Network pharmacology and molecular docking technology for exploring the effect and mechanism of high-dose vitamin c on ferroptosis of tumor cells: A review.

To investigate the mechanism by which high-dose vitamin C (HVC) promotes ferroptosis in tumor cells via network pharmacology, vitamin C-related and ferroptosis-related targets were obtained from the PharmMapper and GeneCards databases, respectively, and their common targets were compared using the Venn diagram. Common targets were imported into the STRING database for protein-protein interaction analysis, and core targets were defined. Core targets were enriched for Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways using the R language packages. A map of the core target-based interaction network and a map of the mechanism by which HVC regulates ferroptosis were constructed. A total of 238 vitamin C-related and 721 ferroptosis-related targets were identified, of which 21 targets were common to both. Furthermore, ALDOA, AHCY, LDHB, HSPA8, LGALS3, and GSTP1 were identified as core targets. GO enrichment analysis suggested that the main biological processes included the extrinsic apoptotic signaling pathway and pyruvate metabolic process. KEGG enrichment analysis suggested that HVC regulates ferroptosis mainly through the amino acid and carbohydrate metabolic pathways. The targets were validated by molecular docking. In conclusion, HVC may promote ferroptosis in tumor cells by regulating metabolic pathways, and there is a synergistic effect between HVC and type I ferroptosis inducers. Glycolysis-dependent tumors may be beneficial for HVC therapy. Our study provides a reference for further clinical studies on HVC antitumor therapy.

Colorectal cancer with low SLC35A3 is associated with immune infiltrates and poor prognosis.

The expression level of SLC35A3 is associated with the prognosis of many cancers, but its role in colorectal cancer (CRC) is unclear. The purpose of our study was to elucidate the role of SLC35A3 in CRC. The expression levels of SLC35A3 in CRC were evaluated through tumor immune resource assessment (TIMER), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), Human Protein Atlas (HPA), qRT-PCR, and immunohistochemical evaluation. TCGA, GEO, and ICGC databases were used to analyze the diagnostic and prognostic value of SLC35A3 in CRC. A overall survival (OS) model was constructed and validated based on the expression level of SLC35A3 and multivariable analysis results. The cBioPortal tool was used to analyze SLC35A3 mutation in CRC. The UALCAN tool was used to analyze the promoter methylation level of SLC35A3 in colorectal cancer. In addition, the role of SLC35A3 in CRC was determined through GO analysis, KEGG analysis, gene set enrichment analysis (GSEA), immune infiltration analysis, and immune checkpoint correlation analysis. In vitro experiments validated the function of SLC35A3 in colorectal cancer cells. Compared with adjacent normal tissues and colonic epithelial cells, the expression of SLC35A3 was decreased in CRC tissues and CRC cell lines. Low expression of SLC35A3 was associated with N stage, pathological stage, and lymphatic infiltration, and it was unfavorable for OS, disease-specific survival (DSS), recurrence-free survival (RFS), and post-progression survival (PPS). According to the Receiver Operating Characteristic (ROC) analysis, SLC35A3 is a potential important diagnostic biomarker for CRC patients. The nomograph based on the expression level of SLC35A3 showed a better predictive model for OS than single prognostic factors and TNM staging. SLC35A3 has multiple types of mutations in CRC, and its promoter methylation level is significantly decreased. GO and KEGG analysis indicated that SLC35A3 may be involved in transmembrane transport protein activity, cell communication, and interaction with neurotransmitter receptors. GSEA revealed that SLC35A3 may be involved in energy metabolism, DNA repair, and cancer pathways. In addition, SLC35A3 was closely related to immune cell infiltration and immune checkpoint expression. Immunohistochemistry confirmed the positive correlation between SLC35A3 and helper T cell infiltration. In vitro experiments showed that overexpression of SLC35A3 inhibited the proliferation and invasion capability of colorectal cancer cells and promoted apoptosis. The results of this study indicate that decreased expression of SLC35A3 is closely associated with poor prognosis and immune cell infiltration in colorectal cancer, and it can serve as a promising independent prognostic biomarker and potential therapeutic target.

Mechanism of Bazhen decoction in the treatment of colorectal cancer based on network pharmacology, molecular docking, and experimental validation.

Objective: Bazhen Decoction (BZD) is a common adjuvant therapy drug for colorectal cancer (CRC), although its anti-tumor mechanism is unknown. This study aims to explore the core components, key targets, and potential mechanisms of BZD treatment for CRC. Methods: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) was employed to acquire the BZD's active ingredient and targets. Meanwhile, the Drugbank, Therapeutic Target Database (TTD), DisGeNET, and GeneCards databases were used to retrieve pertinent targets for CRC. The Venn plot was used to obtain intersection targets. Cytoscape software was used to construct an "herb-ingredient-target" network and identify core targets. GO and KEGG pathway enrichment analyses were conducted using R language software. Molecular docking of key ingredients and core targets of drugs was accomplished using PyMol and Autodock Vina software. Cell and animal research confirmed Bazhen Decoction efficacy and mechanism in treating colorectal cancer. Results: BZD comprises 173 effective active ingredients. Using four databases, 761 targets related to CRC were identified. The intersection of BZD and CRC yielded 98 targets, which were utilized to construct the "herb-ingredient-target" network. The four key effector components with the most targets were quercetin, kaempferol, licochalcone A, and naringenin. Protein-protein interaction (PPI) analysis revealed that the core targets of BZD in treating CRC were AKT1, MYC, CASP3, ESR1, EGFR, HIF-1A, VEGFR, JUN, INS, and STAT3. The findings from molecular docking suggest that the core ingredient exhibits favorable binding potential with the core target. Furthermore, the GO and KEGG enrichment analysis demonstrates that BZD can modulate multiple signaling pathways related to CRC, like the T cell receptor, PI3K-Akt, apoptosis, P53, and VEGF signaling pathway. In vitro, studies have shown that BZD dose-dependently inhibits colon cancer cell growth and invasion and promotes apoptosis. Animal experiments have shown that BZD treatment can reverse abnormal expression of PI3K, AKT, MYC, EGFR, HIF-1A, VEGFR, JUN, STAT3, CASP3, and TP53 genes. BZD also increases the ratio of CD4+ T cells to CD8+ T cells in the spleen and tumor tissues, boosting IFN-γ expression, essential for anti-tumor immunity. Furthermore, BZD has the potential to downregulate the PD-1 expression on T cell surfaces, indicating its ability to effectively restore T cell function by inhibiting immune checkpoints. The results of HE staining suggest that BZD exhibits favorable safety profiles. Conclusion: BZD treats CRC through multiple components, targets, and metabolic pathways. BZD can reverse the abnormal expression of genes such as PI3K, AKT, MYC, EGFR, HIF-1A, VEGFR, JUN, STAT3, CASP3, and TP53, and suppresses the progression of colorectal cancer by regulating signaling pathways such as PI3K-AKT, P53, and VEGF. Furthermore, BZD can increase the number of T cells and promote T cell activation in tumor-bearing mice, enhancing the immune function against colorectal cancer. Among them, quercetin, kaempferol, licochalcone A, naringenin, and formaronetin are more highly predictive components related to the T cell activation in colorectal cancer mice. This study is of great significance for the development of novel anti-cancer drugs. It highlights the importance of network pharmacology-based approaches in studying complex traditional Chinese medicine formulations.

Probiotics and Prebiotics as Dietary Supplements for the Adjunctive Treatment of Type 2 Diabetes.

