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1.
Int J Nanomedicine ; 14: 9577-9586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824152

RESUMO

Purpose: Quantum dots (QDs) are widely used semiconductor nanomaterials. Indium phosphide/zinc sulfide (InP/ZnS) QDs are becoming potential alternatives to toxic heavy metal-containing QDs. However, the potential toxicity and, in particular, the immunotoxicity of InP/ZnS QDs are unknown. This study aimed to investigate the impacts of InP/ZnS QDs on inflammatory responses both in vivo and in vitro. Methods: Mice and mouse bone marrow-derived macrophages (BMMs) were exposed to polyethylene glycol (PEG) coated InP/ZnS QDs. The infiltration of neutrophils and the release of interleukin-6 (IL-6) were measured using a hematology analyzer and an enzyme-linked immunosorbent assay (ELISA) for the in vivo test. Cytotoxicity, IL-6 secretion, oxidative stress and endoplasmic reticulum (ER) stress were studied in the BMMs, and then, inhibitors of oxidative stress and ER stress were used to explore the mechanism of the InP/ZnS QDs. Results: We found that 20 mg/kg PEG-InP/ZnS QDs increased the number of neutrophils and the levels of IL-6 in both peritoneal lavage fluids and blood, which indicated acute phase inflammation in the mice. PEG-InP/ZnS QDs also activated the BMMs and increased the production of IL-6. In addition, PEG-InP/ZnS QDs triggered oxidative stress and the ER stress-related PERK-ATF4 pathway in the BMMs. Moreover, the inflammatory response caused by the PEG-InP/ZnS QDs could be attenuated in the macrophages by blocking the oxidative stress or the ER stress with inhibitors. Conclusion: InP/ZnS QDs can activate macrophages and induce acute phase inflammation both in vivo and in vitro, which may be regulated by oxidative stress and ER stress. Our present work is expected to help clarify the biosafety of InP/ZnS QDs and promote their safe application in biomedical and engineering fields.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Índio/farmacologia , Macrófagos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfinas/farmacologia , Pontos Quânticos/química , Sulfetos/farmacologia , Compostos de Zinco/farmacologia , Animais , Feminino , Depuradores de Radicais Livres/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Inflamação/patologia , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Pontos Quânticos/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo
2.
ACS Appl Mater Interfaces ; 11(39): 35630-35640, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31496235

RESUMO

Many attempts have been made to synthesize cadmium-free quantum dots (QDs), using nontoxic materials, while preserving their unique optical properties. Despite impressive advances, gaps in knowledge of their intracellular fate, persistence, and excretion from the targeted cell or organism still exist, precluding clinical applications. In this study, we used a simple model organism (Hydra vulgaris) presenting a tissue grade of organization to determine the biodistribution of indium phosphide (InP)-based QDs by X-ray fluorescence imaging. By complementing elemental imaging with In L-edge X-ray absorption near edge structure, unique information on in situ chemical speciation was obtained. Unexpectedly, spectral profiles indicated the appearance of In-O species within the first hour post-treatment, suggesting a fast degradation of the InP QD core in vivo, induced mainly by carboxylate groups. Moreover, no significant difference in the behavior of bare core QDs and QDs capped with an inorganic Zn(Se,S) gradient shell was observed. The results paralleled those achieved by treating animals with an equivalent dose of indium salts, confirming the preferred bonding type of In3+ ions in Hydra tissues. In conclusion, by focusing on the chemical identity of indium along a 48 h long journey of QDs in Hydra, we describe a fast degradation process, in the absence of evident toxicity. These data pave the way to new paradigms to be considered in the biocompatibility assessment of QD-based biomedical applications, with greater emphasis on the dynamics of in vivo biotransformations, and suggest strategies to drive the design of future applied materials for nanotechnology-based diagnosis and therapeutics.


Assuntos
Hydra/metabolismo , Índio , Fosfinas , Pontos Quânticos/química , Espectrometria por Raios X , Animais , Índio/química , Índio/farmacocinética , Índio/farmacologia , Fosfinas/química , Fosfinas/farmacocinética , Fosfinas/farmacologia
3.
Inorg Chem ; 58(9): 5988-5999, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-30985125

RESUMO

A series of alkynylgold(I) phosphine complexes containing methoxy-substituted cinnamide moieties (3a-3c and 4a-4c) have been synthesized and characterized. All of the synthesized complexes were evaluated for their cytotoxicity against three human cancer cell lines A549 (lung), D24 (melanoma), and HT1080 (fibrosarcoma) and the human embryonic kidney 293 cell line (Hek293T) as a proxy model for noncancer cells. Most of the synthesized compounds showed antiproliferative activity against cancer cell lines at low micromolar concentrations. Among these, complex 3c showed a broad spectrum of anticancer activity with IC50 values in the range of 1.53-6.05 µM against all tested cancer lines. Complex 3c possessed 20 times higher cytotoxicity than the reference drug cisplatin against D24 melanoma cells and showed significant anticancer activity in 3D spheroidal models of melanoma cells. Mechanistic investigations of 3c activity indicate thioredoxin reductase inhibition through steric and hydrogen-bonding interactions, followed by the induction of oxidative stress and a mitochondrial pathway of cell death. Compound 3c also showed significant antiangiogenic properties in a transgenic zebrafish Tg(fli1a:EGFP) in vivo model.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Melanoma/tratamento farmacológico , Compostos Organoáuricos/química , Compostos Organoáuricos/farmacologia , Inibidores da Angiogênese/síntese química , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Cinamatos/síntese química , Cinamatos/química , Cinamatos/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Compostos Organoáuricos/síntese química , Fosfinas/síntese química , Fosfinas/química , Fosfinas/farmacologia , Esferoides Celulares , Células Tumorais Cultivadas , Peixe-Zebra
4.
Int J Mol Sci ; 20(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30979096

RESUMO

A class of gold(I) phosphane complexes have been identified as inhibitors of dihydrofolate reductase (DHFR) from E. coli, an enzyme that catalyzes the reduction of dihydrofolate (DHF) to tetrahydrofolate (THF), using NADPH as a coenzyme. In this work, to comprehend the nature of the interaction at the basis of these inhibitory effects, the binding properties of bis- and tris-phosphane gold(I) chloride compounds in regards to DHFR have been studied by emission spectroscopy and spectrophotometric assays. The lack of cysteine and seleno-cysteine residues in the enzyme active site, the most favorable sites of attack of Au(I) moieties, makes this work noteworthy. The interaction with the gold compounds results into the quenching of the DHFR tryptophan's emissions and in an enhancement of their intrinsic emission intensities. Moreover, a modulating action of NADPH is highlighted by means of an increase of the gold compound affinity toward the enzyme; in fact, the dissociation constants calculated for the interactions between DHFR and each gold compound in the presence of saturating NADPH were lower than the ones observed for the apo-enzyme. The fluorimetric data afforded to Kd values ranged from 2.22 ± 0.25 µM for (PPh3)2AuCl in the presence of NADPH to 21.4 ± 3.85 µM for 4L3AuTf in the absence of NADPH. By elucidating the energetic aspects of the binding events, we have attempted to dissect the role played by the gold phosphane/protein interactions in the inhibitory activity, resulting in an exothermic enthalpy change and a positive entropic contribution (ΔH° = -5.04 ± 0.08 kcal/mol and ΔS° = 7.34 ± 0.005 cal/mol·K).


Assuntos
Escherichia coli/enzimologia , Antagonistas do Ácido Fólico/farmacologia , NAD/metabolismo , Compostos Organoáuricos/farmacologia , Fosfinas/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/microbiologia , Antagonistas do Ácido Fólico/química , Ouro/química , Ouro/farmacologia , Humanos , Compostos Organoáuricos/química , Fosfinas/química
5.
Dalton Trans ; 48(16): 5183-5192, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30838370

RESUMO

Cleavage of the bromide bridges in [Pd2(µ-Br)2{κ2(Sn,As)-2-MeBrSnC6F4AsPh2}2] (1) by diphosphine ligands gave the mono- and dinuclear palladacycles [Pd(L)Br{κ2(Sn,As)-2-MeBrSnC6F4AsPh2}] [L = dppe (2) dppm (3), ortho-dppBz (4)] and [Pd2Br2(para-dppBz){κ2(Sn,As)-2-MeBrSnC6F4AsPh2}2] (5). The interactions of these complexes with DNA (CT-DNA) and proteins (human serum albumin) were studied by UV-Vis and fluorescence spectroscopy, respectively. The results confirmed the interaction of these palladium complexes with CT-DNA through groove binding, and their strong binding affinity to HSA. The anti-proliferative activities of complexes 1-5 were tested against four human cancer cell lines (HeLa, A549, PC-3, and HT1080) and normal keratinocytes (HaCaT). Among the series, the palladium(ii) complex containing the 1,2-bis(diphenylphosphino)benzene ligand (4) showed the highest cytotoxicity against HeLa, PC-3 and HT1080 cells, with IC50 values of 0.25 ± 0.08, 0.85 ± 0.11, and 0.66 ± 0.15 µM, respectively. Interestingly, compound 4 exhibited lower cytotoxic activity toward normal HaCaT cells (IC50 = 4.65 ± 0.16 µM). Additionally, this complex exhibited lower toxicity and better anti-cancer activity than cisplatin. Further mechanistic studies, including Hoechst staining and flow cytometry, confirmed that complex 4 induced G2/M phase cell cycle arrest and apoptotic cell death in HeLa cells.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Arsênico/química , Arsênico/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quelantes/síntese química , Quelantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Paládio/química , Paládio/farmacologia , Fosfinas/química , Fosfinas/farmacologia , Relação Estrutura-Atividade , Estanho/química , Estanho/farmacologia
6.
J Inorg Biochem ; 193: 70-83, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30684760

