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1.
Molecules ; 26(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917440

RESUMO

Periodontitis is a set of chronic inflammatory diseases caused by the accumulation of Gram-negative bacteria on teeth, resulting in gingivitis, pocket formation, alveolar bone loss, tissue destruction, and tooth loss. In this study, the contents of ginsenosides isolated from Panax ginseng fruit extract were quantitatively analyzed, and the anti-inflammatory effects were evaluated in human periodontal ligament cells. The major ginsenosides, Re, Ra8, and Rf, present in ginseng fruit were simultaneously analyzed by a validated method using high-performance liquid chromatography with a diode-array detector; Re, Ra8, and Rf content per 1 g of P. ginseng fruit extract was 1.01 ± 0.03, 0.33 ± 0.01, and 0.55 ± 0.04 mg, respectively. Ginsenosides-Re, -Ra8, and -Rf inhibited the production of pro-inflammatory factors and the expression of important cytokines in periodontitis by inducing the expression of heme oxygenase 1 (HO-1), promoting osteoblast differentiation of periodontal ligament cells, suppressing alveolar bone loss, and promoting the expression of osteoblast-specific genes, such as alp, opn, and runx2. An inhibitory effect of these ginsenosides on periodontitis and alveolar bone loss was observed via the regulation of HO-1 and subsequent epidermal growth factor receptor (EGFR) signaling. Silencing EGFR with EGFR siRNA confirmed that the effect of ginsenosides on HO-1 is mediated by EGFR. In conclusion, this study evaluated the contents of ginsenosides-Re, -Ra8, and -Rf isolated from P. ginseng fruit extract. Therefore, these results provide important basic data for future P. ginseng fruit component studies and suggest that ginsenosides Re, Ra8, and Rf have potential as future treatment options for periodontitis.


Assuntos
Anti-Inflamatórios/farmacologia , Receptores ErbB/metabolismo , Ginsenosídeos/isolamento & purificação , Ginsenosídeos/farmacologia , Heme Oxigenase-1/metabolismo , Osteogênese/efeitos dos fármacos , Panax/química , Ligamento Periodontal/citologia , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Frutas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/química , Humanos , Mediadores da Inflamação/metabolismo , Limite de Detecção , Lipopolissacarídeos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Extratos Vegetais/química , Porphyromonas gingivalis/química , Análise de Regressão , Transdução de Sinais/efeitos dos fármacos
2.
Molecules ; 26(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803599

RESUMO

BACKGROUND: Ginseng is widely used as herb or food. Different parts of ginseng have diverse usages. However, the comprehensive analysis on the ginsenosides in different parts of ginseng root is scarce. METHODS: An ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) combined with UNIFI informatics platform and ultra-high-performance liquid chromatography-charged aerosol detection (UHPLC-CAD) were employed to evaluate the different parts of cultivated ginseng root. RESULTS: 105 ginsenosides including 16 new compounds were identified or tentatively characterized. 22 potential chemical markers were identified, 20, 17, and 19 for main root (MR) and fibrous root (FR), main root (MR) and branch root (BR), and main root (MR) and rhizome (RH), respectively. The relative contents of Re, Rb1, 20(R)-Rh1, Rd, and Rf were highest in FR. The relative content of Rg1 was highest in RH. The total relative content of pharmacopoeia indicators Rg1, Re, and Rb1 was highest in FR. CONCLUSION: The differences among these parts were the compositions and relative contents of ginsenosides. Under our research conditions, the peak area ratio of Rg1 and Re could distinguish the MR and FR samples. Fibrous roots showed rich ingredients and high ginsenosides contents which should be further utilized.


Assuntos
Ginsenosídeos/química , Ginsenosídeos/isolamento & purificação , Panax/química , China , Cromatografia Líquida de Alta Pressão , Jardins , Humanos , Espectrometria de Massas , Medicina Tradicional Chinesa , Estrutura Molecular , Raízes de Plantas/química , Plantas Medicinais/química , Rizoma/química , Distribuição Tecidual
3.
Molecules ; 26(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671522

RESUMO

Pro-inflammatory cytokines and anti-inflammatory cytokines are important mediators that regulate the inflammatory response in inflammation-related diseases. The aim of this study is to evaluate different New Zealand (NZ)-grown ginseng fractions on the productions of pro-inflammatory and anti-inflammatory cytokines in human monocytic THP-1 cells. Four NZ-grown ginseng fractions, including total ginseng extract (TGE), non-ginsenoside fraction extract (NGE), high-polar ginsenoside fraction extract (HPG), and less-polar ginsenoside fraction extract (LPG), were prepared and the ginsenoside compositions of extracts were analyzed by HPLC using 19 ginsenoside reference standards. The THP-1 cells were pre-treated with different concentrations of TGE, NGE, HPG, and LPG, and were then stimulated with lipopolysaccharide (LPS). The levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), and anti-inflammatory cytokines, such as interleukin-10 (IL-10), and transforming growth factor beta-1 (TGF-ß1), were determined by enzyme-linked immunosorbent assay (ELISA). TGE at 400 µg/mL significantly inhibited LPS-induced TNF-α and IL-6 productions. NGE did not show any effects on inflammatory secretion except inhibited IL-6 production at a high dose. Furthermore, LPG displayed a stronger effect than HPG on inhibiting pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) productions. Particularly, 100 µg/mL LPG not only significantly inhibited the production of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6, but also remarkably enhanced the production of anti-inflammatory cytokine IL-10. NZ-grown ginseng exhibited anti-inflammatory effects in vitro, which is mainly attributed to ginsenoside fractions (particularly less-polar ginsenosides) rather than non-saponin fractions.


Assuntos
Citocinas/antagonistas & inibidores , Ginsenosídeos/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Citocinas/análise , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Ginsenosídeos/química , Ginsenosídeos/isolamento & purificação , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células THP-1
4.
Molecules ; 26(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546225

RESUMO

Aiming at seeking an effective anti-hepatocarcinoma drug with low toxicity, a total of 24 amino acid derivatives (20 new along with 4 known derivatives) of two active ocotillol-type sapogenins (pyxinol and ocotillol) were synthesized. Both in vitro and in vivo anti-hepatocarcinoma effects of derivatives were evaluated. At first, the HepG2 human cancer cell was employed to evaluate the anti-cancer activity. Most of the derivatives showed obvious enhanced activity compared with pyxinol or ocotillol. Among them, compound 2e displayed the most excellent activity with an IC50 value of 11.26 ± 0.43 µM. Next, H22 hepatoma-bearing mice were used to further evaluate the anti-liver cancer activity of compound 2e. It was revealed that the growth of H22 transplanted tumor was significantly inhibited when treated with compound 2e or compound 2e combined with cyclophosphamide (CTX) (p < 0.05, p < 0.01), and the inhibition rates of tumor growth were 35.32% and 55.30%, respectively. More importantly, compound 2e caused limited damage to liver and kidney in contrast with CTX causing significant toxicity. Finally, the latent mechanism of compound 2e was explored by serum and liver metabolomics based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. A total of 21 potential metabolites involved in 8 pathways were identified. These results suggest that compound 2e is a promising agent for anti-hepato-carcinoma, and that it also could be used in combination with CTX to increase efficiency and to reduce toxicity.


Assuntos
Aminoácidos/química , Antineoplásicos , Carcinoma Hepatocelular/tratamento farmacológico , Ginsenosídeos/química , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Molecules ; 26(2)2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429987

RESUMO

Ginseng berry pomace (GBP) is a byproduct of ginseng berry processing and is rich in numerous bioactive components, including ginsenosides and their derivatives. The application of GBP as a beneficial biomaterial is currently limited. In this study, we aimed to evaluate their potential as a promising source of bioactive compounds using metabolite profiling. The GBP obtained after different ultra-high-pressure (UHP) treatments was analyzed by GC-TOF-MS and UHPLC-LTQ-Orbitrap-MS/MS. In multivariate analyses, we observed a clear demarcation between the control and UHP-treated groups. The results demonstrated that the relative abundance of primary metabolites and a few ginsenosides was higher in the control, whereas UHP treatment contained higher levels of fatty acids and sugars. Furthermore, GBPs were fractionated using different solvents, followed by UHPLC-LTQ-Orbitrap-MS/MS analyses. The heatmap revealed that phenolics (e.g., quercetin, kaempferol) and fewer polar ginsenosides (e.g., F4, Rh2) were abundant in the ethyl acetate fraction, whereas the levels of lignans (e.g., 7-hydroxysecoisolariciresinol, syringaresinol) and fatty acids (e.g., trihydroxy-octadecenoic acid, oxo-dihydroxy-octadecenoic acid) were high in chloroform. Correlation analysis showed that phenolics, less polar ginsenosides, and fatty acids were positively correlated with the antioxidant activity of GBP. Our study highlights GBP as a functional ingredient for the development of high-quality ginseng berry products.


Assuntos
Antioxidantes/química , Frutas/química , Ginsenosídeos/química , Panax/química , Extratos Vegetais/química , Antioxidantes/análise , Cromatografia Líquida de Alta Pressão , Cromatografia Gasosa-Espectrometria de Massas , Ginsenosídeos/análise , Pressão , Espectrometria de Massas em Tandem
6.
Anticancer Res ; 41(1): 227-235, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419817

RESUMO

BACKGROUND: 20(S)-Ginsenoside Rh2 (G-Rh2) has demonstrated therapeutic effects in many types of cancers. We aimed to investigate the potential anticancer activity and underlying mechanisms of G-Rh2 in oral cancer cells. MATERIALS AND METHODS: The antigrowth effect of G-Rh2 in oral cancer cells was stimulated by cell proliferation, soft agar colony formation, and migration and invasion assay. The cell cycle and apoptosis were detected by flow cytometry. The underlying mechanism of G-Rh2 in oral cancer cells was explored by immunoblotting. RESULTS: G-Rh2 significantly inhibited oral cancer cell growth by inducing apoptosis and cell cycle G0/G1-phase arrest. G-Rh2 inhibited oral cancer cell migration and invasion through regulation of epithelial-mesenchymal transition (EMT)-related proteins. G-Rh2 inhibited the Src/Raf/ERK signaling pathway in YD10B and Ca9-22 cells. CONCLUSION: G-Rh2 exerted anticancer activity in vitro by inhibiting the Src/Raf/ERK signaling pathway in oral cancer. G-Rh2 is a potential therapeutic drug for oral cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ginsenosídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Quinases raf/metabolismo , Quinases da Família src/metabolismo , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Ginsenosídeos/química , Humanos , Neoplasias Bucais/metabolismo
7.
Biochem Biophys Res Commun ; 534: 73-78, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310191

RESUMO

Glycosylation catalyzed by uridine diphosphate-dependent glycosyltransferases (UGT) contributes to the chemical and functional diversity of a number of natural products. Bacillus subtilis Bs-YjiC is a robust and versatile UGT that holds potentials in the biosynthesis of unnatural bioactive ginsenosides. To understand the molecular mechanism underlying the substrate promiscuity of Bs-YjiC, we solved crystal structures of Bs-YjiC and its binary complex with uridine diphosphate (UDP) at resolution of 2.18 Å and 2.44 Å, respectively. Bs-YjiC adopts the classical GT-B fold containing the N-terminal and C-terminal domains that accommodate the sugar acceptor and UDP-glucose, respectively. Molecular docking indicates that the spacious sugar-acceptor binding pocket of Bs-YjiC might be responsible for its broad substrate spectrum and unique glycosylation patterns toward protopanaxadiol-(PPD) and PPD-type ginsenosides. Our study reveals the structural basis for the aglycone promiscuity of Bs-YjiC and will facilitate the protein engineering of Bs-YjiC to synthesize novel bioactive glycosylated compounds.


Assuntos
Bacillus subtilis/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Glicosiltransferases/química , Glicosiltransferases/metabolismo , Proteínas de Bactérias/genética , Sítios de Ligação , Cristalografia por Raios X , Ginsenosídeos/química , Ginsenosídeos/metabolismo , Glicosilação , Glicosiltransferases/genética , Modelos Moleculares , Simulação de Acoplamento Molecular , Domínios Proteicos , Sapogeninas/metabolismo , Especificidade por Substrato , Difosfato de Uridina/química , Difosfato de Uridina/metabolismo , Uridina Difosfato Glucose/metabolismo
8.
J Agric Food Chem ; 69(1): 315-324, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33372793

RESUMO

A compound K-producing fungus was isolated from meju (fermented soybean brick) and identified as the generally recognized as safe (GRAS) strain Aspergillus tubingensis. The extracellular enzymes obtained after the cultivation of 6 days in the medium with 20 g/L citrus pectin as an inducer showed the highest compound K-producing activity among the inducers tested. Under the optimized conditions of 0.05 mM MgSO4, 55 °C, pH 4.0, 13.4 mM protopanaxadiol (PPD)-type ginsenosides, and 11 mg/mL enzymes, the extracellular enzymes from A. tubingensis completely converted PPD-type ginsenosides in the ginseng extract to 13.4 mM (8.35 mg/mL) compound K after 20 h, with the highest concentration and productivity among the results reported so far. As far as we know, this is the first GRAS enzyme to completely convert all PPD-type ginsenosides to compound K.


Assuntos
Aspergillus/enzimologia , Proteínas Fúngicas/metabolismo , Ginsenosídeos/química , Extratos Vegetais/metabolismo , Sapogeninas/metabolismo , Aspergillus/química , Aspergillus/metabolismo , Biotransformação , Proteínas Fúngicas/química , Estrutura Molecular , Panax/química , Extratos Vegetais/química , Sapogeninas/química
9.
Mol Pharmacol ; 99(2): 163-174, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33334897

RESUMO

P2X7 is an important ligand-gated ion channel expressed in multiple immune cell populations. This study aimed to investigate the chemical requirements of triterpenoid glycosides within a new binding pocket to characterize the structure-activity relationship. A set of glycosides were screened for positive modulator activity at human P2X7 using a YO-PRO-1 dye uptake assay in HEK-293 cells stably expressing the wild-type human P2X7 variant (HEK-hP2X7 cells). The highest positive modulator activity was with ginsenoside-compound K (CK), containing a monosaccharide (glucose) attached at carbon-20. Ginsenoside-20(S)-Rg3, containing a disaccharide group (glucose-glucose) at carbon-3, displayed positive modulator activity with a reduced EC50 for ATP and increased maximal response at human P2X7. The epimer 20(R)-Rg3 was inactive. A similar stereo-specific pattern was observed for 20(S)-Rh2. Ginsenoside-F1, highly similar to ginsenoside-CK but containing a single additional hydroxyl group, was also inactive at P2X7. Computational docking suggests hydrophobic residues in the pocket are involved in steric discrimination between triterpenoids, whereas the position and identity of the carbohydrate group are important for positive modulator activity at human P2X7. Ginsenosides containing monosaccharide attachments perform better than di- or trisaccharide glycosides. Additional modifications to the triterpenoid scaffold at carbon-6 are not tolerated. Gypenosides from plant sources other than Panax ginseng (gypenoside XVII, gypenoside XLIX, stevenleaf) can also act as positive allosteric modulators of P2X7. We also investigated the effect of positive allosteric modulators on endogenous P2X7 in THP-1 monocytes and confirmed our findings in a calcium response assay. A cell viability assay showed potentiation of ATP-induced cell death with ginsenoside-CK in THP-1 and HEK-hP2X7 cells. SIGNIFICANCE STATEMENT: Ginsenosides are active as positive allosteric modulators at P2X7, and this study determines the chemical features important for mediating this effect. The position and identity of the sugar group is important for activity, as is the position of a number of hydroxyl groups on the triterpenoid scaffold. Diastereomers of ginsenoside-Rg3 and ginsenoside-Rh2 demonstrate the importance of the location of hydroxyl groups relative to the hydrophobic face of the predicted binding pocket.


Assuntos
Ginsenosídeos/farmacologia , Glicosídeos/farmacologia , Receptores Purinérgicos P2X7/química , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/metabolismo , Regulação Alostérica , Ginsenosídeos/química , Glicosídeos/química , Células HEK293 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Simulação de Acoplamento Molecular , Conformação Proteica , Receptores Purinérgicos P2X7/genética , Relação Estrutura-Atividade
10.
Phytomedicine ; 79: 153325, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920289

RESUMO

BACKGROUND: Panax notoginseng (Burk.) F.H. Chen is a traditional medicinal plant widely used to prevent and treat cardiovascular diseases. Ginsenoside Rd (GRd) is a major bioactive component of P. notoginseng, but specific effects on cardiovascular disease-related pathogenic processes are rarely studied, especially vascular endothelial injury. PURPOSE: This study investigated the potential protective efficacy of GRd against nicotine-induced vascular endothelial cell injury, disruption of vascular nitric oxide (NO) signaling, aberrant endothelium-monocyte adhesion, platelet aggregation, and vasoconstriction. STUDY DESIGN/METHODS: Vascular endothelial injury and functional disruption were investigated in cultured human umbilical vein endothelial cells (HUVECs) by biochemical assays for nitric oxide (NO) and angiotensin II (Ang II), immunofluorescence (IF) and western blotting for expression analyses of apoptosis- related proteins, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), Ang II type receptor 1 (AGTR1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). In addition, vascular protection by GRd was examined in nicotine-administered Sprague-Dawley (SD) rats by serum NO and Ang II assays, and by hematoxylin-eosin (HE) and immunostaining of aorta. We also examined effects of GRd on monocyte (THP-1 cells) adhesion assays, adenosine diphosphate (ADP)-induced platelet aggregation, and phenylephrine (PE)-induced vasoconstriction of isolated rat aortic rings. RESULTS: In HUVECs, nicotine significantly suppressed NO production, enhanced Ang II production, downregulated eNOS expression, and upregulated expression levels of AGTR1, TLR4, MyD88, NF-κB, iNOS, Bax/Bcl-2 ratio, cleaved caspase-3, and cytochrome c (cyt c). All of these changes were significantly reversed by GRd. In rats, oral GRd reversed the reduction NO and enhanced Ang II production in serum induced by nicotine administration, and HE staining revealed protection of aortic endothelial cells. In addition, GRd reversed nicotine-mediated enhancement of HUVECs-monocyte adhesion, inhibited ADP-induced platelet aggregation and PE-induced vasoconstriction. CONCLUSION: GRd may prevent nicotine-induced cardiovascular diseases by preserving normal vascular endothelial NO signaling, suppressing platelet aggregation and vasoconstriction, and by preventing endothelial cell-monocyte adhesion.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Ginsenosídeos/farmacologia , Nicotina/toxicidade , Angiotensina II/sangue , Angiotensina II/metabolismo , Animais , Aorta/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ginsenosídeos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fenilefrina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor 4 Toll-Like/metabolismo , Triterpenos/química , Vasoconstrição/efeitos dos fármacos
11.
Yakugaku Zasshi ; 140(8): 1063-1069, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741864

RESUMO

Quantitative NMR (qNMR) has been developed as an absolute quantitation method to determine the purity or content of organic compounds including marker compounds in crude drugs. The "qNMR test" has been introduced into the crude-drug section of the Japanese Pharmacopoeia (JP) for determining the purity of reagents used for the assay in the JP. In Supplement II to the JP 17th edition published in June 2019, fifteen compounds adopted qNMR test were listed as the reagents for the assay. To establish the "qNMR test" in the crude drug section of the JP, there were several problems to be solved. Previously, we reported that the handling impurity signals from reference substances and targeted marker compounds, chemical shifts of reference substances, and peak unity of signals of targeted marker compounds are important factors to conduct qNMR measurements with intended accuracy. In this study, we investigated that the hygroscopicity of reagents could cause the changes in the compounds' purity depending on increasing their water content. Twenty-one standard products used for the crude-drug test in JP were examined by water sorption-desorption analysis, and ginsenosides and saikosaponins were found to be hygroscopic. To prepare a sample solution of saikosaponin b2 for qNMR analysis, samples need to be maintained for 18 h at 25°C and 76% relative humidity; further, samples need to be weighed at the same humidity for the qNMR analysis.


Assuntos
Contaminação de Medicamentos/prevenção & controle , Higroscópicos/química , Higroscópicos/normas , Indicadores e Reagentes/normas , Espectroscopia de Ressonância Magnética/métodos , Farmacopeias como Assunto/normas , Ginsenosídeos/química , Ginsenosídeos/normas , Umidade , Japão , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/normas , Psicoterapia Breve , Saponinas/química , Saponinas/normas , Temperatura , Água/análise
12.
Life Sci ; 258: 118107, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682919

RESUMO

Cognitive impairment has been widely recognized as a common symptom of chronic stress. Ginsenoside Rd (GRd), the major active compound in Panax ginseng, was previously reported in various neurological researches. However, little research is available regarding on the effect of GRd on cognitive improvement in mice subjected to chronic stress. In the present study, we investigated the neuroprotective effects of GRd in chronic restraint stress (CRS)-induced cognitive deficits and explored the potential mechanism in male C57BL/6J mice. Our results demonstrated that oral administration of GRd for 28 days markedly increased the spontaneous alternation in Y-maze and the relative discrimination index in novel object or location recognition tests following CRS. Additionally, GRd treatment considerably increased the antioxidant enzymes activities in the hippocampus. The expression levels of hippocampus and serum inflammation factors in the CRS groups were also counter-regulated by GRd treatment. Meanwhile, GRd treatment could reverse CRS-induced the decrease in phosphorylated phosphoinositide 3-kinase (PI3K), camp-reflecting element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expression in the hippocampus. These findings provided evidences that GRd improves cognitive impairment in CRS mice by mitigating oxidative stress and inflammation, while upregulating the hippocampal BDNF-mediated CREB signaling pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ginsenosídeos/uso terapêutico , Restrição Física , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Animais , Doença Crônica , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia
13.
Sci Rep ; 10(1): 4967, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188912

RESUMO

Aging is associated with increased prevalence of skeletal and cardiac muscle disorders, such as sarcopenia and cardiac infarction. In this study, we constructed a compendium of purified ginsenoside compounds from Panax ginseng C.A. Meyer, which is a traditional Korean medicinal plant used to treat for muscle weakness. Skeletal muscle progenitor cell-based screening identified three compounds that enhance cell viability, of which 20(R)-ginsenoside Rh2 showed the most robust response. 20(R)-ginsenoside Rh2 increased viability in myoblasts and cardiomyocytes, but not fibroblasts or disease-related cells. The cellular mechanism was identified as downregulation of cyclin-dependent kinase inhibitor 1B (p27Kip1) via upregulation of Akt1/PKB phosphorylation at serine 473, with the orientation of the 20 carbon epimer being crucially important for biological activity. In zebrafish and mammalian models, 20(R)-ginsenoside Rh2 enhanced muscle cell proliferation and accelerated recovery from degeneration. Thus, we have identified 20(R)-ginsenoside Rh2 as a p27Kip1 inhibitor that may be developed as a natural therapeutic for muscle degeneration.


Assuntos
Ginsenosídeos/farmacologia , Músculo Esquelético/citologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/citologia , Panax/química , Saponinas/química , Células-Tronco/metabolismo , Adulto , Animais , Sobrevivência Celular , Ginsenosídeos/química , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Regeneração , Peixe-Zebra
14.
Phytomedicine ; 69: 153197, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32146298

RESUMO

BACKGOUND: Ginsenoside Rb1, the main active constituent of Panax ginseng, displays significant anti-inflammatory activity, although the mechanism has not been clearly unraveled. In this study, Rb1's mechanism of anti-inflammatory effects were investigated. METHODS: The flow cytometry and enzyme-linked immunosorbent assay (ELISA) were empolyed to detect pro-inflammatory cytokines release. The related protein and gene expression was investigated by western blotting and qRT-PCR. The dimerization of TLR4 was measured by co-immunoprecipitation and molecular docking assays. Cellular thermal shift assay was used for the determination of the binding of Rb1 and TLR4. For animal moldels, LPS- or cantharidin-induced acute kidney injury, LPS-induced septic death, and dimethyl benzene-induced ear edema were employed to investigate Rb1's anti-inflammatory activity in vivo. RESULTS: Rb1 significantly decreased inflammatory cytokines release in LPS-stimulated RAW264.7 cells and BMDMs, as well as COX-2 and iNOS amounts. Rb1 reduced LPS-associated calcium influx, ROS production, and NO generation. The NF-κB and MAPK axes participated in Rb1's anti-inflammatory effects. Molecular docking simulation indicated Rb1 bound to TLR4 to prevent TLR4 dimerization, as confirmed by co-immunoprecipitation and cellular thermal shift assay. Furthermore, MyD88 recruitment and TAK1 expression were altered by reduced TLR4 dimerization, indicating the TLR4-MyD88-NF-κB/MAPK pathways contributed to Rb1's anti-inflammatory process. In animal models, Rb1 markedly alleviated LPS- or cantharidin-induced acute kidney injury, rescued LPS-induced septic mice from death, and inhibited dimethyl benzene-induced mouse ear edema. CONCLUSION: Overall, these findings demonstrate Rb1 exhibits marked anti-inflammatory effects, suggesting Rb1 represents an optimal molecule for treating inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ginsenosídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Cantaridina/toxicidade , Ginsenosídeos/química , Células HEK293 , Humanos , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Multimerização Proteica , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor 4 Toll-Like/química
15.
Molecules ; 25(6)2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32204525

RESUMO

Ginseng roots, Panax ginseng C.A. Meyer, obtained from cultivated ginseng grown in the Kaesong province (North Korea) and Primorye (Russia) were extracted using the supercritical CO2 extraction method. The extracts were subsequently analyzed by high-performance liquid chromatography with tandem mass spectrometry identification. The results showed the spectral peaks of typical ginsenosides with some other minor groups, and major differences were observed between the spectra of the two ginseng samples. The use of a pressure of 400 bar and higher allowed an increase in the yield of ginsenosides in comparison with similar previous studies.


Assuntos
Dióxido de Carbono/química , Ginsenosídeos/isolamento & purificação , Panax/química , Cromatografia Líquida de Alta Pressão , Cromatografia com Fluido Supercrítico , República Democrática Popular da Coreia , Ginsenosídeos/química , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Raízes de Plantas/química , Federação Russa , Espectrometria de Massas em Tandem
16.
Z Naturforsch C J Biosci ; 75(1-2): 41-49, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32031984

RESUMO

The overexpression of sialic acids and sialyltransferases (STs) during malignant transformation and progression could result in the aberrant sialylation of cancer cells. Therefore, interfering the sialic acid synthesis might be an effective pathway in cancer therapy. In this study, we assessed that the antitumor inhibitors of 20(S)-ginsenosides Rg3, 20(R)-ginsenosides Rg3, 20(S)-ginsenosides Rh2, and 20(R)-ginsenosides Rh2 could block the sialoglycans in liver cancer cells HepG2. The results showed that these four compounds could inhibit the expressions of the total and free sialic acid at different levels in HepG2, respectively; also, it showed dose dependence. In addition, the results of the enzyme-linked immunosorbent assay showed that the above four compounds can inhibit the expression of STs significantly. We also found that these compounds could mediate the block of sialylation of α2,3- and α2,6-linked sialic acids in HepG2 cells by flow cytometry. Meanwhile, the results of the molecular docking investigation showed that these compounds showed strong interaction with ST6GalI and ST3GalI. These results verified that the ginsenosides have a powerful inhibiting aberrant sialylation, and it laid a theoretical foundation for further research on the investigation of ginsenosides as the target inhibitors on STs.


Assuntos
Ginsenosídeos/farmacologia , Ácidos Siálicos/química , Sialiltransferases/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Sialiltransferases/química
17.
Eur J Med Chem ; 189: 112087, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007667

RESUMO

Based on the definite therapeutic benefits, such as neuroprotective, cardioprotective, anticancer, anti-diabetic and so on, the Panax genus which contains many valuable plants, including ginseng (Panax ginseng C.A. Meyer), notoginseng (Panax notoginseng) and American ginseng (Panax quinquefolius L.), attracts research focus. Actually, the biological and pharmacological effects of the Panax genus are mainly attributed to the abundant ginsenosides. However, the low membrane permeability and the gastrointestinal tract influence seriously limit the absorption and bioavailability of ginsenosides. The acid or base hydrolysates of ginsenosides, 20 (R,S)-panaxadiol and 20 (R,S)-protopanaxadiol showed improved bioavailability and diverse pharmacological activities. Moreover, relative stable skeletons and active hydroxyl group at C-3 position and other reactive sites are suitable for structural modification to improve biological activities. In this review, the pharmacological activities of panaxadiol, protopanaxadiol and their structurally modified derivatives are comprehensively summarized.


Assuntos
Descoberta de Drogas , Ginsenosídeos/farmacologia , Panax/química , Compostos Fitoquímicos/química , Sapogeninas/farmacologia , Triterpenos/química , Antineoplásicos/farmacologia , Ginsenosídeos/química , Humanos , Fármacos Neuroprotetores/farmacologia , Protetores contra Radiação/farmacologia , Sapogeninas/química
18.
Biochem Pharmacol ; 173: 113790, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31911090

RESUMO

Atopic diseases (atopic dermatitis, asthma and allergic rhinitis) affects a huge number of people around the world and their incidence rate is on rise. Atopic dermatitis (AD) is more prevalent in paediatric population which sensitizes an individual to develop allergic rhinitis and asthma later in life. The complex pathogenesis of these allergic diseases though involves numerous cellular signalling pathways but redox imbalance has been reported to be critical for induction/perpetuation of inflammatory process under such conditions. The realm of complementary and alternative medicine has gained greater attention because of the reported anti-oxidant/anti-inflammatory properties. Several case studies of treating atopic diseases with homeopathic remedies have provided positive results. Likewise, pre-clinical studies suggest that various natural compounds suppress allergic response via exhibiting their anti-oxidant potential. Despite the reported beneficial effects of phytochemicals in experimental model system, the clinical success has not been documented so far. It appears that poor absorption and bioavailability of natural compounds may be one of the reasons for realizing their full potential. The current paper throws light on impact of phytochemicals in the redox linked cellular and signalling pathways that may be critical in manifestation of atopic diseases. Further, an effort has been made to identify the gaps in the area so that future strategies could be evolved to exploit the medicinal value of various phytochemicals for an improved efficiency.


Assuntos
Asma/prevenção & controle , Dermatite Atópica/prevenção & controle , Hipersensibilidade/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Asma/imunologia , Asma/patologia , Catecóis/química , Catecóis/uso terapêutico , Curcumina/química , Curcumina/uso terapêutico , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Álcoois Graxos/química , Álcoois Graxos/uso terapêutico , Flavonoides/química , Flavonoides/uso terapêutico , Ginsenosídeos/química , Ginsenosídeos/uso terapêutico , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Estrutura Molecular , Compostos Fitoquímicos/química , Resveratrol/química , Resveratrol/uso terapêutico
19.
Biomed Pharmacother ; 124: 109891, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31991384

RESUMO

20(S)-Rh2 is a ginsenoside isolated from Panax ginseng, which exhibits anti-cancer activities on various human cancer cells. A novel 20(S)-Rh2 derivative, 2-Deoxy-Rh2 was synthesized and hybridized with protopanaxadiol and 2-deoxy-glucose in an attempt to enhance the anticancer activity. Through screening the antitumor effect against various cell lines by MTT assay, 2-Deoxy-Rh2 especially resulted in a concentration-dependent and time-dependent inhibition of viability in MCF-7 human breast cancer cells. Multiple methods were used to explore the cellular and molecular mechanisms of 2-Deoxy-Rh2 as a potent anti-cancer agent. In MCF-7 cells, 2-Deoxy-Rh2 triggered apoptosis, stimulated ROS production and disrupted normal mitochondrial membrane potential. Meantime, 2-Deoxy-Rh2 eff ;ectively suppressed the glucose uptake capabilities and intracellular ATP production. The cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were significantly decreased in response to 2-Deoxy-Rh2, which were carried out to assess the overall glycolytic flux and mitochondrial respiration. Docking studies and molecular dynamics simulations were performed to verify the binding mode of 2-DG and 2-Deoxy-Rh2 with hexokinase II, with results showing that 2-Deoxy-Rh2 could easily fit into the similar active site of 2-DG, finally binding to hexokinase II to suppress glycolysis. Taken together, the results suggest that 2-Deoxy-Rh2 exhibited remarkable anticancer activity based on regulating mitochondrial apoptosis pathway, dampening glycolysis and inhibiting mitochondrial respiration, which support development of 2-Deoxy-Rh2 as a potential agent for cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ginsenosídeos/farmacologia , Neoplasias/tratamento farmacológico , Panax/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ginsenosídeos/química , Ginsenosídeos/isolamento & purificação , Glicólise/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/patologia , Fatores de Tempo
20.
Carbohydr Polym ; 230: 115576, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887962

RESUMO

Ginsenoside compound K (CK), a major metabolite of protopanaxadiol ginsenosides, exhibits significant anticancer activities against various cancer cells. However, CK has poor water solubility and low bioavailability, which have limited its application. In this study, A54 peptide was utilized to fabricate CK-loaded micelles (APD-CK) for liver targeting, using deoxycholic acid-O-carboxymethyl chitosan as the vehicle. The average particle size of APD-CK micelles was about 171.4 nm by dynamic light scattering in the hydrated state and their morphology were spherical with good dispersion. An in vitro release assay indicated pH-responsive and sustained release behavior through a mechanism of non-Fickian diffusion. Moreover, the in vitro cytotoxicity of the APD-CK micelles against HepG2 and Huh-7 cells was significantly stronger than that of CK up to 20 µg/mL. Enhanced cellular uptake of micelles in both cell types was established using confocal fluorescence scanning microscopy and flow cytometry. In addition, western blot analysis revealed that APD-CK micelles could promote the protein expression levels of caspase-3, caspase-9, and poly (ADP-ribose) polymerase. Therefore, APD-CK micelles are a potential vehicle for delivering hydrophobic drugs in liver cancer therapy, enhancing drug targeting and anticancer activity.


Assuntos
Quitosana/farmacologia , Ginsenosídeos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Peptídeos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Citoplasma/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ginsenosídeos/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Micelas , Peptídeos/química , Polietilenoglicóis/química
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