In modern lifestyles, high-fat diets and prolonged inactivity lead to more people developing type 2 diabetes (T2D). Based on the modern pathogenesis of T2D, food, and its components have become one of the top concerns for patients. Recent studies have found that dysbiosis and gut-related inflammation are more common in T2D patients. Probiotics and prebiotics play complementary roles in the gut as dietary supplements. Together, they may help improve dysbiosis and intestinal inflammation in people with T2D, increase the production of blood glucose-lowering hormones such as incretin, and help reduce insulin resistance and lower blood glucose. Therefore, changing the dietary structure and increasing the intake of probiotics and prebiotics is expected to become a new strategy for the adjuvant treatment of T2D.

Network pharmacology-based analysis of heat clearing and detoxifying drug JC724 on the treatment of colorectal cancer.

BACKGROUND: Heat-clearing and detoxifying drugs has protective effect on colorectal cancer (CRC). Given the complicated features of Traditional Chinese medicine formulas, network pharmacology is an effective approach for studying the multiple interactions between drugs and diseases. AIM: To systematically explore the anticancer mechanism of heat-clearing and detoxifying drug JC724. METHODS: This study obtained the active compounds and their targets in JC724 from Traditional Chinese Medicine System Pharmacology Database. In addition, the CRC targets were obtained from Drugbank, TTD, DisGeNET and GeneCards databases. We performed transcriptome analysis of differentially expressed genes in CRC treated with JC724. Venn diagram was used to screen the JC724-CRC intersection targets as candidate targets. Core targets were selected by protein-protein interaction network and herb ingredient-target-disease network analysis. The functional and pathway of core targets were analysed by enrichment analysis. RESULTS: We found 174 active ingredients and 283 compound targets from JC724. 940 CRC-related targets were reserved from the four databases and 304 CRC differentially expressed genes were obtained by transcriptome analysis. We constructed the network and found that the five core ingredients were quercetin, ß Beta sitosterol, wogonin, kaempferol and baicalein. The core JC724-CRC targets were CYP1A1, HMOX1, CXCL8, NQO1 and FOSL1. JC724 acts on multiple signaling pathways associated with CRC, including the Nrf2 signaling pathway, oxidative stress, and the IL-17 signaling pathway. CONCLUSION: In this study, we systematically analyzed the active ingredients, core targets and main mechanisms of JC724 in the treatment of CRC. This study could bring a new perspective to the heat-clearing and detoxifying therapy of CRC.

Correlations between serum lipid and Ki-67 levels in different breast cancer molecular subcategories.

Breast cancer has the highest incidence rate among all cancer types worldwide, seriously threatening women's health. The present retrospective study explored differences in serum lipid contents in different breast cancer (BC) subcategories and their correlation with Ki-67 expression levels in patients with invasive BC with the aim of identifying novel diagnostic and prognostic indicators for personalized BC treatment. The study included 170 patients diagnosed with BC who were diagnosed with invasive BC by postoperative pathological examination. Data on patient age, body mass index and menopausal status were collected, in addition to estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2) and antigen Ki-67 expression levels and pathological tumor type. Preoperative circulating lipid levels, specifically the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and apolipoproteins A1 (ApoA1) and B (ApoB) were also obtained. Molecular subcategories of BC were grouped based on their immunohistochemistry. Differences in serum lipid levels between the groups were assessed, and correlations between serum lipid and Ki-67 expression levels were explored. While TC, LDL-C, HDL-C and ApoA1 levels differed significantly among molecular subcategories. TG and ApoB levels did not. Circulating TC and LDL-C levels were considerably higher in patients with triple-negative BC (TNBC) and HER2-positive [hormone receptor (HR)-negative] BC than in those with luminal A and B (HER2-negative) BC. Serum HDL-C levels were significantly diminished in the TNBC and HER2-positive (HR-negative) groups compared with the luminal A and B (HER2-negative) groups. ApoA1 levels were significantly reduced in cases of TNBC and HER2-positive (HR-negative) BC compared with luminal A and B BC. Ki-67 expression levels were positively correlated with circulating TC and LDL-C levels and inversely correlated with circulating HDL-C and ApoA1 levels but exhibited no correlation with serum ApoB and TG levels. The results indicate that elevated TC and LDL-C levels and diminished HDL-C and ApoA1 levels were high-risk factors in patients with TNBC and HER2-positive (HR-negative) BC, but not patients with luminal subcategories of BC. Abnormal serum lipid levels were correlated with Ki-67 expression levels, with elevated circulating TC and LDL-C levels and reduced circulating HDL-C and ApoA1 levels indicating a poor prognosis in patients with BC.

Faecal microbiota transplantation is better than probiotics for tissue regeneration of type 2 diabetes mellitus injuries in mice.

CONTEXT: Western diet and unhealthy lifestyle have contributed to the continued growth of type 2 diabetes mellitus (T2DM). T2DM is associated with dysbacteriosis, and studies have found that altering the gut microbiota has a positive effect on treatment. OBJECTIVE: In addition to hyperglycaemia, T2DM often causes damage to multiple organs. However, there are few studies on organ damage from faecal microbiota transplantation (FMT). MATERIALS AND METHODS: T2DM mice were divided into four groups and were given phosphate buffered saline (PBS) (T2DM group), FMT (FMT group), Lactobacillus (LAB group), and Bifidobacterium (BIO group) by gavage for six weeks, respectively. Mice on a normal diet (control group) were gavaged with PBS for six weeks. RESULTS: After gavage treatment, FMT, LAB, and BIO groups were similar in lowering glucose, endotoxemia was slightly reduced, and the colonic mucus layer and liver lobules developed towards normal tissue. Surprisingly, we found that the FMT group had unique effects on islet cell regeneration, increased functional ß cells, and insulin sensitivity. DISCUSSION AND CONCLUSION: Lactobacillus has the best glucose-lowering effect, but FMT has obvious advantages in ß-cell regeneration, which provides new treatment ideas for tissue damage caused by T2DM.

Molecular Targets and Mechanisms of Hedyotis diffusa-Scutellaria barbata Herb Pair for the Treatment of Colorectal Cancer Based on Network Pharmacology and Molecular Docking.

Objective: Hedyotis diffusa-Scutellaria barbata herb pair (HS) has therapeutic effects on a variety of cancers, and this study aims to systematically explore the multiple mechanisms of HS in the treatment of colorectal cancer (CRC). Methods. The active ingredients of HS were obtained from TCMSP, and the potential targets related to these ingredients were screened from the STITCH, SuperPred, and Swiss TargetPrediction databases. Targets associated with CRC were retrieved by Drugbank, TTD, DisGeNET, and GeneCards. We used a Venn diagram to screen the intersection targets and used Cytoscape to construct the herb-ingredient-target-disease network, and the core targets were selected. The Go analysis and KEGG pathway annotation were performed by R language software. We used PyMol and Autodock Vina to achieve molecular docking of core ingredients and targets. Results: A total of 33 active ingredients were obtained from the HS, and 762 CRC-related targets were reserved from the four databases. We got 170 intersection targets to construct the network and found that the four ingredients with the most targets were quercetin, luteolin, baicalein, and dinatin, which were the core ingredients. The PPI analysis showed that the core targets were STAT3, TP53, MAPK3, AKT1, JUN, EGFR, MYC, VEGFA, EGF, and CTNNB1. Molecular docking results showed that these core ingredients had good binding potential with core targets, especially the docking of each component with MAPK obtained the lowest binding energy. HS acts simultaneously on various signaling pathways related to CRC, including the PI3K-Akt signaling pathway, proteoglycans in cancer, and the MAPK signaling pathway. Conclusions: This study systematically analyzed the active ingredients, core targets, and central mechanisms of HS in the treatment of CRC. It reveals the role of HS targeting PI3K-Akt signaling and MAPK signaling pathways in the treatment of CRC. We hope that our research could bring a new perspective to the therapy of CRC and find new anticancer drugs.

Relationship between serum lipid level and colorectal cancer: a systemic review and meta-analysis.

OBJECTIVE: Investigative studies report contradictory results of the relationship between serum lipid levels and the risk of colorectal cancer (CRC). We conducted a meta-analysis of prospective published studies to clarify the relationship between serum lipid and CRC risk. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed and Embase from inception until December 2020. ELIGIBILITY CRITERIA: We considered prospective cohort and case-control studies that evaluated differences in serum lipid levels with the risk of developing CRC. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers screened and included the studies using standardised electronic data extraction forms. The relative risks of the studies were combined with random-effect and fixed-effect models and were analysed for heterogeneity, publication bias and sensitivity. RESULTS: Twenty-four prospective studies, including 4 224 317 individuals with 29 499 CRC cases, were included in the meta-analysis. The total pooled risk ratio (RR) for high vs low concentrations of triglyceride (TG) concentrations was reported at 1.21 (95% CI 1.09 to 1.34; I2=46.8%), total cholesterol (TC) was at 1.15 (95% CI 1.08 to 1.22; I2=36.8%), high-density lipoprotein cholesterol (HDL-C) was 0.86 (95% CI 0.77 to 0.97; I2=28.8%) and low-density lipoprotein cholesterol (LDL-C) was observed at 1.03 (95% CI 0.75 to 1.41; I2=69.4%). CONCLUSIONS: This meta-analysis shows that high levels of serum TG and TC are positively correlated with the incidence rate of CRC, while high levels of serum HDL-C are negatively correlated with CRC incidence rate. Furthermore, no association was found between LDL-C and the risk of developing CRC. Nevertheless, the heterogeneity brought about by comparative methods, demographic differences and pathological differences between the research subjects limits the effectiveness of the overall pooled results.

Prognostic prediction of preoperative nutritional status in low-grade appendiceal mucinous neoplasms.

To describe the preoperative nutritional status of Low-grade Appendiceal Mucinous Neoplasms (LAMNs) and identify prognostic factors for survival. Medical records from 165 patients with LAMNs who attended the Aerospace Center Hospital, Beijing, China between January 2017, and December 2018 were retrospectively reviewed. Survival analysis was performed with the Kaplan-Meier method, the log-rank test, and a Cox proportional hazards model. Among 165 patients, 59 (36%) were male and 106 (64%) were female. Patient's median age was 58 years (range 20 to 78 years). Univariate analysis indicated that gender, weight loss, prior surgical score (PSS), red blood cell, albumin, peritoneal cancer index (PCI), completeness of cytoreduction (CCR), and hyperthermic intraperitoneal chemotherapy (HIPEC) were related to prognosis. Multivariate analysis showed that PSS, CCR and HIPEC were independent predictors of prognosis. The preoperative nutritional status of patients plays an important role in predicting prognosis. Patients can benefit from a complete cytoreductive surgery (CCRS) and HIPEC in an experienced institution for the first medical treatment.

Associations between omega-3 polyunsaturated fatty acids supplementation and surgical prognosis in patients with gastrointestinal cancer: A systematic review and meta-analysis.

Background: Surgical resection remains the primary treatment for gastrointestinal (GI) cancer, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to improve the prognosis of patients undergoing gastrointestinal tumor surgery. This meta-analysis aims to explore the efficacy of n-3 PUFAs on GI cancer patients undergoing surgery. Methods: A systematic search of PubMed, Cochrane Library databases, EMBASE (until December 2021) was conducted. PRISMA checklist was followed. The data were analyzed by RevMan v5.3.0. Results: A total of ten RCTs articles including 663 patients were studied. The analysis demonstrated that the n-3 PUFAs group significantly reduced levels of interleukin-6 (IL-6) (P = 0.001), C-reactive protein (CRP) (P < 0.00001), tumor necrosis factor-ɑ (TNF-α) (P = 0.0003) compared with the control group. and higher levels of CD4+T cells (P = 0.03), CD8+T cells (P = 0.02) and CD4+/CD8+ratio (P = 0.03) compared with the control group. but there was no significant difference in infection complications rate (P = 0.50) and the level of prealbumin (P = 0.80), albumin (P = 0.21), retinol-binding protein(P = 0.80) between the two groups. In addition, the n-3 PUFAs group significantly reduced the length of hospital stay (P = 0.007). Conclusion: Our meta-analysis shows that n-3 PUFAs can effectively improve the immune function of patients undergoing gastrointestinal cancer surgery, reduce inflammatory response and reduce the length of hospital stay, But it has no significant impact on the incidence of infectious-related complications and the level of nutrient protein.

A Novel Defined Necroptosis-Related miRNAs Signature for Predicting the Prognosis of Colon Cancer.

OBJECTIVE: This study aims at exploring the relationship between necroptosis-related miRNAs and colon cancer prognosis. METHODS: We downloaded the miRNA sequencing data from the TCGA, and eight differentially expressed necroptosis-related miRNAs were screened. Then, we used Cox regression analysis to establish a prediction model of necroptosis-related miRNA. Finally, the prognosis related miRNAs were used to predict the target genes, and functional analysis was used to explore the potential mechanism of these target genes. RESULTS: The miRNA-seq data of 444 COAD cases were downloaded from TCGA. We identified 8 differentially expressed miRNAs (has-miR-16-5p, has-miR-141-3p, has-miR-148a-3p, has-miR-425-5p, has-miR-7-5p, has-miR-223-3p, has-miR-200a-5p, and has-miR-500a-3p), then Cox analysis was performed for determining eight-miRNA signature prognostic biomarkers with obviously different OS. The area under the curve (AUC) of receiver operating characteristic (ROC) curve for predicting 1-, 3-, and 5-year survival were 0.663, 0.653 and 0.639, respectively. The multivariate analysis also implied that the risk score was an independent prognostic factor considering other confounding factors (HR = 1.847, 95% CI = 1.197-2.848, P = 0.006). According to the Kaplan-Meier analysis, the expression of hsa-miR-500a-3p (P = 0.003), hsa-miR-16-5p (P = 0.004) and hsa-miR-148a-3p (P = 0.035) significantly affected OS outcomes. We predicted the target genes of these three miRNAs and then screened 10 hub genes (CCND1, SMAD3, SMAD2, CDK1, TGFB2, CDC25A, CHEK1, VEGFA, CCNE1, WEE1). In addition, CHEK1 was associated with the survival prognosis. CONCLUSION: Our study demonstrated that necroptosis is closely associated with colon cancer, and the model of eight necroptosis-related miRNAs are potentially useful prognostic biomarkers and therapeutic targets for colon cancer.

Prognostic value of the ascites characteristics in pseudomyxoma peritonei originating from the appendix.

Background: Pseudomyxoma peritonei (PMP) is a rare disease, with the overall survival (OS) influenced by many factors. To date, no ascites characteristics have been reported to predict OS of patients with PMP. The present study therefore aims to describe the ascites characteristics for PMP and identify prognostic factors for survival. Methods: Between June 2010 and June 2020, 473 PMP patients who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were included in a retrospective study. Survival analysis was performed with the Kaplan-Meier method by the log-rank test and a Cox proportional hazards model. Associations between categorical variables were analyzed using the chi-squared test. Results: Among all included patients, 61% were women. The median OS was 47 months (range, 4-124 months) at the last follow-up in December 2020. Ascites characteristics can be divided into light blood ascites, "Jelly" mucus ascites, and faint yellow and clear ascites. Multivariate Cox analysis showed that the degree of radical surgery, ascites characteristics, and pathological grade were independently associated with OS in PMP patients. The chi-squared test documented that faint yellow "Jelly" ascites were related to low-grade PMP and light blood ascites were associated with high-grade PMP (P < 0.01). Conclusions: Light blood ascites, incomplete cytoreduction surgery, and high-grade histopathology may predict poor OS in appendix-derived PMP.