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1.
Life Sci ; 244: 117336, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972206

RESUMO

AIMS: Postmenopausal osteoporosis and other osteolytic bone diseases are often caused by the elevation in osteoclastogenesis and/or increased osteoclastic bone resorption, leading to excessive bone loss. Hederagenin (Hed) is a pentacyclic triterpenoid saponin extracted from various natural medicinal plants and exhibits numerous biological activities and may offer benefits against bone-related conditions. We evaluated the effects of Hed on osteoclast formation and bone resorption in vitro and the in vivo therapeutic benefits in the mouse model of ovariectomy (OVX)-induced bone loss. MAIN METHODS: In vitro, osteoclast formation were determined by TRAcp staining; bone resorption were examined using Hydroxyapatite resorption assay and Podosomal actin belt formation assay; Related molecular mechanisms were determined by western blot assay. Construction of OVX mice by bilateral oophorectomy to simulate bone loss in vivo. KEY FINDINGS: In vitro cellular assays showed that Hed inhibited RANKL-induced osteoclast formation and osteoclast bone (hydroxyapatite) resorption as well as marker gene expression from BMM culture. Mechanistically, Hed attenuated RANKL-induced intracellular reactive oxygen species (ROS) production, and MAPK signaling pathway (ERK and p38) activation which curbed the downstream induction of c-Fos and NFATc1. Consistent with the in vitro findings, Hed administration effectively protected OVX mice from bone loss by reducing osteoclast number and activity on bone surface. SIGNIFICANCE: Our data provided promising evidence for the potential use of Hederagenin in the treatment of osteoclast-mediated osteolytic bone diseases such as postmenopausal osteoporosis.


Assuntos
Reabsorção Óssea/prevenção & controle , Ácido Oleanólico/análogos & derivados , Osteogênese/efeitos dos fármacos , Ovariectomia/efeitos adversos , Substâncias Protetoras/farmacologia , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Feminino , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Ácido Oleanólico/farmacologia , Ligante RANK/genética , Transdução de Sinais
2.
Eur J Med Chem ; 185: 111806, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677446

RESUMO

In this work, 35 new derivatives of betulonic, dihydrobetulonic and ursonic acid were prepared including 30 aminothiazoles and all of them were tested for their in vitro cytotoxic activity in eight cancer cell lines and two non-cancer fibroblasts. Compounds with the IC50 below 5 µM in CCRF-CEM cells and low toxicity in non-cancer fibroblasts (4m, 5c, 5m, 6c, 6m, 7b, and 7c) were further subjected to tests of pharmacological parameters yielding the final set for advanced biological evaluation (4m, 5m, 6m, and 7b). It was proved by several methods, that all of them trigger apoptosis via the intrinsic pathway and derivatives 5m and 7b are the most effective (IC50 2.4 µM and 3.6 µM). They are the best candidates to become potentially new anticancer drugs and will be subjected to in vivo tests in mice. In addition, compounds 6b and 6c deserve more attention because their activity is not limited only to chemosensitive CCRF-CEM cell line. Specifically, compound 6b is highly active against K562 leukemic cell line (0.7 µM) and its IC50 activity in colon cancer HCT116 cell line is 1.0 µM. Compound 6c is active in both normal K562 and resistant K562-TAX cell lines (IC50 3.4 µM and 5.4 µM) and both colon cancer cell lines (HCT116 and HCT116p53-/-, IC50 3.5 µM and 3.4 µM).


Assuntos
Antineoplásicos/farmacologia , Ácido Oleanólico/análogos & derivados , Terpenos/farmacologia , Tiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microssomos/química , Microssomos/metabolismo , Estrutura Molecular , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Relação Estrutura-Atividade , Terpenos/síntese química , Terpenos/química , Tiazóis/síntese química , Tiazóis/química
3.
Zhongguo Zhong Yao Za Zhi ; 44(14): 2966-2971, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602841

RESUMO

To study the effects of saikosaponin b2( SS-b2) on inflammatory factors and energy metabolism against lipopolysaccharide/galactosamine( LPS/Gal N) induced acute liver injury in mice. Mice were randomly divided into normal group( equal amount of normal saline),model group( 100 g·kg~(-1) LPS and 400 mg·kg~(-1) Gal N),low,medium,high dose group of SS-b2( SS-b25,10,20 mg·kg~(-1)·d-1) and positive control group( dexamethasone,10 mg·kg~(-1)). All of the groups except for the normal group were treated with LPS/Gal N though intraperitoneally injection to establish the acute liver injury model. The organ indexes were calculated. The levels of serum transaminases( ALT and AST) and the activities of ATPase( Na+-K+-ATPase,Ca2+-Mg2+-ATPase) in liver were detected. The activity of tumor necrosis factor-α( TNF-α),interleukin-1ß( IL-1ß) and interleukin-6( IL-6) were determined by the enzyme-linked immunosorbent assay( ELISA). The contents of lactate dehydrogenase( LDH) in liver were determined by micro-enzyme method. HE staining was used to observe the histopathological changes of the liver. Histochemical method was used to investigate the protein expression of liver lactate dehydrogenase-A( LDH-A). The protein expressions of Sirt-6 and NF-κB in the liver were detected by Western blot. According to the results,compared with the model group,there were significant changes in organ indexes in the high-dose group of SS-b2( P<0. 05). The level of ALT,AST,TNF-α,IL-1ß,IL-6 and the activities of LDH in serum of mice with liver injury were significantly reduced in the medium and high dose groups of SS-b2( P<0. 01). With the increase of the concentration of SS-b2,the range of hepatic lesions and the damage in mice decreased. The activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in liver of mice were significantly enhanced in each dose group( P<0. 01). The expression of NF-κB in liver tissues was significantly down-regulated in the medium and high dose group( P<0. 01). Meanwhile,the expression of Sirt-6 protein in the liver of mice with acute liver injury was significantly increased in each dose group( P<0. 01).In summary,SS-b2 has a significant protective effect on LPS/Gal N-induced acute liver injury in mice,which may be related to the down-regulation of NF-κB protein expression and up-regulation of Sirt-6 protein expression to improve inflammatory injury and energy metabolism.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Metabolismo Energético , Inflamação/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Citocinas/metabolismo , Galactosamina , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Ácido Oleanólico/farmacologia , Distribuição Aleatória , Sirtuínas/metabolismo
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 595-600, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537243

RESUMO

Objective To observe the effect of esculentoside A (EsA) on Th17 cell-related factors in psoriasis-like mouse model. Methods A total of 48 female BALB/c mice were randomly divided into blank control group, model group, Tuiyin decoction group [66.60 g/(kg.d)], low-, middle- and high-dose groups of EsA [5, 10, 20 mg/(kg.d), respectively], 8 mice in each group. Psoriasis mouse model was induced by imiquimod. Pathological changes of skin lesions in mice were assessed by psoriasis area and severity index (PASI) and HE staining. ELISA was used to detect the changes of interleukin-17 (IL-17), IL-22, IL-6 and tumor necrosis factor-α (TNF-α). Results Compared with the model group, the skin lesions, pathological changes and PASI scores were improved after the treatments with either Tuiyin decoction or EsA, among which the PASI score of Tuiyin decoction group and high-dose group of EsA decreased significantly. The expression of Th17 cell-related factors of the model group was obviously higher than that of the blank control group. Each treated group had obviously lower expression than the model group, and the expression of IL-6 of high-dose group of EsA was close to the blank control group. Conclusion EsA may improve the skin lesions of the psoriasis-like mice by down-regulating the expression of Th17 cell-related cytokines.


Assuntos
Dermatite/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Psoríase/tratamento farmacológico , Saponinas/farmacologia , Células Th17/imunologia , Animais , Citocinas/imunologia , Dermatite/imunologia , Feminino , Imiquimode , Camundongos , Camundongos Endogâmicos BALB C , Ácido Oleanólico/farmacologia , Psoríase/induzido quimicamente , Distribuição Aleatória , Pele/imunologia , Pele/patologia
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(8): 904-910, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31511209

RESUMO

OBJECTIVE: To investigate the effect of calenduloside E on lipopolysaccharide (LPS)-induced inflammatory response in RAW264.7 cells and explore the underlying molecular mechanism. METHODS: CCK-8 assay was used to examine the effect of different concentrations of calenduloside E (0-30 µg/mL) on the viability of RAW264.7 cells. The release of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in RAW264.7 cells in response to pretreatment with 6, 8, and 10 µg/mL calenduloside E for 2 h followed by stimulation with 100 ng/mL LPS was detected using enzyme-linked immunosorbent assay (ELISA). The expression levels of iNOS and COX-2 and the activation of JAK-stats, MAPKs and NF-кB signaling pathways in the treated cells were determined using Western blotting. A reactive oxygen species (ROS) detection kit was used to detect ROS production in the cells, and the nuclear translocation of the transcription factor stat3 was observed by laser confocal microscopy. RESULTS: Calenduloside E below 20 µg/mL did not significantly affect the viability of RAW264.7 cells. Calenduloside E dose-dependently decreased the expression levels of iNOS and COX-2 induced by LPS, inhibited LPS-induced release of TNF-α and IL-1ß, and suppressed LPS-induced JAK1-stat3 signaling pathway activation and stat3 nuclear translocation. Calenduloside E also significantly reduced ROS production induced by LPS in RAW264.7 cells. CONCLUSIONS: Calenduloside E inhibits LPS-induced inflammatory response by blocking ROS-mediated activation of JAK1-stat3 signaling pathway in RAW264.7 cells.


Assuntos
Transdução de Sinais , Animais , Lipopolissacarídeos , Camundongos , NF-kappa B , Ácido Oleanólico/análogos & derivados , Células RAW 264.7 , Espécies Reativas de Oxigênio , Saponinas
6.
Chem Biol Interact ; 311: 108786, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401087

RESUMO

Naturally occurring oleanolic acid (OA) possesses a hepatoprotective activity and ability to inhibit proliferation of human hepatocellular carcinoma cells. Both properties might be related to its anti-inflammatory activity. Its low bioavailability justifies the search for more hydrophilic OA derivatives. The aim of this study was the design and synthesis of four novel OA oxime derivatives conjugated with succinic acid at the C-3 position of oleanane skeleton structure and evaluation of their effect on NF-κB and STATs expression and activation in HepG2 cells. The expression of NF-κB and cyclooxygenase-2 (COX-2), STAT5A/B and STAT3 with its target genes: BAX, BCL-XL and MYC was evaluated after 24 h treatment with tested compounds. The comparison of the levels of cytosolic and nuclear NF-κB subunits p50, p65 and STATs proteins was used as the measure of their activation. The results pointed out the 3-succinyloxyiminoolean-12-en-28-oic acid morpholide (SMAM) as the most potent modulator of NF-κB and STAT3. SMAM significantly reduced the expression and activation of NF-κB as well as its nuclear protein level of p65 subunit. This compound also reduced the expression and activation of STAT3 and STAT5A/B. Combined effect of SMAM on these transcription factors resulted in reduced expression of COX-2, MYC and anti-apoptotic BCL-XL genes. Simultaneously, the increased expression of pro-apoptotic BAX gene was observed. In the cells treated with 3-succinyloxyiminoolean-12-en-28-oic acid (SMAA) the increased expression of BAX was also found. The effects of 3-succinyloxyiminoolean-12-en-28-oic acid benzyl ester (SMAEB) and 3-succinyloxyiminoolean-12-en-28-oic acid methyl ester (SMAEM) were moderate and ambiguous in relation to the tested factors. Moreover, the coordinated action of SMAM on NF-κB and STAT3 confirms their close association in HepG2 cells. We conclude that SMAM efficiently downregulates the key elements of signaling pathways involved in inflammatory driven HCC. Thus, may be considered as a potential chemopreventive or therapeutic agent in this type of cancer.


Assuntos
NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Oximas/farmacologia , Fatores de Transcrição STAT/metabolismo , Ácido Succínico/química , Carcinoma Hepatocelular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas , NF-kappa B/genética , Oximas/química , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição STAT/genética , Transcrição Genética/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
7.
Phytomedicine ; 63: 153056, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31398661

RESUMO

BACKGROUND: T helper 17 (Th17) cells, which are differentiated from CD4+ T cells, drive inflammation, leading to autoimmune diseases such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Therefore, inhibiting Th17 polarization could be a therapeutic target for inflammatory diseases. PURPOSE: We investigated the inhibitory effect of Fraxinus rhynchophylla (Oleaceae) on Th17 differentiation and found its active component. STUDY DESIGN: The activity of F. rhynchophylla and its active constituent was verified using CD4+ cells extracted from C57BL/6 mice. METHODS: Micro-environment for Th17 polarization was provided to CD4+ cells and the effect of treatment with samples was measured by enzyme linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and Western blot. RESULTS: The extract of F. rhynchophylla Hance and its chemical constituent, α-amyrin acetate, which was isolated via bioassay-guided isolation, significantly inhibited Th17 polarization as revealed when interleukin (IL)-17, a characteristic cytokine produced by Th17 cells, was measured. Furthermore, the inhibitory effect of α-amyrin acetate was compared to the amyrin derivatives, α-amyrin and ß-amyrin. All displayed a suppressive effect on Th17 polarization and all reduced the expression of single transducer and activator of transcription 3 (STAT3) and retinoic acid receptor-related orphan receptor γt (RORγt), which are crucial transcription factors regulating Th17 differentiation. α-Amyrin acetate, however, exhibited the most prominent effects, which indicates that the functional group, acetate, might strengthen the inhibitory effect on Th17 differentiation. CONCLUSION: Taken together, these results suggest that the extract of F. rhynchophylla and its active constituent, α-amyrin acetate, could be applied as a potential therapeutic agent for autoimmune disorders such as rheumatoid arthritis.


Assuntos
Fraxinus/química , Ácido Oleanólico/análogos & derivados , Extratos Vegetais/farmacologia , Células Th17/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Extratos Vegetais/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
8.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370334

RESUMO

Hyperpigmentation is considered by many to be a beauty problem and is responsible for photoaging. To treat this skin condition, medicinal cosmetics containing tyrosinase inhibitors are used, resulting in skin whitening. In this study, taraxerol methyl ether (1), spinasterol (2), 6-hydroxyflavanone (3), (+)-dihydrokaempferol (4), 3,4-dihydroxybenzoic acid (5), taraxerol (6), taraxerone (7), and lupeol acetate (8) were isolated from Manilkara zapota bark. Their chemical structures were elucidated by analysis of their nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) data, and by comparing them with data found in the literature. The in vitro antityrosinase, antioxidant, and cytotoxic activities of the isolated compounds (1-8) were evaluated. (+)-Dihydrokaempferol (4) exhibited higher monophenolase inhibitory activity than both kojic acid and α-arbutin. However, it showed diphenolase inhibitory activity similar to kojic acid. (+)-Dihydrokaempferol (4) was a competitive inhibitor of both monophenolase and diphenolase activities. It exhibited the strongest 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and ferric reducing antioxidant power (FRAP) activities of the isolated compounds. Furthermore, (+)-dihydrokaempferol (4) also demonstrated potent cytotoxicity in breast carcinoma cell line (BT474), lung bronchus carcinoma cell line (Chago-K1), liver carcinoma cell line (HepG2), gastric carcinoma cell line (KATO-III), and colon carcinoma cell line (SW620). These results suggest that M. zapota bark might be a good potential source of antioxidants and tyrosinase inhibitors for applications in cosmeceutical products.


Assuntos
Manilkara/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Arbutina/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/isolamento & purificação , Monofenol Mono-Oxigenase/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Compostos Fitoquímicos/química , Pironas/química , Estigmasterol/análogos & derivados , Estigmasterol/química , Estigmasterol/isolamento & purificação
9.
Molecules ; 24(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426477

RESUMO

Ginsenoside Ro (Ro), a major saponin derived and isolated from Panax ginseng C.A. Meyer, exerts multiple biological activities. However, the anti-tumour efficacy of Ro remains unclear because of its poor in vitro effects. In this study, we confirmed that Ro has no anti-tumour activity in vitro. We explored the anti-tumour activity of Ro in vivo in B16F10 tumour-bearing mice. The results revealed that Ro considerably suppressed tumour growth with no significant side effects on immune organs and body weight. Zingibroside R1, chikusetsusaponin IVa, and calenduloside E, three metabolites of Ro, were detected in the plasma of Ro-treated tumour-bearing mice and showed excellent anti-tumour effects as well as anti-angiogenic activity. The results suggest that the metabolites play important roles in the anti-tumour efficacy of Ro in vivo. Additionally, the haemolysis test demonstrated that Ro has good biocompatibility. Taken together, the findings of this study demonstrate that Ro markedly suppresses the tumour growth of B16F10-transplanted tumours in vivo, and its anti-tumour effects are based on the biological activity of its metabolites. The anti-tumour efficacy of these metabolites is due, at least in part, to its anti-angiogenic activity.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ginsenosídeos/farmacologia , Melanoma Experimental/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Biotransformação , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacocinética , Hemólise/efeitos dos fármacos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/farmacologia , Panax/química , Extratos Vegetais/química , Saponinas/metabolismo , Saponinas/farmacocinética , Neoplasias Cutâneas/patologia
10.
Molecules ; 24(16)2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31443189

RESUMO

Alpha-hederin (α-HN), a pentacyclic triterpene saponin, has recently been identified as one of the active compounds of Nigella sativa, as a potential anticancer agent. However, no extensive studies on α-HN have been done as yet, as it was in the case of thymoquinone-the main ingredient of the N. sativa essential oil. To our knowledge, there are also no data available on how α-HN acts on the human cancer ovarian cell line SKOV-3. In this study we attempt to present the cytotoxic influence of α-HN on the SKOV-3 cell line by means of two methods: Real-Time xCELLigence and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The obtained IC50 values are 2.62 ± 0.04 µg/mL and 2.48 ± 0.32 µg/mL, respectively. An induction of apoptosis in SKOV-3 cells was confirmed by staining cellular nuclei with Hoechst 33342 dye and by flow cytometry analysis by binding annexin V to the cell membranes. We found that α-HN induces apoptosis in a dose-dependent manner. In the first stages of apoptosis, the mitochondrial membrane potential was found to decrease. Also, inactivation of anti-apoptotic protein Bcl-2 was observed, as well as the caspase-9 and then caspase-3/7 activation. In addition, the treatment of SKOV-3 cells with α-HN induced the cell cycle arrest of cancer cells in G0/G1 phase. The results of our investigations indicate that α-HN induces apoptosis in the SKOV-3 cell line and that the intrinsic mitochondrial pathway is involved in the programmed cancer cell death.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Nigella sativa/química , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Antineoplásicos Fitogênicos/química , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Saponinas/química
11.
Fitoterapia ; 138: 104345, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31470063

RESUMO

The present study reports the phytochemical investigation of n-butanol-soluble extracts of Glechoma longituba. Five new oleanane-type triterpenoid saponins with an 11α, 12α-epoxy unit, named glechomanosides A - E, were isolated from the n-butanol soluble fraction of G. longituba. Their chemical structures were established using HRESIMS, IR, 1D NMR, and 2D NMR techniques. The compounds were all evaluated for their antithrombus activities by monitoring thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and antiplatelet aggregation assays. These results suggest that G. longituba might be a candidate plant source of an interesting antithrombotic activity.


Assuntos
Plaquetas/efeitos dos fármacos , Lamiaceae/química , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , China , Feminino , Masculino , Camundongos , Estrutura Molecular , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Tempo de Tromboplastina Parcial , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Agregação Plaquetária , Tempo de Protrombina , Coelhos , Saponinas/isolamento & purificação , Tempo de Trombina
12.
Int J Mol Sci ; 20(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311103

RESUMO

Amyrins are the immediate precursors of many pharmaceutically important pentacyclic triterpenoids. Although various amyrin synthases have been identified, little is known about the relationship between protein structures and the constituent and content of the products. IaAS1 and IaAS2 identified from Ilex asprella in our previous work belong to multifunctional oxidosqualene cyclases and can produce α-amyrin and ß-amyrin at different ratios. More than 80% of total production of IaAS1 is α-amyrin; while IaAS2 mainly produces ß-amyrin with a yield of 95%. Here, we present a molecular modeling approach to explore the underlying mechanism for selective synthesis. The structures of IaAS1 and IaAS2 were constructed by homology modeling, and were evaluated by Ramachandran Plot and Verify 3D program. The enzyme-product conformations generated by molecular docking indicated that ASP484 residue plays an important role in the catalytic process; and TRP611 residue of IaAS2 had interaction with ß-amyrin through π-σ interaction. MM/GBSA binding free energy calculations and free energy decomposition after 50 ns molecular dynamics simulations were performed. The binding affinity between the main product and corresponding enzyme was higher than that of the by-product. Conserved amino acid residues such as TRP257; TYR259; PHE47; TRP534; TRP612; and TYR728 for IaAS1 (TRP257; TYR259; PHE473; TRP533; TRP611; and TYR727 for IaAS2) had strong interactions with both products. GLN450 and LYS372 had negative contribution to binding affinity between α-amyrin or ß-amyrin and IaAS1. LYS372 and ARG261 had strong repulsive effects for the binding of α-amyrin with IaAS2. The importance of Lys372 and TRP612 of IaAS1, and Lys372 and TRP611 of IaAS2, for synthesizing amyrins were confirmed by site-directed mutagenesis. The different patterns of residue-product interactions is the cause for the difference in the yields of two products.


Assuntos
Transferases Intramoleculares/química , Simulação de Acoplamento Molecular , Ácido Oleanólico/análogos & derivados , Triterpenos Pentacíclicos/metabolismo , Proteínas de Plantas/química , Sítios de Ligação , Ilex/enzimologia , Ilex/metabolismo , Transferases Intramoleculares/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/metabolismo , Triterpenos Pentacíclicos/química , Proteínas de Plantas/metabolismo , Ligação Proteica
13.
Mol Med Rep ; 20(2): 1943-1951, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257464

RESUMO

Saikosaponin b2 (SSb2) can be extracted from Bupleurum spp. roots (Radix Bupleuri), which belongs to the Umbelliferae family. The current study aimed to explore the effects of SSb2 on proliferation of breast cancer cells and to identify the mechanism by which SSb2 affects breast cancer cell migration. mRNA expression levels of STAT3 and vasodilator­stimulated phosphoprotein (VASP) were determined and increased expression was observed in 16 breast cancer tissues compared with the paracancerous tissues. MTT, wound healing, colony formation assays and western blot suggested that SSb2 inhibited MCF­7 proliferation and migration. It was further identified by western blot analysis that SSb2 treatment reduced levels of phosphorylated STAT3, VASP, matrix metallopeptidase (MMP) 2 and MMP9 in MCF­7 compared with the untreated cells. In addition, it was demonstrated that inhibition of STAT3 phosphorylation decreased VASP expression levels and induction of STAT3 phosphorylation increased VASP levels. Furthermore, it was observed that the treatment of Kunming mice with SSb2 at 30 mg/kg/day for 30 days induced no obvious changes in the liver or kidney tissues, as determined by haematoxylin and eosin staining. In conclusion, these results indicated that SSb2 may be a potential antitumor drug for the treatment of breast cancer, which acts by suppressing proliferation and migration by downregulating the STAT3 signalling pathway and inhibiting the expression of VASP, MMP2 and MMP9 expression.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Moléculas de Adesão Celular/genética , Proteínas dos Microfilamentos/genética , Ácido Oleanólico/análogos & derivados , Fosfoproteínas/genética , Fator de Transcrição STAT3/genética , Saponinas/farmacologia , Adolescente , Adulto , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Camundongos , Pessoa de Meia-Idade , Ácido Oleanólico/farmacologia , Adulto Jovem
15.
Zhongguo Zhong Yao Za Zhi ; 44(13): 2662-2666, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31359674

RESUMO

Bupleuri Radix has both liver protection and hepatotoxicity. Saponins are the main pharmacodynamic and toxic components of Bupleuri Radix. Based on zebrafish physical model and the model of alcoholic fatty liver( AFL) pathology,the liver toxic and protective effect of saikosaponin a( SSa) were assessed. The results indicated that 1. 77 µmol·L-1 SSa showed protective effect to AFL zebrafish. 5. 30 µmol·L-1 SSa was hepatotoxic to healthy zebrafish,but it showed protective effect to AFL zebrafish. 5. 62 µmol·L-1 SSa was hepatotoxic to healthy and AFL zebrafish. This study is benefit for clinical safety of saikosaponin a.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fígado Gorduroso Alcoólico/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Saponinas/toxicidade , Animais , Ácido Oleanólico/farmacologia , Ácido Oleanólico/toxicidade , Peixe-Zebra
16.
Fitoterapia ; 137: 104242, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202889

RESUMO

Seven oleanane-type glycosides were extracted and isolated by various chromatographic methods from the roots of Weigela x "Bristol Ruby" (1-7), six previously undescribed (1-6) and a known one (7). Their structures were assigned by spectroscopic analysis mainly 2D NMR and mass spectrometry (ESIMS). Selected triterpenoid glycosides (1-3, 6, 7) displayed a good cytotoxic activity against a mouse colon cancer cell line CT26.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Caprifoliaceae/química , Glicosídeos/farmacologia , Ácido Oleanólico/análogos & derivados , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Glicosídeos/isolamento & purificação , Camundongos , Estrutura Molecular , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Raízes de Plantas/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia
17.
Life Sci ; 231: 116557, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194994

RESUMO

AIMS: Vinegar-baked Radix Bupleuri (VBRB) potentiates the activity of anticancer drugs in the liver by increasing their hepatic distribution. However, this phenomenon may be associated with drug transporters. We investigated the effect of saikosaponin b2 (SSb2; the main component of VBRB) on the activity and expression of different drug transporters in both normal cells and those that overexpress the transporter. MAIN METHODS: The activities of transporters were analyzed by concentration of their cellular substrates. Concentrations of colchicine (substrate of Pgp and MRP1) and cisplatin (substrate of OCT2 and MRP2) were determined by high-performance liquid chromatography (HPLC). The concentration of rhodamine B was determined by flow cytometry. The expression of transporter gene and protein were determined by qRT-PCR and Western blotting analysis. KEY FINDINGS: SSb2 increased colchicine efflux in HEK293 cells by primarily increasing Mrp1 activity, independent of gene and protein expression. SSb2 enhanced Mrp2 function and increased cisplatin efflux in BRL3A cells by upregulating Mrp2 gene expression, with a marginal effect on Pgp in normal cells. SSb2 increased OCT2 activity in OCT2-HEK293 cells by increasing the expression of OCT2 protein and mRNA; however, SSb2 inhibited MRP2 activity in MRP2-HEK293 cells by decreasing MRP2 protein expression, and decreased Pgp and MRP1 activity in Pgp- and MRP1-HEK293 cells. SIGNIFICANCE: SSb2 might potentially be the key active component of VBRB that enhances the hepatotargeting of anticancer drugs through the inhibition of multidrug resistance-associated drug transporters (Pgp, MRP1, and MRP2) in an environment-dependent manner.


Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/metabolismo , Saponinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Cisplatino/análise , Cisplatino/metabolismo , Cisplatino/farmacologia , Colchicina/análise , Colchicina/metabolismo , Colchicina/farmacologia , Resistência a Múltiplos Medicamentos/fisiologia , Células HEK293 , Humanos , Medicina Tradicional Chinesa , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , RNA Mensageiro/metabolismo , Rodaminas/análise , Rodaminas/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
Plant Cell Rep ; 38(9): 1181-1197, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165250

RESUMO

KEY MESSAGE: Drastic changes in soil water content can activate the short-term high expression of key enzyme-encoding genes involved in secondary metabolite synthesis thereby increasing the content of secondary metabolites. Bupleurum chinense DC. is a traditional medicinal herb that is famous for its abundant saikosaponins. In the current study, the effects of drought-re-watering-drought on the photosynthesis physiology and biosynthesis of saikosaponins were investigated in 1-year-old B. chinense. The results showed that alterations in soil moisture altered the photosynthesis physiological process of B. chinense. The dry weight and fresh weight of the roots, photosynthesis capacity, chlorophyll fluorescence parameters, and SOD, POD and CAT activities were significantly reduced, and the contents of SP, soluble sugars, PRO and MDA increased. There were strong correlations between different physiological stress indices. All indices promoted and restricted each other, responded to soil moisture changes synergistically, maintained plant homeostasis and guaranteed normal biological activities. It was found that RW and RD_1 were the key stages of the water-control experiment affecting the expression of saikosaponin-related genes. At these two stages, the expression of multiple genes was affected by changes in soil moisture, with their expression levels reaching several-fold higher than those at the previous stage. We noticed that the expression of saikosaponin synthesis genes (which were rapidly upregulated at the RW and RD_1 stages) did not coincide with the rapid accumulation of saikosaponins (at the RD-2 stage), which were found to correspond to each other at the later stages of the water-control experiment. This finding indicates that there is a time lag between gene expression and the final product synthesis. Rapid changes in the external environment (RW to RD_1) have a short-term promoting effect on gene expression. This study reveals that short-term stress regulation may be an effective way to improve the quality of medicinal materials.


Assuntos
Bupleurum/fisiologia , Ácido Oleanólico/análogos & derivados , Fotossíntese/fisiologia , Saponinas/biossíntese , Metabolismo Secundário , Água/fisiologia , Bupleurum/química , Secas , Ácido Oleanólico/biossíntese , Raízes de Plantas/química , Raízes de Plantas/fisiologia , Plantas Medicinais , Solo/química , Estresse Fisiológico
19.
Artigo em Inglês | MEDLINE | ID: mdl-31252254

RESUMO

Radix Bupleuri (RB) has been widely used in Traditional Chinese Medicine with a long history. Saikosaponins (SSs), the major constituents of RB, are assumed to be transformed into saikogenins (SGs) by human intestinal microflora prior to absorption and then exert pharmacological effects. There have been detailed reports on the deglycosylation of SSs in the gastrointestinal tract. But to date, there is very limited research addressing the further absorption, distribution, metabolism, and excretion of these deglycosylated derivatives in vivo. In this study, a rapid UFLC-MS/MS method was established and fully validated for simultaneously determining four SGs (SGF, SGA, SGD, and SGG) in rat plasma. The developed method was successfully applied to the pharmacokinetics of three SGs (SGF, SGD, and SGG) in rats after oral and intravenous administrations. Finally, the absolute bioavailabilities were calculated at 0.71% for SGF and 0.66% for SGD. However, the oral bioavailability of SGG was not obtained due to the extremely poor absorption in rats.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Ácido Oleanólico/análogos & derivados , Saponinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Disponibilidade Biológica , Bupleurum/química , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Masculino , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/farmacocinética , Raízes de Plantas/química , Ratos , Ratos Sprague-Dawley , Saponinas/administração & dosagem
20.
Mol Med Rep ; 20(1): 332-340, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115535

RESUMO

Saikosaponin­D (SSD), which is the main bioactive component in the traditional Chinese medicine Chai Hu (Bupleurum falcatum L), possesses estrogen­like properties and is widely used in treating estrogen­related neurological disorders. The current study aimed to investigate the protective effects of SSD on the fear memory deficit in ovariectomized (OVX) rats and the potential underlying mechanism. SSD treatment significantly prolonged freezing time in OVX rats in a manner similar to that of estradiol (E2), whereas this effect was markedly suppressed by co­administration of ICI182780, a non­selective estrogen receptor (ER) inhibitor. The expression of ERα in the hippocampus of OVX rats was significantly elevated by SSD; however, Erß expression and E2 synthesis were not markedly affected by SSD treatment. Collectively, this study demonstrated that SSD­mediated fear memory improvement in OVX rats may be attributed not to E2 levels or ERß activity, but to ERα activation in the hippocampus.


Assuntos
Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Medo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Animais , Bupleurum/química , Estradiol/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/antagonistas & inibidores , Medo/fisiologia , Feminino , Fulvestranto/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Medicina Tradicional Chinesa , Transtornos da Memória/genética , Transtornos da Memória/patologia , Ácido Oleanólico/farmacologia , Ovariectomia , Ratos , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologia
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