Erzsebet Osz

Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock

The lack of efficacy of anti-inflammatory drugs, anti-coagulants, anti-oxidants, etc. in critically ill patients has shifted interest towards developing alternative treatments. Since inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) were found to be beneficial in many pathophysiological conditions associated with oxidative stress and PARP-1 knock-out mice proved to be resistant to bacterial lipopolysaccharide (LPS)-induced septic shock, PARP inhibitors are candidates for such a role. In this study, the mechanism of the protective effect of a potent PARP-1 inhibitor, PJ34 was studied in LPS-induced (20mg/kg, i.p.) septic shock in mice. We demonstrated a significant inflammatory response by magnetic resonance imaging in the dorsal subcutaneous region, in the abdominal regions around the kidneys and in the inter-intestinal cavities. We have found necrotic and apoptotic histological changes as well as obstructed blood vessels in the liver and small intestine. Additionally, we have detected elevated tumor necrosis factor-alpha levels in the serum and nuclear factor kappa B activation in liver of LPS-treated mice. Pre-treating the animals with PJ34 (10mg/kg, i.p.), before the LPS challenge, besides rescuing the animals from LPS-induced death, attenuated all these changes presumably by activating the phosphatidylinositol 3-kinase-Akt/protein kinase B cytoprotective pathway.

BGP-15 — a novel poly(ADP-ribose) polymerase inhibitor — protects against nephrotoxicity of cisplatin without compromising its antitumor activity

Nephrotoxicity is one of the major dose limiting side effects of cisplatin chemotherapy. The antitumor and toxic effects are mediated in part by different mechanisms, thus, permitting a selective inhibition of certain side effects. The influence of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) - a poly(ADP-ribose) polymerase (PARP) inhibitor - on the nephrotoxicity and antitumor efficacy of cisplatin has been evaluated in experimental models. BGP-15 either blocked or significantly reduced (60-90% in 100-200 mg/kg oral dose) cisplatin induced increase in serum urea and creatinine level in mice and rats and prevented the structural degeneration of the kidney, as well. The nephroprotective effect of BGP-15 treatment was revealed also in living mice by MRI analysis manifesting in the lack of oedema which otherwise developed as a result of cisplatin treatment. The protective effect was accompanied by inhibition of cisplatin-induced poly-ADP-ribosylation and by the restoration of the disturbed energy metabolism. The preservation of ATP level in the kidney was demonstrated in vivo by localized NMR spectroscopy. BGP-15 decreased cisplatin-induced ROS production in rat kidney mitochondria and improved the antioxidant status of the kidney in mice with cisplatin-induced nephropathy. In rat kidney, cisplatin caused a decrease in the level of Bcl-x, a mitochondrial protective protein, and this was normalized by BGP-15 treatment. On the other hand, BGP-15 did not inhibit the antitumor efficacy of cisplatin in cell culture and in transplantable solid tumors of mice. Treatment with BGP-15 increased the mean survival time of cisplatin-treated P-388 leukemia bearing mice from 13 to 19 days. PARP inhibitors have been demonstrated to diminish the consequences of free radical-induced damage, and this is related to the chemoprotective effect of BGP-15, a novel PARP inhibitor. Based on these results, we propose that BGP-15 represents a novel, non-thiol chemoprotective agent.

In vivo water quantification in mouse brain at 9.4 Tesla in a vasogenic edema model.

The aim of our study was to establish a simple in vivo method for water quantification in vasogenic edema, and provide data on imaging of mouse brain at 9.4 Tesla. Apparent T1 and spin density values determined by MRI were found to strongly correlate with the gravimetric water content of mouse brain undergoing cold injury. Using a two‐point calibration line between the spin density values for pure water and cortex of mouse brain, as well as the corresponding water contents in vivo, water could be quantified with satisfactory accuracy. Magn Reson Med 46:1246–1249, 2001.

Fast in vivo water quantification in rat brain oedema based on T1 measurement at high magnetic field

Summary.Summary. Background: In vivo water content determination based on magnetic resonance (MR) method is of importance in clinical practice as well as in animal studies to follow up the treatment given in order to reduce brain oedema. The methods proposed in the literature so far are largely time consuming. The aim of this study was to find a fast in vivo water quantification method having real advantage for patients suffering from critical conditions. Method: Cold injury was applied to provoke brain oedema in fourteen rats. T1 values of both the oedematous area and the contralateral normal cortex were determined by two independent methods 24 hours after the cold impact. First, from a series of images recorded by inversion recovery spin echo (IRSE) sequence and then by progressive saturation experiment performed by localised MR spectroscopy using stimulated echo acquisition mode (STEAM). To reduce the acquisition time, a two-element repetition time array was optimised for the STEAM experiment, whereas four inversion times were used for T1 mapping. Both methods were validated against gel phantoms with known T1 values. After the MR measurements the animals were sacrificed and the water contents of the regions of interest were determined by gravimetric wet-dry method. Findings: The reciprocals of the in vivo measured T1 values were correlated with the reciprocals of the brain water contents. STEAM experiment showed stronger correlation (r=0.96) than IRSE (r=0.93). In addition, STEAM provided more accurate T1 values in the phantom study. Determination of brain water content based on T1 measurement does work also at high magnetic field. Determination of brain water content by Magnetic Resonance Spectroscopy is feasible within 2 minutes. Interpretation: Using the presented fast method, water content can be determined within a couple of minutes in animal experiments as well as in the daily clinical practice.

Analysis of carotenoids in the fruits of Asparagus falcatus: Isolation of 5,6-diepikarpoxanthin

SummaryIn an investigation of carotenoids present in the fruits ofAsparagus falcatus capsanthin (1), capsorubin (2), 5,6-diepikarpoxanthin (7), capsanthin 5,6-epoxide (18), capsochrome (17), mutatoxanthin (19), antheraxanthin (11), and capsanthone (20) (Figure 1) have been isolated by preparative CLC and characterized by spectroscopic methods. On the basis of spectroscopic data the absolute configuration of 5,6-diepikarpoxanthin (7) was determined as 3S,5S,6S, which is identical with that occurring in samples originating from paprika andLilium.

Improved Solvent‐Free Synthesis and Structure Elucidation of (E)‐ and (Z)‐4‐(Arylmethylene)‐3‐isochromanones

A series of new 4-(arylmethylene)-3-isochromanones 1−17 has been prepared by base-catalyzed Knoevenagel condensations. Stereochemical and conformational analyses were performed by 1H and 13C NMR methods, and X-ray crystallography was used to complement the configurational assignment for a representative product. The reaction generally yields the (E) isomer, but the isomeric composition of the products was influenced by the aromatic aldehyde and usually governed by the stability of the products. Several aldehydes exclusively afforded the (Z) isomer, due to intramolecular steric/electronic interactions reflected in the increased stability of the product. The condensation performed with ortho-hydroxyarenecarbaldehydes furnished the unexpected 3-arylcoumarins or 3-arylbenzocoumarins. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)