Recently, oxidative stress and inflammatory responses have been shown to directly impact tumor growth and the tumor microenvironment (TME). However, more research is necessary to fully understand the relationship between oxidative stress and inflammatory responses and colorectal cancer (CRC).

The FindCluster algorithm was used to extract CRC Single-cell RNA sequencing (scRNA-seq) data and identify tumor cell groupings. From the MSigDB database, genes associated with oxidative stress and the inflammatory response were taken. We identified molecular subtypes and built a predictive risk model with the LASSO-Cox method using the ConsensusClusterPlus software suite. We incorporated the prognostic risk model and other clinicopathological parameters into a column-line chart. Finally, we used Quantitative Polymerase Chain Reaction (qPCR) and immunohistochemistry to check the expression of the unreported hub model genes. Cell proliferation was assessed using EDU and colony formation assays. Reactive Oxygen Species (ROS) tests were used to quantitatively determine the ROS content in CRC cells. The ability of CRC cells to invade and migrate was examined using transwell experiments. The regulatory functions of hub model genes were discovered in vivo using a xenograft model tumor assay.

Oxidative stress and inflammatory response factors in monocytic/macrophages of CRC were significantly upregulated, and their oxidative stress and inflammatory response functions were significantly higher than those of other cell subgroups, as indicated by the enrichment score. These factors showed significant synergistic overexpression and enrichment in this cell population. We constructed a prognostic risk model consisting of seven signatures. The good and stable prognostic evaluation efficacy of the model was confirmed, and risk scores were determined to be independent prognostic factors for CRC. We explored the relationship between the risk score model and malignant progression of tumor cells, tumor immune microenvironment, genomic variation, chemotherapy resistance, and immune response. Further qPCR and immunohistochemistry analysis showed that the expression of ZNF385A was high in CRC tissues. The functional experiment results indicated that interfering with the expression of ZNF385A could suppress the proliferation, ROS, migration and invasion of SW620 cells in vitro and the growth of xenograft tumors in vivo.

In this study, we investigated the critical expression patterns of oxidative stress- and inflammatory response-related genes in CRC, which may contribute to the prognosis and immunotherapy of CRC. Additionally, we discovered ZNF385A to be a novel oncogene in CRC. These findings imply that this model may be applied to assess prognostic risk and identify potential therapeutic targets for CRC patients.

Colony-stimulating factor 3 (CSF3) is a cytokine that promotes inflammation by stimulating the maturation, proliferation, and trafficking of myeloid progenitor cells. However, the functional importance of CSF3 in colorectal cancer (CRC) remains unclear.

CSF3 expression levels in CRC cells and tissues were detected by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the oncogenic function of CSF3 in the tumor associated malignant phenotypes and the tumorigenic capability of CRC cells. Immunocoprecipitation was performed to verify the regulatory effects of CSF3 on IκBα ubiquitination.

We found that CSF3 was overexpressed in CRC tissues compared to adjacent normal tissues, which correlated with poor patient survival. In vitro, silencing CSF3 significantly impaired cell proliferation, colony formation, and migration, while enhancing apoptosis. In vivo, silencing CSF3 resulted in reduced tumor growth, weight, and volume, indicating its potential as a therapeutic target. Mechanistically, CSF3 was found to mediate CRC development by activating the NF-κB signaling pathway, as evidenced by the decreased phosphorylation of p65 and reduced IκBα ubiquitination in CSF3-silenced cells. Furthermore, CSF3 silencing modulated immune infiltration in CRC, promoting an anti-tumor immune response and altering the tumor microenvironment.

CSF3 modulated the NF-κB signaling pathway through a distinct mechanism involving p65 phosphorylation and the activation of NF-κB by enhancing IκBα ubiquitination, thereby effectively promoting CRC development, and CSF3 may serve as a potential therapeutic target for repressing CRC advance and metastasis.

Periodontitis is an inflammatory disease, and contributes to several inflammatory conditions, such as cancer. The relationship between periodontal disorders and different human malignancies is not well understood. The purpose of this study is to assess the association of periodontitis severity with cancers in the oral cavity, oropharyngeal and parapharyngeal regions.

