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31.
Attila Sipos Zsolt Török Erzsébet Rőth Attila Kiss-Szikszai Gyula Batta Ilona Bereczki Zsolt Fejes Anikó Borbás Eszter Ostorházi Ferenc Rozgonyi Lieve Naesens Pál Herczegh 《Bioorganic & medicinal chemistry letters》2012,22(23):7092-7096
The primary amino function of teicoplanin pseudoaglycon has been transformed into arylthioisoindole or benzoisoindole and glycosylthioisoindole derivatives, in a reaction with o-phthalaldehyde or naphtalene-2,3-dicarbaldehyde and various thiols. All of the obtained semisynthetic antibiotics exhibited potent antibacterial activities against Gram-positive bacteria in the ng per ml concentration range. A few of them showed antiviral activity, in particular against influenza virus. 相似文献
32.
Benita Wolf Adrian Schwarzer Anik L. C?té Thomas H. Hampton Thomas Schwaab Eduardo Huarte Craig R. Tomlinson Jiang Gui Jan L. Fisher Camilo E. Fadul Joshua W. Hamilton Marc S. Ernstoff 《PloS one》2012,7(12)
Lymphocytes are a key component of the immune system and their differentiation and function are directly influenced by cancer. We examined peripheral blood lymphocyte (PBL) gene expression as a biomarker of illness and treatment effect using the Affymetrix Human Gene ST1 platform in patients with metastatic renal cell carcinoma (mRCC) who received combined treatment with IL-2, interferon-?-2a and dendritic cell vaccine. We examined gene expression, cytokine levels in patient serum and lymphocyte subsets as determined by flow cytometry (FCM). Pre-treatment PBLs from patients with mRCC exhibit a gene expression profile and serum cytokine profile consistent with inflammation and proliferation not found in healthy donors (HD). PBL gene expression from patients with mRCC showed increased mRNA of genes involved with T-cell and TREG-cell activation pathways, which was also reflected in lymphocyte subset distribution. Overall, PBL gene expression post-treatment (POST) was not significantly different than pre-treatment (PRE). Nevertheless, treatment related changes in gene expression (post-treatment minus pre-treatment) revealed an increased expression of T-cell and B-cell receptor signaling pathways in responding (R) patients compared to non-responding (NR) patients. In addition, we observed down-regulation of TREG-cell pathways post-treatment in R vs. NR patients. While exploratory in nature, this study supports the hypothesis that enhanced inflammatory cytotoxic pathways coupled with blunting of the regulatory pathways is necessary for effective anti-cancer activity associated with immune therapy. This type of analysis can potentially identify additional immune therapeutic targets in patients with mRCC. 相似文献
33.
34.
Dávid Kurszán Jász Ágnes Lilla Szilágyi Eszter Tuboly Bálint Baráth Anett Roxána Márton Petra Varga Gabriella Varga Dániel Érces Árpád Mohácsi Anna Szabó Renáta Bozó Kamilla Gömöri Anikó Görbe Mihály Boros Petra Hartmann 《Journal of cellular and molecular medicine》2021,25(11):5113-5123
Albeit previous experiments suggest potential anti-inflammatory effect of exogenous methane (CH4) in various organs, the mechanism of its bioactivity is not entirely understood. We aimed to investigate the potential mitochondrial effects and the underlying mechanisms of CH4 in rat cardiomyocytes and mitochondria under simulated ischaemia/reperfusion (sI/R) conditions. Three-day-old cultured cardiomyocytes were treated with 2.2% CH4-artificial air mixture during 2-hour-long reoxygenation following 4-hour-long anoxia (sI/R and sI/R + CH4, n = 6-6), with normoxic groups serving as controls (SH and SH + CH4; n = 6-6). Mitochondrial functions were investigated with high-resolution respirometry, and mitochondrial membrane injury was detected by cytochrome c release and apoptotic characteristics by using TUNEL staining. CH4 admixture had no effect on complex II (CII)-linked respiration under normoxia but significantly decreased the complex I (CI)-linked oxygen consumption. Nevertheless, addition of CH4 in the sI/R + CH4 group significantly reduced the respiratory activity of CII in contrast to CI and the CH4 treatment diminished mitochondrial H2O2 production. Substrate-induced changes to membrane potential were partially preserved by CH4, and additionally, cytochrome c release and apoptosis of cardiomyocytes were reduced in the CH4-treated group. In conclusion, the addition of CH4 decreases mitochondrial ROS generation via blockade of electron transport at CI and reduces anoxia-reoxygenation-induced mitochondrial dysfunction and cardiomyocyte injury in vitro. 相似文献
35.
Shavanthi Rajatileka David Odd Matthew T. Robinson Alexandra C. Spittle Louis Dwomoh Maggie Williams David Harding Miles Wagstaff Marie Owen Charlene Crosby Jared Ching Elek Molnár Karen Luyt Anikó Váradi 《Molecular neurobiology》2018,55(3):2013-2024
Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200C>A and g.-181A>C) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181 bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies. 相似文献
36.
