RESUMO
Species from Candida parapsilosis complex are frequently found in neonatal candidemia. The antifungal agents to treat this infection are limited and the occurrence of low in vitro susceptibility to echinocandins such as micafungin has been observed. In this context, the chaperone Hsp90 could be a target to reduce resistance. Thus, the objective of this research was to identify isolates from the C. parapsilosis complex and verify the action of Hsp90 inhibitors associated with micafungin. The fungal identification was based on genetic sequencing and mass spectrometry. Minimal inhibitory concentrations were determined by broth microdilution method according to Clinical Laboratory and Standards Institute. The evaluation of the interaction between micafungin with Hsp90 inhibitors was realized using the checkerboard methodology. According to the polyphasic taxonomy, C. parapsilosis sensu stricto was the most frequently identified, followed by C. orthopsilosis and C. metapsilosis, and one isolate of Lodderomyces elongisporus was identified by genetic sequencing. The Hsp90 inhibitor geladanamycin associated with micafungin showed a synergic effect in 31.25% of the isolates, a better result was observed with radicicol, which shows synergic effect in 56.25% tested yeasts. The results obtained demonstrate that blocking Hsp90 could be effective to reduce antifungal resistance to echinocandins.
Assuntos
Antifúngicos , Candida parapsilosis , Candidemia , Proteínas de Choque Térmico HSP90 , Micafungina , Humanos , Recém-Nascido , Antifúngicos/farmacologia , Benzoquinonas/farmacologia , Candida parapsilosis/efeitos dos fármacos , Candida parapsilosis/isolamento & purificação , Candida parapsilosis/genética , Candidemia/microbiologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Equinocandinas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/genética , Lactamas Macrocíclicas/farmacologia , Lipopeptídeos/farmacologia , Micafungina/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
Prion Diseases or Transmissible Spongiform Encephalopathies are neurodegenerative conditions associated with a long incubation period and progressive clinical evolution, leading to death. Their pathogenesis is characterized by conformational changes of the cellular prion protein-PrPC-in its infectious isoform-PrPSc-which can form polymeric aggregates that precipitate in brain tissues. Currently, there are no effective treatments for these diseases. The 2,5-diamino-1,4-benzoquinone structure is associated with an anti-prion profile and, considering the biodynamic properties associated with 4-quinolones, in this work, 6-amino-4-quinolones derivatives and their respective benzoquinone dimeric hybrids were synthesized and had their bioactive profile evaluated through their ability to prevent prion conversion. Two hybrids, namely, 2,5-dichloro-3,6-bis((3-carboxy-1-pentyl-4-quinolone-6-yl)amino)-1,4-benzoquinone (8e) and 2,5-dichloro-3,6-bis((1-benzyl-3-carboxy-4-quinolone-6-yl)amino)-1,4-benzoquinone (8f), stood out for their prion conversion inhibition ability, affecting the fibrillation process in both the kinetics-with a shortening of the lag phase-and thermodynamics and their ability to inhibit the formation of protein aggregates without significant cytotoxicity at ten micromolar.
Assuntos
Doenças Priônicas , Príons , Quinolonas , Humanos , Proteínas Priônicas , Príons/química , Doenças Priônicas/metabolismo , Polímeros , Translocação Genética , Benzoquinonas/farmacologiaRESUMO
OBJECTIVES: Black cumin is widely used as a spice and as a traditional treatment. The active ingredient in black cumin seeds is thymoquinone. Thymoquinone has shown anticancer effects in some cancers. We planned to investigate its anticancer effect on pancreatic cancer cell lines. METHODS: Thymoquinone chemical component in various doses was prepared and inoculated on pancreatic cancer cell culture, healthy mesenchymal stem cells, and peripheral blood mononuclear cell culture. IC50 values were calculated by absorbance data and measuring cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide staining of cells incubated with thymoquinone at 24, 48, and 72 h. RESULTS: There was dose-related cytotoxicity. Maximal cytotoxicity was observed at 24 h and 100 µM thymoquinone concentrations in pancreatic cancer cell culture and mesenchymal stem cells. Any concentration of thymoquinone was not cytotoxic to peripheral blood mononuclear cell. Thymoquinone even caused proliferation at a concentration of 6.25 µM. CONCLUSIONS: Since the cytotoxic concentration of thymoquinone on pancreatic cancer cell culture and mesenchymal stem cells is the same, it is not appropriate to use thymoquinone to achieve cytotoxicity in pancreatic cancer. However, since thymoquinone provides proliferation in peripheral blood mononuclear cell at a noncytotoxic dose, it may have an immune activator effect. Therefore, in vivo studies are needed to investigate the effect of thymoquinone on the immune system.