The sample comprised 300 participants divided into four case groups: 75 oral, oropharyngeal, or parapharyngeal cancer patients with periodontitis (CA-with-P); 75 oral, oropharyngeal, or parapharyngeal cancer patients without periodontitis (CA-without-P); 75 periodontitis (P) patients without cancers; and a control (C) group of 75 healthy individuals. All participants were subjected to a periodontal examination that considered parameters such as bleeding on probing (BOP), plaque index (PI), probing pocket depth (PPD), and clinical attachment loss (CAL). The type of tumours was identified via a histological analysis of a biopsy sample. Saliva samples were also collected, and an enzyme-linked immunosorbent assay (ELISA) kit was used to determine interleukin 8 (IL-8) and nuclear factor kappa B (NF-κB) levels.

The research findings indicated a significant increase in the number of sites with clinical observations of BOP (85.11,73.84), PI (87.23.88.14), PPD (8.03,6.82), and CAL (8.67,7.34) in groups CA-with-P and P. The CA-with-P, CA-without-P, and P groups had higher levels of salivary IL-8 (192.03, 121.89,89.22) and NF-κB (10.242, 8.172, 6.324) than the C group. Moreover, there was a significant correlation between the severity of periodontitis and the malignancies in the oral, oropharynx, and parapharyngeal regions.

This study assessed the mechanisms underlying the correlation between these two disorders, as elucidated by higher levels of salivary IL-8, NF-κB and an increase in clinical periodontal parameters. Periodontal bacteria, which contributes to the development of periodontal disorders, could have a major impact on the onset of oral cancers.

Colorectal cancer (CRC) is a prevalent malignant tumor of the digestive tract. Traditional Chinese medicine (TCM) has a long history of treating CRC, with advantages such as effectiveness, multi-target, multi-pathway, and minimal side effects. TCM Magnolia officinalis (M. officinalis) refers to the dried bark, root bark, and branch bark of either Magnolia officinalis Rehd.et Wils. or Magnolia officinalis Rehd.et Wils. var. biloba Rehd.et Wils. It is commonly utilized to alleviate the side effects of chemotherapy for CRC, owing to its anti-inflammatory and anti-tumor properties. However, current research primarily focuses on the individual components and does not take into consideration the characteristics of multi-component-multi-target action.

Our aim is to study the new action characteristics of M. officinalis in the treatment of CRC.

Utilizing network pharmacology to identify potential active ingredients, key targets, and main signaling pathways of M. officinalis for the treatment of CRC. The binding effect was further validated through molecular docking analysis. Furthermore, the aforementioned components were identified using liquid chromatography-mass spectrometry (LC-MS), and the cleavage pathways of the main components were analyzed. Subsequently, both in vitro and in vivo experiments were carried out to investigate the anti-CRC effect of the active ingredients of M. officinalis and its potential mechanism.

Network pharmacology and Molecular docking identified 5 main active ingredients and 6 core targets of M. officinalis for the treatment of CRC. Then, LC-MS identified the active components of M. officinalis. At the same time, both in vitro and in vivo experiments have confirmed the ability of Eucalyptol (Euc) and Obovatol (Obo)to inhibit inflammation and tumor cell proliferation. The possible mechanism involved is that Euc and Obo counteract CRC by inhibiting the over-activation of NF-κBp65/JAK and Bcl-2/Caspase signaling pathways, respectively. They also play a role in the anti-CRC effect of M. officinalis.

Magnolol (MAG), Honokiol (HK), Euc, Obo, and Neohesperidin (NHP) in M. officinalis may be the pharmacological substance basis for its anti-cancer effect on CRC. The treatment of CRC with M. officinalis is characterized by its multi-component, multi-target, and multi-pathway approach. These findings provide a theoretical basis for further inspiring the clinical application of M. officinalis and the development of efficacy targets.

