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1.
Fitoterapia ; 139: 104411, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31705951

RESUMO

Eleven sesquiterpenoids including four new eudesmane sesquiterpenoids, solanoids A-D (1-4), and seven known compounds (5-11) were isolated from the herbs of Solanum lyratum. By analyzing the UV, MS and NMR data, the gross structures of all isolates were established. The absolute configurations of these new compounds were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. The in vitro cytotoxicity of all isolates against the hepatocellular carcinoma Hep3B and HepG2 cell lines was evaluated. Among them, compounds 7 and 11 exhibited moderate cytotoxicity against two cell lines.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Sesquiterpenos de Eudesmano/farmacologia , Solanum/química , Antineoplásicos Fitogênicos/isolamento & purificação , China , Células Hep G2 , Humanos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Sesquiterpenos de Eudesmano/isolamento & purificação
2.
Int J Mol Med ; 44(3): 1026-1038, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31524219

RESUMO

Lung cancer is one of the leading causes of cancer­associated mortality in China and globally. Gemcitabine (GEM), as a first­line therapeutic drug, has been used to treat lung cancer, but GEM resistance poses a major limitation on the efficacy of GEM chemotherapy. Alantolactone (ALT), a sesquiterpene lactone compound isolated from Inula helenium, has been identified to exert anticancer activity in various types of cancer, including breast, pancreatic, lung squamous and colorectal cancer. However, the underlying mechanisms of the anticancer activity of ALT in lung cancer remain to be fully elucidated. The present study aimed to determine whether ALT enhances the anticancer efficacy of GEM in lung cancer cells and investigated the underlying mechanisms. The cell viability was assessed with a Cell Counting Kit­8 assay. The cell cycle, apoptosis and the level of reactive oxygen species (ROS) were assessed by flow cytometry, and the expression of cell cycle­associated and apoptosis­associated proteins were determined by western blot analysis. The results demonstrated that ALT inhibited cell growth and induced S­phase arrest and cell apoptosis in A549 and NCI­H520 cells. Furthermore, ALT increased the level of ROS, inhibited the Akt/glycogen synthase kinase (GSK)3ß pathway and induced endoplasmic reticulum (ER) stress in A549 and NCI­H520 cells. Additionally, ALT treatment sensitized lung cancer cells to GEM. Analysis of the molecular mechanisms further revealed that ALT enhanced the anticancer effects of GEM via ROS­mediated activation of the Akt/GSK3ß and ER stress pathways. In conclusion, combined treatment with ALT and GEM may have potential as a clinical strategy for lung cancer treatment.


Assuntos
Desoxicitidina/análogos & derivados , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Lactonas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/química , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Lactonas/química , Neoplasias Pulmonares , Sesquiterpenos de Eudesmano/química
3.
Cells ; 8(7)2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323885

RESUMO

Neuroinflammation is a major cause of central nervous system (CNS) damage and can result in long-term disability and mortality. Therefore, the development of effective anti-neuroinflammatory agents for neuroprotection is vital. To our surprise, the naturally occurring molecule alantolactone (Ala) was reported to significantly inhibit tumor growth and metastasis as a result of its excellent anti-inflammatory effects. Thus, we proposed that it could also act as an anti-neuroinflammatory agent. Thus, in this study, a coculture system of BV2 cells and PC12 cells were used as an in vitro neuroinflammatory model to investigate the anti-neuroinflammatory mechanism of Ala. The results indicated that Ala downregulated the expression of proinflammatory factors by suppressing the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Further evaluation using a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model supported the conclusion that Ala could (1) alleviate cerebral ischemia-reperfusion injury; (2) reduce neurological deficits, cerebral infarct volume, and brain edema; and (3) attenuate the apoptosis and necrosis of neurons. In sum, Ala demonstrates anti-neuroinflammatory properties that contribute to the amelioration of CNS damage, and it could be a promising candidate for future applications in CNS injury treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos de Eudesmano/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lactonas/uso terapêutico , Masculino , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Ratos , Ratos Sprague-Dawley , Sesquiterpenos de Eudesmano/uso terapêutico
4.
Hum Exp Toxicol ; 38(10): 1132-1144, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31203647

