RESUMO
Although metallic nanomaterials with high X-ray attenuation coefficients have been widely used as X-ray computed tomography (CT) contrast agents, their intrinsically poor biodegradability requires them to be cleared from the body to avoid any potential toxicity. On the other hand, extremely small-sized nanomaterials with outstanding renal clearance properties are not much effective for tumor targeting because of their too rapid clearance in vivo. To overcome this dilemma, here we report on the hollow bismuth subcarbonate nanotubes (BNTs) assembled from renal-clearable ultrasmall bismuth subcarbonate nanoclusters for tumor-targeted imaging and chemoradiotherapy. The BNTs could be targeted to tumors with high efficiency and exhibit a high CT contrast effect. Moreover, simultaneous radio- and chemotherapy using drug-loaded BNTs could significantly suppress tumor volumes, highlighting their potential application in CT imaging-guided therapy. Importantly, the elongated nanotubes could be disassembled into isolated small nanoclusters in the acidic tumor microenvironment, accelerating the payload release and kidney excretion. Such body clearable CT contrast agent with high imaging performance and multiple therapeutic functions shall have a substantial potential for biomedical applications.
Assuntos
Bismuto/química , Meios de Contraste/química , Portadores de Fármacos/química , Nanotubos/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Bismuto/metabolismo , Carbonatos , Linhagem Celular Tumoral , Quimiorradioterapia , Meios de Contraste/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Rim/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/metabolismo , Tomografia Computadorizada por Raios XRESUMO
Glutathione and multidrug resistance protein (MRP) play an important role on the metabolism of a variety of drugs. Bismuth drugs have been used to treat gastrointestinal disorder and Helicobacter pylori infection for decades without exerting acute toxicity. They were found to interact with a wide variety of biomolecules, but the major metabolic pathway remains unknown. For the first time (to our knowledge), we systematically and quantitatively studied the metabolism of bismuth in human cells. Our data demonstrated that over 90% of bismuth was passively absorbed, conjugated to glutathione, and transported into vesicles by MRP transporter. Mathematical modeling of the system reveals an interesting phenomenon. Passively absorbed bismuth consumes intracellular glutathione, which therefore activates de novo biosynthesis of glutathione. Reciprocally, sequestration by glutathione facilitates the passive uptake of bismuth and thus completes a self-sustaining positive feedback circle. This mechanism robustly removes bismuth from both intra- and extracellular space, protecting critical systems of human body from acute toxicity. It elucidates the selectivity of bismuth drugs between human and pathogens that lack of glutathione, such as Helicobacter pylori, opening new horizons for further drug development.
Assuntos
Bismuto/metabolismo , Glutationa/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Bismuto/farmacologia , Compartimento Celular/efeitos dos fármacos , Linhagem Celular , Coloides/metabolismo , Coloides/farmacologia , Escherichia coli/metabolismo , Humanos , Inativação Metabólica/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Modelos Biológicos , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Proteômica , Estatística como Assunto , Fatores de TempoRESUMO
BACKGROUND: Hydrogen sulfide (H2S) is a toxic foul-smelling gas produced by subgingival biofilms in patients with periodontal disease and is suggested to be part of the pathogenesis of the disease. We studied the H2S-producing protein expression of bacterial strains associated with periodontal disease. Further, we examined the effect of a cysteine-rich growth environment on the synthesis of intracellular enzymes in F. nucleatum polymorphum ATCC 10953. The proteins were subjected to one-dimensional (1DE) and two-dimensional (2DE) gel electrophoresis An in-gel activity assay was used to detect the H2S-producing enzymes; Sulfide from H2S, produced by the enzymes in the gel, reacted with bismuth forming bismuth sulfide, illustrated as brown bands (1D) or spots (2D) in the gel. The discovered proteins were identified with liquid chromatography - tandem mass spectrometry (LC-MS/MS). RESULTS: Cysteine synthase and proteins involved in the production of the coenzyme pyridoxal 5'phosphate (that catalyzes the production of H2S) were frequently found among the discovered enzymes. Interestingly, a higher expression of H2S-producing enzymes was detected from bacteria incubated without cysteine prior to the experiment. CONCLUSIONS: Numerous enzymes, identified as cysteine synthase, were involved in the production of H2S from cysteine and the expression varied among Fusobacterium spp. and strains. No enzymes were detected with the in-gel activity assay among the other periodontitis-associated bacteria tested. The expression of the H2S-producing enzymes was dependent on environmental conditions such as cysteine concentration and pH but less dependent on the presence of serum and hemin.