RESUMO

The rational design of anticancer agents that acts in specific biological targets is one of the most effective strategies for developing chemotherapeutic agents. Aiming at obtaining new ruthenium (II) compounds with good cytotoxicity against tumor cells, a series of new complexes of general formula [RuCl(PPh3)(Hdpa)(NN)]Cl [PPh3 = triphenylphosphine, N-N = 2,2'-dipyridylamine (Hdpa) (1), 1,2-diaminoethane (en) (2), 2,2'-bipyridine (bipy) (3), 5,5'-dimethyl-2,2'-bipyridine (dmbipy) (4), 1,10-phenanthroline (phen) (5) and 4,7-diphenyl-1,10-phenanthroline (dphphen) (6)] were synthesized. The complexes were characterized by elemental analysis and spectroscopic techniques (IR, UV/Visible, and 1D and 2D NMR) and three of their X-ray structures were determined: [RuCl(PPh3)(Hdpa)2]Cl, [RuCl(PPh3)(Hdpa)(en)]Cl and [RuCl(PPh3)(Hdpa)(dmbipy)]Cl. All the complexes are more cytotoxic against the cancer cell line than against the non-tumor cell line, highlighting complexes 1 and 5, which have an index selectivity of 18 and 15, respectively. The binding constants of compounds 1-6 with human serum albumin (HSA) were determined by tryptophan fluorescence quenching, indicating moderate to strong interactions. The binding mode of the complexes to calf thymus (CT) DNA was explored by several techniques, which reveal that only the dphphen compound 6 causes distortions in the secondary and tertiary structures of DNA. The studies demonstrated that the nature of the NN co-ligand and the presence of the PPh3 and Hdpa ligands are features that can influence the binding affinity of the complexes by the biomolecules and in the cytotoxic activity of the complexes. Overall, the complexes with diimine co-ligand are much more cytotoxic than compound 2 with the aliphatic diamine.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Fosfinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , DNA/química , DNA/metabolismo , Humanos , Ligantes , Fosfinas/síntese química , Fosfinas/metabolismo , Ligação Proteica , Albumina Sérica Humana/metabolismo , Viscosidade
7.
Dalton Trans ; 48(3): 1108-1117, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605200

RESUMO

Owing to their lipophilic nature and chemical stability, ferrocene and its derivatives have been widely explored as antimicrobial agents, in combination with other active chemical 'war heads'. A prime example is ferroquine, an analogue of chloroquine obtained by covalently bonding ferrocene to 4-aminoquinoline, which possesses superior efficacy against multi-drug resistant malaria parasites. Herein, we explored the possibility of combining the ferrocenyl moiety with a phosphine unit and the subsequent inclusion of gold(i) to derive a molecular framework with demonstrated potential in inhibiting parasitic diseases. A library of 24 compounds consisting of 5 non-functionalized ferrocenyl enones and 19 ferrocenyl phosphine derivatives were synthesized, verified and tested against Plasmodium (P.) falciparum, which allowed us to identify compounds with low micromolar potency against both normal and chloroquine-resistant strains. Through flow cytometry combined with microscopic examination of Giemsa-stained thin smears, we observed that most of the active compounds interfered with trophozoite development as well as schizont maturation. The gold complex, namely G3, derived from the hydrophosphination of the terminal furan bearing an enone substrate showed the highest inhibitory potential. We demonstrate that G3 is affecting the parasite's metabolic processes as evident from the swollen digestive vacuole. Furthermore, G3 significantly affected heme de-toxification as determined through the ß-hematin assay, which caused apparent oxidative stress on parasites leading to death. Collectively, these results point out the potential of gold-conjugated ferrocenyl phosphine derivatives as antimalarials targeting the digestive vacuole function and metabolism of parasites.


Assuntos
Antimaláricos/farmacologia , Compostos Ferrosos/farmacologia , Malária Falciparum/tratamento farmacológico , Metalocenos/farmacologia , Fosfinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Vacúolos/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Compostos Ferrosos/síntese química , Compostos Ferrosos/química , Ouro/química , Ouro/farmacologia , Hemeproteínas/antagonistas & inibidores , Hemeproteínas/biossíntese , Células Endoteliais da Veia Umbilical Humana , Humanos , Malária Falciparum/microbiologia , Metalocenos/síntese química , Metalocenos/química , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Fosfinas/síntese química , Fosfinas/química , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Vacúolos/metabolismo
8.
Chemosphere ; 220: 811-817, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30612050

RESUMO

Tris (1-chloro-2-propyl) phosphate (TCIPP) and tris (2-chloroethyl)phosphate (TCEP) are two widely used chlorinated organophosphate flame retardants (ClOPFRs), and have been frequently detected in various environmental media. Concern is now growing whether TCIPP and TCEP can cause neurotoxicity since they have similar chemical structure with organophosphorus pesticide. Therefore, in this study, zebrafish embryos (2-120 h post-fertilization [hpf]) were exposed to TCIPP or TCEP (0, 100, 500 or 2500 µg/L) or a model neurotoxicant, chlorpyrifos (CPF, 100 µg/L) to investigate the adverse effects and possible mechanisms of TCIPP and TCEP on neurodevelopment. Our results showed that CPF exposure resulted in developmental toxicity including decreased hatching, survival rates and increased malformation rates (e.g., spinal curvature) as well as behavior changes such as decreased locomotive activity in dark stimulation. In contrast, TCIPP and TCEP showed no significant effects on developmental parameters, but caused similar effects on locomotive activity at high concentration, indicating that although not as potent as CPF, TCIPP and TCEP may still cause adverse effects on neurodevelopment. Furthermore, our results suggest that TCIPP and TCEP showed no effects on acetylcholine content or AChE activity, which were considered as the main targets of CPF. However, TCIPP and TCEP exposure can significantly down-regulate the expression of selected genes and proteins related to neurodevelopment (e.g., mbp, syn2a, and α1-tubulin) similar as CPF did. Besides that, TCIPP and TCEP can also affect the transcription of shha and gap43, which were not affected by CPF, pointing out a complex mechanism underlying TCIPP and TCEP's neurodevelopmental toxicity. Overall, our results demonstrated that TCEP and TCIPP may have adverse effect on the neurodevelopment of zebrafish embryos/larvae, but the underlying mechanism is not via the inhibition of acetyl cholinesterase activity.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Retardadores de Chama/toxicidade , Transtornos do Neurodesenvolvimento/induzido quimicamente , Compostos Organofosforados , Peixe-Zebra/embriologia , Animais , Clorpirifos/toxicidade , Inibidores da Colinesterase/farmacologia , Retardadores de Chama/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Halogenação , Larva/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Compostos Organofosforados/toxicidade , Fosfinas/farmacologia
9.
Inorg Chem ; 58(2): 1657-1673, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30601653

RESUMO

Two series of neutral luminescent pentafluorophenyl cycloplatinated(II) complexes [Pt(C^N)(C6F5)L] [C^N = C-deprotonated 2-phenylpyridine (ppy; a), 2-(2,4-difluorophenylpyridine (dfppy; b)] incorporating dimethyl sulfoxide [L = DMSO for 1 (1a reported by us in ref (14) )] or biocompatible phosphine [L = PPh2C6H4COOH (dpbH; 2), PPh2C6H4CONHCH2COOMe (dpbGlyOMe; 3), P(C6H4SO3Na)3 (TPPTS; 4)] ligands have been prepared and characterized and their optical properties studied. Their cytotoxic activities against tumor A549 (lung carcinoma), HeLa (cervix carcinoma), and nontumor NL-20 (lung epithelium) cell lines, as well as the ability to interact with DNA (plasmid pBR322), were evaluated. Complexes 2 exhibit higher cytotoxicity (IC50 3.89-20.29 µM) than compounds 1 (9.03-20.50 µM), whereas the activities of complexes 3 and 4 are negligible. All cytotoxic complexes show low selective toxicities toward cancer cells. Interestingly, except 1a, these complexes do not show evidence of DNA intercalation. Along the same lines, fluorescence costaining with Hoechst (2,5'-bi-1 H-benzimidazole, 2'-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl), a nuclear DNA stain) reveals that all complexes easily internalize, being mainly localized in the cytoplasm. In order to deepen the mechanism of biological action, the effect of the most cytotoxic complex 2b toward the dynamics of tubulin was explored. This complex displays tubulin depolymerization activity, exhibiting more potent inhibition of microtubule formation in A549 than in HeLa cells, in accordance with its higher antiproliferative activity (IC50 6.98 vs 12.45 µM), placing this complex as a potential antitubulin agent.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Luminescência , Compostos Organoplatínicos/farmacologia , Fosfinas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Imagem Óptica , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Fosfinas/química , Relação Estrutura-Atividade
10.
Pest Manag Sci ; 75(7): 1847-1854, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30632260

RESUMO

BACKGROUND: Effective management of ground squirrels relies on an integrated pest management (IPM) approach. Rodenticides may be included in an IPM program, but they must be efficacious with minimal impact on nontarget species. A zinc phosphide-coated green bait may meet these requirements. We established a study in northeastern California to test zinc phosphide-coated cabbage as a management tool for Belding's ground squirrels (Urocitellus beldingi). We specifically addressed factors that would influence the efficacy of a baiting program, as well as potential exposure risk to nontarget species. RESULTS: We found that prebaiting was an important application strategy, and efficacy increased as ground squirrel abundance increased. Efficacy was also greater in western portions of the study area, likely due to greater bait consumption at western sites. Belding's ground squirrels fed most heavily on cabbage during mid-morning and late afternoon; bait applications shortly before these time periods would increase bait consumption while minimizing nontarget risk. Bait uptake was greatest around burrow entrances. The only nontarget species observed feeding on cabbage was the California kangaroo rat (Dipodomys californicus), although they were never observed feeding on treated cabbage. CONCLUSION: Zinc phosphide-coated cabbage can be an efficacious tool for managing ground squirrels, but there will be limitations on where and how it can be used effectively. It posed a low risk to nontarget species present in our study area, but nontarget risk could vary regionally. The use of a zinc phosphide-coated green bait should only be one part of an IPM strategy for managing ground squirrels. © 2019 Society of Chemical Industry.


Assuntos
Fosfinas/farmacologia , Controle de Roedores/métodos , Rodenticidas/farmacologia , Sciuridae/fisiologia , Compostos de Zinco/farmacologia , Animais , Brassica , California , Dipodomys/fisiologia , Comportamento Alimentar
11.
Toxicol Sci ; 167(2): 419-425, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30304530

RESUMO

Phosphine is the only fumigant approved globally for general use to control insect pests in stored grain. Due to the emergence of resistance among insect pests and the lack of suitable alternative fumigants, we are investigating ways to synergistically enhance phosphine toxicity, by studying the mechanism of action of known synergists, such as oxygen, temperature, and arsenite. Under normoxia, exposure of the model organism Caenorhabditis elegans for 24 h at 20°C to 70 ppm phosphine resulted in 10% mortality, but nearly 100% mortality if the oxygen concentration was increased to 80%. In wild-type C. elegans, toxicity of phosphine was negatively affected by a decrease in temperature to 15°C and positively affected by an increase in temperature to 25°C. The dld-1(wr4) strain of C. elegans is resistant to phosphine due to a mutation in the dihydrolipoamide dehydrogenase gene. It also exhibits increased mortality that is dependent on hyperoxia, when exposed to 70 ppm phosphine at 20°C. As with the wild-type strain, mortality decreased when exposure was carried out at 15°C. At 25°C, however, the strain was completely resistant to the phosphine exposure at all oxygen concentrations. Arsenite is also a synergist of phosphine toxicity, but only in the dld-1(wr4)-mutant strain. Thus, exposure to 4 mM arsenite resulted in 50% mortality, which increased to 89% mortality when 70 ppm phosphine and 4 mM arsenite were combined. In stark contrast, 70 ppm phosphine rendered 4 mM arsenite nontoxic to wild-type C. elegans. These results reveal two synergists with distinct modes of action, one of which targets individuals that carry a phosphine resistance allele in the dihydrolipoamide dehydrogenase gene.


Assuntos
Arsenitos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Oxigênio/farmacologia , Fosfinas/farmacologia , Animais , Caenorhabditis elegans/genética , Di-Hidrolipoamida Desidrogenase/genética , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Sinergismo Farmacológico , Temperatura Alta , Modelos Teóricos , Mutação , Controle de Pragas/métodos
12.
Pest Manag Sci ; 75(4): 1091-1098, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30255667

RESUMO

BACKGROUND: Next-generation sequencing can enable genetic surveys of large numbers of individuals. We developed a genotyping-by-sequencing assay for detecting strong phosphine resistance alleles in the dihydrolipoamide dehydrogenase (dld) gene of Rhyzopertha dominica populations. The assay can estimate the distribution and frequency of resistance variants in thousands of individual insects in a single run. RESULTS: We analysed 1435 individual insects collected over a 1-year period from 59 grain-storage sites including farms (n = 29) and central storages (n = 30) across eastern Australia. Resistance alleles were detected in 49% of samples, 38% of farms and 60% of central storages. Although multiple alleles were detected, only two resistance variants (P49S and K142E) were widespread and each appeared to have a distinct but overlapping geographical distribution. CONCLUSION: The type of structure in which the grain is stored had a strong effect on resistance allele frequency. We observed higher frequencies of resistance alleles in bunker storages at central sites compared with other storage types. This contributed to the higher frequencies of resistance alleles in bulk-handling facilities relative to farms. The discovery of a storage structure that predisposes insects to resistance highlights the utility of our high-throughput assay system for improvement of phosphine resistance management practices. © 2018 Society of Chemical Industry.


Assuntos
Besouros/genética , Di-Hidrolipoamida Desidrogenase/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Insetos/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Fosfinas/farmacologia , Animais , Besouros/efeitos dos fármacos , Besouros/enzimologia , Di-Hidrolipoamida Desidrogenase/metabolismo , Controle de Insetos , Proteínas de Insetos/metabolismo , New South Wales , Queensland
13.
Eur J Med Chem ; 161: 310-322, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368130

