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861.
Oxidation Potentials of N‐Modified Derivatives of the Analgesic Flupirtine Linked to Potassium KV7 Channel Opening Activity But Not Hepatocyte Toxicity
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Christian J. Lemmerhirt Mirko Rombach Dr. Anja Bodtke Prof. Dr. Patrick J. Bednarski Prof. Dr. Andreas Link 《ChemMedChem》2015,10(2):368-379
Openers of neuronal voltage‐gated potassium channels (KV) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone diimines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity. 相似文献
862.
Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties
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Dr. Sanjay R. Borhade Dr. Richard Svensson Dr. Peter Brandt Prof. Dr. Per Artursson Prof. Dr. Per I. Arvidsson Dr. Anja Sandström 《ChemMedChem》2015,10(3):455-460
Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pKa, lipophilicity, in vitro metabolic stability, plasma protein binding, Caco‐2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9–7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates. 相似文献
863.
Svingen T Beverdam A Bernard P McClive P Harley VR Sinclair AH Koopman P 《Reproduction (Cambridge, England)》2007,133(5):983-989
During mouse embryogenesis, the fate of the bipotential gonads is sealed around 10.5 days post coitum (dpc) when the Y-linked gene Sry specifies the differentiation of testes in males, whereas in females, absence of Sry results in ovary formation. Apart from the pivotal action of Sry, many other genes are known to be involved in sex determination and subsequent differentiation. Much is still unknown regarding the regulatory hierarchy governing these events and many more sex differentiation genes are yet to be discovered. In this study, we investigated the expression of Tmem184a, a novel gene encoding a protein of unknown function, but with predicted kinase activity, during mouse embryogenesis. We show that Tmem184a is expressed at high levels in the developing testis from 11.5 dpc, a time of active proliferation and differentiation. Tmem184a expression is further shown to be expressed exclusively within the Sertoli cells of the developing testis cords, suggesting that it may mediate sex-specific signaling events during Sertoli cell differentiation. 相似文献
864.
Claudia Unterberger Florian Luber Anja Demmel Karola Grünwald Ingrid Huber Karl-Heinz Engel Ulrich Busch 《European Food Research and Technology》2014,239(4):559-566
People suffering from food allergy rely on correct food labelling as the ingestion of minimal amounts of the respective allergen can trigger severe allergenic reactions. Probes for the detection of DNA from allergenic fish, shellfish and cephalopod species in food using multiplex ligation-dependent probe amplification were developed. The specificity and the sensitivity of the detection system were investigated. The limit of detection was 20 mg kg?1 for scallop, fish and bivalve species and 100 mg kg?1 for cephalopod, gastropod and crustacean species using self-prepared sushi spiked with the analytes in different concentration levels. The analysis of 10 commercial food samples demonstrates the applicability of the developed method and its suitability for food quality control. Therefore, the method can be used to monitor the compliance with labelling rules regarding food allergens. 相似文献
865.
Julia Post Anja Schaffrath Ian Gering Sonja Hartwig Stefan Lehr N. Jon Shah Karl-Josef Langen Dieter Willbold Janine Kutzsche Antje Willuweit 《International journal of molecular sciences》2021,22(13)
Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and plays a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS). It has been implicated as driver of disease progression and is observed in ALS patients, as well as in the transgenic SOD1G93A mouse model. Here, we explore and validate the therapeutic potential of the d-enantiomeric peptide RD2RD2 upon oral administration in SOD1G93A mice. Transgenic mice were treated daily with RD2RD2 or placebo for 10 weeks and phenotype progression was followed with several behavioural tests. At the end of the study, plasma cytokine levels and glia cell markers in brain and spinal cord were analysed. Treatment resulted in a significantly increased performance in behavioural and motor coordination tests and a decelerated neurodegenerative phenotype in RD2RD2-treated SOD1G93A mice. Additionally, we observed retardation of the average disease onset. Treatment of SOD1G93A mice led to significant reduction in glial cell activation and a rescue of neurons. Analysis of plasma revealed normalisation of several cytokines in samples of RD2RD2-treated SOD1G93A mice towards the levels of non-transgenic mice. In conclusion, these findings qualify RD2RD2 to be considered for further development and testing towards a disease modifying ALS treatment. 相似文献
866.