Assuntos
Proteínas de Bactérias/metabolismo , Cisteína/metabolismo , Fusobacterium/enzimologia , Fusobacterium/metabolismo , Sulfeto de Hidrogênio/metabolismo , Proteínas de Bactérias/análise , Biofilmes , Bismuto/metabolismo , Cisteína Sintase/metabolismo , Placa Dentária , Eletroforese em Gel Bidimensional/métodos , Humanos , Concentração de Íons de Hidrogênio , Doenças Periodontais/microbiologia , Proteômica , Sulfetos/metabolismo , Espectrometria de Massas em TandemRESUMO
As with many metals, bismuth can be accumulated or transformed by microorganisms. These interactions affect microbial consortia and bismuth environmental behaviour, mobility, and toxicity. Recent research focused specifically on bismuth anaerobic transformation by bacteria and archaea has inspired the evaluation of the mutual interactions between bismuth and filamentous fungi as presented in this article. The Aspergillus clavatus fungus proved resistant to adverse effects from bismuth contamination in culture medium with up to a concentration of 195 µmol L(-1) during static 15- and 30-day cultivation. The examined resistance mechanism includes biosorption to the fungal surface and biovolatilization. Pelletized fungal biomass has shown high affinity for dissolved bismuth(III). Bismuth biosorption was rapid, reaching equilibrium after 50 min with a 0.35 mmol g(-1) maximum sorption capacity as calculated from the Langmuir isotherm. A. clavatus accumulated ≤70 µmol g(-1) of bismuth after 30 days. Preceding isotherm study implications that most accumulated bismuth binds to cell wall suggests that biosorption is the main detoxification mechanism. Accumulated bismuth was also partly volatilized (≤1 µmol) or sequestrated in the cytosol or vacuoles. Concurrently, ≤1.6 µmol of bismuth remaining in solution was precipitated by fungal activity. These observations indicate that complex mutual interactions between bismuth and filamentous fungi are environmentally significant regarding bismuth mobility and transformation.
Assuntos
Aspergillus/metabolismo , Bismuto/metabolismo , Aerobiose , Biodegradação Ambiental , VolatilizaçãoRESUMO
Bi7O9I3, a kind of visible-light-responsive photocatalyst, with hierarchical micro/nano-architecture was successfully synthesized by oil-bath heating method, with ethylene glycol as solvent, and applied to degrade sulfonamide antibiotics. The as-prepared product was characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-visible diffuse reflection spectra and scanning electron microscopy (SEM). XRD and XPS tests confirmed that the product was indeed Bi7O9I3. The result of SEM observation shows that the as-synthesized Bi7O9I3 consists of a large number of micro-sheets with parallel rectangle structure. The optical test exhibited strong photoabsorption in visible light irradiation, with 617 nm of absorption edges. Moreover, the difference in the photocatalytic efficiency of as-prepared Bi7O9I3 at different seasons of a whole year was investigated in this study. The chemical oxygen demand removal efficiency and concentration of NO(3)(-) and SO(4)(2-) of solution after reaction were also researched to confirm whether degradation of the pollutant was complete; the results indicated a high mineralization capacity of Bi7O9I3. The as-synthesized Bi7O9I3exhibits an excellent oxidizing capacity of sulfadiazine sodium and favorable stability during the photocatalytic reaction.
