RESUMO
Gastric cancer (GC) represents the fifth most human malignant disease and the third-most common cause of cancer-related death. Gambogic acid (GA) is a natural compound with a polyprenylated xanthone structure and possesses remarkable antitumor activity in a variety of cancer cells. However, the mechanism underlying the inhibitory effect of GA in GC is far from being completely understood. The goal of the present study is to investigate whether potential microRNAs are involved in antitumor effect of GA toward GC and to elucidate the possible mechanisms. We identified that miR-26a-5p was significantly increased by GA in GC cell lines and xenograft tumor. Downregulation of miR-26a-5p not only prevented GA-induced inhibition on GC cell growth, but also suppressed GA-induced apoptosis of GC cells. Informatics assay predicted that Wnt5a was regulated by miR-26a-5p and GA-induced downregulation of Wnt5a was prevented by anti-miR-26a-5p. Reporter gene assay showed that miR-26a-5p could negatively regulate Wnt5a through direct binding with 3'-UTR messenger RNA of Wnt5a. Thus, upregulation of Wnt5a exhibited the same action tendency for GA-induced GC cell growth and apoptosis as observed by downregulation of miR-26a-5p. In conclusion, these results indicated that the inhibitory effect of GA on GC was mediated by the upregulation of miR-26a-5p and downregulation of Wnt5a. Our study provided new clues for the potential therapeutic effect of GA against GC and highlighted the importance of miR-26a-5p/Wnt5a pathway in the regulation of GC development.
Assuntos
MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Neoplasias Gástricas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt-5a/metabolismo , Xantonas/toxicidade , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genética , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/genética , Proteína Wnt-5a/genéticaRESUMO
We recently isolated the prenylated xanthones 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB) from the South American tree fern Metaxya rostrata. This study explores the mechanisms underlying the FoxM1 downregulation induced by both xanthones. Analysis of cell viability and cell-death induction in SW480, HCT116, Caco-2, DLD1 and HT29 exposed to xanthones found cell-loss and activation of caspase in all cell lines except HT29 that do not have high FoxM1 protein levels. To determine the cellular mechanism of xanthone-induced FoxM1 loss, protein stability was analyzed by cycloheximide-chase experiments and showed reduction of FoxM1 stability by XB but not OH-XB. Destabilization was prevented by inhibiting proteasome activity using MG-132 and moderately by the lysosomal inhibitor bafilomycin A1 (baf A1). OH-XB had a stronger impact than XB on FoxM1 mRNA expression by qRT-PCR, and MG-132 positively affected FoxM1 protein level in OH-XB exposed cells even though no decrease in protein abundance had been induced by the xanthone. Additionally, the compound inhibited topoisomerase I causing DNA DSB and early cell cycle arrest. This may reduce FoxM1 gene expression, which may in turn compromise DNA repair and enhance xanthone-induced cell death. With regard to xanthone-induced cell death, MG-132 protected cultures from cell loss induced by both compounds, and baf A1 was active against these XB-induced effects. In summary, both destabilization of FoxM1 protein and topoisomerase I inhibition contribute to both XB and OH-XB cytotoxic activity albeit at different ratios.
Assuntos
DNA Topoisomerases Tipo I , Xantonas , Células CACO-2 , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Gleiquênias/química , Proteína Forkhead Box M1/genética , Humanos , Xantonas/toxicidadeRESUMO
Thioxanthone and its analogues, 2- or 4-isopropylthioxanthone, 2-chlorothioxanthone, 2,4-diethylthioxanthone (DETX) and xanthone, are used as photoinitiators of ultraviolet (UV) light-initiated curable inks. As these photoinitiators were found in numerous food/beverage products packaged in cartons printed with UV-cured inks, the cytotoxic effects and mechanisms of these compounds were studied in freshly isolated rat hepatocytes. The toxicity of DETX was greater than that of other compounds. DETX elicited not only concentration (0-2.0 mm)- and time (0-3 hours)-dependent cell death accompanied by the depletion of cellular adenosine triphosphate (ATP), and reduced glutathione (GSH) and protein thiol levels, but also the accumulation of GSH disulfide and malondialdehyde. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or N-acetyl-l-cysteine (NAC) at a concentration of 5.0 mm ameliorated DETX (1 mm)-induced cytotoxicity. Further, the exposure of hepatocytes to DETX resulted in the induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential, both of which were partially prevented by the addition of NAC. These results indicate that: (1) DETX-induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were, at least in part, ameliorated by the addition of fructose; and (3) GSH loss and/or ROS formation was prevented by NAC. Taken collectively, these results suggest that the onset of toxic effects caused by DETX may be partially attributable to cellular energy stress as well as oxidative stress.
Assuntos
Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Luz , Tioxantenos/toxicidade , Xantonas/toxicidade , Animais , Ratos , Ratos Endogâmicos F344RESUMO
We investigated alpha-mangostin (α-mangostin, α-MG), a xanthone natural product extracted from the pericarp of mangosteen (Garcinia mangostana), for its antifungal activities and possible mechanism against Colletotrichum gloeosporioides, which causes mango anthracnose. The results demonstrated that α-MG had a relatively high in vitro inhibitory activity against C. gloeosporioides among 20 plant pathogenic fungi. The median effective concentration (EC50) values of α-MG against mycelial growth were nearly 10 times higher than those of spore germination inhibition for both strains of C. gloeosporioides, the carbendazim-sensitive (CBD-s) and carbendazim-resistant (CBD-r). The results suggested that α-MG exhibited a better inhibitory effect on spore germination than on the mycelial growth of C. gloeosporioides. Further investigation indicated that the protective effect could be superior to the therapeutic effect for mango leaves for scab development. The morphological observations of mycelium showed that α-MG caused the accumulation of dense bodies. Ultrastructural observation further revealed that α-MG caused a decrease in the quantity and shape of the swelling of mitochondria in the mycelium cells of C. gloeosporioides. In addition, bioassays disclosed that the inhibitory activity of α-MG on spore germination was reduced by adding exogenous adenosine triphosphate (ATP). These results suggested that the mode of action of α-MG could be involved in the destruction of mitochondrial energy metabolism. The current study supports α-MG as a natural antifungal agent in crop protection.
Assuntos
Antifúngicos/farmacologia , Colletotrichum/efeitos dos fármacos , Xantonas/farmacologia , Trifosfato de Adenosina/farmacologia , Antifúngicos/química , Colletotrichum/ultraestrutura , Testes de Sensibilidade Microbiana , Micélio/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Micélio/ultraestrutura , Folhas de Planta/química , Esporos Fúngicos/efeitos dos fármacos , Xantonas/química , Xantonas/toxicidadeRESUMO
BACKGROUND/AIMS: Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported to be a potential novel antitumor drug. Whether GA inhibits putative cancer stem cells (CSCs), which are considered to be the major cause of cancer treatment failure, remains largely unknown. This study investigated whether GA inhibits the CSCs of colorectal cancer (CRC) and its possible mechanisms. METHODS: We performed CCK8 and tumor sphere formation assays, percentage analysis of both side population and CD133+CD44+ cells, and the detection of stem cells markers, in order to assess the role of GA in inhibiting the stem celllike features of CRC. An mRNA microarray was performed to identify the downstream gene affected by GA and rescue assays were performed to further clarify whether the downstream gene is involved in the GA induced decrease of the stem cell-like CRC population. CRC cells were engineered with a CSC detector vector encoding GFP and luciferase (Luc) under the control of the Nanog promoter, which were utilized to investigate the effect of GA on putative CSC in human tumor xenograft-bearing mice using in vivo bioluminescence imaging. RESULTS: Our results showed that GA significantly reduced tumor sphere formation and the percentages of side population and CD133+CD44+ cells, while also decreasing the expression of stemness and EMT-associated markers in CRC cells in vitro. GA killed stem-like CRC cells by upregulating the expression of ZFP36, which is dependent on the inactivation of the EGFR/ ERK signaling pathway. GFP+ cells harboring the PNanog-GFP-T2A-Luc transgene exhibited CSC characteristics. The in vivo results showed that GA significantly inhibited tumor growth in nude mice, accompanied by a remarkable reduction in the putative CSC number, based on whole-body bioluminescence imaging. CONCLUSION: These findings suggest that GA significantly inhibits putative CSCs of CRC both in vitro and in vivo by inhibiting the activation of the EGFR/ ERK/ZFP36 signaling pathway and may be an effective drug candidate for anticancer therapies.
Assuntos
Apoptose/efeitos dos fármacos , Tristetraprolina/metabolismo , Regulação para Cima/efeitos dos fármacos , Xantonas/toxicidade , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Tristetraprolina/genética , Xantonas/uso terapêuticoRESUMO
BACKGROUND/AIMS: α-mangostin has anti-carcinogenic effects against several cancers. We investigated the molecular mechanism of this compound on the metastasis of human renal carcinoma cells. METHODS: Cell viability was measured using the MTT assay, and cell cycle distribution using flow cytometry. A Matrigel-based assay was used to measure in vitro cell migration and invasion. MAPK-related proteins and matrix metalloproteinase (MMP)-9 and MMP-2 expression were measured by western blotting, and MMP2/-9 activities were determined by gelatin zymography. RT-qPCR and a luciferase assay were used to examine the transcriptional activity of MMP-9. RESULTS: α-mangostin inhibited the migration and invasion of RCC cells in a dose-dependent manner, but had no evident cytotoxic effects. Treatment of 786-O cells with α-mangostin inhibited activation of MEK and ERK. Treatment with a specific MEK inhibitor (U0126) enhanced the inhibitory effects of α-mangostin on cell migration and invasion, and the phosphorylation of ERK and MEK. Moreover, α-mangostin inhibited the expression of the MMP-9 mRNA levels as well as the activity of MMP-9 promoter, and these suppressive effects were further enhanced by U0126. CONCLUSIONS: Our results suggest that α-mangostin suppresses cell migration and invasion via MEK/ERK/MMP9 pathway, and might be a promising anti-metastatic agent against human renal cell carcinoma.
Assuntos
Anticarcinógenos/toxicidade , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Xantonas/toxicidade , Anticarcinógenos/química , Butadienos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Nitrilas/farmacologia , Xantonas/químicaRESUMO
BACKGROUND/AIMS: Glioma is the most devastating cancer in the brain and has a poor prognosis in adults. Therefore, there is a critical need for novel therapeutic strategies for the management of glioma patients. Isogambogenic acid, an active compound extracted from the Chinese herb Garcinia hanburyi, induces autophagic cell death. METHODS: Cell viability was detected with MTT assays. Cell proliferation was assessed using the colony formation assay. Morphological changes associated with autophagy and apoptosis were tested by TEM and Hoechst staining, respectively. The apoptosis rate was measured by flow cytometry. Western blot, immunofluorescence and immunohistochemical analyses were used to detect protein expression. U87-derived xenografts were established for the examination of the effect of isogambogenic acid on glioma growth in vivo. RESULTS: Isogambogenic acid induced autophagic death in U87 and U251 cells, and blocking late-stage autophagy markedly enhanced the antiproliferative activities of isogambogenic acid. Moreover, we observed the activation of AMPK-mTOR signalling in isogambogenic acid-treated glioma cells. Furthermore, the activation of AMPK or the inhibition of mTOR augmented isogambogenic acid-induced autophagy. Inhibition of autophagy attenuated apoptosis in isogambogenic acid-treated glioma cells. Finally, isogambogenic acid inhibited the growth of U87 glioma in vivo. CONCLUSION: Isogambogenic acid inhibits the growth of glioma via activation of the AMPK-mTOR signalling pathway, which may provide evidence for future clinical applications in glioma therapy.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Xantonas/toxicidade , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Xantonas/química , Xantonas/uso terapêuticoRESUMO
Jacareubin is a xanthone isolated from the heartwood of Calophyllum brasiliense with antibacterial and gastroprotective properties and the intention for clinical use as an anti-cancer treatment (due to the similar chemical structure to other anti-neoplastic drugs) requires an investigation of whether this compound can generate adverse effects on non-transformed cells. Jacareubin (0.5-1000µM in DMSO) was more cytotoxic on phytohemagglutinin (PHA)-stimulated normal human peripheral blood mononuclear cells (PBMCs; IC50 at 72h by MTT: 85.9µM) than on G0 phase-PBMCs (IC50 315.6µM) using trypan blue exclusion and formazan metabolism assays. Jacareubin had lower toxicity on PBMCs than Taxol (1µM). Jacareubin presented cytostatic activity because it inhibited PHA-stimulated PBMCs proliferation (from 2.5µM; CFSE dilution and replication index). Jacareubin induced PBMCs arrest in G0/G1 phase of the cell cycle (from 5µM) as evaluated by DNA content. Moreover, Jacareubin generated genotoxicity by breaking DNA strands selectively in PHA-stimulated PBMCs (from 5µM) rather than on resting PBMCs using the single-cell gel electrophoresis assay and increasing the frequency of micronucleated (MN) PBMCs in vitro (from 5µM) and frequency of hypodiploid cells (from 10µM). When 100mg/kg Jacareubin was injected i.p. into mice (a fifth of the LD50; 0.548g/kg. Approximately to 300µM in vitro), we observe no increase in the MN level in bone marrow cells. Jacareubin can be consider for further anti-tumoural activity due to its preferential genotoxic, cytotoxic and cytostatic actions on proliferating cells rather than on resting cells and the lack of in vivo genotoxicity.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Calophyllum/química , Dano ao DNA , Eritrócitos/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Extratos Vegetais/farmacologia , Xantonas/farmacologia , Adulto , Aneuploidia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Eritrócitos/patologia , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/patologia , Masculino , Camundongos Endogâmicos BALB C , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Medição de Risco , Fatores de Tempo , Xantonas/isolamento & purificação , Xantonas/toxicidade , Adulto JovemRESUMO
We developed a nitroreductase responsive theranostic probe 1; it comprises biotinylated rhodol in conjunction with p-nitrobenzyl functionality. The probe 1 showed a remarkable fluorescence 'turn-on' signal in the presence of nitroreductase under physiological conditions. The probe is considerably stable within a wide biological pH range (6-8) and also is very sensitive toward a reducing micro-environment e.g. liver microsome. Further, it enables providing cellular and in vivo nematode images in a reducing microenvironment.
Assuntos
Biotina/análogos & derivados , Biotina/farmacologia , Corantes Fluorescentes/farmacologia , Hipóxia/diagnóstico por imagem , Nitrorredutases/metabolismo , Xantonas/farmacologia , Animais , Biotina/síntese química , Biotina/toxicidade , Caenorhabditis elegans , Linhagem Celular Tumoral , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Humanos , Lepidópteros , Limite de Detecção , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/toxicidade , Ratos , Nanomedicina Teranóstica , Xantonas/síntese química , Xantonas/química , Xantonas/toxicidadeRESUMO
The benefits of α-mangostin for various tissues have been reported, but its effect on the heart has not been clarified. This study aimed to evaluate the effects of α-mangostin on cardiac function. Using a cardiac sarcoplasmic reticulum (SR) membrane preparation, α-mangostin inhibited SR Ca2+ -ATPase activity in a dose-dependent manner (IC50 of 6.47 ± 0.7 µM). Its suppressive effect was specific to SR Ca2+ -ATPase but not to myofibrillar Ca2+ -ATPase. Using isolated cardiomyocytes, 50 µM of α-mangostin significantly increased the duration of cell relengthening and increased the duration of Ca2+ transient decay, suggesting altered myocyte relaxation. The relaxation effect of α-mangostin was also supported in vivo after intravenous infusion. A significant suppression of both peak pressure and rate of ventricular relaxation (-dP/dt) relative to DMSO infusion was observed. The results from the present study demonstrated that α-mangostin exerts specific inhibitory action on SR Ca2+ -ATPase activity, leading to myocardial relaxation dysfunction.