RESUMO

Following promising recent in vitro and in vivo studies of the anticancer efficacies of heterometallic titanocene-gold chemotherapeutic candidates against renal cancer, we report here on the synthesis, characterization, stability studies and biological evaluation of a new titanocene complex containing a gold-triethylphosphane fragment [(η-C5H5)2TiMe(µ-mba)Au(PEt3)] (4) Titanofin. The compound is more stable in physiological fluid than those previously reported, and it is highly cytotoxic against a line of human clear cell renal carcinoma. We describe here preliminary mechanistic data for this compound and previously reported [(η-C5H5)2TiMe(µ-mba)Au(PPh3)] (2) Titanocref which displayed remarkable activity in an in vivo mouse model. Mechanistic studies were carried out in the human clear cell renal carcinoma Caki-1 line for the bimetallic compounds [(η-C5H5)2TiMe(µ-mba)Au(PR3)] (PR3 = PPh32 Titanocref and PEt34 Titanofin), the two monometallic gold derivatives [Au(Hmba)(PR3)] (PR3 = PPh31 cref; PEt33 fin), titanocene dichloride and Auranofin as controls. These studies indicate that bimetallic compounds Titanocref (2) and Titanofin (4) are more cytotoxic than gold monometallic derivatives (1 and 3) and significantly more cytotoxic than titanocene dichloride while being quite selective. Titanocref (2) and Titanofin (4) inhibit migration, invasion, and angiogenic assembly along with molecular markers associated with these processes such as prometastatic IL(s), MMP(s), TNF-α, and proangiogenic VEGF, FGF-basic. The bimetallic compounds also strongly inhibit the mitochondrial protein TrxR often overexpressed in cancer cells evading apoptosis and also inhibit FOXC2, PECAM-1, and HIF-1α whose overexpression is linked to resistance to genotoxic chemotherapy. In summary, bimetallic titanocene-gold phosphane complexes (Titanocref 2 and Titanofin 4) are very promising candidates for further preclinical evaluations for the treatment of renal cancer.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Neoplasias Renais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Compostos Organometálicos/farmacologia , Fosfinas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Renais/patologia , Conformação Molecular , Neovascularização Patológica/patologia , Compostos Organometálicos/química , Fosfinas/química , Relação Estrutura-Atividade
14.
Mol Biol Rep ; 46(1): 639-645, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30484105

RESUMO

Rapid and on-site DNA-based molecular detection has become increasingly important for sensitive, specific, and timely detection and treatment of various diseases. To prepare and store biomolecule-containing reagents stably, reducing agents are used during protein preparation, and freeze-drying technology has been applied to the protein reagents. Some of the additives used during these processes may affect subsequent processes such as polymerase chain reaction (PCR). In this study, we evaluated the impact of TCEP, a reducing agent, and TBA, a freeze-drying medium, on the performance of convection PCR (cPCR) using a battery-operable PCR device. Singleplex cPCR detection of a 249 bp amplicon from human genomic DNA suggested that approximately 82% of performance was achieved in the presence of 0.1 mM TCEP and 1% TBA. The limit of detection and the minimum number of cycles at which amplicons began to appear was a little lower (~ 82% efficiency) or higher (20 vs 15 cycles), respectively, in the chemical-treated group than in the control group. With larger amplicons of 500 bp, the chemical-treated group revealed approximately 78% of performance and amplicons started to appear at 20 cycles of cPCR in both groups. Similar results were obtained with multiplex cPCR amplification.


Assuntos
Convecção , Fosfinas/farmacologia , Reação em Cadeia da Polimerase/métodos , terc-Butil Álcool/farmacologia , Células HEK293 , Humanos , Limite de Detecção , Reação em Cadeia da Polimerase Multiplex
15.
ACS Appl Mater Interfaces ; 10(42): 35676-35680, 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30288974

RESUMO

Cancer cell invasion is the main reason for high mortality in patients with malignant cancers. There has been little improvement in cancer prognosis because of a high rate of infiltration. Therefore, successful treatment requires inhibition of cancer cell invasion. Here, we suggest a new approach to inhibit cancer cell invasion through mild reduction of cell surface proteins to expose free thiols. Through mild reduction, the cancer cell surfaces present free active thiols at the membranes, enhancing cell adhesion to extracellular matrix and decreasing motility. Collectively, we suggest cell surface modification as a new therapeutic approach to treat invading malignant cancers.


Assuntos
Membrana Celular/metabolismo , Glioma/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Fosfinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo
16.
Eur J Med Chem ; 158: 534-547, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30243155

RESUMO

[M(sac)2(dppp)] (1 and 2), [M(dppp)2](sac)2 (3 and 4) and [M(sac)2(dppb)] (5 and 6) complexes, where M = PdII (1, 3 and 5) and PtII (2, 4 and 6), sac = saccharinate, dppp = 1,3-bis(diphenylphosphino)propane and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes against human lung (A549), breast (MCF-7), prostate (DU145) and colon (HCT116) cancer cell lines showed that the cationic complexes of dppp (3 and 4) and neutral Pt complex of dppb (6) were the most active agents of series. 3 and 4 exhibited antiproliferative activity, while 6 was highly cytotoxic compared to cisplatin. These complexes were therefore subjected to further investigations to ascertain the possible role of lipophilicity, cellular uptake and DNA/HSA binding in their biological activity. Flow cytometry analysis revealed that complex 6 induced apoptotic cell death in A549 and HCT116 cells and caused the cell cycle arrest at the S phase and overproduction of reactive oxygen species (ROS), giving rise to mitochondrial depolarization and DNA damage.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Paládio/química , Paládio/farmacologia , Células A549 , Antineoplásicos/síntese química , Butanos/síntese química , Butanos/química , Butanos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Células HCT116 , Humanos , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/síntese química , Fosfinas/síntese química , Fosfinas/química , Fosfinas/farmacologia , Propano/síntese química , Propano/química , Propano/farmacologia
17.
Parasit Vectors ; 11(1): 480, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143025

RESUMO

BACKGROUND: Bovine babesiosis is caused by apicomplexan pathogens of the genus Babesia such as B. bigemina and B. bovis. These tick-borne pathogens have a complex life-cycle involving asexual multiplication in vertebrate hosts and sexual reproduction in invertebrate vectors. In the tick midgut, extracellular Babesia parasites transform into gametes that fuse to form zygotes. Understanding the mechanisms that underlie formation of extracellular Babesia tick stages is an important step towards developing control strategies for preventing tick infection and subsequent parasite transmission. RESULTS: We induced B. bigemina sexual stages in vitro by exposing parasites to Tris 2-carboxyethyl phosphine (TCEP). Subsequently, we identified a novel putative methyltransferase gene (BBBOND_0204030) that is expressed uniquely in all B. bigemina tick stages but not in blood stages. In vitro TCEP-exposed B. bigemina presented diverse morphology including parasites with long projections, round forms and clusters of round forms indicative of sexual stage induction. We confirmed the development of sexual stages by detecting upregulation of previously defined B. bigemina sexual stage marker genes, ccp2 and 3, and their respective protein expression in TCEP-induced B. bigemina cultures. Next, transcription analysis of in vitro TCEP-induced B. bigemina culture based on an in silico derived list of homologs of Plasmodium falciparum gamete-specific genes demonstrated differential expression of the gene BBBOND_0204030 in induced cells. Further examination of ex vivo infected ticks demonstrated that BBBOND_0204030 is transcribed by multiple stages of B. bigemina during parasite development in tick midgut, ovary and hemolymph. Interestingly, ex vivo results confirmed our in vitro observation that blood stages of B. bigemina do not express BBBOND_0204030 and validated the in vitro system of inducing sexual stages. CONCLUSIONS: Herein we describe the identification of a B. bigemina gene transcribed exclusively by parasites infecting ticks using a novel method of inducing B. bigemina sexual stages in vitro. We propose that this gene can be used as a marker for parasite development within the tick vector. Together, these tools will facilitate our understanding of parasite-tick interactions, the identification of novel vaccine targets and, consequently, the development of additional strategies to control bovine babesiosis.


Assuntos
Babesia/genética , DNA de Protozoário/genética , Expressão Gênica , Estágios do Ciclo de Vida/genética , Metiltransferases/genética , Rhipicephalus/parasitologia , Animais , Babesia/efeitos dos fármacos , Babesia/enzimologia , Babesia/crescimento & desenvolvimento , Babesiose/parasitologia , Biomarcadores/análise , Bovinos , Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/parasitologia , Simulação por Computador , Técnicas In Vitro , Metiltransferases/isolamento & purificação , Fosfinas/farmacologia , Reprodução/genética
18.
PLoS One ; 13(7): e0192628, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30024882

RESUMO

The red palm weevil Rhynchophorus ferrugineus (Olivier) is an important pest of date palms in many regions of the world. This paper reports the first survey of insecticide resistance in field populations of R. ferrugineus in Pakistan which were collected from seven date palm growing areas across Punjab and Khyber Pakhtunkhwa (KPK) provinces, Pakistan. The resistance was assessed by the diet incorporation method against the formulated commonly used chemical insecticides profenophos, imidacloprid, chlorpyrifos, cypermethrin, deltamethrin, spinosad, lambda-cyhalothrin and a fumigant phosphine. Elevated levels of resistance were recorded for cypermethrin, deltamethrin and phosphine after a long history of insecticide use in Pakistan. Resistance Ratios (RRs) were 63- to 79-fold for phosphine, 16- to 74-fold for cypermethrin, 13- to 58-fold for deltamethrin, 2.6- to 44-fold for profenophos, 3- to 24-fold for chlorpyrifos, 2- to 12-fold for lambda-cyhalothrin and 1- to 10-fold for spinosad compared to a susceptible control line. Resistant R. ferrugineus populations were mainly found in southern Punjab and to some extent in KPK. The populations from Bahawalpur, Vehari, Layyah and Dera Ghazi Khan were most resistant to chemical insecticides, while all populations exhibited high levels of resistance to phosphine. Of the eight agents tested, lower LC50 and LC90 values were recorded for spinosad and lambda-cyhalothrin. These results suggest that spinosad and lambda-cyhalothrin exhibit unique modes of action and given their better environmental profile, these two insecticides could be used in insecticide rotation or assist in phasing out the use of older insecticides. A changed pattern of both insecticides can be used sensibly be recommended without evidence of dose rates and frequencies used.