Katrin Reincke Elisa Vilvert Anja Fasse Frieder Graef Stefan Sieber Marcos A. Lana 《Food Security》2018,10(4):911-924
Due to beneficial characteristics of cassava such as robustness and versatility for multiple uses, it can have a major role in contributing to local food security. The objective of this study was to find out whether and how the cultivation of cassava benefits smallholder farmers in the regions of Dodoma and Morogoro, Tanzania. In addition, the study assessed the main factors that support or threaten food security of smallholder farmer households in the survey region and analysed whether cassava cultivation could counteract them. We applied a mixed methods approach. Quantitative data were provided by a comprehensive household survey of the Trans-SEC project, and qualitative data were collected by conducting semi-structured interviews. To approach the complexity of our chosen food security definition, three approaches for household food security measurement were applied. These covered the components of food availability, food access, and food utilization. Additionally, dependent variables for regression models were constructed and a multivariate analysis was run. The results show that cassava contributes to food security in the households, but achieving food security through cassava cultivation was constrained by several factors, including pests, missing markets, poor processing, social perception and lack of knowledge. Besides these, other factors affecting food security in the study area were found, uncovering some roots of local food insecurity and serving as a basis for further research and action on how to enhance food security. 相似文献
867.
868.
Thorsten H. Ecke Paula Carolin Voß Thorsten Schlomm Anja Rabien Frank Friedersdorff Dimitri Barski Thomas Otto Michael Waldner Elke Veltrup Friederike Linden Roland Hake Sebastian Eidt Jenny Roggisch Axel Heidenreich Constantin Rieger Lucas Kastner Steffen Hallmann Stefan Koch Ralph M. Wirtz 《International journal of molecular sciences》2022,23(14)
Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome—rate of ypT0 status—to justify subsequent prospective validation within the “BladderBRIDGister”. Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal–Wallis, Mann–Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy. 相似文献
869.
Diana Lindner Claudia Arndt Liliana Rodrigues Loureiro Anja Feldmann Alexandra Kegler Stefanie Koristka Nicole Berndt Nicola Mitwasi Ralf Bergmann Marcus Frenz Michael P. Bachmann 《International journal of molecular sciences》2022,23(14)
Radiation of tumor cells can lead to the selection and outgrowth of tumor escape variants. As radioresistant tumor cells are still sensitive to retargeting of T cells, it appears promising to combine radio- with immunotherapy keeping in mind that the radiation of tumors favors the local conditions for immunotherapy. However, radiation of solid tumors will not only hit the tumor cells but also the infiltrated immune cells. Therefore, we wanted to learn how radiation influences the functionality of T cells with respect to retargeting to tumor cells via a conventional bispecific T cell engager (BiTE) and our previously described modular BiTE format UNImAb. T cells were irradiated between 2 and 50 Gy. Low dose radiation of T cells up to about 20 Gy caused an increased release of the cytokines IL-2, TNF and interferon-γ and an improved capability to kill target cells. Although radiation with 50 Gy strongly reduced the function of the T cells, it did not completely abrogate the functionality of the T cells. 相似文献
870.
Nico Dreymann Julia Wuensche Wiebke Sabrowski Anja Moeller Denise Czepluch Dana Vu Van Susanne Fuessel Marcus M. Menger 《International journal of molecular sciences》2022,23(9)
Urokinase-type plasminogen activator is widely discussed as a marker for cancer prognosis and diagnosis and as a target for cancer therapies. Together with its receptor, uPA plays an important role in tumorigenesis, tumor progression and metastasis. In the present study, systematic evolution of ligands by exponential enrichment (SELEX) was used to select single-stranded DNA aptamers targeting different forms of human uPA. Selected aptamers allowed the distinction between HMW-uPA and LMW-uPA, and therefore, presumably, have different binding regions. Here, uPAapt-02-FR showed highly affine binding with a KD of 0.7 nM for HMW-uPA and 21 nM for LMW-uPA and was also able to bind to pro-uPA with a KD of 14 nM. Furthermore, no cross-reactivity to mouse uPA or tissue-type plasminogen activator (tPA) was measured, demonstrating high specificity. Suppression of the catalytic activity of uPA and inhibition of uPAR-binding could be demonstrated through binding with different aptamers and several of their truncated variants. Since RNA aptamers are already known to inhibit uPA-uPAR binding and other pathological functions of the uPA system, these aptamers represent a novel, promising tool not only for detection of uPA but also for interfering with the pathological functions of the uPA system by additionally inhibiting uPA activity. 相似文献