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1.
Cell Biochem Biophys ; 77(4): 367-377, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31659617

RESUMO

Cisplatin is a widely used anti-cancer drug. However, cisplatin is limited in clinical treatment because of its severe nephrotoxicity. This study reported whether O-GSP can antagonize the cisplatin-induced cytotoxicity in HEK293 cells through inducing HO-1 protein expression. We previously demonstrated O-GSP can increase the survival rate of HEK293 and have protective effect on HEK293 cells. Herein, We found that O-GSP can antagonize cisplatin nephrotoxicity through regulating the expression of HO-1. O-GSP promotes the translocation of Nrf2 in the nucleus, and activates the ERKN JNK pathway and p38 MAPK pathway. Interestingly, p38 MAPK plays a major role in HO-1 expression induced by O-GSP. And O-GSP can modulate the decrease of Nrf2 and HO-1 expression induced by cisplatin, and improve the cisplatin-induced activity and apoptosis rate of cells by stimulating the expression of HO-1. However, the protective effects of O-GSP are inhibited by ZnPP IX. Collectively, the results indicated that O-GSP induced the expression of HO-1 through p38MAPK and Nrf2 pathway in HEK293 cells.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Catequina/farmacologia , Cisplatino/farmacologia , Heme Oxigenase-1/metabolismo , Proantocianidinas/farmacologia , Regulação para Cima/efeitos dos fármacos , Vitis/química , Apoptose/efeitos dos fármacos , Núcleo Celular/metabolismo , Células HEK293 , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Sementes/química , Sementes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitis/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Anticancer Res ; 39(7): 3641-3649, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262890

RESUMO

BACKGROUND/AIM: Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer. MATERIALS AND METHODS: Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro. RESULTS: Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 µM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone. CONCLUSION: Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína Ligante Fas/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/fisiopatologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/fisiopatologia , Receptor fas/metabolismo
3.
Anticancer Res ; 39(7): 3669-3675, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262893

RESUMO

BACKGROUND/AIM: Amentoflavone has been implicated in reducing the metastatic potential of osteosarcoma (OS) cells in vitro. The aim of the present study was to verify the antitumoral efficacy and the potential mechanism of amentoflavone osteosarcoma progression inhibition in vivo. MATERIALS AND METHODS: A U-2 OS osteosarcoma xenograft mouse model was used in this study. Mice were treated with a vehicle control or amentoflavone (100 mg/kg/day) for 15 days. Tumor growth, signal transduction, and expression of tumor progression-associated proteins were evaluated using a digital caliper, bioluminescence imaging (BLI), animal computed tomography (CT), and ex vivo western blotting assay. RESULTS: Amentoflavone significantly inhibits tumor growth and reduces protein levels of phospho-extracellular signal-regulated kinase (P-ERK), nuclear factor-kappaB (NF-κB) p65 (Ser536), vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP-9), X-linked inhibitor of apoptosis protein (XIAP), and cyclin-D1 in osteosarcoma in vivo. CONCLUSION: The inhibition of ERK/NF-κB activation is associated with amentoflavone-inhibited osteosarcoma progression in vivo.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , NF-kappa B/metabolismo , Osteossarcoma/metabolismo , Animais , Antineoplásicos/uso terapêutico , Biflavonoides/uso terapêutico , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Nus , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Fitoterapia ; 137: 104255, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271785

RESUMO

Nine biflavonoids (1-9) were isolated from ethanolic extract of Selaginella uncinata (Desv.) Spring. Their structures were determined by spectra analysis. Compounds 1-9 were classified into four types according to the connection styles of the two flavonoid parts. Among them, 1 was elucidated as a new compound, while 4 was one with a new configuration. All isolates exhibited inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) in an enzyme assay with IC50 values ranging from 4.6 to 16.1 µM, and the relationship between the structures and activities was discussed. Docking simulations of these compounds demonstrated they had tight binding capacities towards the allosteric site of PTP1B. Additionally, the glucose uptake activities of 1-9 were evaluated in insulin-resistant HepG2 cells, while the effect of 1 on the activation of IRS-1/PI3K/Akt pathway was revealed by Western Blot analysis.


Assuntos
Biflavonoides/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Selaginellaceae/química , Biflavonoides/isolamento & purificação , China , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Transdução de Sinais/efeitos dos fármacos
5.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(3): 250-255, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31257808

RESUMO

OBJECTIVE: To investigate the protective effects of procyanidin on periprosthetic osteolysis caused by tricalcium phosphate (TCP) wear particles in the mouse calvaria and its mechanism. METHODS: Forty-eight male ICR mice were randomly divided into sham group, TCP group, and procyanidin (0.2 mg/kg, 1 mg/kg, 5 mg/kg)-treated group (n=12). A periprosthetic osteolysis model in the mouse calvaria was established by implanting 30 mg of TCP wear particles onto the surface of bilateral parietal bones following removal of the periosteum. On the 2nd day post-operation, procyanidin (1 mg/kg, 5 mg/kg) was locally injected to the calvaria under the periosteum every other day. After 2 weeks, all the mice were sacrificed to collect the blood samples and the calvaria. Periprosthetic osteolysis and osteoclastogenesis in the mouse calvaria were observed by tartrate resistant acid phosphatase (TRAP) staining and HE staining. mRNA levels of TRAP, capthesin K, c-Fos and NFATc1 in the periprosthestic bone tissue were examined by real-time fluorescence quantitative PCR. Serum contents of total anti-oxidation capacity (T-AOC) and MDA, and superoxide dismutase (SOD) activity were determined by chemical colorimetry. Protein expressions of autophagic biomarkers such as Beclin-1 and LC-3 in periprosthetic bone tissue of the calvaria were examined by Western blot. RESULTS: Compared with sham group, periprosthetic osteolysis, osteoclastogenesis, mRNA levels of TRAP, capthesin K, c-Fos and NFATc1, and serum MDA content were increased significantly in the TCP group (P<0.05), whereas serum T-AOC level and SOD activity were decreased. The protein expressions of Beclin-1 and LC-3, and the conversion of LC3-II from LC3-I were both up-regulated markedly in the mouse calvaria of TCP group (P<0.05). Compared with TCP group, osteolysis, osteoclastogenesis, mRNA levels of TRAP, capthesin K, c-Fos and NFATc1 and serum MDA content were decreased obviously in the procyanidine group (P<0.05), serum T-AOC level and SOD activity were increased, the expressions of Beclin-1 and LC-3, and the conversion of LC3-II from LC3-I were down-regulated obviously in the mouse calvaria of procyanidin group (P<0.05). CONCLUSION: Procyanidin has a protective effect of periprosthetic osteolysis caused by TCP wear particles in the mouse calvaia, its mechanism may be mediated by inhibition of oxidative stress and autophagy.


Assuntos
Biflavonoides/farmacologia , Fosfatos de Cálcio/efeitos adversos , Catequina/farmacologia , Osteólise , Proantocianidinas/farmacologia , Próteses e Implantes/efeitos adversos , Animais , Autofagia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo , Distribuição Aleatória , Crânio
6.
J Agric Food Chem ; 67(32): 8839-8846, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31334651

RESUMO

Natural products are one of the main sources for discovering new lead compounds. We previously reported that cinnamon extract has a promising effect in regulating lipid tissue volume and insulin sensitivity in vivo. However, its effective component and the underlying mechanism are not known. In the present study, we analyzed the effect of different components of cinnamon on regulating insulin sensitivity in 3T3-L1 adipocytes. Functional assay revealed that, of the six major components of cinnamon extracts, the B-type procyanidin, procyanidin C1, improves the differentiation of 3T3-L1 cells (TG content: 1.10 ± 0.09 mM at a dosage of 25 µM vs 0.67 ± 0.02 mM in vehicle group, p < 0.001) and promotes insulin-induced glucose uptake (8.58 ± 1.43 at a dosage of 25 µM vs 3.05 ± 1.24 in vehicle group, p < 0.001). Mechanism studies further suggested that procyanidin C1 activates the AKT-eNOS pathway, thus up-regulating glucose uptake and enhancing insulin sensitivity in mature adipocytes. Taken together, our study identified B-type procyanidin C1, a component of cinnamon extract, that stimulates preadipocyte differentiation and acts as a potential insulin action enhancer through the AKT-eNOS pathway in mature adipocytes.


Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Biflavonoides/farmacologia , Catequina/farmacologia , Cinnamomum zeylanicum/química , Insulina/metabolismo , Extratos Vegetais/farmacologia , Proantocianidinas/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Animais , Transporte Biológico/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Glucose/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
7.
Pestic Biochem Physiol ; 157: 169-177, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31153465

RESUMO

To explore the toxicity mechanisms of neochamaejasmin A (NCA), extracted from Stellera chamaejasme L., we first evaluated its cytotoxicity on the Spodoptera frugiperda (Sf9) cell line. The results confirmed that NCA inhibited Sf9 cell survival in both a dose- and time-dependent manner. Then, intracellular biochemical assays showed that NCA induced apoptosis in Sf9 cells. Evidence of apoptosis was confirmed by morphological changes and the activation of caspases-3/9. We also observed that NCA induced apoptosis via mitochondrial-dependent intrinsic apoptotic pathway by upregulating cytochrome c and proapoptotic protein (Bax) and downregulating the mitochondrial membrane potential (MMP) and antiapoptotic protein (Bcl-2). Moreover, we found a dose-dependent increase in reactive oxygen species (ROS), accumulation of lipid peroxidation product and an inactivation of the antioxidant enzymes in treated cells. Additionally, the cleavage of PARP and G2/M arrest were also detected in Sf9 cells exposed to NCA. These findings provide critical information that NCA effectively induced apoptosis in Sf9 cells through mitochondrial pathways.


Assuntos
Biflavonoides/química , Biflavonoides/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Thymelaeaceae/química , Animais , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Células Sf9 , Transdução de Sinais/efeitos dos fármacos , Spodoptera
8.
Int J Mol Sci ; 20(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195622

RESUMO

Diabetes is a contributor to morbidity across the globe and is often associated with obesity, metabolic syndrome and other inflammatory diseases associated with aging. In addition to genetic and lifestyle factors, environmental factors such as metals and persistent organic pollutants may increase the severity or lower the threshold of these conditions. In cell culture, methylmercury is toxic to adipocytes and may impact adipokine secretions. In this study, we determined the effects of different concentrations of theaflavin digallate on methylmercury exposed 3T3-L1 adipocytes in cell culture. Secretions of resistin, adiponectin and lipid peroxidation product, 4-hydroxynonenal (4-HNE) were monitored using ELISA assays. Cell morphology of methylmercury and theaflavin-3,3'-digallate treated adipocytes was assessed using Lipid (Oil Red O) staining. Exposure to methylmercury increased the levels of resistin and adiponectin as well as 4-HNE when compared to the control cells. Methylmercury treated cells resulted in smaller number of adipocytes and clumped lipid droplets. These results suggest that methylmercury induces reactive oxygen species leading to development of an inflammatory response. Theaflavin-3,3'-digallate reduced the impact of methylmercury by maintaining the adipocytes morphology and secretion patterns of adiponectin, resistin and 4-hydroxynonenal. With this experimental model system other anti-inflammatory and signaling agents could be tested at the biochemical level before eventually leading to studies in animal models.


Assuntos
Adipócitos/citologia , Adipocinas/metabolismo , Biflavonoides/farmacologia , Catequina/farmacologia , Diferenciação Celular , Ácido Gálico/análogos & derivados , Compostos de Metilmercúrio/toxicidade , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adiponectina/metabolismo , Aldeídos/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Ácido Gálico/farmacologia , Camundongos , Resistina/metabolismo
9.
Molecules ; 24(11)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212585

RESUMO

AIM: To investigate the anti-diabetic activity of amentoflavone (AME) in diabetic mice, and to explore the potential mechanisms. METHODS: Diabetic mice induced by high fat diet and streptozotocin were administered with amentoflavone for 8 weeks. Biochemical indexes were tested to evaluate its anti-diabetic effect. Hepatic steatosis, the histopathology change of the pancreas was evaluated. The activity of glucose metabolic enzymes, the expression of Akt and pAkt, and the glucose transporter type 4 (GLUT4) immunoreactivity were detected. RESULTS: AME decreased the level of glucose, total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and glucagon, and increased the levels of high density lipoprotein cholesterol (HDL-C) and insulin. Additionally, AME increased the activity of glucokinase (GCK), phosphofructokinase-1 (PFK-1), and pyruvate kinase (PK), and inhibited the activity of glycogen synthase kinase-3 (GSK-3), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G-6-Pase). Mechanistically, AME increased superoxide dismutase (SOD), decreased malondialdehyde (MDA), activation of several key signaling molecules including pAkt (Ser473), and increased the translocation to the sedimenting membranes of GLUT4 in skeletal muscle tissue. CONCLUSIONS: AME exerted anti-diabetic effects by regulating glucose and lipid metabolism, perhaps via anti-oxidant effects and activating the PI3K/Akt pathway. Our study provided novel insight into the role and underlying mechanisms of AME in diabetes.


