Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.667
Filtrar
1.
Proc Natl Acad Sci U S A ; 117(24): 13730-13739, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482869

RESUMO

Merkel cell carcinoma (MCC) is a lethal skin cancer that metastasizes rapidly. Few effective treatments are available for patients with metastatic MCC. Poor intratumoral T cell infiltration and activation are major barriers that prevent MCC eradication by the immune system. However, the mechanisms that drive the immunologically restrictive tumor microenvironment remain poorly understood. In this study, we discovered that the innate immune regulator stimulator of IFN genes (STING) is completely silenced in MCCs. To reactivate STING in MCC, we developed an application of a human STING mutant, STINGS162A/G230I/Q266I, which we found to be readily stimulated by a mouse STING agonist, DMXAA. This STING molecule was efficiently delivered to MCC cells via an AAV vector. Introducing STINGS162A/G230I/Q266I expression and stimulating its activity by DMXAA in MCC cells reactivates their antitumor inflammatory cytokine/chemokine production. In response to MCC cells with restored STING, cocultured T cells expressing MCPyV-specific T cell receptors (TCRs) show increased cytokine production, migration toward tumor cells, and tumor cell killing. Our study therefore suggests that STING deficiency contributes to the immune suppressive nature of MCCs. More importantly, DMXAA stimulation of STINGS162A/G230I/Q266I causes robust cell death in MCCs as well as several other STING-silenced cancers. Because tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive responses, our finding indicates that targeted delivery and activation of STINGS162A/G230I/Q266I in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-deficient cancers.


Assuntos
Carcinoma de Célula de Merkel/imunologia , Proteínas de Membrana/imunologia , Neoplasias Cutâneas/imunologia , Carcinoma de Célula de Merkel/genética , Linhagem Celular Tumoral , Humanos , Imunidade Inata , Proteínas de Membrana/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/genética , Xantonas/farmacologia
2.
Environ Toxicol ; 35(10): 1070-1081, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32420661

RESUMO

Non-small cell lung cancer (NSCLC) is often complicated by pulmonary infection, which affects treatment and prognosis. Bacterial lipopolysaccharide (LPS) is an effective stimulator of inflammatory cytokine production, and previous studies have reported that LPS promotes tumor invasion and metastasis. Mangiferin is a plant-derived C-glucosylxanthone with many biological activities, such as antioxidation and anti-inflammation. This research mainly explored the mechanism of its antitumor activities on LPS-induced A549, NCI-H460, and NCI-H520 NSCLC cells. We determined that mangiferin exhibits growth inhibiting activity against LPS-induced NSCLC cells through the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. In addition, mangiferin reversed the LPS-induced downregulation of E-cadherin (epithelial marker); conversely, it significantly inhibited the expression of raised vimentin (mesenchymal markers). Moreover, the ability of NSCLC cells to migrate, as evidenced by the wound healing and transwell migration assays, and the expression of CXCR4 increased by LPS were significantly repressed by mangiferin. In addition, mangiferin markedly mediated protein levels of PER1 and NLRP3 in LPS-induced NSCLC cells and reduced the secretion of IL-1ß. These results indicate that mangiferin is not only a remarkable anti-inflammatory compound but also an antitumor agent; thus, it has the potential for being developed into anti-inflammatory and antitumor drugs in the future.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas Circadianas Period/genética , Xantonas/farmacologia , Células A549 , Antígenos CD/genética , Caderinas/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Humanos , Lipopolissacarídeos/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , RNA Interferente Pequeno/genética , Receptores CXCR4/genética , Transdução de Sinais , Vimentina/metabolismo
3.
Metabolism ; 107: 154228, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32289346

RESUMO

OBJECTIVE: Mangiferin (MF), a xanthonoid derived from Mangifera indica, has shown therapeutic effects on various human diseases including cancer, diabetes, and obesity. Nonetheless, the influence of MF on non-shivering thermogenesis and its underlying mechanism in browning remains unclear. Here, our aim was to investigate the effects of MF on browning and its molecular mechanisms in murine C3H10T1/2 mesenchymal stem cells (MSCs). MATERIALS/METHODS: To determine the function of MF on browning, murine C3H10T1/2 MSCs were treated with MF in an adipogenic differentiation cocktail and the thermogenic and correlated metabolic responses were assessed using MF-mediated signalling. Human adipose-derived MSCs were differentiated and treated with MF to confirm its role in thermogenic induction. RESULTS: MF treatment induced the expression of a brown-fat signature, UCP1, and reduced triglyceride (TG) in C3H10T1/2 MSCs. MF also induced the expression of major thermogenesis regulators: PGC1α, PRDM16, and PPARγ and up-regulated the expression of beiging markers CD137, HSPB7, TBX1, and COX2 in both murine C3H10T1/2 MSCs and human adipose-derived mesenchymal stem cells (hADMSC). We also observed that MF treatment increased the mitochondrial DNA and improved mitochondrial homeostasis by regulating mitofission-fusion plasticity via suppressing PINK1-PRKN-mediated mitophagy. Furthermore, MF treatment improved mitochondrial respiratory function by increasing mitochondrial oxygen consumption and expression of oxidative-phosphorylation (OXPHOS)-related proteins. Chemical-inhibition and gene knockdown experiments revealed that ß3-AR-dependent PKA-p38 MAPK-CREB signalling is crucial for MF-mediated brown-fat formation via suppression of mitophagy in C3H10T1/2 MSCs. CONCLUSIONS: MF promotes the brown adipocyte phenotype by suppressing mitophagy, which is regulated by PKA-p38MAPK-CREB signalling in C3H10T1/2 MSCs. Thus, we propose that MF may be a good browning inducer that can ameliorate obesity.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Mitofagia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Xantonas/farmacologia , Adipócitos Marrons/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C3H , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Proteínas Quinases/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Termogênese/genética , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos
4.
Life Sci ; 249: 117476, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32119962

RESUMO

Mangiferin is a well-known xanthone extracted from mango leaves (Mangifera indica Linn). Mangiferin is widely distributed in the bark, peel, leaf, seed, stalk, and kernel of mango and higher plants. The pharmacological properties of mangiferin, including its antioxidant, anticancer, antiaging, antiviral, hepatoprotective, analgesic, and immunomodulatory activities, have been described in several studies. We investigated the effect of mangiferin on isoproterenol-induced apoptosis. Experimental heart failure was induced in rats by intraperitoneal administration of isoproterenol (5 mg/kg) for 7 consecutive days. Rats were divided into five groups: group I (sham rats), group II (isoproterenol alone control), group III (isoproterenol + 25 mg/kg mangiferin), group IV (isoproterenol + 50 mg/kg mangiferin), and group V (isoproterenol + 0.0225 mg/kg digitalis as a positive control). Hemodynamic parameters and body weight, heart weight and liver weight, apoptosis induction, and caspase-3, Bax, and Bcl-2 protein levels were measured, and a histopathological analysis of cardiomyocytes was performed. In addition, apoptosis and protein expression of caspase-3, cleaved caspase-3, Bax, and Bcl-2 were measured in cardiac H9c2 cells. Mangiferin supplementation significantly increased heart rate and improved the maximum rate of decrease in left ventricular (LV) pressure, the maximum rate of increase in LV pressure, and LV systolic pressure. Mangiferin reduced inflammatory cell infiltration and the number of broken myocardial fibers, and decreased apoptosis in cardiomyocytes by reducing proteins levels of caspase-3 and Bax and increasing those of Bcl-2. Our findings suggest that mangiferin has a cardioprotective effect against isoproterenol-induced apoptosis in cardiomyocytes.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotônicos/farmacologia , Insuficiência Cardíaca/induzido quimicamente , Coração/efeitos dos fármacos , Xantonas/farmacologia , Animais , Cardiotônicos/administração & dosagem , Injeções Intraperitoneais , Isoproterenol/administração & dosagem , Isoproterenol/farmacologia , Ratos
5.
Molecules ; 25(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019180

RESUMO

Inflammation is the body's self-protective response to multiple stimulus, from external harmful substances to internal danger signals released after trauma or cell dysfunction. Many diseases are considered to be related to inflammation, such as cancer, metabolic disorders, aging, and neurodegenerative diseases. Current therapeutic approaches include mainly non-steroidal anti-inflammatory drugs and glucocorticoids, which are generally of limited effectiveness and severe side-effects. Thus, it is urgent to develop novel effective anti-inflammatory therapeutic agents. Xanthones, a unique scaffold with a 9H-Xanthen-9-one core structure, widely exist in natural sources. Till now, over 250 xanthones were isolated and identified in plants from the families Gentianaceae and Hypericaceae. Many xanthones have been disclosed with anti-inflammatory properties on different models, either in vitro or in vivo. Herein, we provide a comprehensive and up-to-date review of xanthones with anti-inflammatory properties, and analyzed their drug likeness, which might be potential therapeutic agents to fight against inflammation-related diseases.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Xantonas/química , Xantonas/farmacologia , Humanos , Relação Estrutura-Atividade
6.
Int J Nanomedicine ; 15: 735-747, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099362

RESUMO

Introduction: Gambogic acid (GA) is proved to have anti-tumor effects on gastric cancer. Due to poor solubility, non-specific biological distribution, toxicity to normal tissues and short half-life, it is hard to be applied into the clinic. To overcome these issues, we developed a thermosensitive and injectable hydrogel composed of hydroxypropyl cellulose, silk fibroin and glycerol, with short gelling time, good compatibility and sustained release, and demonstrated that the hydrogel packaged with gambogic acid nanoparticles (GA-NPs) and tumor-penetrating peptide iRGD could improve the anti-tumor activity. Methods: The Gelling time and micropore size of the hydrogels were regulated through different concentrations of glycerol. Controlled release characteristics of the hydrogels were evaluated with a real-time near-infrared fluorescence imaging system. Location of nanoparticles from different carriers was traced by confocal laser scanning microscopy. The in vivo antitumor activity of the hydrogels packaging GA-NPs and iRGD was evaluated by investigating tumor volume and tumor size. Results: The thermo-sensitive properties of hydrogels were characterized by 3-4 min, 37°C, when glycerol concentration was 20%. The hydrogels physically packaged with GA-NPs and iRGD showed higher fluorescence intensity than other groups. The in vivo study indicated that the co-administration of GA-NPs and iRGD by hydrogels had higher antitumor activity than the GA-loaded hydrogels and free GA combining with iRGD. Free GA group showed few antitumor effects. Compared with the control group, the body weight in other groups had no obvious change, and the count of leukocytes and hemoglobin was slightly decreased. Discussion: The hydrogel constructed iRGD and GA-NPs exerted an effective anti-tumor effect possibly due to retention effect, local administration and continuous sustained release of iRGD promoting the penetration of nanoparticles into a deep part of tumors. The delivery system showed little systemic toxicity and would provide a promising strategy to improve anti-gastric cancer efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Hidrogéis/química , Nanopartículas/química , Oligopeptídeos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Temperatura , Xantonas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Bombyx , Linhagem Celular Tumoral , Fibroínas/química , Glicerol/química , Humanos , Derivados da Hipromelose/química , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Porosidade , Neoplasias Gástricas/patologia , Distribuição Tecidual , Xantonas/farmacologia
7.
Hum Cell ; 33(2): 347-355, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32078151

RESUMO

Alpha-mangostin (α-mangostin) has been identified as a naturally occurring compound with potential anticancer properties. It can induce apoptosis and inhibit the growth and metastasis of cancer cells. Moreover, α-mangostin reduces the mechanical stiffness of lung cancer cells. The objective of this study was to determine the effect of α-mangostin on the mechanical stiffness of various cells, as well as cell viability. The following cell types were examined: human fibroblast TIG-1 cells, human cancerous HeLa cells, human embryonic kidney HEK293 cells, mouse macrophage RAW 264.7 cells, and human myeloblasts KG-1 cells. Cells were treated with α-mangostin, and then examined for cell viability, actin cytoskeletal structures, and surface mechanical stiffness using atomic force microscopy. α-Mangostin demonstrated cytotoxicity against TIG-1, HeLa, HEK293, and KG-1 cells, but not against RAW 264.7 cells. The cytotoxic effect of α-mangostin varies according to cell type. On the other hand, α-mangostin reduced the mechanical stiffness of all cell types, including RAW 264.7 cells. Upon treatment with α-mangostin, F-actin was slightly reduced but the actin cytoskeletal structures were little altered in these cells. Thus, reducing mechanical stiffness of animal cells is an inherent effect of α-mangostin. Our results show that α-mangostin is a naturally occurring compound with potential to change the actin cytoskeletal micro-structures and reduce the surface stiffness of various cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Fenômenos Biomecânicos/efeitos dos fármacos , Neoplasias/patologia , Xantonas/farmacologia , Animais , Células HeLa , Humanos , Camundongos , Células RAW 264.7
8.
Biomed Pharmacother ; 124: 109927, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31982725

RESUMO

According to cancer stem cell theory, only a limited number of self-renewing and cloning cells are responsible for tumor relapse after a period of remittance. The aim of the present study was to investigate the effects of Doxorubicin and α-Mangostin, two antiproliferative drugs, on both tumor bulk and stem cells in multicellular tumor spheroids originated from the luminal MCF-7 breast cancer cell line. A new and original fluorimetric assay was used to selectively measure the activity of the retinaldehyde-dependent isoenzymes of aldehyde dehydrogenase (RALDH), which are markers of a subpopulation of breast cancer stem cells. The administration of 5 µg/ml (12.2 µM) α-Mangostin for 48 h provoked: i) a marked disaggregation of the spheroids, leading to a doubling of their volume (p < 0.01), ii) a 40 % decrease in cell viability (p < 0.01), evaluated by the acid phosphatase assay, and iii) a reduction by more than 90 % of RALDH activity. By contrast, Doxorubicin given for 48 h in the range of 0.1-40 µM did not significantly reduce cell viability and caused only a modest modification of the spheroid morphology. Moreover, 40 µM Doxorubicin increased RALDH activity 2.5-fold compared to the untreated sample. When the two drugs were administered together using 5 µg/ml α-Mangostin, the IC50 of Doxorubicin referred to cell viability decreased six-fold and the RALDH activity was further reduced. In conclusion, the combined administration of Doxorubicin and α-Mangostin provoked a significant cytotoxicity and a remarkable inhibition of RALDH activity in MCF-7 tumor spheroids, suggesting that these drugs could be effective in reducing cell stemness in luminal breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Xantonas/farmacologia , Aldeído Desidrogenase/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Humanos , Concentração Inibidora 50 , Células MCF-7 , Retinaldeído/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Xantonas/administração & dosagem
9.
mSphere ; 5(1)2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915228

RESUMO

The cell wall-targeting echinocandin antifungals, although potent and well tolerated, are inadequate in treating fungal infections due to their narrow spectrum of activity and their propensity to induce pathogen resistance. A promising strategy to overcome these drawbacks is to combine echinocandins with a molecule that improves their activity and also disrupts drug adaptation pathways. In this study, we show that puupehenone (PUUP), a marine-sponge-derived sesquiterpene quinone, potentiates the echinocandin drug caspofungin (CAS) in CAS-resistant fungal pathogens. We have conducted RNA sequencing (RNA-seq) analysis, followed by genetic and molecular studies, to elucidate PUUP's CAS-potentiating mechanism. We found that the combination of CAS and PUUP blocked the induction of CAS-responding genes required for the adaptation to cell wall stress through the cell wall integrity (CWI) pathway. Further analysis showed that PUUP inhibited the activation of Slt2 (Mpk1), the terminal mitogen-activated protein (MAP) kinase in this pathway. We also found that PUUP induced heat shock response genes and inhibited the activity of heat shock protein 90 (Hsp90). Molecular docking studies predicted that PUUP occupies a binding site on Hsp90 required for the interaction between Hsp90 and its cochaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves a disruption of Hsp90 activity and the CWI pathway. Given the requirement of the Hsp90-Cdc37 complex in Slt2 activation, we suggest that inhibitors of this complex would disrupt the CWI pathway and synergize with echinocandins. Therefore, the identification of PUUP's CAS-potentiating mechanism has important implications in the development of new antifungal combination therapies.IMPORTANCE Fungal infections cause more fatalities worldwide each year than malaria or tuberculosis. Currently available antifungal drugs have various limitations, including host toxicity, narrow spectrum of activity, and pathogen resistance. Combining these drugs with small molecules that can overcome these limitations is a useful strategy for extending their clinical use. We have investigated the molecular mechanism by which a marine-derived compound potentiates the activity of the antifungal echinocandin caspofungin. Our findings revealed a mechanism, different from previously reported caspofungin potentiators, in which potentiation is achieved by the disruption of Hsp90 activity and signaling through the cell wall integrity pathway, processes that play important roles in the adaptation to caspofungin in fungal pathogens. Given the importance of stress adaptation in the development of echinocandin resistance, this work will serve as a starting point in the development of new combination therapies that will likely be more effective and less prone to pathogen resistance.


Assuntos
Caspofungina/farmacologia , Parede Celular/efeitos dos fármacos , Farmacorresistência Fúngica/genética , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Saccharomyces cerevisiae/genética , Sesquiterpenos/farmacologia , Xantonas/farmacologia , Antifúngicos/farmacologia , Parede Celular/metabolismo , Proteínas Fúngicas/genética , Simulação de Acoplamento Molecular , Saccharomyces cerevisiae/efeitos dos fármacos , Análise de Sequência de RNA
10.
PLoS One ; 15(1): e0227979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31995599

RESUMO

Techno-biofunctional characteristics of nanoemulsion and (nano)emulgel loaded with mangostin extracts were elucidated. Crude mangostins from mangosteen peels recovered by virgin coconut oil (VCO), mixed VCO and propylene glycol (PG), and pure PG were used. The extracts were loaded in the dispersed phase in the presence of mixed surfactants (Tween20/Span20) with a varying hydrophilic-lipophilic balance (HLB) from 10.2 to 15.1. Results showed that globular and uniformly distributed droplets of the nanoemulsion were observed. The small particle sizes (typically 18-62 nm) with the zeta potential of -39 to -54.5 mV were obtained when mixed emulsifiers with HLB values of 12.6 and 15.1 were employed. With HLB values of 12.6 and 15.1, nanoemulsions loaded with mangostin extracts prepared with mixed VCO-PG and pure PG-based extracts showed approximately a 2 to 3-fold lower droplet size diameter when compared with the VCO-based extract. For the stability test, all nanoemulsions were stable over three freeze-thaw cycles with some changes in pH, zeta potential, and droplet size. The DPPH● scavenging activity, H2O2 scavenging activity, reducing power and antibacterial activities (E. coli and S. aureus) of the nanoemulsions were greater than their corresponding bulk extracts. Nanoemulgels produced by embedding the nanoemulsions in a hydrogel matrix was homogeneous and creamy yellow-white in appearance. The nanoemulgels had a higher mangostin release (87-92%) than their normal emulgels (74-78%). Therefore, this study presented the feasibility of nanoemulsions and nanoemulgels loaded with mangostin extracts as a promising delivery system for bioactive polyphenol in food supplements, pharmaceuticals and cosmetics.


Assuntos
Antibacterianos/química , Nanopartículas/química , Extratos Vegetais/farmacologia , Xantonas/química , Antibacterianos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Óleo de Coco/química , Emulsões/química , Emulsões/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/patogenicidade , Depuradores de Radicais Livres/química , Peróxido de Hidrogênio/química , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Picratos/química , Picratos/farmacologia , Extratos Vegetais/química , Propilenoglicol/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Xantonas/farmacologia
11.
Chem Biodivers ; 17(2): e1900640, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31805214

RESUMO

The extract of the strain Aspergillus flavipes DL-11 exerted antibacterial activities against six Gram-positive bacteria. During the following bioassay-guided separation, ten diphenyl ethers (1-10), two benzophenones (11-12), together with two xanthones (13-14) were isolated. Among them, 4'-chloroasterric acid (1) was a new chlorinated diphenyl ether. Their structures were elucidated by extensive spectroscopic data analysis, including IR, HR-ESI-MS, NMR experiments, and by comparison with the literature data. All compounds showed moderate to strong antibacterial effects on different Gram-positive bacteria with MIC values that ranged from 3.13 to 50 µg/mL, but none of the compounds exhibited activity against Gram-negative bacteria Vibrio parahaemolyticus ATCC17802 (MIC>100 µg/mL). In particular, the MICs of some compounds are at the level of positive control.


Assuntos
Antibacterianos/química , Aspergillus/química , Benzofenonas/química , Éteres Fenílicos/química , Xantonas/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Aspergillus/metabolismo , Benzofenonas/isolamento & purificação , Benzofenonas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Conformação Molecular , Éteres Fenílicos/isolamento & purificação , Éteres Fenílicos/farmacologia , Xantonas/isolamento & purificação , Xantonas/farmacologia
12.
Crit Rev Food Sci Nutr ; 60(3): 494-514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30582344

RESUMO

The tumor is becoming a critical threat to our lives in these years. Searching for antitumor substances from natural products is a great interest of scientists. Cudrania tricuspidata (C. tricuspidata) is a regional plant containing 158 flavonoids and 99 xanthones, and others ingredients with favorable bioactivity. This review comprehensively analyzes the antitumor compounds from C. tricuspidata against different tumors, and 78 flavonoids plus xanthones are considered as underlying antineoplastic. Importantly, the structure of preylation groups is the primary source of antitumor activity among 45 flavonoids plus xanthones, which could be a direction of structural modification for a better antitumor ability. Additionally, the fruits are also preferable sources of antitumor compounds compared to the roots and barks due to the abundant isoflavones and sustainability. However, many studies only focused on the cells viability inhibition of the compounds, the underlying molecular mechanisms, and the intracellular targets remain ambiguous. In conclusion, C. tricuspidata has a great potential for anti-tumor prevention or therapy, but more attention should be paid to deeper research in vitro and in vivo models.


Assuntos
Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Flavonoides/farmacologia , Moraceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Xantonas/farmacologia , Antineoplásicos/química , Flavonoides/isolamento & purificação , Frutas/química , Humanos , Xantonas/isolamento & purificação
13.
Nat Prod Res ; 34(6): 868-871, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30417675

RESUMO

The present study explored the antidepressant-like activity of α-mangostin (α-MG) and the possible mechanism in this process in the tail suspension test (TST) in mice. The results revealed that α-MG (5 mg/kg, i.p.) exhibited markedly antidepressant-like activity, which could be reversed by pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist), p-chlorophenylalanine (an inhibitor of 5-HT synthesis). Meanwhile, α-MG also effectively increased the brain DA, 5-HT and GABA levels in mice exposed to TST, indicating that the antidepressant-like effect of α-MG might be mediated by the GABAergic, serotonergic and dopaminergic systems.[Formula: see text].


Assuntos
Antidepressivos/isolamento & purificação , Dopamina/metabolismo , Serotonina/metabolismo , Xantonas/farmacologia , Ácido gama-Aminobutírico/metabolismo , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Camundongos , Xantonas/uso terapêutico
14.
Mol Carcinog ; 59(2): 193-201, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31782573

RESUMO

Gartanin, a 4-prenylated xanthone, has been identified from the purple mangosteen fruit as a potent growth inhibitor of various cancer cell lines, including prostate cancer. However, much of Gartanin's anticancer mechanism remains unknown. We have discovered that Gartanin docked onto the regulatory subunit of the precursor cell-expressed developmentally downregulated 8 (NEDD8)-activating enzyme (NAE) complex and next to the NEDD8 binding complex, which leads to inhibit NEDD8 conjugations to both Cullin1 and Ubc12 in prostate cancer cell lines and Ubc12 NEDDylation in an in vitro assay. The S phase kinase-associated protein (Skp2) and F-box and WD-repeat domain-containing 2 (FBXW2), the NEDD8 family members of E3 ubiqutin ligases, were also downregulated and upregulated by Gartainin, respectively. Knock-down of NEDD8 expression by short harpin (Sh) RNAs blocked or attenuated these effects of Gartainin. Finally, Gartanin demonstrated its ability to inhibit growth of prostate cancer lines via autophagy initiation. Our data support that Gartanin is a naturally occurring NEDDylation inhibitor and deserves further investigation for prostate cancer prevention and treatment.


Assuntos
Autofagia/efeitos dos fármacos , Proteínas F-Box/metabolismo , Proteína NEDD8/antagonistas & inibidores , Neoplasias da Próstata/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Xantonas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas F-Box/genética , Humanos , Masculino , Proteína NEDD8/metabolismo , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Interferência de RNA
15.
Drug Des Devel Ther ; 13: 4239-4246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31853172

RESUMO

Purpose: Xanthones demonstrated an array of pharmacological activities via non-covalent DNA interaction and have been widely utilized in new drug research. The introduction of the polar 1,2,3-triazole ring located at the C3-position of xanthone has not been reported thus far. Methods: In the present study, a series of xanthone derivatives were designed, synthesized, and characterized through 1H NMR, 13C NMR, and MS. The methyl thiazolyl tetrazolium method was used to evaluate the cytotoxic activity of compounds. Furthermore, the structure-activity relationship and the potential mechanism of target compounds were investigated. Results: The IC50 showed that the inhibitory activity of 18 target compounds was higher than that of the original xanthone intermediate 4. In particular, compound 1j was the most active agent against A549 cancer cells (IC50 = 32.4 ± 2.2 µM). Moreover, apoptosis analysis indicated different contributions of early/late apoptosis to cell death for compounds 1h and 1j. The results of Western blotting analysis showed that compound 1j significantly increased the expression of caspase 3, Bax, and c-Jun N-terminal kinase, and regulated p53 to a better healthy state in cancer cells. Conclusion: We synthesized several derivatives of xanthone and evaluated their cytotoxicity. The evidence suggested that compound 1j possessed greater anticancer potential for further evaluations.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Xantonas/síntese química , Xantonas/farmacologia , Células A549 , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Xantonas/química
16.
Int J Mol Sci ; 20(21)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717777

RESUMO

The molecular chaperone heat shock protein 90 (Hsp90) is a current inhibition target for the treatment of diseases, including cancer. In humans, there are two major cytosolic isoforms of Hsp90 (Hsp90α and Hsp90ß). Hsp90α is inducible and Hsp90ß is constitutively expressed. Most Hsp90 inhibitors are pan-inhibitors that target both cytosolic isoforms of Hsp90. The development of isoform-selective inhibitors of Hsp90 may enable better clinical outcomes. Herein, by using virtual screening and binding studies, we report our work in the identification and characterisation of novel isoform-selective ligands for the middle domain of Hsp90ß. Our results pave the way for further development of isoform-selective Hsp90 inhibitors.


Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Xantonas/química , Sítios de Ligação , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Domínios Proteicos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Espectrometria de Fluorescência , Xantonas/farmacologia
17.
J Agric Food Chem ; 67(50): 13929-13938, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31674780

RESUMO

Lipid accumulation is a typical characteristic of nonalcoholic fatty liver disease (NAFLD). The inhibition of lipid accumulation is regarded as a potential treatment for NAFLD. In this study, we investigated the effects of γ-mangostin or α-mangostin on lipid accumulation in a cell model. Analysis of the inhibitory effects of γ-mangostin on lipid accumulation revealed that it downregulated NAFLD-related biochemical parameters and stimulated the SIRT1/LKB1/AMPK pathway. Consequently, it suppressed lipid synthesis and enhanced fatty acid oxidation. Moreover, we demonstrated that the blockage of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C abrogated the promoting effect of AMPK. Similar results were also observed for α-mangostin. The effects of α-mangostin on lipid accumulation were inferior to those of γ-mangostin. The differences in CPT1A activity might be originated from their different chemical structures. Our results suggested that γ-mangostin and α-mangostin can be exploited as potential candidates for NAFLD treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sirtuína 1/metabolismo , Xantonas/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas Serina-Treonina Quinases/genética , Sirtuína 1/genética
18.
J Orthop Surg Res ; 14(1): 325, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623650

RESUMO

BACKGROUND: TLR2 (Toll-like receptor 2) signaling and its downstream proinflammatory cytokines are considered to be important in the progression of peri-implantitis. A natural medicine, mangiferin has exhibited modulatory effect on TLR2 signaling and anti-inflammatory effects on different diseases. The objective of the present study is to investigate the effect of mangiferin on peri-implantitis and the potential mechanisms by administering this drug to an experimental peri-implantitis mouse model. METHODS: Maxillary left first, second, and third molars of mice were extracted, and dental implants were placed in the region of the maxillary left second molars. Then, peri-implantitis was induced by tying ligatures around implants, and mangiferin was given orally to the mice. After 6-week mangiferin treatment, bone loss around the implants was detected using micro-computerized tomography (micro-CT). Alveolar bone and inflammatory infiltrate in peri-implant tissues were examined using hematoxylin and eosin (H&E) staining. Production of interleukin-6 (IL6), a TLR2 downstream proinflammatory cytokine, in the tissue surrounding implants was measured using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis. IL6 protein expression and TLR2 signaling pathway activation in peri-implant tissues were detected using western blot analysis. RESULTS: Micro-CT demonstrated reduced bone loss in peri-implantitis upon mangiferin administration. Additionally, H&E staining showed more alveolar bone and less inflammatory infiltrate in peri-implant tissues after mangiferin application. Moreover, qRT-PCR analysis demonstrated lower levels of IL6 gene expression, and western blot analysis showed decreased protein expression of IL6 and TLR2, and suppressed phosphorylation of TLR2 downstream nuclear factor-κB, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase after mangiferin treatment. CONCLUSIONS: These results suggest the suppressive effect of mangiferin on bone damage and inflammatory infiltrate in peri-implantitis. These therapeutic effects may be associated with inhibited IL6 production and reduced TLR2 signaling activation in peri-implant tissues.


Assuntos
Peri-Implantite/tratamento farmacológico , Xantonas/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Peri-Implantite/metabolismo , Receptor 2 Toll-Like/metabolismo , Xantonas/farmacologia
19.
J BUON ; 24(4): 1581-1586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31646812

RESUMO

PURPOSE: Pancreatic cancer causes considerable mortality across the globe and the treatment options for pancreatic cancer are limited. Besides, the development of drug resistance among the pancreatic cancer cells makes it even difficult to manage. In this study the anticancer effects of mangiferin were examined against the Mia-PaCa2 gemcitabine-resistant pancreatic cancer cells. MATERIALS/METHODS: Cell proliferation was examined by MTT assay while as apoptosis was detected by fluorescent microscopy and western blot. Effects on cell cycle, reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were evaluated by flow cytometry. The fact that mangiferin induced autophagy was demonstrated by fluorescent microscopy in combination with western blot method. RESULTS: The results revealed that mangiferin inhibited the growth of the Mia-PaCa2 cells and exhibited an IC50 of 10 µM. Nonetheless, the toxic effects of mangiferin were less on the normal cells. Mangiferin induces apoptosis in the Mia-PaCa2 cells which was associated with enhancement of Bax/Bcl-2 ratio. Further investigations revealed that mangiferin triggered autophagy in the Mia-PaCa2 cells as evident from the elevated expressions of the LC3 II and Beclin-1. The antiproliferative effects of mangiferin were also accompanied by the generation of endogenous ROS and cell cycle arrest. Investigation of the effects of mangiferin on the invasion and migration of the Mia-PaCa2 cells showed that mangiferin suppressed the migration and invasion potential of the Mia-PaCa2 cells. CONCLUSIONS: These findings suggest that mangiferin could be utilised for the development of chemotherapy for pancreatic cancer provided further in depth experiments are carried out along with its toxicological studies.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Xantonas/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Potencial da Membrana Mitocondrial , Mitocôndrias/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo
20.
Int J Mol Sci ; 20(19)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569691

RESUMO

Xanthones are important chemical constituents of Garcinia xanthochymus and varied bioactivities including cytotoxicity. However, their anti-tumor mechanism has remained unknown. Here, we isolated and identified a new xanthone named garciniaxanthone I (1) and five known compounds from the bark of G. xanthochymus. Their structures were elucidated by NMR analysis and HRESIMS. The anti-proliferation activities of all isolated compounds were evaluated on four human tumor cell lines (HepG2, A549, SGC7901, MCF-7). The results demonstrated that the anti-proliferation activity of xanthone was related to the number and location of prenyl groups. We further found that garciniaxanthone I (GXI) could induce HepG2 apoptosis and enhance the expression of cleaved caspase-8, caspase-9, and caspase-3. GXI could also increase Bax level and concurrently reduce the overexpression of Bcl-2, Bcl-XL, Mcl-1, and surviving in HepG2 cells. Moreover, GXI could inhibit cell migration of HepG2 cells by inhibiting the expressions of MMP-7 and MMP-9. In summary, our study suggests that GXI could induce HepG2 apoptosis via the mitochondrial pathway and might become a lead compound for liver cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Garcinia/química , Mitocôndrias/efeitos dos fármacos , Casca de Planta/química , Extratos Vegetais/farmacologia , Xantonas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Mitocôndrias/metabolismo , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Xantonas/química , Xantonas/isolamento & purificação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA