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Εναλλακτικές φυσικές πηγές παραγώγων ινδιρουβίνης: ανάλυση αυτών στό πλάσμα και τους ιστούς: τοξικολογικές μελέτες
No full textIndirubins are bis-indole alkaloid compounds occurring naturally in various indigocontainingplants and mollusk gastropods. These molecules were initially known fortheir long history in the dye industry. However, during the last two decades, thechemical and biological studies of indirubins have increased tremendously due to thediscovery of their bio-activities against numerous human cancer cell lines mainlythrough the inhibition of protein kinases. Therefore, the aim of this work was firstly toseveral potential new sources of indirubins using a UHPLC-ESI-MS/MS platform.Thus, three marine mollusks (Hexaplex trunculus, Rapana venosa, and Plicopurpurapansa), one plant (Isatis tomentella), and one pharmaceutical product (DangguiLonggui Wan) were analyzed for the identification of the indirubins thereof. Theindirubins and the major components of the mollusk Hexaplex trunculus and the plantIsatis tomentella were further isolated using newly developed FCPC methodology.The glands of R. venosa were studied here for the very first time; several extractswere produced and analyzed. The ethyl acetate extract which was the richest insecondary metabolites revealed in LC-MS-ESI(-) the presence of several brominatedand non-brominated indirubin precursors namely. The milk of P. pansa displayedeleven brominated compounds, among which eight are previously reported and threeare unknown. Indirubin and indigo were detected in I. tomentella which also contained several amino acids, nucleosides, glycosylated and non-glycosylatedflavonoids. A total of forty-six metabolites were detected in this extract and its majorconstituents were isolated using step-gradient CPC technique, and structurallyelucidated using NMR and HRMS technique and comparison to data in the literature. In the third chapter of this thesis, the toxicological studies of 7-Bromo-indirubin-3΄-oxime (7BIO) on Wistar rats are reported. 7BIO is a synthetic derivative of indirubincausing rapid cell death in tumor cells in different tumor cell lines, but with no priordata regarding its in vivo toxicity. Hence, healthy rats were daily administered (i.p)with either vehicle (Control), or 20 mg/kg BW (low dose), 50 mg/kg BW (mediumdose), and 100 mg/kg BW (high dose) of 7BIO for 9 consecutive days. By the end ofthe treatment period, 1/6 and 3/6 animals deceased in the medium dose and high dosegroups, respectively. Regarding the histopathology parameters, no treatment-relatedeffects with regard to any of the toxicological biomarkers considered were observedin kidneys, testis, pancreas, spleen, stomach, and colon. However, granulomas wereprominent throughout the peritoneal cavity in a dose-dependent manner; and lungsand intense liver toxicity signs were evident in high dose group. The safety profile of6-Bromo-indirubin-3΄-oxime (6BIO) was further assessed on Wistar rats followingthe same concept described for 7BIO. 6-bromoindirubin-3′-oxime (6BIO) is a semisyntheticanalogue of 6BI that was developed as a potent and selective GSK-3βinhibitor and is currently considered and commercialized as a prototype inhibitor ofthat mammalian kinase. After a 14-day treatment of rats 6BIO, traditionalhematological and biochemical endpoints were evaluated and revealed no significant signs of toxicity. Furthermore, UHPLC-MS/MS was applied for the analysis ofendogenous metabolites in rat serum. Principal component analysis (PCA), partialleast-squares-discriminant analysis (PLS-DA), and orthogonal partial least-squaresdiscriminantanalysis (OPLS-DA) were adopted to investigate the metabolicdifferences between 6BIO treated and untreated groups. And the potential biomarkerswere identified accordingly. Our LC-MS metabolomics platform was provedsufficiently robust and accurate to identify and exhibit perturbations in the circulating small metabolites. The results revealed that the metabolite profiles of 6BIO-treatedgroups deviated obviously from that of control groups (PCA & PLS-DA). Thepotential biomarkers extracted from the S-plot, were primary involved in themetabolic pathways of phosphatidylcholines and phosphatidylserines, which are bothimportant groups of phospholipids class of cellular components with critical roles incellular membranes. It is therefore speculated that the administration of 6BIO maypertubate cell metabolism, specifically from it surface. Finally, a UHPLC-MS/MSmethod was developed and validated to quantify 6BIO and its more soluble derivative6BIO-pip in mice plasma. The validated method was applied to pharmacokineticstudies of the two molecules after oral administration in mice. The results show that6BIO-pip is highly absorbed > 200-fold and more stable in the circulatory system ofmice as compared to 6BIO.Overvall, the comprehensive metabolites profiling of marine, plant andpharmaceutical sources of indirubins were reported with isolation of somerepresentative major constitutens. UHPLC-HRMS were proved to be an efficient toolin the analysis of these natural products as well as the monitoring of their bioanalysis
Alternative Natural Sources of Indirubin Derivatives. Analysis thereof in Plasma and Tissues – Toxicological studies.
No full textΟι ινδιρουβίνες είναι αλκαλοειδείς ενώσεις δι-ινδόλης που απαντώνται φυσικά σε διάφορα φυτά που φέρουν την χρωστική indigoαλλά και στα γαστερόποδα μαλάκια. Τα μόρια αυτά γίναν αρχικά γνωστά για την μακρά ιστορία τους στην βιομηχανία της βαφής. Ωστόσο, τις δύο τελευταίες δεκαετίες, οι χημικές και βιολογικές μελέτες των ινδιρουβίνων έχουν αυξηθεί δραματικά λόγω της βιο-δραστικότητάς τους ενάντια σε πολυάριθμες καρκινικές σειρές ανθρώπινων κυττάρων με κύριο μηχανισμό δράσης την αναστολή των πρωτεϊνικώνκινασών. Ως εκ τούτου, ο σκοπός της εργασίας αυτής ήταν αρχικά η διερεύνηση και ανάλυση νέων πιθανών πηγών που φέρουν ινδιρουβίνες, χρησιμοποιώντας ένα σύστημα προηγμένων αναλυτικών τεχνικών (UHPLC-ESI-MS/MS).Οι πηγές που αναλύθηκαν και πραγματοποιήθηκε η ταυτοποίηση ιντιρουμπίνων είναι τρία θαλάσσια μαλάκια (Hexaplex trunculus, Rapana venosa και Plicopurpura Pansa), ένα φυτό (Isatis tomentella) και ένα φαρμακευτικό προϊόν (Danggui Longgui Wan).Η απομόνωση των ινδιρουβίνων αλλά και των κύριων μεταβολιτών του Hexaplex trunculusκαι του Isatis tomentellaπραγματοποιήθηκε με Χρωματογραφία Κατανομής με Φυγοκέντριση(FCPC).Αρκετά εκχυλίσματα των αδένων του Rapana venosaμελετήθηκαν για πρώτη φορά,με LC-MS-ESI(-), αναδεικνύοντας το εκχύλισμα του οξικού αιθυλεστέρα ωςτο πλουσιότερο σε δευτερογενείς μεταβολίτες αλλά και σε πολλές βρωμιομένες και μη βρωμιομένες πρόδρομες ενώσειςινδιρουβίνων. Στο γάλα της Plicopurpura Pansaταυτοποιήθηκαν έντεκα βρωμιούχες ενώσεις, μεταξύ των οποίων οι τρείς δεν φέρουν καμία επιστημονική αναφοράς.,ΣτοφυτόIsatis tomentellaανιχνεύθηκαν ινδιρουβίνες, η χρωστική indigo, διάφορα αμινοξέα, νουκλεοσίδια και γλυκοζυλιωμένα και μη γλυκοζυλιωμένα φλαβονοειδή. Στομεθανολικό εκχύλισμα τουI. tomentellaσυνολικά ανιχνεύθηκαν 46 μεταβολίτεςενώ πραγματοποιήθηκε περαιτέρω απομόνωση τους με την τεχνική FCPC. Η απόδοση δομής και καθαρότητας των απομονωμένων φυσικών μορίωνπραγματοποιήθηκε με έναν συνδυασμό προηγμένων φασματοσκοπικών (1 και 2D-NMR) και φασματομετρικών (LC-HRMSn ) τεχνικών και σύγκριση με τα δεδομένα στη βιβλιογραφία.Indirubins are bis-indole alkaloid compounds occurring naturally in various indigo-containing plants and mollusk gastropods. These molecules were initially known for their long history in the dye industry. However, during the last two decades, the chemical and biological studies of indirubins have increased tremendously due to the discovery of their bio-activities against numerous human cancer cell lines mainly through the inhibition of protein kinases. Therefore, the aim of this work was firstly to several potential new sources of indirubins using a UHPLC-ESI-MS/MS platform.Thus, three marine mollusks (Hexaplex trunculus, Rapana venosa, and Plicopurpura pansa), one plant (Isatis tomentella), and one pharmaceutical product (Danggui Longgui Wan) were analyzed for the identification of the indirubins thereof. The indirubins and the major components of the mollusk Hexaplex trunculus and the plant Isatis tomentella were further isolated using newly developed FCPC methodology.The glands of R. venosa were studied here for the very first time; several extracts were produced and analyzed.The ethyl acetate extract which was the richest in secondary metabolites revealed in LC-MS-ESI(-) the presence of several brominated and non-brominated indirubin precursors namely. The milk of P. pansadisplayed eleven brominated compounds, among which eight are previously reportedand three are unknown.Indirubin and indigo were detected in I. tomentella which also contained several amino acids, nucleosides, glycosylated and non-glycosylated flavonoids. A total of forty-six metabolites were detected in this extract and its major constituents were isolated using step-gradient CPC technique, and structurally elucidated using NMR and HRMS technique and comparison to data in the literature
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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