RESUMEN
Correction for 'Emerging pollutants in the Esmeraldas watershed in Ecuador: discharge and attenuation of emerging organic pollutants along the San Pedro-Guayllabamba-Esmeraldas rivers' by A. Voloshenko-Rossin et al., Environ. Sci.: Processes Impacts, 2015, 17, 41-53, https://doi.org/10.1039/C4EM00394B.
RESUMEN
The therapeutic and preventive activities of retinoids in cancer are due to their ability to modulate the growth, differentiation, and survival or apoptosis of cancer cells. Here we show that in NB4 acute promyelocytic leukemia cells, retinoids selective for retinoic-acid receptor-alpha induced an autoregulatory circuitry of survival programs followed by expression of the membrane-bound tumor-selective death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand, also called Apo-2L). In a paracrine mode of action, TRAIL killed NB4 as well as heterologous and retinoic-acid-resistant cells. In the leukemic blasts of freshly diagnosed acute promyelocytic leukemia patients, retinoic-acid-induced expression of TRAIL most likely caused blast apoptosis. Thus, induction of TRAIL-mediated death signaling appears to contribute to the therapeutic value of retinoids.
Asunto(s)
Apoptosis , Leucemia Promielocítica Aguda/tratamiento farmacológico , Glicoproteínas de Membrana/metabolismo , Tretinoina/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Antineoplásicos/uso terapéutico , Proteínas Reguladoras de la Apoptosis , Trióxido de Arsénico , Arsenicales/uso terapéutico , Caspasas/metabolismo , Diferenciación Celular , Técnicas de Cocultivo , Humanos , Immunoblotting , Proteínas Inhibidoras de la Apoptosis , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Glicoproteínas de Membrana/uso terapéutico , FN-kappa B/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Óxidos/uso terapéutico , Comunicación Paracrina , Proteínas/genética , Proteínas/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor 1 Asociado a Receptor de TNF , Ligando Inductor de Apoptosis Relacionado con TNF , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
New neutral bis(alkyl) Sc and Y complexes [N,Npy,N-]Ln(CH2SiMe3)2(THF)n [n = 0, Ln = Sc (1Sc), Y (1Y); n = 1, Ln = Y (1YTHF)] stabilized by a tridentate monoanionic amidopyridinate ligand were straightforwardly prepared by alkane elimination, upon mixing ligand [N,Npy,N-]H and metal precursor Ln(CH2SiMe3)3(THF)2 in toluene at 0 °C. Depending on the work-up conditions, yttrium bis(alkyl)s were isolated as either a pentacoordinate Lewis base free complex [N,Npy,N-]Y(CH2SiMe3)2 (1Y) or as a hexacoordinate THF adduct [N,Npy,N-]Y(CH2SiMe3)2THF (1YTHF). For the smaller Sc ion the only solvent-free complex [N,Npy,N-]Y(CH2SiMe3)2 (1Sc) was isolated as a pentacoordinate species irrespective of the reaction/work-up/crystallization conditions applied. Complexes 1Ln (Ln = Y, Sc) and 1YTHF were scrutinized as pre-catalysts in ternary catalytic systems Ln/borate/AliBu3 (borate = [HNMe2Ph][B(C6F5)4] or [Ph3C][B(C6F5)4]), applied to isoprene (IP) polymerization, providing moderate activity albeit high selectivity with predominant formation of 1,4-cis polyisoprene (up to 99%). The same complexes proved to be effcient catalysts also for the intermolecular hydrolelementation of styrene with various EH sustrates (pyrrolidine, morpholine, Ph2PH, PhPH2, PhSH) affording linear anti-Markovnikov addition products exclusively. After a preliminary activation by B(C6F5)3, selected bis(alkyl) complexes from this series have been finally used as valuable pre-catalysts for the CO2 hydrosylilation to CH4 in the presence of organosilanes as reducing agents (PhMe2SiH, PhSiH3, Et2MeSiH).