RESUMO

BACKGROUND: Gastric cancer is a malignant tumor with high incidence rate and mortality rate. PURPOSE: In this study, we investigated the anti-cancer effect of alantolactone, a sesquiterpene lactone, on gastric cancer cell lines BGC-823 and SGC-7901. METHODS: BGC-823 and SGC-7901 cells were treated with different concentrations of alantolactone, Hoechst 33258 staining, flow cytometry, wound healing assay, invasion assay, colony forming assay, quantative polymerase chain reaction, and western blot analysis were used to evaluate the anticancer activity of alantolactone to gastric cancer. RESULTS: Alantolactone induced apoptosis of gastric cancer cells by regulating the expression of Bax, Bcl-2, and p53, which related to intrinsic apoptotic pathway, and suppressed colony formation, migration, and invasion by mediating the expression of matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9. Cell signaling pathway analysis showed that alantolactone enhanced the phosphorylation of p38 and decreased the translocation of nucleus p65, suggesting that the apoptosis-promoting and migration-suppressing effect of alantolactone might at least partially rely on regulating p38 mitogen-activated protein kinase (p38MAPK) pathway and nuclear factor-κB (NF-κB) pathway. CONCLUSIONS: Alantolactone can be used as a potential therapeutic agent for treating gastric cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Lactonas/farmacologia , NF-kappa B/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Humanos , Inula/química , Lactonas/isolamento & purificação , Sesquiterpenos de Eudesmano/isolamento & purificação , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
5.
Artif Cells Nanomed Biotechnol ; 47(1): 1961-1970, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31116036

RESUMO

Alantolactone (Ala), a major sesquiterpene lactone extracted from Inula helenium, exerts potent anti-tumour activities in various cancers. However, the underlying mechanism of such activities is still ambiguous. This study focused on evaluating the anti-tumour effects and molecular mechanisms of Ala on HepG2 cells. Our results demonstrated that Ala might inhibit cellular proliferation, induce G2/M phase arrest and apoptosis in HepG2 cells. Specifically, this study confirmed that Ala induced G2/M phase arrest by upregulating p21, downregulating cyclin A1 and cyclin B1, and promoting cellular apoptosis by increasing the expression of cleaved caspase-3 and PARP. Furthermore, Ala caused an increase in reactive oxygen species (ROS) level and inhibition of ROS production significantly prevented Ala-induced apoptosis. Interestingly, the accumulation of ROS, in turn, suppressed the downstream AKT signalling. Finally, mitophagy of Ala-treated HepG2 cells was observed by Mito/Lyso staining. Mitophagy was significantly inhibited by downregulation of the expression of PINK1 and Parkin proteins. The inhibition of mitophagy by a mitophagy inhibitor was found to markedly enhance Ala-mediated apoptosis and growth inhibition in HepG2 cells. Consequently, Ala induced cellular apoptosis via ROS-mediated suppression of AKT signalling and inhibition of PINK1-mediated mitophagy. Thus, Ala has potential to be used for the treatment of liver cancer.


Assuntos
Apoptose/efeitos dos fármacos , Lactonas/farmacologia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Fosfoproteínas/metabolismo
6.
Life Sci ; 227: 153-165, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31004657

RESUMO

AIMS: Alantolactone (ALT) is active component of natural product Inula helenium with a lot of pharmacological effects, including anti-tumor effect. The present work aimed to explore the antitumor effect of ALT in B cell acute lymphoblastic leukemia (B-ALL). MAIN METHODS: B-ALL cells were treated with various concentrations of ALT, and then trypan blue assay, Annexin V/PI staining assay, PI staining assay, western blot analysis were employed to measure the effect of ALT on viability, apoptosis and cell cycle in B-ALL cells. In addition, a synthetic bioinformatics method was used to predict the underlying mechanism of antitumor effect of ALT. Then Reactive Oxygen Species (ROS) probe Dihydroethidium (DHE) and 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) were used to detect accumulation of cellular ROS. Meanwhile, DNA damage was identified by 8-oxoG, p-ATM1987, γ-H2AX and comet assay. In addition, activity of glutathione reductase (GR), thioredoxin reductase (TrxR) and catalase were measured and overexpressed in SEM and RS4;11 cells to study the inhibition on these enzymes. Finally, B-ALL NOD-SCID mouse model was used to test its performance in vivo. KEY FINDINGS: ALT showed good antitumor effect in B-ALL in vivo and in vitro through inducing ROS overload, which led to DNA damage. In addition, we found ROS overload caused by ALT was due to its direct inhibition on reductase. SIGNIFICANCE: We found that ALT, a natural product, showing a promising tactic in the therapy of B-ALL by targeting ROS pathway.


Assuntos
Lactonas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Lactonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos de Eudesmano/metabolismo
7.
Zhongguo Zhong Yao Za Zhi ; 44(1): 95-99, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30868818

RESUMO

Six compounds were isolated from the aerial part of cultivated Clerodendranthus spicatus in Hainan with various chromatographic techniques,and their structures were determined as:1-dehydroxy-1-oxo-rupestrinol(1),N-trans-feruloyltyramine(2),methyl 3,4-dihydroxyphenyllactate(3),caffein acid(4),methyl caffeate(5) and ethyl caffeate(6),via analysis of physicochemical properties and spectroscopic evidence.Compound 1 was a new compound,while compounds 2 and 3 were isolated from C.spicatus for the first time.Biological activity results showed that compounds 2-4 exhibited α-glucosidase inhibitory activity with different inhibition ratio.


Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Lamiaceae/química , Sesquiterpenos de Eudesmano/farmacologia , China , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Sesquiterpenos de Eudesmano/isolamento & purificação
8.
Free Radic Res ; 53(1): 104-114, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30668191

RESUMO

Thioredoxin reductase 1 (TrxR1) has emerged as a potential target for cancer therapy, because it is overexpressed in several types of cancers and associated with increased tumour growth and poor patient prognosis. Alantolactone (ALT), a natural sesquiterpene lactone originated from traditional folk medicine Inula helenium L., has been reported to exert antitumor activity in various tumours. However, the effect of ALT on human gastric cancer cells and its underlying mechanism remains unknown. In this study, we showed that ALT inhibited cell proliferation and induced cell apoptosis in gastric cancer cells. Mechanistically, our data found that ALT induced reactive oxygen species (ROS) production by inhibiting TrxR1 activity, resulting in the activation of p38 mitogen-activated protein kinase (MAPK) pathway and eventually cell apoptosis in gastric cancer cells. And the effects of ALT were reversed by pre-treatment with NAC (a scavenger of ROS). Further investigation revealed that ALT displayed synergistic lethality with erastin against gastric cancer cells, which demonstrating combined inhibition of TrxR1 and glutathione (GSH) leads to a synergistic effect in gastric cancer cells. More importantly, ALT treatment markedly reduced the activity of TrxR1 in vivo and inhibited the growth of gastric cancer xenografts without exhibiting significant toxicity. Taken together, these findings suggest that ALT may be used as a novel therapeutic agent against human gastric cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Tiorredoxina Redutase 1/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Inula/química , Lactonas/química , Lactonas/isolamento & purificação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/isolamento & purificação , Neoplasias Gástricas/metabolismo , Relação Estrutura-Atividade , Tiorredoxina Redutase 1/metabolismo , Células Tumorais Cultivadas
9.
Mol Carcinog ; 58(4): 565-576, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30520143

RESUMO

Several studies have implicated the feedback activation of signal transducer and activator of transcription 3 (STAT3) as a new cancer drug-resistance mechanism and linked it to the failure of epidermal growth factor receptor (EGFR)-targeted therapies. In this study, we discovered that Alantolactone, a natural sesquiterpene lactone, potently inhibited human pancreatic cancer cells and suppressed constitutively activated STAT3. In contrast, Alantolactone had little effect on the EGFR pathway. Moreover, combination of Alantolactone and an EGFR inhibitor, Erlotinib or Afatinib, demonstrated a remarkable synergistic anti-cancer effect against pancreatic cancer cells both in vitro and in vivo. Our results suggested that Alantolactone could sensitize human pancreatic cancer cells to EGFR inhibitors possibly through down-regulating the STAT3 signaling. Alantolactone, when combined with other EGFR targeted agents, could be further developed as a potential therapy for pancreatic cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lactonas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Sesquiterpenos de Eudesmano/farmacologia , Animais , Apoptose , Ciclo Celular , Movimento Celular , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fator de Transcrição STAT3 , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nutrients ; 11(1)2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577513

RESUMO

Hops, the immature inflorescences of the female hop plant (Humulus lupulus L.) are one of the main components of beer and provides flavor and bitterness. ß-Eudesmol, an oxygenated sesquiterpene, is reported to accumulate in a particular hop cultivar. Recently, we revealed that ß-Eudesmol ingestion affected autonomic nerve activity in an animal model. The effect on humans has not been elucidated, therefore, we investigated the effects of ß-Eudesmol on reducing objective and subjective markers related to sympathetic nerve activity after the application of mental stress in healthy participants. Fifty participants (male and female aged 20 to 50 years) were randomly assigned to two groups. Five minutes before taking the Trier Social Stress Test (TSST) as a mental stressor, participants in each group ingested a beverage containing ß-Eudesmol, the active beverage, or a placebo beverage that did not contain ß-Eudesmol. Saliva 3-methoxy-4-hydroxyphenylglycol (MHPG), a major product of noradrenaline breakdown and a representative marker of sympathetic nerve activity, was significantly lower just after the TSST in the active group compared with the placebo group. Saliva cortisol, a marker of the endocrine stress response system, was not significantly different between the two groups. No adverse events related to test beverage ingestion were observed. This is the first experimental evidence of ß-Eudesmol effect for mental stress in human.


Assuntos
Humulus , Metoxi-Hidroxifenilglicol/metabolismo , Saliva/efeitos dos fármacos , Sesquiterpenos de Eudesmano/farmacologia , Estresse Psicológico/metabolismo , Adulto , Bebidas/análise , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Fitoterapia ; 130: 265-271, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30243779

RESUMO

Gracilistones A (1) and B (2), two new eudesmane-type sesquiterpenoids with an unusual tetrahydrofuran-fused 6/6/5 tricyclic ring system, were obtained from Acanthopanax gracilistylus under the guidance of LC-MS investigation. Their structures and absolute configurations were assigned by extensive spectroscopic analyses and quantum calculation methods. Compounds 1 and 2 showed potent inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages, compared with the positive control L-NMMA. In addition, compounds 1 and 2 were also evaluated for their antioxidant (DPPH• and ABTS•+) and xanthine oxidase (XO) inhibitory activities, and they exhibited weak inhibitory effects at 100 µM.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Eleutherococcus/química , Sesquiterpenos de Eudesmano/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , China , Cromatografia Líquida , Furanos , Espectrometria de Massas , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Células RAW 264.7 , Sesquiterpenos de Eudesmano/isolamento & purificação
12.
Chem Biol Interact ; 294: 101-106, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30148989

RESUMO

Allergic rhinitis (AR) is a global health problem because of its steadily increasing incidence and prevalence that currently affects about 30% of people worldwide. ß-eudesmol has various beneficial effects, including anti-cancer and anti-allergic activities. However, the effects of ß-eudesmol on AR have not yet been clarified; thus, we investigated the effects of ß-eudesmol in an ovalbumin-induced AR animal model using enzyme-linked immunosorbent assay, histamine assay, Western blotting, and hematoxylin and eosin staining methods. ß-eudesmol reduced the nasal rubs score and levels of histamine and immunoglobulin E in serum of AR mouse. In addition, the levels of thymic stromal lymphopoietin, interleukin-1ß, tumor necrosis factor-α, and macrophage inflammatory protein-2 were down-regulated and infiltration of eosinophils and the level of intercellular adhesion molecule-1 were inhibited by ß-eudesmol administration. ß-eudesmol administration also reduced active caspase-1 and nuclear factor-κB DNA binding activity in nasal mucosa tissues of AR mice. Taken together, these results indicate that ß-eudesmol would be effective for the treatment of allergic and inflammatory diseases, such as AR.