Assuntos
Diástole/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Xantonas/toxicidade , Animais , Ventrículos do Coração/fisiopatologia , Masculino , Coelhos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
Gambogic acid (GA) has been proven to be a potent chemotherapeutic agent for the treatment of lung cancer in clinical trials. However, GA is limited in its therapeutic value by properties such as poor water solubility and low chemical stability. In clinical trials, cationic arginine (Arg) was added to solubilize GA, and this may also cause other side effects. Here, we have designed and developed a more efficient human serum albumin (HSA)-based delivery system for GA with low toxicity which helps improve its solubility, chemical stability and increases its antitumor efficacy. The GA-HSA nanoparticles (NPs) were prepared by albumin-bound (nabTM) technology, with a particle size of 135.2 ± 35.03 nm, a zeta potential of -21.81 ± 1.24 mV, and a high entrapment efficiency. Compared with GA-Arg solution, the physical and chemical stability of the NPs were improved when stored at pH 7.4 in PBS or freeze-dried. The in vitro drug release showed that GA-HSA NPs had a more sustained release than GA-Arg solution. Furthermore, HSA NPs improved the therapeutic efficacy of GA and were less toxic compared with GA-Arg solution in A549-bearing mice. Therefore, this delivery system is a promising polymeric carrier for GA when used for tumor therapy.
Assuntos
Portadores de Fármacos/toxicidade , Neoplasias Pulmonares/tratamento farmacológico , Albumina Sérica/toxicidade , Carga Tumoral/efeitos dos fármacos , Xantonas/toxicidade , Células A549 , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/toxicidade , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos SCID , Nanopartículas/química , Tamanho da Partícula , Albumina Sérica/química , Resultado do Tratamento , Carga Tumoral/fisiologia , Xantonas/químicaRESUMO
Total of 22 caged xanthones were subjected to susceptibility testing of global epidemic MRSA USA300. Natural morellic acid showed the strongest potency (MIC of 12.5µM). However, its potent toxicity diminishes MRSA therapeutic potential. We synthetically modified natural morellic acid to yield 13 derivatives (3a-3m). Synthetically modified 3b retained strong potency in MRSA growth inhibition, yet the toxicity was 20-fold less than natural morellic acid, permitting the possibility of using caged xanthones for MRSA therapeutic.
Assuntos
Antibacterianos/farmacologia , Compostos Heterocíclicos de Anel em Ponte/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Xantonas/farmacologia , Células A549 , Aminoácidos/síntese química , Aminoácidos/farmacologia , Aminoácidos/toxicidade , Ampicilina/farmacologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Aderência Bacteriana/efeitos dos fármacos , Garcinia , Células HEK293 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/isolamento & purificação , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/toxicidade , Compostos Heterocíclicos de Anel em Ponte/síntese química , Compostos Heterocíclicos de Anel em Ponte/isolamento & purificação , Compostos Heterocíclicos de Anel em Ponte/toxicidade , Humanos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana , Oxacilina/farmacologia , Xantonas/síntese química , Xantonas/química , Xantonas/isolamento & purificação , Xantonas/toxicidadeRESUMO
The aims of this study were to develop α-mangostin liposomes as well as to evaluate their physicochemical properties and cytotoxic activity. α-Mangostin liposomes were prepared using the reverse-phase evaporation method with lipid composition of phosphatidylcholine to cholesterol at 7 : 3 molar ratios; their physicochemical properties and antiproliferative activity were assessed using an MTT assay in four human carcinoma cells [that is, human lung epithelial carcinoma (Calu-3), human colon carcinoma (HT-29), human breast carcinoma (MCF-7), and human colon carcinoma (Caco-2) cells], and two human normal cells [that is, human dermal fibroblasts (HDF) and human adult low-calcium elevated temperature (HaCaT) keratinocytes]. Determinations of morphological changes and oligonucleosomal DNA fragments were also carried out. The liposomal dispersions obtained were unilamellar vesicles as confirmed by cryotransmission and freeze-fracture electron microscopy with a particle size of 114 nm and a ζ potential of -2.56 mV. The P-NMR spectra showed that α-mangostin molecules orientated in the phospholipid bilayer membrane. The α-mangostin could appreciably be entrapped with an efficiency and loading of 81 and 4%, respectively. The antiproliferative activity of α-mangostin liposomes in various cancer and normal cells showed a dose-dependent inhibition in all treated cell lines. The antiproliferative effect of α-mangostin liposomes was found to be associated with apoptosis, with differences in sensitivity among the cell lines treated.
