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Introduction: Dehydrocostus lactone (Dehy), a natural sesquiterpene lactone from Saussurea lappa Clarke, displays remarkable efficacy in treating cancer and gastrointestinal disorders. However, its anti-gastric cancer (GC) effect remains poorly understood., Objectives: Our study aimed to elucidate the anti-GC effect of Dehy and its putative mechanism., Methods: The anti-GC effect was assessed with MTT, colony formation, wound healing and transwell invasion assays. Cell apoptosis rate was detected by Annexin V-FITC/PI binding assay. Network pharmacology analysis and XF substrate oxidation stress test explored the underlying mechanism and altered metabolic phenotype. Lipogenic enzyme expressions and neutral lipid pool were measured to evaluate cellular lipid synthesis and storage. Biolayer interferometry and molecular docking investigated the direct target of Dehy. Autophagosomes were observed by transmission electron microscopy and MDC staining, while the autophagic flux was detected by mRFP-GFP-LC3 transfection. The clinical significance of ACLY was confirmed by tissue microarrays. Patient-derived xenograft (PDX) models were adopted to detect the clinical therapeutic potential of Dehy., Results: Dehy prominently suppressed GC progression both in vitro and in vivo. Mechanistically, Dehy down-regulated the lipogenic enzyme ACLY, thereby reducing fatty acid synthesis and lipid reservation. Moreover, IKKβ was identified as the direct target of Dehy. Dehy inhibited the phosphorylation of IKKβ, promoting the ubiquitination and degradation of ACLY, thereby resulting in lipid depletion. Subsequently, GC cells initiated autophagy to replenish the missing lipids, whereas Dehy impeded this cytoprotective mechanism by down-regulating LAMP1 and LAMP2 expressions, which disrupted lysosomal membrane functions, ultimately leading to apoptosis. Additionally, Dehy exhibited potential in GC clinical therapy as it enhanced the efficacy of 5-Fluorouracil in PDX models., Conclusions: Our work identified Dehy as a desirable agent for blunting abnormal lipid metabolism and highlighted its inhibitory effect on protective autophagy, suggesting the future development of Dehy as a novel therapeutic drug for GC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Cachexia affects approximately 50-80 % of advanced cancer patients, particularly those with gastric cancer (GC). Therefore, early detection of cachexia is essential to prevent its progression. Targeting the gut microbiota may be a promising approach for preventing and treating cachexia in patients with GC. Chemotherapy significantly reduced gut microbiota diversity in GC patients. Specifically, the abundance of bacterial genera such as Bacteroides, Streptococcus, and Prevotella was increased in the gut of patients postchemotherapy, which was closely associated with the development of cachexia. Serum metabolic analysis revealed a strong link between specific microbes and metabolite in patients with chemotherapy-induced GC cachexia. We further constructed a random forest model based on the top 6 genera in terms of abundance for the prediction of chemotherapy-related GC cachexia development; this model had an area under the receiver operating characteristic curve (AUC) of 93.5 % [95 % confidence interval (CI), 86.6 %-100 %], with a specificity and accuracy above 75 %. Additionally, we identified Enterotoxin Bacteroides fragilis (ETBF) as a key factor in chemotherapy-induced GC cachexia. In an in vivo GC model, the colonization of ETBF in the intestines of mice significantly accelerated the muscle and adipose tissue consumption induced by chemotherapy, resulting in cachexia symptoms. Furthermore, ETBF damaged the intestinal mucosal barrier by disrupting cell connections and attracting M1 macrophages, which advances GC cachexia. In conclusion, our findings indicate that gut microbiota imbalance is crucial in GC cachexia development, suggesting potential biomarkers for early diagnosis. Clinical trial registration: http://www.chictr.org.cn, Identification No: ChiCTR2200064547., Competing Interests: Declaration of Competing Interest All affiliations are listed on the title page of the manuscript. All funding sources for this study are listed in the “acknowledgments” section of the manuscript. The authors declare no competing interests. We declare that I have disclosed all competing interests related to this work. If any exist, they have been included in the “declaration of interests” section of the manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Myeloid-derived suppressor cells (MDSCs) are the major factor in gastric cancer (GC) immune evasion. Nevertheless, the molecular process underlying the expansion of MDSCs induced by tumor-derived exosomes (TDEs) remains elusive., Methods: The levels of exosomal and soluble PD-L1 in ninety GC patients were examined via enzyme-linked immunosorbent assay (ELISA) to determine their prognostic value. To investigate the correlation between exosomal PD-L1 and MDSCs, the percentage of MDSCs in the peripheral blood of 57 GC patients was assessed via flow cytometry. Through ultracentrifugation, the exosomes were separated from the GC cell supernatant and detected via Western blotting, nanoparticle tracking analysis (NTA), and transmission electron microscopy (TEM). The function of exosomal PD-L1 in MDSCs was evaluated via immunofluorescence, Western blotting and flow cytometry in a GC cell-derived xenograft (CDX) model., Results: The overall survival (OS) of GC patients in the high exosomal PD-L1 group was significantly lower than that of patients in the low exosomal PD-L1 group (P = 0.0042); however, there was no significant correlation between soluble PD-L1 and OS in GC patients (P = 0.0501). Furthermore, we found that the expression of exosomal PD-L1 was positively correlated with the proportions of polymorphonuclear MDSCs (PMN-MDSCs, r = 0.4944, P < 0.001) and monocytic MDSCs (M-MDSCs, r = 0.3663, P = 0.005) in GC patients, indicating that exosomal PD-L1 might induce immune suppression by promoting the aggregation of MDSCs. In addition, we found that exosomal PD-L1 might stimulate MDSC proliferation by triggering the IL-6/STAT3 signaling pathway in vitro. The CDX model confirmed that exosomal PD-L1 could stimulate tumor development and MDSC amplification., Conclusions: Exosomal PD-L1 has the potential to become a prognostic and diagnostic biomarker for GC patients. Mechanistically, MDSCs can be activated by exosomal PD-L1 through IL-6/STAT3 signaling and provide a new strategy against GC through the use of exosomal PD-L1 as a treatment target., (© 2024. The Author(s).)

Zolbetuximab (IMAB362), a monoclonal antibody targeting Claudin18.2 (CLDN 18.2), demonstrates a significant clinical benefit in patients with advanced gastroesophageal cancers. The noninvasive assessment of CLDN18.2 expression through molecular imaging offers a potential avenue for expedited monitoring and the stratification of patients into risk groups. This study elucidates that CLDN18.2 is expressed at a noteworthy frequency in primary gastric cancers and their metastases. The iodogen method was employed to label IMAB362 with 123 I/ 131 I. The results demonstrated the efficient and reproducible synthesis of 123 I-IMAB362, with a specific binding affinity to CLDN18.2. Immuno-single-photon emission computed tomography (SPECT) imaging revealed the rapid accumulation of 123 I-IMAB362 in gastric cancer xenografts at 12 h, remaining stable for 3 days in patient-derived tumor xenograft models. Additionally, tracer uptake of 123 I-IMAB362 in MKN45 cells surpassed that in MKN28 cells at each time point, with tumor uptake correlating significantly with CLDN18.2 expression levels. Positron emission tomography/computed tomography imaging indicated that tumor uptake of 18 F-FDG and the functional/viable tumor volume in the 131 I-IMAB362 group were significantly lower than those in the 123 I-IMAB362 group on day 7. In conclusion, 123 I-IMAB362 immuno-SPECT imaging offers an effective method for direct, noninvasive, and whole-body quantitative assessment of tumor CLDN18.2 expression in vivo. This approach holds promise for accelerating the monitoring and stratification of patients with gastric cancer.

Background: Autophagy could sense metabolic conditions and safeguard cells against nutrient deprivation, ultimately supporting the survival of cancer cells. Nobiletin (NOB) is a kind of bioactive component of the traditional Chinese medicine Citri Reticulatae Pericarpium and has been proven to induce GC cell death by reducing de novo fatty acid synthesis in our previous study. Nevertheless, the precise mechanisms by which NOB induces cell death in GC cells still need further elucidation., Objectives: To examine the mechanism by which NOB inhibits gastric cancer progression through the regulation of autophagy under the condition of lipid metabolism inhibition., Methods/ Study Design: Proliferation was detected by the CCK-8 assay. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Electron microscopy and mRFP-GFP-LC3 lentiviral transfection were performed to observe autophagy in vitro. Western blot, plasmid transfection, immunofluorescence staining, and CUT & Tag-qPCR techniques were utilized to explore the mechanisms by which NOB affects GC cells. Molecular docking and molecular dynamics simulations were conducted to predict the binding mode of NOB and SREBP1. CETSA was adopted to verify the predicted of binding model. A patient-derived xenograft (PDX) model was employed to verify the therapeutic efficacy of NOB in vivo., Results: We conducted functional studies and discovered that NOB inhibited the protective effect of autophagy via the PI3K/Akt/mTOR axis in GC cells. Based on previous research, we found that the overexpression of ACLY abrogated the NOB-induced autophagy-dependent cell death. In silico analysis predicted the formation of a stable complex between NOB and SREBP1. In vitro assays confirmed that NOB treatment increased the thermal stability of SREBP1 at the same temperature conditions. Moreover, CUT&TAG-qPCR analysis revealed that NOB could inhibit SREBP1 binding to the ACLY promoter. In the PDX model, NOB suppressed tumor growth, causing SREBP1 nuclear translocation inhibition, PI3K/Akt/mTOR inactivation, and autophagy-dependent cell death., Conclusion: NOB demonstrated the ability to directly bind to SREBP1, inhibiting its nuclear translocation and binding to the ACLY promoter, thereby inducing autophagy-dependent cell death via PI3K/Akt/mTOR pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

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&#95;Lachnospiraceae, Rikenellaceae&#95;RC9&#95;gut&#95;group and uncultured&#95;bacterium&#95;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: Bioactive lipids involved in the progression of various diseases. Nevertheless, there is still a lack of biomarkers and relative regulatory targets. The lipidomic analysis of the samples from platinum-resistant in gastric cancer patients is expected to help us further improve our understanding of it., Methods: We employed LC-MS based untargeted lipidomic analysis to search for potential candidate biomarkers for platinum resistance in GC patients. Partial least squares discriminant analysis (PLS-DA) and variable importance in projection (VIP) analysis were used to identify differential lipids. The possible molecular mechanisms and targets were obtained by metabolite set enrichment analysis and potential gene network screened. Finally, verified them by immunohistochemical of a tissue microarray., Results: There were 71 differential lipid metabolites identified in GC samples between the chemotherapy-sensitivity group and the chemotherapy resistance group. According to Foldchange (FC) value, VIP value, P values (FC > 2, VIP > 1.5, p < 0.05), a total of 15 potential biomarkers were obtained, including MGDG(43:11)-H, Cer(d18:1/24:0) + HCOO, PI(18:0/18:1)-H, PE(16:1/18:1)-H, PE(36:2) + H, PE(34:2p)-H, Cer(d18:1 + hO/24:0) + HCOO, Cer(d18:1/23:0) + HCOO, PC(34:2e) + H, SM(d34:0) + H, LPC(18:2) + HCOO, PI(18:1/22:5)-H, PG(18:1/18:1)-H, Cer(d18:1/24:0) + H and PC(35:2) + H. Furthermore, we obtained five potential key targets (PLA2G4A, PLA2G3, DGKA, ACHE, and CHKA), and a metabolite-reaction-enzyme-gene interaction network was built to reveal the biological process of how they could disorder the endogenous lipid profile of platinum resistance in GC patients through the glycerophospholipid metabolism pathway. Finally, we further identified PLA2G4A and ACHE as core targets of the process by correlation analysis and tissue microarray immunohistochemical verification., Conclusion: PLA2G4A and ACHE regulated endogenous lipid profile in the platinum resistance in GC patients through the glycerophospholipid metabolism pathway. The screening of lipid biomarkers will facilitate earlier precision medicine interventions for chemotherapy-resistant gastric cancer. The development of therapies targeting PLA2G4A and ACHE could enhance platinum chemotherapy effectiveness., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Jianpi Yangzheng decoction (JPYZ) possesses a potential anti-tumor activity in gastric cancer. However, potential effect of JPYZ on regulating tumor-associated macrophage (TAM)-derived exosomes to affect gastric cancer is still unclear., Aim of Study: We aimed to clarify the role of tumor-associated macrophage derived exosomes (TAM-exos) in invasive and metastasis of gastric cancer and the mechanism of JPYZ regulate TAM-exos against gastric cancer., Materials and Methods: Flow cytometry was performed to demonstrate whether JPYZ involved in TAM polarization. After JPYZ treatment, TAM conditioned medium (TAM-CM)/TAM-exos were co-cultured with gastric cancer cells and were detected by wound healing and transwell assay. Transcriptome sequencing and bioinformatics analysis predicted the exosomal miRNA after JPYZ intervention in TAM. miRNA mimic and inhibitor were used to verify the effect of miRNA in exosomes on gastric cancer cells. Q-PCR and luciferase reporter assay were employed to clarify the targeting relationship between miRNA and target gene. Western blot assay detected the expression levels of epithelial-mesenchymal transition (EMT) markers and related signaling pathways proteins., Results: We firstly demonstrated that TAM-CM intervened by JPYZ significantly inhibited the invasion and migration of gastric cancer. Furthermore, exosomes in TAM supernatants play a key role in migration of gastric cancer. Meanwhile, transcriptome sequencing and q-PCR revealed that miR-513b-5p expression was significantly reduced in TAM-exos intervened by JPYZ. And miR-513b-5p in TAM aggravated TAM-exos mediated invasion and migration of gastric cancer cells, the inhibitor of miR-513b-5p reversed TAM-exos mediated promotion. Bioinformatics analysis and luciferase reporter assay confirmed that PTEN was a direct target of miR-513b-5p in gastric cancer. MiR-513b-5p inhibited PTEN to activate AKT/mTOR signaling pathway thus promoting gastric cancer invasion and metastasis in vivo and in vitro. Importantly, JPYZ inhibited TAM derived exosomal miR-513b-5p, and alleviated AKT/mTOR activation by PTEN depended manner in gastric cancer., Conclusion: TAM-exos containing miR-513b-5p lead to gastric cancer invasion and migration. Our findings clarify a novel TAM-exos mechanism of JPYZ for inhibiting gastric cancer progression., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Similar to other types of tumors, GC cells undergo metabolic reprogramming and switch to a "predominantly glycolytic" metabolic pattern to promote its survival and metastasis, also known as "the Warburg effect", which is characterized by enhanced glucose uptake and lactate production. A large number of studies have shown that targeting cancer cells to enhanced glycolysis is a promising strategy, that can make cancer cells more susceptible to other conventional treatment methods of treatment, including chemotherapy, radiotherapy and immunotherapy, and so on. Therefore, this review summarizes the metabolic characteristics of glycolysis in GC cells and focuses on how abnormal lactate concentration can lead to immunosuppression through its effects on the differentiation, metabolism, and function of infiltrating immune cells, and how targeting this phenomenon may be a potential strategy to improve the therapeutic efficacy of GC., (© 2023. The Author(s).)

Background: Saikosaponin A (SSA) shows a series of pharmacological activities, such as anti-inflammatory, antioxidant and antitumor. However, there is a lack of comprehensive research or sufficient evidence regarding the efficacy of SSA in treating gastric cancer (GC), and the specific mechanisms by which it inhibits GC growth and progression are still not fully understood., Methods: MTT and clonogenic assays were employed to detect the effect of SSA on the proliferation of GC cells. Bioinformatics predicted the SSA targets in the treatment of GC. The core genes and the underlying mechanism of SSA in anti-GC were obtained by analyzing the intersecting targets; molecular docking and Western blot were used to check the reliability of core genes. Flow cytometry was used to analyze apoptosis and cell cycle in GC cells treated with varying concentrations of SSA. Western blot was employed to detect the expression levels of related proteins., Results: SSA significantly blocked GC cells in the S phase of the cell cycle and induced apoptosis to suppress the proliferation of GC cells. Network pharmacology revealed that the underlying mechanisms through which SSA acts against GC involve the modulation of several signaling pathways, including the PI3K-Akt, MAPK, RAS, and T-cell signaling pathways. Molecular docking showed pivotal target genes with a high affinity to SSA, including STAT3, MYC, TNF, STAT5B, Caspase-3 and SRC. Furthermore, western blot results revealed that SSA significantly increased the protein levels of Bax and Cleaved Caspase-3, whereas decreased the expression levels of p-JAK, p-STAT3, MYC, Bcl-2, p-PI3K, p-AKT and p-mTOR, confirming that the reliability of hub targets and SSA could promote GC cell apoptosis by suppressing PI3K/AKT/mTOR pathway., Conclusions: The results suggest that SSA has the ability to trigger apoptosis in GC cells by blocking the PI3K/AKT/mTOR pathway. These findings highlight the potential of SSA as a promising natural therapeutic agent for the treatment of GC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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-β, 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Liu, Chen, Zhang, Tao, Chen, Wang, Sun, Wu and Liu.)

