Understanding apoptotic induction by Sargentodoxa cuneata-Patrinia villosa herb pair via PI3K/AKT/mTOR signalling in colorectal cancer cells using network pharmacology and cellular studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Sargentodoxa cuneata (Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson, DXT)-Patrinia villosa(Patrinia villosa (Thunb.) Dufr, BJC) constitutes a commonly employed herb pair in Chinese medicine for colorectal cancer (CRC) treatment. Modern pharmacological investigations have revealed the anticancer activities of both Sargentodoxa cuneata and Patrinia villosa. Nevertheless, comprehensive studies are required to discern the specific antitumor active ingredients and mechanism of action when these two herbs are used in combination. AIM OF THE STUDY: Through the integration of network pharmacology, molecular docking techniques, experimental assays, and bioinformatics analysis, our study aims to forecast the active ingredients, potential targets, and molecular mechanisms underlying the therapeutic efficacy of this herb pair against CRC. MATERIALS AND METHODS: Plant names (1, Sargentodoxa cuneata (Oliv.) Rehder & E.H.Wilson; 2, Patrinia villosa (Thunb.) Dufr.) have been verified through WorldFloraOnline (www.worldFloraonline.org) and MPNs (http://mpns.kew.org). The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) were utilized for screening the active ingredients of the herb pair. The PharmMapper database was employed to predict the target proteins for each active ingredient. CRC-related targets were obtained from the Genecards database, Online Mendelian Inheritance in Man (OMIM) database, Disease Gene Network (DisGeNET) database, and Therapeutic Target Database (TTD). Common targets were identified by intersecting the target proteins of all active ingredients with CRC-related targets. Protein-protein interactions (PPI) for the common target proteins were constructed using the String database and Cytoscape 3.9.1 software. Network topology analysis facilitated the identification of core targets. These core targets were subjected to enrichment analysis of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) using the Metascape database. Molecular docking was performed using Discovery Studio 2019 to investigate the interactions between the active ingredients and core target proteins. The core targets were validated through bioinformatics analysis using GEPIA, HPA, and the cBioPortal database. Finally, a series of experiments were conducted to further validate the results in vitro. RESULT: A total of 15 active ingredients and 255 herb targets were identified, resulting in 66 common targets in conjunction with 6113 disease targets. The PPI analysis highlighted AKT1, EGFR, CASP3, SRC, and ESR1 as core targets. KEGG enrichment analysis indicated significant enrichment in the PI3K-AKT signaling pathway, a pathway associated with cancer. Molecular docking experiments confirmed favorable interactions between dihydroguaiaretic acid and the core target proteins (AKT1, EGFR, CASP3, and ESR1). Bioinformatics analysis revealed differential expression of EGFR and CASP3 in normal and CRC tissues. Cellular experiments further verified that dihydroguaiaretic acid induces apoptosis in colorectal cancer cells through the PI3K-AKT signaling pathway. CONCLUSION: Our network pharmacology study has elucidated that the Sargentodoxa cuneata-Patrinia villosa herb pair exerts the negative regulation of the PI3K/AKT/mTOR signaling pathway, ultimately leading to the induction of apoptosis in colorectal cancer cells. This research has predicted and validated the active ingredients, potential targets, and molecular mechanisms of Sargentodoxa cuneata-Patrinia villosa in the treatment of CRC, providing scientific evidence for the use of traditional Chinese medicine in managing CRC.

Jianpi Yangzheng Xiaozheng decoction alleviates gastric cancer progression via suppressing exosomal PD-L1.