Assuntos
Antineoplásicos/administração & dosagem , Xantonas/administração & dosagem , Antineoplásicos/química , Antineoplásicos/toxicidade , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Lipossomos , Espectroscopia de Ressonância Magnética , Xantonas/química , Xantonas/toxicidadeRESUMO
This study aimed to fabricate mucoadhesive electrospun nanofiber mats containing α-mangostin for the maintenance of oral hygiene and reduction of the bacterial growth that causes dental caries. Synthesized thiolated chitosan (CS-SH) blended with polyvinyl alcohol (PVA) was selected as the mucoadhesive polymer. α-Mangostin was incorporated into the CS-SH/PVA solution and electrospun to obtain nanofiber mats. Scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, and tensile strength testing were used to characterize the mats. The swelling degree and mucoadhesion were also determined. The nanofiber mats were further evaluated regarding their α-mangostin content, in vitro α-mangostin release, antibacterial activity, cytotoxicity, in vivo performance, and stability. The results indicated that the mats were in the nanometer range. The α-mangostin was well incorporated into the mats, with an amorphous form. The mats showed suitable tensile strength, swelling, and mucoadhesive properties. The loading capacity increased when the initial amount of α-mangostin was increased. Rapid release of α-mangostin from the mats was achieved. Additionally, a fast bacterial killing rate occurred at the lowest concentration of nanofiber mats when α-mangostin was added to the mats. The mats were less cytotoxic after use for 72 h. Moreover, in vivo testing indicated that the mats could reduce the number of oral bacteria, with a good mouth feel. The mats maintained the amount of α-mangostin for 6 months. The results suggest that α-mangostin-loaded mucoadhesive electrospun nanofiber mats may be a promising material for oral care and the prevention of dental caries.
Assuntos
Antibacterianos/administração & dosagem , Quitosana/química , Cárie Dentária/prevenção & controle , Portadores de Fármacos , Mucosa Bucal/metabolismo , Nanofibras , Álcool de Polivinil/química , Compostos de Sulfidrila/química , Xantonas/administração & dosagem , Adesividade , Administração Bucal , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/toxicidade , Varredura Diferencial de Calorimetria , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quitosana/análogos & derivados , Quitosana/metabolismo , Quitosana/toxicidade , Cárie Dentária/microbiologia , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Cinética , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Nanotecnologia/métodos , Álcool de Polivinil/metabolismo , Álcool de Polivinil/toxicidade , Solubilidade , Streptococcus mutans/efeitos dos fármacos , Streptococcus mutans/crescimento & desenvolvimento , Streptococcus sanguis/efeitos dos fármacos , Streptococcus sanguis/crescimento & desenvolvimento , Compostos de Sulfidrila/metabolismo , Compostos de Sulfidrila/toxicidade , Suínos , Resistência à Tração , Difração de Raios X , Xantonas/química , Xantonas/metabolismo , Xantonas/toxicidadeRESUMO
Glyphosate is the most widely used herbicide in the world with application in agriculture, forestry, industrial weed control, garden and aquatic environments. However, its use is highly controversial for the possible impact on not-target organisms, such as amphibians, which are vanishing at an alarming and rapid rate. Due to the high solubility in water and ionic nature, the glyphosate requires of surfactants to increase activity. In addition, for the control of coca (Erythroxylum coca) and agricultural weeds in Colombia, formulated glyphosate is mixed and sprayed with the adjuvant Cosmo-Flux 411F to increase the penetration and activity of the herbicide. This study evaluates the acute toxic and sublethal effects (embryonic development, tadpole body size, tadpole swimming performance) of the mixture of the formulated glyphosate Roundup Active and Cosmo-Flux 411F to anuran embryos and tadpoles of four Colombian species under 96h laboratory standard tests and microcosms, which are more similar to field conditions as they include soil, sand and macrophytes. In the laboratory, embryos and tadpoles of Engystomops pustulosus were the most tolerant (LC50 = 3904 microg a.e./L; LC50=2 799 pg a.e./L, respectively), while embryos and tadpoles of Hypsiboas crepitans (LC50=2 203 microg a.e./L; LC50=1424 microgg