Assuntos
Caspase 1/metabolismo , Citocinas/metabolismo , NF-kappa B/metabolismo , Rinite Alérgica/patologia , Sesquiterpenos de Eudesmano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Quimiocina CXCL2/metabolismo , Citocinas/antagonistas & inibidores , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Ovalbumina/imunologia , Rinite Alérgica/tratamento farmacológico , Rinite Alérgica/imunologia , Sesquiterpenos de Eudesmano/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
13.
Toxicol Appl Pharmacol ; 356: 159-171, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30086361

RESUMO

The lysosome is emerging as a central regulator of the autophagic process, which plays a critical role in tumor growth and chemoresistance. Alantolactone, which is a natural compound produced by Inula helenium, has been shown to induce apoptosis in numerous cancer types. However, the mechanism by which alantolactone regulates apoptosis is still poorly understood. In this work, we observed that alantolactone caused the accumulation of autophagosomes due to impaired autophagic degradation and substantially inhibited the activity and expression of CTSB/CTSD proteins that when depleted caused lysosomal dysfunction. Furthermore, we found that alantolactone inhibited the proliferation of pancreatic cancer cells in vitro and in vivo and enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin. In addition, a reduction in TFEB levels was a critical event in the apoptosis and cell death caused by alantolactone. Our data demonstrated that alantolactone, which impaired autophagic degradation, was a pharmacological inhibitor of autophagy in pancreatic cancer cells and markedly enhanced the chemosensitivity of pancreatic cancer cells to oxaliplatin.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/efeitos dos fármacos , Lactonas/farmacologia , Lisossomos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Sesquiterpenos de Eudesmano/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sinergismo Farmacológico , Humanos , Oxaliplatina/farmacologia , Neoplasias Pancreáticas/patologia , Fagossomos/efeitos dos fármacos
14.
Eur J Med Chem ; 157: 229-247, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30096654

RESUMO

In this study, anti-IPF lead compounds 42 and 44, derived from natural sesquiterpene lactones Isoalantolactone and alantolactone, were discovered by screening from a high-throughput TGF-ß1 reporter luciferase assay. Notably, they could reduce the myofibroblast activation and extracellular matrix deposition both in vitro and in vivo. Additionally, compounds 42 and 44 could significantly attenuate bleomycin-induced pulmonary fibrosis in mice. Further validation of pharmacokinetics study and toxicity evaluation indicated that compound 44 might be a promising anti-IPF drug candidate.


Assuntos
Descoberta de Drogas , Fibrose Pulmonar Idiopática/tratamento farmacológico , Lactonas/farmacologia , Sesquiterpenos de Eudesmano/farmacologia , Sesquiterpenos/farmacologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Bleomicina , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Lactonas/síntese química , Lactonas/química , Camundongos , Estrutura Molecular , Células NIH 3T3 , Sesquiterpenos/síntese química , Sesquiterpenos/química , Sesquiterpenos de Eudesmano/síntese química , Sesquiterpenos de Eudesmano/química , Relação Estrutura-Atividade , Fator de Crescimento Transformador beta1/metabolismo
15.
Int J Mol Med ; 42(4): 1847-1856, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30015828

RESUMO

Human breast cancer is a malignant type of cancer with high prevalence. In the present study, the anticancer effects of alantolactone, a sesquiterpene lactone, on the human breast cancer cell line MCF­7 were investigated in vitro. The MCF­7 cell morphology changed from diamond to round subsequent to treatment with alantolactone, and the cell viability reduced significantly compared with that of the control cells. Alantolactone induced apoptosis of MCF­7 cells by regulating the protein expression levels of B­cell lymphoma 2 (Bcl­2), Bcl­2­associated X protein, p53, caspase­3 and caspase­12, which are associated with the apoptotic pathway, and suppressed colony formation and migration by regulating the protein expression of matrix metalloproteinase (MMP)­2, MMP­7 and MMP­9. Cell signaling pathway analysis confirmed that alantolactone increased the phosphorylation of p38, and decreased the nuclear expression levels of p65 and nuclear factor erythroid 2­related factor 2 (Nrf2), suggesting that the apoptosis­promoting and migration­suppressing effect of alantolactone may partially depend on regulating the p38 MAPK, NF­κB and Nrf2 pathways. These results also suggested that alantolactone may become a potential therapeutic strategy for treating breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Proteínas de Neoplasias/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
16.
Neurosci Lett ; 684: 18-24, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-29966754