Jianpi Yangzheng Xiaozheng decoction (JPYZXZ) is an empirical traditional Chinese medicine formula that has been reported to significantly prolong the survival of patients with advanced gastric cancer (GC). However, its underlying mechanism have not been fully elucidated. The present work aims to explore the possible mechanism of JPYZXZ on regulating GC progression. We firstly confirmed the inhibitory effect of JPYZXZ in GC MKN74 cells and 615-strain mice, which was possibly mediated with IL-6/JAK2/STAT3 pathway dependent PD-L1 expression. Moreover, we showed that JPYZXZ diminished the expression levels of GC-derived exosomal PD-L1 in MFC murine cells and xenograft GC model, as well as stage IIA-IIIB GC patients. We further found that in different types of tumor-infiltrating immune cells, PD-L1 expression was most positively correlated with myeloid-derived suppressor cells (MDSCs) in GC in the TISIDB database. We isolated exosomes derived from supernatants of MFC cells and co-cultured with bone marrow cells derived from C57BL/6 mice, and further revealed that the expansion of MDSCs was mediated by GC-derived exosomal PD-L1. Meanwhile, our results indicated that JPYZXZ inhibited the delivery of exosomal PD-L1 from GC cells to bone marrow cells, thereby alleviating exosomal PD-L1-induced differentiation and expansion of MDSCs in the tumor microenvironment. This led to a decrease in the levels of several immunosuppressive factors, including iNOS, Arg-1, TGF-ß, IL-10, and IL-6, in 615-strain mice. Moreover, clinical data also revealed a significant positive relationship between exosomal PD-L1 and polymorphonuclear MDSCs under the JPYZXZ treatment in stage IIA-IIIB GC patients. In conclusion, our study confirmed that exosomal PD-L1 could be a key factor in controlling MDSCs differentiation in GC. JPYZXZ alleviated GC progression via suppressing exosomal PD-L1 mediated expansion of MDSCs, thereby remodeling the immunosuppressive tumor microenvironment, which provided the experimental evidence for the clinical application of JPYZXZ in the treatment of GC via PD-L1.

Jianpi Yangzheng decoction suppresses gastric cancer progression via modulating the miR-448/CLDN18.2 mediated YAP/TAZ signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Developing complementary and effective drugs with less toxicity is urgent for gastric cancer (GC) therapy. Jianpi Yangzheng Decoction (JPYZ) is a curative medical plants formula against GC in clinic while its molecular mechanism remains to be further elucidated. AIM OF THE STUDY: To evaluate the in vitro and in vivo anticancer efficacy of JPYZ against GC and its potential mechanisms. MATERIALS AND METHODS: The effect of JPYZ on regulating the candidate targets were screened and examined by RNA-Seq, qRT-PCR, luciferase reporter assay, and immunoblotting. Rescue experiment was conducted to authenticate the regulation of JPYZ on the target gene. Molecular interaction, intracellular localization and function of target genes were elucidated via Co-IP and cytoplasmic-nuclear fractionation. The impact of JPYZ on the abundance of target gene in clinical specimens of GC patients was evaluated by IHC. RESULTS: JPYZ treatment suppressed the proliferation and metastasis of GC cells. RNA seq revealed JPYZ significantly downregulated miR-448. A reporter plasmid containing CLDN18 3'-UTR WT exhibited significant decrease in luciferase activity when co-transfected with miR-448 mimic in GC cells. CLDN18.2 deficiency promoted the proliferation and metastasis of GC cells in vitro, as well as intensified the growth of GC xenograft in mice. JPYZ reduced the proliferation and metastasis of GC cells with CLDN18.2 abrogation. Mechanically, suppressed activities of transcriptional coactivator YAP/TAZ and its downstream targets were observed in GC cells with CLDN18.2 overexpression and those under JPYZ treatment, leading to cytoplasmic retention of phosphorylated YAP at site Ser-127. High abundance of CLDN18.2 was detected in more GC patients who received chemotherapy combined with JPYZ. CONCLUSION: JPYZ has an inhibitory effect on GC growth and metastasis partly by elevating CLDN18.2 abundance in GC cells, indicating more patients may benefit from combination therapy of JPYZ and the upcoming CLDN18.2 target agents.

Effect of modified Jianpi Yangzheng on regulating content of PKM2 in gastric cancer cells-derived exosomes.

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.

PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression.

Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Rutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542).

The Effects of Erchen Decoction on Gut Microbiota and Lipid Metabolism Disorders in Zucker Diabetic Fatty Rats.

Obesity is a chronic metabolic disease caused by genetic and environmental factors that has become a serious global health problem. There is evidence that gut microbiota is closely related to the occurrence and development of obesity. Erchen Decoction (ECD), a traditional Chinese medicine, has been widely used for clinical treatment and basic research of obesity and related metabolic diseases in recent years. It can significantly improve insulin resistance (IR) and lipid metabolism disorders. However, there is no microbiological study on its metabolic regulation. In this study, we investigated the effects of ECD on obesity, especially lipid metabolism and the composition and function of gut microbiota in Zucker diabetic fatty (ZDF) rats, and explored the correlation between the biomarkers of gut microbiota and metabolite and host phenotype. The results showed that ECD could reduce body weight, improve IR and lipid metabolism, and reduce the concentration of free fatty acids (FFA) released from white adipose tissue (WAT) due to excessive lipolysis by interfering with the insulin receptor substrate 1 (IRS1)/protein kinase B (AKT)/protein kinase A (PKA)/hormone-sensitive triglyceride lipase (HSL) signaling pathway in ZDF rats. Additionally, ECD gradually adjusted the overall structure of changed gut microbiota, reversed the relative abundance of six genera, and changed the function of gut microbiota by reducing the content of propionic acid, a metabolite of gut microbiota, in ZDF rats. A potentially close relationship between biomarkers, especially Prevotella, Blautia, and Holdemania, propionic acid and host phenotypes were demonstrated through correlation analysis. The results suggested that the beneficial effects of ECD on obesity, especially lipid metabolism disorders, are related to the regulation of gut microbiota in ZDF rats. This provides a basis for further research on the mechanism and clinical application of ECD to improve obesity via gut microbiota.

The Gut Microbiota and Traditional Chinese Medicine: A New Clinical Frontier on Cancer.

Gut microbiota is a complex microecosystem, which is called the second genome of the human body. Herbal medicine can balance tumor-suppressing bacteria and tumor-promoting bacteria and exert its anti-cancer effect by regulating gut microbiota. Traditional Chinese medicine (TCM) has a history of thousands of years in prevention and treatment of diseases in China. In recent decades, TCM has been shown to have an obvious advantage in prolonging the survival time and improving the living quality of patients with cancer. Notably, gut microbiota has become a new pathway to understanding TCM. In this review, we will focus on gut microbiota and tumor progression, especially the diversity, functionality and metabolites of gut microbiota affected by TCM in various cancer. We will also discuss the potential mechanism of gut microbiota for exploring TCM in anti-cancer effect. This article aims to comprehensively review the anti-cancer research of TCM by regulating gut microbiota, and address future perspectives and challenges of gut microbiota in TCM intervention for cancer.

Corrigendum to "Yiqi Huayu Jiedu Decoction Inhibits the Invasion and Metastasis of Gastric Cancer Cells through TGF-ß/Smad Pathway".

[This corrects the article DOI: 10.1155/2017/1871298.].

Modular characteristics and the mechanism of Chinese medicine's treatment of gastric cancer: a data mining and pharmacology-based identification.

BACKGROUND: Traditional Chinese medicine (TCM) is increasingly extensively being applied as a complementary and alternative therapy for gastric cancer (GC); however, there is a lack of large-scale evidence-based deep learning for the guidance of its clinical prescription. METHODS: The combinational search terms of "Gastric cancer and/or gastric malignancy" and "Traditional Chinese Medicine" were used to retrieve clinical study-based herbal prescriptions from public database over the past 3 decades [1990-2020]. Association rules mining (ARM) was used to analyze the prescription patterns of the herbs extracted from the eligible studies. Deep machine learning and computational prediction were conducted to explore candidate prescriptions with general applicability for GC. The action mechanism of the preferred prescription was investigated through network pharmacology, and further validated via in vivo and in vitro experiments. RESULTS: A total of 194 clinical study-based herbal prescriptions with good efficacy for GC were collected. TCM with focus on invigorating the Spleen and tonifying the vital-Qi is a promising adjuvant therapy for GC. The preferred prescription is composed of Atractylodis Macrocephalae Rhizoma, Astragali Radix, Pinelliae Rhizoma, Citri Reticulatae Pericarpium, Herba Hedyotidis Diffusae, Crataegi Fructus, and so on. We screened 74 bioactive compounds and 2,128 predictive targets of the preferred prescription from public databases. Eventually, 135 GC-related genes were identified as the targets of the preferred prescription. The compound-target network revealed that the crucial substances in the preferred prescription are quercetin, kaempferol, baicalein, and nobiletin. Experimentally, the preferred prescription was validated to modulate GC cell survival and inhibit tumor progression mainly via the hTERT/MDM2-p53 signaling pathway in vivo and in vitro. CONCLUSIONS: TCM aimed at invigorating the Spleen and tonifying the vital-Qi is a promising adjuvant therapy for GC, which offers a guidance for worldwide use of TCM in the treatment of GC.

A clinical study on the efficacy of Yiqi Huayu Jiedu decoction for reducing the risk of postoperative recurrence and metastasis of gastric cancer: Protocol for a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Gastric cancer (GC) is one of the top 10 malignant tumors worldwide and poses a great threat to human life and health, the prevention and treatment of which has become the focus and difficulty of medical research. With its unique advantages, traditional Chinese medicine (TCM) is widely used in the prevention and treatment of postoperative recurrence and metastasis of GC as well as the improvement of patients' quality of life. The aim of this study is to elucidate the curative effect and the underlying mechanism of Yiqi Huayu Jiedu (YQHYJD) decoction. METHODS/DESIGN: This is a prospective, multicenter, randomized controlled trial continuing 3 years. Two hundred ninety-eight eligible patients will be randomly divided into 2 groups, the chemotherapy combined with placebo and the chemotherapy combined with YQHYJD group at a ratio of 1:1. All patients will receive the treatment for 6 months and follow up for 3 years. The primary outcomes are disease-free survival, and 1-year, 2-year, 3-year progression-free survival rate, while the secondary outcomes are tumor makers, TCM syndrome score, quality of life score, overall chemotherapy completion rate, intestinal flora diversity test, immune function (T, B lymphocyte subsets and NK cells) test. The Security index includes blood, urine and stool routine, electrocardiogram, liver function (ALT), and renal function (BUN, Scr). All of these outcomes will be analyzed at the end of the trial. DISCUSSION: This research will provide the valuable evidence for the efficacy and safety of Yiqi Huayu Jiedu decoction in postoperative GC. Furthermore, it will be helpful to form a higher level of evidence-based medical basis for TCM in the treatment of GC recurrence and metastasis. TRIAL REGISTRATION: ChiCTR2000039038.

A clinical study of Yiqi Huayu Jiedu decoction reducing the risk of postoperative gastric cancer recurrence and metastasis: Study protocol for a randomized controlled trail.

BACKGROUND: Gastric cancer is a common gastrointestinal tumor, seriously threatening human health. Radical surgery is the preferred treatment for gastric cancer. However, due to the late diagnosis and postoperative recurrence and metastasis, the prognosis is dismal. In China, traditional Chinese medicine (TCM) has been used to treat gastric cancer for many years. The purpose of this study is to explore the efficacy and safety of Yiqi Huayu Jiedu decoction in the treatment of postoperative gastric caner. METHODS/DESIGN: 226 eligibility patients altogether will be randomly allocated to the treatment group and the control group at a ratio of 1:1. After enrollment, every patients will obtain 6 months of treatment, as well as 2 years of follow-up. At the end of this study, primary outcomes including 1-year progression-free survival rate, 2-year progression-free survival rate and disease-free survival, secondary outcomes containing tumor markers, TCM syndrome points, quality of life scale, imageological examination and the safety indicators will be assessed. DISCUSSION: This study will provide the evidence-based evidence for the efficacy of Yiqi Huayu Jiedu decoction reducing the risk of postoperative gastric cancer recurrence and metastasis, which will be beneficial to form the therapeutic regimen in postoperative gastric cancer with integrated TCM and Western medicine. TRAIL REGISTRATION: ChiCTR2000032802.

Modified Jian-pi-yang-zheng decoction inhibits gastric cancer progression via the macrophage immune checkpoint PI3Kγ.

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-1ß, 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.

ß-Asarone Increases Chemosensitivity by Inhibiting Tumor Glycolysis in Gastric Cancer.

ß-asarone is the main active ingredient of the Chinese herb Rhizoma Acori Tatarinowii, which exhibits a wide range of biological activities. It was confirmed to be an efficient cytotoxic agent against gastroenteric cancer cells. However, the exact mechanism of ß-asarone in gastric cancer (GC) remains to be elucidated. The present study showed the inhibitory effect of ß-asarone on three types of different differentiation stage GC cell lines (MGC803, SGC7901, and MKN74) in a dose-dependent manner. Meanwhile, the synergistic sensitivity of ß-asarone and cisplatin was confirmed by using the median-effect principle. Flow cytometry assay revealed that under both normoxia and CoCl2-induced hypoxia conditions, ß-asarone can induce apoptosis of GC cells, which can block GC cells in the cell cycle G2/M phase, showing obvious subdiploid peak. Moreover, the activity of lactic dehydrogenase (LDH), an enzyme that plays an important role in the final step of tumor glycolysis, was significantly decreased in GC cells following treatment with ß-asarone. Mechanistically, ß-asarone can reduce pyruvate dehydrogenase kinase (PDK) 1, phospho(p)-PDK1, PDK4, hypoxia-inducible factor 1-α (HIF1α), c-myc, STAT5, and p-STAT5 expression, which revealed how ß-asarone affects tumor glycolysis. In conclusion, the present study provided evidence in support of the hypothesis that the increase of chemotherapy sensitization by ß-asarone is associated with the inhibition of tumor glycolysis.

A clinical study of traditional Chinese medicine prolonging the survival of advanced gastric cancer patients by regulating the immunosuppressive cell population: A study protocol for a multicenter, randomized controlled trail.

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.

Modified Bu-zhong-yi-qi decoction synergies with 5 fluorouracile to inhibits gastric cancer progress via PD-1/PD- L1-dependent T cell immunization.

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.

Traditional Chinese Medicine in Oncotherapy: The Research Status.

In China, Traditional Chinese Medicine (TCM) plays a vital role in the comprehensive treatment of cancer. As an auxiliary and supplement of major treatment modalities for cancer such as surgery, chemotherapy, and radiotherapy, both clinical observations and biomolecular research have confirmed the therapeutic efficacy of TCM in cancer.

Effect of Yiqi Huayu Jiedu decoction on stages II and III gastric cancer: A multicenter, prospective, cohort study.

BACKGROUND: This study aimed to explore the effect of YHJD (Yiqi Huayu Jiedu decoction) in patients with stages II and III gastric cancer. METHODS: A multicenter, prospective, cohort study was conducted in Jiangsu Province Hospital of Traditional Chinese Medicine, Jiangsu Cancer Hospital, Nanjing Drum Tower Hospital, People's Liberation Army Bayi Hospital, Changzhou Traditional Chinese Medicine Hospital, Changzhou Tumor Hospital, Traditional Chinese Medicine Hospital of Kunshan, Yangzhou Hospital of Traditional Chinese Medicine, and Yixing Tumor Hospital. A total of 489 patients with stage II or III gastric cancer were enrolled after radical gastrectomy. Among them, 238 were included in the chemotherapy group (received chemotherapy alone) and 251 in the YHJD group (received chemotherapy combined with YHJD). The DFS (disease-free survival) rate, 5-year survival rate, quality of life, and traditional Chinese medicine (TCM) symptoms of the 2 groups were compared. RESULTS: The DFS curve of the YHJD group was higher than that of the chemotherapy group (P = .0042). The HR (hazard ratio) was 0.672, and its corresponding 95% CI (confidence interval) was 0.511 to 0.884. For stage II patients, the P value was .8323, which indicated that the difference was not significant. The risk HR was 0.938, and the corresponding 95% CI was 0.521 to 1.689. For stage III patients, the P value was .0072, indicating a statistically significant difference. The HR was 0.653, and the corresponding 95% CI was 0.477 to 0.893. The 5-year survival rate of the YHJD group was 85.29%, which was higher than that of the chemotherapy group (71.05%). Compared with the chemotherapy group, the YHJD group had better quality of life and lower TCM symptom scores. CONCLUSION: YHJD decoction is effective in improving DFS rate in patients with gastric cancer stage III after radical gastrectomy. Moreover, it can reduce the risk of recurrence and metastasis and improve the quality of life in patients with gastric cancer stage II or III after radical gastrectomy.

The modified Si-Jun-Zi Decoction attenuates colon cancer liver metastasis by increasing macrophage cells.

BACKGROUND: The modified Si-Jun-Zi Decoction (SJZ), a Chinese medicine formula, is clinically used against multiple malignancies including colorectal cancer (CRC). This study aims to evaluate the effect of modified SJZ on CRC liver metastasis and identify the therapeutic mechanisms. METHODS: Human CRC cells with GFP fluorescence were transplanted into Balb/c nude mice spleens. Modified SJZ, 5-fluorouracil or the combined treatment was given for 3 weeks. CRC liver metastasis was measured by fluorescence imaging and plasma cytokines were analyzed. Furthermore, the effects of administration time and doses for the modified SJZ were investigated in nude mice. RESULTS: Modified SJZ could increase the survival rate and reduce CRC liver metastasis in the nude mice model. Plasma GM-CSF level was elevated. Three weeks of treatment with the modified SJZ at the full dose (45 g/kg) could significantly increase the number of macrophages but not neutrophils in the spleen. CONCLUSIONS: These results indicate that modified SJZ can inhibit CRC liver metastasis by activating the innate immune system, providing a complementary and alternative therapy for CRC.

