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1.
Molecules ; 29(7)2024 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-38611732

RESUMO

The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents. Newly synthesized azines were evaluated against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cells, showing in five cases acceptable to good anticancer activity associated with low cytotoxicity on healthy fibroblasts. Finally, ADME in vitro studies were conducted on the best derivatives of the two series showing good passive permeability and resistance to metabolic degradation.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antineoplásicos/farmacologia , Antivirais/farmacologia , Compostos Azo
2.
R Soc Open Sci ; 10(10): 230187, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37859836

RESUMO

International institutions' attention to work-life balance (WLB) demonstrates the global breadth of this issue. Yet the scientific community has thus far paid little attention to its structural underpinnings and to the interplay between these macro-level underpinnings and individual psychological factors. We examine the contextual role of economic inequality at the national level as a significant factor influencing working time and WLB perceptions using multiple empirical strategies. In the first set of studies (1a and 1b), we compared countries with different levels of inequality (Study 1a with 37 countries, Study 1b with longitudinal data from 34 countries, N = 254) and found increased working time and reduced WLB in highly unequal countries. In a pilot study (N = 81) and in the pre-registered Studies 2 (N = 338) and 3 (N = 499) we corroborated this evidence with an experimentally induced inequality perception, reporting an indirect effect of inequality on WLB (Studies 2 and 3) and working time (Study 3) through status anxiety and competitiveness. In Study 2, we manipulated socio-economic class in addition to economic inequality, showing that the detrimental effect of inequality on WLB is especially marked for participants assigned to a low-class condition. This research contributes to an integrated understanding of the impact of economic inequality and socio-economic class in shaping WLB and provides useful insights for organizations to develop context-specific policies to improve employees' WLB that take both individual and structural factors into account.

3.
ACS Med Chem Lett ; 14(5): 599-605, 2023 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-37197457

RESUMO

Current therapy against melanoma relies on surgical treatment or, in alternative, on conventional drug therapy. Often these therapeutic agents are ineffective due to the development of resistance phenomena. For this purpose, chemical hybridization emerged as an effective strategy to overcome the development of drug resistance. In this study, a series of molecular hybrids were synthesized combining the sesquiterpene artesunic acid with a panel of phytochemical coumarins. Cytotoxicity, antimelanoma effect, and cancer selectivity of the novel compounds were evaluated by MTT assay on primary and metastatic cells and on healthy fibroblasts as a reference. The two most active compounds showed lower cytotoxicity and higher activity against metastatic melanoma than paclitaxel and artesunic acid. Further tests, including cellular proliferation, apoptosis, confocal microscopy, and MTT analyses in the presence of an iron chelating agent, were conducted with the aim of tentatively addressing the mode of action and the pharmacokinetic profile of selected compounds.

4.
Eur J Cell Biol ; 102(2): 151325, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37216802

RESUMO

Mutations in CSA and CSB proteins cause Cockayne syndrome, a rare genetic neurodevelopment disorder. Alongside their demonstrated roles in DNA repair and transcription, these two proteins have recently been discovered to regulate cytokinesis, the final stage of the cell division. This last finding allowed, for the first time, to highlight an extranuclear localization of CS proteins, beyond the one already known at mitochondria. In this study, we demonstrated an additional role for CSA protein being recruited at centrosomes in a strictly determined step of mitosis, which ranges from pro-metaphase until metaphase exit. Centrosomal CSA exerts its function in specifically targeting the pool of centrosomal Cyclin B1 for ubiquitination and proteasomal degradation. Interestingly, a lack of CSA recruitment at centrosomes does not affect Cyclin B1 centrosomal localization but, instead, it causes its lasting centrosomal permanence, thus inducing Caspase 3 activation and apoptosis. The discovery of this unveiled before CSA recruitment at centrosomes opens a new and promising scenario for the understanding of some of the complex and different clinical aspects of Cockayne Syndrome.


Assuntos
Síndrome de Cockayne , Humanos , Ciclina B1/genética , Ciclina B1/metabolismo , Síndrome de Cockayne/genética , Síndrome de Cockayne/metabolismo , Mitose , Centrossomo/metabolismo , Ubiquitinação
5.
Ann Ist Super Sanita ; 59(1): 68-75, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36974707

RESUMO

INTRODUCTION: Mono-(2-ethylhexyl) phthalate (MEHP) represents a toxicological risk for marine organisms due to its widespread presence in aquatic environments. METHODS: MEHP effects on cell viability, cell death and genotoxicity were investigated on the DLEC cell line, derived from early embryos of the European sea bass Dicentrarchus labrax L. RESULTS: A dose-dependent cytotoxic effect, with no induction of necrotic process, except at its highest concentration, was observed. Moreover, chromosomal instability was detected, both in binucleated and mononucleated cells, coupled with a minor inhibition of cell proliferation, whereas genomic instability was not revealed. To our knowledge, the overall results suggest the first evidence of a possible aneugenic effect of this compound in the DLEC cell line, that is the induction of chromosomal loss events without the induction of primary DNA damage. CONCLUSIONS: MEHP should be considered more harmful than its parent compound DEHP, because it induces genomic instability in the DLEC cell line without triggering cell death.


Assuntos
Organismos Aquáticos , Bass , Instabilidade Cromossômica , Citotoxinas , Mutagênicos , Organismos Aquáticos/citologia , Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/metabolismo , Bass/embriologia , Bass/genética , Linhagem Celular , Citotoxinas/toxicidade , Mutagênicos/toxicidade , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Instabilidade Cromossômica/efeitos dos fármacos , Instabilidade Cromossômica/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Relação Dose-Resposta a Droga , Dano ao DNA
6.
Br J Soc Psychol ; 62(1): 104-118, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35758713

RESUMO

Taxation is one of the most widely acknowledged strategies to reduce inequality, particularly if based on progressivity. In a high-powered sample study (N = 2119) we investigated economic inequality and conspiracy beliefs as two key predictors of tax attitude and support for progressive taxation. We found that participants in the high economic inequality condition had lower levels of tax compliance and higher levels of conspiracy beliefs and support for progressive taxation. Furthermore, the effect of the experimental condition on tax compliance was mediated by conspiracy beliefs. Finally, conspiracy belief scores were positively associated with support for progressive taxation. Our results provide evidence that attitudes towards taxation are not monolithic but change considering the aims and targets of specific taxes. Indeed, while the perception of economic inequality prompts the desire for equal redistribution, it also fosters conspiracy narratives that undermine compliance with taxes.


Assuntos
Intenção , Impostos , Humanos , Atitude
7.
Biochim Biophys Acta Gen Subj ; 1867(3): 130291, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36529242

RESUMO

BACKGROUND: The use of ionizing radiations in radiotherapy is an effective and very common cancer treatment after surgery. Although ionizing-radiation DNA damages are extensively investigated, little is known about their effects on the other nuclear components, since their variations when studied in whole cells can be difficult to decouple from those of the cytoplasmatic structures. The organization of nuclear components plays a functional role since they are directly involved in some of the nuclear response to chemical or physical stimuli. For this reason, studying the X-ray effects on nuclear components is a crucial step in radiobiology. MATERIALS AND METHODS: We have used Atomic Force Microscopy (AFM) and micro-FTIR to examine the biomechanical and biochemical properties of hydrated fixed nuclei isolated from neuroblastoma (SH-SY5Y) cells irradiated by 2, 4, 6 and 8 Gy X-ray doses. RESULTS: The experimental results have shown that, already at 2 Gy irradiation dose, the nuclei exhibit not only a DNA damage, but also relevant alterations of lipid saturation, protein secondary structure arrangement and a significant decrease in nuclear stiffness, which indicate a remarkable chromatin decondensation. CONCLUSIONS AND GENERAL SIGNIFICANCE: The present work demonstrates that a multi-technique approach, able to disclose multiple features, can be helpful to achieve a comprehensive picture of the X-ray irradiation effects of the nuclear components and distinguish them from those occurring at the level of cytoplasm.


Assuntos
Neuroblastoma , Humanos , Raios X , Núcleo Celular , Radiação Ionizante , Cromatina
8.
Cancers (Basel) ; 14(7)2022 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-35406459

RESUMO

Breast cancer (BC) is the most common cancer with the highest frequency of death among women. BC is highly heterogenic at the genetic, biological, and clinical level. Despite the significant improvements in diagnosis and treatments of BC, the high rate of cancer recurrence and resistance to treatment remains a major challenge in clinical practice. This issue is particularly relevant in Triple-Negative Breast Cancer (TNBC) subtype, for which chemotherapy remains the main standard therapeutic approach. Here, we observed that BC cells, belonging to different subtypes, including the TNBC, display an increased expression of Cockayne Syndrome group A (CSA) protein, which is involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division and that recently was found to confer cell robustness when it is up-regulated. We demonstrated that CSA ablation by AntiSense Oligonucleotides (ASOs) drastically impairs tumorigenicity of BC cells by hampering their survival and proliferative capabilities without damaging normal cells. Moreover, suppression of CSA dramatically sensitizes BC cells to platinum and taxane derivatives, which are commonly used for BC first-line therapy, even at very low doses not harmful to normal cells. Finally, CSA ablation restores drug sensitivity in oxaliplatin-resistant cells. Based on these results, we conclude that CSA might be a very attractive target for the development of more effective anticancer therapies.

9.
Eur J Med Chem ; 231: 114158, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35168113

RESUMO

The ever-faster rise of antimicrobial resistance (AMR) represents a major global Public Health challenge. New chemical entities with innovative Modes of Action (MoAs) are thus desirable. We recently reported the development of a novel class of broad-spectrum bactericidal agents, the AlkylGuanidino Ureas (AGU). Due to their polycationic structure, they likely target bacterial membranes. In order to better understand their MoA, we synthesized a library of AGU derivatives by structural simplification of selected hit compounds and developed specific assays based on membrane models by means of both analytical and computational techniques. Cell-based assays provided experimental evidence that AGUs disrupt bacterial membranes without showing hemolytic behavior. Hence, we herein report a thorough chemical and biological characterization of a new series of AGUs obtained through molecular simplification, allowing the rational design of potent antibacterial compounds active on antibiotic-resistant strains.


Assuntos
Antibacterianos , Ureia , Antibacterianos/química , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Ureia/farmacologia
10.
Int J Mol Sci ; 23(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35055101

RESUMO

We report here the synthesis of novel thymine biomimetic photo-adducts bearing an alkane spacer between nucleobases and characterized by antimelanoma activity against two mutated cancer cell lines overexpressing human Topoisomerase 1 (TOP1), namely SKMEL28 and RPMI7951. Among them, Dewar Valence photo-adducts showed a selectivity index higher than the corresponding pyrimidine-(6-4)-pyrimidone and cyclobutane counterpart and were characterized by the highest affinity towards TOP1/DNA complex as evaluated by molecular docking analysis. The antimelanoma activity of novel photo-adducts was retained after loading into UV photo-protective lignin nanoparticles as stabilizing agent and efficient drug delivery system. Overall, these results support a combined antimelanoma and UV sunscreen strategy involving the use of photo-protective lignin nanoparticles for the controlled release of thymine dimers on the skin followed by their sacrificial transformation into photo-adducts and successive inhibition of melanoma and alert of cellular UV machinery repair pathways.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Mimetismo Biológico , Portadores de Fármacos/química , Lignina , Nanopartículas , Timina/química , Biomimética , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Humanos , Lignina/química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquímica , Dímeros de Pirimidina/química , Solventes , Análise Espectral , Relação Estrutura-Atividade , Raios Ultravioleta
11.
Int J Mol Sci ; 22(23)2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34884564

RESUMO

Milk extracellular vesicles (mEVs) seem to be one of the main maternal messages delivery systems. Extracellular vesicles (EVs) are micro/nano-sized membrane-bound structures enclosing signaling molecules and thus acting as signal mediators between distant cells and/or tissues, exerting biological effects such as immune modulation and pro-regenerative activity. Milk is also a unique, scalable, and reliable source of EVs. Our aim was to characterize the RNA content of cow, donkey, and goat mEVs through transcriptomic analysis of mRNA and small RNA libraries. Over 10,000 transcripts and 2000 small RNAs were expressed in mEVs of each species. Among the most represented transcripts, 110 mRNAs were common between the species with cow acting as the most divergent. The most represented small RNA class was miRNA in all the species, with 10 shared miRNAs having high impact on the immune regulatory function. Functional analysis for the most abundant mRNAs shows epigenetic functions such as histone modification, telomere maintenance, and chromatin remodeling for cow; lipid catabolism, oxidative stress, and vitamin metabolism for donkey; and terms related to chemokine receptor interaction, leukocytes migration, and transcriptional regulation in response to stress for goat. For miRNA targets, shared terms emerged as the main functions for all the species: immunity modulation, protein synthesis, cellular cycle regulation, transmembrane exchanges, and ion channels. Moreover, donkey and goat showed additional terms related to epigenetic modification and DNA maintenance. Our results showed a potential mEVs immune regulatory purpose through their RNA cargo, although in vivo validation studies are necessary.


Assuntos
Anti-Inflamatórios/metabolismo , Vesículas Extracelulares/imunologia , Regulação da Expressão Gênica , Imunomodulação , Leite/imunologia , Transcriptoma , Animais , Bovinos , Equidae , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Feminino , Cabras , MicroRNAs/genética , Leite/química , Leite/metabolismo
12.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576232

RESUMO

Neuroblastoma, the most common extra-cranial solid tumor of early childhood, is one of the major therapeutic challenges in child oncology: it is highly heterogenic at a genetic, biological, and clinical level. The high-risk cases have one of the least favorable outcomes amongst pediatric tumors, and the mortality rate is still high, regardless of the use of intensive multimodality therapies. Here, we observed that neuroblastoma cells display an increased expression of Cockayne Syndrome group B (CSB), a pleiotropic protein involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division, and were recently found to confer cell robustness when they are up-regulated. In this study, we demonstrated that RNAi-mediated suppression of CSB drastically impairs tumorigenicity of neuroblastoma cells by hampering their proliferative, clonogenic, and invasive capabilities. In particular, we observed that CSB ablation induces cytokinesis failure, leading to caspases 9 and 3 activation and, subsequently, to massive apoptotic cell death. Worthy of note, a new frontier in cancer treatment, already proved to be successful, is cytokinesis-failure-induced cell death. In this context, CSB ablation seems to be a new and promising anticancer strategy for neuroblastoma therapy.


Assuntos
Citocinese/fisiologia , DNA Helicases/fisiologia , Enzimas Reparadoras do DNA/fisiologia , Neuroblastoma/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/fisiologia , Interferência de RNA , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Centrossomo , DNA Helicases/genética , DNA Helicases/metabolismo , Reparo do DNA , Enzimas Reparadoras do DNA/genética , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Fuso Acromático
13.
ChemMedChem ; 16(14): 2270-2277, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-33792170

RESUMO

A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo-controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4-hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC50 >300 µM) and high antimelanoma activity (IC50 =0.05 µM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer-type selectivity towards melanoma compared to prostate (PC3) and breast (MDA-MB-231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity.


Assuntos
Antineoplásicos/farmacologia , Artemisininas/farmacologia , Melanoma/tratamento farmacológico , Succinatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Artemisininas/síntese química , Artemisininas/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Succinatos/síntese química , Succinatos/química
14.
ACS Med Chem Lett ; 11(5): 1035-1040, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32435422

RESUMO

Artesunic acid and artemisinin are natural substances with promiscuous anticancer activity against different types of cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested topoisomerase 1 as a possible molecular target for the improvement of the anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human topoisomerase 1 and its enzymatic activity in vitro. These derivatives showed also anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. In silico molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.

15.
ACS Omega ; 5(1): 243-251, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31956771

RESUMO

A library of hybrid and dimer compounds based on the natural scaffold of artemisinin was synthesized. These derivatives were obtained by coupling of artemisinin derivatives, artesunate, and dihydroartemisinin with a panel of phytochemical compounds. The novel artemisinin-based hybrids and dimers were evaluated for their anticancer activity on a cervical cancer cell line (HeLa) and on three complementary metastatic melanoma cancer cell lines (SK-MEL3, SK-MEL24, and RPMI-7951). Two hybrid compounds obtained by coupling of artesunate with eugenol and tyrosol, and one of the dimer compounds containing curcumin, emerged as the most active and cancer-selective derivatives.

16.
Toxicol In Vitro ; 56: 118-125, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30685479

RESUMO

Marine litter is extensively distributed in the marine environment, and plastic debris, of which litter is mostly composed, can be a major source of pollutants. Among them, Di(2-ethylhexyl)-phthalate (DEHP) is the most abundantly used plastic additive, and it has been reported to affect biochemical processes both in humans and wildlife; however, studies on its toxicological effects on marine organisms are still scarce. In this survey, we studied the cytotoxic, genotoxic, and mutagenic effects of DEHP in European sea bass embryonic cell line (DLEC) by applying specific in vitro tests. Results showed a significant decrease in cell viability starting at 0.01 mM of DEHP after 24 h together with a significant increase in apoptosis and necrosis, morphological changes and cell detachment. Consistently, we detected a moderate increase in DNA strand breaks from 0.02 mM, and a dose-dependent increase in of micronucleus frequency from 0.01 mM, accompanied by a significant inhibition of cell proliferation, which suggested a possible aneugenic effect of this phthalate. Our results demonstrate that in vitro exposure to DEHP had a dose-dependent cytotoxic and genotoxic effects in DLEC cell line, encouraging further investigation into its effects in in vivo and/or ex vivo cell systems of marine organisms.


Assuntos
Dietilexilftalato/toxicidade , Mutagênicos/toxicidade , Plastificantes/toxicidade , Animais , Bass , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Embrião não Mamífero , Testes para Micronúcleos
17.
Bioorg Med Chem Lett ; 29(1): 78-82, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30442421

RESUMO

Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles. Surprisingly, the antiproliferative activity of C-2 substituted cambinol derivatives was not correlated to the induction of p53 protein, as evaluated by the analysis of the cell viability on wild-type and p53 mutated cancer cell lines, and further confirmed by western blot analyses. These data suggest that they exert their antiproliferative activity by a mechanism completely different from cambinol.


Assuntos
Antineoplásicos/farmacologia , Naftalenos/farmacologia , Pirimidinonas/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Oxirredução , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-Atividade , Neoplasias da Bexiga Urinária/patologia
18.
Mutat Res Genet Toxicol Environ Mutagen ; 836(Pt A): 109-116, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30389153

RESUMO

Ataxia telangiectasia is a rare autosomal recessive genome instability syndrome caused by mutations in the Ataxia Telangiectasia Mutated gene and characterized by a very high sensitivity to agents inducing double strand breaks such as ionizing radiation. In cells derived from ataxia telangiectasia patients a prominent enhancement of chromosomal aberrations is revealed as a consequence of this radiosensitivity characteristic, arising from defective DNA repair for a small fraction of breaks localized in the less accessible heterochromatin. Moreover, the signaling mediated by ataxia telangiectasia protein kinase also modifies chromatin structure. Even if there is a lot of knowledge concerning biochemical aspects of repair of double strand breaks, no conclusive results on radiosensitivity of structurally- and functionally-different chromatin are available, particularly in ataxia telangiectasia cells. Thus, a wild-type cell line and two ataxia telangiectasia patient derived ones could represent a suitable model to study the possible relationship between chromatin conformation and sensitivity to ionizing radiation. In this context, the effects of both cytosine arabinoside, an inhibitor of DNA repair synthesis, and trichostatin A, a histone deacetylase inhibitor, were tested in normal and ataxia telangiectasia lymphoblastoid cell lines carrying different mutation in the Ataxia Telangiectasia Mutated gene. The response to both inhibitors was investigated analyzing two endpoints, namely, chromosomal aberrations and the removal of DNA lesions by Comet assay, after exposure to X-rays. Results obtained suggest that the modulation of chromatin structure by trichostatin A leading to a more open conformation, decreases radiation-induced chromosomal aberrations in ataxia telangiectasia cells. The reduction in chromosomal instability can be attributed to an enhancement in DNA repair occurring in the presence of the histone deacetylase inhibitor, as its abolishment by the known inhibitor of DNA repair synthesis cytosine arabinoside clearly demonstrates. Data obtained could indicate a pivotal role of chromatin conformation in the radiosensitivity of ataxia telangiectasia cells.


