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1.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205216

RESUMO

Two independent, complementary methods of structural analysis were used to elucidate the effect of divalent magnesium and iron cations on the structure of the protective Dps-DNA complex. Small-angle X-ray scattering (SAXS) and cryo-electron microscopy (cryo-EM) demonstrate that Mg2+ ions block the N-terminals of the Dps protein preventing its interaction with DNA. Non-interacting macromolecules of Dps and DNA remain in the solution in this case. The subsequent addition of the chelating agent (EDTA) leads to a complete restoration of the structure of the complex. Different effect was observed when Fe cations were added to the Dps-DNA complex; the presence of Fe2+ in solution leads to the total complex destruction and aggregation without possibility of the complex restoration with the chelating agent. Here, we discuss these different responses of the Dps-DNA complex on the presence of additional free metal cations, investigating the structure of the Dps protein with and without cations using SAXS and cryo-EM. Additionally, the single particle analysis of Dps with accumulated iron performed by cryo-EM shows localization of iron nanoparticles inside the Dps cavity next to the acidic (hydrophobic) pore, near three glutamate residues.


Assuntos
Proteínas da Membrana Bacteriana Externa/ultraestrutura , DNA/ultraestrutura , Proteínas de Escherichia coli/ultraestrutura , Ferro/química , Magnésio/química , Sequência de Aminoácidos/efeitos dos fármacos , Proteínas da Membrana Bacteriana Externa/química , Proteínas da Membrana Bacteriana Externa/genética , Cátions/química , Microscopia Crioeletrônica , DNA/química , DNA/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/ultraestrutura , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Espalhamento a Baixo Ângulo , Difração de Raios X
2.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206067

RESUMO

Nanozymes, nanomaterials with enzyme-like activities, are becoming powerful competitors and potential substitutes for natural enzymes because of their excellent performance. Nanozymes offer better structural stability over their respective natural enzymes. In consequence, nanozymes exhibit promising applications in different fields such as the biomedical sector (in vivo diagnostics/and therapeutics) and the environmental sector (detection and remediation of inorganic and organic pollutants). Prussian blue nanoparticles and their analogues are metal-organic frameworks (MOF) composed of alternating ferric and ferrous irons coordinated with cyanides. Such nanoparticles benefit from excellent biocompatibility and biosafety. Besides other important properties, such as a highly porous structure, Prussian blue nanoparticles show catalytic activities due to the iron atom that acts as metal sites for the catalysis. The different states of oxidation are responsible for the multicatalytic activities of such nanoparticles, namely peroxidase-like, catalase-like, and superoxide dismutase-like activities. Depending on the catalytic performance, these nanoparticles can generate or scavenge reactive oxygen species (ROS).


Assuntos
Ferrocianetos/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Nanoestruturas/química , Catalase , Catálise , Complexos de Coordenação/química , Ferro/química , Oxirredução , Peroxidase , Espécies Reativas de Oxigênio
3.
Nat Commun ; 12(1): 4403, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285238

RESUMO

Sulfur cycling is ubiquitous in sedimentary environments, where it mediates organic carbon remineralization, impacting both local and global redox budgets, and leaving an imprint in pyrite sulfur isotope ratios (δ34Spyr). It is unclear to what extent stratigraphic δ34Spyr variations reflect local aspects of the depositional environment or microbial activity versus global sulfur-cycle variations. Here, we couple carbon-nitrogen-sulfur concentrations and stable isotopes to identify clear influences on δ34Spyr of local environmental changes along the Peru margin. Stratigraphically coherent glacial-interglacial δ34Spyr fluctuations (>30‰) were mediated by Oxygen Minimum Zone intensification/expansion and local enhancement of organic matter deposition. The higher resulting microbial sulfate reduction rates led to more effective drawdown and 34S-enrichment of residual porewater sulfate and sulfide produced from it, some of which is preserved in pyrite. We identify organic carbon loading as a major influence on δ34Spyr, adding to the growing body of evidence highlighting the local controls on these records.


Assuntos
Bactérias Anaeróbias/metabolismo , Sedimentos Geológicos/microbiologia , Ferro/metabolismo , Oxigênio/metabolismo , Sulfetos/metabolismo , Enxofre/metabolismo , Carbono/metabolismo , Ciclo do Carbono , Geografia , Sedimentos Geológicos/análise , Sedimentos Geológicos/química , Ferro/química , Oxirredução , Peru , Sulfetos/química , Isótopos de Enxofre/análise
4.
Int J Nanomedicine ; 16: 3789-3802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103915

RESUMO

Introduction: It has been reported that low-molecular-weight hyaluronic acid (LMWHA) exhibits a potentially beneficial effect on cancer therapy through targeting of CD44 receptors on tumor cell surfaces. However, its applicability towards tumor detection is still unclear. In this regard, LMWHA-conjugated iron (Fe3O4) nanoparticles (LMWHA-IONPs) were prepared in order to evaluate its application for enhancing the T2* weighted MRI imaging sensitivity for tumor detection. Methods: LMWHA and Fe3O4 NPs were produced using γ-ray irradiation and chemical co-precipitation methods, respectively. First, LMWHA-conjugated FITC was prepared to confirm the ability of LMWHA to target U87MG cells using fluorescence microscopy. The hydrodynamic size distribution and dispersion of the IONPs and prepared LMWHA-IONPs were analyzed using dynamic light scattering (DLS). In addition, cell viability assays were performed to examine the biocompatibility of LMWHA and LMWHA-IONPs toward U87MG human glioblastoma and NIH3T3 fibroblast cell lines. The ability of LMWHA-IONPs to target tumor cells was confirmed by detecting iron (Fe) ion content using the thiocyanate method. Finally, time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging and in vitro magnetic resonance imaging (MRI) were performed to confirm the contrast enhancement effect of LMWHA-IONPs. Results: Florescence analysis results showed that LMWHA-FITC successfully targeted the surfaces of both tested cell types. The ability of LMWHA to target U87MG cells was higher than for NIH3T3 cells. Cell viability experiments showed that the fabricated LMWHA-IONPs possessed good biocompatibility for both cell lines. After co-culturing test cells with the LMWHA-IONPs, detected Fe ion content in the U87MG cells was much higher than that of the NIH3T3 cells in both thiocyanate assays and TOF-SIMs images. Finally, the addition of LMWHA-IONPs to the U87MG cells resulted in an obvious improvement in T2* weighted MR image contrast compared to control NIH3T3 cells. Discussion: Overall, the present results suggest that LMWHA-IONPs fabricated in this study provide an effective MRI contrast agent for improving the diagnosis of early stage glioblastoma in MRI examinations.


Assuntos
Raios gama , Glioblastoma/diagnóstico por imagem , Ácido Hialurônico/química , Ferro/química , Imageamento por Ressonância Magnética , Nanopartículas Metálicas/química , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Ácido Hialurônico/ultraestrutura , Nanopartículas Metálicas/ultraestrutura , Camundongos , Peso Molecular , Células NIH 3T3 , Ácido Oleico/química , Tamanho da Partícula
5.
ACS Appl Mater Interfaces ; 13(23): 26759-26769, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34076419

RESUMO

Glioblastoma (GBM) is one of the deadliest and most invasive brain cancers/gliomas, and there is currently no established way to treat this disease. The treatment of GBM typically involves intracranial surgery followed by chemotherapy. However, the blood-brain barrier (BBB) impedes the delivery of the chemotherapeutic drug, making the treatment challenging. In this study, we embedded a chemotherapeutic drug and other nanomaterials into a nanobubble (NB), utilized active tracking and other guidance mechanisms to guide the nanocomposite to the tumor site, and then used high-intensity focused ultrasound oscillation to burst the nanobubbles, generating a transient cavitation impact on the BBB and allowing the drug to bypass it and reach the brain. FePt enhances the resolution of T2-weighted magnetic resonance imaging images and has magnetic properties that help guide the nanocomposite to the tumor location. FePt nanoparticles were loaded into the hydrophobic core of the NBs along with doxorubicin to form a bubble-based drug delivery system (Dox-FePt@NB). The surface of the NBs is modified with a targeting ligand, transferrin (Dox-FePt@NB-Tf), giving the nanocomposite active tracking abilities. The Dox-FePt@NB-Tf developed in the present study represents a potential breakthrough in GBM treatment through improved drug delivery and biological imaging.


Assuntos
Barreira Hematoencefálica/metabolismo , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Ferro/química , Nanopartículas Metálicas/administração & dosagem , Platina/química , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Proliferação de Células , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Humanos , Imageamento por Ressonância Magnética , Nanopartículas Metálicas/química , Camundongos , Nanocompostos/química , Medicina de Precisão , Células Tumorais Cultivadas , Ultrassom/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072092

RESUMO

Heme and nonheme-type flavone synthase enzymes, FS I and FS II are responsible for the synthesis of flavones, which play an important role in various biological processes, and have a wide range of biomedicinal properties including antitumor, antimalarial, and antioxidant activities. To get more insight into the mechanism of this curious enzyme reaction, nonheme structural and functional models were carried out by the use of mononuclear iron, [FeII(CDA-BPA*)]2+ (6) [CDA-BPA = N,N,N',N'-tetrakis-(2-pyridylmethyl)-cyclohexanediamine], [FeII(CDA-BQA*)]2+ (5) [CDA-BQA = N,N,N',N'-tetrakis-(2-quinolilmethyl)-cyclohexanediamine], [FeII(Bn-TPEN)(CH3CN)]2+ (3) [Bn-TPEN = N-benzyl-N,N',N'-tris(2-pyridylmethyl)-1,2-diaminoethane], [FeIV(O)(Bn-TPEN)]2+ (9), and manganese, [MnII(N4Py*)(CH3CN)]2+ (2) [N4Py* = N,N-bis(2-pyridylmethyl)-1,2-di(2-pyridyl)ethylamine)], [MnII(Bn-TPEN)(CH3CN)]2+ (4) complexes as catalysts, where the possible reactive intermediates, high-valent FeIV(O) and MnIV(O) are known and well characterised. The results of the catalytic and stoichiometric reactions showed that the ligand framework and the nature of the metal cofactor significantly influenced the reactivity of the catalyst and its intermediate. Comparing the reactions of [FeIV(O)(Bn-TPEN)]2+ (9) and [MnIV(O)(Bn-TPEN)]2+ (10) towards flavanone under the same conditions, a 3.5-fold difference in reaction rate was observed in favor of iron, and this value is three orders of magnitude higher than was observed for the previously published [FeIV(O)(N2Py2Q*)]2+ [N,N-bis(2-quinolylmethyl)-1,2-di(2-pyridyl)ethylamine] species.


Assuntos
Ferro/química , Manganês/química , Oxigenases de Função Mista/química , Antimaláricos/química , Antineoplásicos/química , Antioxidantes/química , Catálise , Sistema Enzimático do Citocromo P-450/química , Flavanonas/química , Flavonas/química , Radicais Livres , Íons , Cinética , Ligantes , Modelos Moleculares , Conformação Molecular , Oxirredução , Oxigênio/química , Espectrofotometria Ultravioleta , Água/química
7.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071361

RESUMO

Nuclear receptor REV-ERBß is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBß to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBß. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBß in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBß binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBß were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBß was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBß, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBß to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects.


Assuntos
Cobalto/química , Neoplasias/tratamento farmacológico , Protoporfirinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/química , Proteínas Repressoras/química , Sítios de Ligação , Química Farmacêutica/métodos , Heme/química , Humanos , Ferro/química , Cinética , Ligantes , Metais , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Ligação Proteica , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Transdução de Sinais
8.
Science ; 373(6551): 236-241, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34083449

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.


Assuntos
Coenzimas/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , RNA-Polimerase RNA-Dependente de Coronavírus/química , Óxidos N-Cíclicos/farmacologia , Ferro/metabolismo , SARS-CoV-2/efeitos dos fármacos , Enxofre/metabolismo , Motivos de Aminoácidos , Animais , Antivirais/farmacologia , Sítios de Ligação , Domínio Catalítico , Chlorocebus aethiops , Coenzimas/química , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Inibidores Enzimáticos/farmacologia , Ferro/química , Domínios Proteicos , RNA Helicases/metabolismo , SARS-CoV-2/enzimologia , SARS-CoV-2/fisiologia , Marcadores de Spin , Enxofre/química , Células Vero , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Zinco/metabolismo
9.
Nat Commun ; 12(1): 3393, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099712

RESUMO

The iron gall ink-triggered chemical corrosion of hand-written documents is a big threat to Western cultural heritages, which was demonstrated to result from the iron gall (GA-Fe) chelate-promoted reactive oxygen species generation. Such a phenomenon has inspired us to apply the pro-oxidative mechanism of GA-Fe to anticancer therapy. In this work, we construct a composite cancer nanomedicine by loading gallate into a Fe-engineered mesoporous silica nanocarrier, which can degrade in acidic tumor to release the doped Fe3+ and the loaded gallate, forming GA-Fe nanocomplex in situ. The nanocomplex with a highly reductive ligand field can promote oxygen reduction reactions generating hydrogen peroxide. Moreover, the resultant two-electron oxidation form of GA-Fe is an excellent Fenton-like agent that can catalyze hydrogen peroxide decomposition into hydroxyl radical, finally triggering severe oxidative damage to tumors. Such a therapeutic approach by intratumoral synthesis of GA-Fe nano-metalchelate may be instructive to future anticancer researches.


Assuntos
Antineoplásicos/administração & dosagem , Ácido Gálico/administração & dosagem , Ferro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Catálise , Complexos de Coordenação/administração & dosagem , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Portadores de Fármacos/química , Feminino , Ácido Gálico/química , Ácido Gálico/metabolismo , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Injeções Intravenosas , Ferro/química , Ferro/metabolismo , Ligantes , Nanopartículas Metálicas/química , Camundongos , Neoplasias/patologia , Oxirredução , Oxigênio/metabolismo , Dióxido de Silício/química , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Med Chem ; 64(11): 7272-7274, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33988992

RESUMO

Halogenated phenazines (HPs) are potent antimicrobial agents. A newly developed halogenated phenazine, HP-29, displays remarkable minimum inhibitory concentration (MIC) of 0.08 µM against methicillin-resistant Staphylococcus aureus, MRSA. HP-29 eradicates preformed biofilm via iron starvation, is nontoxic to mammalian cell lines and is efficacious in wound infection models.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Ferro/química , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Quelantes/química , Quelantes/farmacologia , Quelantes/uso terapêutico , Modelos Animais de Doenças , Halogenação , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Fenazinas/química , Fenazinas/farmacologia , Fenazinas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico
11.
Int J Biol Macromol ; 183: 1495-1504, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34029580

RESUMO

Guar gum is a neutral, non-ionic polysaccharide that has been extensively utilized in the food industry as a stabilizer, excipients, and emulsifier agent. An oxidized derivative of this edible guar gum was prepared and used as a complexing agent for iron to obtain a polysaccharide-bound iron (II) complex. The degree of oxidation varies between 30.12 and 60.63% with a corresponding aldehyde content (0.59-1.79 mmol/g) and carboxyl contents (0.49-1.62 mmol/g), which were determined by the titrimetry method. Sophisticated spectroscopic techniques characterized all the products. The natural polymer-based hydrophilic and hydrophobic formulations as coating were used for achieving the sustained or prolonged release from the complex tablets. Release studies of the tablets were carried out in different mediums of varying pH. The total iron available from the tablets was compared with that obtained from ferrous fumarate prepared under similar conditions, and the results were found to be comparable. Release results demonstrate the pH-sensitive behaviour of the guar gum-based delivery system towards the controlled release of iron. Antianemic effect of new functionalized guar gum iron complexes was investigated on male albino rats. The complexes may exhibit the potential to recover the hematological index of the albino rats with some positive effects on improving rat's growth with iron deficiency anaemia.


