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1.
Pestic Biochem Physiol ; 170: 104705, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980068

RESUMO

Magnolia officinalis, as a well-known herb worldwide, has been widely used to treat multiple diseases for a long time. In this study, the petroleum ether extract from M. officinalis showed effective antifungal activity against seven plant pathogens (particularly against R. solani with an inhibition rate of 100.00% at 250 µg/mL). Honokiol and magnolol, isolated by the bioassay-guided method, exhibited greater antifungal activity than tebuconazole (EC50 = 3.07 µg/mL, p ≤ 0.001) against R. solani, which EC50 values were 2.18 µg/mL and 3.48 µg/mL, respectively. We used transcriptomics to explore the mechanism of action of honokiol against R. solani. Results indicated that honokiol may exert antifungal effects by blocking the oxidative phosphorylation metabolic pathway. Further studies indicated that honokiol induced ROS overproduction, disrupted the mitochondrial function, affected respiration, and blocked the TCA cycle, which eventually inhibited ATP production. Besides, honokiol also damaged cell membranes and caused morphological changes. This study demonstrated that the lignans isolated from M. officinalis possess the potential to be developed as botanical fungicides.


Assuntos
Lignanas/farmacologia , Magnolia , Antifúngicos/farmacologia , Bioensaio , Compostos de Bifenilo
2.
Cells ; 9(9)2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32911794

RESUMO

All-trans-retinoic acid (atRA) is the essential derivative of vitamin A and is of interest due to its various biological key functions. As shown in the recent literature, atRA also plays a role in the failing heart during myocardial infarction, the leading cause of death globally. To date insufficient mechanistic information has been available on related hypoxia-induced cell damage and reperfusion injuries. However, it has been demonstrated that a reduction in cellular atRA uptake abrogates hypoxia-mediated cell and tissue damage, which may offer a new route for intervention. Consequently, in this study, the effect of the novel cardio-protective compound 5-methoxyleoligin (5ML) on cellular atRA uptake was tested in human umbilical-vein endothelial cells (HUVECs). For this purpose, a high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to assess intra-cellular levels of the active substance and corresponding levels of vitamin A and its derivatives, including potential cis/trans isomers. This work also focused on light-induced isomerization and the stability of biological sample material to ensure sample integrity and avoid biased conclusions. This study provides evidence of the inhibitory effect of 5ML on cellular atRA uptake, a promising step toward a novel therapy for myocardial infarction.


Assuntos
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Oxigênio/metabolismo , Tretinoína/metabolismo , Hipóxia Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lignanas/farmacologia
3.
Int J Nanomedicine ; 15: 5239-5252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801689

RESUMO

Introduction: The main pathological mechanism of restenosis after percutaneous coronary intervention (PCI) is intimal hyperplasia, which is mainly caused by proliferation and migration of vascular smooth muscle cells (VSMCs). Our previous study found that honokiol (HNK), a small-molecule polyphenol, can inhibit neointimal hyperplasia after balloon injury, but its specific mechanism is still unclear. Moreover, poor water solubility as well as low bioavailability of honokiol has limited its practical use. Methods: We used mesoporous silica nanoparticles (MSNPs) as a standard substance to encapsulate HNK and then assemble into honokiol-mesoporous silica nanoparticles, and we investigated the effect of these nanoparticles on the process of restenosis after common carotid artery injury in rats. Results: We report a promising delivery system that loads HNK into MSNPs and finally assembles it into a nanocomposite particle. These HNK-MSNPs not merely inhibited proliferation and migration of VSMCs by reducing phosphorylation of Smad3, but also showed a higher suppression of intimal thickening than the free-honokiol-treated group in a rat model of balloon injury. Conclusion: To sum up, this drug delivery system supplies a potent nano-platform for improving the biological effects of HNK and provides a promising strategy for preventing vascular restenosis.


Assuntos
Compostos de Bifenilo/farmacologia , Reestenose Coronária/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Lignanas/farmacologia , Nanopartículas/química , Intervenção Coronária Percutânea/efeitos adversos , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/metabolismo , Modelos Animais de Doenças , Humanos , Lignanas/administração & dosagem , Lignanas/farmacocinética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nanopartículas/administração & dosagem , Poloxâmero/química , Ratos Sprague-Dawley , Dióxido de Silício/química
4.
Life Sci ; 256: 117983, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32565252

RESUMO

Estrogen receptor (ER) positive accounts for a large proportion of breast cancer. Although there are many targeted therapeutic drugs, the emergence of drug resistance urgently requires the development of new drugs. Arctigenin (Arc), a lignan found in certain plants of the Asteraceae, has the effect on inhibiting breast cancer, but its molecular mechanism has not been clear. AIMS: To this end, the current study focuses on understanding the mechanism of Arc on ER-positive breast cancer cells. MAIN METHODS: Colony formation experiments and sulforhodamine B methods were used to determine the growth-inhibitory effect of Arc. The cell cycle and apoptosis were analyzed by flow cytometry. Alterations of signaling proteins were measured by Western blotting. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. KEY FINDINGS: The experimental results show that Arc did not induce apoptosis in ER-positive breast cancer cell, rather caused G1 cycle arrest by decreasing cyclin D1 levels without effect on altering CDK4/6 levels. Moreover, we have demonstrated that Arc decreases cyclin D1 levels through prompting Akt/GSK3ß-mediated degradation. SIGNIFICANCE: These findings warrant the potential of Arc as a candidate treatment for ER-positive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Ciclina D1/metabolismo , Furanos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Lignanas/farmacologia , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Feminino , Furanos/uso terapêutico , Humanos , Lignanas/uso terapêutico , Células MCF-7 , Proteólise/efeitos dos fármacos
5.
Exp Anim ; 69(3): 363-373, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32336744

RESUMO

Schisandrin, an active component extracted from Schisandra chinensis (Turcz.) Baill has been reported to alleviate the cognitive impairment in neurodegenerative disorder like Alzheimer's disease (AD). However, the mechanism by which schisandrin regulates the cognitive decline is still unclear. In our study, intracerebroventricular injection of streptozotocin (STZ) was employed to establish AD model in male Wistar rats, and indicated dose of schisandrin was further administered. The Morris water maze test was performed to evaluate the ability of learning and memory in rats with schisandrin treatment. The results indicated that schisandrin improved the capacity of cognition in STZ-induced rats. The contents of pro-inflammatory cytokines in brain tissue were determined by ELISA, and the expressions of these cytokines were assessed by western-blot and immunohistochemistry. The results showed that treatment of schisandrin significantly reduced the production of inflammation mediators including tumor necrosis factor-α, interleukin-1ß and interleukin-6. Further study suggested a remarkable decrease in the expressions of ER stress maker proteins like C/EBP-homologous protein, glucose-regulated protein 78 and cleaved caspase-12 in the presence of schisandrin, meanwhile the up-regulation of sirtuin 1 (SIRT1) was also observed in the same group. Additionally, the results of western-blot and EMSA demonstrated that schisandrin inhibited NF-κB signaling in the brain of STZ-induced rats. In conclusion, schisandrin ameliorated STZ-induced cognitive dysfunction, ER stress and neuroinflammation which may be associated with up-regulation of SIRT1. Our study provides novel mechanisms for the neuroprotective effect of schisandrin in AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lignanas/farmacologia , Lignanas/uso terapêutico , Fitoterapia , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêutico , Schisandra/química , Estreptozocina , Animais , Modelos Animais de Doenças , Masculino , Ratos Wistar , Sirtuína 1/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Invest Ophthalmol Vis Sci ; 61(4): 48, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32347916