Assuntos
Bismuto/metabolismo , Iodetos/metabolismo , Compostos de Iodo/metabolismo , Luz , Óxidos/metabolismo , Sulfadiazina/metabolismo , Adsorção , Bismuto/química , Catálise , Cristalização , Iodetos/química , Microscopia Eletrônica de Varredura , Oxigênio/química , Oxigênio/metabolismo , Espectroscopia Fotoeletrônica , Energia Solar , Espectrofotometria Ultravioleta , Sulfadiazina/química , Sulfadiazina/efeitos da radiação , Difração de Raios XRESUMO
AIMS: Tellurium-based devices, such as photovoltaic (PV) modules and thermoelectric generators, are expected to play an increasing role in renewable energy technologies. Tellurium, however, is one of the scarcest elements in the earth's crust, and current production and recycling methods are inefficient and use toxic chemicals. This study demonstrates an alternative, bacterially mediated tellurium recovery process. METHODS AND RESULTS: We show that the hydrothermal vent microbe Pseudoalteromonas sp. strain EPR3 can convert tellurium from a wide variety of compounds, industrial sources and devices into metallic tellurium and a gaseous tellurium species. These compounds include metallic tellurium (Te(0)), tellurite (TeO3(2-)), copper autoclave slime, tellurium dioxide (TeO2), tellurium-based PV material (cadmium telluride, CdTe) and tellurium-based thermoelectric material (bismuth telluride, Bi2Te3). Experimentally, this was achieved by incubating these tellurium sources with the EPR3 in both solid and liquid media. CONCLUSIONS: Despite the fact that many of these tellurium compounds are considered insoluble in aqueous solution, they can nonetheless be transformed by EPR3, suggesting the existence of a steady state soluble tellurium concentration during tellurium transformation. SIGNIFICANCE AND IMPACT OF THE STUDY: These experiments provide insights into the processes of tellurium precipitation and volatilization by bacteria, and their implications on tellurium production and recycling.
Assuntos
Pseudoalteromonas/metabolismo , Telúrio/metabolismo , Bismuto/metabolismo , Compostos de Cádmio/metabolismoRESUMO
UNLABELLED: Biovolatilization and bioaccumulation capabilities of different elements by microscopic filamentous fungus Scopulariopsis brevicaulis were observed. Accumulation of As(III), As(V), Se(IV), Se(VI), Sb(III), Sb(V), Te(IV), Te(VI), Hg(II), Tl(I) and Bi(III) by S. brevicaulis was quantified by analysing the amount of elements in biomass of the fungus using ICP AAS. The highest amounts of bioaccumulated metal(loid)s were obtained as follows: Bi(III) > Te(IV) > Hg(II) > Se(IV) > Te(VI) > Sb(III) at different initial contents, with Bi(III) accumulation approximately 87%. The highest percentages of volatilization were found using Hg(II) (50%) and Se(IV) (46·5%); it was also demonstrated with all studied elements. This proved the biovolatilization ability of microscopic fungi under aerobic conditions. The highest removed amount was observed using Hg(II) (95·30%), and more than 80% of Se(IV), Te(IV), Bi(III) and Hg(II) was removed by bioaccumulation and biovolatilization, which implies the possibilities of use of these processes for bioremediations. There were reported significant differences between bioaccumulation and biovolatilization of almost all applied metal(loid)s if valence is mentioned. SIGNIFICANCE AND IMPACT OF THE STUDY: Microbial accumulation and volatilization are natural processes involved in biogeochemical cycles of elements. Despite their impact on mobility, bioavailability and toxicity of various metal(loid)s, only few papers deal with these processes under aerobic conditions with microscopic fungi. Thus, the proving of ability of microscopic fungus Scopulariopsis brevicaulis to accumulate and transform metals and metalloids by methylation or alkylation and quantification of these processes were demonstrated. The results can provide basic information on natural elements cycling and background for more specific studies focusing, for example, on application of these processes in mitigation of metal(loid) contamination.
Assuntos
Scopulariopsis/metabolismo , Antimônio/metabolismo , Biodegradação Ambiental , Bismuto/metabolismo , Mercúrio/metabolismo , Scopulariopsis/crescimento & desenvolvimento , Selênio/metabolismo , Esporos Fúngicos/crescimento & desenvolvimento , Esporos Fúngicos/metabolismo , Telúrio/metabolismo , VolatilizaçãoRESUMO
BACKGROUND: For a metal to follow the iron acquisition pathway, four conditions are required: 1-complex formation with transferrin; 2-interaction with receptor 1; 3-metal release in the endosome; and 4-metal transport to cytosol. SCOPE OF THE REVIEW: This review deals with the mechanisms of aluminum(III), cobalt(III), uranium(VI), gallium(III) and bismuth(III) uptake by transferrin and interaction with receptor 1. MAJOR CONCLUSIONS: The interaction of the metal-loaded transferrin with receptor 1 takes place in one or two steps: a very fast first step (µs to ms) between the C-lobe and the helical domain of the receptor, and a second slow step (2-6h) between the N-lobe and the protease-like domain. In transferrin loaded with metals other than iron, the dissociation constants for the interaction of the C-lobe with TFR are in a comparable range of magnitudes 10 to 0.5µM, whereas those of the interaction of the N-lobe are several orders of magnitudes lower or not detected. Endocytosis occurs in minutes, which implies a possible internalization of the metal-loaded transferrin with only the C-lobe interacting with the receptor. GENERAL SIGNIFICANCE: A competition with iron is possible and implies that metal internalization is more related to kinetics than thermodynamics. As for metal release in the endosome, it is faster than the recycling time of transferrin, which implies its possible liberation in the cell. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.
Assuntos
Metais/metabolismo , Receptores da Transferrina/metabolismo , Transferrina/metabolismo , Alumínio/metabolismo , Animais , Bismuto/metabolismo , Cobalto/metabolismo , Endocitose , Gálio/metabolismo , Humanos , Íons/metabolismo , Ferro/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Transferrina/química , Urânio/metabolismoRESUMO
GroES is an indispensable chaperonin virtually found throughout all life forms. Consequently, mutations of this protein must be critically scrutinized by natural selection. Nevertheless, the homolog from a potentially virulent gastric pathogen, Helicobacter pylori, strikingly features a histidine/cysteine-rich C terminus that shares no significant homology with other family members. Additionally, three more (H45, C51, and C53) are uniquely present in its apical domain. The statistical analyses show that these residues may have originated from negative selection, presumably driven by either dependent or independent amino acid mutations. In the absence of the C-terminal metal-binding domain, the mutant protein still exhibits a substantial capacity for zinc binding in vivo. The biochemical properties of site-directed mutants indicate that H45, C51, and C53 make up an oxidation-sensitive zinc-binding site that may donate the bound metal to a zinc acceptor. Of interest, bismuth antiulcer drugs strongly bind at this site (K(d) of approximately 7 x 10(-26) M), replacing the bound zinc and consequently inducing the disruption of the quaternary structure. Because biological features by negative selection are usually inert to change during evolution, this study sheds light on a promising field whereby medicines can be designed or improved to specifically target the residues that uniquely evolved in pathogenic proteins so as to retard the emergence of drug resistance.
Assuntos
Chaperonina 10/metabolismo , Resistência a Medicamentos/genética , Helicobacter pylori/metabolismo , Seleção Genética , Zinco/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Sítios de Ligação , Ligação Competitiva , Bismuto/metabolismo , Chaperonina 10/química , Cisteína/metabolismo , Escherichia coli/crescimento & desenvolvimento , Histidina/metabolismo , Cinética , Dados de Sequência Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Oxirredução , Estrutura Quaternária de Proteína , Estrutura Terciária de ProteínaRESUMO
Metal acquisition and intracellular trafficking are crucial for all cells and metal ions have been recognized as virulence determinants in bacterial pathogens. Nickel is required for the pathogenicity of H. pylori. This bacterial pathogen colonizes the stomach of about half of the human population worldwide and is associated with gastric cancer that is responsible for 800,000 deaths per year. H. pylori possesses two nickel-enzymes that are essential for in vivo colonization, a [NiFe] hydrogenase and an abundant urease responsible for resistance to gastric acidity. Because of these two enzymes, survival of H. pylori relies on an important supply of nickel, implying tight control strategies to avoid its toxic accumulation or deprivation. H. pylori possesses original mechanisms for nickel uptake, distribution, storage and trafficking that will be discussed in this review. During evolution, acquisition of nickel transporters and specific nickel-binding proteins has been a decisive event to allow Helicobacter species to become able to colonize the stomach. Accordingly, many of the factors involved in these mechanisms are required for mouse colonization by H. pylori. These mechanisms are controlled at different levels including protein interaction networks, transcriptional, post-transcriptional and post-translational regulation. Bismuth is another metal used in combination with antibiotics to efficiently treat H. pylori infections. Although the precise mode of action of bismuth is unknown, many targets have been identified in H. pylori and there is growing evidence that bismuth interferes with the essential nickel pathways. Understanding the metal pathways will help improve treatments against H. pylori and other pathogens.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Animais , Proteínas de Bactérias/metabolismo , Bismuto/metabolismo , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/metabolismo , Camundongos , Níquel/metabolismo , Virulência , Fatores de Virulência/metabolismoRESUMO
Bacterial antibiotic resistance is a major threat to human health. A combination of antibiotics with metals is among the proposed alternative treatments. Only one such combination is successfully used in clinics; it associates antibiotics with the metal bismuth to treat infections by Helicobacter pylori. This bacterial pathogen colonizes the human stomach and is associated with gastric cancer, killing 800,000 individuals yearly. The effect of bismuth in H. pylori treatment is not well understood in particular for sublethal doses such as those measured in the plasma of treated patients. We addressed this question and observed that bismuth induces the formation of homogeneously sized membrane vesicles (MVs) with unique protein cargo content enriched in bismuth-binding proteins, as shown by quantitative proteomics. Purified MVs of bismuth-exposed bacteria were strongly enriched in bismuth as measured by inductively coupled plasma optical emission spectrometry (ICP-OES), unlike bacterial cells from which they originate. Thus, our results revealed a novel function of MVs in bismuth detoxification, where secreted MVs act as tool to discard bismuth from the bacteria. Bismuth also induces the formation of intracellular polyphosphate granules that are associated with changes in nucleoid structure. Nucleoid compaction in response to bismuth was established by immunogold electron microscopy and refined by the first chromosome conformation capture (Hi-C) analysis of H. pylori. Our results reveal that even low doses of bismuth induce profound changes in H. pylori physiology and highlight a novel defense mechanism that involves MV-mediated bismuth extrusion from the bacteria and a probable local DNA protective response where polyphosphate granules are associated with nucleoid compaction. IMPORTANCE Bacterial resistance to antibiotics is a major threat to human health. Treatments combining antibiotics with metals were proposed to circumvent this hurdle. Only one such combination is successfully used in clinics associating antibiotics with the metal bismuth to treat infections by the human pathogen Helicobacter pylori. H. pylori causes 800,000 deaths by gastric cancer yearly. How bismuth impacts H. pylori and its response to this toxic metal were ill defined. We discovered that upon bismuth exposure, H. pylori secretes membrane vesicles that are enriched in bismuth. Bismuth also induces the formation of intracellular polyphosphate granules associated with compaction of the chromosome. Upon bismuth exposure, H. pylori displays both defense and protection mechanisms, with bismuth extrusion by vesicles and shielding of the chromosome.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Helicobacter pylori/genética , Bismuto/farmacologia , Bismuto/metabolismo , Bismuto/uso terapêutico , Infecções por Helicobacter/microbiologia , Antibacterianos/metabolismo , Polifosfatos/metabolismo , Quimioterapia CombinadaRESUMO
Two types of bismuth modified electrodes, a bismuth-film modified glassy carbon (BiF-GCE) and a bismuth bulk modified carbon paste, were applied for the determination of selected nitroguanidine neonicotinoid insecticides. The method based on an ex situ prepared BiF-GCE operated in the differential pulse voltammetric (DPV) mode was applied to determine clothianidin in the concentration range from 2.5 to 23 µg cm⻳ with a relative standard deviation (RSD) not exceeding 1.5%. The tricresyl phosphate-based carbon paste electrodes (TCP-CPEs), bulk modified with 5 and 20 w/w% of bismuth, showed a different analytical performance in the determination of imidacloprid, regarding the peak shape, potential window, and noise level. The TCP-CPE with 5% Bi was advantageous, and the developed DPV method based on it allowed the determination in the concentration range from 1.7 to 60 µg cm⻳ with an RSD of 2.4%. To get a deeper insight into the morphology of the bismuth-based sensor surfaces, scanning electron microscopic measurements were performed of both the surface film and the bulk modified electrodes.
Assuntos
Bismuto/metabolismo , Carbono/química , Eletrodos , Guanidina/análogos & derivados , Inseticidas/química , Eletroquímica , Guanidina/química , Guanidinas/química , Neonicotinoides , Reprodutibilidade dos Testes , Tiazóis/químicaRESUMO
Near infrared (NIR) light detonated phototherapy for cancer treatment based on photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted increasing attention owing to its deep tissue penetration. However, the low absorption ability and therapeutic efficiency of the photosensitive drug have restricted the development of phototherapy to a great degree. Herein, a kind of IR808 dye sensitized glutathione (GSH) cladded Au-Bi bimetallic nanoparticles (Au-Bi-GSH@IR808) was prepared to enhance the inhibition effect of tumors. In this nanoplatform, the construction of GSH cladded Au-Bi bimetallic nanoparticles can effectively generate 1O2 while exhibiting outstanding photothermal conversion efficiency (η = 34.2%) upon 808 nm laser irradiation. Furthermore, IR808 as a small molecule dye endows the Au-Bi-GSH@IR808 with a higher 808 nm light absorption ability and stronger photothermal and photodynamic effects. The IR808 sensitized Au-Bi bimetallic nanoparticles with a small size (5 nm), hydrophilia and dispersible nature, exhibit a noticeably enhanced therapeutic peculiarity. Additionally, the prominent CT imaging property of Au-Bi-GSH@IR808 means it is expected to be used as a CT imaging contrast agent in clinical applications. The results of the in vitro and in vivo experiments indicate that the synthesized nanoparticles have an excellent ablation effect on cancer cells, and they are expected to be widely used in the accurate diagnosis and treatment of cancer.
Assuntos
Bismuto/metabolismo , Ouro/metabolismo , Nanopartículas Metálicas , Fotoquimioterapia/métodos , Fototerapia/métodos , Compostos de Sulfidrila/metabolismo , Animais , Bismuto/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Ouro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Camundongos , Imagem Molecular/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Compostos de Sulfidrila/administração & dosagemRESUMO
Bismuth compounds are currently used to treat gastric ailments and to prevent the toxic side effects of cancer treatments. The affinity of bismuth for binding to sulfur compounds has been reported and one such target biomolecule is the cysteine-rich metalloprotein metallothionein. Renal mammalian metallothionein has been shown to be induced by Bi salts, with the Bi(3+) binding to the renal MT. However, the exact metal-to-metallothionein stoichiometric ratios for the 2-domain betaalpha mammalian protein and the individual beta and alpha domain fragments remain unknown. We now report that the maximum metal-to-MT stoichiometries for the individual domain fragments and the entire 2-domain protein are Bi(3)-S(9)-betahMT, Bi(4)-S(11)-alphahMT, and Bi(7)-S(20)-betaalphahMT, respectively. Electrospray mass spectrometry data also unambiguously show the existence of partially metalated Bi-containing MT species during the titration of apo-MT with Bi(3+), which demonstrates that Bi-metalation to MT occurs in a noncooperative manner.
Assuntos
Antiácidos/metabolismo , Bismuto/metabolismo , Cisteína/metabolismo , Metalotioneína/metabolismo , Antiácidos/química , Sítios de Ligação , Bismuto/química , Cisteína/química , Humanos , Metalotioneína/química , Ligação Proteica , Estrutura Terciária de Proteína , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Bismuth is a well-known therapeutic agent that is used primarily for treatment against peptic ulcers. It has also had success in protecting against nephrotoxicity caused by the anticancer compound cisplatin by inducing the liver and kidney metalloprotein, metallothionein (MT) that then binds to the cisplatin. MT is a small, ubiquitous protein that binds monovalent, divalent, and trivalent metals using its abundant cysteine thiols (20 cysteines in the mammalian protein). It is important in the understanding of both these therapeutic applications to explore in detail the earliest stages of MT binding to bismuth salts. In this paper, we explored the binding of [Bi(cit)]- and [Bi(EDTA)]- to apo-MT 1a as the most basic of binding motifs. It was found that both Bi3+ salts bound in a non-cooperative stepwise manner to terminal cysteinal thiolates at pH 2.6, 5.0, and 7.4. We report that [Bi(EDTA)]- only binds stepwise up to Bi6MT, whereas [Bi(cit)]- forms up to Bi8MT, where the 7th and 8th Bi3+ appear to be adducts. Stepwise speciation analysis provided the 7 binding constants that decreased systematically from K1 to K7 indicating a non-cooperative binding profile. They are reported as log K1 = 27.89, log K2 = 27.78, log K3 = 27.77, log K4 = 27.62, log K5 = 27.32, log K6 = 26.75, and log K7 = 26.12, with log K[Bi(cit)]- determined to be 24.17. Cysteine modifications with benzoquinone and iodoacetamide revealed that when apoMT is fully metallated with Bi3+ there are two free cysteines, meaning 18 cysteines are used in binding the 6 Bi3+. Kinetic studies showed that [Bi(EDTA)]- binds very slowly at pH 2.6 (k = 0.0290 × 106 M-1 s-1) and approximately 2000 times faster at pH 7.4 (k = 66.5 × 106 M-1 s-1). [Bi(cit)]- binding at pH 2.6 was faster than [Bi(EDTA)]- (k = 672 × 106 M-1 s-1) at either pH level. The data strongly support a non-clustered binding motif, emphasizing the non-traditional pathway reported previously for As3+.
Assuntos
Bismuto/metabolismo , Metalotioneína/metabolismo , Sítios de Ligação , Cátions/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Cinética , Metalotioneína/química , Modelos Moleculares , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMO
Tyrosine sulfation is a common modification of many proteins, and the ability to phosphorylate tyrosine residues is an intrinsic property of many growth-factor receptors. In the present study, we have utilized the peptide hormone CCK(8) (cholecystokinin), which occurs naturally in both sulfated and unsulfated forms, as a model to investigate the effect of tyrosine modification on metal-ion binding. The changes in absorbance and fluorescence emission on Fe(3+) binding indicated that tyrosine sulfation or phosphorylation increased the stoichiometry from 1 to 2, without greatly affecting the affinity (0.6-2.8 microM at pH 6.5). Measurement of Ca(2+) binding with a Ca(2+)-selective electrode revealed that phosphorylated CCK(8) bound two Ca(2+) ions. CCK(8) and sulfated CCK(8) each bound only one Ca(2+) ion with lower affinity. Binding of Ca(2+), Zn(2+) or Bi(3+) to phosphorylated CCK(8) did not cause any change in absorbance, but substantially increased the change in absorbance on subsequent addition of Fe(3+). The results of the present study demonstrate that tyrosine modification may increase the affinity of metal-ion binding to peptides, and imply that metal ions may directly regulate many signalling pathways.
Assuntos
Cálcio/metabolismo , Colecistocinina/química , Compostos Férricos/metabolismo , Fragmentos de Peptídeos/química , Tirosina/análogos & derivados , Tirosina/química , Tirosina/metabolismo , Animais , Bismuto/metabolismo , Células COS , Chlorocebus aethiops , Colecistocinina/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismo , Fosforilação , Receptores da Colecistocinina/metabolismo , Espectrometria de Fluorescência , Zinco/metabolismoRESUMO
UNLABELLED: We quantitatively and qualitatively investigated 2-dimensional (2D) and 3-dimensional (3D) imaging with scan-time reduction in 14 patients with 17 lesions, who had known or suspected head and neck cancer, using a bismuth germanate (BGO) crystal based PET/CT scanner with noise-matched images. METHODS: A 2D and 3D acquisition protocol using scan-time reduction on an axial single field of view resulted in a 2D 4-, 3D 4-, 3D 3-, 2D 3-, 2D 2-, and 3D 2-min scan sequence to minimize redistribution and decay bias. Tumor maximum standardized uptake values (SUVmax) and tumor mean standardized uptake values (SUV(mean)) were recorded, and two observers in consensus investigated lesion conspicuity between 2D and 3D paired 4-, 3-, and 2-min noise-matched images. RESULTS: We found some minor advantages quantitatively in favor of 2D scanning, with higher mean SUVmax, and qualitatively in favor of 3D scanning, with lesion conspicuity preference. In our cohort, no great advantage or disadvantage to using either acquisition mode was observed, and all lesions were seen irrespective of acquisition mode and scan time. CONCLUSION: In head and neck cancer patients, we can recommend a scan-time reduction from 4 to 3 min/bed position in 2D acquisitions with a BGO-based PET/CT scanner, using our imaging protocol and reconstruction defaults.
Assuntos
Bismuto , Germânio , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Imageamento Tridimensional , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Bismuto/metabolismo , Feminino , Germânio/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Fatores de TempoRESUMO
At present, various organic pollutants and pathogenic microorganisms presented in wastewater have severely threatened aquatic ecosystem and human health. Meanwhile, semiconductor photocatalysis technology for water purification has attracted increasingly significant attention. Herein, we successfully constructed a series of novel visible-light-driven (VLD) Bi4O5I2/AgI hybrid photocatalysts with different AgI amounts. Compared with pristine AgI and Bi4O5I2, Bi4O5I2/AgI with the optimal AgI contents exhibited remarkably enhanced photocatalytic performance in probe experiment for Escherichia coli (E. coli) disinfection and tetracycline (TC) degradation. The efficiency for TC degradation and E. coli inactivation reached 82% and 100% in 30â¯min, respectively. The enhanced electron-hole separation efficiency was responsible for improved photocatalytic activity. In addition, the destruction process of the chemical structure of TC molecules was further investigated by three-dimensional excitation-emission matrix fluorescence spectra (3D EEMs). The activity and crystal phase of the catalysts did not change significantly after four cycles, demonstrating their excellent recyclability and stability of catalysts. The Ag+ ion leaking experiments, radical trapping experiments and ESR tests demonstrated that OH, O2- and h+ were the main active species in photocatalytic disinfection processes. Furthermore, the photocatalytic mechanism of Bi4O5I2/AgI nanomaterials was discussed in detail in conjunction with the energy band structure, and a reasonable Z-scheme interfacial charge transfer mechanism was proposed. This work is expected to provide an efficient water disinfection method.
Assuntos
Bismuto/química , Escherichia coli/metabolismo , Iodetos/química , Iodo/química , Luz , Compostos de Prata/química , Tetraciclina/metabolismo , Bismuto/metabolismo , Catálise , Iodetos/metabolismo , Iodo/deficiência , Iodo/metabolismo , Tamanho da Partícula , Processos Fotoquímicos , Compostos de Prata/metabolismo , Propriedades de SuperfícieRESUMO
Bismuth-containing nanoparticles (BNPs) are potential enhancers for tumor radiotherapy. Improving the bioavailability and developing synergistic therapeutic regimens benefit the drug transformation of BNPs. In the present study, we prepare a mesoporous silica-coated bismuth nanorod (BMSNR) camouflaged by a platelet membrane (PM). This biomimetic material is termed BMSNR@PM. The PM camouflage enhances the immune escape of the BMSNRs by lowering endocytosis by macrophages in the reticuloendothelial system. Additionally, the PM camouflage strengthens the material tumor-targeting capacity and leads to better radiotherapeutic efficacy compared with bare BMSNRs. Owing to the photothermal effect, BMSNR@PMs alters the cell cycle of 4T1 cancer cells post-treatment with 808 nm near-infrared irradiation (NIR). The proportions of S phase and G2/M phase cells decrease and increase, respectively, which explains the synergistic effect of NIR on BMSNR@PM-based radiotherapy. BMSNR@PMs efficiently eradicates cancer cells by the combined action of photothermal therapy (PTT) and radiotherapy in vivo and markedly improves the survival of 4T1-tumor-bearing mice. The synergistic therapeutic effect is superior to the outcomes of PTT and radiotherapy performed alone. Our study demonstrates a versatile bismuth-containing nanoplatform with tumor-targeting, immune escape, and radiosensitizing functionalities using an autologous cell membrane biomimetic concept that may promote the development of radiotherapy enhancers.