作者: He, Shulin ; Sun, Tianheng ; Qi, Xin ; Li, Juan ; Liu, Rui ; Zhang, Guanghui ; Luo, Yue ; Hua, Baojin ; Shi, Bolun ; Ren, Xiaoling ; Li, Yue ; Maolan, Ayidana ; Hu, Jiaqi ; Zhang, Xinyue

BACKGROUND:

Based on the proposed lung-intestinal axis, there is a significant correlation between the microbiota and lung metastasis. Targeting the microbial composition is valuable in modulating the host response to cancer therapeutics. As a traditional Chinese medicine (TCM) formula, Shuangshen granules (SSG) are clinically useful in delaying lung metastasis, but its underlying mechanisms remain unknown.

METHODS:

The C57BL/6N mice were chosen to establish the Lewis lung cancer models. The broad-spectrum antibiotics (ABX) group was set up to estimate the effect of microbiota composition on metastasis. The therapeutic effects of different doses of SSG in treating lung metastasis were investigated through histopathology, immunohistochemistry, and Western blot analysis methods. Additionally, the phenotype of tumor-associated macrophages (TAMs) in the lung and blood was evaluated by flow cytometry. The fecal microbiota transplantation (FMT) and negative control (ABX plus high dose SSG group) experiments were also designed to assess intestinal microbiota's role in SSG intervention's outcome in lung metastasis. The 16S rRNA amplicon sequencing and Untargeted metabolomic analysis were used to analyze intestinal microbiota and metabolite changes mediated by SSG in tumor-bearing mice with lung metastasis.

RESULT:

ABX could observably lead to intestinal microbiota dysbiosis and enhance metastasis. SSG showed a significant chemopreventive effect in lung metastasis, reduced metastatic nodules and the expression levels of pre-metastatic niche biomarkers, and enriched the ratio of CD86+F4/80+CD11b+ cells, while FMT delayed metastasis similarly. The analysis of microbiota and metabolites revealed that SSG significantly enriched probiotics in feces, including Akkermansia muciniphila, Lachnoclostridium sp YL32, Limosilactobacillus reuteri, and potential anti-cancer serum metabolites, including Ginsenoside Rb1, Isoquinoline, Betulin and so on. We also investigated the mechanism of SSG protection against lung metastasis and showed that SSG regulated microbiota, improved TAMs polarization, and inhibited the expression of the NF-κB pathway.

CONCLUSION:

The results presented in our article demonstrated that SSG improved TAMs polarization and inhibited the NF-κB pathway by alleviating intestinal microbiota imbalance and metabolic disorders in tumor-bearing mice, resulting in delayed lung metastasis.

2024-03-01·Journal of ethnopharmacology

Bioinformatics analyses of infiltrating immune cell participation on pancreatic ductal adenocarcinoma progression and in vivo experiment of the therapeutic effect of Shuangshen granules

Article

作者: He, Shulin ; Zheng, Honggang ; Xu, Bowen ; Li, Yue ; Zhang, Xing ; Wang, Bei ; Jiang, Juling ; Ren, Xiaoling ; Liu, Rui ; Hu, Jiaqi ; Hua, Baojin ; Shi, Bolun

ETHNOPHARMACOLOGICAL RELEVANCE:

Shuangshen granules (SSG), a nationally patented Chinese medicinal formula, including Panax quinquefolium L., Panax notoginseng (Burkill) F. H. Chen, and Cordyceps sinensis (Berk.) Sacc., has demonstrated remarkable therapeutic effects on pancreatic cancer in clinical treatment for nearly 10 years. Previous pharmacological researches have found that its main components, including ginsenosides and cordycepin have anticancer or preventive effects on pancreatic ductal adenocarcinoma (PDAC), which may be associated with immune metabolism. However, the underlying pharmacological mechanism of SSG in the truncation effect of PDAC progression is still unclear.

AIM OF THE STUDY:

To comprehensively understand the infiltrating immune cells during the different stages of the PDAC development chain and search for immune-related biomarkers that could potentially serve as drug targets through bioinformatic analysis. Meanwhile, the truncation effect of SSG on PDAC progression was also investigated.

MATERIALS AND METHODS:

The gene expression profiles at different PDAC developmental stages, including normal pancreas, pancreatic intraepithelial neoplasia (PanIN), and PDAC, were retrieved from the GEO database. The GEO2R tool was used to identify differentially expressed genes among the three groups. Functional enrichment analysis was performed with the GSEA software and Metascape platform. The CIBERSORT algorithm evaluated immune cell infiltration in the three groups, and immune-related biomarkers were identified. Correlation analysis was employed to examine the association between immune cells and the biomarkers. One of these biomarkers was selected for immunohistochemistry validation in human samples. Lastly, the effectiveness of SSG against PDAC progression and the influence on the selected biomarker were validated in vivo. The underlying pharmacological mechanisms were also explored.

RESULTS:

One dataset was obtained, where the functional enrichment of DEGs primarily involved immune effector processes and cytokine production of immune cells. The differential immune cells reflected during the progression from PanIN to PDAC were B memory cells, monocytes, M2 macrophages, and activated dendritic cells. The upregulation of ACTA2 was closely associated with M2 macrophage regulation. The immunohistochemistry on human samples validated significant differences in ACTA2 expression levels as the PDAC progressed. Moreover, animal experiments revealed that the national patented drug SSG ameliorated the pathological changes, decreased the expression of ACTA2 and its functional protein α-smooth muscle actin during PDAC progression. The underlying pharmacological mechanism was related to the regulation of macrophage polarization and downregulation of TGF-β/Smad signaling pathway.

CONCLUSIONS:

The immunosuppressive environment changes during the PDAC progression. ACTA2 is a potential immuned-target for drug prevention of PDAC, while SSG could be a promising drug candidate.

2024-01-01·Phytomedicine : international journal of phytotherapy and phytopharmacology

Investigation of the active ingredients of Shuangshen Ningxin Fomula and the mechanism underlying their protective effects against myocardial ischemia-reperfusion injury by mass spectrometric imaging

Article

作者: Wang, Aoao ; Fu, Jianhua ; Guo, Fan ; Ren, Junguo ; Lin, Li ; Liu, Zixin ; Liu, Jianxun ; Li, Lei ; Meng, Hongxu ; Li, Lingmei ; Xin, Gaojie ; Cao, Ce ; Zhang, Peng

BACKGROUND:

Traditional Chinese medicine, particularly Shuangshen Ningxin Capsule (SSNX), has been studied intensely. SSNX includes total ginseng saponins (from Panax ginseng Meyer), total phenolic acids from Salvia miltiorrhiza Bunge, and total alkaloids from Corydalis yanhusuo W. T. Wang. It has been suggested to protect against myocardial ischemia by a mechanism that has not been fully elucidated.

METHODS:

The composition and content of SSNX were determined by UHPLC-Q-TOFQ-TOF / MS. Then, a rat model of myocardial ischemia-reperfusion injury was established, and the protective effect of SSNX was measured. The protective mechanism was investigated using spatial metabolomics.

RESULTS:

We found that SSNX significantly improved left ventricular function and ameliorated pathological damages in rats with myocardial ischemia-reperfusion injury. Using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), the protective mechanism of SSNX was examined by comparing the monomer components of drugs targeted in myocardial tissue with the distribution of myocardial energy metabolism-related molecules and phospholipids. Interestingly, some lipids display inconsistent content distribution in the myocardial ischemia risk and non-risk zones. These discrepancies reflect the degree of myocardial injury in different regions.

CONCLUSION:

These findings suggest that SSNX protects against myocardial ischemia-reperfusion injury by correcting abnormal myocardial energy metabolism, changing the levels and distribution patterns of phospholipids, and stabilizing the structure of the myocardial cell membrane. MALDI-TOF MS can detect the spatial distribution of small molecule metabolites in the myocardium and can be used in pharmacological research.

100 项与双参芎连颗粒相关的药物交易

登录后查看更多信息