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1.
Molecules ; 29(3)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38338314

RESUMO

Radical reactions in water or aqueous media are important for organic synthesis, realizing high-yielding processes under non-toxic and environmentally friendly conditions. This overview includes (i) a general introduction to organic chemistry in water and aqueous media, (ii) synthetic approaches in, on, and with water as well as in heterogeneous phases, (iii) reactions of carbon-centered radicals with water (or deuterium oxide) activated through coordination with various Lewis acids, (iv) photocatalysis in water and aqueous media, and (v) synthetic applications bioinspired by naturally occurring processes. A wide range of chemical processes and synthetic strategies under different experimental conditions have been reviewed that lead to important functional group translocation and transformation reactions, leading to the preparation of complex molecules. These results reveal how water as a solvent/medium/reagent in radical chemistry has matured over the last two decades, with further discoveries anticipated in the near future.

2.
Int J Mol Sci ; 25(1)2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38203317

RESUMO

In recent years, nucleic acids have emerged as powerful biomaterials, revolutionizing the field of biomedicine. This review explores the multifaceted applications of nucleic acids, focusing on their pivotal role in various biomedical applications. Nucleic acids, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), possess unique properties such as molecular recognition ability, programmability, and ease of synthesis, making them versatile tools in biosensing and for gene regulation, drug delivery, and targeted therapy. Their compatibility with chemical modifications enhances their binding affinity and resistance to degradation, elevating their effectiveness in targeted applications. Additionally, nucleic acids have found utility as self-assembling building blocks, leading to the creation of nanostructures whose high order underpins their enhanced biological stability and affects the cellular uptake efficiency. Furthermore, this review delves into the significant role of oligonucleotides (ODNs) as indispensable tools for biological studies and biomarker discovery. ODNs, short sequences of nucleic acids, have been instrumental in unraveling complex biological mechanisms. They serve as probes for studying gene expression, protein interactions, and cellular pathways, providing invaluable insights into fundamental biological processes. By examining the synergistic interplay between nucleic acids as powerful biomaterials and ODNs as indispensable tools for biological studies and biomarkers, this review highlights the transformative impact of these molecules on biomedical research. Their versatile applications not only deepen our understanding of biological systems but also are the driving force for innovation in diagnostics and therapeutics, ultimately advancing the field of biomedicine.


Assuntos
Ácidos Nucleicos , Ácidos Nucleicos/uso terapêutico , Oligonucleotídeos/uso terapêutico , RNA , Materiais Biocompatíveis/uso terapêutico , Transporte Biológico
3.
Int J Mol Sci ; 23(12)2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35742994

RESUMO

Hydroxyl radicals (HO•) have long been regarded as a major source of cellular damage. The reaction of HO• with methionine residues (Met) in peptides and proteins is a complex multistep process. Although the reaction mechanism has been intensively studied, some essential parts remain unsolved. In the present study we examined the reaction of HO• generated by ionizing radiation in aqueous solutions under anoxic conditions with two compounds representing the simplest model peptide backbone CH3C(O)NHCHXC(O)NHCH3, where X = CH2CH2SCH3 or CH2SCH3, i.e., the Met derivative in comparison with the cysteine-methylated derivative. We performed the identification and quantification of transient species by pulse radiolysis and final products by LC-MS and high-resolution MS/MS after γ-radiolysis. The results allowed us to draw for each compound a mechanistic scheme. The fate of the initial one-electron oxidation at the sulfur atom depends on its distance from the peptide backbone and involves transient species of five-membered and/or six-membered ring formations with different heteroatoms present in the backbone as well as quite different rates of deprotonation in forming α-(alkylthio)alkyl radicals.


Assuntos
Radical Hidroxila , Metionina , Cisteína , Radical Hidroxila/química , Metionina/química , Oxirredução , Peptídeos/química , Radiólise de Impulso , Sulfetos , Espectrometria de Massas em Tandem
4.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682708

RESUMO

Fatty acids have an important place in both biological and nutritional contexts and, from a clinical point of view, they have known consequences for diseases' onset and development, including cancer. The use of fatty acid-based food and nutraceuticals to support cancer therapy is a multidisciplinary subject, involving molecular and clinical research. Knowledge regarding polyunsaturated fatty acids essentiality/oxidizability and the role of lipogenesis-desaturase pathways for cell growth, as well as oxidative reactivity in cancer cells, are discussed, since they can drive the choice of fatty acids using their multiple roles to support antitumoral drug activity. The central role of membrane fatty acid composition is highlighted for the application of membrane lipid therapy. As fatty acids are also known as biomarkers of cancer onset and progression, the personalization of the fatty acid-based therapy is also possible, taking into account other important factors such as formulation, bioavailability and the distribution of the supplementation. A holistic approach emerges combining nutra- and pharma-strategies in an appropriate manner, to develop further knowledge and applications in cancer therapy.


Assuntos
Ácidos Graxos , Neoplasias , Suplementos Nutricionais , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Humanos , Lipídeos de Membrana , Neoplasias/tratamento farmacológico
5.
Molecules ; 27(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35408441

RESUMO

Some of the most interesting aspects of free radical chemistry that emerged in the last two decades are radical enzyme mechanisms, cell signaling cascades, antioxidant activities, and free radical-induced damage of biomolecules. In addition, identification of modified biomolecules opened the way for the evaluation of in vivo damage through biomarkers. When studying free radical-based chemical mechanisms, it is very important to establish biomimetic models, which allow the experiments to be performed in a simplified environment, but suitably designed to be in strict connection with cellular conditions. The 28 papers (11 reviews and 17 articles) published in the two Special Issues of Molecules on "Biomimetic Radical Chemistry and Applications (2019 and 2021)" show a remarkable range of research in this area. The biomimetic approach is presented with new insights and reviews of the current knowledge in the field of radical-based processes relevant to health, such as biomolecular damages and repair, signaling and biomarkers, biotechnological applications, and novel synthetic approaches.


Assuntos
Biomimética , Biomarcadores/química , Radicais Livres/química
6.
Chemistry ; 27(3): 971-983, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-32519773

RESUMO

We report a series of copper(II) artificial metallo-nucleases (AMNs) and demonstrate their DNA damaging properties and in-vitro cytotoxicity against human-derived pancreatic cancer cells. The compounds combine a tris-chelating polypyridyl ligand, di-(2-pycolyl)amine (DPA), and a DNA intercalating phenanthrene unit. Their general formula is Cu-DPA-N,N' (where N,N'=1,10-phenanthroline (Phen), dipyridoquinoxaline (DPQ) or dipyridophenazine (DPPZ)). Characterisation was achieved by X-ray crystallography and continuous-wave EPR (cw-EPR), hyperfine sublevel correlation (HYSCORE) and Davies electron-nuclear double resonance (ENDOR) spectroscopies. The presence of the DPA ligand enhances solution stability and facilitates enhanced DNA recognition with apparent binding constants (Kapp ) rising from 105 to 107 m-1 with increasing extent of planar phenanthrene. Cu-DPA-DPPZ, the complex with greatest DNA binding and intercalation effects, recognises the minor groove of guanine-cytosine (G-C) rich sequences. Oxidative DNA damage also occurs in the minor groove and can be inhibited by superoxide and hydroxyl radical trapping agents. The complexes, particularly Cu-DPA-DPPZ, display promising anticancer activity against human pancreatic tumour cells with in-vitro results surpassing the clinical platinum(II) drug oxaliplatin.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , DNA/análise , DNA/química , Fenantrenos/química , Fenantrenos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Dano ao DNA/efeitos dos fármacos , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Neoplasias Pancreáticas/genética , Fenantrolinas/química
7.
J Appl Toxicol ; 41(12): 1980-1997, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33982300