Assuntos
Anemia/tratamento farmacológico , Galactanos/química , Ferro/química , Mananas/química , Gomas Vegetais/química , Anemia Ferropriva/tratamento farmacológico , Animais , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Masculino , Ratos , Solubilidade , Comprimidos/química , Comprimidos/uso terapêutico
12.
Biochemistry (Mosc) ; 86(5): 533-539, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33993863

RESUMO

Binding of dinitrosyl iron complex (DNIC) to albumin was studied using time-resolved fluorescence (TRF) and electron spin resonance (ESR) spectroscopy. It was found that the fluorescence lifetime of bovine serum albumin (BSA) and human serum albumin (HSA) decreases with binding and depends on DNIC concentration. The observed biexponential pattern of the BSA tryptophan (Trp) fluorescence decay is explained by the presence of two tryptophan residues in the protein molecule. We believe that DNIC forms stable complexes with the cysteine (Cys34) residue in the domain I of albumin. It was shown that the lifetime of albumin tryptophan fluorescence decreased during co-incubation of BSA with DNICs and glutathione. Effects of DNIC on the binding of specific spin-labeled fatty acids with albumin in human blood plasma were studied in vitro. The presence of DNIC in blood plasma does not change conformation of albumin domains II and III. We suggest that the most possible interaction between DNICs and albumin is the formation of a complex; and nitrosylation of the cysteine residue in the albumin domain I occurs without the changes in albumin conformation.


Assuntos
Ferro/farmacologia , Óxidos de Nitrogênio/farmacologia , Soroalbumina Bovina/efeitos dos fármacos , Albumina Sérica/efeitos dos fármacos , Albumina Sérica/metabolismo , Adulto , Idoso , Animais , Bovinos , Espectroscopia de Ressonância de Spin Eletrônica , Glutationa/química , Humanos , Ferro/química , Masculino , Pessoa de Meia-Idade , Óxidos de Nitrogênio/química , Conformação Proteica , Albumina Sérica/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Espectrometria de Fluorescência
13.
J Environ Sci Health B ; 56(6): 523-531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33979272

RESUMO

This study describes the experimental design and optimization of application TiO2 catalysts doped with 0.5, 1, 1.5, 2.0% of Fe. The catalysts were prepared using the impregnation method applied in Paraquat herbicide degradation. The catalysts were characterized by the following techniques: specific surface area and volume, mean pore diameter (BET method), scanning electron microscopy and photoacoustic spectroscopy. The characterization presented results indicating that both calcination temperature and the increase nominal metallic load affected by the structure of catalysts, changing the textural properties, as well as the band gap. The catalyst that presented the best herbicide removal percentage was TiO2 calcined at 773 K with removal of 90.2%. However, according to the experimental design and optimization, both variables (calcination temperature and Fe percentage) are significant in the process. In addition, a positive effect was found in the interaction between the two variables. The values show that a third order kinetic model better described the Paraquat photocatalytic degradation.


Assuntos
Herbicidas/química , Ferro/efeitos da radiação , Paraquat/química , Titânio/efeitos da radiação , Raios Ultravioleta , Catálise , Ferro/química , Microscopia Eletrônica de Varredura , Fotólise , Temperatura , Titânio/química
14.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33809032

RESUMO

Iron is essential for multiple bacterial processes and is thus required for host colonization and infection. The antimicrobial activity of multiple iron chelators and gallium-based therapies against different bacterial species has been characterized in preclinical studies. In this review, we provide a synthesis of studies characterizing the antimicrobial activity of the major classes of iron chelators (hydroxamates, aminocarboxylates and hydroxypyridinones) and gallium compounds. Special emphasis is placed on recent in-vitro and in-vivo studies with the novel iron chelator DIBI. Limitations associated with iron chelation and gallium-based therapies are presented, with emphasis on limitations of preclinical models, lack of understanding regarding mechanisms of action, and potential host toxicity. Collectively, these studies demonstrate potential for iron chelators and gallium to be used as antimicrobial agents, particularly in combination with existing antibiotics. Additional studies are needed in order to characterize the activity of these compounds under physiologic conditions and address potential limitations associated with their clinical use as antimicrobial agents.


Assuntos
Infecções Bacterianas/tratamento farmacológico , Gálio/uso terapêutico , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/uso terapêutico , Ferro/química , Quelantes de Ferro/química , Testes de Sensibilidade Microbiana
15.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804129

RESUMO

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.


Assuntos
Antivirais/química , Metais/química , Metisazona/química , Simulação de Acoplamento Molecular , SARS-CoV-2/química , Antivirais/metabolismo , COVID-19/tratamento farmacológico , Cálcio/química , Cálcio/metabolismo , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/química , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Desenho de Fármacos , Humanos , Ferro/química , Ferro/metabolismo , Magnésio/química , Magnésio/metabolismo , Manganês/química , Manganês/metabolismo , Metais/metabolismo , Metisazona/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Zinco/química , Zinco/metabolismo
16.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808898

RESUMO

Ferroptosis is gaining followers as mechanism of selective killing cancer cells in a non-apoptotic manner, and novel nanosystems capable of inducing this iron-dependent death are being increasingly developed. Among them, polydopamine nanoparticles (PDA NPs) are arousing interest, since they have great capability of chelating iron. In this work, PDA NPs were loaded with Fe3+ at different pH values to assess the importance that the pH may have in determining their therapeutic activity and selectivity. In addition, doxorubicin was also loaded to the nanoparticles to achieve a synergist effect. The in vitro assays that were performed with the BT474 and HS5 cell lines showed that, when Fe3+ was adsorbed in PDA NPs at pH values close to which Fe(OH)3 begins to be formed, these nanoparticles had greater antitumor activity and selectivity despite having chelated a smaller amount of Fe3+. Otherwise, it was demonstrated that Fe3+ could be released in the late endo/lysosomes thanks to their acidic pH and their Ca2+ content, and that when Fe3+ was co-transported with doxorubicin, the therapeutic activity of PDA NPs was enhanced. Thus, reported PDA NPs loaded with both Fe3+ and doxorubicin may constitute a good approach to target breast tumors.


Assuntos
Antineoplásicos/farmacologia , Ferroptose/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Nanopartículas/química , Polímeros/química , Polímeros/farmacologia , Animais , Neoplasias da Mama , Cálcio/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Ferro/química , Ferro/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo
17.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925312

RESUMO

Red cabbage (RC) and purple sweet potato (PSP) are naturally rich in acylated cyanidin glycosides that can bind metal ions and develop intramolecular π-stacking interactions between the cyanidin chromophore and the phenolic acyl residues. In this work, a large set of RC and PSP anthocyanins was investigated for its coloring properties in the presence of iron and aluminum ions. Although relatively modest, the structural differences between RC and PSP anthocyanins, i.e., the acylation site at the external glucose of the sophorosyl moiety (C2-OH for RC vs. C6-OH for PSP) and the presence of coordinating acyl groups (caffeoyl) in PSP anthocyanins only, made a large difference in the color expressed by their metal complexes. For instance, the Al3+-induced bathochromic shifts for RC anthocyanins reached ca. 50 nm at pH 6 and pH 7, vs. at best ca. 20 nm for PSP anthocyanins. With Fe2+ (quickly oxidized to Fe3+ in the complexes), the bathochromic shifts for RC anthocyanins were higher, i.e., up to ca. 90 nm at pH 7 and 110 nm at pH 5.7. A kinetic analysis at different metal/ligand molar ratios combined with an investigation by high-resolution mass spectrometry suggested the formation of metal-anthocyanin complexes of 1:1, 1:2, and 1:3 stoichiometries. Contrary to predictions based on steric hindrance, acylation by noncoordinating acyl residues favored metal binding and resulted in complexes having much higher molar absorption coefficients. Moreover, the competition between metal binding and water addition to the free ligands (leading to colorless forms) was less severe, although very dependent on the acylation site(s). Overall, anthocyanins from purple sweet potato, and even more from red cabbage, have a strong potential for development as food colorants expressing red to blue hues depending on pH and metal ion.


Assuntos
Antocianinas/química , Brassica/química , Ipomoea batatas/química , Pigmentos Biológicos/química , Acilação , Alumínio/química , Alumínio/metabolismo , Antocianinas/metabolismo , Brassica/metabolismo , Quelantes/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Cor , Corantes de Alimentos , Concentração de Íons de Hidrogênio , Íons/metabolismo , Ipomoea batatas/metabolismo , Ferro/química , Ferro/metabolismo , Cinética , Metais/metabolismo , Fenóis/metabolismo , Extratos Vegetais/química
18.
Molecules ; 26(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917054

RESUMO

A new coumarin-acridone fluorescent probe S was designed and synthesized, and the structure was confirmed with 1H/13C NMR spectrometry, single-crystal X-ray diffraction, and high-resolution mass spectrometry. This probe has high sensitivity and selectivity for Fe3+ over other testing metal ions at 420 or 436 nm in acetonitrile-MOPS (3-Morpholinopropanesulfonic Acid) buffer solution (20.0 µM, pH = 6.9, 8:2 (v/v)). Under physiological conditions, the probe displayed satisfying time stability with a detection limit of 1.77 µM. In addition, probe S was successfully used to detect intracellular iron changes through a fluorescence-off mode, and the imaging results of cells and zebrafish confirmed their low cytotoxicity and satisfactory cell membrane permeability, as well as their potential biological applications.


Assuntos
Acridonas/química , Rastreamento de Células , Cumarínicos/química , Corantes Fluorescentes/química , Imagem Óptica , Espectrometria de Fluorescência , Animais , Linhagem Celular , Rastreamento de Células/métodos , Técnicas de Química Sintética , Corantes Fluorescentes/síntese química , Humanos , Concentração de Íons de Hidrogênio , Ferro/química , Conformação Molecular , Estrutura Molecular , Imagem Óptica/métodos , Espectrometria de Fluorescência/métodos , Peixe-Zebra
19.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805147

RESUMO

The liquid state NMR chemical shift of protons is a parameter frequently used to characterize host-guest complexes. Its theoretical counterpart, that is, the 1H NMR chemical shielding affected by the solvent (1H CS), may provide important insights into spatial arrangements of supramolecular systems, and it can also be reliably obtained for challenging cases of an aggregation of aromatic and antiaromatic molecules in solution. This computational analysis is performed for the complex of coronene and an antiaromatic model compound in acetonitrile by employing the GIAO-B3LYP-PCM approach combined with a saturated basis set. Predicted 1H CS values are used to generate volumetric data, whose properties are thoroughly investigated. The 1H CS isosurface, corresponding to a value of the proton chemical shift taken from a previous experimental study, is described. The presence of the 1H CS isosurface should be taken into account in deriving structural information about supramolecular hosts and their encapsulation of small molecules.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Compostos Policíclicos/química , Solventes/química , Acetonitrilas/química , Isótopos de Carbono , Ferro/química , Substâncias Macromoleculares , Níquel/química , Distribuição Normal , Espectroscopia de Prótons por Ressonância Magnética , Prótons , Difração de Raios X
20.
Int J Mol Sci ; 22(7)2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33805195

RESUMO

Iron loading in some brain regions occurs in Parkinson's Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that iron is sequestered within cells as a result of the "anaemia of chronic disease" and remains unavailable to the chelator. In this review, the extent of neuroinflammation in PD is discussed together with the role played by glia cells, specifically microglia and astrocytes, in controlling iron metabolism during inflammation, together with the results of MRI studies. The current use of chelators in clinical medicine is presented together with a discussion of two clinical trials of PD patients where an iron chelator was administered and showed encouraging results. It is proposed that the use of anti-inflammatory drugs combined with an iron chelator might be a better approach to increase chelator efficacy.


Assuntos
Terapia por Quelação/métodos , Inflamação , Microglia/metabolismo , Doença de Parkinson/terapia , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Quelantes/farmacologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Ferro/química , Quelantes de Ferro/uso terapêutico , Imageamento por Ressonância Magnética , Neuroglia/metabolismo , Neurônios/patologia
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