Assuntos
Biflavonoides/química , Biflavonoides/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Animais , Biomarcadores , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental , Jejum , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Glucagon/sangue , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Lipoproteínas/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução/efeitos dos fármacos , Fosforilação
10.
Talanta ; 200: 279-287, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31036185

RESUMO

Plants are well-recognized sources of inhibitors for α-glucosidase - a key target enzyme for management of type 2 diabetes. Recently, two advanced bioactivity-profiling techniques, i.e., ligand fishing and high-resolution inhibition profiling, have shown great promises for accelerating identification of α-glucosidase inhibitors from complex plant extracts. Non-specific affinities and non-specific inhibitions are major sources of false positive hits from ligand fishing and high-resolution inhibition profiling, respectively. In an attempt to minimize such false positive hits, we describe a new screening approach based on ligand fishing and high-resolution inhibition profiling for detection of high-affinity ligands and assessment of inhibitory activity, respectively. The complementary nature of ligand fishing and high-resolution inhibition profiling was explored to identify α-glucosidase inhibitory ligands from a complex mixture, and proof-of-concept was demonstrated with crude ethyl acetate extract of Ginkgo biloba. In addition to magnetic beads with a 3-carbon aliphatic linker, α-glucosidase was immobilized on magnetic beads with a 21-carbon aliphatic linker; and the two different types of magnetic beads were compared for their hydrolytic activity and fishing efficiency.


Assuntos
Biflavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Extratos Vegetais/farmacologia , alfa-Glucosidases/metabolismo , Biflavonoides/química , Biflavonoides/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos , Ginkgo biloba/química , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Ligantes , Fenômenos Magnéticos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Saccharomyces cerevisiae/enzimologia , Relação Estrutura-Atividade
11.
Molecules ; 24(10)2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109031

RESUMO

The structure of a new procyanidin tetramer, which we call a crown procyanidin tetramer, with an unprecedented macrocyclic structure has been characterized for the first time. Its comprehensive spectroscopic analysis revealed that it is a symmetric procyanidin tetramer composed of four (-)-epicatechin sub-units linked alternatively via 4ß→8 or 4ß→6 B-type interflavanyl linkages to form the macrocyclic structure. This NMR-characterized carbon skeleton has never been reported before for procyanidins in grape or in wine, neither in the plant kingdom. Surprisingly, the crown procyanidin tetramer appeared to be specifically localized in grape skin, contrasting with the oligomeric and polymeric procyanidins present in seed, skin, and bunch stem. Moreover, this crown procyanidin tetramer showed promising protective effects against amyloid-ß induced toxicity.


Assuntos
Biflavonoides/química , Biflavonoides/farmacologia , Catequina/química , Catequina/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Multimerização Proteica , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/toxicidade , Animais , Biflavonoides/isolamento & purificação , Catequina/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Proantocianidinas/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Substâncias Protetoras/farmacologia , Vitis/química
12.
Am J Chin Med ; 47(4): 913-931, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096773

RESUMO

Glioblastoma is the most common primary malignant tumor of the central nervous system, with an annual incidence of 5.26 per 100000 people. The clinical outcome of standard therapy and the survival rate remain poor; therefore, there is an unmet need for a new strategy to treat this lethal disease. Although amentoflavone was known to have anticancer potential in various types of cancers, its antiglioblastoma ability and mechanism remain unrecognized. We demonstrated that amentoflavone may suppress glioblastoma invasion and migration by transwell assay. Moreover, we established NF- κ B reporter gene system and used that for verifying NF- κ B inhibition efficacy of amentoflavone on in vitro and in vivo studies. Here, we indicated that amentoflavone not only diminished NF- κ B activation, but also reduced NF- κ B-mediated downstream oncogenes expression, such as MMP-2, MMP-9, XIAP, cyclinD1 and VEGF, which was elucidated by Western blot and immunohistochemistry (IHC). Tumor growth inhibition and NF- κ B reduction was found in the amentoflavone treatment group, which was revealed by the glioblastoma-bearing animal model. In this study, we also used ERK inhibitor and NF- κ B inhibitor (QNZ) to confirm whether the beneficial result of amentoflavone on glioblastoma was mainly regulated by blockage of ERK/NF- κ B signaling. In summary, ERK/NF- κ B signaling pathway has a role in the inhibition of tumor growth by amentoflavone in glioblastoma.


Assuntos
Antineoplásicos Fitogênicos , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , NF-kappa B/metabolismo , Fitoterapia , Animais , Progressão da Doença , Glioblastoma/genética , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/fisiologia , Oncogenes , Células Tumorais Cultivadas
13.
Folia Neuropathol ; 57(1): 16-23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038184

RESUMO

The present investigation evaluates the protective effect of Ginkgetin aglycone (GA) against ischemic stroke-induced neuronal injury. Ischemic stroke was produced by the middle cerebral artery occlusion (MCAO) model and animals were a group that received GA 100 and 200 mg/kg, i.p. five days before the induction of MCAO. The effect of GA against stroke was determined by estimating the neurological deficit score and brain water content was also observed. Moreover terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay was done for determining the neuronal apoptosis and Western blot assay also performed for estimating the expression of several proteins. Results of the study suggest that the neurological deficit score and brain water content was found to be lower in the GA treated group than the ischemia/reperfusion (I/R) group of rats. Moreover the number of TUNEL positive cells was found to be lower in the GA treated group than in the I/R group of rats. There was a significant (p < 0.01) decrease in the oxidative stress parameters and cytokine in the tissue homogenate of the GA treated group compared to the I/R group of rats. Further treatment with GA attenuates altered expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein kinase B (Akt), B-cell lymphoma 2 (Bcl-2), signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa light chain enhancer of activated B cells (NF-B), toll-like receptor 4 (TLR-4), Janus kinase 2 (JAK-2) and sirtuin-1 (SIRT-1) protein in the brain tissues of stroke rats. In conclusion, data of the report reveal that treatment with Ginkgetin aglycone protects the neuronal injury against stroke in rats by reducing oxidative stress and inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Biflavonoides/farmacologia , Neurônios/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/patologia , Animais , Inflamação/metabolismo , Inflamação/patologia , Janus Quinase 2/efeitos dos fármacos , Janus Quinase 2/metabolismo , Masculino , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/metabolismo , Acidente Vascular Cerebral/metabolismo
14.
Zhongguo Zhong Yao Za Zhi ; 44(7): 1442-1449, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090303

RESUMO

The research of anti-hepatocellular carcinoma(HCC) drug has attracted more and more attention. Natural products are the important source of active compounds for cancer treatment. A biflavonoid HIS-4 was isolated from Resina draconis in our previous study. MTT assay, hoechst staining, and flow cytometry analysis were used to investigate the effects of HIS-4 on the proliferation and apoptosis of human hepatoma HepG2 and SK-HEP-1 cells. Moreover, the effects of HIS-4 on the migration and invasion ability of HepG2 and SK-HEP-1 cells were evaluated by wound healing assay and Transwell assay. In addition, MTT assay, flow cytometry analyses, Hoechst staining, wound healing assay, Transwell assay, and tube formation assay were used to explore the anti-angiogenic activity of HIS-4 in human umbilical vein endothelial cells(HUVECs). Mechanistically, the HIS-4 regulatory of signal pathways in H9 epG2 and SK-HEP-1 cells were analyzed by Western blot. This results showed that HIS-4 suppressed the proliferation of human hepatoma HepG2 and SK-HEP-1 cells. Moreover HIS-4 induced their apoptosis of HepG2 and SK-HEP-1 cells. HIS-4 inhibited the migration and invasion of HepG2 and SK-HEP-1 cells. Additionally, HIS-4 exhibited angiogenesis effects. Mechanistically, up-regulation of MAPK signaling pathway and down-regulation of mTOR signaling pathway may be responsible for anti-hepatoma activity of HIS-4. Therefore, HIS-4 may be a promising candidate drug for HCC treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Biflavonoides/farmacologia , Carcinoma Hepatocelular/patologia , Dracaena/química , Neoplasias Hepáticas/patologia , Apoptose , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular , Proliferação de Células , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Compostos Fitoquímicos/farmacologia
15.
Molecules ; 24(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072069

RESUMO

Nandina domestica (Berberidaceae) has been used in traditional medicine for the treatment of cough. This plant is distributed in Korea, Japan, China, and India This study aimed to investigate the anti-inflammatory phytochemicals obtained from the N. domestica fruits. We isolated a biflavonoid-type phytochemical, robustaflavone (R), from N. domestica fruits through bioactivity-guided fractionation based on its capacity to inhibit inflammation. The anti-inflammatory mechanism of R isolated from N. domestica has not yet been studied. In the present study, we evaluated the anti-inflammatory activities of R using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We have shown that R reduces the production of nitric oxide (NO), pro-inflammatory cytokine interleukin-1 beta (IL-1ß), and IL-6. Western blot analysis showed that R suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and downregulates the expression of LPS-induced nuclear factor-kappa B (NF-κB) and the phosphorylation of extracellular-regulated kinases (pERK 1/2). Moreover, R inhibited IL-8 release in LPS-induced human colonic epithelial cells (HT-29). These results suggest that R could be a potential therapeutic candidate for inflammatory bowel disease (IBD).


Assuntos
Berberidaceae/química , Biflavonoides/isolamento & purificação , Biflavonoides/farmacologia , Regulação para Baixo , Mediadores da Inflamação/metabolismo , Animais , Biflavonoides/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HT29 , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/biossíntese , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Células RAW 264.7
16.
Cell Mol Biol (Noisy-le-grand) ; 65(4): 79-82, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31078156

RESUMO

Effect of ginkgetin on proliferation of human cervical cancer (HeLa) cells and the underlying mechanism   were investigated. Human cervical cancer (HeLa) cells were cultured at 37 °C in 10 % fetal bovine serum (FBS) supplemented RPMI 1640 medium in a humidified incubator containing 5 % CO2. Cell proliferation was determined using MTT assay, while real-time quantitative polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to determine the levels of expression of interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin 8 (IL-8). The expressions of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) were determined using Western blotting. Treatment of HeLa cells with ginkgetin significantly and time- and dose-dependently inhibited their proliferation (p < 0.05). The invasion of the cells were also significantly and dose-dependently decreased, when compared with control cells (p < 0.05). The expressions of p-p38 and p-NF-κB were significantly and dose-dependently down-regulated, relative to control group (p < 0.05). However, the expressions of p38 and NF-κB in ginkgetin-treated cells were not significantly different from those of control group (p > 0.05). The results of qRT-PCR and ELISA showed that the levels of expression of TNF-α, IL-1ß and IL-8 mRNAs were significantly and dose-dependently reduced in HeLa cells after 48 h of treatment with ginkgetin, when compared with the control group (p < 0.05). The anti-proliferative effect of ginkgetin on HeLa cells is exerted via a mechanism involving the p38/NF-κB pathway.


Assuntos
Biflavonoides/farmacologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Biflavonoides/química , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Mol Nutr Food Res ; 63(10): e1801413, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31018035

RESUMO

SCOPE: The aim is to assess the action of an aqueous extract from cocoa shell (CAE) and its main phenolic compounds to prevent the loss of obesity-induced mitochondrial function and insulin sensitivity, targeting inflammation between macrophages-adipocytes in vitro. METHODS AND RESULTS: CAE (31-500 µg mL-1 ) inhibits 3T3-L1 adipocytes lipid accumulation and induces browning during differentiation. LPS-stimulated RAW264.7 macrophages show reduced inducible nitric oxide synthase and cyclooxygenase-2 expression and lowered pro-inflammatory cytokine production when treated with CAE and pure phenolics. Inflammatory crosstalk created by stimulating adipocytes with macrophage-conditioned media (CM) is arrested; CAE diminishes tumor necrosis factor-α (67%) and promotes adiponectin secretion (12.3-fold). Mitochondrial function, measured by reactive oxygen species production, mitochondrial content, and activity, is preserved in CM-treated adipocytes through up-regulating peroxisome proliferator-activated receptor gamma coactivator 1-α expression. Increases in insulin receptor (9-fold), phosphoinositide 3-kinase (3-fold), protein kinase B (4-fold) phosphorylation, and a decrease in insulin receptor substrate 1 serine phosphorylation induce increased glucose uptake (34%) and glucose transporter 4 translocation (14-fold) in CM-induced adipocytes. CONCLUSION: CAE phenolics promote a beige phenotype in adipocytes. Macrophages-adipocytes inflammatory interaction is reduced preventing mitochondrial dysfunction and insulin resistance. For the first time, CAE shows a positive effect on adipogenesis and inflammation-related disorders.