RESUMEN
With 12 percent of U.S. electricity now being supplied by nuclear power, Commonwealth Edison has found nuclear plants to be good investments relative to other base load energy sources. The country's largest user of nuclear power, Commonwealth Edison, estimates that its commitment to nuclear saved its customers about 10 percent on their electric bills in 1977, compared to the cost with the next best alternative, coal. This advantage is seen as continuing, contrary to criticisms of the economics and reliability of nuclear power and claims that it has hidden subsidies. It is concluded that there is a need for both nuclear and coal and that government policy precluding or restricting either would be unwise.
RESUMEN
The protein Daxx promotes Fas-mediated cell death through activation of apoptosis signal-regulating kinase 1, leading to the activation of the MAPKs JNK and p38. Owing to the in utero lethality of daxx-deficient mice, the in vivo role of Daxx has been so far difficult to analyze. We have generated transgenic mice expressing a dominant-negative form of Daxx (Daxx-DN) in the T-cell lineage. We show that Daxx is recruited to the Fas receptor upon FasL engagement and that Daxx-DN expression protects activated T cells from Fas-induced cell death, by preventing the death-inducing signal complex to be properly formed. Normal lymphocyte development and homeostasis are nevertheless observed. Interestingly, we report that both in vitro and in vivo stimulation of Daxx-DN T-lymphocytes leads to increased proliferative T-cell responses. This increased proliferation is associated with a marked increase in tyrosine phosphorylation of LAT and ZAP70 as Daxx-DN favor their recruitment to the T-cell receptor (TCR) complex. These findings identify Daxx as a critical regulator of T-lymphocyte homeostasis by decreasing TCR-induced cell proliferation and by promoting Fas-mediated cell death.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Portadoras/metabolismo , Proteína Ligando Fas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Activación de Linfocitos , Proteínas Nucleares/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Receptor fas/fisiología , Animales , Apoptosis/fisiología , Caspasas/metabolismo , Proliferación Celular , Proteínas Co-Represoras , Genes Dominantes , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Células Jurkat , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Chaperonas Moleculares , Linfocitos T/químicaRESUMEN
Retinoic acid (RA), used as first-line therapy for acute promyelocytic leukemia (APL), exerts its antileukemic activity by inducing blast differentiation and activating tumor-selective TNF-related apoptosis-inducing ligand (TRAIL) signaling. To identify downstream mediators of RA signaling, we used retrovirus-mediated insertion mutagenesis in PLB985 leukemia cells and established the RA-resistant cell line WY-1. In PLB985, but not WY-1 cells, RA induced TRAIL and its DR4 and DR5 receptors. Knocking down TRAIL expression by RNA interference blocked RA-induced apoptosis. WY-1 cells are defective for RA-induced differentiation, G1 arrest and exhibit co-resistance to TRAIL. In WY-1 cells, a single virus copy is integrated into a novel RA-regulated gene termed RAM (retinoic acid modulator). RAM is expressed in the myelomonocytic lineage and extinguished by RA in PLB985, but not WY-1 cells. Whereas knocking down RAM expression by RNA interference promoted RA-induced differentiation and TRAIL-triggered apoptosis of PLB985 and WY-1 cells, overexpression of the predicted 109 amino-acid RAM open reading frame did not alter RA signaling in PLB985 cells. This indicates that, apart from encoding the putative RAM protein, RAM RNA may exert additional functions that are impaired by the retrovirus insertion. Our study demonstrates that RA induction of the TRAIL pathway is also operative in leukemia cells lacking an RARalpha oncofusion protein and identifies RAM as a novel RA-dependent modulator of myeloid differentiation and death.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Resistencia a Antineoplásicos/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Glicoproteínas de Membrana/metabolismo , Tretinoina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas de Unión al GTP rab/genética , Secuencia de Aminoácidos , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/farmacología , Secuencia de Bases , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Mieloide/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/farmacología , Datos de Secuencia Molecular , Mutagénesis Insercional , ARN Largo no Codificante , Receptores de Ácido Retinoico/efectos de los fármacos , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/efectos de los fármacos , Receptores del Factor de Necrosis Tumoral/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Receptor alfa de Ácido Retinoico , Receptores X Retinoide/efectos de los fármacos , Receptores X Retinoide/metabolismo , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNF , Tretinoina/metabolismo , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/farmacología , Proteínas de Unión al GTP rab/efectos de los fármacos , Proteínas de Unión al GTP rab/metabolismo , Proteínas rab27 de Unión a GTPRESUMEN
