In the occurrence and development of colorectal cancer, p53 is an important regulator downstream of the MAPK signaling pathway and plays an important role in inhibiting abnormal proliferation signals generated by KRAS mutations. The purpose of this study is to explore the correlation between KRAS mutations and p53 expression and evaluate their prognosis values in colorectal cancer.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mgg3.1905

Effect of KRAS mutations and p53 expression on the postoperative prognosis of patients with colorectal cancer

The herb pair Astragali Radix (AR) and Curcumae Rhizoma (vinegar-processed, VPCR), derived from the traditional Chinese medicine (TCM) text 'Yixuezhongzhongcanxilu', have long been used to treat gastrointestinal diseases, notably colitis-associated colorectal cancer (CAC). Hedysari Radix (HR), belonging to the same Leguminosae family as AR but from a different genus, is traditionally used as a substitute for AR when paired with VPCR in the treatment of CAC. However, the optimal compatibility ratio for HR-VPCR against CAC and the underlying mechanisms remain unclear.To investigate the optimal compatibility ratio and underlying mechanisms of HR-VPCR against CAC using a combination of comparative pharmacodynamics, network pharmacology, and experimental verification.The efficacy of different compatibility ratios of HR-VPCR against CAC was evaluated using various indicators, including the body weight, colon length, tumor count, survival rate, disease activity index (DAI) score, Haemotoxylin and Eosin (H&E) pathological sections, inflammation cytokines (IL-1β, IL-6, IL-10, TNF-α), tumor markers (K-Ras, p53), and intestinal permeability proteins (claudin-1, E-cadherin, mucin-2). Then, the optimal compatibility ratio of HR-VPCR against CAC was determined based on the fuzzy matter-element analysis by integrating the above indicators. After high-performance liquid chromatography (HPLC) analysis for the optimal compatibility ratio of HR-VPCR, potential active components of HR-VPCR were identified by TCMSP and the previous bibliographies. Swiss Targets and GeneCards were adopted to predict the targets of the active components and the targets of CAC, respectively. Then, the common targets of HR-VPCR against CAC were obtained by Venn analysis. PPI networks were constructed in STRING. GO and KEGG enrichments were visualized by the David database. Finally, the predicted pathway was experimentally validated via Western blot.Various compatibility ratios of HR-VPCR demonstrated notable therapeutic effects to some extent, evidenced by improvements in body weight, colon length, tumor count, pathological symptoms (DAI score), colon and organ indexes, survival rate, and modulation of inflammation factors (IL-1β, IL-6, IL-10, TNF-α), as well as tumor markers (K-Ras, p53), and down-regulation of intestinal permeability proteins (claudin-1, E-cadherin, mucin-2) in CAC mice. Among these ratios, the ratio 4:1 represents the optimal compatibility ratio by the fuzzy matter-element analysis. Thirty active components of HR-VPCR were carefully selected, targeting 553 specific genes. Simultaneously, 2022 targets associated with CAC were identified. 88 common targets were identified after generating a Venn plot. Following PPI network analysis, 29 core targets were established, with AKT1 ranking highest among them. Further analysis via GO and KEGG enrichment identified the PI3K-AKT signaling pathway as a potential mechanism. Experimental validation confirmed that HR-VPCR intervention effectively reversed the activated PI3K-AKT signaling pathway.The optimal compatibility ratio for the HR-VPCR herb pair in alleviating CAC is 4:1. HR-VPCR exerts its effects by alleviating intestinal inflammation, improving intestinal permeability, and regulating the PI3K-AKT signaling pathway. 

Network pharmacology and experimental verification reveal the mechanism of Hedysari Radix and Curcumae Rhizoma with the optimal compatibility ratio against colitis-associated colorectal cancer.

Abstract Intensive uses of Calcium hydroxide (Ca(OH) 2 NPs), calcium titanate (CaTiO 3 NPs) and yttrium oxide (Y 2 O 3 NPs) nanoparticles increase their environmental release and human exposure separately or together through contaminated air, water and food. However, too limited data are available on their genotoxicity. Therefore, this study explored the effect of Ca(OH) 2 NPs, CaTiO 3 NPs or/and Y 2 O 3 NPs administration on the genotoxicityand oxidative stress induction in mice hepatic tissue. Mice were orally administered Ca(OH) 2 NPs, CaTiO 3 NPs and Y 2 O 3 NPs separately or simultaneously together at a dose level of 50 mg/kg b.w. for two successive weeks (3 days per week). Marked induction of DNA damage noticed after oral administration of Ca(OH) 2 NPs or CaTiO 3 NPs alone together with high Ca(OH) 2 NPs induced reactive oxygen species (ROS) generation and a slight CaTiO 3 NPs induced ROS production were highly decreased after simultaneous coadministration of administration of Y 2 O 3 NPs with Ca(OH) 2 NPs and CaTiO 3 NPs up to the negative control level. Oral administration of Y 2 O 3 NPs alone also did not cause observable changes in the genomic DNA integrity and the ROS generation level compared to the negative control levels. Similarly, significant elevations in P53 gene expression and high reductions in Kras and HSP-70 genes expression were observed only after administration of Ca(OH) 2 NPs alone, while, remarkable increases in the Kras and HSP-70 genes expression and non-significant changes in p53 gene expression were noticed after administration of CaTiO 3 NPs and Y 2 O 3 NPs separately or simultaneously together with Ca(OH) 2 NPs. Conclusion: Ca(OH) 2 NPs exhibited the highest genotoxic effect through oxidative stress induction and disruption of apoptotic (p53 and Kras) and protective (HSP-70) genes expression. Slight DNA damage was noticed after CaTiO 3 NPs administration. However, administration of Y 2 O 3 NPs alone was non-genotoxic and coadministration of Y 2 O 3 NPs with Ca(OH) 2 NPs and CaTiO 3 NPs restored genomic DNA integrity and normal expression of apoptotic p53 and protective HSP-70 genes disrupted by Ca(OH) 2 NPs and CaTiO 3 NPs. Thus co-administration of Y 2 O 3 NPs with Ca(OH) 2 NPs and CaTiO 3 NPs is recommended to counter Ca(OH) 2 NPs and CaTiO 3 NPs induced genotoxicity and oxidative stress. 

Genotoxicity and oxidative stress induction by calcium hydroxide, calcium titanate or/and yttrium oxide nanoparticles in mice

Colorectal cancer (CRC) is a heterogeneous disease caused by molecular changes, as driver mutations, gene methylations, etc., and influenced by tumor microenvironment (TME) pervaded with immune cells with both pro- and anti-tumor effects. The studying of interactions between the immune system (IS) and the TME is important for developing effective immunotherapeutic strategies for CRC. In our study, we focused on the analysis of expression profiles of inflammatory and immune-relevant genes to identify aberrant signaling pathways included in carcinogenesis, metastatic potential of tumors, and association of Kirsten rat sarcoma virus (KRAS) gene mutation.A total of 91 patients were enrolled in the study. Using NGS, differential gene expression analysis of 11 tumor samples and 11 matching non-tumor controls was carried out by applying a targeted RNA panel for inflammation and immunity genes containing 475 target genes. The obtained data were evaluated by the CLC Genomics Workbench and R library. The significantly differentially expressed genes (DEGs) were analyzed in Reactome GSA software, and some selected DEGs were used for real-time PCR validation.After prioritization, the most significant differences in gene expression were shown by the genes TNFRSF4, IRF7, IL6R, NR3CI, EIF2AK2, MIF, CCL5, TNFSF10, CCL20, CXCL11, RIPK2, and BLNK. Validation analyses on 91 samples showed a correlation between RNA-seq data and qPCR for TNFSF10, RIPK2, and BLNK gene expression. The top differently regulated signaling pathways between the studied groups (cancer vs. control, metastatic vs. primary CRC and KRAS positive and negative CRC) belong to immune system, signal transduction, disease, gene expression, DNA repair, and programmed cell death.Analyzed data suggest the changes at more levels of CRC carcinogenesis, including surface receptors of epithelial or immune cells, its signal transduction pathways, programmed cell death modifications, alterations in DNA repair machinery, and cell cycle control leading to uncontrolled proliferation. This study indicates only basic molecular pathways that enabled the formation of metastatic cancer stem cells and may contribute to clarifying the function of the IS in the TME of CRC. A precise identification of signaling pathways responsible for CRC may help in the selection of personalized pharmacological treatment.

Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing

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Effect of KRAS mutations and p53 expression on the postoperative prognosis of patients with colorectal cancer