzymes might be a basis for adjunctive therapy, or new therapeutic approaches in periodontitis.
Life Sciences 01/2002; 70(3):279-90. · 2.53 Impact Factor
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J G Mabley,
P Jagtap,
M Perretti,
S J Getting,
A L Salzman,
L Virág,
E Szabó,
F G Soriano,
L Liaudet,
G E Abdelkarim,
G Haskó,
A Marton,
G J Southan, C Szabó
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ABSTRACT: Oxygen- and nitrogen-derived free radicals and oxidants play an important role in the pathogenesis of various forms of inflammation. Recent work emphasizes the importance of oxidant-induced DNA strand breakage and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in the pathogenesis of various inflammatory diseases. We have recently demonstrated the efficacy of PJ34, a novel, potent phenanthridinone derivative PARP inhibitor, in rodent models of diabetic vascular dysfunction and stroke. Here we tested the efficacy of PARP inhibition in various models of local inflammation in rodents.
PJ34 (at doses of 0.03-30 mg/kg) was tested in rats and mice subjected to standard models of inflammation, with relevant parameters of inflammation measured using standard methods.
PJ34 treatment (s.c, i.p. and i.v.) dose-dependently suppressed neutrophil infiltration and nitric oxide (but not KC and IL-1beta) production in peritonitis. In a model of systemic endotoxemia, PJ34 pretreatment significantly reduced plasma levels of TNF-alpha, IL-1beta and nitrite/nitrate (breakdown products of nitric oxide) production. PJ34 treatment (oral gavage) induced a significant suppression of the inflammatory response in dextran sulfate colitis, multiple low dose streptozotocin diabetes and cyclophosphamide-accelerated autoimmune diabetes in the non-obese diabetic mice, and reduced the degree of mononuclear cell infiltration into the iris in an endotoxin-induced uveitis model. Delaying the start of PJ34 administration in the colitis model conferred significant protective effects, while in the arthritis model the post-treatment paradigm lacked protective effects.
PJ34 provides significant, dose-dependent, anti-inflammatory effects in a variety of local inflammation models. Some of its actions are maintained in the post-treatment regimen and/or after discontinuation of treatment. We conclude that PARP inhibition offers a powerful means for reducing the severity of various forms of local inflammatory responses.
Inflammation Research 12/2001; 50(11):561-9. · 2.11 Impact Factor
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ABSTRACT: Inosine is a naturally occurring purine formed from the breakdown of adenosine. Here we have evaluated the effects of inosine in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice subjected to CLP were treated with either inosine (100 mg/kg, intraperitoneally) or vehicle 1 h before and 6 h after CLP. After 12 h tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-10 were measured in plasma. Biochemical markers of organ damage, liver NAD+/NADH (indicator of the mitochondrial redox state), plasma nitrate, tissue myeloperoxidase (MPO, indicator of neutrophil accumulation) and malondialdehyde (MDA, indicator of lipid peroxidation), liver and lung chemokines (macrophage inflammatory protein 1alpha [MIP-1alpha] and MIP-2), and ex vivo vascular reactivity in aortic rings were also measured. Mice treated with inosine had significantly lower levels of circulating cytokines. Organ damage was significantly reduced by inosine treatment, which was associated at the tissue level with an increased hepatic NAD+/NADH ratio, decreased MPO activity in the lung, reduced MDA formation in the gut and liver, and decreased MIP-1alpha and MIP-2 in the lung and liver. Furthermore, inosine significantly improved endothelium-dependent relaxant responses of aortic rings. These effects were associated with significant improvement of the survival of CLP mice treated with inosine, an effect that was still observed when inosine treatment was delayed 1 h after CLP, especially when it was associated with appropriate antibiotic treatment. Thus, inosine reduced systemic inflammation, organ damage, tissue dysoxia, and vascular dysfunction, resulting in improved survival in septic shock.
American Journal of Respiratory and Critical Care Medicine 11/2001; 164(7):1213-20. · 11.08 Impact Factor