The interaction of the η(1)-tetrahydroborate copper(i) complex (triphos)Cu(η(1)-BH4) () with proton donors [CF3CH2OH (TFE), (CF3)2CHOH (HFIP), (CF3)3COH (PFTB), PhOH, p-NO2C6H4OH (PNP), p-NO2C6H4N[double bond, length as m-dash]NC6H4OH (PNAP), CF3OH] was a subject of a combined IR spectroscopic and theoretical investigation. Spectral (Δν) and thermodynamic (ΔH) parameters of dihydrogen bond (DHB) formation were determined experimentally. The terminal hydride ligand (characterized by the basicity factor Ej(BH) = 0.87 ± 0.01) is found to be a site of proton transfer which begins with nucleophilic substitution of BH4(-) by the alcohol oxygen atom on the copper center (BH pathway). The activation barrier computed for (CF3)2CHOH in CH2Cl2 - ΔG = 20.6 kcal mol(-1) - is in good agreement with the experimental value (ΔG = 20.0 kcal mol(-1)). An abnormal dependence of the reaction rate on the proton donor strength found experimentally in dichloromethane is explained computationally on the basis of the variation of the structural and energetic details of this process with the proton donor strength. In the second reaction mechanism found (CuH pathway), DHB complexes with the initial ROH coordination to the bridging hydride lead to B-Hbr bond cleavage with BH3 elimination. "Copper assistance" via the CuO interaction is not involved. This mechanism can be evoked to explain the occurrence of proton transfer in coordinating solvents.
RESUMEN
On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.
Asunto(s)
Apoptosis/efectos de los fármacos , Leucemia Promielocítica Aguda/patología , Receptores de Ácido Retinoico/metabolismo , Retinoides/farmacología , Transducción de Señal , Factores de Transcripción/metabolismo , Sangre , Diferenciación Celular/efectos de los fármacos , Línea Celular , Medios de Cultivo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Fragmentación del ADN , Dimerización , Resistencia a Medicamentos , Etiquetado Corte-Fin in Situ , FN-kappa B/metabolismo , Receptores de Ácido Retinoico/antagonistas & inhibidores , Receptores X Retinoide , Retinoides/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Células Tumorales CultivadasRESUMEN
The death receptor Fas undergoes a variety of post-translational modifications including S-palmitoylation. This protein acylation has been reported essential for an optimal cell death signaling by allowing both a proper Fas localization in cholesterol and sphingolipid-enriched membrane nanodomains, as well as Fas high-molecular weight complexes. In human, S-palmitoylation is controlled by 23 members of the DHHC family through their palmitoyl acyltransferase activity. In order to better understand the role of this post-translational modification in the regulation of the Fas-mediated apoptosis pathway, we performed a screen that allowed the identification of DHHC7 as a Fas-palmitoylating enzyme. Indeed, modifying DHHC7 expression by specific silencing or overexpression, respectively, reduces or enhances Fas palmitoylation and DHHC7 co-immunoprecipitates with Fas. At a functional level, DHHC7-mediated palmitoylation of Fas allows a proper Fas expression level by preventing its degradation through the lysosomes. Indeed, the decrease of Fas expression obtained upon loss of Fas palmitoylation can be restored by inhibiting the lysosomal degradation pathway. We describe the modification of Fas by palmitoylation as a novel mechanism for the regulation of Fas expression through its ability to circumvent its degradation by lysosomal proteolysis.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Receptor fas/metabolismo , Acetiltransferasas , Sustitución de Aminoácidos , Apoptosis , Línea Celular Tumoral , Cicloheximida/farmacología , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Lipoilación , Lisosomas/metabolismo , Procesamiento Proteico-Postraduccional , Estabilidad Proteica/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptor fas/genéticaRESUMEN
Water quality characteristics and emerging organic pollutants were sampled along the San Pedro-Guayllabamba-Esmeraldas River and its main water pollution streams in the summer of 2013. The annual flow rate of the stream is 22 000 Mm(3) y(-1) and it collects the wastewater of Quito-Ecuador in the Andes and supplies drinking water to the city of Esmeraldas near the Pacific Ocean. The most persistent emerging pollutants were carbamazepine and acesulfame, which were found to be stable along the San Pedro-Guayllabamba-Esmeraldas River, whereas the concentration of most other organic emerging pollutants, such as caffeine, sulfamethoxazole, venlafaxine, O-desmethylvenlafaxine, and steroidal estrogens, was degraded to a large extent along the 300 km flow. The mass rate of the sum of cocaine and benzoylecgonine, its metabolite, was increased along the stream, which may be attributed to coca plantations and wild coca trees. This raises the possibility of using river monitoring as an indirect way to learn about changes in coca plantations in their watersheds. Several organic emerging pollutants, such as venlafaxine, carbamazepine, sulphamethoxazole, and benzoylecgonine, survived even the filtration treatment at the Esmeraldas drinking water system, though all except for benzoylecgonine are found below 20 ng L(-1), and are therefore not likely to cause adverse health effects. The research provides a way to compare drug consumption in a major Latin American city (Quito) and shows that the consumption of most sampled drugs (carbamazepine, venlafaxine, O-desmethylvenlafaxine, sulphamethoxazole, ethinylestradiol) was below their average consumption level in Europe, Israel, and North America.