Assuntos
Resistência a Inseticidas/efeitos dos fármacos , Inseticidas/farmacologia , Macrolídeos/farmacologia , Nitrilos/farmacologia , Fosfinas/farmacologia , Piretrinas/farmacologia , Gorgulhos/efeitos dos fármacos , Animais , Clorpirifos/farmacologia , Combinação de Medicamentos , Concentração Inibidora 50 , Resistência a Inseticidas/fisiologia , Neonicotinoides/farmacologia , Nitrocompostos/farmacologia , Organotiofosfatos/farmacologia , Paquistão , Phoeniceae/parasitologia , Doenças das Plantas/parasitologia , Gorgulhos/fisiologia
19.
J Inorg Biochem ; 186: 162-175, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29945023

RESUMO

The main disadvantage of conventional anticancer chemotherapy is the inability to deliver the correct amount of drug directly to cancer. Those molecular delivering systems are very important to destroy cancer cells selectively. Herein we report synthesis of phosphine-peptide conjugate (Ph2PCH2-Sar-Gly-OH, PSG) derived from SarGly (sarcosine-glycine), which can be easily exchanged to other peptide carriers, its oxide (OPh2PCH2-Sar-Gly-OH, OPSG) and the first copper(I) complex ([CuI(dmp)(P(Ph)2CH2-Sar-Gly-OH)], 1-PSG, where dmp stands for 2,9-dimethyl-1,10-phenanthroline). The compounds were characterized by elemental analysis, NMR (1D, 2D), UV-Vis spectroscopy and DFT (Density Functional Theory) methods. PSG and 1-PSG proved to be stable in biological medium in the presence of atmospheric oxygen for several days. The cytotoxicity of the compounds and cisplatin was tested against cancer cell lines: mouse colon carcinoma (CT26; 1-PSGIC50 = 3.12 ±â€¯0.1), human lung adenocarcinoma (A549; 1-PSGIC50 = 2.01 ±â€¯0.2) and human breast adenocarcinoma (MCF7; 1-PSGIC50 = 0.98 ±â€¯0.2) as well as against primary line of human pulmonary fibroblasts (MRC-5; 1-PSGIC50 = 78.56 ±â€¯1.1). Therapeutic index for 1-PSG (MCF7) equals 80. Intracellular accumulation of 1-PSG complex increased with time and was much higher (96%) inside MCF7 cancer cells than in normal MRC5 cells (20%). Attachment of SarGly to cytotoxic copper(I) complex via phosphine motif improved selectivity of copper(I) complex 1-PSG into the cancer cells. Precise mechanistic study revealed that the 1-PSG complex causes apoptotic cells MCF7 death with simultaneous decrease of mitochondrial membrane potential and increase of caspase-9 and -3 activities. Additionally, 1-PSG generated high level of reactive oxygen species that was the reason for oxidative damages to the sugar-phosphate backbone of plasmid DNA.


Assuntos
Antineoplásicos , Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação , Cobre , Peptídeos , Fosfinas , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Feminino , Humanos , Células MCF-7 , Peptídeos/química , Peptídeos/farmacologia , Fosfinas/química , Fosfinas/farmacologia
20.
J Inorg Biochem ; 186: 104-115, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29885553

RESUMO

The search for modulating ligand substitution reaction in gold complexes is essential to find new active metallo compounds for medical applications. In this work, a new linear and hydrosoluble goldI complex with tris-(2-carboxyethylphosphine) (AuTCEP). The two phosphines coordinate linearly to the metal as solved by single crystal X-ray diffraction. Complete spectroscopic characterization is also reported. In vitro growth inhibition (GI50) in a panel of nine tumorigenic and one non-tumorigenic cell lines demonstrated the complex is highly selective to ovarium adenocarcinoma (OVCAR-03) with GI50 of 3.04 nmol mL-1. Moreover, non-differential uptake of AuTCEP was observed between OVCAR-03 (tumor) and HaCaT (non-tumor) two cell lines. Biophysical evaluation with the sulfur-rich biomolecules showed the compound does not interact with two types of zinc fingers, bovine serum albumin, N-acetyl-l-cysteine and also l-histidine, revealing to be inert to ligand substitution reactions with these molecules. However, AuTCEP demonstrated to cleave plasmidial DNA, suggesting DNA as a possible target. No antibacterial activity was observed in the strains evaluated. Besides, it inhibits 15% of the activity of a mixture of serine-ß-lactamase and metallo-ß-lactamase from Bacillus cereus in the enzymatic activity assay, similarly to EDTA. These results suggest AuTCEP is selective to metallo-ß-lactamase but the cell uptake is hindered, and the compound does not reach the periplasmic space of Gram-positive bacteria. The unique inert behavior of AuTCEP is interesting and represent the modulation of the reactivity through coordination chemistry to decrease the toxicity associated with AuI complexes and its lack of specificity, generating very selective compounds with unexpected targets.


Assuntos
Antibacterianos , Antineoplásicos , Complexos de Coordenação , Ouro , Bactérias Gram-Positivas/crescimento & desenvolvimento , Fosfinas , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Ouro/química , Ouro/farmacologia , Humanos , Células MCF-7 , Fosfinas/química , Fosfinas/farmacologia , Soroalbumina Bovina/química
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