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1.
Lett Appl Microbiol ; 72(3): 292-298, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32790923

RESUMO

Dermatophytoses are infections that affect keratinized tissues. Their main etiologic agents are fungi of the genera Microsporum and Trichophyton. The emergence of resistant fungi and the clinical relevance of dermatophytosis have encouraged studies that aim to increase the arsenal of drugs or act on mechanisms that confer multiple drug resistance. This study investigated the modulating activity of terbinafine promoted by dihydrojasmone and terpinolene against Microsporum canis LM 216, Trichophyton interdigitale H6 and T. interdigitale Δmdr2. The minimum inhibitory concentration (MIC) of test drugs was determined by broth microdilution. The effect of the drugs tested on plasma membrane functionality was analysed. Terbinafine MIC was determined in sub-inhibitory concentrations of monoterpenes. Finally, it was performed an association study with terbinafine and monoterpenes. Dihydrojasmone presented lower MIC values than terpinolene. All fungi were sensitive to terbinafine, starting at 1 µg ml-1 . All tested drugs increased K+ release (P < 0·05), affecting the functionality of the plasma membrane. Dihydrojasmone modulated the sensitivity of all strains against terbinafine, and terpinolene modulated the sensitivity of M. canis LM 216 and T. interdigitale Δmdr2. The monoterpenes and terbinafine drug associations presented synergism. In conclusion, the results suggest that the dihydrojasmone and terpinolene are promising antifungal agents that potentiate the antifungal activity of terbinafine against dermatophytes.


Assuntos
Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Monoterpenos Cicloexânicos/farmacologia , Dermatomicoses/tratamento farmacológico , Microsporum/efeitos dos fármacos , Terbinafina/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Monoterpenos/farmacologia
2.
J Phys Chem A ; 124(46): 9542-9551, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33169998

RESUMO

Since their discovery, carbon nanotubes and other related nanomaterials are in the spotlight due to their unique molecular structures and properties, having a wide range of applications. The cage-like structure of carbon nanotubes is especially appealing as a route to confine molecules, isolating them from the solvent medium. This study aims to explore and characterize, through density functional theory (DFT) calculations, covalent tip-functionalization of single-walled carbon nanotubes (SWCNTS) with carboxymethyl moieties that establish pH sensitive molecular gates. The response of the molecular gate to pH fluctuations arises from variations in the noncovalent interactions between functionalized groups, which depend on the extent of protonation, leading to conformational changes. Overall, the hydrogen bonds present in the molecular models under study, as evaluated through topological analysis and pKa calculations, suggest that functionalized SWCNTs may be suitable for the design of drug delivery systems to enhance the efficiency of some pharmacological treatments, or even in the area of catalysis and separation processes, through their incorporation in nanocomposites.

3.
J Stomatol Oral Maxillofac Surg ; 119(1): 56-60, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29037869

RESUMO

Renal osteodystrophy is a common complication of end-stage renal failure patients. It's most severe osseous complication is characterized by massive thickening of the cranial vault and facial bones, called uremic leontiasis ossea (ULO), with only few cases reported in the literature. A case of a 47-year-old female patient with ULO is presented. Physical examination showed enlargement of the jaws, which hinders proper ventilation and feeding. The computed tomography examination showed marked osseous proliferation in the jaws causing severe bony expansion and loss of normal bony architecture in the skull and the skull base. The most relevant clinical, histopathological and laboratory findings are discussed. The uremic leontiasis ossea causes significant aesthetic and functional changes. Correct diagnosis and management of the factors responsible for the development of bone lesions due to altered bone metabolism are key factors. The maxillofacial surgeon must have the proper knowledge of patient's medical condition and bone maturation status to address an adequate surgical strategy.


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperostose Frontal Interna , Falência Renal Crônica , Estética Dentária , Ossos Faciais , Feminino , Humanos , Pessoa de Meia-Idade
4.
Toxicol In Vitro ; 26(4): 585-94, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22386657

RESUMO

In this study, the cytotoxicity, genotoxicity and early ROS generation of 2,2-dimethyl-(3H)-3-(N-3'-nitrophenylamino)naphtho[1,2-b]furan-4,5-dione (QPhNO(2)) were investigated and compared with those of its precursor, nor-beta-lapachone (nor-beta), with the main goal of proposing a mechanism of antitumor action. The results were correlated with those obtained from electrochemical experiments held in protic (acetate buffer pH 4.5) and aprotic (DMF/TBABF(4)) media in the presence and absence of oxygen and with those from dsDNA biosensors and ssDNA in solution, which provided evidence of a positive interaction with DNA in the case of QPhNO(2). QPhNO(2) caused DNA fragmentation and mitochondrial depolarization and induced apoptosis/necrosis in HL-60 cells. Pre-treatment with N-acetyl-l-cysteine partially abolished the observed effects related to the QPhNO(2) treatment, including those involving apoptosis induction, indicating a partially redox-dependent mechanism. These findings point to the potential use of the combination of pharmacology and electrochemistry in medicinal chemistry.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Naftoquinonas/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Células HL-60 , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
5.
Parasitology ; 139(1): 26-36, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21939585

RESUMO

Chagas' disease, caused by the protozoan Trypanosoma cruzi, represents a serious health problem in Latin America, and the available chemotherapy, which is based on 2 nitro-derivatives, is not satisfactory. In folk medicine, natural products including naphthoquinones have been employed for the treatment of different parasitic diseases. In the pursuit of alternative drugs for Chagas' disease, we investigated the mechanism of action of the triazolic naphthoquinone (TN; 2,2-dimethyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2,3-dihydronaphtho[1,2-b]furan-4,5-dione), which is the most active compound against T. cruzi trypomastigotes among a series of naphthofuranquinones. TN was active against the 3 parasite forms producing a dose-dependent inhibitory effect. In epimastigotes, TN induced reservosome disruption, flagellar blebbing, Golgi disorganization, the presence of cytosolic concentric membrane structures and abnormal multiflagellar parasites. The treatment also led to the appearance of well-developed endoplasmic reticulum profiles surrounding organelles that associated with an increase in monodansylcadaverine labelling, suggesting autophagy as part of the TN mechanism of action. Interestingly, no ultrastructural damage was detected in the mitochondria of naphthoquinone-treated epimastigotes. Flow cytometric analysis demonstrated an impairment of mitosis, an increase in ROS production and the maintenance of mitochondrial membrane potential. TN could be a good starting point in the investigation of a chemotherapeutic approach for the treatment of Chagas' disease.


Assuntos
Naftoquinonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Citometria de Fluxo , Concentração Inibidora 50 , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Mitose/efeitos dos fármacos , Organelas/efeitos dos fármacos
6.
Artigo em Espanhol | LILACS | ID: lil-592011

RESUMO

La periodontitis apical asintomática (PAa) es una patología infecciosa caracterizada por destrucción ósea perirradicular asociada a un proceso inflamatorio crónico y producción de mediadores inflamatorios, entre los cuales se encuentran las metaloproteinasas de matriz extracelular (MMPs). Entre éstas, las MMPs-13, -14, -2 y -9, son producidas por el tejido óseo y degradan sinérgicamente el colágeno tipo I, principal componente de los tejidos periodontales, y gelatina, producto de la degradación y desnaturación del colágeno. El objetivo de este estudio fue determinar el patrón de expresión de las MMPs-2, -9, -13 y -14 en granulomas periapicales (GPAs), quistes radiculares inflamatorios (QRIs) y ligamento periodontal sano (LS). Materiales y Métodos: Se seleccionaron 12 pacientes con diagnóstico clínico de PAa e indicación de exodoncia a partir de los cuales se obtuvieron biopsias de lesiones periapicales (LPAs). Como controles, se seleccionaron 7 individuos con indicación de exodoncia de premolares por ortodoncia, obteniéndose biopsias de LS. Se efectuó el diagnóstico anátomo-patológico de los especímenes y se caracterizó la expresión de las MMPs en estudio mediante inmunohistoquímica. Resultados: Las MMPs en estudio sólo se detectaron en GPAs y QRIs, y se inmunolocalizaron principalmente en el infiltrado inflamatorio de éstos. Adicionalmente, la MMP-2 se identificó en fibroblastos del tejido conectivo. Conclusiones: MMPs-2, -9, -13 y -14 se expresan predominantemente en el infiltrado inflamatorio de las LPAs y no en LS, y por tanto se sugiere la participación de estos mediadores en la patogénesis de la PAa.


Asymptomatic apical periodontitis (aAP) is an infectious disease characterized by perirradicular bone destruction associated with chronic inflammation and release of inflammatory mediators, such as matrix metalloproteinases (MMPs). MMPs-13, -14 and -2, -9 are bone-expressed enzymes that can synergistically degrade collagen I, the main component of periodontal extracellular matrix, and gelatin, the product of degradation and denaturation of collagen. The aim of this study was to characterize the expression pattern of MMPs-2, -9, -13, and -14 in periapical granulomas (PGs), radicular cysts (RCs) and healthy periodontal ligament (PDL). Materials and Methods: Individuals with clinical diagnosis of aAP and indication of extraction were selected (N=12), and biopsies of periapical lesions (PLs) were obtained. For controls, 7 subjects with indication of premolar extraction for orthodontic reasons were selected, and PDL biopsies were obtained. Samples were diagnosed by anatomopathological examination and immunohistochemical staining was carried out to characterize MMPs expression. Results: MMPs-2, -9, -13 and -14 detection was limited to PLs and were localized mainly to inflammatory infiltrate on both, PGs and RCs. Additionally, MMP-2 was immunolocalized to fibroblasts from the connective tissue. Conclusions: Whereas MMPs-2, -9, -13 and -14 were not detected in healthy periodontal ligament, they were highly expressed on inflammatory infiltrate from PGs and RCs, suggesting a role of these mediators in aAP pathogenesis.


Assuntos
Humanos , Masculino , Feminino , Adulto , Metaloproteinases da Matriz/análise , Periodontite Periapical/enzimologia , Tecido Periapical/patologia , Estudos Transversais , Imuno-Histoquímica , Matriz Extracelular/enzimologia , /análise , Metaloproteinase 9 da Matriz/análise , /análise , /análise , Tecido Periapical/enzimologia
7.
Artigo em Espanhol | LILACS | ID: lil-582936

RESUMO

El carcinoma verrucoso (CV) es una variante rara del carcinoma de células escamosas con características morfológicas y comportamiento específico. El presente estudio relata el caso de una paciente de género femenino, de 68 años de edad, que presenta un carcinoma verrucoso en lengua, indoloro y con 8 meses de evolución. Además, se realizó una breve revisión de casos clínicos del Instituto de Referencia en Patología Oral (IREPO) de la Facultad de Odontología de la Universidad de Chile, diagnosticados entre enero de 1984 y octubre de 2010, encontrándose 20 casos, con un promedio de edad de 70 años, localizados con mayor frecuencia en encía inferior y lengua.


Verrucous carcinoma (VC), a rare variant of squamous cell carcinoma is an established entity with distinctive morphology and specific clinical behavior. The present study describe a case report of a 68-year-old women who presented a tongue verrucous carcinoma, asymptomatic, that had about 8 months of evolution. A brief review of VC cases diagnosed in Oral Pathology Referral Institute (IREPO), Faculty of Odontology, University of Chile, between 1984 and 2010. It was found 20 cases of verrucous carcinoma with a median age of70-years-old, the most common places were lower gingiva and tongue.


Assuntos
Humanos , Feminino , Idoso , Carcinoma Verrucoso/diagnóstico , Carcinoma Verrucoso/patologia , Neoplasias da Língua/diagnóstico , Neoplasias da Língua/patologia , Carcinoma Verrucoso/cirurgia , Diagnóstico Diferencial , Neoplasias da Língua/cirurgia
8.
Parasitology ; 136(5): 499-510, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19281638

RESUMO

SUMMARY: In a screening of 65 derivatives of natural quinones using bloodstream trypomastigotes of Trypanosoma cruzi, the 3 naphthoimidazoles derived from beta-lapachone - N1, N2 and N3--were selected as the most active. Investigation of their mode of action led to the characterization of mitochondrion, reservosomes and DNA as their main targets, and stimulated further studies on death pathways. Ultrastructural analysis revealed both autophagic (autophagosomes) and apoptotic-like (membrane blebbing) phenotypes. Flow cytometry analysis showed, in N2-treated trypomastigotes, a small increase of phosphatidylserine exposure, and a large increase in the percentage of necrosis, caused by N1 or N2. These death phenotypes were not detected in treated epimastigotes. The strong increase in labelling of monodansyl cadaverine, the inhibition of the death process by wortmannin or 3-methyladenine, the overexpression of ATG genes in treated epimastigotes, together with ultrastructural evidence point to autophagy as the predominant phenotype induced by the naphthoimidazoles. However, there are other pathways occurring concomitantly with variable intensities, justifying the need to detail the molecular features involved.


Assuntos
Autofagia/efeitos dos fármacos , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Citometria de Fluxo , Imidazóis/síntese química , Imidazóis/química , Microscopia Eletrônica , Naftoquinonas/síntese química , Naftoquinonas/química , Testes de Sensibilidade Parasitária , Fenótipo , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/genética , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
9.
Parasitol Res ; 101(4): 895-905, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17546464

RESUMO

Three naphthoimidazoles presenting aromatic groups attached to the imidazole ring were the most active against trypomastigotes of Trypanosoma cruzi between 45 derivatives from beta-lapachone. N1 is active against the three forms of the parasite. In this work, we investigated N2 and N3 and analyzed the effect of the three derivatives on metacyclogenesis, endocytosis, and cell cycle. In epimastigotes, N2 and N3 blocked the cell cycle, inhibited succinate cytochrome c reductase, metacyclogenesis, and induced damage to mitochondrion, Golgi, and reservosomes. In treated trypomastigotes, there were alterations in the mitochondrion, nucleus and kinetoplast, and DNA fragmentation. Preincubation with cysteine protease inhibitors reversed the effect of N1, N2, and N3. Such reversion and ultrastructural alterations suggest the involvement of autophagy in parasite death. Ultrastructural, flow cytometry, and biochemical studies suggest that naphthoimidazoles interferes with the energetic metabolism and induces DNA fragmentation.


Assuntos
Antiprotozoários/farmacologia , Bignoniaceae/química , Fragmentação do DNA/efeitos dos fármacos , Imidazóis/farmacologia , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Ciclo Celular/efeitos dos fármacos , DNA Mitocondrial/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/química , Concentração Inibidora 50 , Camundongos , Microscopia Eletrônica de Varredura , Naftoquinonas/síntese química , Naftoquinonas/química , Testes de Sensibilidade Parasitária , Trypanosoma cruzi/citologia , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
10.
Int J Antimicrob Agents ; 21(3): 279-84, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12636992

RESUMO

Fourteen extracts from Brazilian traditional medicinal plants used to treat infectious diseases were used to look for potential antimicrobial activity against multiresistant bacteria of medical importance. Staphylococcus aureus strains were susceptible to extracts of Punica granatum and Tabebuia avellanedae. The minimum inhibitory concentrations (MICs) of the total extracts and of additional fractions of these plants were determined by employing strains of methicillin-resistant (MRSA) and -sensitive (MSSA) S. aureus, including isolates of the PFGE clone A, which is prevalent in Brazil and two ATCC reference strains. A mixture of ellagitannins isolated from P. granatum and two naphthoquinones isolated from T. avellanedae demonstrated antibacterial activity against all S. aureus strains tested. Semi-synthetic furanonaphthoquinones (FNQs) showed lower MICs than those exhibited by natural occurring naphthoquinones. The results indicate that these natural products can be effective potential candidates for the development of new strategies to treat MRSA infections.


Assuntos
Taninos Hidrolisáveis , Naftoquinonas/farmacologia , Plantas Medicinais , Staphylococcus aureus/efeitos dos fármacos , Brasil , Humanos , Técnicas In Vitro , Lythraceae , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Naftoquinonas/administração & dosagem , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação , Tabebuia , Taninos/administração & dosagem , Taninos/química , Taninos/isolamento & purificação , Taninos/farmacologia
11.
Int J Parasitol ; 30(11): 1199-202, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11027788

RESUMO

In the search for new molluscicidal agents we tested the activity of lapachol and other 2-hydroxy-3-alkylnaphthoquinones possessing nitrogenated alkyl chains, against the snail Biomphalaria glabrata. Lapachol, isolapachol and nor-lapachol showed strong molluscicidal activity against the adult snail (LD(90)<10 ppm) and significant toxicity against snail egg masses (LD(90)<0.2 ppm). As lapachol is easily extracted, and the derivatives can be synthesised without any difficulty, large-scale synthesis and field tests can be conducted, with a view to large-scale molluscicidal programs.


Assuntos
Moluscocidas/farmacologia , Naftoquinonas/farmacologia , Caramujos/crescimento & desenvolvimento , Animais , Anti-Infecciosos/farmacologia , Bioensaio , Brasil , Naftoquinonas/química , Caramujos/efeitos dos fármacos
12.
Arzneimittelforschung ; 50(12): 1120-8, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11190779

RESUMO

The biological activities of the naphthoquinones lapachol and its cyclization product beta-lapachone, extracted from trees of the genus Tabebuia, have been intensively studied. Given continuity to the studies about heterocyclic derivatives obtained from the reaction of these naphtoquinones with amino-containing reagents, 22 derivatives of beta-lapachone, nor-beta-lapachone and lapachol were synthesised and their activities against trypomastigote forms of T. cruzi were evaluated. The compounds were grouped as oxazolic, imidazolic, phenoxazinic, indolic, pyranic and cyclopentenic derivatives. The variability of the new structures is based on the great electrophilicity of 1,2-quinoidal carbonyls towards reagents containing nitrogen or carbon as nucleophilic centres. In relation to the trypanocidal activity of the synthesised compounds, in view of their structural diversity, tendencies only could be verified. Among the cyclofunctionalised products the oxazolic and imidazolic derivatives showed +/- 1.5 to 34.8 times higher activity than crystal violet, the standard drug for the sterilization of stored blood. These results corroborate the tendency of trypanocidal activity in imidazolic skeletons, and indicate that this moiety could be used as a guide for architectural delineation of molecules with potential value for the chemotherapy of Chagas disease.


Assuntos
Naftoquinonas/farmacologia , Plantas Medicinais/química , Tripanossomicidas/farmacologia , Animais , Brasil , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Espectroscopia de Ressonância Magnética , Naftoquinonas/isolamento & purificação , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Tripanossomicidas/isolamento & purificação , Trypanosoma cruzi/efeitos dos fármacos
13.
Proc Natl Acad Sci U S A ; 96(23): 13369-74, 1999 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-10557327

RESUMO

Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of beta-lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after beta-lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. beta-Lapachone causes cell-cycle delays in late G(1) and S phase, and taxol arrests cells at G(2)/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone "collisions" at cell-cycle checkpoints.


Assuntos
Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Naftoquinonas/farmacologia , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/enzimologia , Células Tumorais Cultivadas
14.
Mol Med ; 5(4): 232-9, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10448645

RESUMO

BACKGROUND: There are two fundamental forms of cell death: apoptosis and necrosis. Molecular studies of cell death thus far favor a model in which apoptosis and necrosis share very few molecular regulators. It appears that apoptotic processes triggered by a variety of stimuli converge on the activation of a member of the caspase family, such as caspase 3, which leads to the execution of apoptosis. It has been suggested that blocking of caspase activation in an apoptotic process may divert cell death to a necrotic demise, suggesting that apoptosis and necrosis may share some upstream events. Activation of caspase is preceded by the release of mitochondrial cytochrome C. MATERIALS AND METHODS: We first studied cell death induced by beta-lapachone by MTT and colony-formation assay. To determine whether the cell death induced by beta-lapachone occurs through necrosis or apoptosis, we used the PI staining procedure to determine the sub-G1 fraction and the Annexin-V staining for externalization of phophatidylserine. We next compared the release of mitochondrial cytochrome C in apoptosis and necrosis. Mitochondrial cytochrome C was determined by Western blot analysis. To investigate changes in mitochondria that resulted in cytochrome C release, the mitochondrial membrane potential (delta psi) was analyzed by the accumulation of rhodamine 123, a membrane-permeant cationic fluorescent dye. The activation of caspase in apoptosis and necrosis were measured by using a profluorescent substrate for caspase-like proteases, PhiPhiLuxG6D2. RESULTS: beta-lapachone induced cell death in a spectrum of human carcinoma cells, including nonproliferating cells. It induced apoptosis in human ovary, colon, and lung cancer cells, and necrotic cell death in four human breast cancer cell lines. Mitochondrial cytochrome C release was found in both apoptosis and necrosis. This cytochrome C release occurred shortly after beta-lapachone treatment when cells were fully viable by trypan blue exclusion and MTT assay, suggesting that cytochrome C release is an early event in beta-lapachone induced apoptosis as well as necrosis. The mitochondrial cytochrome C release induced by beta-lapachone is associated with a decrease in mitochondrial transmembrane potential (delta psi). There was activation of caspase 3 in apoptotic cell death, but not in necrotic cell death. This lack of activation of CPP 32 in human breast cancer cells is consistent with the necrotic cell death induced by beta-lapachone as determined by absence of sub-G1 fraction, externalization of phosphatidylserine. CONCLUSIONS: beta-lapachone induces either apoptotic or necrotic cell death in a variety of human carcinoma cells including ovary, colon, lung, prostate, and breast, suggesting a wide spectrum of anti-cancer activity in vitro. Both apoptotic and necrotic cell death induced by beta-lapachone are preceded by a rapid release of cytochrome C, followed by the activation of caspase 3 in apoptotic cell death but not in necrotic cell death. Our results suggest that beta-lapachone is a potential anti-cancer drug acting on the mitochondrial cytochrome C-caspase pathway, and that cytochrome C is involved in the early phase of necrosis.


Assuntos
Carcinoma/metabolismo , Morte Celular/fisiologia , Grupo dos Citocromos c/metabolismo , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/farmacologia , Antibióticos Antineoplásicos/farmacologia , Apoptose , Caspase 3 , Caspases/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática , Feminino , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/metabolismo , Necrose , Células Tumorais Cultivadas
15.
Arzneimittelforschung ; 47(1): 74-9, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9037448

RESUMO

Continuing a program on the chemistry and biological activity of compounds from the Brazilian flora, the lytic activity against bloodstream forms of T. cruzi of nine new heterocyclic naphthooxazole and naphthoimidazole derivatives obtained from the reaction of naphtoquinones isolated from Tabebuia sp. (Tecoma) with amino-containing reagents has been studied. Also for the first time the biological activity of allyl derivatives of lawsone, a natural quinone from Lausonia alba inactive against T. cruzi, is reported. The introduction of an allyl group in lawsone gives rise to O-allyl-lawsone and C-allyl-lawsone that showed activity against the parasite, with ID50 values of 420.7 +/- 71.1 and 330.7 +/- 62.4 mumol/l, respectively. The trypanocidal activity of the naphtho heterocyclics synthesized from the original quinones showed no concordant behavior in relation to the parent compound. Six of nine of the synthesized compounds presented lower ID50 values than crystal violet, indicating a general trend of activity among naphthalenic heterocyclics of the oxazole/imidazole type. However, their chemical structures do not endow them with the capacity of free radical generation by biological reduction as the quinoidal moiety, nor do they have chemical reducible appendage like the nitro group of nifurtimox and benznidazole, responsible for such behaviour. As a hypothesis, the pattern of their biological actions should be focused in other aspects of their chemical structures. Because of their polycyclic planar topology, these derivatives are potential candidates for experimental tests as DNA intercalating agents.


Assuntos
Compostos Heterocíclicos/síntese química , Plantas Medicinais/química , Quinonas/síntese química , Tripanossomicidas/síntese química , Animais , Brasil , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Compostos Heterocíclicos/farmacologia , Substâncias Intercalantes/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Quinonas/isolamento & purificação , Quinonas/farmacologia , Espectrofotometria Infravermelho , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos
16.
Phytochemistry ; 43(2): 465-9, 1996 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8862038

RESUMO

Three new steroidal saponins were isolated from the rhizomes of Smilax officinalis. The structures of these saponins were established by extensive spectral data, hydrolysis and chemical correlation as sarsasapogenin 3-O-beta-D-glucopyranosyl-(1-->4)-[alpha-L-arabinopyranosyl-(1-->6 )-beta- D-glucopyranoside, neotigogenin 3-O-beta-D-glucopyranosyl-(1-->4)-[alpha-L-arabinopyranosyl-(1-->6 )]-beta- D-glucopyranoside and 25S-spirostan-6 beta-ol 3-O-beta-D-glucopyranosyl-(1-->4)-[alpha-L-arabinopyranosyl-(1-->6 )]-beta- D-glucopyranoside. Acid hydrolysis of the latter compound gave a sapogenin which has a new orientation of an hydroxyl on the steroidal skeleton. A route is proposed for the biogenesis of the latter sapogenin which is an uncommon steroidal aglycone.


Assuntos
Plantas Medicinais , Saponinas/química , Esteroides/química , Configuração de Carboidratos , Sequência de Carboidratos , Carboidratos/análise , Espectroscopia de Ressonância Magnética , Medicina Tradicional , Dados de Sequência Molecular , Estrutura Molecular , Saponinas/isolamento & purificação , Esteroides/isolamento & purificação
18.
Microbios ; 78(315): 83-90, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8047025

RESUMO

The activity of 45 compounds against bloodstream forms of Trypanosoma cruzi was investigated. The aim was to consider new agents which might subsequently be assayed for chemoprophylaxis in donated blood. In a preliminary screening the drugs were assayed (50 to 1,000 microM at 29 degrees C) and those active against bloodstream forms at concentrations below 600 microM were selected for further assays under blood-bank conditions (4 degrees C/24 h). Three compounds isolated from natural sources and six synthetic agents were selected. The active compounds of plant origin included purpurin, a member of the trihydroxylated anthraquinone group, which is known to exhibit trypanocidal activity. Among the active synthetic compounds, five displayed a common structural feature in that they were potentially one-electron acceptors, via reductive functional groups. All five compounds form tricentered C or N intermediates, joined in a hypothetical 'Y' radical pattern. It is possible that the trypanocidal mechanisms initiated by these compounds are similar to those found with crystal violet, since this dye, which is already used in endemic areas for the treatment of banked blood, also conforms to this general Y structural pattern.


Assuntos
Antraquinonas , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Ácido Aurintricarboxílico/análogos & derivados , Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacologia , Corantes/síntese química , Corantes/farmacologia , Avaliação Pré-Clínica de Medicamentos , Violeta Genciana/farmacologia , Hematoxilina/farmacologia , Lectinas/farmacologia , Naftóis/síntese química , Naftóis/farmacologia , Fenolftaleínas/síntese química , Fenolftaleínas/farmacologia , Picratos/síntese química , Picratos/farmacologia , Relação Estrutura-Atividade , Estricnina/farmacologia , Tripanossomicidas/química
19.
Mem. Inst. Oswaldo Cruz ; 87(3): 345-51, jul.-set. 1992. tab, ilus
Artigo em Inglês | LILACS | ID: lil-116333

RESUMO

Accidental transmission of Chagas' disease to man by blood transfusion is a serious problem in Latin-America. This paper describes the testing of several synthetic, semi-synthetic, and natural compounds for their activity against blood trypomastigotes in vitro at 4-C. The compounds embody several types of chemical structures: benzoquinone, naphthoquinone, anthracenequinone, phenanthrenequinone, imidazole, piperazine, quinoline, xanthene, and simple benzenic and naphthalenic derivates. Some of them are for the first time tested against Trypanosoma cruzi. The toxic effect these compounds on this parasite was done by two quite distinct sets of experiments. In one set, the compounds were added to infected blood as ethanolic solution. In this situation the most active one was a furan-1, 2-naphthoquinone, in the same range as gentian violet, a new fact to be considered in the assessment of structure-activity relationships in this class of compounds. In other set, we tentatively evaluated the biological activity of water insoluble compounds by adding them in a pure form without solvent into infected blood. In this way some appear to be very active and it was postulated that the effectiveness of such compounds must result from interactions between them and specific blood components


Assuntos
Animais , Transfusão de Sangue , Doença de Chagas/transmissão , Trypanosoma cruzi , Doença de Chagas/prevenção & controle
20.
Rev Saude Publica ; 26(2): 88-95, 1992 Apr.
Artigo em Português | MEDLINE | ID: mdl-1307433

RESUMO

Three hundred and sixty-three pregnant women enrolled in the Pregnancy Medical Care Program of S. Paulo Health Department in the district of Butantan, S. Paulo city, Brazil, were studied at their first routine consultation between April and October, 1988. Their average age was 25 and 65.9% of them belonged to families with a monthly income below US$50.00 per capita. Only 3.1% presented an income above US$150.00 per capita. Taking the minimum transferrin saturation threshold of 15% as determining iron deficiency, a 4.6% prevalence of iron deficiency was observed in the first trimester, 17.3% in the second trimester and 42.8% in the third trimester, resulting in an overall prevalence of 12.4%. There was no significant difference between prevalences of iron deficiency according to the number of pregnancies. The prevalence of iron deficiency was higher in women presenting incomes below US$50.00 per capita.


Assuntos
Anemia Hipocrômica/epidemiologia , Deficiências de Ferro , Complicações Hematológicas na Gravidez/epidemiologia , Adulto , Anemia Hipocrômica/sangue , Brasil/epidemiologia , Distribuição de Qui-Quadrado , Feminino , Deficiência de Ácido Fólico/sangue , Hemoglobinas/análise , Humanos , Ferro/sangue , Gravidez , Complicações Hematológicas na Gravidez/sangue , Cuidado Pré-Natal , Prevalência , Fatores Socioeconômicos , Transferrina/análise
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