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2.
Mikrochim Acta ; 187(1): 3, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31797060

RESUMO

A turn on-off fluorometric assay for clioquinol (CQ) is described here. It is based on modulation of the fluorescence of sulfur quantum dots (SQDs; best measured at excitation/emission wavelengths of 360/426 nm) by using the Zn2+-CQ affinity pair. Although the fluorescence enhancement effect of Zn2+ on SQDs was not obvious, a good quenching modulation effect was observed in the presence of CQ. This resulted in a linear analytical range that is increased by two orders of magnitude (from 0.024 µM to 0.24 µM, and 0.62 µM to 30 µM), with a detection limit (3 s) of 0.015 µM. The selectivity of the method is also improved. Graphical abstractSchematic illustration of the turn on-off fluorometric assay for for clioquinol (CQ) based on Zn2+-modulated sulfur quantum dots (SQDs).


Assuntos
Antifúngicos/análise , Antifúngicos/química , Clioquinol/análise , Clioquinol/química , Pontos Quânticos/química , Enxofre/química , Zinco/química , Limite de Detecção , Espectrometria de Fluorescência
3.
J Clin Neurosci ; 68: 128-133, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326286

RESUMO

Subacute myelo-optico neuropathy (SMON) patients typically suffer from sequelae that cause sleep disturbances. We sought to examine the prevalence of sleep problems among SMON patients. We conducted a questionnaire-based survey concerning sleep problems among 106 SMON patients, and 110 age- and gender-matched control participants. The prevalence of subjective insomnia (6 ≤ Athens Insomnia Scale score) was 89.6% among SMON patients, which was significantly higher than among control participants 54.4%. Sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI) revealed that the prevalence of poor sleepers (6 ≤ PSQI score) was higher among SMON patients than control participants (75.6% vs 39.6%, respectively). Subscale analyses of rapid eye movement sleep behavior disorder screening questionnaire revealed that scores on two items ("dreams match nocturnal behavior" and "limb movements") were significantly higher among SMON patients than control participants. In addition, daytime sleepiness scores were significantly higher among SMON patients than control participants (4 ≤ Epworth Sleepiness Scale scores: 54.0% vs 29.0%, respectively). The current study revealed that most SMON patients suffer from insomnia with dissatisfactory sleep quality, likely due to their long-term physical sequelae. Moreover, SMON patients showed higher rates of daytime sleepiness and sleep medication intake, which could be related to reduced activity during the day, as well as insomnia.


Assuntos
Clioquinol/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/complicações , Distúrbios do Início e da Manutenção do Sono/etiologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Inquéritos e Questionários
4.
PLoS One ; 14(5): e0217602, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141575

RESUMO

Gram-negative pathogens resistant to amikacin and other aminoglycosides of clinical relevance usually harbor the 6'-N-acetyltransferase type Ib [AAC(6')-Ib], an enzyme that catalyzes inactivation of the antibiotic by acetylation using acetyl-CoA as donor substrate. Inhibition of the acetylating reaction could be a way to induce phenotypic conversion to susceptibility in these bacteria. We have previously observed that Zn2+ acts as an inhibitor of the enzymatic acetylation of aminoglycosides by AAC(6')-Ib, and in complex with ionophores it effectively reduced the levels of resistance in cellulo. We compared the activity of 8-hydroxyquinoline, three halogenated derivatives, and 5-[N-Methyl-N-Propargylaminomethyl]-8-Hydroxyquinoline in complex with Zn2+ to inhibit growth of amikacin-resistant Acinetobacter baumannii in the presence of the antibiotic. Two of the compounds, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) and 5,7-diiodo-8-hydroxyquinoline, showed robust inhibition of growth of the two A. baumannii clinical isolates that produce AAC(6')-Ib. However, none of the combinations had any activity on another amikacin-resistant A. baumannii strain that possesses a different, still unknown mechanism of resistance. Time-kill assays showed that the combination of clioquinol or 5,7-diiodo-8-hydroxyquinoline with Zn2+ and amikacin was bactericidal. Addition of 8-hydroxyquinoline, clioquinol, or 5,7-diiodo-8-hydroxyquinoline, alone or in combination with Zn2+, and amikacin to HEK293 cells did not result in significant toxicity. These results indicate that ionophores in complex with Zn2+ could be developed into potent adjuvants to be used in combination with aminoglycosides to treat Gram-negative pathogens in which resistance is mediated by AAC(6')-Ib and most probably other related aminoglycoside modifying enzymes.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Amicacina/farmacologia , Clioquinol/farmacologia , Acetilação , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/patogenicidade , Amicacina/efeitos adversos , Aminoglicosídeos/farmacologia , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Hipersensibilidade a Drogas/microbiologia , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HEK293 , Humanos , Zinco/química
5.
Mol Med Rep ; 20(1): 655-663, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115566

RESUMO

The high glucose (HG)­induced epithelial­mesenchymal transition (EMT) of peritoneal mesothelial cells (PMCs) serves an important role in peritoneal fibrosis (PF) during peritoneal dialysis. Our previous study reported that zinc (Zn) supplementation prevented the HG­induced EMT of rat PMCs in vitro. In the present study, the role of Zn in HG­induced EMT was investigated in vivo using a rat model of PF. Additionally, the molecular mechanisms underlying HG­induced EMT were studied in human PMCs (HPMCs). In the rat model of PF, HG treatment increased the glucose transfer capacity and decreased the ultrafiltration volume. Histopathological analysis revealed peritoneal thickening, increased expression of vimentin and decreased expression of E­cadherin. ZnSO4 significantly ameliorated the aforementioned changes, whereas Zn inhibition by clioquinol significantly aggravated the effects of HG on rats. The effects of Zn on HPMCs was assessed using western blot analysis, Transwell assays and flow cytometry. It was revealed that Zn also significantly suppressed the extent of the EMT, and reduced reactive oxygen species production and the migratory ability of HG­induced HPMCs, whereas Zn inhibition by N',N',N',N'­tetrakis (2­pyridylmethyl) ethylenediamine significantly potentiated the HG­induced EMT of HPMCs. HG­stimulated HPMCs exhibited increased expression of nuclear factor­like 2 (Nrf2) in the nucleus, and total cellular NAD(P)H quinone dehydrogenase 1 (NQO1) and heme oxygenase-1 (HO­1), the target proteins of the Nrf2 antioxidant pathway. Zn supplementation further promoted nuclear Nrf2 expression, and increased the expression of target proteins of the Nrf2 antioxidant pathway, whereas Zn depletion decreased nuclear Nrf2, NQO1 and HO­1 expression compared with the HG group. In conclusion, Zn supplementation was proposed to suppress the effects of HG on the EMT by stimulating the Nrf2 antioxidant pathway and subsequently reducing oxidative stress in PMCs.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose Peritoneal/tratamento farmacológico , Peritônio/efeitos dos fármacos , Zinco/farmacologia , Animais , Caderinas/genética , Clioquinol/farmacologia , Suplementos Nutricionais , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucose/efeitos adversos , Glucose/farmacologia , Humanos , NAD(P)H Desidrogenase (Quinona)/genética , Fator 2 Relacionado a NF-E2/genética , Diálise Peritoneal , Fibrose Peritoneal/genética , Peritônio/metabolismo , Peritônio/patologia , Ratos
6.
Pharmacol Ther ; 199: 155-163, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30898518

RESUMO

Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.


