Isolation and Identification of Flavonoids Found in Zostera marina Collected in Norwegian Coastal Waters

In extracts of the seagrass Zostera marina, collected in coastal waters of West-Norway, fourteen different flavones and high amounts of rosmarinic acid were identified. Five of the flavones were found to be sulphated, among these were luteolin 7,3'-disulphate and chrysoeriol 7-sulphate structures previously not published with complete NMR assignments. Luteolin 7-O-β-(6''-malonyl) glucoside, and two other malonylated flavone compounds occurring in trace amounts, were identified for the first time in Z. marina. The sulphated flavones were fairly stable in slightly acidified (0.1% trifluoroacetic acid) extracts stored for months, however, under more acidic conditions (0.5% trifluoroacetic acid in the extracts) they were susceptible to undergo hydrolyses. When the solvents of purified fractions were removed by rotary evaporation, the sulphated flavones quickly decomposed to their corresponding aglycones due to the increased acid concentrations.publishedVersio

Anthocyanin Profile and Antioxidant Property of Anti-asthma Flowers of Cordyline terminalis (L.) Kunth (Agavaceae)

Cordyline terminalis flower is traditionally used to treat asthma and the purple color of the flower is suggestive of anthocyanins. The purpose of this study was to characterize and determine the antioxidant property of anthocyanins from C. terminalis purple flowers. Five anthocyanins, cyanidin 3,5-di-O-β-glucopyranoside (2.6 ± 0.2 mg/g fr. wt) (1), peonidin 3,5-di-O-β-glucopyranoside (2.8 ± 0.3 mg/g fr. wt) (2), cyanidin 3-O-β-(6″-O-E-p-caffeoylglucopyranoside)-5-O-β-glucopyranoside (3.2 ± 0.2 mg/g fr. wt) (3), cyanidin 3-O-β-(6″-O-E-p-coumaroylglucopyranoside)-5-O-β-glucopyranoside (6.2 ± 0.4 mg/g fr. wt) (4), and peonidin 3-O-β-(6″-O-E-p-coumaroylglucopyranoside)-5-O-β-glucopyranoside (9.8 ± 0.2 mg/g fr. wt) (5), were isolated from the flowers of C. terminalis by a combination of chromatographic techniques. Their structures were established by UV-visible, NMR, and ESI-MS. The extract exhibited appreciable antioxidant activity (IC50 ± SD = 13.1 ± 0.8 μg/mL) against quercetin (IC50 ± SD = 4.5 ± 0.4 μg/mL) compared to the individual anthocyanins (IC50 ± SD = 13.8 ± 0.5 to 16.4 ± 0.7 μg/mL) when measured using the 2,2-diphenyl-1-picryl-hydrazyl method. Cordyline terminalis flowers extract may be justified for use and standardization as herbal remedy for asthma.publishedVersio

Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair

Purpose: The ERCC1–XPF 5′–3′ DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs. Methods: We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein–protein interaction in cancer cells using proximity ligation assay. Results: Compound B9 showed the best activity being synergistic with cisplatin and mitomycin C in both colon and lung cancer cells. Also, B9 abolished the interaction between ERCC1 and XPF in cancer cells as shown by proximity ligation assay. Results of different compounds correlated with values from our previously obtained in silico predictions. Conclusion: Our results confirm the feasibility of the approach of targeting the protein–protein interaction between ERCC1 and XPF to sensitize cancer cells to alkylating agents, thanks to the improved binding affinity of the newly synthesized compounds

Ethical conference economies? Reimagining the costs of convening academic communities when moving online