Õrfi László Wáczek Frigyes Kövesdi István Mészáros György Idei Miklós Horváth Anikó Hollósy Ferenc Mák Marianna Szegedi Zsolt Szende Béla Kéri György 《International journal of peptide research and therapeutics》1999,6(5-6):325-333
A parallel combinatorial library of over 1600 compounds has been designed and synthesized for the development of new potential peptidomimetic protein tyrosine kinase (PTK) inhibitor leads. These peptidomimetic molecules are aimed at intervening with the substrate binding site of the pp60c-src enzyme. The new structures were based on known PTK inhibitors with at least two variously substituted aromatic moieties attached by spacer groups of different length and flexibility. Eleven bis-aryl-type inhibitory compounds were found in the range of 18–100 μM IC50 concentrations from combinations of 12 different substituents. Molecular modeling of the active compounds showed a characteristic distance of 12–14 Å between the farthest sp2 carbon atoms of the two aromatic rings. Conformational analysis of several peptide substrates recently found for pp60c-src PTK showed that the energy-minimized conformers had the same distance between the two aromatic moieties. Several compounds in the library not only showed remarkable PTK inhibitory activity but also a significant apoptosis-inducing effect on HT-29 human colon tumor cells. 相似文献
37.
Peter G. C. Campbell Lisa D. Kraemer Anik Giguère Landis Hare Alice Hontela 《人类与生态风险评估》2008,14(2):290-316
The objective of this study was to investigate metal detoxification in chronically exposed juvenile yellow perch (YP: Perca flavescens) and to field test the commonly assumed threshold toxicity model. Fish were collected from lakes located along a cadmium (Cd) and nickel (Ni) concentration gradient. Ambient dissolved metal concentrations were measured to evaluate exposure and total hepatic metal concentrations were determined as a measure of metal bioaccumulation. Hepatic metal partitioning among potentially metal-sensitive fractions (heat-denatured proteins, organelles) and detoxified metal fractions (metallothionein) was determined after differential centrifugation of YP liver homogenates. Major proportions of hepatic Cd were found in the heat-stable cytosolic peptides and proteins fraction (HSP; including metallothioneins), whereas Ni was mainly found in the potentially metal-sensitive heat-denaturable proteins fraction (HDP). For these chronically exposed fish there was no threshold exposure concentration below which binding of Cd or Ni to the heat-denaturable protein fraction or the organelle fraction did not occur. Metal detoxification was clearly incomplete and P. flavescens was subject to some metal-related stress, as evidenced notably by endocrine perturbations. Similar subcellular partitioning results were obtained when juvenile yellow perch were transferred from a reference lake to a Cd-contaminated lake and Cd accumulation was followed over time; there was no accumulation threshold below which Cd binding to the putative metal-sensitive fractions (HDP and organelles) did not occur. The presence of Cd and Ni in these fractions, even for low exposure concentrations and low hepatic accumulation, contradicts the threshold toxicity model that underpins metal toxicology theory and that is implicitly used in setting water quality guidelines for metals. Chronically exposed YP appear to have settled for a tradeoff between the cost of turning on their detoxification apparatus at full capacity, to completely suppress metal binding to metal-sensitive sites, and the alternative cost of allowing some binding of inappropriate metals to metal-sensitive sites. 相似文献
38.
Miyazaki A Tsuda Y Fukushima S Yokoi T Vántus T Bökönyi G Szabó E Horváth A Kéri G Okada Y 《Bioorganic & medicinal chemistry letters》2008,18(23):6199-6201
Novel somatostatin analogues containing a pyrazinone ring, compounds 1 and 2, exhibited good antiproliferative activity on A431 tumor cells. To increase antitumor activity and binding affinity on somatostatin receptors (SSTRs), we substituted Tyr in the critical sequence, Tyr-D-Trp-Lys, with more hydrophobic aromatic residue. The substituted compounds dramatically lost antitumor activity, indicating that Tyr residue was an essential residue. 相似文献
39.
Erdélyi P Fodor T Varga AK Czugler M Gere A Fischer J 《Bioorganic & medicinal chemistry》2008,16(9):5322-5330
The inhibition of cyclooxygenase enzymes plays an important role in the treatment of inflammatory diseases. N-Hydroxy-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide (3)—a primary metabolite of the highly selective COX-2 inhibitor valdecoxib—was synthesized and stabilized as its monohydrate (3a·H2O). The anti-inflammatory properties of 3a·H2O were investigated in carrageenan-induced edema and in acute and chronic pain models. Based on our biological investigation, we conclude that N-hydroxy-valdecoxib 3a is an active metabolite of valdecoxib. 相似文献
40.
Peter G.C. Campbell Alice Hontela Joseph B. Rasmussen Anik Giguère Amélie Gravel Lisa Kraemer 《人类与生态风险评估》2003,9(4):847-866
The objectives of this field project were to test relationships between the physiological and population status of indigenous fish and (a) ecological factors (habitat quality, food resources), (b) toxicological factors (ambient and tissue metal concentrations), and (c) metal detoxification factors (metallothionein induction and subcellular metal partitioning). The sentinel species, yellow perch (YP: Perca flavescens), was collected from lakes with contrasting metal levels located on the Canadian Precambrian Shield, downwind and downstream from metal smelters. In lakes at the high end of our exposure gradient, metals (Cu, Ni, and especially Cd) accumulate in YP to concentrations well above background tissue values; increases in tissue Zn concentrations were much more modest, despite the existence of a very marked gradient in ambient [Zn]. Metal accumulation in YP is accompanied by metallothionein induction, but all evidence to date suggests that metal detoxification by metallothionein is incomplete. Indeed, direct effects of metal toxicity are detected at multiple levels of biological organization, from effects at the cellular level, to effects in organs and tissues, to individuals and populations, in a pattern linked to accumulated metal concentrations (i.e., along the contamination gradient). In addition to direct or physiological effects, we also documented indirect, food-web-mediated effects of metals on YP in the most contaminated lakes. The most common indication of such indirect effects on YP is severely stunted growth coupled with a high degree of zooplankton dependence throughout their life. 相似文献