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Balázs Kui Zsolt Balla Béla Vasas Eszter T. Végh Petra Pallagi Eszter S. Kormányos Viktória Venglovecz Béla Iványi Tamás Takács Péter Hegyi Zoltán Rakonczay Jr. 《PloS one》2015,10(2)
Animal models are ideal to study the pathomechanism and therapy of acute pancreatitis (AP). The use of L-arginine-induced AP model is nowadays becoming increasingly popular in mice. However, carefully looking through the literature, marked differences in disease severity could be observed. In fact, while setting up the L-arginine (2×4 g/kg i.p.)-induced AP model in BALB/c mice, we found a relatively low rate (around 15%) of pancreatic necrosis, whereas others have detected much higher rates (up to 55%). We suspected that this may be due to differences between mouse strains. We administered various concentrations (5–30%, pH = 7.4) and doses (2×4, 3×3, or 4×2.5 g/kg) of L-arginine-HCl in BALB/c, FVB/n and C57BL/6 mice. The potential gender-specific effect of L-arginine was investigated in C57BL/6 mice. The fate of mice in response to the i.p. injections of L arginine followed one of three courses. Some mice (1) developed severe AP or (2) remained AP-free by 72 h, whereas others (3) had to be euthanized (to avoid their death, which was caused by the high dose of L-arginine and not AP) within 12 h., In FVB/n and C57BL/6 mice, the pancreatic necrosis rate (about 50%) was significantly higher than that observed in BALB/c mice using 2×4 g/kg 10% L–arginine, but euthanasia was necessary in a large proportion of animals, The i.p. injection of lower L-arginine concentrations (e.g. 5–8%) in case of the 2×4 g/kg dose, or other L-arginine doses (3×3 or 4×2.5 g/kg, 10%) were better for inducing AP. We could not detect any significant differences between the AP severity of male and female mice. Taken together, when setting up the L-arginine-induced AP model, there are several important factors that are worth consideration such as the dose and concentration of the administered L arginine-HCl solution and also the strain of mice. 相似文献
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Doleviczényi Z Vizi ES Gacsályi I Pallagi K Volk B Hársing LG Halmos G Lendvai B Zelles T 《Neurochemical research》2008,33(11):2364-2372
In humans, serotonin (5-HT) has been implicated in numerous physiological and pathological processes in the peripheral auditory
system. Dopamine (DA), another transmitter of the lateral olivocochlear (LOC) efferents making synapses on cochlear nerve
dendrites, controls auditory nerve activation and protects the sensory nerve against overactivation. Using in vitro microvolume
superfusion techniques we tested 5-HT6 and 5-HT7 receptor antagonists whether they can influence dopamine (DA) release from the guinea-pig cochlea in control and in ischemic
conditions using currently available and new 5-HT6 and 5-HT7 antagonists and mixed antagonists, which were synthesized and characterized for the current study. While the 5-HT7 antagonist SB-258719 was ineffective, SB-271046, which blocks the 5-HT6 receptor, caused a significant increase in cochlear DA release what is contradictory with the excitatory nature of this type
of receptor. Moreover, the mixed 5-HT6/7 antagonist EGIS-12233 induced an even more pronounced increase in the resting DA release. To understand why the block of
an excitatory receptor results in an increase instead of a decrease in function, we investigated the possible involvement
of an indirect neural mechanism through an inhibitory system. In the presence of the GABAA receptor blocker bicuculline, EGIS-12233 failed to increase the release of DA, suggesting that the serotonin receptor modulation
of DA release from the lateral olivocochlear efferents in the cochlea was produced indirectly by decreasing the GABAergic
inhibitory tone on dopaminergic nerve endings. The mixed 5-HT7/D4 receptor antagonist EGIS-11983 significantly increased both the stimulation-evoked and the resting DA release, while the
selective D4 blocker L-741,741 alone had no significant effect. Ischemia, simulated by oxygen and glucose deprivation from
the perfusion solution had no action on the effect of the drugs. Drugs that can increase the release of DA from LOC terminals
in the cochlea may have a role in the treatment of sensorineural hearing loss. 相似文献
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Simon Trapp Ali A. Aghdassi Juliane Glaubitz Matthias Sendler Frank Ulrich Weiss Jens Peter Kühn Marie-Luise Kromrey Ujjwal M. Mahajan Petra Pallagi Zoltán Rakonczay Jr Viktória Venglovecz Markus M. Lerch Peter Hegyi Julia Mayerle 《Journal of cellular and molecular medicine》2021,25(10):4658-4670
Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) are an established risk factor for cystic fibrosis (CF) and chronic pancreatitis. Whereas patients with CF usually develop complete exocrine pancreatic insufficiency, pancreatitis patients with CFTR mutations have mostly preserved exocrine pancreatic function. We therefore used a strain of transgenic mice with significant residual CFTR function (CFTRtm1HGU) to induce pancreatitis experimentally by serial caerulein injections. Protease activation and necrosis were investigated in isolated acini, disease severity over 24h, pancreatic function by MRI, isolated duct stimulation and faecal chymotrypsin, and leucocyte function by ex vivo lipopolysaccharide (LPS) stimulation. Pancreatic and lung injury were more severe in CFTRtm1HGU but intrapancreatic trypsin and serum enzyme activities higher than in wild-type controls only at 8h, a time interval previously attributed to leucocyte infiltration. CCK-induced trypsin activation and necrosis in acini from CFTRtm1HGU did not differ from controls. Fluid and bicarbonate secretion were greatly impaired, whereas faecal chymotrypsin remained unchanged. LPS stimulation of splenocytes from CFTRtm1HGU resulted in increased INF-γ and IL-6, but decreased IL-10 secretion. CFTR mutations that preserve residual pancreatic function significantly increase the severity of experimental pancreatitis—mostly via impairing duct cell function and a shift towards a pro-inflammatory phenotype, not by rendering acinar cells more susceptible to pathological stimuli. 相似文献
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Abrahám G Sólyom S Csuzdi E Berzsenyi P Ling I Tarnawa I Hámori T Pallagi I Horváth K Andrási F Kapus G Hársing LG Király I Patthy M Horváth G 《Bioorganic & medicinal chemistry》2000,8(8):2127-2143
New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity. 相似文献
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Summary The accessibility of pyridoxal 5′-phosphates of the phosphorylaseab hybrid to resolution by imidazole citrate and cysteine was studied and compared with that of theb anda forms. Promotion of resolution of phosphorylated forms by raising the temperature or in the presence of glycogen indicates
that the resistance of phosphorylasea andab to resolution at 0°C is due rather to their tetrameric state than their phosphorylation-related active conformation. The
pattern of resolution of theab hybrid was similar to that of thea and differed from that of theb forms in that it occurred at 30°C and 37°C but not at 0°C, moreover, it did not show first-order kinetics. On the other hand,
inhibition of resolution by ligands binding to the nucleotide site of phosphorylase reflected an intermediate sensitivity
of theab form between that of theb anda forms. We conclude that partial phosphorylation of phosphorylaseb elicits conformational change(s) in both subunits which influence the monomer-monomer interactions and resolution of pyridoxal
5′-phosphates. Resistance ofab hybrid to monomerizing agents as imidazole citrate, comparable to that of other forms, argues for its stability, ruling out
its reshuffling into mixtures of phosphorylaseb anda. 相似文献
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Csuzdi E Migléczi K Hazai I Berzsenyi P Pallagi I Horváth G Lengyel G Sólyom S 《Bioorganic & medicinal chemistry letters》2005,15(21):4662-4665
Putative metabolites of an AMPA antagonist imidazo-2,3-benzodiazepine (2) were synthesized and compared to constituents formed from the parent compound by a rat liver perfusion method. As metabolic transformations, hydroxylation of the 2-methyl group and N-acetylation of the amino functionality in parent compound (2) were registered. The hydroxylated analogue 12 of 2 exhibits a weak AMPA antagonist activity. 相似文献
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Complexation of d-gluconate (Gluc−) with Ca2+ has been investigated via 1H, 13C and 43Ca NMR spectroscopy in aqueous solutions in the presence of high concentration background electrolytes (1 M ? I ? 4 M (NaCl) ionic strength). From the ionic strength dependence of its formation constant, the stability constant at 6 ? pH ? 11 and at I → 0 M has been derived (). The protonation constant of Gluc− at I = 1 M (NaCl) ionic strength was also determined and was found to be log Ka = 3.24 ± 0.01 (13C NMR) and log Ka = 3.23 ± 0.01 (1H NMR). It was found that 1H and 13C NMR chemical shifts upon complexation (both with H+ and with Ca2+) do not vary in an unchanging way with the distance from the Ca2+/H+ binding site. From 2D 1H-43Ca NMR spectra, simultaneous binding of Ca2+ to the alcoholic OH on C2 and C3 was deduced. Molecular modelling results modulated this picture by revealing structures in which the Gluc− behaves as a multidentate ligand. The five-membered chelated initial structure was found to be thermodynamically more stable than that derived from a six-membered chelated initial structure. 相似文献
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Nagy Katalin Marko Bernadett Zsilla Gabriella Matyus Peter Pallagi Katalin Szabo Geza Juranyi Zsolt Barkoczy Jozsef Levay Gyorgy Harsing Laszlo G. 《Neurochemical research》2010,35(12):2096-2106
The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic
and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical
antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D2 dopamine receptors. N-methyl-d-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors,
which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D2 dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of
positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined
drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461.
Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA,
glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular
concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461
injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of
serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular
dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular
concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1
inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side
effects characteristic for antipsychotic medication. 相似文献
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