Online conferences are widely thought to reduce many of the costs of convening academic communities. From lower carbon emissions, lower fees, less difficulty in attending (particularly for marginalised researchers), and greater accessibility, virtual events promise to address many of the issues that in-person events take for granted. In this article, we draw on a community economies framing from geographers J.K. Gibson-Graham to argue for centring the work of convening within efforts to explore reparative possibilities within the academy. Reflecting on the changing costs arising from moving an originally in-person conference series online, we argue for embracing the opportunities offered. We explore how organising teams might enact alternative values through allocating the material, financial and labour resources traditionally spent for these events differently. We look particularly at how our carbon and financial costs changed, and how, by retaining a fee, we were able to allocate our budgets in ways which redistributed the surplus to participants in need (rather than bolster conference centre profits). We then explore what these changing costs meant in terms of our attendance levels across career stages and geographical locations. Looking at whether our experiment resulted in increased support for online events, we examine the continued ambivalence felt for the virtual. Finally, while we largely explore the benefits of online options, our last section urges caution over assumptions that this move will result in a more sustainable academia, particularly given the intensifications surrounding high quality streaming video, and suggest that we treat current trends as ongoing experiments, rather than solutions

‘What about the coffee break?’: Designing virtual conference spaces for conviviality

Geography, like many other disciplines, is reckoning with the carbon intensity of its practices and rethinking how activities such as annual meetings are held. The Climate Action Task Force of the American Association of Geographers (AAG), for example, was set up in 2019 and seeks to transform the annual conference in light of environmental justice concerns. Mirroring shifts it geographic practice across the globe, these efforts point to a need to understand how new opportunities for knowledge production such as online events can operate effectively. In this article, we offer suggestions for best practice in virtual spaces arising from our Material Life of Time conference held in March 2021, a two day global event that ran synchronously across 15 time zones. Given concerns about lack of opportunities for informal exchanges at virtual conferences, or the “coffee break problem”, we designed the event to focus particularly on opportunities for conviviality. This was accomplished through a focus on three key design issues: the spatial, the temporal and the social. We review previous work on the benefits and drawbacks of synchronous and asynchronous online conference methods and the kinds of geographic communities they might support. We then describe our design approach and reflect on its effectiveness via a variety of feedback materials. We show that our design enabled high delegate satisfaction, a sense of conviviality, and strong connections with new colleagues. However we also discuss the problems with attendance levels and external commitments which hampered shared time together. We thus call for collective efforts to support the ‘event time’ of online meetings, rather than expectations to fit them around everyday tasks. Even so, our results suggest that synchronous online events need not result in geographical exclusions linked to time zone differences, and we outline further recommendations for reworking the spacetimes of the conference

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

This study assessed the antiproliferative activity of sapacitabine (CYC682, CS-682) in a panel of 10 human cancer cell lines with varying degrees of resistance or sensitivity to the commonly used nucleoside analogues ara-C and gemcitabine. Growth inhibition studies using sapacitabine and CNDAC were performed in the panel of cell lines and compared with both nucleoside analogues and other anticancer compounds including oxaliplatin, doxorubicin, docetaxel and seliciclib. Sapacitabine displayed antiproliferative activity across a range of concentrations in a variety of cell lines, including those shown to be resistant to several anticancer drugs. Sapacitabine is biotransformed by plasma, gut and liver amidases into CNDAC and causes cell cycle arrest predominantly in the G2/M phase. No clear correlation was observed between sensitivity to sapacitabine and the expression of critical factors involved in resistance to nucleoside analogues such as deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1, cytosolic 5′-nucleotidase and DNA polymerase-α. However, sapacitabine showed cytotoxic activity against dCK-deficient L1210 cells indicating that in some cells, a dCK-independent mechanism of action may be involved. In addition, sapacitabine showed a synergistic effect when combined with gemcitabine and sequence-specific synergy with doxorubicin and oxaliplatin. Sapacitabine is therefore a good candidate for further evaluation in combination with currently used anticancer agents in tumour types with unmet needs

ADP Ribosylation Factor Like 2 (Arl2) Regulates Breast Tumor Aggressivity in Immunodeficient Mice

We have previously reported that ADP ribosylation factor like 2 (Arl2), a small GTPase, content influences microtubule dynamics and cell cycle distribution in breast tumor cells, as well as the degree and distribution of phosphorylated P53. Here we show, in two different human breast adenocarcinoma models, that Arl2 content has a major impact on breast tumor cell aggressivity both in vitro and in vivo. Cells with reduced content of Arl2 displayed reduced contact inhibition, increased clonogenic or cluster formation as well as a proliferative advantage over control cells in an in vitro competition assay. These cells also caused larger tumors in SCID mice, a phenotype which was mimicked by the in vivo administration of siRNA directed against Arl2. Cells with increased Arl2 content displayed reduced aggressivity, both in vitro and in vivo, with enhanced necrosis and were also found to contain increased PP2A phosphatase activity. A rt-PCR analysis of fresh human tumor breast samples suggested that low Arl2 expression was associated with larger tumor size and greater risk of lymph node involvement at diagnosis. These data underline the role of Arl2, a small GTPase, as an important regulator of breast tumor cell aggressivity, both in vitro and in vivo

Structural Insights into the Inhibition of Cytosolic 5′-Nucleotidase II (cN-II) by Ribonucleoside 5′-Monophosphate Analogues

Cytosolic 5′-nucleotidase II (cN-II) regulates the intracellular nucleotide pools within the cell by catalyzing the dephosphorylation of 6-hydroxypurine nucleoside 5′-monophosphates. Beside this physiological function, high level of cN-II expression is correlated with abnormal patient outcome when treated with cytotoxic nucleoside analogues. To identify its specific role in the resistance phenomenon observed during cancer therapy, we screened a particular class of chemical compounds, namely ribonucleoside phosphonates to predict them as potential cN-II inhibitors. These compounds incorporate a chemically and enzymatically stable phosphorus-carbon linkage instead of a regular phosphoester bond. Amongst them, six compounds were predicted as better ligands than the natural substrate of cN-II, inosine 5′-monophosphate (IMP). The study of purine and pyrimidine containing analogues and the introduction of chemical modifications within the phosphonate chain has allowed us to define general rules governing the theoretical affinity of such ligands. The binding strength of these compounds was scrutinized in silico and explained by an impressive number of van der Waals contacts, highlighting the decisive role of three cN-II residues that are Phe 157, His 209 and Tyr 210. Docking predictions were confirmed by experimental measurements of the nucleotidase activity in the presence of the three best available phosphonate analogues. These compounds were shown to induce a total inhibition of the cN-II activity at 2 mM. Altogether, this study emphasizes the importance of the non-hydrolysable phosphonate bond in the design of new competitive cN-II inhibitors and the crucial hydrophobic stacking promoted by three protein residues

Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway

PurposeDeoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway involved in the production and maintenance of a balanced pool of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. dCK phosphorylates and therefore activates nucleoside analogs such as cytarabine, gemcitabine, decitabine, cladribine, and clofarabine that are used routinely in cancer therapy. Imaging probes that target dCK might allow stratifying patients into likely responders and nonresponders with dCK-dependent prodrugs. Here we present the biodistribution and radiation dosimetry of three fluorinated dCK substrates, (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, developed for positron emission tomography (PET) imaging of dCK activity in vivo.MethodsPET studies were performed in nine healthy human volunteers, three for each probe. After a transmission scan, the radiopharmaceutical was injected intravenously and three sequential emission scans acquired from the base of the skull to mid-thigh. Regions of interest encompassing visible organs were drawn on the first PET scan and copied to the subsequent scans. Activity in target organs was determined and absorbed dose estimated with OLINDA/EXM. The standardized uptake value was calculated for various organs at different times.ResultsRenal excretion was common to all three probes. Bone marrow had higher uptake for L: -(18)F-FAC and L: -(18)F-FMAC than (18)F-FAC. Prominent liver uptake was seen in L: -(18)F-FMAC and L: -(18)F-FAC, whereas splenic activity was highest for (18)F-FAC. Muscle uptake was also highest for (18)F-FAC. The critical organ was the bladder wall for all three probes. The effective dose was 0.00524, 0.00755, and 0.00910 mSv/MBq for (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, respectively.ConclusionThe biodistribution of (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC in humans reveals similarities and differences. Differences may be explained by different probe affinities for nucleoside transporters, dCK, and catabolic enzymes such as cytidine deaminase (CDA). Dosimetry demonstrates that all three probes can be used safely to image the deoxyribonucleoside salvage pathway in humans