Background: Gastric cancer (GC) is a common malignant tumor with limited treatment options. The natural flavonoid nobiletin (NOB) is a beneficial antioxidant that possesses anticancer activity. However, the mechanisms by which NOB inhibits GC progression remain unclear., Methods: A CCK-8 assay was performed to determine cytotoxicity. Cell cycle and apoptosis analyses were performed by flow cytometry. RNA-seq was performed to detect differential gene expression after NOB treatment. RT‒qPCR, Western blot and immunofluorescence staining were used to examine the underlying mechanisms of NOB in GC. Xenograft tumor models were constructed to verify the effect of NOB and its specific biological mechanism in GC., Results: NOB inhibited cell proliferation, caused cell cycle arrest and induced apoptosis in GC cells. KEGG classification identified that the inhibitory effect of NOB on GC cells mainly involved the lipid metabolism pathway. We further showed that NOB reduced de novo fatty acid (FA) synthesis, as evidenced by the decreased levels of neutral lipids and the expression levels of ACLY, ACACA and FASN, and ACLY abrogated the effect of NOB on lipid deposits in GC cells. In addition, we also found that NOB triggered endoplasmic reticulum (ER) stress by activating the IRE-1α/GRP78/CHOP axis, but overexpression of ACLY reversed ER stress. Mechanistically, inhibiting ACLY expression with NOB significantly reduced neutral lipid accumulation, thereby inducing apoptosis by activating IRE-1α-mediated ER stress and inhibiting GC cell progression. Finally, in vivo results also demonstrated that NOB inhibited tumor growth by decreasing de novo FA synthesis., Conclusion: NOB could inhibit the expression of ACLY to activate IRE-1α-induced ER stress, which ultimately led to GC cell apoptosis. Our results provide novel insight into the use of de novo FA synthesis for GC treatment and are the first to reveal that NOB inhibits GC progression by ACLY-dependent ER stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Lipid metabolism reprogramming plays an important role in cell growth, proliferation, angiogenesis and invasion of cancer. However, the prognostic value of lipid metabolism during gastric cancer (GC) progression and the relationship with the immune microenvironment are still unclear. The aim of this study was to clarify the correlation between lipid metabolism genes and GC immunity., Method: We obtained 350 patients from The Cancer Genome Atlas (TCGA) and 355 patients from Gene Expression Omnibus (GEO) databases. Lipid metabolism-related gene datasets were obtained from the Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Molecular subtypes were obtained by Consensus clustering, and subtype immune status was analyzed using ESTIMATE, TIMER and microenvironmental cell population counter (MCP Counter) algorithm for immune analysis. Functional analyses included the application of Gene Set Enrichment Analysis (GSEA), KEGG, gene ontology (GO), and Protein-Protein Interaction Networks (PPI) to evaluate the molecular mechanisms of different subtypes. Weighted gene co-expression network analysis (WGCNA) was used to identify genes associated with immunity. The LASSO algorithm and multivariate Cox regression analysis were used to construct prognostic risk models., Result: Based on the lipid metabolism genes found in GC, patients with GC can be divided into two subgroups with significantly different survival. The subgroup with a better prognosis presented higher immune scores and immune infiltrating cell abundance. 1170 immune-related genes were screened by WGCNA, and further screening by PPI network analysis revealed that PTPRC, CD4, ITGB2 and LCP2 were closely associated with immune cells. Combined with the TIDE score results, it was found that the population with high expression of the above genes might be more sensitive to immunotherapy. In addition, a survival prediction model for GC was developed based on five survival-related lipid metabolism genes, PIAS4, PLA2R1, PRKACA, SLCO1A2 and STARD4. The ROC analysis over time showed that the risk prediction score model had good stability., Conclusion: Lipid metabolism gene expression is correlated with the immune microenvironment in GC patients and can accurately predict their prognosis. Studies on lipid metabolism and GC immunity can help to screen the population for immunotherapy benefits., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: The importance of metabolism-related alterations in the development of gastric cancer (GC) is increasingly recognized. The present study aimed to identify metabolism-related genes to facilitate prognosis of GC patients., Methods: Gene expression datasets and clinical information of GC patients were downloaded from TCGA and GEO databases. We scored the enrichment of human metabolism-related pathways (n = 86) in GC samples by GSV, constructed prognostic risk models using LASSO algorithm and multivariate Cox regression analysis, combined with clinical information to construct a nomogram, and finally cis score algorithm to analyze the abundance of immune-related cells in different subtypes. We used Weka software to screen for prognosis-related marker genes and finally validated the expression of the selected genes in clinical cancer patient tissues., Results: We identified that two GC metabolism-related signatures were strongly associated with OS and the levels of immune cell infiltration. Moreover, a survival prediction model for GC was established based on six GC metabolism-related genes. Time-dependent ROC analysis showed good stability of the risk prediction scoring model. The model was successfully validated in an independent ACRG cohort, and the expression trends of key genes were also verified in the GC tissues of patients. DLX1, LTBP2, FGFR1 and MMP2 were highly expressed in the cluster with poorer prognosis while SLC13A2 and SLCO1B3 were highly expressed in the cluster with better prognosis., Conclusions: We identified a risk predictive score model based on six metabolism-related genes related to survival, which may serve as prognostic indicators and potential therapeutic targets for GC., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

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.)

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)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Yuan, Wang, Zhang, Zhang, Wang, Chen, Zhu, Liu and Wu.)

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., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-6301). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Aims: Epidemiological data on diabetic retinopathy (DR) in Chinese population is still rather scarce, and risk factors for diabetic retinopathy are inconsistent because of study designs, grading standards, and population samples., Materials and Methods: This hospital-based retrospective study included 1052 type 2 diabetes patients. Diabetic retinopathy was diagnosed by nonmydriatic fundus photography and/or fundus examination apparatus. Logistic regression analysis was performed to evaluate the risk of diabetic retinopathy., Results: A total of 352 (33.5% prevalence) subjects were diagnosed with diabetic retinopathy based on our population. The patients in the DR group not only had significantly higher hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), urinary microalbumin-creatinine ratio (ACR), and systolic blood pressure but also had higher follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin (SHBG) levels compared to those in the non-DR group. Moreover, we confirmed that diabetes duration and HbA1c are strongly associated with DR risk. We also found that serum LH was an independent risk factor in male diabetic retinopathy patients (OR = 1.086, 95% CI 1.024-1.152), and the levels of LH were significantly associated with diabetic retinopathy prevalence ( P = 0.018)., Conclusions: Our study strengthens the argument that diabetes duration and HbA1c are risk factors for patients with DR. Additionally; we firstly confirmed that serum LH was an independent risk factor in male diabetic retinopathy patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Qingmin Sun et al.)

