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Aim of the Study: To evaluate the in vitro and in vivo anti-metastasis efficacy of Jianpi Yangzheng (JPYZ) decoction against gastric cancer (GC) and its potential mechanisms., Materials and Methods: The distant metastasis of GC cells administered via tail vein injection was assessed using the pre-metastatic niche (PMN) model. 16S rRNA sequencing and GC-MS/MS were applied to determine the component of the gut microbiota and content of short-chain fatty acids (SCFAs) in feces of mice, respectively. The proportion of myeloid-derived suppressor cells (MDSCs) in the lung was evaluated by flow cytometry and immunofluorescence. Serum or tissue levels of inflammation factors including IL-6, IL-10 and TGF-β were determined by ELISA or Western blot respectively., Results: Injecting GC cells into the tail vein of mice led to the development of lung metastases and also resulted in alterations in the composition of gut microbiota and the levels of SCFAs produced. Nevertheless, JPYZ treatment robustly impeded the effect of GC cells administration. Mechanically, JPYZ treatment not only prevented the alteration in gut microbiota structure, but also restored the SCFAs content induced by GC cells administration. Specifically, JPYZ treatment recovered the relative abundance of genera Moryella, Helicobacter, Lachnoclostridium, Streptococcus, Tuzzerella, GCA-900066575, uncultured_Lachnospiraceae, Rikenellaceae_RC9_gut_group and uncultured_bacterium_Muribaculaceae to near the normal control levels. In addition, JPYZ abrogated MDSCs accumulation in the lung tissue and blocked inflammation factors overproduction in the serum and lung tissues, which subsequently impede the formation of the immunosuppressive microenvironment. Correlation analysis revealed that the prevalence of Rikenellaceae in the model group exhibited a positive correlation with MDSCs proportion and inflammation factor levels. Conversely, the scarcity of Muribaculaceae in the model group showed a negative correlation with these parameters. This suggests that JPYZ might exert an influence on the gut microbiota and their metabolites, such as SCFAs, potentially regulating the formation of the PMN and consequently impacting the outcome of GC metastasis., Conclusion: These findings suggest that GC cells facilitate metastasis by altering the gut microbiota composition, affecting the production of SCFAs, and recruiting MDSCs to create a pro-inflammatory pre-metastatic niche. JPYZ decoction counteracts this process by reshaping the gut microbiota structure, enhancing SCFA production, and inhibiting the formation of the pre-metastatic microenvironment, thereby exerting an anti-metastatic effect., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Modified Jianpi Yangzheng decoction (mJPYZ), as an empirical decoction of Traditional Chinese medicine has been shown significantly to prolong the survival of patients with advanced stage gastric cancer. Pyruvate kinase M2 (PKM2), has attracted attention for its important role on cellular aerobic glycolysis, however, few studies focus on PKM2 non-metabolic roles in tumor progression., Purpose: Our study aimed to investigate the potential role of gastric cancer exosomes containing PKM2 in regulating tumor-associated macrophages (TAM) and the mechanism of mJPYZ against gastric cancer., Methods: Colony Formation Assay, flow cytometry and TUNEL staining were employed to estimate the effect of mJPYZ on gastric cancer in tumor-bearing mice and cells. Western blot analyzed apoptosis-related protein expression changes. Network pharmacology and bioinformatics predicted potential exosomes modulation of mJPYZ in gastric cancer. Exosomes were isolated and co-cultured with TAM. Diff-Quik Staining observed the TAM morphological changes when incubating with gastric cancer cells exosomes. Flow cytometry and immunofluorescence were performed to demonstrate whether exosomes PKM2 involved in TAM polarization., Results: mJPYZ induced apoptosis of gastric cancer cells by targeting PKM2 and downregulating PI3K/Akt/mTOR axis in vivo and in vitro. Network pharmacology showed potential exosomes modulation of mJPYZ in gastric cancer. We extracted exosomes and found mJPYZ decreased the abundance of serum exosomes PKM2 in patients with advanced gastric cancer and xenograft tumor model. Additionally, we firstly detected and confirmed that PKM2 is a package protein of exosomes extracted from gastric cancer cells, and mJPYZ could diminish the content of exosomal PKM2 in gastric cancer cells. Importantly, mJPYZ reduced the delivery of exosomal PKM2 from tumor cells to macrophages, and alleviated exosomal PKM2-induced differentiation of M2-TAM in tumor microenvironment, eventually inhibited gastric cancer progression., Conclusion: Gastric cancer exosomes containing PKM2 could lead to M2 macrophages differentiation, thereby promoting gastric cancer progression. Our findings provide a rationale for potential application of mJPYZ in the treatment of gastric cancer via PKM2., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Jian-pi-yang-zheng Decoction (JPYZ) is a traditional Chinese medicine that is used for the treatment of advanced gastric cancer, and it shows good efficacy in patients. A previous study indicated that JPYZ inhibited the progression of gastric cancer via the regulation of tumor-associated macrophages (TAMs), but the underlying molecular target of JPYZ regulation of TAMs has not been determined. The present study used modified-JPYZ (mJPYZ) to extend our investigation of gastric cancer. Our results showed that mJPYZ inhibited gastric cancer progression in vivo and in vitro. We found that mJPYZ decreased the activity of PI3-kinase γ (PI3Kγ) in TAMs, reduced the anti-inflammatory factor IL-10 and increased the expression of pro-inflammatory cytokines, such as TNF-α and IL-1β, which ultimately promoted the conversion of TAMs from M2 to M1. Our findings also indicated that mJPYZ inhibited the growth and metastasis of gastric cancer by alleviating the unfavorable differentiation of TAMs via the PI3Kγ signaling cascades. In conclusion, the present findings indicated that mJPYZ inhibited gastric cancer cell EMT via PI3Kγ-dependent TAM reprogramming, which eventually suppressed gastric cancer growth and metastasis. Our study provides an underlying mechanism of a Chinese medicine in the treatment of gastric cancer via PI3Kγ in macrophages., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Gastric cancer (GC) is a common high-mortality disease, causing a serious social burden. Traditional Chinese medicine has been utilized to prevent and treat GC for many years but its effects remain unclear. The aim of our study is to elucidate the anti-tumor effects and the possible mechanism of Jianpi Yangzheng Xiaozheng decoction., Methods/design: This is a prospective, multicenter, randomized controlled trial continuing 1.5 years. Two hundred ten eligible patients will be randomly divided into 2 groups, the chemotherapy alone and the chemotherapy combined with JPYZXZ group at a ratio of 1:2. All patients will receive the treatment for 24 weeks and follow up for 1.5 years. The primary outcomes are one-year survival rate, progression-free survival, and overall survival (OS), while the secondary outcomes are immune related hematology test, objective response rate, tumor makers, traditional Chinese medicine syndrome points, fatigue scale, and quality of life scale. All of these outcomes will be analyzed at the end of the trail., Discussion: This study will provide the objective evidence for the efficacy and safety of Jianpi Yangzheng Xiaozheng decoction in advanced GC. Furthermore, it will be helpful to form a therapeutic regimen in advanced GC by the combination of traditional medicine and western medicine.Trail registration: ChiCTR1900028147.

Gastric cancer remains the second most common tumor in China. Modified-Bu-zhong-yi-qi decoction (mBYD) as an adjuvant therapy for gastric cancer patients after chemotherapy could significantly prolong the survival time of patients. However, the potential anticancer mechanism for mBYD has not been well characterized. Here, we conducted a comprehensive study of mBYD on a gastric cancer xenograft model with MFC cells in 615 mice and patients. Our results showed that the survival times of the 5-FU + mBYD and mBYD groups were significantly longer than that of the control group. Moreover, the 5-FU + mBYD group had a longer survival time than the 5-FU group. Flow cytometry revealed that the value of CD4 + /CD8 + in the mBYD group increased and that the proportions of CD8 + PD-1 + T cells and PD-1 + Treg cells were decreased when compared to the control group. Compared with the 5-FU group, CD8 + PD-1 + T cells and Treg cells were both decreased when 5-FU was combined with mBYD. Further analysis showed that mBYD inhibited PD-L1 expression by the PI3K/AKT pathway in gastric cancer. An in vitro study also showed that mBYD directly promoted the proliferation, activation and cytotoxicity of T lymphocytes. Meanwhile, mBYD reduced the upregulation of CD8 + PD-1 + T cells induced by chemotherapy in patients with gastric cancer. In conclusion, mBYD could modulate peripheral immunity and suppress the immune escape of tumors, which may be a promising therapy for gastric cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflict of Interests., (Copyright © 2019 Elsevier Ltd. All rights reserved.)