Assuntos
Anti-Infecciosos/uso terapêutico , Clioquinol/uso terapêutico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Anti-Infecciosos/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Clioquinol/efeitos adversos , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Mielite/induzido quimicamente , Mielite/genética , Doenças Neurodegenerativas/metabolismo , Neurite Óptica/induzido quimicamente , Neurite Óptica/genética , Polimorfismo de Nucleotídeo Único , Síndrome
7.
Artigo em Inglês | MEDLINE | ID: mdl-30865872

RESUMO

Clioquinol has recently been proposed for the treatment of Alzheimer's disease. It is able to diminish ß-amyloid protein aggregation and to restore cognition of Alzheimer's mice. However, its therapeutic benefits for Alzheimer's disease in human remain controversy and need further confirmation. Herein, we have explored the interaction mechanism of clioquinol toward bovine serum albumin (BSA) by means of multi-spectroscopic and docking simulation approaches. Clioquinol interacts with BSA by a combined mechanism of static and dynamic processes. Application of the Hill's equation to fluorescence quenching experiment revealed that the binding constant of the BSA-clioquinol complex is extremely high at 108 M-1 level. Competitive displacement and docking analysis consistently suggested that there are the multiple binding modes of clioquinol toward BSA. Competitive binding study showed that clioquinol shares the binding sites with ibuprofen and digitoxin on albumin, referring to be site II and site III binding compounds. Besides, partial binding in site I was also observed. Docking simulation confirmed that clioquinol favors to bind in site I, site II, site III, fatty acid binding site 5, and the protein cleft between subdomain IB and IIIB of the BSA. Due to its small size and electric dipole property, clioquinol may easily fit in multiple pockets of the BSA. Our finding suggests the potential role of BSA as a clioquinol carrier in the vascular system. Nonetheless, clioquinol-induced BSA aggregation has been observed by the three-dimensional fluorescence technique. This phenomenon may not only impair the BSA, but may also affect other endogenous proteins, which eventually causes adverse effects to human. Therefore, the redesigned or modified molecular structure of clioquinol may reduce its toxicity and improve its bioavailability.


Assuntos
Clioquinol/metabolismo , Soroalbumina Bovina/metabolismo , Animais , Sítios de Ligação , Bovinos , Clioquinol/química , Simulação de Acoplamento Molecular , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica , Soroalbumina Bovina/química , Termodinâmica
8.
Artigo em Inglês | MEDLINE | ID: mdl-30885898

RESUMO

Mucormycosis is an emerging disease with high mortality rates. Few antifungal drugs are active against Mucorales. Considering the low efficacy of monotherapy, combination-therapy strategies have been described. It is known that fungi are susceptible to zinc deprivation, so we tested the in vitro effect of the zinc chelators clioquinol, phenanthroline, and N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine combined with amphotericin B or posaconazole against 25 strains of Mucorales. Clioquinol-posaconazole was the most active combination, although results were strain dependent.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Quelantes/farmacologia , Mucorales/efeitos dos fármacos , Triazóis/farmacologia , Zinco/química , Clioquinol/farmacologia , Testes de Sensibilidade Microbiana , Fenantrolinas/farmacologia
9.
Mycoses ; 62(5): 475-481, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30600560

RESUMO

BACKGROUND: Clioquinol was used in the 1950s-1970s as antimicrobial but its oral formulations were withdrawn from the market due to suspected neurotoxicity. Currently, there is possibility of repositioning of oral clioquinol formulations. OBJECTIVES: To evaluate the antifungal activity and toxicological parameters of clioquinol and the other two 8-hydroxyquinoline derivatives using alternative animal models and to study the interaction dynamic of clioquinol with Candida albicans. METHODS: We used Toll-deficient Drosophila melanogaster to test the protective effect of 8-hydroxyquinolines against C. albicans infection. Toxicological parameters were investigated in chicken embryo. A mathematical model-based analysis of the time-kill data of clioquinol was performed to obtain pharmacodynamic characteristics. RESULTS: Clioquinol fully protected D. melanogaster from the infection. The 8-hydroxyquinolines did not cause changes in opening of the beak and movement of the chicken embryo; however, clioquinol and compound 2 increased arterial pulsation. Compound 3 was lethal at 1 mg mL-1 . Effective concentration found in modelling indicated that clioquinol was highly effective against C. albicans (0.306 µg mL-1 ) in easily achievable serum levels; clioquinol rapidly achieved kill rate reaching the maximum effect after 13 hours. CONCLUSIONS: These results support the potential of clioquinol to be used as a systemic antifungal agent.


Assuntos
Antifúngicos/administração & dosagem , Candidíase/tratamento farmacológico , Clioquinol/administração & dosagem , Administração Oral , Animais , Antifúngicos/efeitos adversos , Embrião de Galinha , Galinhas , Clioquinol/efeitos adversos , Modelos Animais de Doenças , Drosophila melanogaster , Modelos Teóricos , Resultado do Tratamento
10.
Parasitol Int ; 68(1): 63-72, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30339837

RESUMO

Clioquinol (5-chloro-7-iodoquinolin-8-ol or ICHQ) was recently showed to presents an in vitro effective antileishmanial action, causing changes in membrane permeability, mitochondrial functionality, and parasite morphology. In the present study, ICHQ was incorporated into a Poloxamer 407-based polymeric micelles system (ICHQ/M), and its antileishmanial activity was in vivo evaluated in L. amazonensis-infected BALB/c mice. Amphotericin B (AmpB) and its liposomal formulation (Ambisome®) were used as controls. Parasitological and immunological evaluations were performed 30 days after the treatment. Results indicated more significant reductions in the average lesion diameter and parasite burden in ICHQ or ICHQ/M-treated mice, which were associated with the development of a polarized Th1 immune response, based on production of high levels of IFN-γ, IL-12, TNF-α, GM-CSF, and antileishmanial IgG2a antibody. Control groups´ mice produced high levels of IL-4, IL-10, and IgG1 isotype antibody. No organic toxicity was found by using ICHQ or ICHQ/M to treat the animals, although those receiving AmpB and Ambisome® have presented higher levels of renal and hepatic damage markers. In conclusion, results suggested that the ICHQ/M composition can be considered as an antileishmanial candidate to be tested against human leishmaniasis.


Assuntos
Antiprotozoários/imunologia , Antiprotozoários/uso terapêutico , Clioquinol/imunologia , Clioquinol/uso terapêutico , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Poloxâmero/administração & dosagem , Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Anfotericina B/toxicidade , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/administração & dosagem , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/uso terapêutico , Antiprotozoários/administração & dosagem , Antiprotozoários/toxicidade , Clioquinol/administração & dosagem , Citocinas/biossíntese , Citocinas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , Imunoglobulina G/sangue , Interferon gama/biossíntese , Interferon gama/imunologia , Leishmania mexicana/crescimento & desenvolvimento , Leishmaniose Visceral/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Carga Parasitária , Poloxâmero/química , Células Th1
11.
Eur J Med Chem ; 163: 512-526, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30553143

RESUMO

Considering the importance of PDE4D inhibition and the modulation of biometals in Alzheimer's disease (AD) therapeutics, we have designed, synthesized and evaluated a series of new clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of AD. In vitro studies demonstrated that some of the molecules processed remarkable inhibitory activity against phosphodiesterase 4D (PDE4D), strong intracellular antioxidant capacity, potent inhibition of metal-induced aggregation of Aß, and potential blood-brain barrier permeability. Compound 7a demonstrated significant improvement in cognitive and spatial memory in an Aß25-35-induce mouse model in Morris water-maze test (MWM). These results indicate that compound 7a is a promising multifunctional candidate that is worthy of further study.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminopiridinas/farmacologia , Benzamidas/farmacologia , Clioquinol/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Desenho de Fármacos , Rolipram/farmacologia , Aminopiridinas/síntese química , Animais , Benzamidas/síntese química , Clioquinol/síntese química , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Humanos , Ligantes , Camundongos , Ratos , Rolipram/síntese química
12.
mBio ; 9(6)2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30538186

RESUMO

The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we report the synergy between ionophore-induced physiological stress in Gram-positive bacteria and antibiotic treatment. PBT2 is a safe-for-human-use zinc ionophore that has progressed to phase 2 clinical trials for Alzheimer's and Huntington's disease treatment. In combination with zinc, PBT2 exhibits antibacterial activity and disrupts cellular homeostasis in erythromycin-resistant group A Streptococcus (GAS), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). We were unable to select for mutants resistant to PBT2-zinc treatment. While ineffective alone against resistant bacteria, several clinically relevant antibiotics act synergistically with PBT2-zinc to enhance killing of these Gram-positive pathogens. These data represent a new paradigm whereby disruption of bacterial metal homeostasis reverses antibiotic-resistant phenotypes in a number of priority human bacterial pathogens.IMPORTANCE The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus are leading causes of community- and hospital-acquired infection and present a significant clinical challenge. These pathogens have acquired resistance to broad classes of antimicrobials. Furthermore, Streptococcus pyogenes, a significant disease agent among Indigenous Australians, has now acquired resistance to several antibiotic classes. With a rise in antibiotic resistance and reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. As stated by the WHO Director-General, "On current trends, common diseases may become untreatable. Doctors facing patients will have to say, Sorry, there is nothing I can do for you."


Assuntos
Antibacterianos/farmacologia , Clioquinol/análogos & derivados , Farmacorresistência Bacteriana/efeitos dos fármacos , Sinergismo Farmacológico , Bactérias Gram-Positivas/efeitos dos fármacos , Ionóforos/metabolismo , Zinco/metabolismo , Clioquinol/metabolismo , Testes de Sensibilidade Microbiana
13.
Metallomics ; 10(9): 1339-1347, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30168573

RESUMO

Tauopathies are characterized by the pathological accumulation of the microtubule associated protein tau within the brain. We demonstrate here that a copper/zinc chaperone (PBT2, Prana Biotechnology) has rapid and profound effects in the rTg(tauP301L)4510 mouse model of tauopathy. This was evidenced by significantly improved cognition, a preservation of neurons, a decrease in tau aggregates and a decrease in other forms of "pathological" tau (including phosphorylated tau and sarkosyl-insoluble tau). Our data demonstrate that one of the primary mechanisms of action of PBT2 in this model may be driven by an interaction on the pathways responsible for the dephosphorylation of tau. Specifically, PBT2 increased protein levels of both the structural and catalytic subunits of protein phosphatase 2A (PP2A), decreased levels of the methyl esterase (PME1) that dampens PP2A activity, and increased levels of the prolyl isomerase (Pin1) that stimulates the dephosphorylation activity of PP2A. None of these effects were observed when the metal binding site of PBT2 was blocked. This highlights the potential utility of targeting metal ions as a novel therapeutic strategy for diseases in which tau pathology is a feature, which includes conditions such as frontotemporal dementia and Alzheimer's disease.


Assuntos
Clioquinol/análogos & derivados , Tauopatias/tratamento farmacológico , Animais , Clioquinol/uso terapêutico , Feminino , Masculino , Memória/efeitos dos fármacos , Camundongos , Aprendizagem Espacial/efeitos dos fármacos
14.
J Med Microbiol ; 67(11): 1655-1663, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30256190

