Jianpi Jiedu decoction suppresses colorectal cancer growth by inhibiting M2 polarization of TAMs through the tryptophan metabolism-AhR pathway.

BACKGROUND: Traditional Chinese medicine, JianpiJiedu decoction (JPJDF), has been utilized in colorectal cancer (CRC) treatment for over forty years. The potential of JPJDF to inhibit CRC through modulation of intestinal microbiota and their metabolites remains uncertain. AIMS: This study aims to further investigate the therapeutic mechanisms of JPJDF in CRC. METHODS: CAC mouse models were developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissues and contents underwent 16S rRNA gene sequencing and untargeted metabolomics analysis. Serum levels of IL-1ß and TNF-α were measured using ELISA. Immunohistochemistry was utilized to assess the expression of Ki67, ZO-1, Occludin, CD68, and CD206. Furthermore, western blotting was performed to evaluate the protein expression of AhR and NF-κB. RESULTS: JPJDF inhibited colorectal tumourigenesis in AOM/DSS treated mice, while also suppressing tumor cell proliferation and upregulating the expression of tight junction proteins. The results of 16S rRNA gene sequencing analysis revealed that JPJDF altered intestinal microbiota composition by increasing the abundance of beneficial bacteria. Additionally, JPJDF reduced tryptophan metabolites, effectively alleviating inflammation and significantly restoring intestinal barrier function in CAC mice. Molecular biology experiments confirmed that JPJDF suppressed the expression levels of AhR and M2-type tumor-associated macrophages, thereby promoting anti-tumor immunity and exerting inhibitory effects on CAC growth. CONCLUSION: JPJDF can regulate the tryptophan metabolism-AhR pathway by modulating the gut microbiota, reducing intestinal inflammation, improving intestinal barrier function, enhancing anti-tumor immunity, and effectively inhibiting CAC growth.

Explore the active ingredients and potential mechanisms of JianPi QingRe HuaYu Methods in the treatment of gastric inflammation-cancer transformation by network pharmacology and experimental validation.

BACKGROUND: JianPi QingRe HuaYu Methods (JQH) have been long used to treat chronic atrophic gastritis (CAG) and precancerous lesions of gastric cancer (PLGC). However, whether JQH can inhibit the transformation of gastritis to gastric cancer (GC) remains unclear. METHODS: Herein, we first retrieved the active ingredients and targets of JQH from the TCMSP database and the targets related to the gastric inflammation-cancer transformation from public databases. Differentially expressed genes (DEGs) related to gastric inflammation-cancer transformation were identified from the Gene Expression Omnibus (GEO) database. Then, we obtained the potential therapeutic targets of JQH in treating gastric inflammation-cancer transformation by intersecting drugs and disease targets. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses of the potential therapeutic targets were conducted using R software. Next, we conducted molecular docking and in vitro experiments to validate our results. RESULTS: We obtained 214 potential therapeutic targets of JQH by intersecting drugs and disease targets. We found that the potential mechanisms of JQH in treating gastric inflammation-cancer transformation might be related to JAK-STAT, Wnt, p53 and VEGF signaling pathways. The molecular docking indicated that quercetin, as the main active ingredient of JQH, might inhibit gastric inflammation-cancer transformation by binding with specific receptors. Our experimental results showed that quercetin inhibited cells proliferation (P < 0.001), promoted cell apoptosis (P < 0.001), reduced the secretion of pro-inflammatory cytokines (P < 0.001) and promoted the secretion of anti-inflammatory cytokines (P < 0.001) in MNNG-induced GES-1 cells. Furthermore, quercetin inhibited cells proliferation (P < 0.001) and reduced mRNA and protein level of markers of PLGC (P < 0.001) in CDCA-induced GES-1 cells. CONCLUSION: These results provide the material basis and regulatory mechanisms of JQH in treating gastric inflammation-cancer transformation.

AGAP2-AS1 promotes the assembly of m6A methyltransferases and activation of the IL6/STAT3 pathway by binding with WTAP in the carcinogenesis of gastric cancer.

Owing to the lack of biomarkers for early diagnosis, gastric cancer (GC) is often associated with a poor prognosis. Thus, there is an urgent need to identify early molecular targets in GC. Dysregulated long noncoding RNAs (lncRNAs) have been evaluated by integrated bioinformatics analysis; and we investigate their specific role and potential mechanism via N6-methyladenosine (m6A) methylation modification in the carcinogenesis and progression of GC. In this study, we report upregulation of lncRNA AGAP2-AS1, activated by a gain of H3K4Me3, in GC tissues and cells. AGAP2-AS1 was linked to adverse prognosis in patients with GC. Functionally, AGAP2-AS1 knockdown inhibited cell proliferation and migration of GC cells. Mechanistically, AGAP2-AS1 bound WT1-associated protein (WTAP) to promote the formation of the WTAP/methyltransferase-like 3 (METTL3)/METTL14 m6A methyltransferase complex. AGAP2-AS1 stabilized signal transducer and activator of transcription 3 (STAT3) mRNA in an m6A-dependent manner and, thus, activated the interleukin 6 (IL6)/STAT3 pathway. Importantly, activation of the AGAP2-AS1/WTAP/STAT3 pathways promoted cell proliferation and migration in GC. Collectively, the present findings revealed a novel regulatory relationship between lncRNA and m6A modification. Furthermore, targeting the AGAP2-AS1/WTAP/STAT3 axis may be a promising strategy for the inhibition of inflammation-mediated carcinogenesis and progression in GC.

Mapping the intellectual structure and landscape of nano-drug delivery systems in colorectal cancer.

Background: Colorectal cancer (CRC) is a prevalent malignancy affecting the digestive tract, and its incidence has been steadily rising over the years. Surgery remains the primary treatment modality for advanced colorectal cancer, complemented by chemotherapy. The development of drug resistance to chemotherapy is a significant contributor to treatment failure in colorectal cancer. Nanodrug delivery systems (NDDS) can significantly improve the delivery and efficacy of antitumor drugs in multiple ways. However, there is a lack of visualization of NDDS research structures and research hotspots in the field of colorectal cancer, and the elaboration of potential research areas remains to be discovered. Objective: To comprehensively explore the current research status and development trend of NDDS in CRC research. Methods: Bibliometric analysis of articles and reviews on NDDS for CRC published between 2002 and 2022 using tools including CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel was performed. Results: A total of 1866 publications authored by 9,870 individuals affiliated with 6,126 institutions across 293 countries/regions were included in the analysis. These publications appeared in 456 journals. Abnous Khalil has the highest number of publications in this field. The most published journals are the International Journal of Nanomedicine, International Journal of Pharmaceutics, and Biomaterials. Notably, the Journal of Controlled Release has the highest citation count and the third-highest H-index. Thematic analysis identified "inflammatory bowel disease"," "oral drug delivery," and "ulcerative colitis" as areas requiring further development. Keyword analysis revealed that "ulcerative colitis," "exosomes," and "as1411"have emerged as keywords within the last 2 years. These emerging keywords may become the focal points of future research. Conclusion: Our findings reveal the current research landscape and intellectual structure of NDDS in CRC research which helps researchers understand the research trends and hot spots in this field.

Global research trends and focus on the link between rheumatoid arthritis and neutrophil extracellular traps: a bibliometric analysis from 1985 to 2023.

Rheumatoid arthritis (RA) is an autoimmune disease that currently has an unknown cause and pathogenesis, and is associated with many complications and a high disability rate. The neutrophil extracellular trap network (NETs) is a newly discovered mechanism that allows neutrophils to capture and kill pathogens. Multiple studies in recent years have highlighted its relevance to the progression of rheumatoid arthritis. Despite the growing number of studies indicating the crucial role of NETs in RA, there has been no bibliometric review of research hotspots and trends in this area. In this study, we retrieved articles related to NETs in RA from the Web of Science Core Collection (WoSCC) database from 1985 to 2023 and used visualization tools such as Citespace, VOSviewer, Tableau Public, and Microsoft Office Excel 2021 to analyze the data. After screening, we included a total of 416 publications involving 2,334 researchers from 1,357 institutions in 167 countries/regions, with relevant articles published in 219 journals. The U.S., China, and Germany are the top 3 countries/regions with 124, 57, and 37 publications respectively. Mariana J. Kaplan is the most published author, and journals such as Frontiers in Immunology and International Journal of Molecular Sciences have had a significant impact on research in this field. The clinical application of PAD enzymes and their inhibitors, and the drug development of NETs as therapeutic targets for RA is a trend for future research. Our study provides a comprehensive bibliometric analysis and summary of NETs in RA publications, which will aid researchers in conducting further scientific research.

Hesperidin may improve depressive symptoms by binding NLRP3 and influencing the pyroptosis pathway in a rat model.

OBJECTIVE: Major depressive disorder (MDD) is a debilitating psychiatric disorder which is common and endangers human physical and mental health. Studies have shown that hesperidin could improve the symptoms of depression with unclear mechanisms. METHOD: In this study, hesperidin was administered to chronic unpredictable mild stress (CUMS) depressed mice before behavioral test, network pharmacology analysis, RNA expression microarray analysis, pathway validation and molecular docking experiments. RESULTS: we found that hesperidin intervention could significantly improve the depressive symptoms and downregulate the expression level of pyroptosis pathway including caspase 1 (Casp1), interleukin 18 (IL18), interleukin-1ß (IL-1ß) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). In addition, we found that hesperidin could possibly bind to NLRP3. CONCLUSIONS: Our study demonstrated that hesperidin had huge potential as anti-depressive neuroprotectant, and may play a role in treating MDD by regulating NLRP3-mediated pyroptosis.

Identification of berberine as a potential therapeutic strategy for kidney clear cell carcinoma and COVID-19 based on analysis of large-scale datasets.

Background: Regarding the global coronavirus disease 2019 (COVID)-19 pandemic, kidney clear cell carcinoma (KIRC) has acquired a higher infection probability and may induce fatal complications and death following COVID-19 infection. However, effective treatment strategies remain unavailable. Berberine exhibits significant antiviral and antitumour effects. Thus, this study aimed to provide a promising and reliable therapeutic strategy for clinical decision-making by exploring the therapeutic mechanism of berberine against KIRC/COVID-19. Methods: Based on large-scale data analysis, the target genes, clinical risk, and immune and pharmacological mechanisms of berberine against KIRC/COVID-19 were systematically investigated. Results: In total, 1,038 and 12,992 differentially expressed genes (DEGs) of COVID-19 and KIRC, respectively, were verified from Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively, and 489 berberine target genes were obtained from official websites. After intersecting, 26 genes were considered potential berberine therapeutic targets for KIRC/COVID-19. Berberine mechanism of action against KIRC/COVID-19 was revealed by protein-protein interaction, gene ontology, and Kyoto Encyclopedia of Genes and Genomes with terms including protein interaction, cell proliferation, viral carcinogenesis, and the PI3K/Akt signalling pathway. In COVID-19 patients, ACOX1, LRRK2, MMP8, SLC1A3, CPT1A, H2AC11, H4C8, and SLC1A3 were closely related to disease severity, and the general survival of KIRC patients was closely related to ACOX1, APP, CPT1A, PLK1, and TYMS. Additionally, the risk signature accurately and sensitively depicted the overall survival and patient survival status for KIRC. Numerous neutrophils were enriched in the immune system of COVID-19 patients, and the lives of KIRC patients were endangered due to significant immune cell infiltration. Molecular docking studies indicated that berberine binds strongly to target proteins. Conclusion: This study demonstrated berberine as a potential treatment option in pharmacological, immunological, and clinical practice. Moreover, its therapeutic effects may provide potential and reliable treatment options for patients with KIRC/COVID-19.

Pan-Cancer Analysis of the Characteristics of LY96 in Prognosis and Immunotherapy Across Human Cancer.

Lymphocyte antigen 96 (LY96) is implicated in tumorigenesis by modulating host immunity. However, an integrated pan-cancer analysis of LY96 in prognosis and immunotherapy across human cancers is still lacking. Therefore, we analyzed the LY96 expression and its prognostic role in tumors by multiple databases. We also investigated the correlation between LY96 and copy number, DNA methylation, somatic mutation, microsatellite instability (MSI), tumor mutation burden (TMB), tumor microenvironment (TME), and immune cell infiltration across human cancers. In addition, the biological processes related to LY96 across various tumors and the correlation between LY96 and 50% inhibitive concentration (IC50) of various drugs were investigated. We found that LY96 was differently expressed between tumor and normal tissues and was significantly upregulated in most types of cancers. LY96 was gradually upregulated from stages I to IV in several cancers. Moreover, we found LY96 may play a prognostic role in most cancers, and patients with high or low LY96 expression often show different clinical outcomes. LY96 was also associated with copy number, DNA methylation, somatic mutation, MSI, TMB, TME characteristics, and immune cell infiltration in cancers. LY96 may also regulate classic tumor-associated pathways in several cancers and is related to drug resistance. This article may help to elucidate the role of LY96 in tumorigenesis, which may promote the development of immunotherapy and targeted therapy in cancers.

Puerarin: A Potential Therapeutic for SARS-CoV-2 and Hantavirus Co-Infection.

Patients with Hantavirus-caused epidemic hemorrhagic fever (EHF) are at risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is currently no validated EHF/SARS-CoV-2 strategy. Several studies have recently shown Puerarin, a natural product, has potent antiviral properties. The goal of present study was to determine the mechanism of puerarin in patients with EHF/COVID-19. We use network pharmacology and bioinformatics to investigate the possible pharmacological targets, bioactivities, and molecular mechanisms of puerarin in the treatment of patients with EHF/SARS-CoV-2. The study investigated the pathogenesis of COVID-19 and EHF and the signaling pathway impacted by puerarin. 68 common genes linked to puerarin and EHF/SARS-CoV-2 were discovered during the investigation. By using protein-protein interaction (PPI) network, we identified RELA, JUN, NF-B1, NF-B2, and FOS as potential therapeutic targets. The bioactivity and signaling pathways of puerarin have also been demonstrated in the treatment of EHF and COVID-19. According to present study, puerarin could reduce excessive immune responses and inflammation through the NF-B, TNF, and HIF-1 signaling pathways. This study explored the potential therapeutic targets and mechanisms of Puerarin in the treatment of EHF/COVID-19.

Effects of Meranzin Hydrate On the LncRNA-miRNA-mRNA Regulatory Network in the Hippocampus of a Rat Model of Depression.

Meranzin hydrate (MH) is a frequently used antidepressant drug in China; however it underlying mechanism remains unknown. In this study, we aimed to explore whether MH could ameliorate depression-like behavior in rats by regulating the competitive endogenous RNA (ceRNA) network. We developed a depression-like rat model using an unpredictable chronic mild stress (UCMS) protocol, and the differentially expressed lncRNAs, miRNAs, and mRNAs were identified between the model group and MH group. Then, a ceRNA network responding to MH treatment was constructed by their corresponding relationships in the databases. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore molecular mechanisms associated with MH treatment. The study indicated that rats in the model group showed loss of weight and deteriorated behavior in behavior tests compared with rats in the normal group. A total of 826 lncRNAs, 121 miRNAs, and 954 mRNAs were differentially expressed in the hippocampus of UCMS rats after MH treatment. In addition, 13 miRNAs were selected, and 12 of them were validated in the hippocampus by qRT-PCR. Then, we predicted upstream lncRNAs and downstream mRNAs of the validated miRNAs and interacted with the results of microarrays. Eventually, a lncRNA-miRNA-mRNA regulatory network, responding to MH treatment, was constructed based on the 314 lncRNAs, 11 miRNAs, and 221 mRNAs. KEGG pathways suggested that these genes may be highly related to Wnt signaling, axon guidance, and MAPK signaling pathways. All these results suggest that MH may be a potential representative compound for the treatment of depression, and its mechanism of action is related to the ceRNA modification.

Ferroptosis Patterns Correlate with Immune Microenvironment Characterization in Gastric Cancer.

OBJECTIVE: We aimed to build a ferroptosis-based classifier to characterize the molecular features of gastric cancers (GC) and investigate the relationship between different ferroptosis patterns and GC tumor microenvironment (TME). METHODS: Based on the genomic and clinical information from TCGA portal and GEO database, non-negative matrix factorization (NMF) was used to identify ferroptosis subtypes in GC patients. In order to estimate the ferroptosis levels, we established ferroptosis subtype score (FSS) to quantify ferroptosis patterns and ferroptosis potential index (FPI) by principal component analysis (PCA). The correlations of different ferroptosis patterns with TME cell-infiltrating characteristics (including immune cell infiltration, immune checkpoints expression levels, tumor mutational burden (TMB) and immunotherapy response) were systematically analyzed. RESULTS: Two ferroptosis subtypes, C1 (with lower FSS) and C2 (with higher FSS), were determined. C2 displayed a significantly lower FPI than C1. Besides, C2 was associated with diffuse subtype while C1 with intestinal subtype. As for TME characteristics, C2 was in accordance with the immune-excluded phenotype as it showed more active immune and stromal activities but lower TMB, less probability of immunotherapy response and poorer prognosis. C1 was linked to immune-inflamed phenotype as it had lower stromal activities but increased neoantigen load, enhanced response to immunotherapy and relatively better prognosis. CONCLUSION: The systematic assessment of ferroptosis patterns and ferroptosis levels presented in our study implied that ferroptosis serves as an important factor in the formation of TME, which may expand the understanding of TME and provide a novel perspective for the development of targeted immunotherapeutic strategies for GC patients.

CXCR4 is a Novel Biomarker Correlated With Malignant Transformation and Immune Infiltrates in Gastric Precancerous Lesions.

Background: As early gastric cancer (EGC) has a far better prognosis than advanced gastric cancer (GC), early diagnosis and treatment are essential. However, understanding the mechanism of the process from gastric precancerous lesion (GPL) becoming EGC has made little advances. Besides, biomarkers that can monitor the progression of GPL-to-GC are still much insufficient. Methods: Key gene modules associated with GPL progression to EGC were identified by integrating two GPL-related data sets, GSE55696 and GSE130823, using the WGCNA method. Combining with the TCGA-STAD cohort, hub genes were identified. Immunofluorescence was conducted to validate the expression. To explore the implication of hub genes in GPL malignant transformation, a correlation test was conducted to identify their co-expression genes, co-expression cytokines, and co-expression immune cells. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to shrink CXCR4-related predictors and construct a prognostic model. Functional enrichment was applied for exploring the potential mechanism. Results: The green module in GSE55696 and the yellow module in GSE130823 were regarded as key gene modules associated with GPL progression to EGC, and 219 intersection genes from them were mainly enriched in critical immune biological processes. Combining with the TCGA-STAD cohort, CXCR4 was identified as a novel biomarker correlated with the malignant transformation of GPL, the positive rate of which was increased with GPL progression according to immunofluorescence. CXCR4 co-expression genes were found mainly involved in regulation of actin. CXCR4 co-expression cytokines were enriched in regulation of chemotaxis, cell chemotaxis, mononuclear cell migration, leukocyte chemotaxis, etc. As for co-expression immune cells, the expression level of CXCR4 was positively correlated with the abundance of macrophages but negatively correlated with that of effector memory T cells and NKT cells during GPL malignant transformation. In addition, the CXCR4-related prognostic model was able to predict the prognosis of GC and serve as an independent predictor for overall survival (OS). Conclusions: CXCR4 was a novel biomarker correlated with malignant transformation of GPL and played a vital role in the control of tumor immunity. CXCR4 is possible to serve as a therapeutic target for malignant transformation of GPL.

Development and Validation of a TNF Family-Based Signature for Predicting Prognosis, Tumor Immune Characteristics, and Immunotherapy Response in Colorectal Cancer Patients.

In this study, a comprehensive analysis of TNF family members in colorectal cancer (CRC) was conducted and a TNF family-based signature (TFS) was generated to predict prognosis and immunotherapy response. Using the expression data of 516 CRC patients from The Cancer Genome Atlas (TCGA) database, TNF family members were screened to construct a TFS by using the univariate Cox proportional hazards regression and the least absolute shrinkage and selection operator- (LASSO-) Cox proportional hazards regression method. The TFS was then validated in a meta-Gene Expression Omnibus (GEO) cohort (n = 1162) from the GEO database. Additionally, the tumor immune characteristics and predicted responses to immune checkpoint blockade in TFS-based risk subgroups were analyzed. Eight genes (TNFRSF11A, TNFRSF10C, TNFRSF10B, TNFSF11, TNFRSF25, TNFRSF19, LTBR, and NGFR) were used to construct the TFS. Compared to the high-risk patients, the low-risk patients had better overall survival, which was verified by the GEO data. In addition, a high TFS risk score was associated with high infiltration of regulatory T cells (Tregs), nonactivated macrophages (M0), natural killer cells, immune escape phenotypes, poor immunotherapy response, and tumorigenic and metastasis-related pathways. Conversely, a low TFS risk score was related to high infiltration of resting CD4 memory T cells and resting dendritic cells, few immune escape phenotypes, and high sensitivity to immunotherapy. Thus, the eight gene-based TFS is a promising index to predict the prognosis, immune characteristics, and immunotherapy response in CRC, and our results also provide new understanding of the role of the TNF family members in the prognosis and treatment of CRC.

TBX5-AS1, an enhancer RNA, is a potential novel prognostic biomarker for lung adenocarcinoma.

BACKGROUND: Enhancer RNAs (eRNAs) are demonstrated to be closely associated with tumourigenesis and cancer progression. However, the role of eRNAs in lung adenocarcinoma (LUAD) remains largely unclear. Thus, a comprehensive analysis was constructed to identify the key eRNAs, and to explore the clinical utility of the identified eRNAs in LUAD. METHODS: First, LUAD expression profile data from the Cancer Genome Atlas (TCGA) dataset and eRNA-relevant information were integrated for Kaplan-Meier survival analysis and Spearman's correlation analysis to filtered the key candidate eRNAs that was associated with survival rate and their target genes in LUAD. Then, the key eRNA was selected for subsequent clinical correlation analysis. KEGG pathway enrichment analyses were undertaken to explore the potential signaling pathways of the key eRNA. Data from the human protein atlas (HPA) database were used to validate the outcomes and the quantitative real time-polymerase chain reaction (qRT-PCR) analysis was conducted to measure eRNA expression levels in tumor tissues and paired normal adjacent tissues from LUAD patients. Finally, the eRNAs were validated in pan-cancer. RESULTS: As a result, TBX5-AS1 was identified as the key eRNA, which has T-box transcription factor 5 (TBX5) as its regulatory target. KEGG analysis indicated that TBX5-AS1 may exert a vital role via the PI3K/AKT pathway, Ras signaling pathway, etc. Additionally, the qRT-PCR results and the HPA database indicated that TBX5-AS1 and TBX5 were significantly downregulated in tumour samples compared to matched-adjacent pairs. The pan-cancer validation results showed that TBX5-AS1 was associated with survival in four tumors, namely, adrenocortical carcinoma (ACC), LUAD, lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). Correlations were found between TBX5-AS1 and its target gene, TBX5, in 26 tumor types. CONCLUSION: Collectively, our results indicated that TBX5-AS1 may be a potential prognostic biomarker for LUAD patients and promote the targeted therapy of LUAD.

High Endothelin Receptor Type A Expression as an Independent Prognostic Biomarker and Correlated with Immune Infiltrates in Stomach Adenocarcinoma.

BACKGROUND: Stomach adenocarcinoma (STAD) is the most common gastrointestinal cancer and is associated with high mortality worldwide. Endothelin receptor type A (EDNRA) is associated with guanine-nucleotide-binding (G) proteins and plays important roles in cellular processes and various diseases. PURPOSE: To investigate the prognosis value of EDNRA expression and its correlation with immune infiltrates in patients with STAD. METHODS: The association between clinical characteristics and EDNRA expression in STAD was analyzed using the Wilcoxon signed-rank test and logistic regression. The Kaplan-Meier plotter analysis and Cox regression were constructed to evaluate the influence of EDNRA on prognosis, and a receiver operating characteristic (ROC) curve and nomogram were constructed. Gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were conducted to analyze the correlation between EDNRA and immune infiltrates. In addition, Oncomine, TIMER databases and qRT-PCR of STAD cell lines were used to verify the EDNRA expression in STAD. RESULTS: Our results revealed that EDNRA expression was significantly higher in patients with STAD than normal gastric tissues, and the results have been confirmed by RT-qPCR. KM-plotter analysis revealed that patients with STAD had shorter OS, FP, and PPS (P<0.001). Multivariate Cox analysis further confirmed that high EDNRA expression was an independent risk factor for OS in patients with STAD. Moreover, other clinicopathologic features were related with worse prognosis in STAD, including age, lymph nodes metastases and primary outcome. More importantly, ROC analysis also confirmed the diagnostic value, and a prognostic nomogram involving age, T, M, N classification, pathologic stage, residual tumor and EDNRA was constructed. GSEA revealed that high EDNRA expression was correlated with immunoregulatory interactions between lymphoid and non lymphoid cells pathways, natural killer cell activation involved in immune response, interleukin 1 receptor binding and pathways in cancer, and ssGSEA showed that EDNRA is correlated with macrophages and NK cells. CONCLUSION: Collectively, EDNRA can be an independent prognostic biomarker and correlated with immune infiltration in stomach adenocarcinoma.

Corrigendum: Current Evidence and Future Perspective of Accuracy of Artificial Intelligence Application for Early Gastric Cancer Diagnosis With Endoscopy: A Systematic and Meta-Analysis.

[This corrects the article DOI: 10.3389/fmed.2021.629080.].

The different effects of Chinese Herb Solid Drink and lactulose on gut microbiota in rats with slow transit constipation induced by compound diphenoxylate.

Slow transit constipation (STC) has become an epidemic medical problem. There are several kinds of drugs for constipation; however, each drug has its limitations. The gut microbiota has a close relationship with STC. Lactulose is an effective drug for constipation because it is a kind of bulking laxative and microbioecologic, and it relieves the syndromes of STC. We found that the Chinese Herb Solid Drink (CHSD), which contains medicine food homologous materials such as psyllium husk, sweetalmond, semen sesami nigrum, and hemp seed, has a similar effect on relieving constipation as lactulose, although it has different effects on the gut microbiota. We investigated the mechanisms of CHSD in rats with STC, induced by diphenoxylate, via constipation index and enzyme linked immunosorbent assay (ELISA) analyses using serum and 16S rDNA amplicon and gas chromatography-mass spectroscopy (GC-MS). CHSD enhanced the relative abundance of some types of gut microbiota, such as Blautia, Ruminococcus, Roseburia, Coprococcus, Lachnospira, and Phascolarctobacterium, while lactulose enhanced the relative abundance of Blautia, Phascolarctobacterium, Eubacterium, and Akkernansia in diphenoxylate-induced STC rats. Both CHSD and lactulose enhanced the level of short-chain fatty acids in the faeces of rats; however, the composition of those were different between the two drugs. From the perspective of the gut neuroendocrine system, both CHSD and lactulose could elevate neurotransmitters, such as motilin (MTL) and substance P (SP), which promote intestinal peristalsis and reduce the expression of vasoactive intestinal peptide, which inhibits intestinal peristalsis in the serum of STC rats. CHSD could elevate gastrin expression, which also promoted intestinal peristalsis in serum, while lactulose did not have this effect. Our findings suggest that CHSD may be an effective and safe therapeutic choice for STC.

Current Evidence and Future Perspective of Accuracy of Artificial Intelligence Application for Early Gastric Cancer Diagnosis With Endoscopy: A Systematic and Meta-Analysis.