RESUMO

Despite the widespread use of silver nanoparticles (AgNPs) in different fields and the amount of investigations available, to date, there are many contradictory results on their potential toxicity. In the present study, extensively characterized 20-nm AgNPs were investigated using optimized protocols and standardized methods to test several toxicological endpoints in different cell lines. The agglomeration/aggregation state of AgNPs in culture media was measured by dynamic light scattering (DLS). DNA and chromosomal damage on BEAS-2B and RAW 264.7 cells were evaluated by comet and micronucleus assays, while oxidative DNA damage by modified comet assay and 8-oxodG/8-oxodA detection. We also investigated immunotoxicity and immunomodulation by cytokine release and NO production in RAW 264.7 and MH-S cells, with or without lipopolysaccharide (LPS) stimulus. Transmission electron microscope (TEM) analysis was used to analyze cellular uptake of AgNPs. Our results indicate different values of AgNPs hydrodynamic diameter depending on the medium, some genotoxic effect just on BEAS-2B and no or slight effects on function of RAW 264.7 and MH-S in absence or presence of LPS stimulus. This study highlights the relevance of using optimized protocols and multiple endpoints to analyze the potential toxicity of AgNPs and to obtain reliable and comparable results.


Assuntos
Técnicas In Vitro/métodos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Testes de Toxicidade/métodos , Linhagem Celular , Ensaio Cometa , Testes para Micronúcleos
8.
Int J Mol Sci ; 22(23)2021 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-34884668

RESUMO

Reductive radical stress represents the other side of the redox spectrum, less studied but equally important compared to oxidative stress. The reactivity of hydrogen atoms (H•) and hydrated electrons (e-aq) connected with peptides/proteins is summarized, focusing on the chemical transformations of methionine (Met) and cystine (CysS-SCys) residues into α-aminobutyric acid and alanine, respectively. Chemical and mechanistic aspects of desulfurization processes with formation of diffusible sulfur-centered radicals, such as methanethiyl (CH3S•) and sulfhydryl (HS•) radicals, are discussed. These findings are further applied to biomimetic radical chemistry, modeling the occurrence of tandem protein-lipid damages in proteo-liposomes and demonstrating that generation of sulfur-centered radicals from a variety of proteins is coupled with the cis-trans isomerization of unsaturated lipids in membranes. Recent applications to pharmaceutical and pharmacological contexts are described, evidencing novel perspectives in the stability of formulations and mode of action of drugs, respectively.


Assuntos
Aminoácidos Sulfúricos/metabolismo , Proteínas/metabolismo , Estresse Fisiológico , Animais , Radicais Livres/metabolismo , Raios gama , Humanos , Oxirredução
9.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946289

RESUMO

Within the reactive oxygen species (ROS) generated by cellular metabolisms, hydroxyl radicals (HO•) play an important role, being the most aggressive towards biomolecules. The reactions of HO• with methionine residues (Met) in peptides and proteins have been intensively studied, but some fundamental aspects remain unsolved. In the present study we examined the biomimetic model made of Ac-Met-OMe, as the simplest model peptide backbone, and of HO• generated by ionizing radiation in aqueous solutions under anoxic conditions. We performed the identification and quantification of transient species by pulse radiolysis and of final products by LC-MS and high-resolution MS/MS after γ-radiolysis. By parallel photochemical experiments, using 3-carboxybenzophenone (CB) triplet with the model peptide, we compared the outcomes in terms of short-lived intermediates and stable product identification. The result is a detailed mechanistic scheme of Met oxidation by HO•, and by CB triplets allowed for assigning transient species to the pathways of products formation.


Assuntos
Radical Hidroxila/química , Metionina/química , Peptídeos/química , Raios gama , Oxirredução , Fotólise , Radiólise de Impulso
10.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207639

RESUMO

The guanyl radical or neutral guanine radical G(-H)• results from the loss of a hydrogen atom (H•) or an electron/proton (e-/H+) couple from the guanine structures (G). The guanyl radical exists in two tautomeric forms. As the modes of formation of the two tautomers, their relationship and reactivity at the nucleoside level are subjects of intense research and are discussed in a holistic manner, including time-resolved spectroscopies, product studies, and relevant theoretical calculations. Particular attention is given to the one-electron oxidation of the GC pair and the complex mechanism of the deprotonation vs. hydration step of GC•+ pair. The role of the two G(-H)• tautomers in single- and double-stranded oligonucleotides and the G-quadruplex, the supramolecular arrangement that attracts interest for its biological consequences, are considered. The importance of biomarkers of guanine DNA damage is also addressed.


Assuntos
Dano ao DNA , DNA/química , Radicais Livres/química , Quadruplex G , Guanina/química , Animais , DNA/genética , DNA/metabolismo , Elétrons , Humanos , Oxirredução , Prótons , Estereoisomerismo
11.
Molecules ; 26(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34576900

RESUMO

The conversion of ribonucleosides to 2'-deoxyribonucleosides is catalyzed by ribonucleoside reductase enzymes in nature. One of the key steps in this complex radical mechanism is the reduction of the 3'-ketodeoxynucleotide by a pair of cysteine residues, providing the electrons via a disulfide radical anion (RSSR•-) in the active site of the enzyme. In the present study, the bioinspired conversion of ketones to corresponding alcohols was achieved by the intermediacy of disulfide radical anion of cysteine (CysSSCys)•- in water. High concentration of cysteine and pH 10.6 are necessary for high-yielding reactions. The photoinitiated radical chain reaction includes the one-electron reduction of carbonyl moiety by disulfide radical anion, protonation of the resulting ketyl radical anion by water, and H-atom abstraction from CysSH. The (CysSSCys)•- transient species generated by ionizing radiation in aqueous solutions allowed the measurement of kinetic data with ketones by pulse radiolysis. By measuring the rate of the decay of (CysSSCys)•- at λmax = 420 nm at various concentrations of ketones, we found the rate constants of three cyclic ketones to be in the range of 104-105 M-1s-1 at ~22 °C.


Assuntos
Biomimética , Dissulfetos , Cetonas , Radical Hidroxila/química , Cinética , Água
12.
J Am Chem Soc ; 142(12): 5825-5833, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32129616

RESUMO

The reaction of HO• radical with DNA is intensively studied both mechanistically and analytically for lesions formation. Several aspects related to the reaction paths of purine moieties with the formation of 5',8-cyclopurines (cPu), 8-oxopurines (8-oxo-Pu), and their relationship are not well understood. In this study, we investigated the reaction of HO• radical with a 21-mer double-stranded oligodeoxynucleotide (ds-ODNs) in γ-irradiated aqueous solutions under various oxygen concentrations and accurately quantified the six purine lesions (i.e., four cPu and two 8-oxo-Pu) by LC-MS/MS analysis using isotopomeric internal standards. In the absence of oxygen, 8-oxo-Pu lesions are only ∼4 times more than cPu lesions. By increasing oxygen concentration, the 8-oxo-Pu and the cPu gradually increase and decrease, respectively, reaching a gap of ∼130 times at 2.01 × 10-4 M of O2. Kinetic treatment of the data allows to estimate the C5' radical competition between cyclization and oxygen trapping in ds-ODNs, and lastly the rate constants of the four cyclization steps. Tailored computational studies by means of dispersion-corrected DFT calculations were performed on the CGC and TAT in their double-strand models for each cPu diastereoisomer along with the complete reaction pathways of the cyclization steps. Our findings reveal unheralded reaction mechanisms that resolve the long-standing issues with C5' radical cyclization in purine moieties of DNA sequences.

13.
Chem Res Toxicol ; 33(10): 2565-2572, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-32865980

RESUMO

Bleomycin has a long-studied mechanism of action through the formation of a complex with metals, such as iron. The bleomycin-iron complex was recently shown to induce membrane damage by free radical reactivity. Because the use of Fe nanoparticles is spreading for drug delivery strategies, molecular mechanisms of cell damage must include different compartments in order to observe the progression of the cell reactivity. In this study, human embryonic kidney (HEK-293) cells were exposed for 24 h to bleomycin and polymeric iron oxide nanoparticles (Fe-NPs), alone or in combination. The fatty acid-based membrane lipidomic analysis evidenced the fatty acid remodeling in response to the treatments. Bleomycin alone caused the increase of saturated fatty acid (SFA) moieties in cell membrane glycerophospholipids with concomitant diminution of monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acid levels. Under Fe-NPs treatment, omega-6 PUFA decreased and trans fatty acid isomers increased. Under coadministration bleomycin and Fe-NPs, all membrane remodeling changes disappeared compared to those of the controls, with only an increase of omega-6 PUFA that elevates peroxidation index remaining. Our results highlight the important role of fatty-acid-based membrane lipidome monitoring to follow up the fatty acid reorganization induced by the drug, to be considered as a side effect of the pharmacological activity, suggesting the need of an integrated approach for the investigation of drug and carrier molecular mechanisms.


Assuntos
Bleomicina/farmacologia , Ácidos Graxos/metabolismo , Compostos Férricos/farmacologia , Glicerofosfolipídeos/metabolismo , Nanopartículas/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , Células HEK293 , Humanos
14.
Chem Rev ; 118(14): 6516-6572, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29938502

RESUMO

This review is an update on tris(trimethylsilyl)silane, TTMSS, in organic chemistry, focusing on the advancements of the past decade. The overview includes a wide range of chemical processes and synthetic strategies under different experimental conditions, including functional group insertion and transformations, as well as preparation of complex molecules, natural products, polymers, surfaces, and new materials. These results reveal how TTMSS has matured over the past 30 years, and they further establish its value as a free radical reagent with widespread academic and industrial applications.

15.
Biochemistry ; 58(6): 561-574, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30570250

RESUMO

The nonbulky 5',8-cyclopurine DNA lesions (cP) and the bulky, benzo[ a]pyrene diol epoxide-derived stereoisomeric cis- and trans- N2-guanine adducts (BPDE-dG) are good substrates of the human nucleotide excision repair (NER) mechanism. These DNA lesions were embedded at the In or Out rotational settings near the dyad axis in nucleosome core particles reconstituted either with native histones extracted from HeLa cells (HeLa-NCP) or with recombinant histones (Rec-NCP). The cP lesions are completely resistant to NER in human HeLa cell extracts. The BPDE-dG adducts are also NER-resistant in Rec-NCPs but are good substrates of NER in HeLa-NCPs. The four BPDE-dG adduct samples are excised with different efficiencies in free DNA, but in HeLa-NCPs, the efficiencies are reduced by a common factor of 2.2 ± 0.2 relative to the NER efficiencies in free DNA. The NER response of the BPDE-dG adducts in HeLa-NCPs is not directly correlated with the observed differences in the thermodynamic destabilization of HeLa-NCPs, the Förster resonance energy transfer values, or hydroxyl radical footprint patterns and is weakly dependent on the rotational settings. These and other observations suggest that NER is initiated by the binding of the DNA damage-sensing NER factor XPC-RAD23B to a transiently opened BPDE-modified DNA sequence that corresponds to the known footprint of XPC-DNA-RAD23B complexes (≥30 bp). These observations are consistent with the hypothesis that post-translational modifications and the dimensions and properties of the DNA lesions are the major factors that have an impact on the dynamics and initiation of NER in nucleosomes.


Assuntos
Adutos de DNA/química , Dano ao DNA , Reparo do DNA , DNA/química , Nucleossomos/química , Purinas/química , Adutos de DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HeLa , Humanos , Nucleossomos/genética
16.
Chemistry ; 25(1): 221-237, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30221802