RESUMO

PURPOSE: Candida biofilm infections are frequently linked to the use of biomaterials and are of clinical significance because they are commonly resistant to antifungals. Clioquinol is an antiseptic drug and is effective against multidrug-resistant Candida. We investigated the effect of clioquinol and two other 8-hydroxyquinoline derivatives on Candida biofilm. METHODOLOGY: The ability to inhibit biofilm formation, inhibit preformed biofilm and remove established biofilms was evaluated using in vitro assays on microtitre plates. The action of clioquinol on biofilm in intrauterine devices (IUDs) was also investigated, describing the first protocol to quantify the inhibitory action of compounds on biofilms formed on IUDs. RESULTS: Clioquinol was found to be the most effective 8-hydroxyquinoline derivative among those tested. It prevented more than 90 % of biofilm formation, which can be attributed to blockade of hyphal development. Clioquinol also reduced the metabolic activity of sessile Candida but the susceptibility was lower compared to planktonic cells (0.031-0.5 µg ml-1 required to inhibit 50 % planktonic cells and 4-16 µg ml-1 to inhibit 50 % preformed biofilms). On the other hand, almost complete removal of biofilms was not achieved for the majority of the isolates. Candida spp. also showed the ability to form biofilm on copper IUD; clioquinol eradicated 80-100 % of these biofilms. CONCLUSION: Our results indicate a potential application in terms of biomaterials for 8-hydroxyquinoline derivatives. Clioquinol could be used as a coating to prevent morphological switching and thus prevent biofilm formation. Furthermore, clioquinol may have future applications in the treatment of Candida infections linked to the use of IUDs.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Candidíase/prevenção & controle , Clioquinol/farmacologia , Oxiquinolina/farmacologia , Antifúngicos/química , Antifúngicos/uso terapêutico , Candida/fisiologia , Candidíase/tratamento farmacológico , Candidíase/etiologia , Candidíase/microbiologia , Clioquinol/análogos & derivados , Clioquinol/química , Clioquinol/uso terapêutico , Cobre , Feminino , Humanos , Dispositivos Intrauterinos/efeitos adversos , Dispositivos Intrauterinos/microbiologia , Testes de Sensibilidade Microbiana , Oxiquinolina/análogos & derivados , Oxiquinolina/química
15.
Free Radic Biol Med ; 129: 215-226, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30240704

RESUMO

Higher levels of copper, reduced glutathione (GSH) and reactive oxygen species (ROS) observed in cancer cells than in normal cells, favor the idea of developing copper ionophores as prooxidative anticancer agents (PAAs) to hit the altered redox homeostasis (redox Achilles heel) of cancer cells. In this work, we used salicylaldehyde isonicotinoyl hydrazone (SIH-1) as a basic scaffold to design Cu(II) ionophores with tunable chelation and release of Cu(II) by introducing electron-withdrawing nitro and electron-donating methoxyl groups in the para position to phenolic hydroxyl, or by blocking the phenolic hydroxyl site using methyl. These molecules were used to probe how chelation and release of copper influence their ionophoric role and ability to target redox Achilles heel of cancer cells. Among these molecules, SIH-1 was identified as the most potent Cu(II) ionophore to kill preferentially HepG2 cells over HUVEC cells, and also superior to clioquinol, a copper ionophore evaluated in clinical trials, in terms of its relatively higher cytotoxicity and better selectivity. Higher oxidative potential, despite of lower stability constant, of the Cu(II) complex formed by SIH-1 than by the other molecules, is responsible for its stronger ability in releasing copper by GSH, inducing redox imbalance and triggering mitochondria-mediated apoptosis of HepG2 cells. This work gives useful information on how to design copper ionophores as PAAs for selective killing of cancer cells.


Assuntos
Aldeídos/síntese química , Antineoplásicos/síntese química , Cobre/química , Hidrazonas/síntese química , Ionóforos/síntese química , Quelantes de Ferro/síntese química , Espécies Reativas de Oxigênio/química , Células A549 , Aldeídos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cátions Bivalentes , Sobrevivência Celular/efeitos dos fármacos , Clioquinol/farmacologia , Cobre/metabolismo , Desenho de Fármacos , Técnicas Eletroquímicas , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrazonas/farmacologia , Ionóforos/farmacologia , Quelantes de Ferro/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Especificidade de Órgãos , Oxirredução , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
16.
Neurotoxicology ; 67: 296-304, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29966605

RESUMO

Clioquinol was used in the mid-1900s as an amebicide to treat indigestion and diarrhea. However, it was withdrawn from the market in Japan because it was linked to subacute myelo-optic neuropathy (SMON). The pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of interleukin-8 (IL-8) was significantly increased when SH-SY5Y neuroblastoma cells were treated with clioquinol. An enzyme-linked immunosorbent assay also demonstrated that clioquinol induced the secretion of IL-8 into culture media. Promoter analyses on SH-SY5Y cells revealed that a region responsive to clioquinol exists between -152 and -144 of the human IL-8 gene, which contains a consensus GATA-binding site sequence. The introduction of mutations at this site or the activator protein (AP)-1 site sequence at -126/-120 significantly reduced clioquinol-induced transcriptional activation. Among the GATA transcription factors expressed in SH-SY5Y cells, GATA-2 and GATA-3 protein levels were significantly decreased by the addition of clioquinol. Electrophoresis mobility shift assays using a probe corresponding to -159/-113 of the human IL-8 gene revealed two major shifted bands, one of which was increased and the other was decreased by clioquinol. The introduction of mutations showed that the former corresponded to binding to the AP-1 site, and the latter to binding to the GATA site. Supershift analyses revealed that the binding of c-Jun and c-Fos was increased, whereas that of GATA-3 was decreased by clioquinol. Genome editing against GATA-2 or GATA-3, not GATA-4 significantly enhanced clioquinol-induced IL-8 mRNA expression. On the other hand, the stable expression of GATA-2 or GATA-3 attenuated clioquinol-induced IL-8 mRNA expression and IL-8 secretion. These results suggest that the clioquinol-induced suppression of GATA-2 and GATA-3 expression mediates the up-regulation of IL-8.


Assuntos
Clioquinol/farmacologia , Regulação para Baixo/efeitos dos fármacos , Fator de Transcrição GATA2/metabolismo , Fator de Transcrição GATA3/metabolismo , Interleucina-8/biossíntese , Sequência de Bases , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação para Baixo/fisiologia , Fator de Transcrição GATA2/antagonistas & inibidores , Fator de Transcrição GATA3/antagonistas & inibidores , Expressão Gênica , Humanos , Interleucina-8/genética
17.
Microbiol Res ; 214: 1-7, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30031471

RESUMO

Clioquinol (CQ) has been used as a classical antimicrobial agent for many years. However, its mode of action is still unclear. In our study, the growth of Candida albicans and Saccharomyces cerevisiae was inhibited by CQ. It did not kill yeast cells, but shortened G1 phase and arrested cell cycle at G2/M phase. By using two-dimensional electrophoresis based proteomic approach, six proteins were found to be significantly affected by CQ. Among them, four (PDC1, ADH1, TDH3, IPP1) were up-regulated and the other two (TDH1 and PGK1) were down-regulated. According to the Saccharomyces Genome Database (SGD), these proteins were involved in various biological processes including glycolytic fermentation, gluconeogenesis, glycolytic process, amino acid catabolism, redox reaction and reactive oxygen species metabolic process. It was noted that there was a link between TDH3 and cell cycle. The overexpression of TDH3 phenocopied CQ treatment and arrested the cell cycle at G2/M phase. RT-PCR analysis showed that the mRNA levels of CLN3 and CDC28, critical genes for passage through G1 phase, were up-regulated after the treatment of CQ as well as the overexpression of TDH3. It demonstrates that CQ inhibits the growth of yeast by up-regulating the expression of TDH3 to influence the cell cycle. It is expected to provide new insights for the antimicrobial mechanism of CQ.


Assuntos
Antifúngicos/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Clioquinol/metabolismo , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Regulação para Cima , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Eletroforese em Gel Bidimensional , Viabilidade Microbiana/efeitos dos fármacos , Proteoma/análise , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/citologia
18.
Sci Rep ; 8(1): 9768, 2018 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-29950603

RESUMO

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Cognição/fisiologia , Zinco/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Clioquinol/farmacologia , Cognição/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
19.
Intern Med ; 57(18): 2641-2645, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29780125

RESUMO

Objective The aim of this study was to clarify the clinical conditions related to the depressive mental states in Japanese patients with subacute myelo-optico-neuropathy (SMON), caused by clioquinol intoxication more than 40 years previously. Methods The changes in the mental states with aging were investigated in 25 Japanese SMON patients (mean age: 77.2 years old, range: 53-90) using a Japanese version of the Zung Self-rating Depression Scale (J-SDS) questionnaires with supportive interviews by the clinical psychotherapist and medical checkup records. These mental and medical examinations were repeated more than twice within 2 to 11 years' interval. The J-SDS questionnaires were also examined in 25 age-matched non-SMON elderly people. Results The total J-SDS scores of most of the SMON patients decreased with age without significant changes in the mean Barthel index scores during this study period. The mean J-SDS scores at the first and latest studies were significantly higher than in the age-matched healthy elderly people. The total J-SDS scores of the latest study were significantly correlated with the degree of physical disability, such as the inverse total Barthel index scores, severity of SMON or gait disturbance, but not with the age. Conclusion The total J-SDS scores of most of the SMON patients tended to decrease with age. Repeating mental supportive interviews and medical examinations by experts helped to improve the depressive mental state and revealed close relationship between the mental state and the physical disabilities of the SMON patients.


Assuntos
Transtorno Depressivo/etiologia , Mielite/psicologia , Doenças do Nervo Óptico/psicologia , Doenças do Sistema Nervoso Periférico/psicologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Clioquinol/efeitos adversos , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielite/induzido quimicamente , Doenças do Nervo Óptico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Inquéritos e Questionários
20.
BMC Cancer ; 18(1): 448, 2018 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-29678153

RESUMO

BACKGROUND: We previously reported that clioquinol acts as a zinc ionophore and inhibits the NF-κB signalling pathway. Other research has demonstrated that zinc deficiency plays a vital role in the occurrence and development of some solid tumours, and intracellular zinc supplementation may reverse this process and enhance the tumour sensitivity to anticancer treatment. Thus, we investigated the radiosensitization effects of clioquinol combined with zinc on HeLa and MCF-7 cells in vitro. METHODS: The dose effect of growth inhibition of clioquinol combined with zinc on cell viability was determined by a cell counting kit 8 (CCK-8) assay. The radiosensitization effect of clioquinol combined with zinc and/or MG132 in HeLa and MCF-7 cells was detected by the clonogenic assay. The cell cycle distribution and apoptosis of clioquinol combined with zinc on HeLa cells were analyzed by flow cytometry. A luciferase reporter construct was used to study the effect of clioquinol combined with zinc on NF-κB activity in HeLa cells. DNA double-strand breaks were detected by immunofluorescence. The mRNA and protein levels of ATM were analyzed by quantitative real-time PCR and Western blotting, respectively. RESULTS: Our research showed that clioquinol combined with zinc markedly increased the radiosensitivity of HeLa and MCF-7 cells in low toxic concentrations and resulted in a post-irradiation decrease in G2 phase arrest and an increase in apoptosis. Clioquinol combined with zinc also inhibited NF-κB activation, decreased ATM expression and increased DNA double-strand breaks (DSBs) induced by ionizing radiation. CONCLUSIONS: These findings indicated that clioquinol combined with zinc enhanced the radiosensitivity of HeLa and MCF-7 cells by the down-regulation of ATM through the NF-κB signalling pathway.


Assuntos
Clioquinol/farmacologia , Radiossensibilizantes/farmacologia , Zinco/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Sinergismo Farmacológico , Raios gama/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Células HeLa , Histonas/metabolismo , Humanos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos
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