Despite advances in targeted therapies, primary and acquired resistance make the treatment of colorectal cancer (CRC) a pressing issue to be resolved. According to reports, the development of CRC is linked to miRNA dysregulation. Multiple studies have demonstrated that miR-135b-5p has an aberrant expression level between CRC tissues and adjacent tissues. However, it is unclear whether there is a correlation between miR-135b-5p and cetuximab (CTx) resistance in CRC. Use the GEO database to measure miR-135b-5p expression in CRC. Additionally, RT-qPCR was applied to ascertain the production level of miR-135b-5p in three human CRC cells and NCM460 cells. The capacity of cells to migrate and invade was examined utilizing the wound-healing and transwell assays, while the CCK-8 assay served for evaluating cell viability, as well as colony formation assays for proliferation. The expected target protein of miR-135b-5p in CRC cell cetuximab resistance has been investigated using western blot. Suppression of miR-135b-5p could increase the CTx sensitivity of CTx-resistant CRC cells, as manifested by the attenuation of proliferation, migration, and invasion ability. Mechanistic studies revealed miR-135b-5p regulates the epithelial-to-mesenchymal transition (EMT) process and Wnt/β-catenin signaling pathway through downgulating FOXN3. In short, knockdowning miR-135b-5p could increase FOXN3 expression in CRC cells, promote the EMT process, and simultaneously activate the Wnt/β-catenin signaling pathway to elevate CTx resistance in CRC cells.

Background: Gegen Qinlian Decoction (GQD), is used for intestinal disorders like ulcerative colitis, irritable bowel syndrome, and colorectal cancer. But the precise mechanisms underlying its anti-inflammatory and anti-tumor effects are not fully elucidated. Methods: Use network pharmacology to identify targets and pathways of GQD. In vivo (azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colorectal cancer (CAC) mouse model) and in vitro (lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages) experiments were conducted to explore GQD's anti-inflammatory and anti-tumor effects. We monitored mouse body weight and disease activity index (DAI), and evaluated colon cancer tissues using hematoxylin and eosin staining. Expression of Ki67 and F4/80 was determined by immunohistochemistry analysis. The protein levels of TLR4 signaling pathway were assessed by western blotting analysis. Enzyme-linked immunosorbent assay measured IL-1β, IL-6, and TNF-α levels. Immunofluorescence (IF) staining visualized NF-κB and IRF3 translocation. Results: There were 18, 9, 24 and 77 active ingredients in the four herbs of GQD, respectively, targeting 435, 156, 485 and 691 genes. Through data platform analysis, it was concluded that there were 1104 target genes of GQD and 2022 target genes of CAC. Moreover, there were 99 intersecting genes between GQD and CAC. The core targets of GQD contained NFKB1, IL1B, IL6, TLR4, and TNF, and GQD reduced inflammation by inhibiting the TLR4 signaling pathway. In vivo experiment, GQD increased mouse body weight, lowered DAI scores, while also alleviating histopathological changes in the colon and decreasing the expressions of Ki67 and F4/80 in the AOM/DSS-induced mice. GQD reduced IL-1β, IL-6, and TNF-α levels in the serum and downregulated TLR4, MyD88, and phosphorylation of IκBα, P65, and IRF3 in the colon tissue from AOM/DSS-induced mice. In vitro, GQD suppressed pro-inflammatory cytokines and TLR4 signaling pathway in the LPS-induced RAW264.7 cells, and combined with TAK242, it further reduced the phosphorylation of IκBα, P65. Conclusions: GQD mitigated CAC by inhibiting the TLR4 signaling pathway, offering a potential therapeutic approach for CAC management.

Colorectal cancer (CRC) is currently ranked as the third most common type of cancer, contributing significantly to mortality and morbidity worldwide. Epigenetic and genetic changes occurred during CRC progression resulted in the cell proliferation, cancer progression, angiogenesis, and invasion. Angiogenesis is one of the crucial steps during cancer progression required for the delivery of essential nutrients to cancer cells and removes metabolic waste. During angiogenesis, different molecules are secreted from tumoral cells to trigger vascular formation including epidermal growth factor and the vascular endothelial growth factor (VEGF). The production and regulation of the secretion of these molecules are modulated by different subcellular pathways such as NF-κB. NF-κB is involved in regulation of different homeostatic pathways including apoptosis, cell proliferation, inflammation, differentiation, tumor migration, and angiogenesis. Investigation of different aspects of this pathway and its role in angiogenesis could provide a comprehensive overview about the underlying mechanisms and could be used for development of further therapeutic targets. In this review of literature, we comprehensively reviewed the current understanding and potential of NF-κB-related angiogenesis in CRC. Moreover, we explored the treatments that are based on the NF-κB pathway.

Dysregulation of alternative pre-mRNA splicing plays a critical role in the progression of cancers, yet the underlying molecular mechanisms remain largely unknown. It is reported that metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic and predictive marker in many types of cancers, including lung adenocarcinoma. Here, we reveal that the oncogene MACC1 specifically drives the progression of lung adenocarcinoma through its control over cancer-related splicing events. MACC1 depletion inhibits lung adenocarcinoma progression through triggering IRAK1 from its long isoform, IRAK1-L, to the shorter isoform, IRAK1-S. Mechanistically, MACC1 interacts with splicing factor HNRNPH1 to prevent the production of the short isoform of IRAK1 mRNA. Specifically, the interaction between MACC1 and HNRNPH1 relies on the involvement of MACC1's SH3 domain and HNRNPH1's GYR domain. Further, HNRNPH1 can interact with the pre-mRNA segment (comprising exon 11) of IRAK1, thereby bridging MACC1's regulation of IRAK1 splicing. Our research not only sheds light on the abnormal splicing regulation in cancer but also uncovers a hitherto unknown function of MACC1 in tumor progression, thereby presenting a novel potential therapeutic target for clinical treatment.

Mesenchymal stem cells (MSCs) may play a pivotal role in shaping the tumor microenvironment (TME), influencing tumor growth. Nonetheless, conflicting evidence exists regarding the distinct impacts of MSCs on tumor progression, with some studies suggesting promotion while others indicate suppression of tumor cell growth. Considering that oxidative stress is implicated in the dynamic interaction between components of the TME and tumor cells, we investigated the contribution of exosomes released by hydrogen peroxide (H2O2)-treated MSCs to murine mammary tumor growth and progression. Additionally, we aimed to identify the underlying mechanism through which MSC-derived exosomes affect breast tumor growth and angiogenesis. Our findings demonstrated that exosomes released by H2O2-treated, stress-induced MSCs (St-MSC Exo) promoted breast cancer cell progression by inducing the expression of vascular endothelial growth factor (VEGF) and markers associated with epithelial-to-mesenchymal transition. Further clarification revealed that the promoting effect of St-MSC Exo on VEGF expression may, in part, depend on activating STAT3 signaling in BC cells. In contrast, exosomes derived from untreated MSCs retarded JAK1/STAT3 phosphorylation and reduced VEGF expression. Additionally, our observations revealed that the activation of the transcription factor NF-κB in BC cells, stimulated with St-MSC Exo, occurs concurrently with an increase in intracellular ROS production. Moreover, we observed that the increase in VEGF secretion into the conditioned media of 4T1 BC, mediated by St-MSC Exo, positively influenced endothelial cell proliferation, migration, and vascular behavior in vitro. In turn, our in vivo studies confirmed that St-MSC Exo, but not exosomes derived from untreated MSCs, exhibited a significant promoting effect on breast tumorigenicity. Collectively, our findings provide new insights into how MSCs may contribute to modulating the TME. We propose a novel mechanism through which exosomes derived from oxidative stress-induced MSCs may contribute to tumor progression and angiogenesis.

Colorectal cancer (CRC) remains a significant global health challenge, ranking third in incidence and second in mortality among all cancers [...].

Pathway analysis is a crucial analytical phase in disease research on single-cell RNA sequencing (scRNA-seq) data, offering biological interpretations based on prior knowledge. However, currently available tools for generating cell-level pathway activity scores (PAS) exhibit computational inefficacy in large-scale scRNA-seq datasets. Additionally, disease-related pathways are often identified through cross-condition comparisons within specific cell types, overlooking potential patterns that involve multiple cell types. Here, we present single-cell pathway activity factor analysis (scPAFA), a Python library designed for large-scale single-cell datasets allowing rapid PAS computation and uncovering biologically interpretable disease-related multicellular pathway modules, which are low-dimensional representations of disease-related PAS alterations in multiple cell types. Application on colorectal cancer (CRC) datasets and large-scale lupus atlas over 1.2 million cells demonstrated that scPAFA can achieve over 40-fold reductions in the runtime of PAS computation and further identified reliable and interpretable multicellular pathway modules that capture the heterogeneity of CRC and transcriptional abnormalities in lupus patients, respectively. Overall, scPAFA presents a valuable addition to existing research tools in disease research, with the potential to reveal complex disease mechanisms and support biomarker discovery at the pathway level.

Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.

Nuclear factor kappa-B (NF-κB) is a nuclear transcription factor that plays a key factor in promoting inflammation, which can lead to the development of cancer in a long-lasting inflammatory environment. The activation of NF-κB is essential in the initial phases of tumor development and progression, occurring in both pre-malignant cells and cells in the microenvironment such as phagocytes, T cells, and B cells. In addition to stimulating angiogenesis, inhibiting apoptosis, and promoting the growth of tumor cells, NF-κB activation also causes the epithelial-mesenchymal transition, and tumor immune evasion. Therapeutic strategies that focus on immune checkpoint molecules have revolutionized cancer treatment by enabling the immune system to activate immunological responses against tumor cells. This review focused on understanding the NF-κB signaling pathway in the context of cancer.

In the colorectal cancer (CRC) niche, the transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are hyperactivated in both malignant cells and tumor-infiltrating leukocytes (TILs) and cooperate to maintain cancer cell proliferation/survival and drive protumor inflammation. Through drug repositioning studies, the anthelmintic drug rafoxanide has recently emerged as a potent and selective antitumor molecule for different types of cancer, including CRC. Here, we investigate whether rafoxanide could negatively modulate STAT3/NF-κB and inflammation-associated CRC. The antineoplastic effect of rafoxanide was explored in a murine model of CRC resembling colitis-associated disease. Cell proliferation and/or STAT3/NF-κB activation were evaluated in colon tissues taken from mice with colitis-associated CRC, human CRC cells, and CRC patient-derived explants and organoids after treatment with rafoxanide. The STAT3/NF-κB activation and cytokine production/secretion were assessed in TILs isolated from CRC specimens and treated with rafoxanide. Finally, we investigated the effects of TIL-derived supernatants cultured with or without rafoxanide on CRC cell proliferation and STAT3/NF-κB activation. The results showed that rafoxanide restrains STAT3/NF-κB activation and inflammation-associated colon tumorigenesis in vivo without apparent effects on normal intestinal cells. Rafoxanide markedly reduces STAT3/NF-κB activation in cultured CRC cells, CRC-derived explants/organoids, and TILs. Finally, rafoxanide treatment impairs the ability of TILs to produce protumor cytokines and promote CRC cell proliferation. We report the novel observation that rafoxanide negatively affects STAT3/NF-κB oncogenic activity at multiple levels in the CRC microenvironment. Our data suggest that rafoxanide could potentially be deployed as an anticancer drug in inflammation-associated CRC.

Chronic inflammation is a significant driver in the development of various diseases, including cancer. Colitis-associated colorectal cancer (CA-CRC) refers to the increased risk of colorectal cancer in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease.

This narrative review examines the link between chronic inflammation and CA-CRC. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, focusing on studies published between 2000 and 2024. Studies were selected based on relevance to the role of inflammation in CA-CRC, specifically targeting molecular pathways and clinical implications. Both clinical and mechanistic studies were reviewed.

Sustained inflammation in the colon fosters a pro-tumorigenic environment, leading to the initiation and progression of CA-CRC. Prevention strategies must focus on controlling chronic inflammation, optimizing IBD management, and implementing regular screenings. Emerging therapies targeting key inflammatory pathways and immune responses, along with microbiome modulation, hold promise for reducing CA-CRC risk. Understanding these molecular mechanisms provides a path toward personalized treatment and better outcomes for patients with IBD at risk of colorectal cancer.

Clear cell renal cell carcinoma (ccRCC) arises from the renal parenchymal epithelium and is the predominant malignant entity of renal cancer, exhibiting increasing incidence and mortality rates over time. SEC14-like 3 (SEC14L3) has emerged as a compelling target for cancer intervention; nevertheless, the precise clinical implications and molecular underpinnings of SEC14L3 in ccRCC remain elusive.

By leveraging clinical data and data from the TCGA-ccRCC and GEO datasets, we investigated the association between SEC14L3 expression levels and overall survival rates in ccRCC patients. The biological role and mechanism of SEC14L3 in ccRCC were investigated via in vivo and in vitro experiments. Moreover, siRNA-SEC14L3@PDA@MUC12 nanoparticles (SSPM-NPs) were synthesized and assessed for their therapeutic potential against SEC14L3 through in vivo and in vitro assays.

