Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold({III}) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

Au(2)phen ((2,9-dimethyl-1,10-phenanthroline)(2)Au(2)(µ-O)(2))(PF(6))(2) and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)(2)Au(2)(µ-O)(2))(PF(6))(2) are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase

Synthesis, chemical characterization, and biological evaluation of a novel auranofin derivative as an anticancer agent

A novel gold(I) complex inspired by the known medicinal inorganic compounds auranofin and thimerosal, namely ethylthiosalicylate(triethylphosphine)gold(I) (AFETT hereafter), was synthesized and characterised and its structure was resolved through X-ray diffraction. The solution behavior of AFETT and its interactions with two biologically relevant proteins (i.e. human serum albumin and haemoglobin) and with a synthetic dodecapeptide reproducing the C-terminal portion of thioredoxin reductase were comparatively analyzed through 31P NMR and ESI-MS. Remarkable binding properties toward these biomolecules were disclosed. Moreover, the cytotoxic effects produced by AFETT on two ovarian cancer cell lines (A2780 and A2780 R) and one colorectal cancer cell line (HCT116) were analyzed and found to be strong and nearly superimposable to those of auranofin. Interestingly, for both compounds, the ability to induce downregulation of vimentin expression in A2780 R cells was evidenced. Despite its close similarity to auranofin, AFETT is reported to exhibit some peculiar and distinctive features such as a lower lipophilicity, an increased water solubility and a faster reactivity towards the selected target biomolecules. These differences might confer to AFETT significant pharmaceutical and therapeutic advantages over auranofin itself

Urban consumer trust and food certifications in China

China has experienced frequent food safety incidents that have undermined consumer trust in the food supply chain. To overcome this problem, China requalified the legislative framework and adopted a comprehensive food certification system over the years. Here, we investigated the influences of food traceability and Chinese certifications (QS/SC—food quality safety market access/production system, hazard-free, green, and organic) on Chinese consumer trust of food safety for different types of products: fish, meat, milk, eggs, and rice. Data were collected through face-to-face surveys conducted in rural and urban Chinese areas. With a sample of 757 questionnaires, we ran a logit model. The results show consumers’ uncertainty and skepticism of certifications guaranteeing food safety attributes, especially for animal-based products. We found that price is used as a cue of safety by Chinese consumers. Individuals with higher education seem less influenced by certifications and other cues included in the analysis. The findings demonstrate that Chinese policy makers should implement new strategies to enhance consumer food safety trust, and design policies by considering different categories (e.g., vegetables, meat, fish, etc.) of food

Editorial: The Golden Future in Medicinal Chemistry: Perspectives and Resources From Old and New Gold-Based Drug Candidates

Editorial: The Golden Future in Medicinal Chemistry: Perspectives and Resources From Old and New Gold-Based Drug Candidate

Chemical Modification of Auranofin Yields a New Family of Anticancer Drug Candidates: The Gold(I) Phosphite Analogues

A panel of four novel gold(I) complexes, inspired by the clinically established gold drug auranofin (1-Thio-β-D-glucopyranosatotriethylphosphine gold-2,3,4,6-tetraacetate), was prepared and characterized. All these compounds feature the replacement of the triethylphosphine ligand of the parent compound auranofin with a trimethylphosphite ligand. The linear coordination around the gold(I) center is completed by Cl−, Br−, I− or by the thioglucose tetraacetate ligand (SAtg). The in-solution behavior of these gold compounds as well as their interactions with some representative model proteins were comparatively analyzed through 31PNMR and ESI-MS measurements. Notably, all panel compounds turned out to be stable in aqueous media, but significant differences with respect to auranofin were disclosed in their interactions with a few leading proteins. In addition, the cytotoxic effects produced by the panel compounds toward A2780, A2780R and SKOV-3 ovarian cancer cells were quantitated and found to be in the low micromolar range, since the IC50 of all compounds was found to be between 1 μM and 10 μM. Notably, these novel gold complexes showed large and similar inhibition capabilities towards the key enzyme thioredoxin reductase, again comparable to those of auranofin. The implications of these results for the discovery of new and effective gold-based anticancer agents are discussed

Conjugates of Gold Nanoparticles and Antitumor Gold(III) Complexes as a Tool for Their AFM and SERS Detection in Biological Tissue

Citrate-capped gold nanoparticles (AuNPs) were functionalized with three distinct antitumor gold(III) complexes, e.g., [Au(N,N)(OH)2][PF6], where (N,N)=2,2′-bipyridine; [Au(C,N)(AcO)2], where (C,N)=deprotonated 6-(1,1-dimethylbenzyl)-pyridine; [Au(C,N,N)(OH)][PF6], where (C,N,N)=deprotonated 6-(1,1-dimethylbenzyl)-2,2′-bipyridine, to assess the chance of tracking their subcellular distribution by atomic force microscopy (AFM), and surface enhanced Raman spectroscopy (SERS) techniques. An extensive physicochemical characterization of the formed conjugates was, thus, carried out by applying a variety of methods (density functional theory—DFT, UV/Vis spectrophotometry, AFM, Raman spectroscopy, and SERS). The resulting gold(III) complexes/AuNPs conjugates turned out to be pretty stable. Interestingly, they exhibited a dramatically increased resonance intensity in the Raman spectra induced by AuNPs. For testing the use of the functionalized AuNPs for biosensing, their distribution in the nuclear, cytosolic, and membrane cell fractions obtained from human lymphocytes was investigated by AFM and SERS. The conjugates were detected in the membrane and nuclear cell fractions but not in the cytosol. The AFM method confirmed that conjugates induced changes in the morphology and nanostructure of the membrane and nuclear fractions. The obtained results point out that the conjugates formed between AuNPs and gold(III) complexes may be used as a tool for tracking metallodrug distribution in the different cell fractions

A utilização da terapia genética com Car T Cells no tratamento do HIV

Até os dias atuais não existe uma cura para a infecção por HIV (Human Immunodeficiency Virus), devido à grande capacidade de replicação e variação genética do vírus, o que tende a tornar muito mais complexas as criações de estratégias terapêuticas. A variabilidade do vírus é consequência da rápida replicação viral que tem a capacidade de produzir uma grande quantidade de vibriões por dia e a facilidade de uma recombinação genética dentro do indivíduo infectado. Nos últimos anos vem sendo desenvolvidos grandes interesses em aproveitar as capacidades do sistema imunitário para erradicar cancros avançados, ou seja, trata-se de um contexto oncológico. Sendo assim iniciou-se diversas tentativas para manipular de forma genética os linfócitos T, com isto criou-se a terapira com células CAR-T. A partir de estudos realizados em grupos capazes de realizar o controle da replicação do HIV na ausência do tratamento, foi concluído que o vírus se replica por meio de mediação das respostas do linfócito T CD8+. Com avanços notados por parte da engenharia celular, incluíram domínios de sinalização coestimulatórios que tinham a capacidade de alterar as características das células T, estes domínios foram o CD28 e 4-1BB, sendo este último, de grande importância na regulação de resposta imune com a capacidade de ativar e potencializar os linfócitos TCs