Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 877
Filtrar
1.
Life Sci ; 242: 117214, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884095

RESUMO

Accumulating evidence suggests that aberrant DNA methylation and gene silencing of tumor suppressors are pervasive in gastric malignancies, supporting reactivation of tumor suppressors through DNA demethylation as a potential therapeutic opportunity. Atp4a is an important tumor suppressor gene, encoding H+, K+-ATPase, and mediating gastric acid secretion in the stomach. Using transgenic gastric cancer model K19-Wnt1/C2mE (Gan) mice, by combining the transcriptome and MeDIP (methylated DNA immunoprecipitation) sequencing, together with qRT-PCR, we showed that Atp4a was expressed at low levels in tumor tissues and multiple GC cells, while both 5-aza-CdR and 18ß-glycyrrhetinic acid (GRA) pharmacological treatment triggered Atp4a activation with downregulation of DNMT1. In addition, CpG island (CGI) search showed that the CpG rich region is absent in the promoter region but present in exons 9-14 of Atp4a. Methylation specific PCR (MSP) indicated that Atp4a was fully or partly methylated in multiple GC cells. Further MassArray suggested that the demethylation in the CpG site 75, 183, 196, 262-268 might be responsible for the reactivation of Atp4a. Our research identified that GRA, a bioactive component found in abundance in Radix Glycyrrhiza, reactivated Atp4a expression and inhibited gastric tumorigenesis as a potential demethylation agent.


Assuntos
Metilação de DNA , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Inativação Gênica , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Humanos , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
J Agric Food Chem ; 67(48): 13212-13220, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31702905

RESUMO

Because only a handful of agrochemicals can manage bacterial infections, the discovery and development of innovative, inexpensive, and high-efficiency antibacterial agents targeting these infections are challenging. Herein, a series of novel epimeric and chiral 18ß-glycyrrhetinic acid (GA) ester derivatives with various tertiary amine pendants were designed, synthesized, and screened for pharmacological activity. Results showed that some of the title compounds were conferred with significantly enhanced antibacterial activity toward phytopathogens Xanthomonas oryzae pv oryzae (A2, B1-B3, and C1, EC50 values within 3.81-4.82 µg/mL) and Xanthomonas axonopodis pv citri (B1, EC50 = 3.18 µg/mL; B2, EC50 = 2.76 µg/mL). These activities are superior to those of GA (EC50 > 400 µg/mL), thiodiazole copper, and bismerthiazol. Pharmacophore studies revealed that the synergistic combination of GA skeleton and tertiary amine scaffolds contributed to the biological actions. In vivo experiments displayed their promising applications in controlling bacterial infections. Antibacterial mechanism studies revealed that the title compounds could trigger apoptosis in the tested pathogens, evident by bacteria morphological changes observed in scanning electron microscopy images. This outcome should motivate the development of various apoptosis inducers against plant bacterial diseases by a novel mode of action compared to that of existing agricultural chemicals.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Antibacterianos/síntese química , Desenho de Drogas , Ésteres/química , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Testes de Sensibilidade Microbiana , Doenças das Plantas/microbiologia , Propanolaminas/química , Estereoisomerismo , Relação Estrutura-Atividade , Xanthomonas/citologia , Xanthomonas/efeitos dos fármacos
3.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416117

RESUMO

A series of new glycyrrhetinic acid derivatives was synthesized via the opening of its ring A along with the coupling of an amino acid. The antiproliferative activity of the derivatives was evaluated against a panel of nine human cancer cell lines. Compound 17 was the most active compound, with an IC50 of 6.1 µM on Jurkat cells, which is 17-fold more potent than that of glycyrrhetinic acid, and was up to 10 times more selective toward that cancer cell line. Further biological investigation in Jurkat cells showed that the antiproliferative activity of compound 17 was due to cell cycle arrest at the S phase and induction of apoptosis.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ácido Glicirretínico/análogos & derivados , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
4.
J Agric Food Chem ; 67(34): 9643-9651, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31390199

RESUMO

Licorice is a traditional Chinese medicine, which is often used as sweetener and cosmetic ingredients in food and pharmaceutical industries. Among them, glycyrrhetic acid is one of the most important agents. Studies have shown that glycyrrhetic acid exhibited antitumor activities as PPARγ agonist. However, the limited number of PPARγ glycyrrhetinic agonists and their high toxicity greatly limit the design based on the structure. Therefore, clarifying the binding mode between PPARγ and small molecules, we focused on the introduction of a natural active piperazine skeleton in the position of glycyrrhetinic acid C-3. According to the Combination Principle and the Structure-Based Drug Design, 19 glycyrrhetic acid derivatives were designed and synthesized as potential PPARγ agonists. Compounds 4c and 4q were screened as high-efficiency and low-toxicity lead compounds.


Assuntos
Antineoplásicos Fitogênicos/química , Medicamentos de Ervas Chinesas/química , Ácido Glicirretínico/análogos & derivados , Glycyrrhiza/química , PPAR gama/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Humanos , PPAR gama/metabolismo , Relação Estrutura-Atividade
5.
Chem Biol Interact ; 311: 108749, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31325423

RESUMO

PURPOSE: Excessive proliferation, migration and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the basis for the development of pulmonary vascular remodeling, and it is the driving force for pulmonary arterial hypertension (PAH). 18ß-glycyrrhetinic acid (18ß-GA) is the main active substance extracted from Chinese herbal medicine licorice, with outstanding anti-inflammatory, anti-oxidation and anti-proliferative effects. Our team found in previous studies that 18ß-GA has protective effects on monocrotaline-induced PAH in rats. However, the anti-angiogenic effect of 18ß-GA on PAH remains unclear. Therefore, in order to further investigate whether the beneficial effects of 18ß-GA on PAH are related to its antiproliferative effect, we conducted experiments in vivo and in vitro. METHODS AND RESULTS: In vivo, 18ß-GA relieved mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular hypertrophy index, improving pulmonary remodeling. In vitro, 18ß-GA significantly inhibited PDGF-BB-induced proliferation and DNA synthesis of HPASMCs, blocking the progression of G0/G1 to S phase of the cell cycle. Furthermore, after treatment with 18ß-GA, the expression of Rho A, ROCK1, ROCK2 was decreased and ROCK activity was inhibited in HPASMC. In addition, 18ß-GA also attenuated PDGF-induced changes in p27kip1, Bax and Bcl-2. CONCLUSIONS: In summary, these results indicate that 18ß-GA regulates the activity of RhoA-ROCK signaling pathway, inhibits the proliferation of HPASMCs, and has potential value in the treatment of PAH.


Assuntos
Ácido Glicirretínico/análogos & derivados , Hipertensão Pulmonar/patologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Monocrotalina/toxicidade , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Substâncias Protetoras/uso terapêutico , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
6.
Biofactors ; 45(4): 607-615, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31120605

RESUMO

Enhancing soluble receptor for advanced glycation endproducts (sRAGE) is considered as a potent strategy for diabetes therapy. sRAGE secretion is regulated by calcium and transient receptor potential canonical (TRPC) channels. However, the role of TRPC channels in diabetes remains unknown. 18ß-Glycyrrhetinic acid (18ß-GA), produced from liquorice, has shown antidiabetic properties. This study was aimed to investigate the effect of 18ß-GA on sRAGE secretion via TRPC channels in high glucose (HG)-induced THP-1 cells. HG treatment enhanced TRPC3 and TRPC6 expression and consequently caused reactive oxygen species (ROS) accumulation mediated through p47 nicotinamide-adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase (iNOS) associated with uncoupling protein 2 (UCP2) decline and lower sRAGE secretion. Interestingly, 18ß-GA showed the dramatic effects similar to Pyr3 or 2-aminoethyl diphenyl borinate inhibitors and effectively reversed HG-elicited mechanisms including that blocking TRPC3 and TRPC6 protein expressions, suppressing intracellular [Ca2+] concentration, decreasing expressions of ROS, p47s, and iNOS, but increasing UCP2 level and promoting sRAGE secretion. Therefore, 18ß-GA provides a potential implication to diabetes mellitus and its complications.


Assuntos
Glucose/antagonistas & inibidores , Ácido Glicirretínico/análogos & derivados , Glycyrrhiza/química , Hipoglicemiantes/farmacologia , Receptor para Produtos Finais de Glicação Avançada/genética , Canais de Cátion TRPC/genética , Canal de Cátion TRPC6/genética , Compostos de Boro/farmacologia , Cálcio/metabolismo , Regulação da Expressão Gênica , Glucose/toxicidade , Ácido Glicirretínico/isolamento & purificação , Ácido Glicirretínico/farmacologia , Humanos , Hipoglicemiantes/isolamento & purificação , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Pirazóis/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Células THP-1 , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6/antagonistas & inibidores , Canal de Cátion TRPC6/metabolismo , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismo
7.
Mediators Inflamm ; 2019: 7854389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30948926

RESUMO

Intestinal injury has long been considered to play a crucial role in the pathophysiology of sepsis and has even been characterized as the "motor" of it. Thus, we explored the effects of connexin43 (Cx43) on sepsis-induced intestinal injury in order to provide potential therapeutic strategies. Rat cecal ligation and puncture (CLP) models in vivo and cell models (IEC-6 cells) pretreated with LPS in vitro were used in the current study. Firstly, different methods, such as Cx43 inhibitors (18-α-GA and oleamide) or siRNA targeting Cx43 and N-acetyl cysteine (NAC) (a kind of ROS scavenger), were used to observe the effects of Cx43 channels mediating ROS transfer on intestinal injury. Secondly, the influence of ROS content on the activity of the JNK1/Sirt1/FoxO3a signaling pathway was explored through the application of NAC, sp600125 (a JNK1 inhibitor), and nicotinamide (a Sirt1 inhibitor). Finally, luciferase assays and ChIP were used to determine the direct regulation of FoxO3a on proapoptotic proteins, Bim and Puma. The results showed that sepsis-induced intestinal injury presented a dynamic change, coincident with the alternation of Cx43 expression. The inhibition of Cx43 attenuated CLP-induced intestinal injury in vivo and LPS-induced IEC-6 injury in vitro. The changes of Cx43 channel function regulated ROS transfer between the neighboring cells, which mediated the activation of the JNK1/Sirt1/FoxO3a signaling pathway. FoxO3a directly affected its downstream target genes, Bim and Puma, which are responsible for cell or tissue apoptosis. In summary, our results suggest that Cx43 inhibition suppresses ROS transfer and inactivates the JNK1/Sirt1/FoxO3a signaling pathway to protect against sepsis-induced intestinal injury.


Assuntos
Conexina 43/metabolismo , Proteína Forkhead Box O3/metabolismo , Intestinos/lesões , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Sirtuína 1/metabolismo , Animais , Conexina 43/antagonistas & inibidores , Conexina 43/genética , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Masculino , Ácidos Oleicos/farmacologia , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológico
8.
Molecules ; 24(4)2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30791593

RESUMO

A new series of glycyrrhetinic acid derivatives has been synthesized via the introduction of different heterocyclic rings conjugated with an α,ß-unsaturated ketone in its ring A. These new compounds were screened for their antiproliferative activity in a panel of nine human cancer cell lines. Compound 10 was the most active derivative, with an IC50 of 1.1 µM on Jurkat cells, which is 96-fold more potent than that of glycyrrhetinic acid, and was 4-fold more selective toward that cancer cell line. Further biological studies performed in Jurkat cells showed that compound 10 is a potent inducer of apoptosis that activates both the intrinsic and extrinsic pathways.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/química , Humanos , Estrutura Molecular
9.
Carcinogenesis ; 40(2): 234-245, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30364936

RESUMO

The natural phenolic substance, 18ß-glycyrrhetinic acid (GRA), has shown enormous potential in the chemoprevention of cancers with rich resources and biological safety, but the GRA-regulated genetic and epigenetic profiles are unclear. Deregulated mitochondrial cellular energetics supporting higher adenosine triphosphate provisions relative to the uncontrolled proliferation of cancer cells is a cancer hallmark. The Toll-like receptor 2 (TLR2) signaling pathway has emerged as a key molecular component in gastric cancer (GC) cell proliferation and epithelial homeostasis. However, whether TLR2 influenced GC cell energy metabolism and whether the inhibition effects of GRA on GC relied on TLR2 signaling were not illustrated. In the present study, TLR2 mRNA and protein expression levels were elevated in gastric tumors in the K19-Wnt1/C2mE (Gan) mice model, GC cell lines and human GCs, and the overexpression of TLR2 was correlated with the high histological grade and was a poor prognostic factor in GC patients. Further gain and loss of function showed that TLR2 activation induced GC cell proliferation and promoted reactive oxygen species (ROS) generation, Ca2+ accumulation, oxidative phosphorylation and the electron transport chain, while blocking TLR2 inhibited mitochondrial function and energy metabolism. Furthermore, GRA pretreatment inhibited TLR2-activated GC cell proliferation, energy metabolism and carcinogenesis. In addition, expression of TLR2 was found to be downregulated by GRA through methylation regulation. Collectively, the results demonstrated that GRA inhibited gastric tumorigenesis through TLR2-accelerated energy metabolism, suggesting GRA as a promising therapeutic agency targeting TLR2 signaling in GC.


Assuntos
Carcinogênese/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Metilação/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estômago/efeitos dos fármacos , Receptor 2 Toll-Like/metabolismo , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Humanos , Camundongos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle
10.
Planta Med ; 85(1): 56-61, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30086557

RESUMO

In this study, the biocatalysis of 18ß-glycyrrhetinic acid by two strains of filamentous fungi, namely Rhizopus arrhizus AS 3.2893 and Circinella muscae AS 3.2695, was investigated. Scaled-up biotransformation reactions yielded 14 metabolites. Their structures were established based on extensive nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data analyses, and seven of them are new compounds. The two fungal strains exhibited distinct biocatalytic features. R. arrhizus could catalyze hydroxylation and carbonylation reactions, whereas C. muscae preferred to catalyze hydroxylation and glycosidation reactions. These highly specific reactions are difficult to achieve by chemical synthesis, particularly under mild conditions. Furthermore, we found that most of the metabolites exhibited pronounced inhibitory activities on lipopolysaccharides-induced nitric oxide production in RAW264.7 cells. These biotransformed derivatives of 18ß-glycyrrhetinic acid could be potential anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/farmacologia , Ácido Glicirretínico/análogos & derivados , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Biotransformação , Catálise , Ácido Glicirretínico/química , Ácido Glicirretínico/metabolismo , Ácido Glicirretínico/farmacologia , Hidroxilação , Camundongos , Mucorales/metabolismo , Células RAW 264.7 , Rhizopus/metabolismo
11.
J Microbiol Biotechnol ; 28(11): 1876-1882, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30562883

RESUMO

A series of pentacyclic triterpenoids similar to glycyrrhetinic acid were designed and synthesized via the combination of chemical modification and microbial catalysis. All products were screened for the glycogen phosphorylases inhibitory activities in vitro. Within this series of derivatives, compound 5 displayed good inhibitory activities with IC50 value of 27.7 µM, which is better than that of the other derivatives and glycyrrhetinic acid. Structure-activity relationship (SAR) analysis of these inhibitors was also discussed.


Assuntos
Aspergillus ochraceus/metabolismo , Glicogênio Fosforilase/antagonistas & inibidores , Ácido Oleanólico , Streptomyces griseus/metabolismo , Biotransformação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/química , Concentração Inibidora 50 , Estrutura Molecular , Ácido Oleanólico/biossíntese , Ácido Oleanólico/síntese química , Ácido Oleanólico/química , Ácido Oleanólico/metabolismo , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 28(23-24): 3700-3707, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528976

RESUMO

Novel NF-κB inhibitors based on Glycyrrhetinic acid (GA) derivatives containing aminophosphonate ester moieties were rationally designed and synthesized as well as evaluated their antitumor activities using MTT assay. Many target compounds showed potent antitumor activities against the tested human cancer cell lines including cisplatin-resistant cells, and exhibited significant inhibitory activity to the NF-κB with IC50 values at micromolar concentrations in A549 cells, respectively. Among them, compound 12e possessed excellent antitumor activities against the tested human cancer cell lines and showed low cytotoxicity toward to human normal liver cells. Moreover, 12e caused obvious loss of MMP and significantly induced ROS production, and displayed inhibition of cell migration against A549 cells in vitro. Importantly, 12e arrested the cell cycle at the S phases and ultimately induced cell apoptosis in A549 cells through blockage of NF-κB signaling pathway. Our research provided an efficient strategy for targeting NF-κB antitumor drug development.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , NF-kappa B/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Sci Rep ; 8(1): 15568, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30348944

RESUMO

Pseudoaldosteronism is a common adverse effect associated with traditional Japanese Kampo medicines. The pathogenesis is mainly caused by 3-monoglucuronyl glycyrrhetinic acid (3MGA), one of the metabolites of glycyrrhizin (GL) contained in licorice. We developed an anti-3MGA monoclonal antibody (MAb) and an ELISA system to easily detect 3MGA in the plasma and urine of the patients. However, we found that some metabolites of GL cross-reacted with this MAb. Mrp2-deficient Eisai Hyperbilirubinemia rats (EHBRs) were administered glycyrrhetinic acid (GA), and we isolated 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide (1) from the pooled urine with the guidance of positive immunostaining of eastern blot as the new metabolite of GL. The IC50 of 1 for type 2 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) was 2.0 µM. Similar plasma concentrations of 1 and GA were observed 12 h after oral administration of GA to EHBR. Compound 1 was eliminated via urine, whereas GA was not. In Sprague-Dawley (SD) rats orally treated with GA, compound 1 was absent from both the plasma and the urine. Compound 1 was actively transported into cells via OAT1 and OAT3, whereas GA was not. Compound 1, when produced in Mrp2-deficiency, represents a potential causative agent of pseudoaldosteronism, and might be used as a biomarker to prevent the adverse effect.


Assuntos
Ácido Glicirretínico/análogos & derivados , Ácido Glicirrízico/análogos & derivados , Síndrome de Liddle/etiologia , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Cães , Feminino , Ácido Glicirretínico/farmacocinética , Ácido Glicirretínico/toxicidade , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Eliminação Renal
14.
Acta Pharmacol Sin ; 39(12): 1865-1873, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30061734

RESUMO

Cholestasis is a common feature of liver injury, which manifests as bile acid excretion and/or enterohepatic circulation disorders. However, very few effective therapies exist for cholestasis. Recently, 18ß-Glycyrrhetinic acid (18b-GA), a major metabolic component of glycyrrhizin, which is the main ingredient of licorice, was reported to protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. However, its protective mechanism remains unclear. We hypothesized that 18b-GA may stimulate the signaling pathway of bile acid (BA) transportation in hepatocytes, resulting its hepatoprotective effect. According to the results, 18b-GA markedly attenuated ANIT-induced liver injury as indicated the hepatic plasma chemistry index and histopathology examination. In addition, the expression levels of nuclear factors, including Sirt1, FXR and Nrf2, and their target efflux transporters in the liver, which mainly mediate bile acid homeostasis in hepatocytes, significantly increased. Furthermore, we first revealed that 18b-GA treatment significantly activated FXR, and which can be significantly reduced by EX-527 (a potent and selective Sirt1 inhibitor), indicating that 18b-GA activates FXR through Sirt1. Taken together, 18b-GA confers hepatoprotection against ANIT-induced cholestasis by activating FXR through Sirt1, which promotes gene expression of the efflux transporter, and consequently attenuates dysregulation of bile acid homeostasis in hepatocyte compartments.


Assuntos
Colestase/prevenção & controle , Ácido Glicirretínico/análogos & derivados , Substâncias Protetoras/uso terapêutico , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , 1-Naftilisotiocianato , Animais , Colestase/induzido quimicamente , Ácido Glicirretínico/uso terapêutico , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley
15.
Immunopharmacol Immunotoxicol ; 40(4): 344-352, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30052483

RESUMO

AIM: The aim of this study was to investigate the beneficial effects of 18ß-glycyrrhetinic acid (GA) on the experimental allergic encephalomyelitis (EAE) in C57BL/6 mice. GA is a natural substance found in the root of licorice and is used in traditional Chinese medicine. It has many pharmacological activities such as antioxidant, anti-inflammatory, and anti-cancer effects. MATERIALS AND METHODS: A total of 40 C57BL/6 mice were divided equally into four groups: (1) Control, (2) EAE, (3) GA and (4) GA + EAE. 14 days after induction of EAE with MOG35-55 and pertussis toxin, mice were treated with GA at doses of 100 mg/kg/day for 7 days intraperitoneally. RESULTS: To our results, oxidative stress and lipid peroxidations (elevated TBARS levels, decreased GPx, SOD, CAT, and GSH levels) were significantly (p < .01) increased, causing EAE in brain tissue. Also, histopathological damage (Caspase-3 and IL-17 activity, p ≤ .01) and cytokine levels (TNF-α and IL-1ß, p < .01) were induced with EAE in mice brain tissue. On the other hand, GA treatment significantly (p < .01) reversed oxidative histological and immunological alterations caused by EAE. CONCLUSIONS: In conclusion, the GA treatment can protect the brain tissue against EAE in mice with its antioxidant and anti-inflammatory properties.


Assuntos
Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Ácido Glicirretínico/análogos & derivados , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Encéfalo/patologia , Caspase 3/metabolismo , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Feminino , Ácido Glicirretínico/farmacologia , Camundongos
16.
Mediators Inflamm ; 2018: 6461032, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29861658

RESUMO

Airway epithelial cells secrete diverse inflammatory mediators in response to various stimuli. Thus, early regulation of immune responses in the airway epithelium is likely critical for the control of chronic inflammatory diseases. The purpose of the present study was to evaluate the effects of 18ß-glycyrrhetinic acid (GA) on inflammatory responses generated in response to a fungal protease allergen that induces epithelial damage. To understand the underlying mechanisms, we also investigated the inhibitory effects of GA on the production of mitochondrial reactive oxygen species (ROS) in the human bronchial epithelial cell line BEAS2B. In this study, GA treatment reduced cytokine production and the human neutrophil cell line HL60 migration through decreased mitochondrial ROS production. In addition, GA significantly reduced inflammatory cell infiltration and cytokine levels in the bronchoalveolar lavage (BAL) fluid of fungal allergen-administered mice. Inhibitory effects of GA are dependent on the mitochondrial ROS/MAPK axis. Moreover, the effect of GA on the regulation of mitochondrial ROS depends on the expression of uncoupling protein-2 (UCP-2). Taken together, GA might represent a potential therapeutic agent for blocking inflammatory responses in airways.


Assuntos
Ácido Glicirretínico/análogos & derivados , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Líquido da Lavagem Broncoalveolar , Linhagem Celular , Citocinas/metabolismo , Ácido Glicirretínico/uso terapêutico , Células HL-60 , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Desacopladora 2/metabolismo
17.
Sci Rep ; 8(1): 9365, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29921924

RESUMO

18ß-Glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicine, Glycyrrhrzae Radix et Rhizoma. Here, we explored the effects of GA on hepatocellular carcinoma (HCC) in vitro and in vivo and the underlying molecular mechanisms. We confirmed that GA suppressed proliferation of various HCC cell lines. Treatment of GA caused G0/G1 arrest, apoptosis and autophagy in HCC cells. GA-induced apoptosis and autophagy were mainly due to the unfolded protein response. We compared the roles of the ATF4/CHOP and IRE1α/XBP1s UPR pathways, which were both induced by GA. The ATF4/CHOP cascade induced autophagy and was indispensable for the induction of apoptosis in GA-treated HCC cells. In contrast, the IRE1α/XBP1s cascade protected HCC cells from apoptosis in vitro and in vivo induced by GA. Despite this, activation of autophagy protected HCC cells from apoptosis induced by GA. We concluded that pharmacological inhibition of autophagy or IRE1α may be of benefit to enhance the antitumor activity of GA.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Ácido Glicirretínico/análogos & derivados , Neoplasias Hepáticas/metabolismo , Resposta a Proteínas não Dobradas/genética , Apoptose/genética , Autofagia/genética , Carcinoma Hepatocelular/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Endorribonucleases/genética , Endorribonucleases/metabolismo , Fase G1/efeitos dos fármacos , Fase G1/genética , Ácido Glicirretínico/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo
18.
Cell Death Dis ; 9(6): 623, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795376

RESUMO

Methyl 2-cyano-3,12-dioxo-18ß-olean-1,9(11)-dien-30-oate (CDODO-Me, 10d) derived from glycyrrhetinic acid and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) derived from oleanoic acid are potent apoptosis inducers developed to clinical trials. Both compounds have high affinity for reduced  glutathione (GSH), which needs to be overcome to improve their target selectivity. We generated a new 10d analogue methyl 2-cyano-3-oxo-18ß-olean-1,9(11), 12-trien-30-oate (COOTO, 10e), which retains high apoptosis inducing ability, while displaying decreased affinity for GSH, and explored the acting targets. We found that it induces Noxa level, reduces c-Flip level and causes Bax/Bak activation. Silencing of either Noxa or Bak significantly attenuated apoptosis induction of 10e. We linked these events due to targeting HDAC3/HDAC6 and Ku70 axis. 10e treatment reduced the levels of HDAC3 and HDAC6 with increased DNA damage/repair marker gamma-H2AX (γ-H2AX) and acetylated Ku70. c-Flip dissociates from acetylated Ku70 undergoing degradation, while Bax dissociates from acetylated Ku70 undergoing activation. Silencing of either HDAC3 or HDAC6 enhanced 10e-induced apoptosis. We reveal a new action cascade of this category of compounds that involves targeting of HADC3/6 proteins and Ku70 acetylation.


Assuntos
Apoptose/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/farmacologia , Histona Desacetilases/metabolismo , Autoantígeno Ku/metabolismo , Nitrilos/farmacologia , Acetilação , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Regulação para Baixo/efeitos dos fármacos , Ácido Glicirretínico/química , Células HL-60 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Nitrilos/química , Estabilidade Proteica , Regulação para Cima/efeitos dos fármacos
19.
Mol Biol (Mosk) ; 52(2): 306-313, 2018.
Artigo em Russo | MEDLINE | ID: mdl-29695699

RESUMO

Due to wide spreading of inflammatory disease and imperfection of available anti-inflammatory drugs, mainly associated with their serious side effects, searching for new anti-inflammatory agents is a pressing problem. Natural triterpenoids and their synthetic analogs are a promising source of new drugs. In this study, we have investigated the anti-inflammatory and antitumor effects in vivo of the glycyrrhetinic acid derivative soloxolone methyl (SM), or methyl 2-cyano-3,12-dioxo-18ßH-olean-9(ll),l(2)-dien-30-oate. SM was shown to efficiently suppress the development of edema in a mouse model of carrageenan- or histamine-induced acute inflammation. SM also inhibited the tumor growth and reduced the tumor cell count in the ascitic fluid in mice bearing Krebs-2 carcinoma, the development of which is accompanied by an inflammatory process in the surrounding tissues.


Assuntos
Carcinoma Krebs 2/tratamento farmacológico , Ácido Glicirretínico , Animais , Carcinoma Krebs 2/metabolismo , Carcinoma Krebs 2/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR
20.
Environ Toxicol Pharmacol ; 60: 82-90, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29677640

RESUMO

Radiation-induced inflammation plays an important role in radiation-induced tissue injury. 18ß-glycyrrhetinic acid (18ß-GA) has shown an anti-inflammatory activity. This study aimed to assess the activity of 18ß-GA against radiation-induced skin damage, and explore the underlying mechanisms. In vitro assay revealed 18ß-GA treatment decreased the production of IL-1ß, IL-6, PGE2 and decreased p38MAPK phosphorylation, DNA-binding activity of AP-1, and NF-κB activation in irradiated RAW264.7 macrophages. Additionally, 18ß-GA suppressed NF-κB activation by inhibiting NF-κB/p65 and IκB-α phosphorylation and alleviated ROS overproduction in irradiated RAW264.7 macrophages. In vivo assay showed 18ß-GA alleviated severity of radiation-induced skin damage, reduced inflammatory cell infiltration and TNF-α, IL-1ß and IL-6 levels in cutaneous tissues. Our findings demonstrate that 18ß-GA exhibits anti-inflammatory actions against radiation-induced skin damage probably by inhibiting NADPH oxidase activity, ROS production, activation of p38MAPK and NF-κB signaling, and the DNA binding activities of NF-κB and AP-1, consequently suppressing pro-inflammatory cytokine production.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácido Glicirretínico/análogos & derivados , NADPH Oxidases/metabolismo , Radiodermatite/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/administração & dosagem , Ácido Glicirretínico/farmacologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Radiodermatite/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA