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J Ethnopharmacol ; 264: 113212, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32768643


ETHNOPHARMACOLOGICAL RELEVANCE: Cerebral ischemia-reperfusion (CIR) injury is one of the main diseases leading to death and disability. Acanthopanax senticosus (Rupr. & Maxim.) Harms (AS), also known as Panax ginseng, has neuroprotective effects on anti-CIR injury. However, the underlying molecular mechanism of its therapeutic effects is not clear. AIM OF THE STUDY: To systematically study and explore the mechanism of Acanthopanax senticosus (Rupr. & Maxim.) Harms extract (ASE) in the treatment of CIR injury based on metabolomics and transcriptomics. MATERIALS AND METHODS: The pharmacological basis of ASE in the treatment of CIR was evaluated, and samples were used in plasma metabolomics and brain tissue transcriptomics to reveal potential biomarkers. Finally, according to online database, we analyzed biomarkers identified by the two technologies, explained reasons for the therapeutic effect of ASE, and identify therapeutic targets. RESULTS: A total of 53 differential metabolites (DMs) were identified in plasma and 3138 differentially expressed genes (DEGs) were identified in brain tissue from three groups of rats, including sham, ischemia-reperfusion (I/R), and ASE groups. Enrichment analysis showed that Nme6, Tk1, and Pold1 that are involved in the production of deoxycytidine and thymine were significantly up-regulated and Dck was significantly down-regulated by the intervention with ASE. These findings indicated that ASE participates in the pyrimidine metabolism by significantly regulating the balance between dCTP and dTTP. In addition, ASE repaired and promoted the lipid metabolism in rats, which might be due to the significant expression of Dgkz, Chat, and Gpcpd1. CONCLUSIONS: The findings of this study suggest that ASE regulates the significant changes in gene expression in metabolites pyrimidine, and lipid metabolism in CIR rats and plays an active role in the treatment of CIR injury through multiple targets and pathways.

Sci Rep ; 7(1): 16628, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29192209


Calcium phosphate-based mineralo-organic particles form spontaneously in the body and may represent precursors of ectopic calcification. We have shown earlier that these particles induce activation of caspase-1 and secretion of IL-1ß by macrophages. However, whether the particles may produce other effects on immune cells is unclear. Here, we show that these particles induce the release of neutrophil extracellular traps (NETs) in a size-dependent manner by human neutrophils. Intracellular production of reactive oxygen species is required for particle-induced NET release by neutrophils. NETs contain the high-mobility group protein B1 (HMGB1), a DNA-binding protein capable of inducing secretion of TNF-α by a monocyte/macrophage cell line and primary macrophages. HMGB1 functions as a ligand of Toll-like receptors 2 and 4 on macrophages, leading to activation of the MyD88 pathway and TNF-α production. Furthermore, HMGB1 is critical to activate the particle-induced pro-inflammatory cascade in the peritoneum of mice. These results indicate that mineral particles promote pro-inflammatory responses by engaging neutrophils and macrophages via signaling of danger signals through NETs.

Armadilhas Extracelulares/imunologia , Proteína HMGB1/metabolismo , Imunidade Inata , Imunomodulação , Minerais/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Linhagem Celular , Feminino , Proteína HMGB1/genética , Humanos , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Modelos Moleculares , Fator 88 de Diferenciação Mieloide/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
Carcinogenesis ; 34(4): 874-84, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23275155


Fucoidan, a polysaccharide extracted from brown seaweeds, reduces tumor cell proliferation. Fucoidan inhibits the growth of breast cancer cells such as 4T1 and MDA-MB-231 and decreases their cell colony formation. Moreover, fucoidan reduces metastatic lung nodules in 4T1 xenograft female Balb/c mice. The molecular network of transforming growth factor ß (TGFß) receptors (TGFRs) plays an important role in the regulation of the epithelial to mesenchymal transition (EMT) in cancer cells. Using 4T1 and MDA-MB-231 cells, we found that fucoidan effectively reverses TGFR-induced EMT morphological changes, upregulates epithelial markers, downregulates mesenchymal markers and decreases the expression of transcriptional repressors Snail, Slug and Twist. Moreover, fucoidan inhibits migration and invasion during the EMT, suggesting the involvement of TGFR-mediated signaling in breast cancer cells. Fucoidan decreases TGFRI and TGFRII proteins and affects downstream signaling molecules, including Smad2/3 phosphorylation and Smad4 expression. In order to elucidate how fucoidan decreases TGFRI and TGFRII proteins in MDA-MB-231 cells, we investigated ubiquitination activity downregulation of TGFRs. It was found that fucoidan enhances proteasome-mediated degradation/ubiquitination of TGFR. This study is the first to identify a novel mechanism for fucoidan antitumor activity, namely regulation of the EMT via modulation of TGFR/Smad-dependent signaling, which leads to an inhibition of breast cancer cell growth in vitro and in vivo. Our current findings indicate that fucoidan is a potential therapeutic agent for breast cancer and acts via an ubiquitin-dependent degradation pathway that affects the TGFR/Smad/Snail, Slug, Twist and EMT axes.

Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Metástase Neoplásica/tratamento farmacológico , Polissacarídeos/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Transplante de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/biossíntese , Transplante Heterólogo , Proteína 1 Relacionada a Twist/biossíntese , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos
Colloids Surf B Biointerfaces ; 88(2): 552-8, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21885262


Thrombin, a multifunctional serine protease, has both procoagulant and anticoagulant functions in human blood. Thrombin has two electropositive exosites. One is the fibrinogen-binding site and the other is the heparin-binding site. Over the past decade, two thrombin-binding aptamers (15-mer and 29-mer) were reported by SELEX technique. Recently, many studies examined the interactions between the 15-mer aptamer and thrombin extensively, but the data on the difference of these two aptamers binding to thrombin are still lacking and worth investigating for fundamental understanding. In the present study, we combined conformational data from circular dichroism (CD), kinetics and thermodynamics information from surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) to compare the binding mechanism between the two aptamers with thrombin. Special attentions were paid to the formation of G-quadruplex and the effects of ions on the aptamer conformation on the binding and the kinetics discrimination between specific and nonspecific interactions of the binding. The results indicated reasonably that the 15-mer aptamer bound to fibrinogen-binding site of thrombin using a G-quadruplex structure and was dominated by electrostatic interactions, while the 29-mer aptamer bound to heparin-binding site thrombin using a duplex structure and was driven mainly by hydrophobic effects.

Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Calorimetria/métodos , Dicroísmo Circular/métodos , Ressonância de Plasmônio de Superfície/métodos , Trombina/química , Trombina/metabolismo , Fibrinogênio/metabolismo , Quadruplex G , Heparina/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular