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1.
Arterioscler Thromb Vasc Biol ; 41(3): 1205-1217, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472404

RESUMO

OBJECTIVE: Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs. CONCLUSIONS: These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Basigina/antagonistas & inibidores , Ciclofilina A/antagonistas & inibidores , Hipertensão Arterial Pulmonar/tratamento farmacológico , Triterpenos/uso terapêutico , Disfunção Ventricular Direita/tratamento farmacológico , Animais , Anti-Hipertensivos/uso terapêutico , Basigina/genética , Basigina/metabolismo , Ciclofilina A/metabolismo , Modelos Animais de Doenças , Humanos , Hipóxia/complicações , Indóis/toxicidade , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Hipertensão Arterial Pulmonar/patologia , Hipertensão Arterial Pulmonar/fisiopatologia , Pirróis/toxicidade , Ratos , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia
2.
Mol Immunol ; 130: 122-132, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33308902

RESUMO

Acinar cell necrosis is one of the most prominent pathophysiological changes of acute pancreatitis (AP). Asiaticoside (AS) is a triterpene compound with confirmed apoptosis-and necrosis-related activities. However, the specific effects of AS on AP have not been determined. In this study, we aimed to investigate the protective effect of AS on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, We found that AS administration reduced serum amylase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. And the levels of toll-like receptor 4 (TLR4) and necrotic related proteins (RIP3 and p-MLKL) of pancreatic tissue were reduced after AS administration. In addition, TLR4 deficiency eliminated the protective effect of AS on AP induced by caerulein in mice. Correspondingly, we elucidated the effect of AS in vitro and found that AS protected against pancreatic acinar cells necrosis and TAK-242 counteracted this protective effect. Meanwhile, we found that AS ameliorated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by l-arginine. Furthermore, Molecular docking results revealed interaction between AS and TLR4. Taken together, our data for the first time confirmed the protective effects of AS on AP in mice via TLR4 pathway.


Assuntos
Células Acinares/efeitos dos fármacos , Células Acinares/patologia , Pancreatite/patologia , Receptor 4 Toll-Like/genética , Triterpenos/farmacologia , Animais , Células Cultivadas , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Necrose/prevenção & controle , Pancreatite/tratamento farmacológico , Pancreatite/genética , Pancreatite/metabolismo , Transdução de Sinais/genética , Receptor 4 Toll-Like/fisiologia , Triterpenos/uso terapêutico
3.
Am J Chin Med ; 48(6): 1475-1489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907364

RESUMO

Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein.


Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triterpenos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias dos Ductos Biliares/dietoterapia , Linhagem Celular Tumoral , Colangiocarcinoma/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Triterpenos/uso terapêutico
4.
J Environ Pathol Toxicol Oncol ; 39(3): 213-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865913

RESUMO

Asthma is a chronic, serious allergic inflammatory disease in the airway. The inflammation in the airway is induced by the allergic T-helper 2 cells (Th2 cells), which leads to unfettered production of inflammatory cytokines. The accretion of inflammatory cells in the airway also speeds up the secretion of reactive oxygen species (ROS) and suppresses antioxidative processes. Hence, the present work aimed to study the antiasthmatic efficacy of betulin and its effect in suppressing the inflammatory markers of ovalbumin (OVA) challenged asthmatic mice. The observed results revealed that the levels of inflammatory cells including neutrophils, eosinophils, lymphocytes, and macrophages were effectively decreased by betulin treatment; furthermore, the inflammatory markers IL-4, IL-5, IL-13, and TNF-α levels were notably suppressed by betulin administration in OVA-challenged asthmatic mice. Similarly, the oral administration of betulin showed a reduction in IgE level and elevation in the IFN-γ level in bronchoalveolar lavage fluid (BALF). The elevated levels of antioxidant enzymes like catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) were observed in betulin treated mice. Furthermore, reduced levels of reactive oxygen species like NO2, NO3, and MDA were noted in the betulin treated group. Consistently, airway hyperreactivity (AHR) was depleted in the betulin administered group compared with the OVA-challenged asthmatic group. Betulin treatment was revealed to have noteworthy antiasthmatic effects mediated by the suppression of production of inflammatory cells and the expression of other inflammatory markers. Furthermore, the elevation in the level of antioxidant markers helped to disclose the original regulatory mode of betulin on asthma treatment.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/imunologia , Asma/metabolismo , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinófilos/citologia , Feminino , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória , Triterpenos/administração & dosagem
5.
PLoS One ; 15(7): e0233814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726313

RESUMO

The clinical efficacy for treating of celastrol rheumatoid arthritis (RA) has been well-documented, but its mechanism of action remains unclear. Here we explored through what proteins and processes celastrol may act in activated fibroblast-like synoviocytes (FLS) from RA patients. Differential expression of genes and proteins after celastrol treatment of FLS was examined using RNA sequencing, label-free relatively quantitative proteomics and molecular docking. In this paper, expression of 26,565 genes and 3,372 proteins was analyzed. Celastrol was associated with significant changes in genes that respond to oxidative stress and oxygen levels, as well as genes that stabilize or synthesize components of the extracellular matrix. These results identify several potential mechanisms through which celastrol may inhibit inflammation in RA.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Proteômica/métodos , Transcriptoma/efeitos dos fármacos , Triterpenos/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Células Cultivadas , Cromatografia Líquida , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Espectrometria de Massas por Ionização por Electrospray , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Espectrometria de Massas em Tandem , Triterpenos/uso terapêutico
6.
Exp Parasitol ; 216: 107935, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32569599

RESUMO

Toxoplasma gondii is an important pathogen that causes serious public health problems. Currently, therapeutic drugs for toxoplasmosis cause serious side effects, and more effective and novel substances with relatively low toxicity are urgently needed. Ursolic acid (UA) has many properties that can be beneficial to healthcare. In this study, we synthesized eight series of UA derivatives bearing a tetrazole moiety and evaluated their anti-T. gondii activity in vitro using spiramycin as a positive control. Most of the synthesized derivatives exhibited better anti-T. gondii activity in vitro than UA, among which compound 12a exhibited the most potent anti-T. gondii activity. Furthermore, the results of biochemical parameter determination indicated that 12a effectively restored the normal body weight of mice infected with T. gondii, reduced hepatotoxicity, and exerted significant anti-oxidative effects compared with the findings for spiramycin. Additionally, our molecular docking study indicated that the synthesized compounds could act as potential inhibitors of T. gondii calcium-dependent protein kinase 1 (TgCDPK1), with 12a possessing strong affinity for TgCDPK1 via binding to the key amino acids GLU129 and TYR131.


Assuntos
Anti-Infecciosos/farmacologia , Toxoplasma/efeitos dos fármacos , Toxoplasmose Animal/tratamento farmacológico , Toxoplasmose/tratamento farmacológico , Triterpenos/farmacologia , Alanina Transaminase/sangue , Animais , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Aspartato Aminotransferases/sangue , Coccidiostáticos/química , Coccidiostáticos/farmacologia , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Malondialdeído/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Tamanho do Órgão/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases , Distribuição Aleatória , Espiramicina/farmacologia , Baço/efeitos dos fármacos , Baço/patologia , Triterpenos/química , Triterpenos/uso terapêutico
7.
PLoS One ; 15(6): e0235221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584888

RESUMO

Ficus krishnae stem bark and leaves are used for diabetes treatment in traditional medicines. Stem bark of F. krishnae was sequentially extracted with hexane, methanol and water, and these extracts were tested for their antihyperglyceamic activity by oral glucose tolerance test (OGTT) in overnight fasted glucose loaded normal rats. Hexane extract showed significant glucose lowering activity in OGTT, and the triterpene alcohols (cycloartenol+24-methylenecycloartanol) (CA+24-MCA) were isolated together from it by activity guided isolation and characterized by NMR and mass spectroscopy. The ratio of the chemical constituents CA and 24-MCA in (CA+24-MCA) was determined as 2.27:1.00 by chemical derivatization and gas chromatographic quantification. (CA+24-MCA) in high fat diet-streptozotocin induced type II diabetic rats showed significant antidiabetes activity at 1 mg/kg and ameliorated derailed blood glucose and other serum biochemical parameters. Cytoprotective activity of (CA+24-MCA) from glucose toxicity was evaluated in cultured RIN-5F cells by MTT assay and fluorescent microscopy. (CA+24-MCA) in in vitro studies showed enhanced cell viability in RIN-5F cells and significant protection of beta cells from glucose toxicity. Both in in vivo and in vitro studies (CA+24-MCA) showed enhancement in insulin release from the beta cells. In short term toxicity studies in mice (CA+24-MCA) did not show any conspicuous toxic symptoms. The combination of the phytosterols (CA+24-MCA) obtained through activity guided isolation of the stem bark of F. krishnae showed significant activity, and therefore is a promising candidate for new generation antidiabetes drug development.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Ficus/química , Hipoglicemiantes/uso terapêutico , Fitosteróis/química , Triterpenos/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Ficus/metabolismo , Teste de Tolerância a Glucose , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Conformação Molecular , Fitosteróis/isolamento & purificação , Fitosteróis/uso terapêutico , Caules de Planta/química , Caules de Planta/metabolismo , Ratos , Ratos Wistar , Triterpenos/isolamento & purificação , Triterpenos/uso terapêutico
8.
Sci Rep ; 10(1): 8851, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483248

RESUMO

As one of the main components of Tripterygium wilfordii Hook F, celastrol (CSL) has significant antitumor activity, but its clinical application has been limited by its poor solubility, low oral bioavailability and systemic toxicity. In this study, celastrol nanosuspensions (CSL-NSps) were prepared using an antisolvent precipitation method with poloxamer 188 (P-188) as a stabilizer at a high CSL/P-188 feeding ratio of 8:1. The resultant CSL was spherical in shape with an average particle size of 147.9 nm, a polydispersity index (PDI) of 0.12 and zeta potential of -19.2 mV. The encapsulation efficiency and drug loading content were 98.18% and 86.83%, respectively, and the X-ray diffraction (XRD) pattern showed that CSL existed in an amorphous state in the nanosuspensions. CSL-NSps were quite stable in various physiological media and plasma and were both suitable for oral and intravenous administration. Nanosuspensions greatly enhanced the in vitro dissolution, and the cumulative drug release reached approximately 69.20% within 48 h. In vivo, CSL-NSps (3 mg/kg, i.g.) displayed a significantly enhanced tumor inhibition rate (TIR) in comparison with that of CSL suspension when administered orally (TIR, 50.39%, vs. 41.16%, p < 0.05),  similar to that of PTX injection (8 mg/kg, i.v. TIR, 50.88%). CSL-NSps showed even better therapeutic efficacy than PTX injection (TIR, 64.18%, p < 0.01) when intravenously injected. This has demonstrated that, with the help of nanosuspensions, CSL is likely to be an effective and promising antitumor agent in clinic practice for the treatment of breast cancer.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Nanoestruturas/química , Triterpenos/química , Administração Oral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Temperatura , Transplante Heterólogo , Triterpenos/farmacologia , Triterpenos/uso terapêutico
9.
J Pharmacol Sci ; 143(3): 165-175, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32387002

RESUMO

yeyachun and danshen exist as Chinese patent medicine, Xuemai Tong, and are clearly effective at alleviating liver fibrosis (LF). Previous studies have indicated that triterpenoids from yeyachun (EFT), and phenolic acids from danshen (SMP) are effective in the treatment of LF. The regulation of intestinal flora is an effective method for treating LF. The aim of this study was to investigate the effect of a mixture of EFT and SMP on carbon tetrachloride (CCl4) induced LF. Our results showed the mixture significantly decreased liver damage and fibrosis index, and maintained liver tissue composition, compared to the model group. Moreover, the imbalance of symptoms of intestinal flora was improved. The mixture also caused changes to metabolites of gut flora. Furthermore, the expression of CD68 in liver tissues from the treated groups was significantly decreased when compared to the model group. However, no significant difference was observed from microstructure of gut tissues and LPS concentrations in the serum between mixture treated mice and model mice. This study suggests that the mixture of EFT and SMP had a significant effect on CCl4 induced LF, and the mechanism of this action, at least in part, involved the regulation of intestinal flora and their metabolites.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Hidroxibenzoatos/farmacologia , Hidroxibenzoatos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/microbiologia , Fitoterapia , Salvia miltiorrhiza/química , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Masculino , Camundongos Endogâmicos ICR , Triterpenos/isolamento & purificação
10.
Phytother Res ; 34(10): 2721-2729, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32431006

RESUMO

Dammarane sapogenins (DS), an extract derived from ginseng by alkaline hydrolysis of total ginsenosides, possesses high pharmacological activity and higher bioavailability than ginsenosides. The present study was designed to investigate the anxiolytic-like effects of DS in a mouse model of chronic social defeat stress (CSDS). DS (40 and 80 mg/kg) significantly ameliorated social avoidance and anxiety-like behavior in four test models of CSDS, showing increased time in the interaction zone in the social interaction test and in the center of the field in the open field test, an increased percentage of entries and open arm time in the elevated plus maze, and reduced latency to eat in the novelty-suppressed feeding test. Biochemical analyses showed that DS significantly reduced serum corticosterone levels and increased brain concentration of neurotransmitter 5-HT and noradrenaline in CSDS mice. Treatment with DS significantly upregulated BDNF (brain-derived neurotrophic factor), p-CREB/CREB and p-ERK1/2/ERK1/2 protein expression in the hippocampus and prefrontal cortex of CSDS mice. Collectively, these results suggest that DS exerts anxiolytic-like effects in CSDS model mice and the action is mediated, at least in part, by modulating the HPA (hypothalamic-pituitary-adrenal) axis and monoamine neurotransmitter levels, and via ERK/CREB/BDNF signaling pathway.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Sapogeninas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Ansiolíticos/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Sapogeninas/farmacologia , Triterpenos/farmacologia , Regulação para Cima
11.
Toxicol Appl Pharmacol ; 400: 115075, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470352

RESUMO

NLRP3, one of the HSP-90 clients, has been defined as a critical component of IBD. In a rat model of DSS-induced colitis, we investigated the anti-inflammatory potential of the combined therapy with CP-456773 (CP), an NLRP3 inhibitor, and celastrol (CSR), an NF-κB inhibitor. Our results revealed that the CSR/CP combined therapy (CCCT) attenuated colon shortening, DAI and MDI in addition to improvement of the colonic histological picture. Moreover, the CCCT increased the antioxidant defense machinery of the colonic tissue and decreased MPO activity. Furthermore, the inflammation markers such as TNF-α and IL-6 were downregulated. These effects might be attributed to the inhibitory effect of CSR on the priming step of the NLRP3 inflammasome activation by interrupting NF-κB signalling and inhibition of HSP-90 (at the protein and mRNA levels) along with inhibitory effect of CP on the expression of the NLRP3. These latter effects resulted in decreased tissue expression and activity of the caspase-1 and repressing the subsequent release of the active forms of IL-1ß and IL-18, hence, the pyroptosis process is restrained. Additionally, the CCCT resulted in inducing autophagy by AMPK/mTOR-dependent mechanisms leading to the accumulation of BECN1 protein and a significant decrease in the levels of p62 SQSTM1. The inhibitory effect on HSP-90 in conjunction with induction of autophagy suggest increased autophagic degradation of NLRP3. This novel approach provides a basis for the clinical application of this combination in IBD treatment and might also be promising for the pharmacological intervention of other NLRP3 inflammasome-dependent inflammatory conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Colite/tratamento farmacológico , Proteínas de Choque Térmico HSP90/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sulfonas/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Proteínas de Choque Térmico HSP90/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Masculino , Ratos Sprague-Dawley , Sulfonas/administração & dosagem , Sulfonas/uso terapêutico , Triterpenos/administração & dosagem , Triterpenos/uso terapêutico
12.
Am J Chin Med ; 48(3): 579-595, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329643

RESUMO

Corosolic acid (CA) is the main active component of Lagetstroemia speciosa and has been known to serve as several different pharmacological effects, such as antidiabetic, anti-oxidant, and anticancer effects. In this study, effects of CA on the hepatic lipid accumulation were examined using HepG2 cells and tyloxapol (TY)-induced hyperlipidemia ICR mice. CA significantly inhibited hepatic lipid accumulation via inhibition of SREBPs, and its target genes FAS, SCD1, and HMGCR transcription in HepG2 cells. These effects were mediated through activation of AMPK, and these effects were all abolished in the presence of compound C (CC, an AMPK inhibitor). In addition, CA clearly alleviated serum ALT, AST, TG, TC, low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDL-C) levels, and obviously attenuated TY-induced liver steatosis and inflammation. Moreover, CA significantly upregulated AMPK, ACC, LKB1 phosphorylation, and significantly inhibited lipin1, SREBPs, TNF-α, F4/80, caspase-1 expression, NF-κB translocation, and MAPK activation in TY-induced hyperlipidemia mice. Our results suggest that CA is a potent antihyperlipidemia and antihepatic steatosis agent and the mechanism involved both lipogenesis and cholesterol synthesis and inflammation response inhibition via AMPK/SREBPs and NF-κB/MAPK signaling pathways.


Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Fitoterapia , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Animais , Células Hep G2 , Humanos , Inflamação , Lagerstroemia/química , Camundongos Endogâmicos ICR , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/metabolismo
13.
Proc Natl Acad Sci U S A ; 117(16): 9082-9093, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32253301

RESUMO

Current multiple sclerosis (MS) medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged central nervous system (CNS) tissue; they are thus primarily effective at the acute stage of disease, but much less so at the chronic stage. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that ursolic acid (UA), an antiinflammatory natural triterpenoid, also directly promotes oligodendrocyte maturation and CNS myelin repair. Oral treatment with UA significantly decreased disease severity and CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Importantly, remyelination and neural repair in the CNS were observed even after UA treatment was started on day 60 post immunization when EAE mice had full-blown demyelination and axonal damage. UA treatment also enhanced remyelination in a cuprizone-induced demyelination model in vivo and brain organotypic slice cultures ex vivo and promoted oligodendrocyte maturation in vitro, indicating a direct myelinating capacity. Mechanistically, UA induced promyelinating neurotrophic factor CNTF in astrocytes by peroxisome proliferator-activated receptor γ(PPARγ)/CREB signaling, as well as by up-regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Together, our findings demonstrate that UA has significant potential as an oral antiinflammatory and neural repair agent for MS, especially at the chronic-progressive stage.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Remielinização/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Cuprizona/toxicidade , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/imunologia , Oligodendroglia/patologia , PPAR gama/metabolismo , Triterpenos/uso terapêutico
14.
Arch Med Res ; 51(4): 297-302, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32169299

RESUMO

BACKGROUND: Potential agents that can effectively treat hepatocellular carcinoma (HCC) are being continuously explored. METHODS: Celastrol extracted from roots of an ancient Chinese herb, Tripterygium wilfordii (Thunder god vine), has been identified as a potential anti-tumor agent. In this study, the molecular mechanisms underlying the action of celastrol on cell proliferation and chemokine CXCR4-related signal pathway associated with tumor growth were investigated. RESULTS: The CXCR4 expression was diminished by celastrol treatment in a dose-dependent manner, and its downstream associated pathways, including PI3K and Akt were also downregulated. Celastrol also significantly attenuated proliferation and migration ability of HCC cells, and induced cell apoptosis in vitro. Additionally, significant inhibition of HCC growth was observed in the celastrol-treated group as compared with the control group in vivo as well. CONCLUSION: Celastrol is capable of attenuating cell proliferation and inducing apoptosis, leading to inhibition of HCC growth through the suppression of CXCR4-related signal pathway.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptores CXCR4/metabolismo , Triterpenos/uso terapêutico , Animais , Carcinoma Hepatocelular/patologia , Proliferação de Células , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Transdução de Sinais , Triterpenos/farmacologia
15.
Inflamm Res ; 69(4): 385-400, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112120

RESUMO

OBJECTIVE: Osteoarthritis (OA) is a degenerative articular cartilage disease accompanied by superfluous apoptosis of chondrocytes in the elderly. Celastrol is a potent bioactive medicine which can exert anti-inflammatory and anti-oxidative effects in various diseases. This study aimed to elucidate the possible role of celastrol in OA as well as the specific mechanism of celastrol in vitro and in vivo. METHODS: Autophagy-related biomarkers and apoptotic molecules were evaluated by PCR, Western blot and immunofluorescence staining. The level of autophagy was assessed by MDC staining and transmission electron microscopy. To study the downstream signaling pathway, nuclear factor kappa B (NF-κB) signaling pathway-related proteins were examined by Western blot. Moreover, an anterior cruciate ligament transection (ACLT) rat model was established to observe the protective effect of celastrol on rat cartilage. RESULTS: We found celastrol ameliorated IL-1ß-induced chondrocyte apoptosis and increased the expression of LC3-II and Beclin-1. In addition, the suppression of celastrol-induced autophagy by 3-methyladenine (3MA) prevented the protective effect of celastrol in chondrocytes. Moreover, celastrol decreased the IL-1ß-stimulated phosphorylation degree of IκBα and P65. We also found PDTC (a known NF-κB pathway inhibitor) can promote the activation of autophagy and attenuate the apoptosis of chondrocytes. Meanwhile, the results of rat ACLT model revealed the same effect as in vitro experiments. CONCLUSIONS: In summary, celastrol protected against chondrocyte apoptosis by promoting autophagy and inhibiting NF-κB signaling pathway in vitro and in vivo.


Assuntos
Anti-Inflamatórios/uso terapêutico , Autofagia/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Interleucina-1beta/farmacologia , Masculino , NF-kappa B/imunologia , Osteoartrite/imunologia , Ratos Sprague-Dawley , Transdução de Sinais , Triterpenos/farmacologia
16.
Oxid Med Cell Longev ; 2020: 8565760, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32148658

RESUMO

Catharanthus roseus (C. roseus) and ursolic acid (UA) are ayurvedic medicines with multiple pharmacological activities including antidiabetic activity, but till date, no study is available on their combination. This study documented the antidiabetic efficacy of the combination of C. roseus and UA in rats. Rats were divided into six groups. All groups were given a single dose of Streptozotocin (STZ) at a dose of 50 mg/kg by intraperitoneal route for induction of diabetes, except the normal control group. Group 1 was treated as a normal control (NC) group and fed with saline water, Group 2 as a Diabetes Control group, Group 3 as a STZ+C. roseus ethanolic extract (CREE) group at 50 mg/kg p.o., Group 4 as a STZ+UA group orally at 50 mg/kg, Group 5 as a STZ+CREE (25 mg/kg p.o.)+UA (25 mg/kg p.o.) group, and Group 6 as a STZ+Glimepiride (0.1 mg/kg) group. Diabetes was confirmed after 72 hours by estimation of blood glucose level, and then treatment was given for the next 28 days. During the course of treatment, plasma insulin and blood glucose were measured regularly at the interval of 7 days. At the end of the protocol, blood was collected and animals were sacrificed. The glucose level, insulin level, liver glycogen storage level, and antioxidant enzymes (LPO, CAT, SOD, GPx, GST) were measured. The blood glucose level in Group 5 significantly (P < 0.001) reduced to 98.35 ± 2.45 mg/dl in comparison with that in Group 2 (321.75 ± 5.46 mg/dl). The level of plasma insulin in Group 5 increased (13.65 ± 0.10 µU/ml) significantly (P < 0.01) as compared with that in Group 2 (05.93 ± 0.31 µU/ml). In Group 5, the level of glycogen in liver was significantly (P < 0.01) increased as compared with that in Group 2 rats. The level of antioxidant enzymes in Group 5 restored toward normal values significantly (P < 0.01; P < 0.001) as compared with that in Group 2 animals. These findings suggest that low-dose combination of CREE and UA is effective in the treatment of diabetes.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Catharanthus/química , Diabetes Mellitus Experimental/tratamento farmacológico , Flores/química , Glicogênio/metabolismo , Secreção de Insulina/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Humanos , Masculino , Ratos , Ratos Wistar , Triterpenos/farmacologia
17.
Phytother Res ; 34(8): 2053-2066, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32185829

RESUMO

Gemcitabine (GEM) resistance in pancreatic adenocarcinoma mediated by the receptor for advanced glycation end products (RAGE) has been demonstrated. Therefore, investigating the safety and the potential of new auxiliary methods for pancreatic cancer treatment is urgent. Ursolic acid (UA), a natural pentacyclic triterpenoid found in apple peels, rosemary, and thyme, has been reported to have anticancer capacity. This study aimed to reveal the underlying mechanisms of UA in cell death and drug enhancement, especially in GEM-resistant pancreatic cancer cells. First, GEM-resistant cells (MIA Paca-2GEMR cells) were established by incrementally increasing GEM culture concentrations. UA treatment reduced cell viability through cell cycle arrest and endoplasmic reticulum (ER) stress, resulting in apoptosis and autophagy in a dose-dependent manner in MIA Paca-2 and MIA Paca-2GEMR cells. High RAGE expression in MIA Paca-2GEMR cells was suppressed by UA treatment. Interestingly, knocking down RAGE expression showed similar UA-induced effects in both cell lines. Remarkably, UA had a drug-enhancing effect by decreasing cell viability and increasing cell cytotoxicity when combined with GEM treatment. In conclusions, UA triggered ER stress, subsequently regulating apoptosis- and autophagy-related pathways and increasing GEM chemosensitivity in pancreatic cancer cells by inhibiting the expression of RAGE.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Triterpenos/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pancreáticas/mortalidade , Taxa de Sobrevida , Triterpenos/farmacologia
18.
Arch Biochem Biophys ; 684: 108314, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32088220

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is expressed aberrantly in multiple tumors, including gastric cancer (GC). STAT3 overexpression and excessive activation have been confirmed to play vital roles in tumorigenesis. Cucurbitacin B (CuB) is a natural product with potent anti-cancer activities in solid tumors. Here, we systematically studied the underlying molecular mechanisms of CuB inhibition of GC both in vitro and in vivo. In GC cell lines, nanomolar concentrations of CuB decreased the phosphorylation of TYR-705 in STAT3 and suppressed STAT3 target gene expression, including c-Myc and Bcl-xL. Computational docking analysis showed that CuB interacts with the DNA-binding domain of STAT3 at several hydrophobic residues. In addition, pull-down experiments showed that CuB is a direct inhibitor of STAT3. CuB in combination with the conventional chemotherapy drug cisplatin exerted enhanced cytotoxicity in GC cells, possibly due to the potentiated inhibition of STAT3 activation. Moreover, a xenograft mouse model confirmed the therapeutic effect of CuB in vivo. These characteristics render CuB a promising candidate drug for further development in the design of new effective STAT3 inhibitors for treating GC.


Assuntos
Antineoplásicos/uso terapêutico , Fator de Transcrição STAT3/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Feminino , Humanos , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Invasividade Neoplásica , Ligação Proteica , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/patologia , Triterpenos/metabolismo , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Oxid Med Cell Longev ; 2020: 7540197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089778

RESUMO

As a joint disease, osteoarthritis (OA) is caused by the breakdown of subchondral bone and cartilage damage. Inflammatory factors, such as interleukin- (IL-) 1ß, mediate the progression of OA. Madecassoside (MA), a triterpenoid component derived from the gotu kola herb (Centella asiatica), exhibits various pharmacological effects, including antioxidative and anti-inflammatory properties. In the present study, the protective effects and possible mechanism of MA on the treatment of OA were investigated. MA was demonstrated to significantly suppress the IL-1ß-induced overexpression of matrix metalloproteinase- (MMP-) 3, MMP-13, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and to decrease the IL-1ß-induced degradation of type II collagen and sox9. Additionally, MA was able to reduce the IL-1ß-induced phosphorylation of p65 in osteoarthritic chondrocytes. Furthermore, in a rat OA model, MA prevented cartilage degeneration and reduced the OARSI score in the MA-treated group compared with the OA group. The present study showed that MA suppresses the nuclear factor-κB signaling pathway, reducing IL-1ß-induced chondrocyte inflammation, which indicates the therapeutic potential of MA in patients with OA.


Assuntos
Condrócitos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Condrócitos/patologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Triterpenos/farmacologia
20.
Oxid Med Cell Longev ; 2020: 9894037, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089787

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia among senior citizen. Ganoderma lucidum triterpenoids (GLTs) have nutritional health benefits and has been shown to promote health and longevity, but a protective effect of GLTs on AD damage has not yet been reported. The objective of this research was to elucidate the phylactic effect of GLTs on AD model mice and cells and to explore its underlying mechanisms. Morris water maze (MWM) test was conducted to detect changes in the cognitive function of mice. Hematoxylin-eosin (HE) staining was applied to observe pathological changes in the hippocampus. Silver nitrate staining was applied to observe the hippocampal neuronal tangles (NFTs). Apoptosis of the hippocampal neurons in mouse brain tissue was determined by TUNEL staining. The expression levels of apoptosis-related protein Bcl2, Bax, and caspase 3/cleaved caspase 3; antioxidative protein Nrf2, NQO1, and HO1; and ROCK signaling pathway-associated proteins ROCK2 and ROCK1 were measured by western blot. In vivo experiments show that 5-month-old APP/PS1 mice appeared to have impaired acquisition of spatial learning and GLTs could reduce cognitive impairment in AD mice. Compared to normal mice, the hippocampus of APP/PS1 mouse's brains was severely damaged, while GLTs could alleviate this symptom by inhibiting apoptosis, relieving oxidative damage, and inactivating the ROCK signaling pathway. In in vitro cell experiments, Aß 25-35 was applied to induce hippocampal neurons into AD model cells. GLTs promoted cell proliferation, facilitated superoxide dismutase (SOD) expression, and inhibited malondialdehyde (MDA) and lactic dehydrogenase (LDH) expression of neurons. Our study highlights that GLTs improve cognitive impairment, alleviate neuronal damage, and inhibit apoptosis in the hippocampus tissues and cells in AD through inhibiting the ROCK signaling pathway.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Medicina Tradicional Chinesa/métodos , Reishi/química , Triterpenos/uso terapêutico , Doença de Alzheimer/patologia , Animais , Apoptose , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Transdução de Sinais , Triterpenos/farmacologia
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