Assuntos
Adipócitos/efeitos dos fármacos , Cacau/química , Macrófagos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Biflavonoides/farmacologia , Catequina/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Hidroxibenzoatos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Mitocôndrias/metabolismo , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Proantocianidinas/farmacologia , Células RAW 264.7
18.
Molecules ; 24(8)2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-31013944

RESUMO

Three previously undescribed biflavonoids, oxytrodiflavanone A (1), and oxytrochalcoflavanones A,B (2,3), were isolated from the aerial part of Oxytropis chiliophylla, together with their putative biosynthetic monomers, i.e., (2S)-5,7-dihydroxyflavanone (4), (2S)-7-hydroxyflavanone (5), and 2',4'-dihydroxychalcone (6). The structures of these compounds were elucidated by a combination analysis of spectroscopic data. The cytotoxic activities of all the isolated compounds against PC-3 human prostate cancer cell line are also presented.


Assuntos
Antineoplásicos Fitogênicos , Biflavonoides , Chalconas , Flavanonas , Oxytropis/classificação , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Biflavonoides/química , Biflavonoides/farmacologia , Chalconas/química , Chalconas/farmacologia , Flavanonas/química , Flavanonas/farmacologia , Humanos , Masculino , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
19.
Int J Mol Sci ; 20(7)2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970662

RESUMO

Salicylate-rich plants are an attractive alternative to synthetic anti-inflammatory drugs due to a better safety profile and the advantage of complementary anti-inflammatory and antioxidant effects of the co-occurring non-salicylate phytochemicals. Here, the phytochemical value and biological effects in vitro and ex vivo of the stems of one of such plants, Gaultheria procumbens L., were evaluated. The best extrahent for effective recovery of the active stem molecules was established in comparative studies of five extracts. The UHPLC-PDA-ESI-MS³, HPLC-PDA, and UV-photometric assays revealed that the selected acetone extract (AE) accumulates a rich polyphenolic fraction (35 identified constituents; total content 427.2 mg/g dw), mainly flavanols (catechins and proanthocyanidins; 201.3 mg/g dw) and methyl salicylate glycosides (199.9 mg/g dw). The extract and its model components were effective cyclooxygenase-2, lipoxygenase, and hyaluronidase inhibitors; exhibited strong antioxidant capacity in six non-cellular in vitro models (AE and procyanidins); and also significantly and dose-dependently reduced the levels of reactive oxygen species (ROS), and the release of cytokines (IL-1ß, IL-8, TNF-α) and proteinases (elastase-2, metalloproteinase-9) in human neutrophils stimulated ex vivo by lipopolysaccharide (LPS) and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). The cellular safety of AE was demonstrated by flow cytometry. The results support the application of the plant in traditional medicine and encourage the use of AE for development of new therapeutic agents.


Assuntos
Anti-Inflamatórios/farmacologia , Biflavonoides/farmacologia , Catequina/farmacologia , Gaultheria/química , Neutrófilos/citologia , Proantocianidinas/farmacologia , Salicilatos/farmacologia , Adulto , Anti-Inflamatórios/química , Biflavonoides/química , Catequina/química , Sobrevivência Celular , Citocinas/metabolismo , Humanos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Caules de Planta/química , Proantocianidinas/química , Espécies Reativas de Oxigênio/metabolismo , Salicilatos/química , Adulto Jovem
20.
Molecules ; 24(8)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995808

RESUMO

Ginkgo biloba L., an ancient dioecious gymnosperm, is now cultivated worldwide for landscaping and medical purposes. A novel biflavonoid-amentoflavone 7''-O-ß-D-glucopyranoside (1)-and four known biflavonoids were isolated and identified from the male flowers of Ginkgo. The anti-proliferative activities of five biflavonoids were evaluated on different cancer lines. Bilobetin (3) and isoginkgetin (4) exhibited better anti-proliferative activities on different cancer lines. Their effects were found to be cell-specific and in a dose and time dependent manner for the most sensitive HeLa cells. The significant morphological changes validated their anticancer effects in a dose-dependent manner. They were capable of arresting the G2/M phase of the cell cycle, inducing the apoptosis of HeLa cells dose-dependently and activating the proapoptotic protein Bax and the executor caspase-3. Bilobetin (3) could also inhibit the antiapoptotic protein Bcl-2. These might be the mechanism underlying their anti-proliferation. In short, bilobetin (3) and isoginkgetin (4) might be the early lead compounds for new anticancer agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Biflavonoides/farmacologia , Flores/química , Ginkgo biloba/química , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/química , Biflavonoides/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química
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