The effect of Jianpi Yangzheng Xiaozheng Decoction and its components on gastric cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Yangzheng Xiaozheng Decoction (JPYZXZ) is an empirical compound prescription based on the theory of traditional Chinese medicine. JPYZXZ, which is "Qi-invigorating, spleen-strengthening and stasis-removing," can improve the quality of life of gastric cancer patients and prolong their survival; however, the exact mechanism underlying the antitumor effects of this compound is still not clear. AIM OF THE STUDY: The aim of this study is to clearly define the effect of JPYZXZ and its components, Jianpi Yangzheng Decoction (JPYZ) and Xiao Zheng San Jie Decoction (XZSJ), on inhibiting the progression of gastric cancer. MATERIALS AND METHODS: The effect of JPYZXZ and its components on the motility of gastric cancer MGC-803 cells was measured by MTT, adhesion, transwell assays and wound-healing assays. JPYZXZ, JPYZ and XZSJ were administered to 615 mice with gastric cancer xenografts, and their effect on the inhibition of subcutaneous transplantation was analyzed. THP-1 monocyte cells were used to establish tumor-associated macrophage (TAM) models. The polarized state of the TAMs was detected by Flow Cytometry, ELISA and Immunohistochemistry. The mRNA and protein expression of tumor epithelial-mesenchymal transition (EMT) and TAM-related genes was determined by Real-time PCR and Western Blot, respectively. RESULTS: We determined that both JPYZXZ and its components inhibited the progress of gastric cancer in vitro, and JPYZXZ was clearly more effective than JPYZ or XZSJ. The in vivo results demonstrated that the JPYZXZ and XZSJ group exhibited a significant decrease in the tumor weight compared to the control group. Further analysis indicated that JPYZXZ was more active than JPYZ or XZSJ in inhibiting the gastric cancer EMT transformation both in vivo and in vitro. However, JPYZ was more effective compared with JPYZXZ for inducing the phenotypic change in macrophages from M2 to M1. CONCLUSIONS: Our results demonstrate that both JPYZXZ and its components prevent the progress of gastric cancer. JPYZXZ inhibits the gastric cancer EMT more effectively than JPYZ and XZSJ, but JPYZ primarily works to regulate the phenotypic change in macrophages from M2 to M1.

Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway.

Licochalcone A (LicA) is a chalcone extracted from liquorice which has been used as a traditional Chinese medicine for many generations. Increased glucose consumption and glycolytic activity are important hallmarks of cancer cells, and hexokinase 2 (HK2) upregulation is a major contributor to the elevation of glycolysis. Recently, the antitumor activities of LicA have been reported in various cancers; however, its effect on tumor glycolysis in gastric cancer and the underlying mechanisms are completely unknown. In vitro, cell proliferation and clonogenic survival were substantially inhibited after LicA treatment. LicA reduced HK2 expression, and both glucose consumption and lactate production in gastric cancer cells were significantly suppressed. Mechanistic investigations revealed that multiple signaling pathways including Akt, ERK and NF­κB were suppressed by LicA. Further studies demonstrated that the inhibition of glycolysis by LicA was mainly attributed to the blockade of the Akt signaling pathway, and the suppression of glycolysis was substantially attenuated when Akt was exogenously overexpressed. In addition to the role in the inhibition of glycolysis, reduction in HK2 was confirmed to be involved in the induction of cell apoptosis. The apoptosis induced by LicA was substantially impaired after HK2 overexpression in gastric cancer cells. The in vivo experiment showed that MKN45 xenograft growth was markedly delayed after LicA treatment and HK2 expression in LicA­treated tissues was markedly decreased. All of these data demonstrated that blockade of the Akt/HK2 pathway was the underlying mechanism required for LicA to exert its biological activities in glycolysis inhibition and apoptosis induction.