a.e./L, respectively) were the most sensitive. R. humboldti and R. marina presented an intermediate toxicity. Embryos were significantly more tolerant to the mixture than tadpoles, which could be likely attributed to the exclusion of chemicals by the embryonic membranes and the lack of organs, such as gills, which are sensitive to surfactants. Sublethal effects were observed for the tadpole body size, but not for the embryonic development and tadpole swimming performance. In microcosms, no toxicity (LC50 could not be estimated), or sublethal responses were observed at concentrations up to fourfold (14.76 kg glyphosate a.e./ha) the highest field application rate of 3.69 kg glyphosate a.e./ha. Thus, toxicity was less in the microcosms than in laboratory tests, which may be attributed to the presence of sediments and organic matter which rapidly adsorb glyphosate and surfactants such as POEA. It is concluded that the mixture of glyphosate (Roundup Active) and Cosmo-Flux*411F, as used in the field, has a negligible toxic effect to embryos and tadpoles of the species tested in this study.
Assuntos
Anuros , Glicina/análogos & derivados , Herbicidas/toxicidade , Larva/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Xantonas/toxicidade , Animais , Anuros/classificação , Colômbia , Glicina/toxicidade , Dose Letal Mediana , Testes de Toxicidade Aguda , GlifosatoRESUMO
A new compound, named banganxanthone C (=12-(1,1-dimethylprop-2-en-1-yl)-5,10-dihydroxy-9-methoxy-2-methyl-2-(4-methylpent-3-en-1-yl)-2H,6H-pyrano[3,2-b]xanthen-6-one; 4), together with five known compounds, were isolated from the leaves of Garcinia polyantha. The structures of the compounds were elucidated on the basis of 1D- and 2D-NMR spectroscopy. Among the known compounds, two were xanthones, one was a pentacyclic triterpene, one sterol, and one benzophenone derivative. Isoxanthochymol (2) and 4-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-1,5,8-trihydroxy-3-methoxy-9H-xanthen-9-one (3) exhibited significant antiproliferative activity against the leukemia cell line TPH-1 with IC50 inhibition values of 1.5 and 2.8â µg/ml, respectively. The cytotoxic activity was found to be related to apoptosis induction.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Clusiaceae/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Folhas de Planta/química , Xantonas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação , Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Humanos , Concentração Inibidora 50 , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Xantonas/química , Xantonas/isolamento & purificação , Xantonas/toxicidadeRESUMO
A recently synthesized aminated 3,4-dioxygenated xanthone (Xantifoul2) was found to have promising antifouling (AF) effects against the settlement of the macrofouler Mytilus galloprovincialis larvae. Preliminary assessment indicated that Xantifoul2 has reduced ecotoxicological impacts: e.g., being non-toxic to the marine crustacea Artemia salina (<10 % mortality at 50 µM) and showing low bioconcentration factor in marine organisms. In order to meet the EU Biocidal Product Regulation, a preliminary hazard assessment of this new nature-inspired antifouling (NIAF) agent was conducted in this work. Xantifoul2 did not affect the swimming ability of the planktonic crustacean Daphnia magna, the growth of the diatom Phaeodactylum tricornutum, and the cellular respiration of luminescent Gram-negative bacteria Vibrio fischeri, supporting the low toxicity towards several non-target marine species. Regarding human cytotoxicity, Xantifoul2 did not affect the cell viability of retinal human cells (hTERT-RPE-1) and lipidomic studies revealed depletion of lipids involved in cell death, membrane modeling, lipid storage, and oxidative stress only at a high concentration (10 µM). Accelerated degradation studies in water were conducted under simulated sunlight to allow the understanding of putative transformation products (TPs) that could be generated in the aquatic ecosystems. Both Xantifoul2 and photolytic-treated Xantifoul2 in the aqueous matrix were therefore evaluated on several nuclear receptors (NRs). The results of this preliminary hazard assessment of Xantifoul2, combined with the high degradation rates in water, provide strong evidence of the safety of this AF agent under the evaluated conditions, and provide the support for future validation studies before this compound can be introduced in the market.