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease of unknown etiology with limited survival. IPF incidence and prevalence increase significantly with aging, which is associated with an age-related accumulation of oxidative DNA damage. The Mutyh gene is involved in the base excision repair (BER) system, which is critical for repairing the misincorporated adenine that is opposite to the oxidized guanine base, 8-oxoguanine, and maintaining the fidelity of DNA replication. We used Mutyh knockout mice and a bleomycin-induced pulmonary fibrosis model to test the effect of MUTYH deficiency on lesion progression. Unexpectedly, a much less severe lesion of pulmonary fibrosis was observed in Mutyh -/- than in Mutyh + / + mice, which was supported by assay on protein levels of TGF- β 1 and both fibrotic markers, α -SMA and Vimentin, in pulmonary tissues of the model animals. Mechanically, MUTYH deficiency prevented the genomic DNA of pulmonary tissue cells from the buildup of single-strand breaks (SSBs) of DNA and maintained the integrity of mtDNA. Furthermore, increased mitochondrial dynamic regulation and mitophagy were detected in pulmonary tissues of the bleomycin-induced Mutyh -/- model mice, which could reduce the pulmonary epithelial cell apoptosis. Our results suggested that MUTYH deficiency could even induce protective responses of pulmonary tissue under severe oxidative stress., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Qingmin Sun et al.)

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.)

The liver plays a pivotal role in maintaining euglycemia. Biogenesis and function of mitochondria within hepatocytes are often the first to be damaged in a diabetic population, and restoring its function is recently believed to be a promising strategy on inhibiting the progression of diabetes. Previously, we demonstrated that the gut microbiota metabolite butyrate could reduce hyperglycemia and modulate the metabolism of glycogen in both db/db mice and HepG2 cells. To further explore the mechanism of butyrate in controlling energy metabolism, we investigated its influence and underlying mechanism on the biogenesis and function of mitochondria within high insulin-induced hepatocytes in this study. We found that butyrate significantly modulated the expression of 54 genes participating in mitochondrial energy metabolism by a PCR array kit, both the content of mitochondrial DNA and production of ATP were enhanced, expressions of histone deacetylases 3 and 4 were inhibited, beta-oxidation of fatty acids was increased, and oxidative stress damage was ameliorated at the same time. A mechanism study showed that expression of GPR43 and its downstream protein beta-arrestin2 was increased on butyrate administration and that activation of Akt was inhibited, while the AMPK-PGC-1alpha signaling pathway and expression of p-GSK3 were enhanced. In conclusion, we found in the present study that butyrate could significantly promote biogenesis and function of mitochondria under high insulin circumstances, and the GPR43- β -arrestin2-AMPK-PGC1-alpha signaling pathway contributed to these effects. Our present findings will bring new insight on the pivotal role of metabolites from microbiota on maintaining euglycemia in diabetic population., Competing Interests: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2020 Tingting Zhao et al.)

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.)

Aims/introduction: Type 2 diabetes mellitus is frequently accompanied by fatty liver disease. Lipid accumulation within the liver is considered as one of the risk factors for insulin resistance. Hepatocyte growth factor (HGF) is used to treat liver dysfunction; however, the effect and mechanism of HGF on hepatic lipid metabolism are still not fully understood., Materials and Methods: Male C57BL/6 mice were induced with a high-fat diet for 12 weeks, followed by a 4-week treatment of HGF or vehicle saline. The levels of fasting blood glucose, fasting insulin and homeostatic model assessment of insulin resistance were calculated for insulin sensitivity. Biochemical plasma parameters were also measured to assess the effect of HGF on lipid accumulation. Additionally, genes in the lipid metabolism pathway were evaluated in palmitic acid-treated HepG2 cells and high-fat diet mice., Results: HGF treatment significantly decreased the levels of fasting blood glucose, hepatic triglyceride and cholesterol contents. Additionally, HGF-regulated expression levels of sterol regulatory element-binding protein-1c/fatty acid synthase, peroxidase proliferator-activated receptor-α, and upstream nuclear receptors, such as farnesoid X receptor and small heterodimer partner. Furthermore, c-Met inhibitor could partially reverse the effects of HGF., Conclusions: HGF treatment can ameliorate hepatic insulin resistance and steatosis through regulation of lipid metabolism. These effects might occur through farnesoid X receptor-small heterodimer partner axis-dependent transcriptional activity., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

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 NF‑κB 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 LicA‑treated 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.

Objective: Vasculogenic mimicry (VM) indicates that aggressive cancer cells can form de novo vascular networks and provide a perfusion pathway for rapidly growing tumors. MiR-200a has been reported significantly deregulated in ovarian cancer. However, miR-200a regulation of VM and its clinical significance in ovarian cancer remain not elucidated., Methods: In this study, we identified the VM structure by CD34-PAS staining in ovarian cancer tissue. MiR-200a and protein expression was tested by quantitative RT-PCR and western blot. Bioinformatics prediction, luciferase assay and intervention experiments were employed to identify the target of miR-200a., Results: We certified the VM structure in ovarian cancer, and found that the VM positive rate was significantly associated with tumor grade, stage and metastasis. Further study showed that miR-200a expression levels were significantly lower in VM positive ovarian cancer. In addition, our results suggested that miR-200a inhibited VM by negatively regulated EphA2 expression. Consistently, the inverse correlation of miR-200a and EphA2 has also been found in ovarian cancer patients. Moreover, the expression of miR-200a/EphA2 was significantly associated with patient's clinicopathological parameter, such as tumor stage and metastases. Kaplan-Meier curves confirmed that the patients with low miR-200a expression and/or VM positive had a significantly shorter overall survival., Conclusions: Our research demonstrates that VM, miR-200a and EphA2 play key roles in the progression and prognosis of ovarian cancer, and for the first time suggests that miR-200a inhibits VM by directly regulating EphA2. Therefore, we might have identified a genetic mechanism underlying the involvement of miR-200a in ovarian cancer VM., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: CCN3 plays important roles in growth, differentiation, angiogenesis and adhesion. Recently, the role of CCN3 in human carcinogenesis has become an area of great interest. However, little is known about the function of CCN3 in human cervical cancer., Objectives: The aim of this study was to investigate the expression profile of CCN3 in cervical cancer and to assess its clinical significance., Material and Methods: In this study, qRT-PCR, immunohistochemistry and Western blotting analysis were used in the detection of CCN3 mRNA and protein expression, both in cervical cancer and in corresponding normal tissue, respectively. The data was correlated with clinicopathological features. A survival analysis was performed to assess the prognostic significance., Results: CCN3 mRNA was overexpressed in cervical cancer tissue when compared with corresponding normal tissue, as was CCN3 protein. Upregulation of CCN3 was significantly associated with the stage of the disease (P = 0.017) and with lymph node involvement (P = 0.006). Using the Kaplan-Meier analysis, a comparison of survival curves of low vs. high expressers of CCN3 revealed a highly significant difference in human cervical cancer tissue (P = 0.021), which suggests that overexpression of CCN3 is associated with a poorer prognosis., Conclusions: The results of the current study suggest that CCN3 may play an important role in cervical carcinogenesis and therefore may have potential as a biomarker for prognosis and as a therapeutic target in cervical cancer.

MicroRNAs (miRNAs) are emerging as important regulators in various pathobiological processes in cancer. Genistein, as a major isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities particularly in cancer prevention. However, the molecular mechanisms by which genistein elicits its effects on ovarian cancer cells have not been fully elucidated. In this study, we reported that expression of miR-27a was higher in human ovarian cancer relative to benign ovarian tissues. Meanwhile, transfection of SKOV3 cells with the inhibitor of miR-27a suppressed growth and migration of tumor cells. Our study also found that treatment of ovarian cancer cells with genistein caused an inhibition of ovarian cancer cell growth and migration. Further cellular mechanistic studies revealed that genistein down-regulated miR-27a expression, which was accompanied by significantly increased expression of Sprouty2, a putative miR-27a target gene. Taken together, our findings reveal that oncogenic miR-27a plays an important role in ovarian cancer cell growth and metastasis, and genistein, as nontoxic inactivators of miRNA, can block ovarian cancer cell growth and migration, offering novel insights into the mechanisms of genistein therapeutic actions.

MicroRNA-27a (miR‑27a) is an oncogene that contributes to drug resistance in various types of cancer. However, the involvement of miR‑27a in gastric cancer has yet to be elucidated. Perifosine is an alkylphospholipid exhibiting antitumor activity as shown in both preclinical studies and clinical trials. The effects of perifosine on gastric cancer have yet to be determined. Therefore, this study was conducted to detect the role of miR‑27a and perifosine in human gastric cancer. miR‑27a was found to be expressed in human gastric cancer tissues and cell lines by quantitative reverse-transcription polymerase chain reaction (qRT‑PCR). The correlation between miR‑27a expression and clinicopathological characteristics of gastric cancer. We also explored the growth inhibitory effect of perifosine on human gastric cancer cells with or without co‑targeting miR‑27a by sulforhodamine B (SRB) assay. The results showed that miR‑27a expression was significantly upregulated in gastric cancer tissues, compared with their non‑tumor adjacent tissues. High expression levels of miR‑27a were associated with poor tumor histological grade (P=0.037). MiR‑27a inhibitors suppressed the growth of MGC‑803 cells. Assay results showed that perifosine exerted its activity selectively on the AGS cell line and the growth inhibitory effect of perifosine was enhanced significantly in combination with miR‑27a inhibitors in MGC‑803 cells. In conclusion, our results demonstrated that miR‑27a may be a therapeutic target and potential prognostic biological marker in gastric cancer. MiR‑27a inhibitors alone or in combination with perifosine may be a novel therapeutic approach against gastric cancer.

The aggressive course of uveal melanoma is believed to reflect its unusually invasive and metastatic nature, which is associated with the nuclear factor kappaB (NF-κB) pathway. MicroRNAs (miRNAs) have been implicated in the regulation of various biological and pathological processes in cancer, however, the special role of miR-9 in uveal melanoma metastasis is largely unknown. In the present study, we showed that miR-9 is significantly reduced in highly invasive uveal melanoma cell lines, and suppressed migration and invasion of highly invasive cells. Furthermore, miR-9 negatively modulated NF-κB1 expression by direct targeting at its 3'-UTRs. Additionally, downstream targets of NF-κB1, such as MMP-2, MMP-9 and VEGFA, were regulated by miR-9 in the same pattern as NF-κB1. Therefore, miR-9 suppresses uveal melanoma cell migration and invasion partly through downregulation of the NF-κB1 signaling pathway.

Objective: To evaluate the impact of pharmacist interventions on antibiotic use in inpatients with respiratory tract infections in a tertiary hospital in China., Method: Two independent respiratory wards were randomized into control and intervention group. Between July 2009 and April 2010, all inpatients diagnosed with respiratory tract infections were enrolled. Pharmacist interventions were performed on the physicians in the intervention group. The total cost of hospitalization, cost of antibiotics, length of hospital stay and the scores of 6 items of inappropriate antibiotic use (including indication, choice, dosage, dosing schedule, duration and conversion) were analyzed., Results: The total costs of hospitalization in the intervention group were significant lower compared to the control group ($1442.3 ± 684.9 vs. $1729.6 ± 773.7, P < 0.001), as well as the cost of antibiotics ($832.0 ± 373.0 vs. $943.9 ± 412.0, P = 0.01), and the patients required shorter length of hospital stay (14.2 ± 6.2 vs. 15.8 ± 6.0 days, P = 0.03). The scores with respect to the 6 items of inappropriate antibiotic use were all lower in the intervention group than in the control group., Conclusions: Pharmacist interventions, interacted directly with the physicians at ward level, could play an important role in optimizing antibiotic use, thus lead to the reduction in patients' length of hospital stay and health care cost.

Epidemiologic findings are inconsistent concerning the association of endometrial cancer risk with alcohol consumption. Therefore, we conduct a meta-analysis of studies that assessed the association of alcohol consumption and the risk of endometrial cancer. A systematic literature search up to April 2010 was performed in MEDLINE and EMBASE, and study-specific risk estimates were pooled using a random-effects model. In the present study, six prospective and 14 case-control studies were included. Alcohol intake was not significantly associated with the risk of endometrial cancer among prospective studies (relative risk (RR): 1.04; 95% confidence interval (CI): 0.91-1.18) or among case-control studies (odds ratio (OR): 0.89; 95% CI: 0.76-1.05). However evidence from the results of our stratified analyses revealed that increased risk of endometrial cancer was associated with liquor consumption (RR: 1.22; 95% CI: 1.03-1.45) but null association with wine and beer consumption. In conclusion, alcohol consumption is not associated with the risk of endometrial cancer. Future studies should also examine whether the relation varies according to different type of alcoholic beverages.

Aberrant microRNA (miRNA) expression is presently proposed to correlate with various human cancers and common single-nucleotide polymorphisms (SNP) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. However, whether miRNAs SNP alter gastric cancer susceptibility is still unclear. Here we investigated the possible role of a common A/G polymorphism (rs895819) within hsa-mir-27a in the development or progression of gastric cancer, and assessed the effect of rs895819 on the expression of miR-27a and its target gene Zinc finger and BTB domain containing 10 (ZBTB10). In the present case-control study, we found that subjects with the variant genotypes (AG + GG) showed a significantly increased risk of gastric cancer relative to AA carriers (adjusted odds ratio = 1.48, 95% confidence interval 1.06-2.05; P = 0.019). The elevated risk was especially evident in older subjects (age >58 years), men, nonsmokers and rural subjects. A significant association of hsa-mir-27a variant genotypes with lymph node metastasis was also observed. Further functional analyses indicated that variant genotypes might be responsible for elevated miR-27a levels and reduced ZBTB10 mRNA. Moreover, an inverse correlation was found between ZBTB10 and miR-27a levels. In conclusion, we were the first to show that a common polymorphism (rs895819) in hsa-mir-27a, by modulating miR-27a and ZBTB10 levels, acted as an important factor of the gastric cancer susceptibility., (© 2010 Japanese Cancer Association.)

Background: Vasculogenic mimicry (VM) was increasingly recognized as a form of aggressive melanoma acquiring blood supply. Genistein had attracted much attention as a potential anticancer agent. Therefore, we examined the effect of Genistein on VM in human uveal melanoma cells., Methods: VM structure was detected by periodic acid-Schiff (PAS) staining for uveal melanoma C918 cells cultured on the three-dimensional type I collagen gels after exposed to Genistein. We used reverse transcription polymerase chain reaction (RT-PCR) and Western Blot analysis to examine the effect of Genistein on vascular endothelial cadherin (VE-cadherin) mRNA and protein expression. The nude mice models of human uveal melanoma C918 cells were established to assess the number of VM using immunohistochemical and PAS double-staining., Results: Genistein inhibited the survival of C918 cells in vitro. The ectopic model study showed that VM in tumor tissue sections were significantly reduced by Genistein in vivo. In vitro, the VM structure was found in control, 25 and 50 microM Genistein-treatment groups but not in 100 and 200 microM. RT-PCR and Western Blot showed that 100 and 200 microM concentration of Genistein could significantly decrease VE-cadherin mRNA and protein expression of C918 cells compared with control (P < 0.05). However, the 25 and 50 microM Genistein slightly decreased the VE-cadherin level in vitro (P > 0.05)., Conclusion: Genistein inhibits VM formation of uveal melanoma cells in vivo and in vitro. One possible underlying molecular mechanism by which Genistein could inhibit VM formation of uveal melanoma is related to down-regulation of VE-cadherin.

Genistein, an isoflavone isolated from soybean, has been found to be a potent antitumor agent. However, both the effect of genistein on human uveal melanoma cells and the precise mechanism by which genistein suppresses tumorigenesis remain unclear. In the present study, we explored the possible activity of genistein to inhibit human uveal melanoma cell growth and investigated the possible role of genistein on microRNA-27a (miR-27a) as well as its target gene zinc finger and BTB domain containing 10 (ZBTB10) expression levels. The results suggested a significant inhibition of uveal melanoma cell growth in a time- and dose-related manner. In vivo study also indicated treatment groups with genistein could significantly inhibit the growth of xenografts. Further functional assays revealed that the levels of miR-27a and its target gene ZBTB10 were significantly different based on the dose of genistein. In conclusion, the present study demonstrates that genistein exerts growth inhibitory activities in human uveal melanoma cells. Moreover, we for the first time report a correlation between antitumor activity of genistein and miR-27a mediated regulatory mechanism.

Introduction: The C-31G polymorphism in the survivin promoter could de-repress the cell-cycle-dependent transcription of the human survivin gene, resulting in overexpression of survivin. This survivin mutation has only been studied on cervical carcinoma. However, no study has ever been conducted to evaluate the effect of the polymorphism on other cancers, including gastric cancer., Methods: In this hospital-based, case-control study, we investigated the association between the survivin C-31G polymorphism and risk of gastric cancer in a Chinese population using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocols., Results: No statistically significant association was observed between gastric cancer risk and the variant genotype (GG + GC). However, the variant genotype (GG + GC) was either associated with risk of distal gastric cancer (odds ratios=0.50, 95% confidence interval=0.30-0.83) or with risk of well-differentiated tumor (odds ratios=0.46, 95% confidence interval=0.22-0.97)., Conclusion: Our results demonstrate that the survivin C-31G polymorphism may be involved in distal gastric carcinogenesis and tumor differentiation in a Chinese population.

Purpose: Some studies were undertaken to evaluate the association between cigarette smoking and age-related macular degeneration (AMD). This meta-analysis summarized the risk estimate of smoking and AMD and provided robust evidence for the association., Methods: Relevant studies were identified by searching PubMed and MEDLINE (from 1966 to June 2007) and reviewing the reference lists of key articles. The summary relative risk ratio (RR) or odds ratio (OR) and 95% confidence interval (CI) were calculated. Study-specific risk estimates were pooled using a random-effects model., Results: Five prospective cohort and eight case-control studies met our inclusion criteria. Ever smoking was statistically significant associated with increased risk of AMD among cohort studies (RR, 1.61; 95% CI, 1.01-2.57) or case-control studies (RR, 1.76; 95% CI, 1.56-1.99). Current smokers were at higher risk of AMD than past smokers. Both geographic atrophy (GA) and neovascular AMD (NV) are subtypes of AMD. A significant relationship was found between smoking and GA risk. Smoking increased the risk of NV, with marginal nonsignificance (RR, 1.47; 95% CI, 0.92-2.37) in cohort studies and significance in case-control studies (RR, 1.96; 95% CI, 1.69-2.27)., Conclusions: This meta-analysis indicated smoking, especially current smoking, was significantly associated with increased risks of AMD and its subtypes.

A social health insurance (SHI) program has been established in China to ensure that people can obtain health care economically and equitably. Our analysis indicates that in 2005-06, 66.5 percent of Chinese citizens were non-SHI inpatients. We also found that drug spending for SHI inpatients was significantly higher than that for non-SHI inpatients. After adjusting for other variables, we found that the SHI coverage was also associated positively with higher drug costs. We present evidence to show that drug spending differences are attributable at least in part to differences in insurance courage.

To investigate the association between endothelin-converting enzyme-1b (ECE-1b) C-338A polymorphism and gastric cancer risk, we conducted a hospital-based case-control study of 256 gastric cancer cases and 256 controls matched on age and gender. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism. We found that the genotype frequencies were significantly different (P=0.005) between cases and controls. Compared with the wild genotype CC, the variant genotypes (CA+AA) were associated with a 64% increased risk of gastric cancer [adjusted odds ratio (OR)=1.64, 95% confidence interval (CI) 1.15-2.33]. Further stratification analyses indicated that the increased risk was especially noteworthy in older subjects (age 58) (adjusted OR=1.91, 95% CI 1.18-3.09), women (adjusted OR=2.30, 95% CI 1.11-4.79) and non-smokers (adjusted OR=1.79, 95% CI 1.19-2.67). Our results suggest that the ECE-1b C-338A polymorphism may be associated with increased risk of gastric cancer.

Objective: Epidemiologic findings are inconsistent concerning the association of endometrial cancer risk with cigarette smoking. We conducted a meta-analysis of epidemiologic studies to examine this relation., Methods: A systematic literature search up to June of 2007 was performed in MEDLINE and EMBASE. Study-specific risk estimates were pooled using a random-effects model., Results: Ten prospective and 24 case-control studies were included in the analysis of the effect of ever smoking. Ever smoking was statistically significantly associated with a reduced risk of endometrial cancer among prospective studies (relative risk 0.81; 95% confidence interval [CI], 0.74-0.88) and case-control studies (odds ratio 0.72; 95% CI, 0.66-0.79). The inverse association was significant among current and former smokers. Six prospective and 6 case-control studies were included in the quantitative analysis. We noted that an increase in smoking of 20 cigarettes per day was statistically significantly associated with 16% and 27% reduced risks of endometrial cancer in prospective and case-control studies, respectively. We also found that cigarette smoking was significantly associated with a decreased risk of endometrial cancer among postmenopausal women (relative risk 0.71; 95% CI, 0.65-0.78) but not among premenopausal women. In addition, the risk reduction seemed to be stronger among hormone replacement therapy users than nonusers., Conclusion: Cigarette smoking was found to be significantly associated with a reduced risk of endometrial cancer, especially among postmenopausal women.

Purpose: It has been shown that the expression of the receptor for advanced glycation end products (RAGE) is closely associated with invasion and metastasis in gastric cancer. A Gly82Ser polymorphism in exon 3 of RAGE gene was identified and thought to have an effect on the functions of its protein. Therefore, the goal of the present study was to investigate whether the polymorphism is involved in the development or progression of gastric cancer., Experimental Design: In the hospital-based case-control study, the RAGE genotypes were determined using PCR-RFLP in 566 individuals (283 gastric cancer patients and 283 age- and sex-matched controls)., Results: The distribution of genotype was significantly different between cases and controls (P = 0.038). Compared with the wild-type 82Gly/Gly carriers, subjects with the variant genotypes (82Gly/Ser and 82Ser/Ser) had a significantly higher risk of gastric cancer (adjusted odds ratio, 1.47; 95% confidence interval, 1.05-2.06). Moreover, the elevated gastric cancer risk was especially evident in younger individuals (ages < or =58 years), nonsmokers, and rural subjects. Further analyses revealed that the variant genotypes were associated with adjacent organ invasion in the subanalysis of gastric cancer patients., Conclusions: Our findings indicate that the RAGE Gly82Ser polymorphism may confer not only an increased risk of gastric cancer but also with invasion of gastric cancer in the Chinese population.

Objectives: Epidemiologic findings are inconsistent concerning the risk for ovarian cancer associated with hormone replacement therapy (HRT). We conducted a meta-analysis to summarize the available evidence from observational studies to examine this relation., Methods: We searched PUBMED and MEDLINE for relevant studies that were published from January 1, 1966, through May 1, 2007. Study-specific risk estimates were pooled by the use of a random-effects model., Results: Eight cohort (including 4715 cases and 1,555,374 participants) and 19 case-control studies (involving 8240 cases and 20,996 controls) were included. We found a summary relative risk (RR) of 1.24 (95% confidence interval [CI] 1.15-1.34) from cohort studies and a summary odds ratio [OR] of 1.19 (95%CI 1.02-1.40) from case-control studies for ever HRT use. However, the risk estimates of case-control studies might be upwardly biased. Summary risk estimates of four cohort and six case-control studies that distinguished estrogen replacement treatment (ERT) and estrogen-progestin replacement treatment (EPRT) from HRT both indicated that association was stronger among ERT user than EPRT user. Based on data abstracted from six case-control studies, duration of HRT use was not significant. The summary risk estimates for less than 5 years, 6-10, and more than 10 years use were 1.02, 1.13, and 1.21, respectively and 95%CI for each estimate crossed 1.0., Conclusion: HRT use was associated with increased risk of ovarian cancer. These findings may expand the range of possible risks associated with HRT use. However, this positive association should also be considered in the context of HRT's other favorable effects on health.