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1.
Cell Syst ; 12(8): 780-794.e7, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34139154

RESUMO

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.


Assuntos
Biomarcadores/análise , COVID-19/patologia , Progressão da Doença , Proteoma/fisiologia , Fatores Etários , Contagem de Células Sanguíneas , Gasometria , Ativação Enzimática , Humanos , Inflamação/patologia , Aprendizado de Máquina , Prognóstico , Proteômica , SARS-CoV-2/imunologia
2.
Chem Biol Interact ; 306: 78-88, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954465

RESUMO

SALEN- and SALAN-based complexes with catalytically active metal centers are very promising small molecules to be utilized as part of antioxidant therapies. Here we discuss a modified SALAN-type molecule armed with two phosphonate groups that significantly increase its water solubility and aid to furnish mono- or dinuclear complexes with Cu2+ ions. The regulation of the SOD-mimicking (i.e., catalytic) disproportionation reaction of the superoxide radical anion (O2•-) at pH ~7.5 could be achieved by adjusting the metal-to-ligand stoichiometry as confirmed by McCord-Fridovich and pulse radiolysis tests. The higher antioxidant activity of the dicopper complex can be explained by the better access of O2•- to the copper centers and their more positive Cu(II)/Cu(I) redox potential. Simultaneously the analysis of in vitro effect on cells morphology indicates that cytotoxicity is also affected by the metal-to-ligand ratio, however, the active complex molecules do not show notable cytotoxicity that, together with the observed SOD-like activities, makes them potential candidates for antioxidant therapies.


Assuntos
Antioxidantes/metabolismo , Cobre/farmacologia , Compostos Organometálicos/metabolismo , Superóxido Dismutase/metabolismo , Células 3T3-L1 , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cobre/química , Ligantes , Camundongos , Conformação Molecular , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Oxirredução
3.
FASEB J ; 30(12): 4149-4158, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27601443

RESUMO

Fatty acids are taken up by cells and incorporated into complex lipids such as neutral lipids and glycerophospholipids. Glycerophospholipids are major constituents of cellular membranes. More than 1000 molecular species of glycerophospholipids differ in their polar head groups and fatty acid compositions. They are related to cellular functions and diseases and have been well analyzed by mass spectrometry. However, intracellular imaging of fatty acids and glycerophospholipids has not been successful due to insufficient resolution using conventional methods. Here, we developed a method for labeling fatty acids with bromine (Br) and applied scanning X-ray fluorescence microscopy (SXFM) to obtain intracellular Br mapping data with submicrometer resolution. Mass spectrometry showed that cells took up Br-labeled fatty acids and metabolized them mainly into glycerophospholipids in CHO cells. Most Br signals observed by SXFM were in the perinuclear region. Higher resolution revealed a spot-like distribution of Br in the cytoplasm. The current method enabled successful visualization of intracellular Br-labeled fatty acids. Single-element labeling combined with SXFM technology facilitates the intracellular imaging of fatty acids, which provides a new tool to determine dynamic changes in fatty acids and their derivatives at the single-cell level.-Shimura, M., Shindou, H., Szyrwiel, L., Tokuoka, S. M., Hamano, F., Matsuyama, S., Okamoto, M., Matsunaga, A., Kita, Y., Ishizaka, Y., Yamauchi, K., Kohmura, Y., Lobinski, R., Shimizu, I., Shimizu, T. Imaging of intracellular fatty acids by scanning X-ray fluorescence microscopy.


Assuntos
Membrana Celular/metabolismo , Ácidos Graxos/metabolismo , Glicerofosfolipídeos/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Citoplasma/metabolismo , Metabolismo dos Lipídeos , Lipídeos , Microscopia de Fluorescência/métodos , Raios X
4.
Dalton Trans ; 45(22): 9307-19, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27184620

RESUMO

Currently, the leading approach for extraction of uranium from seawater is selective sorption of UO2(2+) ions onto a poly(acrylamidoxime) fiber. Amidoxime functional groups are the most studied extractant moieties for this application, but are not perfectly selective, and understanding how these groups (and more generally the oxime groups) interact with UO2(2+) and competing ions in seawater is an important step in designing better extractants. We have started a new research programme aiming at in-depth studies of the uranyl-oxime/amidoxime interactions and we report here our first results which cover aspects of the coordination chemistry of 2-pyridyl ketoximes towards UO2(2+). Detailed synthetic investigations of various UO2(2+)/mepaoH and UO2(2+)/phpaoH reaction systems (mepaoH is methyl 2-pyridyl ketoxime and phpaoH is phenyl 2-pyridyl ketoxime) have provided access to the complexes [UO2(mepao)2(MeOH)2]{[UO2(NO3)(mepao)(MeOH)2]}2 (), [UO2(mepao)2(MeOH)2] (), [(UO2)2(O2)(O2CMe)2(mepaoH)2] () and [UO2(phpao)2(MeOH)2] (). The peroxido group in , which was isolated without the addition of external peroxide sources, probably arises from a bis(aquo)- and/or bis(hydroxido)-bridged diuranyl precursor in solution followed by photochemical oxidation of the bridging groups. The U(VI) atom in the [UO2(NO3)(mepao)(MeOH)2] molecules of () is surrounded by one nitrogen and seven oxygen atoms in a very distorted hexagonal bipyramidal geometry; two oxygen atoms from the terminal MeOH ligands, two oxygen atoms from the bidentate chelating nitrato group, and the oxygen and nitrogen atoms from the η(2) oximate group of the 1.110 (Harris notation) mepao(-) ligand define the equatorial plane. This plane consists of two terminal MeOH ligands and two η(2) oximate groups in the [UO2(mepao)2(MeOH)2] molecule () of . The structure of the [UO2(mepao)2(MeOH)2] molecule that is present in is very similar to the structure of the corresponding molecule in . The structure of the dinuclear molecule that is present in consists of two {UO2(O2CMe)(mepaoH)}(+) units bridged by a η(2):η(2):µ O2(2-) group. The equatorial plane of each uranyl site is composed of the pyridyl and oxime nitrogen atoms of a 1.011 mepaoH ligand, the oxygen atoms of an almost symmetrically coordinated bidentate chelating MeCO2(-) group and the two oxygen atoms of the peroxido groups. The core molecular structure of is similar to that of , the only difference being the presence of 1.110 phpao(-) ligands in the former instead of mepao(-) groups in the latter. The free pyridyl nitrogen atoms of mepao(-) and phpao(-) ligands of , and are acceptors of intramolecular H bonds from the ligated MeOH oxygen atoms. H-bonding and π-π stacking interactions build interesting supramolecular networks in the crystal structures of the four complexes. Compounds are the first structurally characterized uranyl complexes with 2-pyridyl aldoximes or ketoximes as ligands. IR data are discussed in terms of the coordination modes of the ligands in the complexes. (1)H NMR data in DMSO-d6 suggest that the complexes decompose in solution. The ESI(-) MS spectrum of dissolved in the NH4(O2CMe) buffer is indicative of the presence of [UO2(O2CMe)3](-), [UO2(O2CMe)2(phpao)](-), [UO2(O2CMe)(phpao)2](-) and [UO2(phpao)3](-) species. A common structural motif of the complexes containing the anionic mepao(-) (, ) and phpao(-) () ligands is that the deprotonated oximate group prefers to bind in the η(2) fashion forming a 3-membered chelating ring in spite of the presence of a pyridyl nitrogen atom, whose coordination would be expected to lead to 5- or 6-membered chelating rings.

5.
Chem Sci ; 7(8): 5249-5259, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155174

RESUMO

This work demonstrates the heterogenization of homogeneous water oxidation electrocatalysts in surface coatings produced by combining the substances with a suitable polyelectrolyte. The electrocatalysts i.e. Cu(ii)-branched peptide complexes involving a 2,3-l-diaminopropionic acid junction unit are heterogenized by building composite layers on indium-tin-oxide (ITO) electrode surface. Alternating deposition of the peptide complexes and poly(l-lysine) or poly(allylamine hydrochloride) were carried out in the presence of phosphate in a pH range of 7.5-10.5. Discussion of the results is divided to (1) characteristics of composite layer buildup and (2) electrocatalytic water oxidation and accompanying changes of these layers. For (1), optical waveguide lightmode spectroscopy (OWLS) has been applied to reveal the layer-by-layer formation of a Cu-ligand/polyelectrolyte/phosphate coating. The fabricated structures had a nanoporous topography (atomic force microscopy). As for (2), electrochemistry employing coated ITO substrates indicated improved water oxidation electrocatalysis vs. neat ITO and dependence of this improvement on the presence or absence of a histidine ligand in the deposited Cu(ii)-complexes equally, as observed in homogeneous systems. Electrochemical OWLS revealed changes in the coatings in operando, upon alternating positive-zero-positive etc. polarization: after some initial loss of the coating mass steady-state electrolysis was sustained by a compact and stable layer. According to X-ray photoelectron spectroscopy Cu remains in an N-donor ligand environment after electrolysis.

6.
Metallomics ; 7(12): 1604-11, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26506398

RESUMO

Uranyl ions (UO2(2+)) were shown to interact with a number of foetal serum proteins, leading to the formation of a complex that could be isolated by ultracentrifugation. The molecular weight of the complex was estimated based on size-exclusion chromatography as 650 000 Da. Online ICP AES detection indicated that UO2(2+) in the complex co-eluted with minor amounts of calcium and phosphorous, but not with magnesium. A 1D gel electrophoresis of the U-complex produced more than 10 bands of similar intensity compared with only 2-3 intense bands corresponding to the main serum proteins in the control serum, indicative of the specific interaction of UO2(2+) with minor proteins. A proteomics approach allowed for the identification of 74 proteins in the complex. Analysis of the protein-protein interaction network in the UO2(2+) complex identified 32 proteins responsible for protein-protein complex formation and 34 with demonstrated ion-binding function, suggesting that UO2(2+) stimulates the formation of protein functional networks rather than using a particular molecule as its target.


Assuntos
Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Mapeamento de Interação de Proteínas/métodos , Proteômica/métodos , Compostos de Urânio/química , Compostos de Urânio/metabolismo , Animais , Bovinos , Ligação Proteica , Mapas de Interação de Proteínas
7.
Metallomics ; 7(7): 1155-62, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25927891

RESUMO

A TAT47-57 peptide was modified on the N-terminus by elongation with a 2,3-diaminopropionic acid residue and then by coupling of two histidine residues on its N-atoms. This branched peptide could bind to Ni under physiological conditions as a 1 : 1 complex. We demonstrated that the complex was quantitatively taken up by human fibrosarcoma cells, in contrast to Ni(2+) ions. Ni localization (especially at the nuclei) was confirmed by imaging using both scanning X-ray fluorescence microscopy and Newport Green fluorescence. A competitive assay with Newport Green showed that the latter displaced the peptide ligand from the Ni-complex. Ni(2+) delivered as a complex with the designed peptide induced substantially more DNA damage than when introduced as a free ion. The availability of such a construct opens up the way to investigate the importance of the nucleus as a target for the cytotoxicity, genotoxicity or carcinogenicity of Ni(2+).


Assuntos
Núcleo Celular/metabolismo , Fibrossarcoma/induzido quimicamente , Fibrossarcoma/metabolismo , Níquel/metabolismo , Níquel/toxicidade , Fragmentos de Peptídeos/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Sequência de Aminoácidos , Carcinógenos/química , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/patologia , Dano ao DNA/efeitos dos fármacos , Fibrossarcoma/genética , Fibrossarcoma/patologia , Humanos , Níquel/administração & dosagem , Imagem Óptica , Fragmentos de Peptídeos/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química
8.
Chem Commun (Camb) ; 51(29): 6322-4, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25760390

RESUMO

Two mononuclear Cu(II) complexes with tetrapeptides incorporating a L-2,3-diaminopropionic acid (dap) branching unit are reported to undergo PCET and catalyse water oxidation. C-terminal His extension of dap (L = 2GH) instead of Gly (L = 3G) lowers the pKa for Cu(III)H-2L (9.36 vs. 9.98) and improves the TOF at pH 11 (53 vs. 24 s(-1)).


Assuntos
Cobre/química , Compostos Organometálicos/química , Peptídeos/química , Água/química , Catálise , Eletroquímica , Oxirredução
9.
Inorg Chem ; 53(15): 7951-9, 2014 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-25019411

RESUMO

Three new branched peptides, namely, H-Gly-Dap(H-Gly)-Gly-NH2 (3G), H-His-Dap(H-His)-Gly-NH2 (2HG), and H-Gly-Dap(H-Gly)-His-NH2 (2GH), where Dap stands for the 2,3-diaminopropionic acid residue, were synthesized by solid phase procedures. Because of the junction at Dap these peptides have three available pending arms for metal chelation. The complex formation between these peptides and 1 equiv of Cu(2+) was investigated as a function of pH by potentiometry ultraviolet-visible absorption, circular dichroism, and X-band electron paramagnetic resonance spectroscopy in aqueous medium. Our results clearly demonstrate that cooperation between all three peptide arms essentially contributes to the stability of copper(II) complexes.


Assuntos
Cobre/química , Peptídeos/síntese química , beta-Alanina/análogos & derivados , Concentração de Íons de Hidrogênio , Potenciometria , Espectrometria de Massas por Ionização por Electrospray , beta-Alanina/química
10.
J Pharm Biomed Anal ; 76: 36-43, 2013 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-23291441

RESUMO

One of the treatments of Parkinson disease is based on increasing the brain dopamine level by L-DOPA (LD) applications. To prevent the peripheral degradation of levodopa, another drug, benserazide is applied. On the other hand, during this neurodegenerative disease changes in the homeostasis of metals are observed and the increasing brain zinc levels are postulated to have therapeutic effects. Here we present studies on interactions of Zn(II), Cu(II), Fe(II) ions with benserazide and with benserazide/levodopa in ternary system. By applying mass spectrometry and UV-vis methods we describe the interactions between selected metal ions and the drug additives in the investigated systems. The results show forming of equimolar complexes in the binary and ternary systems.


Assuntos
Benserazida/farmacologia , Cobre/metabolismo , Ferro/metabolismo , Zinco/metabolismo , Antiparkinsonianos/farmacologia , Combinação de Medicamentos , Levodopa/farmacologia , Espectrometria de Massas/métodos , Espectrofotometria Ultravioleta/métodos
11.
J Inorg Biochem ; 105(2): 297-302, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21194631

RESUMO

The coordination properties of cyclic octapeptides with multi-His motif: c(His-Gly-His-Xaa-His-Gly-His-Xaa) where Xaa = Asp or Lys, were investigated. The binding abilities of this peptides towards Cu(II) ions were studied by using different analytic methods as: potentiometry, spectroscopy and mass spectrometry. The obtained results show that the studied peptides in physiological related pH prefer formation of the species with the {4N(Im)} binding mode. The efficiency of Cu(II) binding depends on additional side chain groups Asp or Lys. Additionally the analysis of results for His containing cyclopeptides with different numbers of amino acid residues in cyclopeptide ring e.g. four, eight shows that in higher pH in both cases the binding by four amide nitrogens is not observed in the case of α-amino acid peptides.


Assuntos
Complexos de Coordenação/química , Cobre , Histidina/química , Oligopeptídeos/química , Peptídeos Cíclicos/química , Animais , Complexos de Coordenação/síntese química , Ligantes , Modelos Moleculares , Oligopeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Potenciometria , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
12.
Inorg Chem ; 49(11): 4750-2, 2010 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-20441208

RESUMO

The heterometallic [2 x 2] grid-type complex [Cu(2)Mn(2)(pop)(4)(OAc)(4)].7H(2)O (1) has been selectively synthesized in a targeted one-pot reaction. Single-crystal X-ray analysis shows the expected structure with identical metal ions located at diagonal vertices of the grid. Magnetochemical studies reveal that 1 has a ferrimagnetic spin ground state with some admixture of low-lying excited states.


Assuntos
Cobre/química , Magnetismo , Manganês/química , Compostos Organometálicos/síntese química , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/química
13.
Inorg Chem ; 48(15): 7330-40, 2009 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-19586023

RESUMO

The homeostasis of metal ions, especially copper and zinc, is a major factor that may influence the prion diseases and the biological function of prion protein (PrP). The His-rich regions are basic sites for metal binding and antioxidant activity of the PrP structures. Animal prion-like proteins contain also His-rich domains, and their coordination chemistry may provide better insight into the chemistry and biology of PrP structures and related diseases. Herein, we report an equilibrium study on heteronuclear Zn(2+)-Cu(2+) complexes with zrel-PrP fragments from zebrafish. Potentiometric, spectroscopic, and mass spectrometric methods showed that the binding of copper is much more effective than the binding of zinc. At physiological pH, both metals bind to the histidine imidazole N donors of the studied peptides.


Assuntos
Cobre/química , Peptídeos/química , Príons/química , Peixe-Zebra/metabolismo , Zinco/química , Animais , Dicroísmo Circular , Cobre/metabolismo , Histidina/química , Histidina/metabolismo , Isomerismo , Ressonância Magnética Nuclear Biomolecular , Peptídeos/metabolismo , Príons/metabolismo , Ligação Proteica , Zinco/metabolismo
14.
Mol Biosyst ; 5(5): 497-510, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19381364

RESUMO

Combined potentiometric, calorimetric and spectroscopic methods were used to investigate the Cu(2+) binding ability and coordination behaviour of some peptide fragments related to the neurotoxic region of chicken Prion Protein. The systems studied were the following protein fragments: chPrP(106-114), chPrP(119-126), chPrP(108-127), chPrP(105-127) and chPrP(105-133).The complex formation always starts around pH 4 with the coordination of an imidazole nitrogen, followed by the deprotonation and binding of amide nitrogens from the peptidic backbone. At neutral pH, the {N(im), 3N(-)} binding mode is the preferred one. The amide nitrogens participating in the binding to the Cu(2+) ion derive from residues from the N-terminus side, with the formation of a six-membered chelate ring with the imidazolic side chain.Comparison of thermodynamic data for the two histydyl binding domains (around His-110 and His-124), clearly indicates that the closest to the hexarepeat domain (His-110) has the highest ability to bind Cu(2+) ions, although both of them have the same coordination mode. Conversely, in the case of the human neurotoxic peptide region, between the two binding sites, located at His-96 and His-111, the farthest from the tandem repeat region is the strongest one. Finally, thermodynamic data show that chicken peptide is a distinctly better ligand for coordination of copper ions with respect to the human fragment.


Assuntos
Cobre/química , Príons/química , Sequências Repetitivas de Aminoácidos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Galinhas/metabolismo , Cobre/metabolismo , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Príons/metabolismo
15.
Dalton Trans ; (42): 9131-40, 2009 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-20449188

RESUMO

The medicinal application of bismuth compounds is focused in two fields: antimicrobial and anticancer. Bi(III) complexes have been used in medicine as an effective treatment of microbial infections, such as peptic ulcers, diarrhoea, gastritis and syphilis. (212)Bi and (213)Bi are strong alpha-particle emitters, which, bound to specific ligands, could be promising targeted radio-therapeutic agents for the treatment of cancer. In this work, the coordination of bismuth to three peptides with the Cys-Xaa-Cys motif was studied by potentiometric, spectroscopic, mass spectrometric and NMR methods. We have shown, that sulfur atoms from cysteines are critical donors for the coordination of Bi(III). Our investigation provides insight towards an understanding of the chemistry of bismuth-containing complexes and may lead to the further application of this metal in medicine.


Assuntos
Bismuto/química , Cisteína/química , Peptídeos/química , Sequência de Aminoácidos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Potenciometria
16.
Dalton Trans ; (44): 6117-20, 2008 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-18985242

RESUMO

Multi-histidine peptide fragments of zebra-fish prion protein are effective ligands for Zn(II) ions. Moreover the formation of a dinuclear complex species with a longer peptide can suggest the existence of the cooperative effect in the metal ion binding.


Assuntos
Príons/metabolismo , Sequências de Repetição em Tandem , Zinco/metabolismo , Animais , Cátions Bivalentes/metabolismo , Potenciometria , Espectrometria de Massas por Ionização por Electrospray , Peixe-Zebra/metabolismo
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