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Monitoreo del Ambiente , Compuestos Orgánicos/análisis , Ríos/química , Contaminantes Químicos del Agua/análisis , Ciudades , EcuadorRESUMEN
The helminth parasite fauna of a natural population of the octodontid, Ctenomys talarum, was studied. Parasites that were found included the nematodes Heligmostrongylus sp. and Trichuris sp. Total prevalence of parasitism was 92.3%, mean intensity of infection was 22.7 worms, and mean abundance was 21 worms. Prevalence and mean abundance of infection with Heligmostrongylus sp. were higher in C. talarum males relative to females. Ecological and physiological causes, as well as the mating system of the host species, influence the likelihood of sex differences in parasite infection. The low parasite burden and diversity of C. talarum are associated with restrictions imposed by the subterranean habitat and with life-history traits of these rodents. Whether these findings apply to other Ctenomys spp. is unknown.
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Helmintiasis Animal/epidemiología , Enfermedades de los Roedores/epidemiología , Factores de Edad , Animales , Argentina/epidemiología , Ambiente , Femenino , Helmintiasis Animal/parasitología , Masculino , Prevalencia , Enfermedades de los Roedores/parasitología , Roedores , Factores Sexuales , Tricuriasis/epidemiología , Tricuriasis/parasitología , Tricuriasis/veterinariaRESUMEN
Fas ligand (FasL) is a transmembrane protein that regulates cell death in Fas-bearing cells. FasL-mediated cell death is essential for immune system homeostasis and the elimination of viral or transformed cells. Because of its potent cytotoxic activity, FasL expression at the cell surface is tightly regulated, for example, via processing by ADAM10 and SPPL2a generating soluble FasL and the intracellular fragments APL (ADAM10-processed FasL form) and SPA (SPPL2a-processed APL). In this study, we report that FasL processing by ADAM10 counteracts Fas-mediated cell death and is strictly regulated by membrane localization, interactions and modifications of FasL. According to our observations, FasL processing occurs preferentially within cholesterol and sphingolipid-rich nanodomains (rafts) where efficient Fas-FasL contact occurs, Fas receptor and FasL interaction is also required for efficient FasL processing, and FasL palmitoylation, which occurs within its transmembrane domain, is critical for efficient FasL-mediated killing and FasL processing.
Asunto(s)
Apoptosis , Proteína Ligando Fas/metabolismo , Proteínas ADAM/metabolismo , Proteína ADAM10 , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Membrana Celular/metabolismo , Humanos , Lipoilación , Proteínas de la Membrana/metabolismo , Unión ProteicaRESUMEN
The cell biological activity of novel retinoids and rexinoids is described. The stereochemistry of the new compounds was analyzed and ligand docking experiments revealed the structural basis of their RAR binding characteristics. The new ligands activate nuclear retinoic acid receptors (RAR, RXR) with distinct selectivity patterns, as determined in genetically engineered 'reporter' cells. The biological activity of the novel retinoids was assessed by differentiation of NB4 acute promyelocytic leukemia cells.