RESUMO

The autonomic nervous system innervates various peripheral tissue functions. Various external stimuli affect autonomic nerve activity, however, there is little information about the involvement of sensory receptors in the responses. The TRPA1 is a calcium-permeable non-selective cation channel which plays a crucial role in the susceptibility to various stimuli. ß-Eudesmol, an oxygenated sesquiterpene found in hop essential oil and beer, activates the TRPA1. Intragastric administration of ß-eudesmol decreased efferent adrenal sympathetic nerve activity (ASNA) in rats, whereas subcutaneous administration did not. ASNA suppression by ß-eudesmol was not observed in TRPA1 knockout rats. The ß-eudesmol derived ASNA suppression was partially, but significantly, eliminated by subdiaphragmatic vagotomy in rats, suggesting the afferent vagal nerve from the gastrointestinal tract to the brain is involved in the effect of ß-eudesmol on ASNA. Our results indicate that ß-eudesmol suppresses ASNA, partly through TRPA1 and the afferent vagus nerve. These findings introduce the physiological significance of the TRPA1 in the control of ASNA.


Assuntos
Glândulas Suprarrenais/inervação , Glândulas Suprarrenais/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Fibras Simpáticas Pós-Ganglionares/metabolismo , Sistema Nervoso Simpático/metabolismo , Canal de Cátion TRPA1/deficiência , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/metabolismo , Epinefrina/metabolismo , Masculino , Ratos , Ratos Transgênicos , Ratos Wistar , Sesquiterpenos de Eudesmano/química , Fibras Simpáticas Pós-Ganglionares/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos
17.
BMC Pharmacol Toxicol ; 19(1): 32, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29914576

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA), an epithelial malignancy of the biliary tree, is one of the aggressive cancers with poor prognosis and unsatisfactory response to chemotherapy with acquired resistance. NAD(P)H-quinone oxidoreductase 1 (NQO1), an antioxidant/detoxifying enzyme, plays important roles in chemo-resistance and proliferation in several cancer cells. The study aimed to investigate the inhibitory effect of ß-eudesmol on NQO1 enhanced chemotherapeutic effects of 5-fluorouracil (5-FU) and doxorubicin (DOX) in the high NQO1-expressing human CCA cell line, NQO1-KKU-100. In addition, the molecular events associated with the inhibition of the cell proliferation, cell migration, and induction of apoptosis were investigated. METHODS: Human CCA KKU-100 cells were exposed to ß-eudesmol at various concentrations. NQO1 enzyme activity and protein expression were measured by enzymatic assay and Western blot analysis, respectively. Sulforhodamine B (SRB) assay and wound healing assay were performed to detect the inhibitory effect of ß-eudesmol on cell proliferation, cell migration, and sensitivity to 5-FU and DOX. Apoptotic induction was detected by flow cytometry with annexin V/PI and DAPI nuclear staining. Caspase 3/7 activation was determined by fluorescence microscopy. The mechanism of enhanced chemo-sensitivity was evaluated by Western blot analysis. RESULTS: ß-Eudesmol significantly suppressed NQO1 enzyme activity (both in KKU-100 cells and cell lysates) and protein expression in KKU-100 cells in a concentration-dependent manner. ß-Eudesmol exhibited potent cytotoxicity on KKU-100 cells with mean ± SD IC50 values of 47.62 ± 9.54 and 37.46 ± 12.58 µM at 24 and 48 h, respectively. In addition, it also potentiated the cytotoxic activities and inhibitory activities of 5-FU and DOX on cell migration through induction of cell apoptosis and activation of caspase 3/7. Western blot analysis suggested that ß-eudesmol enhanced chemosensitivity was associated with the suppression of NQO1 protein and activation of Bax/Bcl-2 protein expression ratio in CCA cells. CONCLUSIONS: ß-Eudesmol may serve as a potential anti-CCA candidate particularly when used in combination with conventional chemotherapeutics. The mechanisms involved may be mediated via NQO1 suppression-related apoptosis pathway.


Assuntos
Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Fluoruracila/farmacologia , Humanos
18.
Mar Drugs ; 16(4)2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29597304

RESUMO

Four new eudesmane-type sesquiterpenoids, penicieudesmol A-D (1-4), were isolated from the fermentation broth of the mangrove-derived endophytic fungus Penicillium sp. J-54. Their structures were determined by spectroscopic methods, the in situ dimolybdenum CD method, and modified Mosher's method. The bioassays results showed that 2 exhibited weak cytotoxicity against K-562 cells.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Penicillium/química , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/farmacologia , Fermentação , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Penicillium/classificação , Penicillium/metabolismo
19.
J Pharmacol Sci ; 136(2): 51-56, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29525035

RESUMO

Cholangiocarcinoma (CCA) is the cancer of bile duct with high mortality rate particularly in Thailand. The clinical efficacy of the standard chemotherapeutics remains unsatisfactory, and therefore, discovery and development of the new alternative drugs with high efficacy and tolerability is needed. The aim of the study was to investigate cytotoxic activity as well as the underlying mechanisms through which atractylodin and ß-eudesmol exert their activities on CCA cell growth inhibition, cell cycle arrest, and cell apoptosis. Effects of the compounds on cell cytotoxicity, cell cycle arrest, and cell apoptosis were analyzed using MTT assay, BD Cycletest™ Plus DNA kit, and FITC Annexin V Apoptosis Detection Kit I, respectively. The cytotoxic activities of both compounds were concentration- and time-dependent. The IC50 [mean (SD)] of atractylodin and ß-eudesmol were 41.66 (2.51) and 39.33 (1.15) µg/ml respectively. Both promoted cell cycle arrest at G1 phase, and induced cell apoptosis through activation of caspase-3/7. The highest activity was observed at 48 h of exposure. Results suggest that these mechanisms are at least in part, explain the cell cytotoxic and anti-CCA activity of atractylodin and ß-eudesmol shown in vitro and in vivo models.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Colangiocarcinoma/patologia , Furanos/farmacologia , Sesquiterpenos de Eudesmano/farmacologia , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Furanos/toxicidade , Fase G1/efeitos dos fármacos , Humanos , Fatores de Tempo
20.
Eur J Pharmacol ; 828: 60-66, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29555504

RESUMO

A high level of APOC3 expression is an independent risk factor for some lipid metabolism-related diseases, such as cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD) and atherosclerosis (AS). This suggests that down-regulating APOC3 expression is a potential way of regulating lipid levels. In this study, we used luciferase reporter screening to identify a natural compound, alantolactone (ALA), that can inhibit the promoter activity of APOC3. ALA decreased APOC3 expression at both mRNA and protein levels. Then we pretreated L02 liver cells with oxLDL to investigate the function of ALA in lipid homeostasis. Intriguingly, ALA attenuated oxLDL-induced foam cell formation by reducing total cholesterol (TC) and triglyceride (TG) contents. Furthermore, these results could be reversed by overexpressing APOC3 protein. ALA inhibited tyrosine phosphorylation (Tyr705pho) of STAT3 to down-regulate APOC3 expression. Intriguingly, overexpression of a wild-type STAT3 or a constitutively active form of STAT3 (STAT3-C) up-regulated APOC3 expression and partly reversed the effect of ALA in oxLDL-induced L02 cells. Overexpression of wild-type STAT3 also increased TC but not TG contents in L02 cells. However, overexpression of STAT3-C significantly increased TC and TG contents, and the effect of ALA was partly attenuated by STAT3-C, although this was not statistically significant. These results suggest that ALA attenuates lipid accumulation through down-regulation of APOC3 expression, at least in part by inhibiting STAT3 signaling.


Assuntos
Apolipoproteína C-III/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Homeostase/efeitos dos fármacos , Lactonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Sesquiterpenos de Eudesmano/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Lipoproteínas LDL/farmacologia , Fator de Transcrição STAT3/metabolismo
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