Assuntos
Antineoplásicos , Nigella sativa , Neoplasias Pancreáticas , Antineoplásicos/uso terapêutico , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Brometos/uso terapêutico , Humanos , Leucócitos Mononucleares/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias PancreáticasRESUMO
Acute myeloid leukemia (AML) belongs to a group of hematological cancer whose relapse cases are often associated with chemoresistance that impairs treatment success and contributes to a poor outcome. For this reason, there is an urgent need for the development of new therapeutic strategies. Herein, we explore the combination of venetoclax, a BCL2 inhibitor, and embelin, an XIAP inhibitor, in the AML cell lines. Combinatory treatment of venetoclax and embelin potentiated cytotoxic effects of these drugs, demonstrating that both in combination present lower IC50 values than single treatment of either venetoclax or embelin alone in both cell lines analyzed. The combinatory treatment further increased the apoptosis-inducing properties of both compounds. Computer simulations suggest that embelin binds to both BIR2 and BIR3 domains of XIAP, reinforcing this inhibitory apoptosis protein as an embelin target. Although all AML cell lines presented similar basal levels of XIAP, the combinatory treatment effectively inhibited XIAP expression in OCI-AML3 cells. In conclusion, the inhibition of both apoptosis inhibitory players, BCL2 and XIAP, by venetoclax and embelin, respectively, potentiated their cytotoxic effects in AML cell lines.
Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Sinergismo Farmacológico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismoRESUMO
Resistance to antimicrobials is a challenging issue that complicates the treatment of infections caused by bacteria and fungi, thus requiring new therapeutic options. Oncocalyxone A, a benzoquinone obtained from Auxemma oncocalyx (Allem) Taub has several biological effects; however, there is no data on its antimicrobial action. In this study, its antimicrobial and antibiofilm activities were evaluated against bacteria and fungi of clinical interest. Strains of Gram-positive and Gram-negative bacteria, and filamentous fungi and yeasts were selected to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of oncocalyxone A. The antibacterial effect of oncocalyxone A was studied using survival curves, atomic force microscopy (AFM), and the involvement of oxidative stress. We examined the inhibitory action of the molecule on biofilm formation and its hemolytic activity against human erythrocytes. Our results showed that among the strains tested, Staphylococcus epidermidis was highly sensitive to the action of oncocalyxone A, with an MIC of 9.43 µg/mL. In most bacterial strains analyzed, a bacteriostatic effect was observed, though the molecule showed no antifungal activity. Antibiofilm activity was observed against the methicillin-resistant S. aureus bacteria. Additionally, results from atomic force microscopy imaging showed that oncocalyxone A significantly altered bacterial morphology. Further, oncocalyxone A showed no hemolytic activity at concentrations ≥151 µg/mL. Together, our results demonstrate the antibacterial and antibiofilm potential of oncocalyxone A, indicating its therapeutic potential against bacterial resistance.
Assuntos
Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Antraquinonas , Antibacterianos/farmacologia , Benzoquinonas/farmacologia , Biofilmes , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Humanos , Testes de Sensibilidade MicrobianaRESUMO
Defensive secretions of millipedes are remarkable for containing toxic quinones known to efficiently repell hematophagous arthropods. Here we show that Endangered blonde capuchin monkeys make use of such secretions. We (i) describe the anointing behavior performed by the monkeys (ii) identify the millipede species used in the process (iii) describe the volatile chemical composition of its secretion. The blonde capuchin monkeys selectively searched for millipedes hidden under the ground. We observed three bouts of anointing behavior, performed by 13 individuals of all age classes (from adults to independent infants), both solitarily (1 event) and socially (10 events). The only millipede species used by the monkeys is an undescribed species of the genus Poecilocricus (Spirobolida, Rhinocricidae). The volatile chemical composition of the secretions was predominantly comprised of a mixture of benzoquinones and hydroquinones. The social nature of the behavior and time of the observations (mosquito season), suggest that social bonding and mosquito avoidance is linked to the anointing behavior of the monkeys.
Assuntos
Artrópodes/metabolismo , Comportamento Animal/efeitos dos fármacos , Benzoquinonas/farmacologia , Cebus/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Hidroquinonas/farmacologia , Animais , Artrópodes/química , Benzoquinonas/isolamento & purificação , Hidroquinonas/isolamento & purificação , Comportamento SocialRESUMO
In this work, we present a computational investigation on the structure and energetics of eleocarpanthraquinone, a newly isolated polyphenolic anthrone-antraquinone. Properties such as bond lengths, angles, atomic charges, bond dissociation enthalpies (BDEs), and ionization potential (IP) were determined through the use of density functional theory (DFT). The B3LYP and M06-2X exchange-correlation functionals were employed along with the 6-31+G(d,p), 6-31+ +G(d,p), and 6-311+G(d,p) basis sets for performing computations in the gas-phase, water, methanol, and ethanol. The conformation presenting all the hydroxyl groups undergoing hydrogen-bond interactions with neighboring oxygen atoms (conformation 5) was assigned as the most stable structure while its counterpart presenting no hydrogen-bond interaction was found to be 36.45 kcal/mol less stable than conformation 5 in the potential energy surface probed at the B3LYP/6-311+G(d,p) level of theory in the gas-phase, for instance. More importantly, the lowest O-H bond dissociation enthalpy was determined to be 93.80 kcal/mol at the B3LYP/6-311+G(d,p) level of theory in water against the 146.58 kcal/mol regarding the IP computed at the same approach, suggesting the hydrogen atom transfer mechanism as being preferred over the single electron transfer mechanism in regards to the antioxidant potential for the case of eleocarpanthraquinone; the same conclusion was drawn from the outcomes of all the other approaches used.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Modelos Moleculares , Teoria da Densidade Funcional , Conformação Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Breast cancer is a complex disease and encompassing different types of tumor. Although advances in understanding of the molecular bases of breast cancer biology, the therapeutic proposals available still are not effective. In this scenario, the present study aimed to evaluate the mechanisms associated to antitumor activity of 7-Epiclusianone (7-Epi), a tetraprenylated benzophenone, on luminal A (MCF-7) and claudin-low (Hs 578T) breast cancer cell lines. We found that 7-Epi efficiently inhibited cell proliferation and migration of these cells; however MCF-7 was slightly more responsive than Hs 578T. Cell cycle analysis showed accumulation of cells at G0/G1 phase with drastic reduction of S population in treated cultures. This effect was associated to downregulation of CDKN1A (p21) and cyclin E in both cell lines. In addition, 7-Epi reduced cyclin D1 and p-ERK expression levels in MCF-7 cell line. Cytotoxic effect of 7-Epi on breast cancer cell lines was associated to its ability to increase BAX/BCL-2 ratio. In conclusion, our findings showed that 7-Epi is a promising antitumor agent against breast cancer by modulating critical regulators of the cell cycle and apoptosis.
Assuntos
Antineoplásicos/farmacologia , Benzofenonas/farmacologia , Benzoquinonas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ciclina D1/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Feminino , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/genéticaRESUMO
17-N-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) is an inhibitor of heat shock protein 90 (Hsp90), which has been studied in the treatment of cancer such as leukemia or solid tumors. Alternatively, 17-AAG may represent a promising therapeutic agent against leishmaniasis. However, the delivery of 17-AAG is difficult due to its poor aqueous solubility. For exploring the therapeutic value of 17-AAG, we developed solid lipid nanoparticles (SLN) by double emulsion method. SLN exhibited ~100 nm, PDI < 0.2 and zeta potential ~20 mV. In addition, SLN were morphologically spherical with negligible aggregation. The entrapment efficiency of 17-AAG into the lipid matrix reached at nearly 80%. In a separate set of experiments, fluorescent SLN (FITC-labeled) showed a remarkable macrophage uptake, peaking within 2 h of incubation by confocal microscopy. Regarding the drug internalization as critical step for elimination of intracellular Leishmania, this finding demonstrates an important feature of the developed SLN. Collectively, these data indicate the feasibility of developing SLN as potential delivery systems for 17-AAG in leishmaniasis chemotherapy.
Assuntos
Benzoquinonas/metabolismo , Benzoquinonas/farmacologia , Lactamas Macrocíclicas/metabolismo , Lactamas Macrocíclicas/farmacologia , Lipídeos/química , Macrófagos/metabolismo , Nanopartículas/química , Animais , Benzoquinonas/administração & dosagem , Benzoquinonas/química , Portadores de Fármacos/uso terapêutico , Proteínas de Choque Térmico HSP90/uso terapêutico , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/química , Leishmania , Leishmaniose/tratamento farmacológico , Estrutura Molecular , SolubilidadeRESUMO
PURPOSE: To investigate whether heat shock protein 90 (HSP90) is involved in complement regulation in ischemic postconditioning (IPC). METHODS: The left coronary artery of rats underwent 30 min of occlusion, followed by 120 min of reperfusion and treatment with IPC via 3 cycles of 30s reperfusion and 30s occlusion. The rats were injected intraperitoneally with 1 mg/kg HSP90 inhibitor geldanamycin (GA) after anesthesia. Eighty rats were randomly divided into four groups: sham, ischemia-reperfusion (I/R), IPC and IPC + GA. Myocardial infarct size, apoptosis index and the expression of HSP90, C3, C5a, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß and c-Jun N-terminal kinase (JNK) were assessed. RESULTS: Compared with the I/R injury, the IPC treatment significantly reduced infarct size, release of troponin T, creatine kinase-MB, and lactate dehydrogenase, and cardiomyocyte apoptosis. These beneficial effects were accompanied by a decrease in TNF-α, IL-1ß, C3, C5a and JNK expression levels. However, all these effects were abrogated by administration of the HSP90 inhibitor GA. CONCLUSION: HSP90 exerts a profound effect on IPC cardioprotection, and may be linked to the inhibition of the complement system and JNK, ultimately attenuating I/R-induced myocardial injury and apoptosis.