The role of a2ß1 integrin in anchorage dependent apoptosis of breast carcinoma and hepatoma cells

The role of collagen specific a2ß1 integrin in anchorage dependent apoptosis (anoikis) was investigated. Stimulation of a2ß1 signaling with immobilized anti-a2 antibody markedly sensitized human MCF-7 breast carcinoma and HepG2 hepatoma cells to anoikis. Accordingly, down-regulation of a2ß1 by a2-specific siRNA decreased the percentage of cells undergoing anoikis. These results for the first time provide direct evidence that a2ß1 receptor can transduce the signal to promote death in matrix deprived cells

Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

Given the immense significance of p53 restoration for anti-cancer therapy and that p53-activating molecules are in clinical trials, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of a novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in allosteric regulation of p53, whose targeting by small molecules RITA, PpIX and licofelone blocks the binding of two p53 inhibitors, MDM2 and MDMX, thereby restoring p53 function. Deletion and mutation analysis followed by molecular modeling and its thorough validation, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site in p53 induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators as targeted drugs. Our study provides a basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacopeia

Glucosinolates, myrosinase hydrolysis products, and flavonols found in rocket (Eruca sativa and Diplotaxis tenuifolia)

Rocket species have been shown to have very high concentrations of glucosinolates and flavonols, which have numerous positive health benefits with regular consumption. In this review we highlight how breeders and processors of rocket species can utilize genomic and phytochemical research to improve varieties and enhance the nutritive benefits to consumers. Plant breeders are increasingly looking to new technologies such as HPLC, UPLC, LC-MS and GC-MS to screen populations for their phytochemical content to inform plant selections. Here we collate the research that has been conducted to-date in rocket, and summarise all glucosinolate and flavonol compounds identified in the species. We emphasize the importance of the broad screening of populations for phytochemicals and myrosinase degradation products, as well as unique traits that may be found in underutilized gene bank resources. We also stress that collaboration with industrial partners is becoming essential for long-term plant breeding goals through research

Fucans, but Not Fucomannoglucuronans, Determine the Biological Activities of Sulfated Polysaccharides from Laminaria saccharina Brown Seaweed

Sulfated polysaccharides from Laminaria saccharina (new name: Saccharina latissima) brown seaweed show promising activity for the treatment of inflammation, thrombosis, and cancer; yet the molecular mechanisms underlying these properties remain poorly understood. The aim of this work was to characterize, using in vitro and in vivo strategies, the anti-inflammatory, anti-coagulant, anti-angiogenic, and anti-tumor activities of two main sulfated polysaccharide fractions obtained from L. saccharina: a) L.s.-1.0 fraction mainly consisting of O-sulfated mannoglucuronofucans and b) L.s.-1.25 fraction mainly composed of sulfated fucans. Both fractions inhibited leukocyte recruitment in a model of inflammation in rats, although L.s.-1.25 appeared to be more active than L.s.-1.0. Also, these fractions inhibited neutrophil adhesion to platelets under flow. Only fraction L.s.-1.25, but not L.s.-1.0, displayed anticoagulant activity as measured by the activated partial thromboplastin time. Investigation of these fractions in angiogenesis settings revealed that only L.s.-1.25 strongly inhibited fetal bovine serum (FBS) induced in vitro tubulogenesis. This effect correlated with a reduction in plasminogen activator inhibitor-1 (PAI-1) levels in L.s.-1.25-treated endothelial cells. Furthermore, only parent sulfated polysaccharides from L. saccharina (L.s.-P) and its fraction L.s.-1.25 were powerful inhibitors of basic fibroblast growth factor (bFGF) induced pathways. Consistently, the L.s.-1.25 fraction as well as L.s.-P successfully interfered with fibroblast binding to human bFGF. The incorporation of L.s.-P or L.s.-1.25, but not L.s.-1.0 into Matrigel plugs containing melanoma cells induced a significant reduction in hemoglobin content as well in the frequency of tumor-associated blood vessels. Moreover, i.p. administrations of L.s.-1.25, as well as L.s.-P, but not L.s.-1.0, resulted in a significant reduction of tumor growth when inoculated into syngeneic mice. Finally, L.s.-1.25 markedly inhibited breast cancer cell adhesion to human platelet-coated surfaces. Thus, sulfated fucans are mainly responsible for the anti-inflammatory, anticoagulant, antiangiogenic, and antitumor activities of sulfated polysaccharides from L. saccharina brown seaweed

In vivo tumor cell adhesion in the pulmonary microvasculature is exclusively mediated by tumor cell - endothelial cell interaction

<p>Abstract</p> <p>Background</p> <p>Metastasis formation is the leading cause of death among colon cancer patients. We established a new in-situ model of in vivo microscopy of the lung to analyse initiating events of metastatic tumor cell adhesion within this typical metastatic target of colon cancer.</p> <p>Methods</p> <p>Anaesthetized CD rats were mechanically ventilated and 10⁶human HT-29LMM and T84 colon cancer cells were injected intracardially as single cell suspensions. Quantitative in vivo microscopy of the lung was performed in 10 minute intervals for a total of 40 minutes beginning with the time of injection.</p> <p>Results</p> <p>After vehicle treatment of HT-29LMM controls 15.2 ± 5.3; 14.2 ± 7.5; 11.4 ± 5.5; and 15.4 ± 6.5 cells/20 microscopic fields were found adherent within the pulmonary microvasculature in each 10 minute interval. Similar numbers were found after injection of the lung metastasis derived T84 cell line and after treatment of HT-29LMM with unspecific mouse control-IgG. Subsequently, HT-29LMM cells were treated with function blocking antibodies against β1-, β4-, and αv-integrins wich also did not impair tumor cell adhesion in the lung. In contrast, after hydrolization of sialylated glycoproteins on the cells' surface by neuraminidase, we observed impairment of tumor cell adhesion by more than 50% (p < 0.05). The same degree of impairment was achieved by inhibition of P- and L-selectins via animal treatment with fucoidan (p < 0.05) and also by inhibition of the Thomson-Friedenreich (TF)-antigen (p < 0.05).</p> <p>Conclusions</p> <p>These results demonstrate that the initial colon cancer cell adhesion in the capillaries of the lung is predominantly mediated by tumor cell - endothelial cell interactions, possibly supported by platelets. In contrast to reports of earlier studies that metastatic tumor cell adhesion occurs through integrin mediated binding of extracellular matrix proteins in liver, in the lung, the continuously lined endothelium appears to be specifically targeted by circulating tumor cells.</p

Пространственная изменчивость изотопного состава и скорости накопления снега на снегомерном полигоне станции Восток (Центральная Антарктида)

The knowledge of the spatial distribution of the snow accumulation rate and isotopic composition in different scales, from local to continental, over the Antarctic Ice Sheet is critically important for the interpretation of the paleoclimate data obtained from deep ice cores, for correct assessment of the ice sheet mass balance, etc. With this in mind, we have synthesized geodetic, glaciological and geochemical data collected in the vicinity of central Antarctic Vostok station in 1970–2017 in order to shed light on the processes governing the spatial distribution of snow isotopic composition and accumulation rate in the spatial scale from 100 to 1000 m. First, we have discovered that snow surface height and snow accumulation rate field are strongly affected by the influence of the logistic convoy route annually operating between Russian Antarctic stations Vostok and Progress. This influence is detectable up to 1 km leeward from the route. At the same time the isotopic composition of the upper 10 cm of the snow does not show any anomalies in the vicinity of the route. This is an unexpected result, because large anomalies of the ice sheet surface (e.g., megadunes) are known to affect the snow isotopic composition. Second, in the undisturbed part of the snow surface near Vostok station we have discovered quasi-periodic (with the wavelength of about 400 m) low-amplitude variations of the surface height that are covariant with the corresponding waves in snow accumulation and isotopic composition. We suggest that spatial variability of the snow isotopic composition is due to the different ratio of summer and winter precipitation deposited in different locations, as evident from a strong negative correlation between δD and dxs parameters. The results of this study may explain the nature of the low-frequency noise (with the time-scale from decades to centuries) observed in the climate records obtained from shallow and deep ice cores in central Antarctica.Изучение пространственного распределения скорости накопления и изотопного состава снега в различных масштабах на поверхности антарктического ледяного покрова критически важно для интерпретации палеоклиматических данных по глубоким ледяным кернам, для корректной оценки баланса массы ледяного щита и т.д. Впервые на основании большого объема геодезических, гляциологических и геохимических данных была детально изучена пространственная изменчивость изотопного состава и скорости накопления снега в районе станции Восток (Центральная Антарктида) в пространственном масштабе от 100 до 1000 м. Показано, что высота снежной поверхности и скорость накопления снега изученной территории существенно преобразованы влиянием проходящей здесь трассы санно-гусеничных походов между станциями Восток и Прогресс. В ненарушенной части данной территории выявлены квазипериодические колебания высоты поверхности с горизонтальными размерами порядка 400 м («мезодюны») и ассоциированные с ними аномалии изотопного состава и скорости накопления снега. Полученные результаты могут прояснить природу низкочастотного шума, наблюдаемого в климатических рядах, полученных по антарктическим ледяным кернам