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K Rutkowski

Publications and source records attributed to K Rutkowski.

18 recordsLinked to original sources
PubMed2000

Co-localization of TFF3 peptide and oxytocin in the human hypothalamus.

TFF-peptides (formerly P domain peptides, trefoil factors) are typical secretory products of many mucous epithelial cells. TFF3 is also synthesized in the hypothalamus and has anxiolytic or anxiogenic activities when injected into the rat amygdala. Here we show by immunohistochemistry that TFF3 is localized to a distinct population of neurons of the human hypothalamic paraventricular and supraoptic nuclei. Generally, TFF3-positive cells are co-localized in oxytocin-producing cells and not in vasopressin-producing cells. Relatively large amounts of TFF3-but not TFF1 and TFF2-are present in the posterior lobe of the human pituitary, where it is probably released into the bloodstream. Furthermore, TFF3 was also detectable in human postmortem cerebrospinal fluid.

Blotting, Western↗
PubMed1999

Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1.

The rate of transcription of several genes encoding proteins involved in O(2) and energy homeostasis is controlled by hypoxia-inducible factor-1 (HIF-1), a heterodimeric DNA binding complex composed of alpha and beta subunits. HIF-1 is considered the primary trans-acting factor for the erythropoietin (EPO) and vascular endothelial growth factor (VEGF) genes. Since EPO gene expression is inhibited by the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), while no such effect has been reported with respect to the VEGF gene, we investigated the effects of IL-1beta and TNF-alpha on the activation of the HIF-1 DNA-binding complex and the amount of HIF-1alpha protein in human hepatoma cells in culture. Under normoxic conditions, both cytokines caused a moderate activation of HIF-1 DNA binding. In hypoxia, cytokines strongly increased HIF-1 activity compared with the effect of hypoxia alone. Only IL-1beta increased HIF-1alpha protein levels. In transient transfection experiments, HIF-1-driven reporter gene expression was augmented by cytokines only under hypoxic conditions. In contrast to their effect on EPO synthesis, neither IL-1beta nor TNF-alpha decreased VEGF production. The mRNA levels of HIF-1alpha and VEGF were unaffected. Thus, cytokine-induced inhibition of EPO production is not mediated by impairment of HIF-1 function. We propose that HIF-1 may be involved in modulating gene expression during inflammation.

Animals↗
PubMed1999

Induction of TFF1 gene expression in pancreas overexpressing transforming growth factor alpha.

BACKGROUND/AIMS: Chronic pancreatitis is an inflammatory disease of the exocrine pancreas associated with extensive fibrosis, enlarged pancreatic ducts, acinar cell degeneration, and the formation of tubular complexes. The molecular and biochemical alterations associated with these histological changes are not kown. Generally, the new family of TFF peptides (formerly known as P-domain peptides or trefoil factors) is aberrantly expressed during chronic inflammatory diseases of the gastrointestinal tract. METHODS: Using human pancreatic tissues obtained from patients with chronic pancreatitis and murine pancreatic tissues obtained from transgenic mice overexpressing transforming growth factor alpha (TGF-alpha), the expression and cellular distribution of TFF1 was analysed using northern blot analysis, polymerase chain reaction (PCR), and immunohistochemistry. RESULTS: In the normal human pancreas, TFF1 was scarce, with only a few ducts exhibiting cytoplasmic TFF1 immunoreactivity. In contrast, human chronic pancreatitis tissue specimens exhibited strong TFF1 immunoreactivity in ductal cells, areas of ductal hyperplasia, and tubular complexes. Semiquantitative PCR analysis of TFF1 mRNA levels showed enhanced expression of TFF1 in the pancreas of patients with chronic pancreatitis. Furthermore, TFF1 mRNA levels were detectable in the pancreas in four of five transgenic mice overexpressing TGF-alpha. In contrast, four of five wild type mice did not exhibit a TFF1 mRNA transcript. In addition, while no specific TFF1 immunoreactivity was present in the pancreas of the wild type mice, ductal epithelial cells and duct-like tubular complexes in the pancreas of the transgenic mice overexpressing TGF-alpha exhibited pronounced TFF1 immunoreactivity. CONCLUSIONS: Ductal cells and tubular complexes in pancreatic fibrosis express TFF1. As the 5'-flanking region of TFF1 contains an epidermal growth factor responsive enhancer region and the expression of epidermal growth factor and TGF-alpha is enhanced in pancreatic fibrosis, the enhanced expression of TFF1 in pancreatic fibrosis may be mediated by TGF-alpha.

Adolescent↗
PubMed1994

Synthesis and pharmacological properties of some new 3-(2-N,N-dialkylaminoethyl)-pyrido [2,3-d]-pyrymidin-4-ones.

