RESUMO
Ruthenium(II) polypyridyl complexes continue to raise increasing interest for the encouraging results in several biomedical areas. Considering their vast chemical-physical repertoire, in particular the possibility to switch from the sensitization of reactive oxygen species (ROS) to ROS-scavenging abilities by tuning the nature of their ligands, it is therefore surprising that their potential as antioxidants has not been largely investigated so far. Herein, we explored the antioxidant behaviour of the novel ruthenium compound [Ru(dbpy)(2,3-DAN)Cl]PF6 (Ru1), featuring a benzoxazole derivative (dpby=2,6-bis(4-methyl-2-benzoxazolyl)pyridine) and the non-innocent 2,3-diamminonaftalene (2,3-DAN) ligand, along with the reference tpy-containing analogue [Ru(tpy)(2,3-DAN)Cl]PF6 (Ru2) (tpy=2,2':6',2''-terpyridine). Following the synthesis and the electrochemical characterization, chemical antioxidant assays highlighted the beneficial role of dpby for the ROS-scavenging properties of Ru1. These data have been corroborated by the highest protective effect of Ru1 against the oxidative stress induced in SH-SY5Y human neuroblastoma, which exerts pro-survival and anti-inflammatory actions. The results herein reported highlight the potential of Ru1 as pharmacological tool in neurodegenerative diseases and specially prove that the antioxidant properties of such compounds are likely the result of a non-trivial synergetic action involving the bioactive ligands in their chemical architectures.
Assuntos
Antioxidantes , Benzoxazóis , Complexos de Coordenação , Piridinas , Espécies Reativas de Oxigênio , Rutênio , Humanos , Rutênio/química , Benzoxazóis/química , Benzoxazóis/farmacologia , Ligantes , Antioxidantes/química , Antioxidantes/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Piridinas/química , Piridinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacosRESUMO
Bis-squaramide receptors L1-L4 bearing a dansyl moiety were synthesised and their potential applications as fluorescent probes towards non steroidal anti-inflammatory drugs naproxen and ketoprofen was investigated. A detailed photophysical characterization in CH3CN/DMSO solution (9 : 1 v/v) was conducted and demonstrated that the two macrocyclic receptors L1 and L2 show good sensitivity towards ketoprofen with an ON-OFF fluorescent response, while the two open chain receptors L3 and L4 behave similarly with the three guests considered. DFT theoretical calculations carried out on L2 and L4 as model receptors allowed to propose a possible coordination mode towards the guests. Finally, 1H-NMR spectroscopy in DMSO-d6/0.5% water solution demonstrated that the four receptors interact with the considered guests via H-bonds.
Assuntos
Cetoprofeno , Naproxeno , Naproxeno/farmacologia , Naproxeno/química , Cetoprofeno/farmacologia , Cetoprofeno/química , Dimetil Sulfóxido , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/químicaRESUMO
In this study, the ligands 23,24-dihydroxy-3,6,9,12-tetraazatricyclo[17.3.1.1(14,18)]eicosatetra-1(23),14,16,18(24),19,21-hexaene, L1, and 26,27-dihidroxy-3,6,9,12,15-pentaazatricyclo[20.3.1.1(17,21)]eicosaepta-1(26),17,19,21(27),22,24-hexaene, L2, were synthesized: they represent a new class of molecules containing a biphenol unit inserted into a macrocyclic polyamine fragment. The previously synthesized L2 is obtained herein with a more advantageous procedure. The acid-base and Zn(II)-binding properties of L1 and L2 were investigated through potentiometric, UV-Vis, and fluorescence studies, revealing their possible use as chemosensors of H+ and Zn(II). The new peculiar design of L1 and L2 afforded the formation in an aqueous solution of stable Zn(II) mono (LogK 12.14 and 12.98 for L1 and L2, respectively) and dinuclear (LogK 10.16 for L2) complexes, which can be in turn exploited as metallo-receptors for the binding of external guests, such as the popular herbicide glyphosate (N-(phosphonomethyl)glycine, PMG) and its primary metabolite, the aminomethylphosphonic acid (AMPA). Potentiometric studies revealed that PMG forms more stable complexes than AMPA with both L1- and L2-Zn(II) complexes, moreover PMG showed higher affinity for L2 than for L1. Fluorescence studies showed instead that the L1-Zn(II) complex could signal the presence of AMPA through a partial quenching of the fluorescence emission. These studies unveiled therefore the utility of polyamino-phenolic ligands in the design of promising metallo-receptors for elusive environmental targets.
RESUMO
The activity and interacting ability of a polyamidoamine (PAMAM) dendrimer modified with 4-N-methylpiperazine-1,8-naphthalimide units (termed D) and complexed by Cu(ii) ions, towards healthy and cancer cells were studied. Comparative electron paramagnetic resonance (EPR) studies of the Cu(ii)-D complex are presented: coordination mode, chemical structure, flexibility and stability of these complexes, in the absence and presence of myeloid cancer cells and peripheral blood mononuclear cells (PBMC). The interactions of Cu(ii) ions in the biological media at different equilibrium times were studied, highlighting different stability and interacting conditions with the cells. Furthermore, flow cytometry and confocal analysis, trace the peculiar properties of the dendrimers in PBMC and U937 cells. Indeed, a new probe (Fly) was used as a potential fluorescent tool for biological imaging of Cu(ii). The study highlights that dendrimer and, mainly, the Cu(ii) metallodendrimer are cytotoxic agents for the cells, specifically for U937 tumor cells, inducing mitochondrial dysfunction, ROS increase and lysosome involvement. The metallodendrimer shows antitumor selectivity, fewer affecting healthy PBMC, inducing a massive apoptotic cell death on U937 cells, in line with the high stability of this complex, as verified by EPR studies. The results underline the potentiality of this metallodendrimer to be used as anticancer drug.
Assuntos
Antineoplásicos , Dendrímeros , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Dendrímeros/química , Dendrímeros/metabolismo , Dendrímeros/farmacologia , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Leucócitos Mononucleares , Naftalimidas/farmacologia , PoliaminasRESUMO
A new series of ligands containing the 2-(2-hydroxy-3- naphthyl)-4-methylbenzoxazole (HNBO) fluorophore showed selectivity for Mg2+ ions, without the interference of Ca2+ . The most promising representative L3 resulted the best performing sensor for Mg2+ both in solution and embedded in an all-solid-state optode, especially towards real samples of drinkable water.
Assuntos
Água Potável , Corantes Fluorescentes , Ionóforos , ÍonsRESUMO
The fluorescent probes represent an important tool in the biological study, in fact characterization of cellular structures and organelles are an important tool-target for understanding the mechanisms regulating most biological processes. Recently, a series of polyamino-macrocycles based on 1,4,7,10-tetraazacyclododecane was synthesized, bearing one or two NBD units (AJ2NBD·4HCl) useful as sensors for metal cations and halides able to target and to detect apolar environment, as lipid membranes. In this paper, we firstly illustrate the chemical synthesis of the AJ2NBD probe, its electronic absorption spectra and its behavior regarding pH of the environment. Lack of any cellular toxicity and an efficient labelling on fresh, living cells was demonstrated, allowing the use of AJ2NBD in biological studies. In particular, this green fluorescent probe may represent a potential dye for the compartments involved in the endosomal/autophagic pathway. This research's field should benefit from the use of AJ2NBD as a vesicular tracer, however, to ensure the precise nature of vesicles/vacuoles traced by this new probe, other more specific tests are needed.
Assuntos
Corantes Fluorescentes , Lisossomos , Autofagia , EndossomosRESUMO
A scorpionate Zn2+ complex, constituted by a macrocyclic pyridinophane core attached to a pendant arm containing a fluorescent pyridyl-oxadiazole-phenyl unit (PyPD), has been shown to selectively recognize chloride anions, giving rise to changes in fluorescence emission that are clearly visible under a 365 nm UV lamp. This recognition event has been studied by means of absorption, fluorescence, and NMR spectroscopy, and it involves the intramolecular displacement of the PyPD unit by chloride anions. Moreover, since the chromophore is not removed from the system after the recognition event, the fluorescence can readily be restored by elimination of the bound chloride anion.
RESUMO
Two maltol-based ligands, N,N'-bis((3-hydroxy-4-pyron-2-yl)methyl)-1,4-piperazine (L1) and N,N',N'-tris((3-hydroxy-4-pyron-2-yl)methyl)-N-methylethylendiamine (L2), were synthesized and characterized. L1 and L2, containing, respectively, two and three maltol units spaced by a diamine fragment, were designed to evaluate how biological and binding features are affected by structural modifications of the parent compound malten. The acid-base behavior and the binding properties towards transition, alkaline-earth (AE) and rare-earth (RE) cations in aqueous solution, studied by potentiometric, UV-Vis and NMR analysis, are reported along with biological studies on DNA and leukemia cells. Both ligands form stable complexes with Cu(II), Zn(II) and Co(II) that were studied as metallo-receptors for AE and RE at neutral pH. L1 complexes are more affected than L2 ones by hard cations, the L1-Cu(II) system being deeply affected by RE. The structural modifications altered the mechanism of action: L1 partially maintains the ability to induce structural alterations of DNA, while L2 provokes single strand (nicks) and to a lesser extent double strand breaks of DNA.
Assuntos
Antineoplásicos , Complexos de Coordenação , Pironas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Humanos , Ligantes , Estrutura Molecular , Células U937 , Zinco/química , Zinco/farmacologiaRESUMO
We synthesized and characterized the ligand N,N'-bis[(2,2'-dihydroxybiphen-3-yl)methyl]-N,N'-dimethylethylenediamine (L), which contains two biphenol moieties linked as side arms to an N,N'-dimethylethylenediamine scaffold. The ligand is highly soluble in a 50/50 (v/v) water/ethanol mixture and, in its deprotonated form H-2L(2-), is able to coordinate transition-metal ions such as Ni(II), Zn(II), Cu(II), Cd(II), and Pd(II). The crystal structures of [Ni(H-2L)·2n-BuOH], [Ni(H-2L)·2MeOH], [Cd(H-2L)·2DMF], [Cu(H-2L)(DMF)], and [Pd(H-2L)(DMF)] were also determined and described. Potentiometric titrations were carried out in a mixed solvent with Zn(II), Cu(II), and Ni(II) metal ions to determine the acid-base and stability constants. L was highly fluorescent in the visible range (400 nm). Moreover, its emission intensity increased upon the addition of Zn(II) or Cd(II) ions in an ethanol/water solution and behaved as a chemosensor for the presence of these ions in the solution.
RESUMO
The N,N'-bis[(3-hydroxy-4-pyron-2-yl)methyl]-N,N'-dimethylethylendiamine (Malten = L) forms the highly stable [CuH(-2)L] species in water, in which the converging maltol oxygen atoms form an electron-rich area able to host hard metal ions. When considering the alkaline earth series (AE), the [Cu(H(-2)L)] species binds all metal ions, with the exception of Mg(2+), exhibiting the relevant property to discriminate Ca(2+) versus Mg(2+) at physiological pHâ 7.4; the binding of the AE metal is visible to the naked eye. The stability constant values of the trinuclear [AE{Cu(H(-2)L)}2](2+) species formed reach the maximum for Ca(2+) (log K=7.7). Ca(2+) also forms a tetranuclear [Ca{Cu(H(-2)L)}]2(4+) species at a high Ca(2+) concentration. Tri- and tetranuclear calcium complexes show blue- and pink-colored crystals, respectively. [Cu(H(-2)L)] is the most active species in inducing DNA alterations. The DNA damages are compatible with its hydrolytic cleavages.
Assuntos
Cálcio/química , Complexos de Coordenação/química , Magnésio/química , Água/química , Complexos de Coordenação/farmacologia , DNA/efeitos dos fármacos , Dano ao DNA , Ligantes , Metaloproteínas/química , Estrutura MolecularRESUMO
BACKGROUND: Identification of new drugs against paediatric sarcomas represents an urgent clinical need that mainly relies on public investments due to the rarity of these diseases. In this paper we evaluated the in vitro and in vivo efficacy of a new maltol derived molecule (maltonis), belonging to the family of molecules named hydroxypyrones. METHODS: Maltonis was screened for its ability to induce structural alteration of DNA molecules in comparison to another maltolic molecule (malten). In vitro antitumour efficacy was tested using a panel of sarcoma cell lines, representative of Ewing sarcoma, osteosarcoma and rhabdomyosarcoma, the three most common paediatric sarcomas, and in normal human mesenchymal primary cell cultures. In vivo efficacy was tested against TC-71 Ewing sarcoma xenografts. RESULTS: Maltonis, a soluble maltol-derived synthetic molecule, was able to alter the DNA structure, inhibit proliferation and induce apoptotic cell death in paediatric sarcoma cells, either sensitive or resistant to some conventional chemotherapeutic drugs, such as doxorubicin and cisplatin. In addition, maltonis was able to induce: i) p21, p15 and Gadd45a mRNA upregulation; ii) Bcl-2, survivin, CDK6 and CDK8 down-regulation; iii) formation of γ-H2AX nuclear foci; iv) cleavage of PARP and Caspase 3. Two independent in vivo experiments demonstrated the tolerability and efficacy of maltonis in the inhibition of tumour growth. Finally maltonis was not extruded by ABCB1, one of the major determinants of chemotherapy failure, nor appeared to be a substrate of the glutathione-related detoxification system. CONCLUSIONS: Considering that treatment of poorly responsive patients still suffers for the paucity of agents able to revert chemoresistance, maltonis may be considered for the future development of new therapeutic approaches for refractory metastatic patients.
Assuntos
Antineoplásicos/farmacologia , Sarcoma/genética , Sarcoma/metabolismo , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Criança , Dano ao DNA/efeitos dos fármacos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/farmacologia , Xenoenxertos , Humanos , Concentração Inibidora 50 , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Sarcoma/tratamento farmacológico , Sarcoma/patologiaRESUMO
Ligand L (2,6-bis{[7-(7-nitrobenzo[1,2,5]oxadiazole-4-yl)-3,10-dimethyl-1,4,7,10-tetraazacyclododeca-1-yl]methyl}phenol) is a fluorescent sensor that is useful for detecting Cu(II), Zn(II), and Cd(II). Some of the complexes formed are able to sense the presence of halides in solution. L passes through the cellular membrane, becoming fluorescent inside cells. The H(-1)L- species is able to form dinuclear complexes with [M(2)H(-1)L]3+ stoichiometry with Cu(II), Zn(II), and Cd(II) ions, experiencing a CHEF effect upon metal coordination in an acetonitrile/water 95:5 (v/v) solution. In all three of the complexes investigated, the metal cations are coordinatively unsaturated and can therefore bind secondary ligands as anionic species. The crystal structure of [Cd(2)(H(-1)L)Cl(2)](ClO(4))·4H(2)O is discussed. The Zn(II) complex behaves as an OFF-ON sensor for fluoride and chloride anions.
Assuntos
Compostos Aza/química , Halogênios/química , Compostos Macrocíclicos/química , Ligantes , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
The new ligand 3,3'-bis(((2-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-6-yl)ethyl)amino)methyl)-[1,1'-biphenyl]-2,2'-diol (L) has been synthesized and characterized. It contains two pyridinacyclophane macrocycles spaced by a 2,2'-biphenol moiety. The acid-base behaviour of L as well as its binding properties towards Zn2+ ion have been investigated. This work is inserted in the field of fluorescent ditopic receptors, formed by two polyamines spaced by a aromatic fragments. This ligand represents a new example of a peculiar case of polyamine fluorescent receptor in which the interaction with Zn2+ is translated into a deactivation of the emission. Enough data to describe and explain this unusual behaviour was obtained through potentiometric, UV-Vis, fluorescence and NMR titrations as well as theoretical calculations. This studies have shown that the metal cation is indirectly affecting the emission favouring a conformation in which the fluorophore is at stacking distance from the electron poor pyridine moieties. This gives rise to an oxidative photoinduced electron transfer from the excited state of the fluorophore to the electron-poor Zn2+ coordined pyridine.
RESUMO
A new palladium(II) complex containing the previously synthesized 4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane ligand maltonis was prepared and characterized both in solution and in the solid state. Hirshfeld surface and energy framework analyses were also performed. Because maltonis already showed antineoplastic activity, the complexation of Pd(II), chosen as an alternative to Pt(II), was investigated to study its possible biological activity. UV-vis and NMR studies confirmed the formation and stability of the complex in aqueous solution at physiological pH. X-ray diffraction data revealed a structure where the Pd(II) ion is lodged in the dimethyl-cyclen cavity, with maltol rings facing each other (closed shape) even if they are not involved in the coordination. DFT analysis was performed in order to understand the most stable shape of the complex. In view of evaluating its possible bioactive conformation, the DFT study suggested a slight energetic preference for the closed one. The resulting closed complex was stabilized in the X-ray structure by intermolecular interactions that replace the intramolecular interactions present in the optimized complex. According to the DFT calculated formation energies, notwithstanding its rarity, the Pd(II) complex of maltonis is the thermodynamically preferred one among analogous complexes containing different metal ions (Pt(II), Co(II), and Cu(II)). Finally, to study its possible biological activity, the interaction between the Pd(II) complex of maltonis and nucleosides was evaluated through NMR and DFT calculations, revealing a possible interaction with purines via the maltol moieties.
RESUMO
In this work, the study of the new ligand 3,3'-bis[N,N-bis(pyridine-2-ylmethyl)aminomethyl]-2,2'-dihydroxybiphenyl (L) is reported, where a central 2,2'-biphenol (BPH) fluorophore was functionalized at 3,3'-positions with two dipicolylamine (DPA) side arms as receptor units. Following the synthesis and full chemical-physical characterization, the acid-base and Zn2+-coordination abilities of L were investigated through a combination of potentiometric, UV-Vis, fluorescence, NMR, XRD and DFT measurements. The optical properties of the ligand turned out to be strongly dependent on the pH, being straightforwardly associated with the protonation state of the BPH moiety, whereas its peculiar design allowed to form stable mono and dinuclear Zn2+ complexes. In the latter species, the presence of two Zn2+ ions coordinatively unsaturated and placed at close distance to each other, prompted us to test their usefulness as metallo-receptors for two environmental pollutants of great relevance, ibuprofen and ketoprofen. Potentiometric and fluorescence investigations evidenced that these important non-steroidal anti-inflammatory drugs (NSAIDs) are effectively coordinated by the metallo-receptors and, of relevance, both the stability and the fluorescence properties of the resulting ternary adducts are markedly affected by the different chemical architectures of the two substrates. This study aims at highlighting the promising perspectives arising from the use of polyamino phenolic ligands as chemosensors for H+/Zn2+ and other additional anionic targets in their metal-complexed forms.
Assuntos
Aminas , Complexos de Coordenação , Corantes Fluorescentes , Ibuprofeno , Cetoprofeno , Ácidos Picolínicos , Zinco , Zinco/química , Ligantes , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Aminas/química , Ácidos Picolínicos/química , Cetoprofeno/química , Ibuprofeno/química , Água/química , Teoria da Densidade Funcional , Fenóis/química , Espectrometria de Fluorescência , Estrutura Molecular , Modelos Moleculares , SoluçõesRESUMO
Several studies have reported the high bioindication capacity of Isopoda (Crustacea, Oniscidea), which is related to their important ability to accumulate contaminants, usefulness in soil ecotoxicology and bioindication activities. Any change in the isopod population, diversity and life cycle can indicate relevant pollution levels. The analysis of target tissues, such as the hepatopancreas, is another emerging approach (from a cytologic/histological level) to detect contaminant accumulation from different sources. In this study, tissue disaggregation procedures were optimised in the hepatopancreas, and flow cytometry (FC) was applied to detect cell viability and several cell functions. After disaggregation, two hepatopancreatic cell types, small (S) and big (B), were still recognisable: they differed in morphology and behaviour. The analyses were conducted for the first time on isopods from sites under different conditions of ecological disturbance through cytometric re-interpretation of ecological-environmental parameters. Significant differences in cell functional parameters were found, highlighting that isopod hepatopancreatic cells can be efficiently analysed by FC and represent standardisable, early biological indicators, tracing environmental-induced stress through cytologic/histologic analyses.
Assuntos
Isópodes , Animais , Isópodes/metabolismo , Biomarcadores Ambientais , Citometria de Fluxo , Hepatopâncreas/metabolismo , Poluição AmbientalRESUMO
Macrocyclic ligand L, in which a 2,6-bis(2-benzoxazolyl)phenol (bis-HBO) group is incorporated in triethylenetetramine, was designed and synthesized with the aim of creating a chemosensor with high selectivity and specificity for metal cations in an aqueous environment. The availability of several proton acceptors and donors, and amine and phenol hydroxy groups, respectively, affects the keto-enol equilibrium in both the ground and excited states, and the ligand properties show dependence on the pH of the solution. L is fluorescent in the visible range, through an excited-state intramolecular proton transfer (ESIPT) mechanism. The results of an exhaustive characterization of L by spectroscopic techniques and DFT calculations, as well as of its Zn(II), Cd(II) and Pb(II) complexes, show promising properties of L as a ratiometric metal cation chemosensor, since metal coordination prevents the ESIPT and gives rise to a peculiar displacement of the fluorescence emission from green to blue with Zn(II) and Cd(II), while with Pb(II) the fluorescence is quenched.
RESUMO
The tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ complex based on Malten ligand has been investigated as a platform for anion binding. Simple organic carboxylates and non-steroidal anti-inflammatory drugs (NSAIDs) have been tested, revealing the ability of the platform to bind them. The receiving platform hosts at least two guests in solution although a third anion can be bound, as suggested by X-ray diffraction analysis. The addition of the anions is accompanied by a color change of the solution, making the system a colorimetric sensor for carboxylates (LOD values comprised between 3.6 and 20.7â ppm). A fluorescent system consisting of the 2-(3-oxido-6-oxoxanthen-9-yl)benzoate (fluorescein anion) linked to the tetranuclear platform has been also prepared and used in a chemosensing ensemble approach to signal the presence of the selected anions (Log K between 2.6 and 5.6 for the addition of two guests). The latter also works in a paper strip test, offering the chemosensor a possible practical application.
Assuntos
Cálcio , Cobre , Colorimetria , Anti-Inflamatórios não Esteroides , ÂnionsRESUMO
Polyethylene (PE) pipes have been widely used in drinking water distribution systems across the world. In many cases, chlorine dioxide (ClO2) is used to maintain a residual disinfectant concentration in potable water. Practical experiences have shown that the lifetime of PE pipes is significantly reduced due to exposure to drinking water with ClO2. Recently, many companies have proposed new PE pipes with a modified formulation, which are more resistant to chlorine dioxide. However, a standardized test method for evaluating the long-term performances of PE pipes is still missing. This literature review was performed to provide a description of chlorine dioxide uses and degradation mechanisms of polyethylene pipes in real water distribution systems. Current accelerated aging methods to evaluate long-term performances of PE pipes exposed to ClO2 are described and discussed along with the common technics used to characterize the specimens. Accelerate aging methods can be distinguished in immersion aging tests and pressurized pipe loop tests. Wide ranges of operational conditions (chlorine dioxide concentration, water pressure, water temperature, etc.) are applied, resulting in a great variety of results. It was concluded that pressurized looping tests applying semi-realistic operational conditions could better replicate the aging mechanisms occurring in service. Despite this, the acceleration and the evaluation of the long-term performance are still difficult to determine precisely. Further experimentation is needed to correlate chemical-mechanical characterization parameters of PE pipes with their lifetime in service.
Assuntos
Compostos Clorados , Desinfetantes , Água Potável , Purificação da Água , Polietileno , Abastecimento de Água , Óxidos , Cloro , Purificação da Água/métodos , DesinfecçãoRESUMO
Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML) in which the PML/RARα fusion protein exerts oncogenic activities by recruiting repressive complexes to the promoter of specific target genes. Other epigenetic perturbations, as alterations of histone H3 lysine 9 trimethylation (H3K9me3), have been frequently found in AMLs and are associated with leukemogenesis and leukemia progression. Here, we characterized the epigenomic effects of maltonis, a novel maltol-derived molecule, in APL cells. We demonstrate that maltonis treatments induce a profound remodulation of the histone code, reducing global H3K9me3 signal and modulating other histone post-translational modifications. Transcriptomic and epigenomic analyses revealed that maltonis exposure induces changes of genes expression associated with a genomic redistribution of histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 acetylation (H3K27ac). Upregulation of interferon alpha and gamma response and downregulation of c-MYC target genes, in function of c-MYC reduced expression (monitored in all the hematopoietic neoplasms tested), represent the most significant modulated pathways. These data demonstrate the ability of maltonis to epigenetically reprogram the gene expression profile of APL cells, inducing an intriguing antiviral-like response, concomitantly with the downregulation of c-MYC-related pathways, thus making it an attractive candidate for antileukemic therapy.