Assuntos
Incrustação Biológica , Incrustação Biológica/prevenção & controle , Animais , Poluentes Químicos da Água/toxicidade , Aliivibrio fischeri/efeitos dos fármacos , Xantonas/toxicidade , Mytilus/efeitos dos fármacos , Mytilus/fisiologia , Diatomáceas/efeitos dos fármacos , Humanos , Daphnia/efeitos dos fármacos , Daphnia/fisiologia , Artemia/efeitos dos fármacosRESUMO
A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED(50) value of 47.57 mg/kg in MES (mice, ip, 1h after administration) and at the same time its TD(50) was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD(50)/ED(50)) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED(50) values in MES test (mice, ip) ranged 80-110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found.
Assuntos
Anticonvulsivantes/química , Xantonas/química , Animais , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/toxicidade , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Eletrochoque , Injeções Intraperitoneais , Camundongos , Neurônios/efeitos dos fármacos , Pentilenotetrazol/uso terapêutico , Pentilenotetrazol/toxicidade , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Relação Estrutura-Atividade , Xantonas/uso terapêutico , Xantonas/toxicidadeRESUMO
The binding mode and affinity of isoeuxanthone (1,6-dihydroxyxanthone) (1) and its piperidinyl derivative (1-hydroxy-6-(2-(1-piperidinyl)ethoxy)xanthone) (2) with calf thymus DNA were studied using absorption spectroscopy, fluorescence spectroscopy, circular dichroism (CD) spectroscopy and viscosity measurements. Results indicate that the two xanthones can intercalate into the DNA base pairs by the plane of xanthone ring and the binding affinity of the piperidinylethoxy substituted xanthone 2 is stronger than 1. In addition, the cytotoxic effects of both compounds were evaluated with the human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using acid phosphatase assay. Analyses show that the piperidinylethoxy substituted xanthone exhibits more effective cytotoxic activity than isoeuxanthone against the two cancer cells. The effects on the inhibition of tumor cells in vitro agree with the studies of DNA-binding.
Assuntos
Antineoplásicos/química , Piperidinas/química , Xantonas/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , DNA/metabolismo , Células HeLa , Células Hep G2 , Humanos , Espectrofotometria Ultravioleta , Xantonas/metabolismo , Xantonas/toxicidadeRESUMO
Gambogic acid (GA) has been reported as a potent apoptosis inducer. Previously, we have reported chemical modification at C(34) and C(39) of GA, leading to some agents with improved activity. To investigate the further structure-activity relationship (SAR) and preliminary mechanism of GA activity, a series of derivatives with modified prenyl side chains of GA were synthesized and evaluated. Most of the derivatives showed potent inhibitory activities against the proliferation of HepG2 and A549 cell lines. Compound 4 was selected for further mechanistic studies due to its outstanding activity. It was established that 4 induces the apoptosis of HepG2 cells by using Annexin-V/PI double staining and Western blot assay, thus, compound 4 can serve as a promising lead compound for the development of novel apoptosis in anticancer treatment.