RESUMO

Purpose: We characterized the effects of Honokiol (HNK) on Aspergillus fumigatus-caused keratomycosis and the underlying mechanisms. HNK is known to have anti-inflammatory and antifungal properties, but the influence on fungal keratitis (FK) remains unknown. Methods: In ex vivo, minimum inhibitory concentration and Cell Count Kit-8 assay were carried out spectrophotometrically to provide preferred concentration applied in vivo. Time kill assay pointed that HNK was fungicidal and fungistatic chronologically. Adherence assay, crystal violet staining, and membrane permeability assay tested HNK effects on different fungal stages. In vivo, clinical scores reflected the improvement degree of keratitis outcome. Myeloperoxidase (MPO) assay, flow cytometry (FCM), and immunohistofluorescence staining (IFS) were done to evaluate neutrophil infiltration. Plate count detected HNK fungicidal potentiality. RT-PCR, Western blot, and enzyme-linked immunosorbent assay (ELISA) verified the anti-inflammatory activity of HNK collaboratively. Results: In vitro, MIC90 HNK was 8 µg/mL (no cytotoxicity), and Minimal Fungicidal Concentration (MFC) was 12 µg/mL for A. fumigatus. HNK played the fungistatic and fungicidal roles at 6 and 24 hours, respectively, inhibiting adherence at the beginning, diminishing biofilms formation, and increasing membrane permeability all the time. In vivo, HNK improved C57BL/6 mice outcome by reducing disease severity (clinical scores), neutrophil infiltration (MPO, FCM, and IFS), and fungal loading (plate count). RT-PCR, Western blot, and ELISA revealed that HNK downregulated mRNA and protein expression levels of Toll-like receptor-2 (TLR-2), high mobility group box 1 (HMGB1), IL-1ß, and TNF-α. Conclusions: Our study suggested HNK played antifungal and anti-inflammatory roles on keratomycosis by reducing survival of fungi, infiltration of leucocytes, and expression of HMGB1, TLR-2, and proinflammatory cytokines, providing a potential treatment for FK.


Assuntos
Anti-Infecciosos/farmacologia , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/isolamento & purificação , Compostos de Bifenilo/farmacologia , Infecções Oculares Fúngicas/tratamento farmacológico , Lignanas/farmacologia , Animais , Aspergilose/diagnóstico , Western Blotting , Citocinas/efeitos dos fármacos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Infecções Oculares Fúngicas/microbiologia , Feminino , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/métodos , Receptor 2 Toll-Like/efeitos dos fármacos , Resultado do Tratamento
7.
Xenobiotica ; 50(9): 1043-1051, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32118504

RESUMO

Pregnane X receptor (PXR) as a ligand dependent transcription factor, is capable of regulating gene expression of cytochromes P450 and transporters involved in xenobiotic/drug metabolism and elimination. Due to the species differences in the regulatory specificity of PXR, gene regulation should not be extrapolated from mammal to fish without research data.The aim of present study was to investigate the effect of 27 natural products on PXR, CYP3A30 and MDR1 genes in channel catfish (Ietalurus punetaus) kidney cells (CC-K). The results showed that bisdemethoxycurcumin, glycyrrhetnic acid, rotenone, artemisinin, dihydroartemisinin, ligustilide and matrine strongly induced the mRNA levels of PXR. Additionally, the up-regulation of CYP3A30 gene ran parallel with PXR gene after the treatment of demethoxycurcumin, glycyrrhetnic acid, artemisinin, matrine, baicalein, schisantherin A, ligustilide, and dihydroartemisinin. Moreover, we found that natural products schisandrin A, schisandrin B, schisandrol A, and schisandrol B significantly up-regulated the mRNA level of MDR1 gene.Our work with a view to provide experimental data support for further research, which will make for the rational application of natural products in channel catfish, such as to avoid adverse herb-drug interactions or accelerating the residue elimination of chemical medicine.


Assuntos
Produtos Biológicos/farmacologia , Biotransformação/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Produtos Biológicos/metabolismo , Linhagem Celular , Ciclo-Octanos/metabolismo , Ciclo-Octanos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Dioxóis/metabolismo , Dioxóis/farmacologia , Ictaluridae , Lignanas/metabolismo , Lignanas/farmacologia , Compostos Policíclicos/metabolismo , Compostos Policíclicos/farmacologia , Receptor de Pregnano X/metabolismo
8.
Carbohydr Polym ; 235: 115981, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32122511

