Qingfei mixture mitigates immunosuppression of tumor microenvironment in non-small cell lung cancer by blocking stat1/Ido1-mediated tryptophan-kynurenine pathway

Article

作者: Shao, Lan ; Chen, Zhuo ; Zhang, Ai-Qin ; Ding, Yu-Heng ; Ji, Xu-Ming ; Qian, Xiang

Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is promising for advanced lung cancer treatment. However, the response rate requires being strengthened. This study aimed to determine whether the combination treatment of Qingfei mixture (QFM) and PD-1 inhibitor could improve the sensitivity of monoclonal antibody by regulating STAT1/IDO1-mediated tryptophan (Trp)-kynurenine (Kyn) pathway. The in vivo imaging system, immunofluorescence, hematoxylin-eosin staining, TUNEL, flow cytometry, HPLC, and ELISA were used to estimate the anti-tumor effects in LLC-luc tumor-bearing C57BL/6 mice treated with QFM, PD-1 inhibitor, 2-NP (enhancer of STAT1 transcription), and FICZ (AhR agonist) alone or in combination. IFN-γ-mediated A549 and LLC cells were treated with QFM-containing serum and fludarabine (FLU, STAT1 inhibitor), and cell viability, apoptosis, and Kyn content were then evaluated using CCK-8 assays, flow cytometry, and HPLC assays, respectively. Additionally, the expressions of STAT1, IDO1, AhR, NFATc1, TRIP12, PD-1, and PD-L1 were measured in vivo and in vitro. We found QFM increased the anti-cancer actions of PD-1 inhibitors by increasing the CD8+IFNγ⁺ T cells infiltration and decreasing the ratio of Kyn/Trp. Besides, QFM-containing serum suppressed the proliferation and promoted apoptosis in A549 and LLC cells, meanwhile, FLU boosted the effects of QFM-containing serum. Moreover, the suppression of tumor growth in the combination therapy was attenuated in the mice receiving 2-NP or FICZ. The occurrence of the above results was accompanied by a decrease in STAT1, IDO1, AhR, PD-1, and PD-L1 expressions. Collectively, the findings suggested that QFM may increase the influences of PD-1 inhibitors at least partially by blocking the STAT1/IDO1-mediated tryptophan-kynurenine pathway in lung cancer.

2020-11-01·Phytomedicine2区 · 医学

A stepwise integrated multi-system to screen quality markers of Chinese classic prescription Qingzao Jiufei decoction on the treatment of acute lung injury by combining ‘network pharmacology-metabolomics-PK/PD modeling’

2区 · 医学

Article

作者: Li, Qing ; Wang, Tianyang ; Liu, Zihan ; Liu, Ran ; Xu, Huarong ; Lin, Song ; Li, Hua ; Bi, Kaishun

BACKGROUNDPreviously, we have investigated the therapeutic mechanism of Qingzao Jiufei Decoction (QZJFD), a Chinese classic prescription, on acute lung injury (ALI), however, which remained to be further clarified together with the underlying efficacy related compounds for quality markers (Q-markers).HYPOTHESIS/PURPOSETo explore Q-markers of QZJFD on ALI by integrating a stepwise multi-system with 'network pharmacology-metabolomics- pharmacokinetic (PK)/ pharmacodynamic (PD) modeling'.METHODSFirst, based on in vitro and in vivo component analysis, a network pharmacology strategy was developed to identify active components and potential action mechanism of QZJFD on ALI. Next, studies of poly-pharmacology and non-targeted metabolomics were used to elaborate efficacy and verify network pharmacology results. Then, a comparative PK study on active components in network pharmacology was developed to profile their dynamic laws in vivo under ALI, suggesting Q-marker candidates. Next, quantified analytes with marked PK variations after modeling were fitted with characteristic endogenous metabolites along drug concentration-efficacy-time curve in a PK-PD modeling to verify and select primary effective compounds. Finally, Q-markers were further chosen based on representativeness among analytes through validity analysis of PK quantitation of primary effective compounds.RESULTSIn virtue of 121 and 33 compounds identified in vitro and in vivo, respectively, 33 absorbed prototype compounds were selected to construct a ternary network of '20 components-47 targets-113 pathways' related to anti-ALI of QZJFD. Predicted mechanism (leukocytes infiltration, cytokines, endogenous metabolism) were successively verified by poly-pharmacology and metabolomics. Next, 18 measurable components were retained from 20 analytes by PK comparison under ALI. Then, 15 primary effective compounds from 18 PK markers were further selected by PK-PD analysis. Finally, 9 representative Q-markers from 15 primary effective compounds attributed to principal (chlorogenic acid), ministerial (methylophiopogonanone A, methylophiopogonanone B), adjuvant (sesamin, ursolic acid, amygdalin), conductant drugs (liquiritin apioside, liquiritigenin and isoliquiritin) in QZJFD, were recognized by substitutability and relevance of plasmatic concentration at various time points.CONCLUSION9 Q-markers for QZJFD on ALI were identified by a stepwise integration strategy, moreover, which was a powerful tool for screening Q-makers involved with the therapeutic action of traditional Chinese medicine (TCM) prescription and promoting the process of TCM modernization and scientification.

2020-09-01·Journal of Pharmaceutical and Biomedical Analysis3区 · 医学

Acute lung injury therapeutic mechanism exploration for Chinese classic prescription Qingzao Jiufei Decoction by UFLC-MS/MS quantification of bile acids, fatty acids and eicosanoids in rats

3区 · 医学

Article

作者: Li, Qing ; Wang, Tianyang ; Liu, Ran ; Liu, Zihan ; Li, Hua ; Xu, Huarong ; Lin, Song ; Bi, Kaishun

Acute lung injury (ALI) is a common and complex inﬂammatory disease, which has been reasonably associated with carboxyl-containing metabolites in our preliminary non-targeted metabolomic strategy. Qingzao Jiufei Decoction (QZJFD), a classic prescription, is widely used in the treatment of pulmonary inflammatory injuries. Successively, in this targeted project, to fill in the research gap and exposit the therapeutic mechanism of QZJFD on ALI, considering the structure similarity and bioactivity correlation, 21 bile acids, 11 fatty acids and 19 eicosanoids were profiled simultaneously in plasma, lung, bronchoalveolar lavage fluid, spleen and feces from rats utilizing a novel ultraperformance liquid chromatography-mass spectrometry approach. As a result, potential biomarkers and ALI characteristic metabolomic spectrums were obtained to distinguish different physical states using discriminative similarity threshold as 0.65 for clinical application. After treatment with QZJFD, obvious reversing ability for various biomarker levels was observed in different bio-samples, providing insights into the systemic intervention of QZJFD on ALI by regulating bile acid synthesis, fatty acid synthesis and eicosanoid metabolism. Conclusively, this investigation represented more information on the comprehensive therapeutic action of QZJFD on ALI involving with multi-targets and multi-pathways for clinical application and traditional Chinese medicine modernization.

100 项与清燥润肺合剂相关的药物交易

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