RESUMO

The building of robust and versatile inorganic scaffolds with artificial metallo-nuclease (AMN) activity is an important goal for bioinorganic, biotechnology, and metallodrug research fields. Here, a new type of AMN combining a tris-(2-pyridylmethyl)amine (TPMA) scaffold with the copper(II) N,N'-phenanthrene chemical nuclease core is reported. In designing these complexes, the stabilization and flexibility of TPMA together with the prominent chemical nuclease activity of copper 1,10-phenanthroline (Phen) were targeted. A second aspect was the opportunity to introduce designer phenazine DNA intercalators (e.g., dipyridophenazine; DPPZ) for improved DNA recognition. Five compounds of formula [Cu(TPMA)(N,N')]2+ (where N,N' is 2,2-bipyridine (Bipy), Phen, 1,10-phenanthroline-5,6-dione (PD), dipyridoquinoxaline (DPQ), or dipyridophenazine (DPPZ)) were developed and characterized by X-ray crystallography. Solution stabilities were studied by continuous-wave EPR (cw-EPR), hyperfine sublevel correlation (HYSCORE), and Davies electron-nuclear double resonance (ENDOR) spectroscopies, which demonstrated preferred geometries in which phenanthrene ligands were coordinated to the copper(II) TPMA core. Complexes with Phen, DPQ, and DPPZ ligands possessed enhanced DNA binding activity, with DPQ and DPPZ compounds showing excellent intercalative effects. These complexes are effective AMNs and analysis with spin-trapping scavengers of reactive oxygen species and DNA repair enzymes with glycosylase/endonuclease activity demonstrated a distinctive DNA oxidation activity compared to classical Sigman- and Fenton-type reagents.


Assuntos
Complexos de Coordenação/química , Cobre/química , Fenantrenos/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , DNA/química , DNA/metabolismo , Dano ao DNA , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Endonucleases/química , Endonucleases/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular
17.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769921

RESUMO

Palmitic acid metabolism involves delta-9 and delta-6 desaturase enzymes forming palmitoleic acid (9cis-16:1; n-7 series) and sapienic acid (6cis-16:1; n-10 series), respectively. The corresponding biological consequences and lipidomic research on these positional monounsaturated fatty acid (MUFA) isomers are under development. Furthermore, sapienic acid can bring to the de novo synthesis of the n-10 polyunsaturated fatty acid (PUFA) sebaleic acid (5cis,8cis-18:2), but such transformations in cancer cells are not known. The model of Caco-2 cell line was used to monitor sapienic acid supplementation (150 and 300 µM) and provide evidence of the formation of n-10 fatty acids as well as their incorporation at levels of membrane phospholipids and triglycerides. Comparison with palmitoleic and palmitic acids evidenced that lipid remodelling was influenced by the type of fatty acid and positional isomer, with an increase of 8cis-18:1, n-10 PUFA and a decrease of saturated fats in case of sapienic acid. Cholesteryl esters were formed only in cases with sapienic acid. Sapienic acid was the less toxic among the tested fatty acids, showing the highest EC50s and inducing death only in 75% of cells at the highest concentration tested. Two-photon fluorescent microscopy with Laurdan as a fluorescent dye provided information on membrane fluidity, highlighting that sapienic acid increases the distribution of fluid regions, probably connected with the formation of 8cis-18:1 and the n-10 PUFA in cell lipidome. Our results bring evidence for MUFA positional isomers and de novo PUFA synthesis for developing lipidomic analysis and cancer research.


Assuntos
Neoplasias do Colo/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Palmíticos/metabolismo , Fosfolipídeos/química , Células CACO-2 , Membrana Celular/química , Membrana Celular/metabolismo , Ésteres do Colesterol/biossíntese , Ésteres do Colesterol/química , Ésteres do Colesterol/metabolismo , Neoplasias do Colo/química , Neoplasias do Colo/patologia , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos Ômega-3/biossíntese , Humanos , Ácidos Linoleicos/química , Ácidos Linoleicos/metabolismo , Ácidos Linoleicos/farmacologia , Linoleoil-CoA Desaturase/química , Microscopia de Fluorescência , Ácido Palmítico/química , Ácido Palmítico/metabolismo , Ácidos Palmíticos/química , Ácidos Palmíticos/farmacologia , Fosfolipídeos/biossíntese
18.
Molecules ; 24(17)2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31470553

RESUMO

Thione-containing nucleobases have attracted the attention of the scientific community for their application in oncology, virology, and transplantology. The detailed understanding of the reactivity of the purine derivative 8-thioguanosine (8-TG) with reactive oxygen species (ROS) and free radicals is crucial for its biological relevance. An extensive investigation on the fate of 8-TG under both reductive and oxidative conditions is here reported, and it was tested by employing steady-state photooxidation, laser flash photolysis, as well as γ-radiolysis in aqueous solutions. The characterization of the 8-TG T1 excited state by laser flash photolysis and the photooxidation experiments confirmed that singlet oxygen is a crucial intermediate in the formation of the unexpected reduced product guanosine, without the formation of the usual oxygenated sulfinic or sulfonic acids. Furthermore, a thorough screening of different radiolytic conditions upon γ-radiation afforded the reduced product. These results were rationalized by performing control experiments in the predominant presence of each reactive species formed by radiolysis of water, and the mechanistic pathway scenario was postulated on these bases.


Assuntos
Guanosina/análogos & derivados , Guanosina/química , Oxigênio Singlete/química , Tionucleosídeos/química , Cinética , Lasers , Luz , Oxirredução , Fotólise , Radiólise de Impulso , Soluções , Água/química
19.
Molecules ; 24(17)2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31450691

RESUMO

The natural peptide somatostatin has hormonal and cytostatic effects exerted by the binding to specific receptors in various tissues. Therapeutic uses are strongly prevented by its very short biological half-life of 1-2 min due to enzymatic hydrolysis, therefore encapsulation methodologies are explored to overcome the need for continuous infusion regimes. Multilamellar liposomes made of natural phosphatidylcholine were used for the incorporation of a mixture of somatostatin and sorbitol dissolved in citrate buffer at pH = 5. Lyophilization and reconstitution of the suspension were carried out, showing the flexibility of this preparation. Full characterization of this suspension was obtained as particle size, encapsulation efficiency and retarded release properties in aqueous medium and human plasma. Liposomal somatostatin incubated at 37 °C in the presence of Fe(II) and (III) salts were used as a biomimetic model of drug-cell membrane interaction, evidencing the free radical processes of peroxidation and isomerization that transform the unsaturated fatty acid moieties of the lipid vesicles. This study offers new insights into a liposomal delivery system and highlights molecular reactivity of sulfur-containing drugs with its carrier or biological membranes for pharmacological applications.


Assuntos
Lipossomos/química , Somatostatina/química , Somatostatina/farmacologia , Soluções Tampão , Cromatografia Líquida , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Radicais Livres/química , Humanos , Lipídeos/química , Espectrometria de Massas , Estrutura Molecular , Somatostatina/farmacocinética
20.
Molecules ; 24(21)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717733

RESUMO

The reaction of hydroxyl radical (HO•) with DNA produces many primary reactive species and many lesions as final products. In this study, we have examined the optical spectra of intermediate species derived from the reaction of HO• with a variety of single- and double-stranded oligodeoxynucleotides and ct-DNA in the range of 1 µs to 1 ms by pulse radiolysis using an Intensified Charged Coupled Device (ICCD) camera. Moreover, we applied our published analytical protocol based on an LC-MS/MS system with isotopomeric internal standards to enable accurate and precise measurements of purine lesion formation. In particular, the simultaneous measurement of the four purine 5',8-cyclo-2'-deoxynucleosides (cPu) and two 8-oxo-7,8-dihydro-2'-deoxypurine (8-oxo-Pu) was obtained upon reaction of genetic material with HO• radicals generated either by γ-radiolysis or Fenton-type reactions. Our results contributed to the debate in the literature regarding absolute level of lesions, method of HO• radical generation, 5'R/5'S diastereomeric ratio in cPu, and relative abundance between cPu and 8-oxo-Pu.


Assuntos
DNA/química , Radical Hidroxila/química , Oligodesoxirribonucleotídeos/química , Animais , Dano ao DNA/genética , Humanos , Peróxido de Hidrogênio/química , Ferro/química , Purinas/química
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