196,776 research outputs found
Therapeutic Opportunities Offered by the Excessive Lactate Production in Cancer
No full textThe majority of cancers of various tissue origin display wide portions suffering from insufficient respiration, due to permanent or transient hypoxia, which occurs during tumor development. This condition leads to the development of a glycolytic phenotype, where a compensatory lactate production takes place, in order to provide the cancer cells with sufficient amounts of energy and anabolites. Lactate is not just as a waste product of the glycolytic process, instead it plays a key role in the progression of cancer, since it promotes angiogenesis, cell migration, immune escape and radioresistance. Moreover, lactate can still constitute a metabolic fuel for oxidative tumor cells or vascular endothelial cells, and it can establish a symbiotic cell-cell shuttling system with stromal cells. Therefore, these peculiar roles of lactate in invasive tumors constitutes a high-priority target for future anti-cancer therapeutics [1].
Therapeutic interventions aimed at reducing lactate production in cancer tissues may consist of: a) reduction of glucose uptake (calorie-restricted ketogenic diet, physical exercise, inhibitors of glucose transporters); b) inhibition of enzymes involved in key-steps of glycolysis (inhibitors of hexokinase, phosphofructokinase, lactate dehydrogenase); c) block of the cellular trafficking of lactate (inhibitors of monocarboxylate transporters); d) enhancement of the mitochondrial oxidative metabolism (hyperbaric oxygen therapy, removal of inhibition of the Krebs cycle, for example, by using inhibitors of pyruvate dehydrogenase kinase) [2].
We have developed compounds that exert an anti-proliferative action on cancer cells by specific interventions on cancer metabolism, such as, inhibition of lactate dehydrogenase (LDH) activity [3,4], or reduction of glucose uptake through specific transmembrane transporters (GLUT) [5]. Furthermore, some of the LDH-inhibitors demonstrated a remarkable synergism with gemcitabine against pancreatic cancer cells in hypoxia [6]. and an improved activation of the redox-sensitive anti-cancer prodrug EO9 by means of an induced increase of the NADH/NAD+ cell ratio [7].
It is important to note that the development of agents that target lactate production, trafficking, and metabolism (by these or other methods) hold promise for treating nearly all invasive cancers, provided they present an appropriate therapeutic window.
References
1) J. R. Doherty, J. L. Cleveland. J. Clin. Invest. 2013, 123, 3685–3692.
2) C. Granchi, F. Minutolo. ChemMedChem 2012, 7, 1318-1350.
3) C. Granchi, S. Roy, C. Giacomelli, et al. J. Med. Chem. 2011, 54, 1599–1612.
4) E. C. Calvaresi, C. Granchi, T. Tuccinardi, et al. ChemBioChem 2013, 14, 2263–2267.
5) T. Tuccinardi, C. Granchi, J. Iegre, et al. Bioorg. Med. Chem. Lett. 2013, 23, 6923–6927.
6) M. Maftouh, A. Avan, R. Sciarrillo, et al. Br. J. Cancer 2014, 110, 172-182.
7) S. J. Allison, J. R. P. Knight, C. Granchi, et al. Oncogenesis 2014, 3, e102; DOI: 10.1038/oncsis.2014.16
Particle Inception in a Laminar Premixed Benzene Flame
No full textSpectral optical techniques, including light extinction and laser induce fluorescence and incandescence measurements, are combined to characterize large-molecule soot precursors and soot in a slightly sooting flame of benzene at atmospheric pressure. Light absorption coupled to in-situ light scattering measurements and ex-situ Atomic Force Microscopy also allowed the evaluation of particle sizes. In the benzene flame high molecular mass structures with typical sizes of 3–4nm are formed in the main oxidation region of the flame. The radical-rich flame environment in which these compounds are formed promotes their dehydrogenation increasing the level of their aromaticity. As a result, nanoparticles with typical sizes of about 5 nm, absorbing and fluorescing in the visible are formed. These compounds reach a maximum concentration just before the appearance of incandescent soot particles
Wall structure finite-element by BEM coupling
No full textThe calculation of structures made of the assembly of several walls requires finite element modeling, henceforth it gives raise to a large number of degrees of freedom. The actual work shows that the number of parameters is reduced by using Boundary Elements to derive the stiffness matrix of the element. The proposed technique gives origin to positive definite and symmetrical matrix due to the use of constant boundary elements. Moreover, the resulting matrix can be assembled together with Finite Element ones in order to obtain the description of complex three dimensional structures. Substructuring and multi region modeling are possible and continuity relaxation between elements as well as interface and non linear constitutive laws can be comprised. Some examples are reported in order to verify the accuracy and the feasibility of the procedure for the elastic case
Una "nuova" cappella Minutolo presso il Duomo di Napoli: questioni di patronato e rapporti di prossimità tra residenze e cappelle gentilizie
No full textThe article presents the rediscovery of a chapel dedicated to the Annunciationwhich, at the beginning of the 15th century, Cardinal Enrico Minutolo wished tohave placed underneath his own funerary monument. This monument is still tobe found against the back wall of the Cappella dei Santi Pietro e Anastasia in thearchiepiscopal complex of Naples.Despite having almost completely disappeared from the historiographicaldiscussion, the chapel was located thanks first to a reassessment of informationthat was already known and second to a careful reading of archival documentsthat had not previously been consulted. In addition, thanks to the introductionof special equipment through the only point of access to the Minutolo chapel, aloophole located in the crypt, it has been possible for the first time to carry outa photographic campaign inside the chapel. The Chapel of the Annunziata is infact inaccessible through its entrance, which was walled up probably after the1980 earthquake; however, the close proximity to Palazzo Minutolo in Vico SedilCapuano, where a filled-in ogival arch survives and corresponds more or less tothe walled space, suggests that in ancient times members of the Minutolo familytook advantage of this gap to access the chapel from their residence.Against this backdrop, it is proposed that the better-known MinutoloChapelin the Cathedral belonged to the family well before 1402, which is thedate of a document commonly used as the first point of reference for the patronageof this aristocratic family. In addition to appealing to aspects of canon law,this claim is reinforced by consulting the will of a certain Pietro Minutolo, whoin the 1370s arranged to be buried there. This same Pietro was also responsiblefor the foundation of another family church near the Cathedral, dedicated toSanta Marta and demolished between the sixteenth and seventeenth centuries.This formed part of a broader strategy of urban settlement pursued by the family,which between the late medieval and the early modern periods possessed twomonumental residences and several noble churches in the area in question.<br
Anthropogenic Sinkholes: simulazione attraverso modellazione numerica dello sprofondamento prodotto in superficie dal collasso di una cavità: il caso della Grotta di Cocceio
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Discovery and optimization of benzoylpiperidine derivatives as new reversible, potent and selective MAGL inhibitors
No full textThe serine hydrolase monoacylglycerol lipase (MAGL) is the main responsible of the degradation of 2-arachidonoylglycerol, an endocannabinoid implicated in several physiological processes. Moreover, MAGL is involved in the formation of pro-tumorigenic signaling molecules. MAGL inhibition is considered a valid therapeutic approach to treat several pathological conditions, including several types of cancer.[1] So far, only a limited number of MAGL inhibitors have been discovered and most of them are characterized by an irreversible mechanism of action, determining the occurrence of undesired effects. In this study we identified a reversible MAGL inhibitor by a structure-based virtual screening analysis. With the aim of identifying more potent and selective MAGL inhibitors, chemical modifications were introduced to the original compound to improve both potency and selectivity.[2] The structural optimization led to the obtainment of nanomolar inhibitors (Figure 1), which are selective over other hydrolases and cannabinoid receptors. These new inhibitors exert an appreciable antiproliferative activity in cancer cells and are able to inhibit MAGL in in vivo assays.
[1] Mulvihill MM, Nomura DK, Life Sci. 2013; 92(8-9):492-497. [2] Granchi C, Rizzolio F, Palazzolo S, Carmignani S, Macchia M, Saccomanni G, Manera C, Martinelli A, Minutolo F, Tuccinardi T, J Med Chem. 2016; 59(22):10299-10314
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