The following new derivatives of pyrido [2,3-d]-pyrimidin-4(3H)-one were synthesized: 3-(2-N,N-dimethylaminoethyl), 3-(2-N-pyrolidynylethyl), 3-(2-piperidinylethyl) and 3-(2-N-morpholidinylethyl). Their chemical structures were confirmed by MS, IR and 1H NMR spectroscopic data. Newly synthesized compounds were investigated pharmacologically for their central properties in mice and rats. It was shown that compound [III] showed anxiolytic action in the four-plate test and two compounds produced analgesic effects in mice.

Analgesics↗
PubMed1991

The stereospecific determination of fluoxetine and norfluoxetine enantiomers in human plasma by high-pressure liquid chromatography (HPLC) with fluorescence detection.

A quantitative method for the simultaneous HPLC resolution and detection of the enantiomers of (R,S) fluoxetine (F) and their metabolites (R,S) norfluoxetine (N) in human plasma has been developed. F is a serotonin uptake inhibitor used in the treatment of depression and is administered as a racemate. After liquid-liquid extraction and derivatization with (R) napthyl ethyl isocyanate (NEI), the separation and detection of the resultant diasteriomers were achieved using normal phase HPLC and fluorescence. The four NEI diastereomers and the internal standard [(-)-N-methyl-gamma-(2-methylphenoxy) benzenepropanamine hydrochloride], representing the enantiomers S-F, R-F, S-N, and R-N were resolved within 15 min. The assay for each analyte was linear using two concentration ranges of 1-10 and 10-500 ng/ml of human plasma. The precision and accuracy are reported as the coefficient of variation (%CV) and relative error (%RE). The sum of the chiral HPLC results from plasma samples were compared to the achiral gas chromatographic/electron capture (GC/EC) results. The correlation between these two methods, for total F and N, resulted in r2 values of 0.98 and 0.89, respectively. The chiral HPLC method is currently being applied to clinical studies for the evaluation of the enantiomeric disposition of F.

Antidepressive Agents, Tricyclic↗
PubMed1989

Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975; NSC-347512) in mice.

Flavone acetic acid (FAA) is a novel antitumor agent with broad solid-tumor activity. However, this drug has shown a steep dose-response curve in preclinical trials, with a narrow sublethal window of efficacy. To investigate this threshold behavior, we studied various aspects of FAA pharmacology in mice after i.v. administration. Mice bearing advanced-stage s.c. colon 38 adenocarcinoma were treated at four dose levels (39, 65, 108 and 180 mg/kg), and only the highest dose produced significant antitumor activity, showing a steep dose-response curve. Using an HPLC assay, FAA pharmacokinetics in both plasma and tumors were found to be dose-dependent. As the dose increased, there was a decrease in both total body clearance and volume of distribution at steady state. The increase in tumor area under the curve (AUC) was more pronounced than the corresponding increase in plasma AUC, showing a better tumor exposure to FAA at high doses. The distribution of FAA in normal tissues showed a short-term retention in the liver and kidneys; low concentrations were observed in the heart, spleen, and brain, with some retention in the latter. The highest FAA concentrations were found in the gastrointestinal (GI) tract, mainly in the duodenum, suggesting an important biliary excretion of the drug. Various possible causes of FAA nonlinear pharmacokinetics were investigated. Serum protein binding was high (79%) and remained constant up to 100 micrograms/ml, but decreased thereafter at higher FAA concentrations, e.g., 76% at 500 micrograms/ml and 64% at 1,000 micrograms/ml. Urinary and biliary clearances were dose-dependent and decreased 5- and 9-fold, from the 39- to the 180-mg/kg dose levels, respectively. A direct assessment of FAA enterohepatic circulation using intercannulated mice showed that 27% of the plasma AUC was accounted for by enterohepatic circulation. FAA acyl glucuronide was identified as the major metabolite in mice and was found to contribute to the nonlinear pharmacokinetics due to its facile hydrolysis under physiological conditions, regenerating FAA. In conclusion, the steep FAA dose-response curve was found to be caused by dose-dependent pharmacokinetics in mice. The nonlinear pharmacokinetics of this drug was attributed to a dose-dependent decrease in both urinary and biliary clearances, concentration-dependent serum protein binding, enterohepatic circulation, and the instability of FAA acyl glucuronide under physiological conditions forming a futile cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMedDate not supplied

[Anxiety and depression in post-traumatic disorders].

The paper presents the research results of those who had PTSD and were examined. The group was of 90 persons, who were former political prisoners in Poland. The State and Trait of Anxiety Inventory and the Hamilton Depression Rating Scale were applied in order to measure the intensity of anxiety and depressive symptoms. 76% of those examined had nightmares. This group is also significant for its' high level momentary anxiety, anxiety as a persistent personality trait as well as uncommon (20%) incidence of depression. The group of those that do not remember nightmares (24% of all those examined) is characterised by a lower level of anxiety reaction and common incidence of depression (84.2%). The article is ended with a discussion on the meaning of the results for the diagnosis and treatment of post-traumatic disorders.

Anxiety↗