RESUMO
Background: Baicalin is an important active flavonoid isolated from the roots of Scutellaria baicalensis (S. baicalensis), a well-known traditional Chinese herb used in treating inflammatory bowel disease (IBD). The objectives of this study were to assess the potential benefit of baicalin in experimental colitis, as well as to investigate metabolic biomarkers of experimental colitis in conjunction with network pharmacology. Methods: Using a widely utilized network pharmacology technique, baicalin's targets and pathways were predicted. Simultaneously, experimental colitis was induced by intrarectal administration of TNBS. Histopathology examinations were performed to confirm pathological changes. Plasma samples were examined by using an untargeted metabolomics technique based on ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) to screen differential metabolites and associated metabolic pathways. Additionally, network pharmacology and integrated analysis of metabolomics were used to identify the primary targets. Results: Through network pharmacology research, tumor necrosis factor (TNF), interleukin 6 (IL6), serine/threonine-protein kinase (AKT1), and other 7 proteins were found to be the main targets of baicalin against IBD. The untargeted metabolomics results showed that 47 metabolites in glycerophospholipids and sphingolipid metabolism were involved as key pathways in the experimental colitis model group. 19 metabolites, including Sphingomyelin (SM d42:2, SM d42:1, SM d34:1), Lysophosphatidic acids (LPA 18:4), 1-Palmitoylglycerophosphocholine, and 17(18)-EpETE were demonstrated as key metabolites for baicalin to exert effects. Moreover, udp-glucose ceramide glucosyltransferase (UGCG), sphingomyelin synthase 1 (SGMS1), and sphingosine kinase (SPHK1) were predicted as sphingolipids-linked targets of baicalin against experimental colitis by integrative analysis. Conclusion: Based on these results, it implies that sphingolipid metabolism and sphingolipid signaling pathway might be acted as therapeutic mechanism for baicalin against experimental colitis.
Assuntos
Anti-Inflamatórios não Esteroides , Colite , Medicamentos de Ervas Chinesas , Doenças Inflamatórias Intestinais , Humanos , Colite/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Metabolômica/métodos , Farmacologia em Rede , Esfingolipídeos , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêuticoRESUMO
Photodynamic therapy (PDT) is promising for clinical cancer therapy; however, the efficacy was limited as an individual treatment regimen. Here, an approach synergistically combining PDT and nitric oxide (NO) gas therapy along with destruction of the tumor extracellular matrix (ECM) was presented to eliminate cancer. Specifically, the NO donor l-arginine (l-Arg) and the photosensitizer indocyanine green (ICG) were co-encapsulated in poly(lactic-glycolic acid) (PLGA) nanoparticles and then loaded into the poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) hydrogel to develop an injectable, thermosensitive dual drug delivery system (PLGA@ICG@l-Arg/Gel). Significantly, reactive oxygen species (ROS) produced by PLGA@ICG@l-Arg/Gel under near-infrared (NIR) light irradiation could not only result in the apoptosis of cancer cells but also oxidize l-Arg to generate NO, which could suppress the proliferation of cancer cells. Moreover, ROS could further oxidize NO to generate peroxynitrite anions (ONOO-). ONOO- could activate matrix metalloproteinases (MMPs), which notably degraded collagen in ECM so as to damage the tumor microenvironment. PLGA@ICG@l-Arg/Gel significantly increased the antitumor efficacy against highly malignant 4T1 tumors in mice. Taken together, PLGA@ICG@l-Arg/Gel is a multifunctional platform that provides a novel strategy for cancer treatment with cascade amplification of the ROS oxidation effect, which holds great potential in clinical translation.
Assuntos
Arginina/química , Colágeno/metabolismo , Hidrogéis/administração & dosagem , Verde de Indocianina/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Óxido Nítrico/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Hidrogéis/química , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fototerapia/métodos , Poliésteres/química , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacosRESUMO
Polyphyllin I (PPI) is a natural compound extracted from the rhizomes of Paris polyphylla and has been used to treat fevers and headaches in China. In the present study, the antitumor activity of PPI in prostate cancer (PC) cells was evaluated. At low doses, PPI decreased proliferation, invasion and epithelial-mesenchymal transition (EMT) in PC cells. PPI decreased the expression of matrix metalloproteinase 7 (MMP7), an enzyme that is critical for tumor metastasis. PPI also decreased the expression of Snail and vimentin, which are EMT-associated factors. Additionally, PPI suppressed AP-1 transcriptional activity and AP-1 binding to the MMP7 and vimentin promoters. The results demonstrated that PPI downregulated the phosphorylation of extracellular signalingrelated kinase (ERK), which is upstream modulator of AP-1. The results of the present study demonstrated that PPI may inhibit the cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A)/ERK axis, downregulate the expression of MMP7, vimentin, and Snail, and suppress tumor invasion and EMT. A PC xenograft mouse model was employed and the results revealed that PPI may decrease tumor growth and weight. Additionally, PPI may inhibit proliferating cell nuclear antigen expression and CIP2A/PP2A/ERK signaling pathway in PPI-treated tumors. Therefore, the results of the present study suggest that PPI may suppress the growth, invasion and EMT of PC cells via inhibition of CIP2A/PP2A/ERK signaling axis. As a result, PPI may be a novel target for the treatment of PC.
Assuntos
Antineoplásicos/farmacologia , Diosgenina/análogos & derivados , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Autoantígenos/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Regulação para Baixo , Avaliação Pré-Clínica de Medicamentos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Melanthiaceae/química , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica/prevenção & controle , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/patologia , Proteína Fosfatase 2/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chemotherapy and photothermal therapy can be efficiently integrated to achieve enhanced antitumor efficacy by using carbon nanotubes (CNTs) which are super in delivering drug and converting near infrared radiation (NIR) into heat. We previously developed an innovative TAT-chitosan functionalized MWCNTs (MWCNTs/TC) based drug delivery system for doxorubicin (DOX) and preliminarily investigated its release profile and antitumor effect. In the present study, the application potential of MWCNTs/DOX/TC in chemo-photothermal combination therapy was further explored. The in vitro drug release, photothermal effect, cellular uptake and cytotoxicity were assessed. The in vivo anti-tumor effect of MWCNTs/DOX/TC was further evaluated by noninvasive bioluminescence imaging. It was demonstrated that this innovative drug delivery system not only realized a conspicuously sustained release of DOX, but also retained the optical properties of MWCNTs for a high photothermal effect upon NIR irradiation, and exhibited remarkably enhanced anti-tumor efficacy through the synergistic function of chemotherapy and photothermal ablation.