RESUMO
The treatment of leishmaniasis still relies on drugs with potentially serious adverse effects. Herein, we tested a topical formulation of bacterial cellulose (BC) membranes containing Diethyldithiocarbamate (DETC), a superoxide dismutase 1 inhibitor. Leishmania-infected macrophages exposed to BC-DETC resulted in parasite killing, without pronounced toxic effects to host cells. This outcome was associated with lower SOD1 activity and higher production of superoxide and cytokine mediators. Topical application of BC-DETC significantly decreased lesion size, parasite load and the inflammatory response at the infection site, as well as the production of both IFN-γ and TNF. Combination of topical BC-DETC plus intraperitoneal Sbv also significantly reduced disease development and parasite load. The leishmanicidal effect of BC-DETC was extended to human macrophages infected with L. braziliensis, highlighting the feasibility of BC-DETC as a topical formulation for chemotherapy of cutaneous leishmaniasis caused by L. braziliensis.
Assuntos
Antiprotozoários/farmacologia , Celulose/química , Ditiocarb/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Meglumina/farmacologia , Compostos Organometálicos/farmacologia , Administração Cutânea , Animais , Antiprotozoários/química , Celulose/isolamento & purificação , Citocinas/biossíntese , Ditiocarb/química , Quimioterapia Combinada , Feminino , Gluconacetobacter/química , Humanos , Injeções Intraperitoneais , Leishmania braziliensis/crescimento & desenvolvimento , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/parasitologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Antimoniato de Meglumina , Camundongos , Camundongos Endogâmicos BALB C , Cultura Primária de Células , Superóxido Dismutase-1/metabolismo , Superóxidos/metabolismoRESUMO
The increase in brain levels of chelatable zinc (Zn) in dysfunctions involving oxygen deprivation has stimulated the treatment with Zn chelators, such as diethyldithiocarbamate (DEDTC). However, DEDTC is a redox-active compound and it should be better evaluated during hypoxia. We use the hypoxia model in zebrafish to evaluate DEDTC effects. The exploratory behavior, chelatable Zn content, activities of mitochondrial dehydrogenases, reactive species levels (nitric oxide, superoxide anion, hydroxyl radical scavenger capacity) and cellular antioxidants (sulfhydryl, superoxide dismutase) of zebrafish brain were assessed after recovery, with or without 0.2 mM DEDTC. The increased brain levels of chelatable Zn induced by hypoxia were mitigated by DEDTC. However, the novel tank task indicated that DEDTC did further enhance the exploratory deficit caused by hypoxia. Furthermore, these behavioral impairments caused by DEDTC were more associated with a negative action on mitochondrial activity and brain oxidative balance. Thus, due to apparent pro-oxidant action of DEDTC, our data do not support its use for neuroprotection in neuropathologies involving oxygen deprivation.
Assuntos
Encéfalo/metabolismo , Quelantes/farmacologia , Ditiocarb/farmacologia , Mitocôndrias/efeitos dos fármacos , Zinco/química , Animais , Antioxidantes/metabolismo , Encéfalo/patologia , Quelantes/química , Ditiocarb/química , Comportamento Exploratório/efeitos dos fármacos , Feminino , Hipóxia , Locomoção/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Peixe-ZebraRESUMO
Objetivo. Evaluar las tendencias de mortalidad por cáncer en México entre 1980 y 2011. Material y métodos. Se calcularon las tasas de mortalidad ajustadas por edad y sexo para todos los cánceres y para las 15 localizaciones más frecuentes mediante el método directo y tomando como población estándar la población mundial de 2010. Las tendencias en las tasas de mortalidad y el cambio porcentual anual para cada tipo de cáncer se estimaron a través de un modelo de regresión joinpoint. Resultados. A partir de 2004 y como consecuencia de la reducción de la mortalidad por cáncer de pulmón (-3.2% en hombres y -1.8% en mujeres), estómago (-2.1% en hombres y -2.4% en mujeres) y cérvix (-4.7%), se observó una disminución significativa (~1% anual) en la mortalidad por cáncer en general tanto en el grupo de todas las edades como en el de 35 a 64 años para ambos sexos. La mortalidad por otros cánceres como el de mama y el de ovario, en las mujeres o el de próstata, en los hombres, mostró un aumento sostenido. Conclusiones. Algunas de las reducciones en la mortalidad por cáncer pueden ser parcialmente atribuidas a la efectividad de los programas de prevención establecidos. Sin embargo, se requiere implementar registros adecuados de cáncer con base poblacional para evaluar el impacto real de estos programas, así como diseñar y evaluar intervenciones innovadoras que permitan desarrollar políticas de prevención más costo-efectivas.
Objective. To evaluate trends in cancer mortality in Mexico between 1980-2011. Material and methods. Through direct method and using World Population 2010 as standard population, mortality rates for all cancers and the 15 most frequent locations, adjusted for age and sex were calculated. Trends in mortality rates and annual percentage change for each type of cancer were estimated by joinpoint regression model. Results. As a result of the reduction in mortality from lung cancer (-3.2% -1.8% in men and in women), stomach (-2.1% -2.4% in men and in women) and cervix (-4.7%); since 2004 a significant (~1% per year) decline was observed in cancer mortality in general, in all ages, and in the group of 35-64 years of both sexes. Other cancers such as breast and ovarian cancer in women; as well as for prostate cancer in men, showed a steady increase. Conclusions. Some of the reductions in cancer mortality may be partially attributed to the effectiveness of prevention programs. However, adequate records of population-based cancer are needed to assess the real impact of these programs; as well as designing and evaluating innovative interventions to develop more cost-effective prevention policies.
Assuntos
Animais , Masculino , Ratos , Endotoxemia/metabolismo , Intestino Delgado/metabolismo , Rim/metabolismo , Fígado/metabolismo , Óxido Nítrico/análise , Ditiocarb/química , Ditiocarb/farmacocinética , Endotoxinas/toxicidade , Compostos Férricos/química , Intestino Delgado/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Ratos Sprague-Dawley , Sensibilidade e Especificidade , Marcadores de Spin , Detecção de Spin/métodos , Fatores de TempoRESUMO
Surface-enhanced Raman scattering (SERS) was used to study the interactions of the normal modes of the bis(diethyldithiocarbamate)zinc(II) complex, [Zn(DDTC)2], on nano-structured silver surfaces. The electronic spectrum of this complex was measured and the charge transfer bands were assigned through the TD-PBE1PBE procedure. To see the electronic dispersion, the Mulliken electronic charges were calculated for each normal mode and correlated with the SERS effect. Full assignment of the SERS spectra was also supported by carefully analysis of the distorted geometries generated by the normal modes.
Assuntos
Complexos de Coordenação/química , Ditiocarb/química , Zinco/química , Elétrons , Modelos Moleculares , Espectrofotometria Ultravioleta , Análise Espectral RamanRESUMO
Theoretical and experimental bands have been assigned for the Fourier Transform Infrared (FT-IR) and Fourier Transform Raman (FT-Raman) spectra of the bis-(diethydithiocarbamate)Zn(II) complex, [Zn(DDTC)(2)]. The calculations and spectra interpretation have been based on the DFT/B3LYP method, infrared and Raman second derivative spectra as well as band deconvolution analysis. To assign the metal-ligand normal modes the deviation percentage of the geometrical parameters was used. Results confirms a pseudo tetrahedral structure around the Zn(II) cation. The calculated infrared and Raman spectra has an excellent agreement with the experimental spectra. The Natural Bond Orbital analysis (NBO) was carried out as a way to study the Zn(II) hybridization leading to the pseudo tetrahedral geometry of the framework of the [Zn(DDTC)(2)] complex, and to study also which are the donor NBO and the acceptor NBO in meaningful charge transfer through the Second Order Perturbation Theory Analysis of Fox Matrix in NBO basis.
Assuntos
Complexos de Coordenação/química , Ditiocarb/química , Zinco/química , Modelos Moleculares , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral RamanRESUMO
Theoretical and experimental bands have been assigned for the Fourier Transform Infrared (FT-IR) and FT-Raman spectra of the bis(diethydithiocarbamate)Cu(II) complex, [Cu(DDTC)(2)]. The calculations and spectra interpretation have been based on the DFT/B3LYP method, infrared and Raman second derivative spectra, and band deconvolution analysis. To better assign the metal-ligand normal modes in the spectral region of low energy, the deviation percentage of the geometrical parameters was used, with values from the interpretation of the normal modes of L matrix. Results indicate a planar structure around the Cu(II) cation. The calculated infrared and Raman spectra, based on the proposed geometrical structure of the bis(diethyldithiocarbamate)copper(II) complex, agreed with the experimental spectra.
Assuntos
Complexos de Coordenação/química , Cobre/química , Ditiocarb/química , Complexos de Coordenação/síntese química , Ditiocarb/síntese química , Modelos Moleculares , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral RamanRESUMO
Since diethyl dithiocarbamate (DEDTC) forms complexes with either zinc or copper, and 8-hydroxyquinoline (8-OHQ) also complexes with copper, we now compared the cytotoxic activity of Cu[DEDTC]2, Zn[DEDTC]2 and Cu[8-OHQ]2. This report shows that at nanomolar levels, only copper-[DEDTC]2, suppresses proliferation and clonogenicity of SKBR3 human breast carcinoma, concurrently with induction of apoptosis-associated PARP fragmentation. Susceptibility to these agents was paralleled by reactive oxygen generation (ROS) and greater expression of anti-oxidant enzymes like MnSOD and catalase, with no comparable effect on Cu/Zn superoxide dismutase. The lethal effects of Cu[DEDTC]2 manifested when adding the two separate aqueous components or the preformed synthetic complexes in DMSO, was prevented by N-acetyl cysteine or glutathione, with no comparable protection afforded by non-thiol anti-oxidants like mannitol or DMSO. Exogenously added catalase also protected cells from Cu[DEDTC]2, suggesting that this complex may kill after the levels of superoxide anion [O2*-] dismutated by MnSOD increase hydrogen peroxide-related stress. Cu[DEDTC]2 also induced p21WAF1, a cdk inhibitor usually not inducible in mutant p53 tumors like SKBR3 carcinoma, correlating with dephosphorylation of the Sp1 transcription factor. Concentrations of Cu[DEDTC]2 cytotoxic for SKBR3 carcinoma did not induce comparable damage versus normal diploid human WI-38 fibroblasts. In contrast to the cytotoxic effect of nM levels of Cu[DEDTC]2 against SKBRR3 cells, no response was seen in the same cells exposed to 20 microM cis-platin. Since neither DEDTC bound to zinc, nor copper bound to 8-OHQ showed comparable cytotoxicity, our results suggest that the greater activity of copper-DEDTC reflects a specific structure-activity relationship for the active complex. Since Cu[DEDTC]2 shows more effectiveness than other metal-chelator complexes, it may be worth further investigation as an alternative to cancer therapies.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Quelantes/farmacologia , Cobre/farmacologia , Ditiocarb/análogos & derivados , Compostos Organometálicos/farmacologia , Antineoplásicos/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quelantes/química , Cobre/química , Ditiocarb/química , Ditiocarb/farmacologia , Fluoresceínas/metabolismo , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Compostos Organometálicos/química , Oxiquinolina , Zinco/química , Zinco/farmacologiaAssuntos
Chumbo/análise , Nebulizadores e Vaporizadores , Espectrofotometria Atômica/métodos , Ultrassom , Abastecimento de Água/análise , Resinas Acrílicas/metabolismo , Resinas de Troca Aniônica/metabolismo , Quelantes/química , Cromatografia por Troca Iônica/métodos , Ditiocarb/química , Chumbo/química , Chumbo/metabolismo , Poliestirenos/metabolismo , Espectrofotometria Atômica/instrumentaçãoRESUMO
Luminol chemiluminescence was used to evaluate the scavenging of superoxide, hydroxyl and alkoxy radicals by four antioxidants: dipyridamole, diethyldithiocarbamic acid, (+)catechin, and ascorbic acid. Different concentrations of these compounds were compared with well-known oxygen radical scavengers in their capacity to inhibit the chemiluminescence produced in the reaction between luminol and specific oxygen radicals. Hydroxyl radicals were generated using the Fenton reaction and these produced chemiluminescence which was inhibited by diethyldithiocarbamate. Alkoxy radicals were generated using the reaction of tert-butyl hydroperoxide and ferrous ion and produced chemiluminescence which was inhibited equally by all of the compounds tested. For the determination of superoxide scavengers we describe a new, simple, economic, and rapid chemiluminescence method consisting of the reaction between luminol and horseradish peroxidase (HRP). With this method it was found that 40 nmol/l dipyridamole, 0.18 mumol/l ascorbic acid, 0.23 mumol/l (+)catechin, and 3 mumol/l diethyldithiocarbamic acid are equivalent to 3.9 ng/ml superoxide dismutase (specific scavenger of superoxide) in causing the same degree of chemiluminescence inhibition. These results not only indicated that the antioxidative properties of these compounds showed different degrees of effectiveness against a particular radical but also that they may exert their action against more than one radical.