RESUMO

In an effort to enhance antitumor and anti-metastasis of breast cancer, honokiol (HNK) was encapsulated into hyaluronic acid (HA) modified cationic liposomes (Lip). The prepared HA-Lip-HNK had a spherical shape with a narrow size distribution. The enhanced antitumor efficacy of HA-Lip-HNK was investigated in 4T1 cells in vitro, wherein flow cytometry and confocal microscopy analysis revealed its HA/CD44-mediated greater cellular internalization. As anticipate, the significant cytotoxicity of the HA-Lip-HNK was also observed in 4T1 tumor spheroids. Furthermore, the superior prevention of tumor metastasis by HA-Lip-HNK was verified by in vitro anti-invasion, wound healing and anti-migration assessments, and in vivo bioluminescence imaging in pulmonary metastasis model. Finally, compared with unmodified liposomes, the HA-Lip-HNK exhibited higher tumor accumulation, and achieved a tumor growth inhibition rate of 59.5 %. As a result, the HA-Lip-HNK may serve as a promising tumor-targeted drug delivery strategy for the efficient therapy of metastatic breast cancer.


Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ácido Hialurônico/farmacologia , Lignanas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Nanopartículas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Injeções Intravenosas , Lignanas/administração & dosagem , Lignanas/química , Neoplasias Pulmonares/patologia , Camundongos , Nanopartículas/administração & dosagem , Tamanho da Partícula , Propriedades de Superfície
9.
J Nat Med ; 74(3): 513-524, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193805

RESUMO

Liver fibrosis is a pathological manifestation induced by chronic liver injury and may cause cirrhosis and liver cancer with the chronic progression of fibrosis. During the onset and progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) is the core mechanism for the secretion of many extracellular matrices to induce fibrosis. Lignans are reportedly the main effective components of Schisandra chinensis with good anti-fibrosis effects. In this study, we compared the inhibiting effects of the seven lignan components from S. chinensis on HSC activation. We found that the seven lignans inhibited the activation of human HSCs (LX-2) in various degrees. Among all lignans, schisanhenol showed the best effect in inhibiting the activation of LX-2 with a dose-effect relationship. Sal also inhibited the phosphorylations of Smad1, Smad2, Smad3, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and nuclear transcription factor-κB (NF-κB), as well as downregulated Smad4. All these findings suggested that schisanhenol may ameliorate liver fibrosis by inhibiting the transforming growth factor ß (TGF-ß)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Remarkably, schisanhenol may be a potential anti-liver fibrosis drug and warrants further research.


Assuntos
Ciclo-Octanos/farmacologia , Células Estreladas do Fígado/metabolismo , Lignanas/farmacologia , Cirrose Hepática/prevenção & controle , Compostos Policíclicos/farmacologia , Schisandra/química , Linhagem Celular , Frutas/química , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Cirrose Hepática/patologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
J Nat Med ; 74(3): 525-532, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32207025

RESUMO

Autophagy is a catabolic process that degrades dysfunctional proteins and organelles and plays critical roles in cancer development. Our preliminary screening identified that extracts of the fruits of Arctium lappa and the fruits of Forsythia suspensa notably suppressed the proliferation of hepatocellular carcinoma HepG2 cells and downregulated the autophagy. In this study, we explored the effect of arctigenin (ARG), a bioactive lignan in both extracts, on cell proliferation and autophagy-related proteins in HepG2 cells. ARG inhibited the proliferation of HepG2 cells. Analysis of autophagy-related proteins demonstrated that ARG might block the autophagy that leads to sequestosome 1/p62 (p62) accumulation. The stage of inhibition in autophagy by ARG differed from those by the autophagy inhibitors 3-methyladenine (3-MA) or chloroquine (CQ). ARG could also inhibit starvation-induced autophagy. Further analysis of apoptosis-related proteins indicated that ARG did not affect caspase-3 activation and PARP cleavage, suggesting that the antiproliferative effect of ARG can occur independently of apoptosis. In summary, our study showed that ARG suppresses cell proliferation and inhibits autophagy, and might lead to the development of agents for autophagy research and cancer chemoprevention.


Assuntos
Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Furanos/farmacologia , Lignanas/farmacologia , Neoplasias Hepáticas/patologia , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Arctium/química , Linhagem Celular Tumoral , Cloroquina/farmacologia , Forsythia/química , Células Hep G2 , Humanos , Proteína Sequestossoma-1
11.
Z Naturforsch C J Biosci ; 75(3-4): 103-112, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32187019

RESUMO

The current study aimed to evaluate the in vivo hypoglycemic potential of Myristica fragrans seed extract co-administered with glimepiride in Swiss albino mice. Computational tools were used to further verify the in vivo findings and to help compare this combination to the glimepiride-pioglitazone combination in terms of the binding affinity of the ligands to their respective target protein receptors and the relative stability of the drug-protein complexes. The effect of the combined therapy was observed both in alloxan- and glucose-induced hyperglycemic Swiss albino mice. The mean fasting blood glucose level of the test groups was measured and statistically evaluated using Student's t test. The combined therapy significantly reduced the blood glucose level in a time-dependent manner compared to glimepiride alone. The binding affinity of glimepiride was found to be -7.6 kcal/mol with sulfonylurea receptor 1 in molecular docking. Conversely, macelignan-peroxisome proliferator-activated receptor (PPAR) α and macelignan-PPAR γ complexes were stabilized with -9.2 and -8.3 kcal/mol, respectively. Molecular dynamic simulation revealed that macelignan-PPAR α and γ complexes were more stable than pioglitazone complexes. The combination shows promise in animal and computer models and requires further trials to provide evidence of its activity in humans.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Lignanas/administração & dosagem , Myristica/química , Compostos de Sulfonilureia/administração & dosagem , Aloxano/efeitos adversos , Animais , Diabetes Mellitus Tipo 2/induzido quimicamente , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Glucose/efeitos adversos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Lignanas/química , Lignanas/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Pioglitazona/administração & dosagem , Pioglitazona/farmacologia , Extratos Vegetais/química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia , Fatores de Tempo
12.
Mol Med Rep ; 21(3): 1374-1382, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016480

RESUMO

Arctigenin is a natural lignan that is found in burdock with anti­viral, ­oxidative, ­inflammatory and anti­tumor activities. In the current study, the effect of arctigenin on metastatic potential was examined in 4T­1 mouse triple­negative breast cancer cells. The results indicated that arctigenin inhibited cell motility and invasiveness, which was determined using wound healing and transwell invasion assays. Arctigenin suppressed matrix metalloprotease­9 (MMP­9) activity via gelatin zymography, and protein expression of cyclooxygenase­2 (COX­2) and MMP­3. Furthermore, arctigenin attenuated the mRNA expression of metastatic factors, including MMP­9, MMP­3 and COX­2. Based on these results, the effect of arctigenin on the mitogen­activated protein kinase (MAPK)/activating protein­1 (AP­1) signaling pathway was assessed in an attempt to identify the regulatory mechanism responsible for its anti­metastatic effects. Arctigenin was demonstrated to inhibit the phosphorylation of extracellular signal­regulated protein kinase (ERK) and c­Jun N­terminal kinase (JNK), and the nuclear translocations of the AP­1 subunits, c­Jun and c­Fos. In summary, the present study demonstrated that in 4T­1 mouse triple­negative breast cancer cells the anti­metastatic effect of arctigenin is mediated by the inhibition of MMP­9 activity and by the inhibition of the metastasis­enhancing factors MMP­9, MMP­3 and COX­2, due to the suppression of the MAPK/AP­1 signaling pathway. The results of the current study demonstrated that arctigenin exhibits a potential for preventing cell migration and invasion in triple negative breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Arctium/química , Furanos/farmacologia , Lignanas/farmacologia , Sistema de Sinalização das MAP Quinases , Inibidores de Metaloproteinases de Matriz/farmacologia , Fator de Transcrição AP-1/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
13.
Toxicol Appl Pharmacol ; 391: 114913, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32032644

RESUMO

Pulmonary fibrosis (PF) is an epithelial/fibroblastic crosstalk disorder of the lungs with highly complex etiopathogenesis. Limited treatment possibilities are responsible for poor prognosis and mean survival rate of 3 to 5 years of PF patients after definite diagnosis. Once thought to be an irreversible disorder, recent evidences have brought into existence the concept of organ fibrosis reversibility due to plastic nature of fibrotic tissues. These findings have kindled interest among the scientific community and given a new direction for research in the arena of fibrosis for developing new anti-fibrotic therapies. The current study is designed to evaluate the anti-fibrotic effects of Honokiol (HNK), a neolignan active constituent from Magnolia officinalis. This study has been conducted in TGF-ß1 induced in vitro model and 21 day in vivo murine model of Bleomycin induced PF. The findings of our study suggest that HNK was able to inhibit fundamental pathways of epithelial to mesenchymal transition (EMT) and TGF-ß/Smad signaling both in vitro and in vivo. Additionally, HNK also attenuated collagen deposition and inflammation associated with fibrosis. We also hypothesized that HNK interfered with IL-6/CD44/STAT3 axis. As hypothesized, HNK significantly mitigated IL-6/CD44/STAT3 axis both in vitro and in vivo as evident from outcomes of various protein expression studies like western blotting, immunohistochemistry and ELISA. Taken together, it can be concluded that HNK reversed pulmonary fibrotic changes in both in vitro and in vivo experimental models of PF and exerted anti-fibrotic effects majorly by attenuating EMT, TGF-ß/Smad signaling and partly by inhibiting IL-6/CD44/STAT3 signaling axis.


Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Compostos de Bifenilo/farmacologia , Bleomicina , Líquido da Lavagem Broncoalveolar , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/sangue , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Receptores de Hialuronatos , Interleucina-6 , Lignanas/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Transcrição STAT3/efeitos dos fármacos , Proteínas Smad/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos
14.
Cancer Res ; 80(7): 1498-1511, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32041837

RESUMO

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.


Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Adulto , Idoso , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína 1 Semelhante à Quitinase-3/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Glioblastoma/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Lignanas/farmacologia , Lignanas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Microambiente Tumoral/efeitos dos fármacos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/antagonistas & inibidores
15.
Mol Cell Biochem ; 467(1-2): 45-56, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32065351

RESUMO

Arctigenin, a mitochondrial complex I inhibitor, has been identified as a potential anti-tumor agent, but the involved mechanism still remains elusive. Herein, we studied the underlying mechanism(s) of action of arctigenin on acidity-tolerant prostate cancer PC-3AcT cells in the lactic acid-containing medium. At concentration showing no toxicity on normal prostate epithelial RWPE-1 and HPrEC cells, arctigenin alone or in combination with docetaxel induced significant cytotoxicity in PC-3AcT cells compared to parental PC-3 cells. With arctigenin treatment, reactive oxygen species (ROS) levels, annexin V-PE positive fractions, sub-G0/G1 peak in cell cycle analysis, mitochondrial membrane depolarization, and cell communication network factor 1 (CCN1) levels were increased, while cellular ATP content and phospho (p)-Akt level were decreased. Pretreatment with ROS scavenger N-acetylcysteine effectively reversed the series of phenomena caused by arctigenin, suggesting that ROS served as upstream molecules of arctigenin-driven cytotoxicity. Meanwhile, arctigenin increased the levels of p-receptor-interacting serine/threonine-protein kinase 3 (p-RIP3) and p-mixed lineage kinase domain-like pseudokinase (p-MLKL) as necroptosis mediators, and pretreatment with necroptosis inhibitor necrostatin-1 restored their levels and cell viability. Treatment of spheroids with arctigenin resulted in necroptotic cell death, which was prevented by N-acetylcysteine. The siRNA-based knockdown of CCN1 suppressed the levels of MLKL, B-cell lymphoma 2 (Bcl-2), and induced myeloid leukemia cell differentiation (Mcl-1) with increased cleavage of Bcl-2-associated X (Bax) and caspase-3. Collectively, these results provide new insights into the molecular mechanisms underlying arctigenin-induced cytotoxicity, and support arctigenin as a potential therapeutic agent for targeting non-Warburg phenotype through induction of necroptosis via ROS-mediated mitochondrial damage and CCN1 upregulation.


