1,721,223 research outputs found
Antimicrobial and Antioxidant Activities of Natural Compounds
No full textOur special issue, which had opened for 6 months in the second half of 2017, focused on scientific evidences for Antimicrobial and Antioxidant Activities of Natural Compound
Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses
Full text linkRhodamine 123 (R123) transport substrate sensitizes P-glycoprotein (P-gp) to
inhibition by compound 2c (cis-cis) N,N-bis(cyclohexanolamine)aryl ester isomer
in a concentration-dependent manner in human MDR1-gene transfected mouse
T-lymphoma L5178 cells as shown previously. By contrast, epirubicin (EPI)
concentration changes left unaltered 2c IC50 values of EPI efflux. To clarify
this discrepancy, defined molecular docking (DMD) analyses of 12
N,N-bis(cyclohexanolamine)aryl esters, the highly flexible aryl ester analog 4,
and several P-gp substrate/non-substrate inhibitors were performed on human P-gp
drug- or nucleotide-binding domains (DBD or NBD). DMD measurements yielded lowest
binding energy (LBE, kcal/mol) values (mean ± SD) ranging from -11.8 ± 0.54
(valspodar) to -3.98 ± 0.01 (4). Lys234, Ser952 and Tyr953 residues formed
H-bonds with most of the compounds. Only 2c docked also at ATP binding site (LBE
value of -6.9 ± 0.30 kcal/mol). Inhibition of P-gp-mediated R123 efflux by 12
N,N-bis(cyclohexanolamine)aryl esters and 4 significantly correlated with LBE
values. DMD analysis of EPI, (3)H-1EPI, (3)H-2EPI, (14)C-1EPI, (14)C-2EPI, R123
and 2c before and after previous docking of each of them indicated that
pre-docking of either 2c or EPI significantly reduced LBE of both EPI and R123,
and that of both (3)H-2EPI and (14)C-2EPI, respectively. Since the clusters of
DBD amino acid residues interacting with EPI were different, if EPI docked alone
or after pre-docking of EPI or 2c, the existence of alternative secondary binding
site for EPI on P-gp is credible. In conclusion, 2c may allocate the drug-binding
pocket and reduce strong binding of EPI and R123 in agreement with P-gp
inhibition experiments, where 2c reduced efflux of EPI and R123
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Small molecules targeting apoptosis and parthanatos in sensitive and drug-resistant tumor cells
Full text linkResisting cell death is one of the hallmarks of carcinogenesis, especially when it is relevant to tumor proliferation pathways and oncogene overexpression. Deregulation of cell death mechanisms (e.g., anti-apoptotic modalities) during cancer therapy also contributes to tumors that display multidrug resistance (MDR), which is a challenging obstacle for successful treatments. The aim of this thesis is two parts: 1) which novel cell death mechanisms that bypass apoptosis can be induced by three synthetic compounds (cardenolide derivative, palladium (II) complexes), 2) how does a natural product derivative of 1,2,4-oxadiazole inhibit the oncogene c-MYC and promotes apoptosis. These investigations in both drug-sensitive and -resistant cancer cells would be a promising way to overcome tumor resistance to apoptosis.
The compound ZINC253504760 showed potent cytotoxicity to different drug-sensitive and multidrug-resistant cell lines, which showed the most lethal effect in CCRF-CEM cells. Transcriptome-wide mRNA expression profiling and pathway analysis pointed out a canonical pathway involved in G2/M phase cell cycle arrest, which was predicted to be linked with MEK1/2 and ERK in the network analysis. Afterward, G2/M phase arrest was measured by flow cytometry in a time- and concentration-dependent manner, which was supported by the microtubule-destabilizing observation using fluorescence microscopy. Interestingly, apoptosis was not the predominant mode of cell death observed by flow cytometry, nor was it autophagy. Using western blotting, ZINC253504760 induced parthanatos accompanied by p-histone H2A.X, PARP, and PAR accumulation, leading to the translocation of AIF from the cytoplasm to the nucleus. The dissipation of the mitochondrial membrane potential, AIF translocation, and DNA damage were further confirmed by flow cytometry, immunofluorescence microscopy, and alkaline single cell electrophoresis. Moreover, ZINC253504760 inhibited the phosphorylation of MEK1/2, which further affected the activation of ERK. Molecular docking also showed ZINC253504760 as an ATP competitive kinase inhibitor bound to the phosphorylation sites of MEK1 and MEK2. Their binding was confirmed in microscale thermophoresis (MST). Therefore, ZINC253504760 induced parthanatos as a major mode of cell death and downregulated MEK1/2 phosphorylation.
Palladium (II) complexes J4 and J6 induced parthanatos-type cell death in CCRF-CEM and its multidrug-resistant CEM/ADR5000 cells. The biomarker p-histone H2A.X, PARP, and PAR were clearly hyperactivated by J4 and J6, followed by AIF translocated into the nucleus, mitochondrial membrane potential dysfunction, and large-scale DNA fragmentation. Furthermore, J4 and J6 specifically suppressed leukemia cells, but not healthy leukocytes. Therefore, J4 and J6 triggered parthanatos for cell death, which offers the prospect of more effective treatment of malignancies with drug resistance that are hampered by the inability to cause cell death.
The 1,2,4-oxadiazoles derivative ZINC15675948 showed profound cytotoxicity towards CCRF-CEM and MDA-MB-231-pcDNA3 cells, while it was cross-resistant in P-glycoprotein-overexpressing CEM/ADR5000 cells and BCRP-overexpressing MDA-MB-BCRP cells. MST and molecular docking revealed a strong binding of ZINC15675948 to c-MYC with an interaction close to the c-MYC/MAX interface. C-MYC reporter assay and western blotting showed a downregulation of c-MYC by ZINC15675948 in a concentration-dependent manner. Furthermore, ZINC15675948 induced apoptosis and DNA damage in leukemia and breast cancer cell lines. Autophagy induction was only observed in CCRF-CEM cells. ZINC15675948 also caused G2/M phase or S phase arrest in CCRF-CEM cells or MDA-MB-231-pcDNA3 cells, accompanied by the downregulation of CDK1 or p-CDK2 in western blotting. Additionally, the microarray profiling of MDA-MB-231-pcDNA3 cells revealed an involvement of ubiquitination toward c-MYC, indicated by the upregulation of a novel ubiquitin ligase (ELL2) in the absence of c-MYC expression. Therefore, ZINC15675948 promoted apoptosis in c-MYC-driven cancers by targeting c-MYC.Getrennte Zählungen ; Illustrationen, Diagramm
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Identification and functional characterization of potential biomarkers in cisplatin resistance through bioinformatic analyses
Full text linkPlatinum-based chemotherapies, particularly cisplatin, are often limited by the emergence ofdrug resistance, driven not only by genetic alterations in DNA repair pathways but also byclinical factors such as patient age, race, gender, metastasis status, and tumor stage. To addressthese challenges, we performed integrative bioinformatics and experimental analyses acrossmore than 7,500 tumors spanning 23 cancer types, aiming to identify key genetic determinantsof chemoresistance.
Through comprehensive mutation profiling and overall survival analyses of genes involved inbase excision repair (BER), mismatch repair (MMR), and double-strand break (DSB) repairpathways, we identified PARP3, MSH6 and ATM as candidate predictive biomarkers.Functional studies using CRISPR/Cas9-and shRNA-mediated gene knockdown revealed thatsilencing these genes significantly increased cisplatin sensitivity in cancer cell lines.
Mechanistic investigations further showed that PARP3 loss disrupted PDGF and G protein-coupled receptor (GPCRs) signalling pathways, enhancing drug efficacy. MSH6depletionshifted the balance of autophagy from pro-survival to pro-death, sensitizing cells to cisplatin.In parallel,ATMknockout induced oxidative stress-mediated senescence via suppression ofNRF2signaling.
Collectively, our findings identifyMSH6,ATM, andPARP3as promising therapeutic targetsfor overcoming chemoresistance. The discovery of their associations with previouslyuncharacterized signalling pathways underscores their clinical and biological relevance. Byintegrating mutational landscapes with functional vulnerabilities, this study provides aconceptual framework for the development of personalized combination therapies tailored tothe molecular profile of individual tumors, ultimately offering innovative strategies to enhancetreatment efficacy in oncology.Platinbasierte Chemotherapien, insbesondere Cisplatin, sind häufig durch das Auftreten vonArzneimittelresistenzen begrenzt, die nicht nur durch genetische Veränderungen in DNA-Reparaturwegen, sondern auch durch klinische Faktoren wie Alter, ethnische Zugehörigkeit,Geschlecht, Metastasierungsstatus und Tumorstadium der Patienten bedingt sind. Um diesenHerausforderungen zu begegnen, führten wir integrative Bioinformatik-und experimentelleAnalysen an über 7.500 Tumoren aus 23 Krebsarten durch, mit dem Ziel, zentrale genetischeDeterminanten der Chemoresistenz zu identifizieren.
Durch umfassende Mutations- und Überlebensanalysen von Genen, die an derBasenexzisionsreparatur (BER), der Mismatch-Reparatur (MMR) und der Reparatur vonDoppelstrangbrüchen (DSB) beteiligt sind, identifizierten wir PARP3,MSH6undATMalspotenzielle prädiktive Biomarker. Funktionelle Studien unter Verwendung von CRISPR/Cas9-und shRNA-vermitteltem Gen-Silencing zeigten, dass die Stilllegung dieser Gene die Cisplatin-Empfindlichkeit in Krebszelllinien signifikant erhöhte.
Mechanistische Untersuchungen zeigten zudem, dass der Verlust von PARP3 die PDGF-undG-Protein-gekoppelten Rezeptor-(GPCRs)Signalwege störte und so die Wirksamkeit desMedikaments erhöhte. Der Verlust von MSH6 verschob das Gleichgewicht der Autophagie vonpro-survival zu pro-death und sensibilisierte die Zellen für Cisplatin. Parallel dazu induzierteder ATM-Knockout eine durch oxidativen Stress vermittelte zelluläre Seneszenz durchUnterdrückung der NRF2-Signalübertragung.
Insgesamt identifizieren unsere Ergebnisse PARP3, MSH6 und ATM als vielversprechendetherapeutische Zielstrukturen zur Überwindung von Chemoresistenz. Die Entdeckung ihrerVerbindungen zu bisher unbekannten Signalwegen unterstreicht ihre klinische und biologischeRelevanz. Durch die Integration von Mutationslandschaften mit funktionellen Schwachstellenbietet diese Studie ein konzeptuelles Rahmenwerk für die Entwicklung personalisierterKombinationstherapien, die auf das molekulare Profil individueller Tumoren zugeschnittensind–mit dem Ziel, innovative Strategien zur Verbesserung der Behandlungseffektivität in derOnkologie zu entwickeln.V, 49 Seiten ; Illustrationen, Diagramm
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