291 research outputs found

    5-(carbamoylmethylene)-oxazolidin-2-ones as a promising class of heterocycles inducing apoptosis triggered by increased ROS levels and mitochondrial dysfunction in breast and cervical cancer

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    Oxazolidinones are antibiotics that inhibit protein synthesis by binding the 50S ribosomal subunit. Recently, numerous worldwide researches focused on their properties and possible involvement in cancer therapy have been conducted. Here, we evaluated in vitro the antiproliferative activity of some 5-(carbamoylmethylene)-oxazolidin-2-ones on MCF-7 and HeLa cells. The tested compounds displayed a wide range of cytotoxicity on these cancer cell lines, measured by MTT assay, exhibiting no cytotoxicity on non-tumorigenic MCF-10A cells. Among the nine tested derivatives, four displayed a good anticancer potential. Remarkably, OI compound showed IC50 values of 17.66 and 31.10 ”M for MCF-7 and HeLa cancer cells, respectively. Furthermore, we assessed OI effect on the cell cycle by FACS analysis, highlighting a G1 phase arrest after 72 h, supported by a low expression level of Cyclin D1 protein. Moreover, mitochondrial membrane potential was reduced after OI treatment driven by high levels of ROS. These findings demonstrate that OI treatment can inhibit MCF-7 and HeLa cell proliferation and induce apoptosis by caspase-9 activation and cytochrome c release in the cytosol. Hence, 5-(carbamoylmethylene)-oxazolidin-2-ones have a promising anticancer activity, in particular, OI derivative could represent a good candidate for in vivo further studies and potential clinical use

    Fractional calculus applied to model arterial viscoelasticity

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    Arterial viscoelasticity can be described using stress-relaxation experiments. To fit these curves, models with springs and dashpots, based on differential equations, were widely studied. However, uniaxial tests in arteries show particular shapes with an initial steep decay and a slow asymptotic relaxation. Recently, fractional order derivatives were used to conceive a new component called spring-pot that interpolates between pure elastic and viscous behaviors. In this work we modified a standard linear solid model replacing a dashpot with a spring-pot of order α. We tested the fractional model in human arterial segments. Results showed an accurate relaxation response during 1-hour with least squares errors below 1%. Fractional orders α were 0.2-0.4, justifying the extra parameter. Moreover, the adapted parameters allowed us to predict frequency responses that were similar to reported Complex Elastic Moduli in arteries. Our results indicate that fractional models should be considered as real alternatives to model arterial viscoelasticity

    Fractional-order viscoelasticity applied to describe uniaxial stress relaxation of human arteries.

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    Viscoelastic models can be used to better understand arterial wall mechanics in physiological and pathological conditions. The arterial wall reveals very slow time-dependent decays in uniaxial stress-relaxation experiments, coherent with weak power-law functions. Quasi-linear viscoelastic (QLV) theory was successfully applied to modeling such responses, but an accurate estimation of the reduced relaxation function parameters can be very difficult. In this work, an alternative relaxation function based on fractional calculus theory is proposed to describe stress relaxation experiments in strips cut from healthy human aortas. Stress relaxation (1 h) was registered at three incremental stress levels. The novel relaxation function with three parameters was integrated into the QLV theory to fit experimental data. It was based in a modified Voigt model, including a fractional element of order α, called spring–pot. The stressrelaxation predictionwas accurate and fast. Sensitivity plots for each parameter presented a minimum near their optimal values. Least-squares errors remained below 2%. Values of order α = 0.1–0.3 confirmed a predominant elastic behavior. The other two parameters of the model can be associated to elastic and viscous constants that explain the time course of the observed relaxation function. The fractional-order model integrated into the QLV theory proved to capture the essential features of the arterial wall mechanical response

    CD90 is regulated by notch1 and hallmarks a more aggressive intrahepatic cholangiocarcinoma phenotype

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    Background: Intrahepatic Cholangiocarcinoma (iCCA) is characterized by a strong stromal reaction playing a role in tumor progression. Thymus cell antigen 1 (THY1), also called Cluster of Differentiation 90 (CD90), is a key regulator of cell–cell and cell–matrix interaction. In iCCA, CD90 has been reported to be associated with a poor prognosis. In an iCCA PDX model, we recently found that CD90 was downregulated in mice treated with the Notch γ-secretase inhibitor Crenigacestat. The study aims to investigate the role of CD90 in relation to the NOTCH pathway. Methods: THY1/CD90 gene and protein expression was evaluated in human iCCA tissues and xenograft models by qRT-PCR, immunohistochemistry, and immunofluorescence. Notch1 inhibition was achieved by siRNA. THY1/CD90 functions were investigated in xenograft models built with HuCCT1 and KKU-M213 cell lines, engineered to overexpress or knockdown THY1, respectively. Results: CD90 co-localized with EPCAM, showing its epithelial origin. In vitro, NOTCH1 silencing triggered HES1 and THY1 down-regulation. RBPJ, a critical transcriptional regulator of NOTCH signaling, exhibited putative binding sites on the THY1 promoter and bound to the latter, implying CD90 as a downstream NOTCH pathway effector. In vivo, Crenigacestat suppressed iCCA growth and reduced CD90 expression in the PDX model. In the xenograft model, Crenigacestat inhibited tumor growth of HuCCT1 cells transfected to overexpress CD90 and KKU-M213 cells constitutively expressing high levels of CD90, while not affecting the growth of HuCCT1 control cells and KKU-M213 depleted of CD90. In an iCCA cohort, patients with higher expression levels of NOTCH1/HES1/THY1 displayed a significantly shorter survival. Conclusions: iCCA patients with higher NOTCH1/HES1/THY1 expression have the worst prognosis, but they are more likely to benefit from Notch signaling inhibition. These findings represent the scientific rationale for testing NOTCH1 inhibitors in clinical trials, taking the first step toward precision medicine for iCCA

    PEGylated Liposomes Loaded with Carbamate Inhibitor ANP0903 Trigger Apoptosis by Enhancing ER Stress in HepG2 Cancer Cells

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    Liver cancer is one of the most common causes of cancer death worldwide. In recent years, substantial progress has been made in the development of systemic therapies, but there is still the need for new drugs and technologies that can increase the survival and quality of life of patients. The present investigation reports the development of a liposomal formulation of a carbamate molecule, reported as ANP0903, previously tested as an inhibitor of HIV-1 protease and now evaluated for its ability to induce cytotoxicity in hepatocellular carcinoma cell lines. PEGylated liposomes were prepared and characterized. Small, oligolamellar vesicles were produced, as demonstrated by light scattering results and TEM images. The physical stability of the vesicles in biological fluids was demonstrated in vitro, alongside the stability during storage. An enhanced cellular uptake was verified in HepG2 cells treated with liposomal ANP0903, resulting in a greater cytotoxicity. Several biological assays were performed to elucidate the molecular mechanisms explaining the proapoptotic effect of ANP0903. Our results allow us to hypothesize that the cytotoxic action in tumor cells is probably due to the inhibition of the proteasome, resulting in an increase in the amount of ubiquitinated proteins within the cells, which in turn triggers activation of autophagy and apoptosis processes, resulting in cell death. The proposed liposomal formulation represents a promising approach to deliver a novel antitumor agent to cancer cells and enhance its activity

    Tuning the selectivity of light hydrocarbons in natural gas in a family of isoreticular MOFs

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    Purification of methane from other light hydrocarbons in natural gas is a topic of intense research due to its fundamental importance in the utilization of natural gas fields. Porous materials have emerged as excellent alternative platforms to conventional cryogenic methodologies to perform this task in a cost- and energy-efficient manner. Here we report a new family of isoreticular chiral MOFs, prepared from oxamidato ligands derived from natural amino acids L-alanine, L-valine and L-leucine, where, by increasing the length of the alkyl residue of the amino acid, the charge density of the MOF's channels can be tuned (1 > 2 > 3), decreasing the adsorption preference towards methane over light hydrocarbons thus improving this purification process. The validity of our rational design strategy has been proved by a combination of single-component adsorption isotherms, adsorption kinetics of CH4, C2H6, C3H8 and n-C4H10, and breakthrough experiments of binary CH4/C2H6 and CH4/C3H8 mixtures.This work was supported by the mineco (Spain) (Projects CTQ2013-46362-P, MAT2013-45008-P, MAT2016-81732-ERC, CTQ2016-75671-P and Excellence Unit “Maria de Maeztu” MDM-2015-0538), the Generalitat Valenciana (Spain) (Project PROMETEOII/2014/070, PROMETEOII/2014/004) and the Ministero dell’Istruzione, dell’Università e della Ricerca (Italy). T. G. and M. M. thank the Universitat de Valùncia and the mineco for predoctoral contracts. Thanks are also extended to the Ramón y Cajal Program (E. P. and E. V. R.-F. (RYC-2012-11427)). B. S. and J. G. acknowledge the financial support of the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 335746, CrystEng-MOF-MMM

    Confined Pt11+ Water Clusters in a MOF Catalyze the Low‐Temperature Water–Gas Shift Reaction with both CO2 Oxygen Atoms Coming from Water

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    The synthesis and reactivity of single metal atoms in a low‐valence state bound to just water, rather than to organic ligands or surfaces, is a major experimental challenge. Herein, we show a gram‐scale wet synthesis of Pt11+ stabilized in a confined space by a crystallographically well‐defined first water sphere, and with a second coordination sphere linked to a metal–organic framework (MOF) through electrostatic and H‐bonding interactions. The role of the water cluster is not only isolating and stabilizing the Pt atoms, but also regulating the charge of the metal and the adsorption of reactants. This is shown for the low‐temperature water–gas shift reaction (WGSR: CO + H2O → CO2 + H2), where both metal coordinated and H‐bonded water molecules trigger a double water attack mechanism to CO and give CO2 with both oxygen atoms coming from water. The stabilized Pt1+ single sites allow performing the WGSR at temperatures as low as 50 °C.This work was supported by the MINECO (Spain) (Projects CTQ2016–75671–P, MAT2013 40823–R, MAT2016–81732–ERC, CTQ2017–86735–P, MAT2017–86992–R, MAT2017–82288–C2–1–P and Excellence Units “Severo Ochoa” and “Maria de Maeztu” SEV–2016–0683 and MDM–2015–0538) the Generalitat Valenciana (PROMETEOII/2014/004) and the Ministero dell’Istruzione, dell’Università e della Ricerca (Italy) and the Junta de Andalucía (FQM–195). M. M. and M.–A. R. C. thanks the MINECO for a predoctoral contract. Thanks are also extended to the Ramón y Cajal Program (E. V. R.–F., E. P. and J.–C. H.–G.) and the “Subprograma atracció de talent–contractes postdoctorals de la Universitat de Valencia” (J. F.–S.). M. L.–H. acknowledges the financial support from the Juan de la Cierva Fellowships Program of MINECO (IJCI–2014–19367)
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