Assuntos
Furanos/farmacologia , Ácido Láctico/farmacologia , Lignanas/farmacologia , Mitocôndrias/metabolismo , Neoplasias da Próstata/metabolismo , Regulação para Cima , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura/química , Ciclina D1 , Docetaxel/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Necroptose , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo
16.
Phytomedicine ; 68: 153147, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32028184

RESUMO

BACKGROUND: Gomisin A (G.A), a lignan compound extracted from the fruits of Schisandra chinensis, is known to exert anti-tumor effects on hepatocarcinoma and colorectal cancer cells. Suppression of proliferation and metastatic abilities of cancer cells are some effective cancer treatment methods. PURPOSE: The objective of this study is to investigate the effects of G.A on metastatic melanoma, and the mechanism by which it affects metastatic melanoma. STUDY DESIGN: The anti-proliferative and anti-metastatic effects of G.A were observed in in vitro and in vivo. METHODS: WST assay and flow cytometry were conducted to investigate the effect of G.A on proliferation, cell cycle arrest, and apoptosis in metastatic melanoma cell lines. Migration and invasion abilities of G.A-treated melanoma cells were observed by wound healing and invasion assays. RESULTS: G.A (25-100 µM) decreased the viability of melanoma cells by inducing cell cycle arrest and apoptosis. These anti-proliferative effects of G.A were found to be mediated by AMPK, ERK, and JNK activation. G.A (5-20 µM) decreased the migration and invasion of melanoma cells by suppressing epithelial-mesenchymal transition (EMT). Consequently, G.A (2-50 mg/kg) inhibited lung metastasis by suppressing EMT and inducing cell cycle arrest and apoptosis in melanoma cells. CONCLUSION: These results conclude that G.A has the potential to reduce metastatic melanoma through its anti-proliferative and anti-metastatic effects.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ciclo-Octanos/farmacologia , Dioxóis/farmacologia , Lignanas/farmacologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , MAP Quinase Quinase 4/metabolismo , Melanoma/metabolismo , Camundongos Endogâmicos C57BL , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Int J Mol Sci ; 21(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936371

RESUMO

Renal fibrosis is a common feature of all progressive chronic kidney diseases. Sirtuin 3(SIRT3) is one of the mitochondrial sirtuins, and plays a role in the regulation of mitochondrialbiogenesis, oxidative stress, fatty acid metabolism, and aging. Recently, honokiol (HKL), as apharmaceutical SIRT3 activator, has been observed to have a protective effect against pressureoverload-induced cardiac hypertrophy by increasing SIRT3 activity. In this study, we investigatedwhether HKL, as a SIRT3 activator, also has protective effects against unilateral ureteral obstruction(UUO)-induced renal tubulointerstitial fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the nuclear factor-κB (NF-κB)/transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway. We found that HKL decreased the UUO-induced increase in tubularinjury and extracellular matrix (ECM) deposition in mice. HKL also decreased myofibroblastactivation and proliferation in UUO kidneys and NRK-49F cells. Finally, we showed that HKLtreatment decreased UUO-induced mitochondrial fission and promoted mitochondrial fusionthrough SIRT3-dependent effects. In conclusion, activation of SIRT3 via HKL treatment might havebeneficial effects on UUO-induced renal fibrosis through SIRT3-dependent regulation ofmitochondrial dynamics and the NF-κB/TGF-ß1/Smad signaling pathway.


Assuntos
Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Sirtuína 3/genética , Fator de Crescimento Transformador beta1/genética , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Fibrose/genética , Fibrose/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/patologia , Nefropatias/genética , Nefropatias/patologia , Lignanas/farmacologia , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética
18.
Food Microbiol ; 88: 103411, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31997759

RESUMO

Fungal pathogens lead to severe quality deterioration and yield loss, making it urgent to explore efficient measures to control fungal diseases at the preharvest and postharvest stages of plants. Therefore, studies on natural substances targeting alternative antimicrobial targets have become hot spots of research. Here, we show that honokiol, a polyphenolic compound obtained from Magnolia officinalis, significantly suppressed mycelial growth and reduced virulence of B. cinerea on harvested fruit by inducing autophagic activities and apoptosis. Moreover, honokiol was capable of abolishing the mitochondrial membrane potential and inducing the accumulation of reactive oxygen species. Some key genes involved in pathogenicity on fruit were also found significantly down-regulated. In summary, honokiol was effective as an alternative agent targeting autophagic and apoptotic machineries to control the incidence of gray mold, which may further enrich the toolkit of crop managers for fighting postharvest diseases caused by this and similar fungi.


Assuntos
Antifúngicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Botrytis/efeitos dos fármacos , Botrytis/patogenicidade , Lignanas/farmacologia , Botrytis/crescimento & desenvolvimento , Regulação para Baixo , Frutas/microbiologia , Genes Fúngicos , Magnolia/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Micélio/efeitos dos fármacos , Micélio/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Virulência
19.
Phytother Res ; 34(6): 1397-1408, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31971313

RESUMO

α-Conidendrin is a polyphenolic compound found mainly in Taxus yunnanensis, as the source of chemotherapy drug paclitaxel, which has been used in traditional medicine for treatment of cancer. This study aimed to investigate the anticancer activity and molecular mechanisms of α-conidendrin on breast cancer cell lines. The results of the present study show that α-conidendrin possesses potent antiproliferative effects on breast cancer cell lines MCF-7 and MDA-MB-231. α-Conidendrin significantly induced apoptosis in breast cancer cells via reactive oxygen species generation, upregulation of p53 and Bax, downregulation of Bcl-2, depolarization of mitochondrial membrane potential (MMP), release of cytochrome c from mitochondria, and activation of caspases-3 and -9. α-Conidendrin remarkably inhibited the proliferation of breast cancer cells through induction of cell cycle arrest by upregulating p53 and p21 and downregulating cyclin D1 and CDK4. Unlike breast cancer cells, the antiproliferative effect of α-conidendrin on human foreskin fibroblast cells (normal cells) was very small. In normal cells, reactive oxygen species levels, loss of MMP, release of cytochrome c, mRNA expression of p53, p21, cyclin D1, CDK4, Bax, and Bcl-2 as well as mRNA expression and activity of caspases-3 and -9 were significantly less affected by α-conidendrin compared with cancer cells. These results suggest that α-conidendrin can be a promising agent for treatment of breast cancer with little or no toxicity against normal cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Lignanas/uso terapêutico , Taxus/química , Tetra-Hidronaftalenos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Lignanas/farmacologia , Tetra-Hidronaftalenos/farmacologia
20.
Molecules ; 25(2)2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940776

RESUMO

Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. The virulence of an intracellular human pathogen C. pneumoniae is tightly linked to its propensity for persistence and means for its chemosensitization are urgently needed. In the current work, persistence of C. pneumoniae clinical isolate CV6 was studied in THP-1 macrophages using quantitative PCR and quantitative culture. A dibenzocyclooctadiene lignan schisandrin reverted C. pneumoniae persistence and promoted productive infection. The concomitant administration of schisandrin and azithromycin resulted in significantly improved bacterial eradication compared to sole azithromycin treatment. In addition, the closely related lignan schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection from the macrophages. The observed chemosensitization of C. pneumoniae was associated with the suppression of cellular glutathione pools by the lignans, implying to a previously unknown aspect of chlamydia-host interactions. These data indicate that schisandrin lignans induce a phenotypic switch in C. pneumoniae, promoting the productive and antibiotic-susceptible phenotype instead of persistence. By this means, these medicinal plant -derived compounds show potential as adjuvant therapies for intracellular bacteria resuscitation.


Assuntos
Bioensaio/métodos , Chlamydophila pneumoniae/fisiologia , Ciclo-Octanos/farmacologia , Lignanas/farmacologia , Macrófagos/microbiologia , Azitromicina/administração & dosagem , Azitromicina/farmacologia , Chlamydophila pneumoniae/efeitos dos fármacos , Chlamydophila pneumoniae/crescimento & desenvolvimento , Ciclo-Octanos/administração & dosagem , Ciclo-Octanos/química , Glutationa/metabolismo , Humanos , Cinética , Lignanas/administração & dosagem , Lignanas/química , Macrófagos/efeitos dos fármacos , Oxirredução , Fenótipo , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células THP-1
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