Background & Aims: Gastric cancer is the common malignancies from cancer worldwide. Endoscopy is currently the most effective method to detect early gastric cancer (EGC). However, endoscopy is not infallible and EGC can be missed during endoscopy. Artificial intelligence (AI)-assisted endoscopic diagnosis is a recent hot spot of research. We aimed to quantify the diagnostic value of AI-assisted endoscopy in diagnosing EGC. Method: The PubMed, MEDLINE, Embase and the Cochrane Library Databases were searched for articles on AI-assisted endoscopy application in EGC diagnosis. The pooled sensitivity, specificity, and area under the curve (AUC) were calculated, and the endoscopists' diagnostic value was evaluated for comparison. The subgroup was set according to endoscopy modality, and number of training images. A funnel plot was delineated to estimate the publication bias. Result: 16 studies were included in this study. We indicated that the application of AI in endoscopic detection of EGC achieved an AUC of 0.96 (95% CI, 0.94-0.97), a sensitivity of 86% (95% CI, 77-92%), and a specificity of 93% (95% CI, 89-96%). In AI-assisted EGC depth diagnosis, the AUC was 0.82(95% CI, 0.78-0.85), and the pooled sensitivity and specificity was 0.72(95% CI, 0.58-0.82) and 0.79(95% CI, 0.56-0.92). The funnel plot showed no publication bias. Conclusion: The AI applications for EGC diagnosis seemed to be more accurate than the endoscopists. AI assisted EGC diagnosis was more accurate than experts. More prospective studies are needed to make AI-aided EGC diagnosis universal in clinical practice.

Systematic Pan-Cancer Analysis Identifies TREM2 as an Immunological and Prognostic Biomarker.

Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although increasing evidence supports a vital role for TREM2 in tumorigenesis of some cancers, no systematic pan-cancer analysis of TREM2 is available. Thus, we aimed to explore the prognostic value, and investigate the potential immunological functions, of TREM2 across 33 cancer types. Based on datasets from The Cancer Genome Atlas, and the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, and Human Protein Atlas, we employed an array of bioinformatics methods to explore the potential oncogenic roles of TREM2, including analyzing the relationship between TREM2 and prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, and immune cell infiltration of different tumors. The results show that TREM2 is highly expressed in most cancers, but present at low levels in lung cancer. Further, TREM2 is positively or negatively associated with prognosis in different cancers. Additionally, TREM2 expression was associated with TMB and MSI in 12 cancer types, while in 20 types of cancer, there was a correlation between TREM2 expression and DNA methylation. Six tumors, including breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, and stomach adenocarcinoma, were screened out for further study, which demonstrated that TREM2 gene expression was negatively correlated with infiltration levels of most immune cells, but positively correlated with infiltration levels of M1 and M2 macrophages. Moreover, correlation with TREM2 expression differed according to T cell subtype. Our study reveals that TREM2 can function as a prognostic marker in various malignant tumors because of its role in tumorigenesis and tumor immunity.

Construction and Validation of a Ferroptosis-Related Prognostic Model for Gastric Cancer.

BACKGROUND: Gastric cancer (GC), an extremely aggressive tumor with a very different prognosis, is the third leading cause of cancer-related mortality. We aimed to construct a ferroptosis-related prognostic model that can be distinguished prognostically. METHODS: The gene expression and the clinical data of GC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). The ferroptosis-related genes were obtained from the FerrDb. Using the "limma" R package and univariate Cox analysis, ferroptosis-related genes with differential expression and prognostic value were identified in the TCGA cohort. Last absolute shrinkage and selection operator (LASSO) Cox regression was applied to shrink ferroptosis-related predictors and construct a prognostic model. Functional enrichment, ESTIMATE algorithm, and single-sample gene set enrichment analysis (ssGSEA) were applied for exploring the potential mechanism. GC patients from the GEO cohort were used for validation. RESULTS: An 8-gene prognostic model was constructed and stratified GC patients from TCGA and meta-GEO cohort into high-risk groups or low-risk groups. GC patients in high-risk groups have significantly poorer OS compared with those in low-risk groups. The risk score was identified as an independent predictor for OS. Functional analysis revealed that the risk score was mainly associated with the biological function of extracellular matrix (ECM) organization and tumor immunity. CONCLUSION: In conclusion, the ferroptosis-related model can be utilized for the clinical prognostic prediction in GC.