Assuntos
Ataxia Telangiectasia/tratamento farmacológico , Cromatina/química , Reparo do DNA , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Linfócitos/patologia , Radiação Ionizante , Ataxia Telangiectasia/enzimologia , Ataxia Telangiectasia/patologia , Cromatina/efeitos dos fármacos , Cromatina/efeitos da radiação , Ensaio Cometa , Quebras de DNA de Cadeia Dupla , Replicação do DNA , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação
19.
J Agric Food Chem ; 66(46): 12274-12284, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30350961

RESUMO

Treatment of olive vegetation waste with tyrosinase immobilized on multiwalled carbon nanotubes increased the antioxidant activity as a consequence of the conversion of phenols to corresponding catechol derivatives, as evaluated by DPPH, Comet assay, and micronucleus analyses. During this transformation, 4-hydroxyphenethyl alcohol (tyrosol) was quantitatively converted to bioactive 3,4-dihydroxyphenethyl alcohol (hydroxytyrosol). The hydroxytyrosol-enriched olive vegetation waste also promoted autophagy and inhibited the inflammatory response in human THP-1 monocytes.


Assuntos
Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Monócitos/citologia , Monócitos/imunologia , Olea/química , Álcool Feniletílico/análogos & derivados , Extratos Vegetais/farmacologia , Resíduos/análise , Antioxidantes/química , Biocatálise , Linhagem Celular , Humanos , Monócitos/efeitos dos fármacos , Monofenol Mono-Oxigenase/química , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Extratos Vegetais/química
20.
Ecotoxicology ; 27(2): 234-243, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29404870

RESUMO

Coal plants can be a major source of mutagenic pollutants. In this study we used the common land snail Helix aspersa, to detect the mutagenic effect of pollution from a coal plant in central Italy applying the micronucleus test (MN) on snail's haemocytes and evaluating trace elements concentration (As Cd, Pb, Hg, and Zn) in soil and snails. Snails from a biological farm were exposed for 13 days in five locations at different distances from the plant. Wild snails collected in the same locations were also analysed. MN frequency in exposed snails was significantly higher in four locations within 10 km from to the plant, with respect to the control and the farthest location. Comparing the MN frequency between farmed and wild snails, a significantly higher frequency emerged for the exposed snails in all locations except the farthest, likely indicating adaptation or selection of the wild organisms due to chronic exposure to pollutants. In natural snails significantly higher MN frequencies with near the plant emerged as well. Trace elements analysis showed significant correlations between MN frequencies and both Zn and As concentrations in soil, for both exposed and wild snails, and Zn and Pb concentrations in exposed snails. Our results were consistent with those previously obtained when evaluating primary DNA damage in natural snails from the same area and show that the snails near the plant were affected by a permanent cytogenetic damage. Moreover, they confirm the suitability of snails for biomonitoring the presence of pollutants with mutagenic effect.


Assuntos
Monitoramento Ambiental/métodos , Caracois Helix/fisiologia , Testes para Micronúcleos , Poluentes do Solo/toxicidade , Animais , Carvão Mineral , Dano ao DNA , Centrais Elétricas
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