Our investigation revealed upregulated SEC14L3 expression in ccRCC tissues, and exogenous downregulation of SEC14L3 robustly suppressed the malignant traits of ccRCC cells. Mechanistically, knocking down SEC14L3 facilitated the ubiquitination-mediated degradation of ribosomal protein S3 (RPS3) and augmented IκBα accumulation in ccRCC. This concerted action thwarted the nuclear translocation of P65, thereby abrogating the activation of the nuclear factor kappa B (NFκB) signaling pathway and impeding ccRCC cell proliferation and metastasis. Furthermore, diminished SEC14L3 levels exerted a suppressive effect on NFKB1 expression within the NFκB signaling cascade. NFKB1 functions as a transcriptional regulator capable of binding to the SEC14L3 enhancer and promoter, thereby promoting SEC14L3 expression. Consequently, the inhibition of SEC14L3 expression was further potentiated, thus forming a positive feedback loop. Additionally, we observed that downregulation of SEC14L3 significantly increased the sensitivity of ccRCC cells to sunitinib. The evaluation of SSPM-NPs nanotherapy highlighted its effectiveness in combination with sunitinib for inhibiting ccRCC growth.

Our findings not only underscore the promise of SEC14L3 as a therapeutic target but also unveil an SEC14L3/RPS3/NFκB positive feedback loop that curtails ccRCC progression. Modulating SEC14L3 expression to engage this positive feedback loop might herald novel avenues for ccRCC treatment.

Despite significant advancements in chemotherapy, effective treatments for advanced cancer stages remain largely elusive due to chemoresistance. Resistance to anticancer agents in cancer cells can arise through various mechanisms, including multi-drug resistance, inhibition of apoptosis, modification of drug targets, and enhancement of DNA repair capabilities. Consequently, there is a critical need for agents that can suppress the molecular signatures responsible for drug resistance. Piperine, an active alkaloid extracted from Piper nigrum L. (black pepper), is one such agent that has been extensively studied for its potential in addressing chronic diseases, including cancer. Piperine's antineoplastic properties are mediated through the regulation of numerous key cellular signaling pathways and the modulation of various biological processes. Its capability to enhance drug bioavailability and counteract mechanisms of drug resistance, such as the inhibition of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP-1), emphasizes its potential as an adjunct in cancer therapy. Research across various cancer types has demonstrated piperine's role in chemosensitization by targeting P-gp and MRP-1 and altering drug-metabolizing enzymes. This review provides a comprehensive analysis of piperine's pharmacological characteristics and its capacity to modulate several cellular signaling pathways involved in drug resistance. Furthermore, the review emphasizes how piperine, when used in conjunction with other chemotherapeutic agents or natural compounds, can enhance therapeutic effects, leading to improved outcomes in cancer treatment.

Transforming growth factor β-activated protein kinase-1 (TAK1) plays an important role in MAPK and NFκB pathways and has been associated with colorectal cancer. The aim of this study was to determine how cytoplasmic and juxtanuclear punctate staining of TAK1 relates to immune checkpoint expression and cancer specific survival in colorectal cancer.

Protein expression was assessed by immunohistochemistry on tissue microarrays from primary curative colorectal cancer resected specimens. Expression levels of cytoplasmic TAK1 by QuPath digital quantification and punctate TAK1 staining was scored using a manual point scoring technique and correlated with clinicopathological features, immune checkpoint expression and cancer-specific survival. Bulk RNA sequencing was performed in specimens to determine mutational profiles and differentially expressed genes.

A cohort of 875 patients who had undergone colorectal cancer resection were assessed for TAK1 expression. Higher levels of cytoplasmic TAK1 expression correlated with elevated PD1 and PD-L1 expression (p < 0.010). High punctate TAK1 expression was more commonly identified in poorly differentiated colorectal cancers (p = 0.036), had dysregulated mutational and transcriptional profiles with decreased insulin-like growth factor 2(IGF2) expression (p < 0.010), and independently predicted poor cancer-specific survival (HR 2.690, 95% CI 1.419-5.100, p = 0.002). The association of punctate TAK1 expression and recurrence remained after subgroup analysis for microsatellite-stable colorectal cancer (p = 0.028).

Punctate TAK1 expression is associated with worse cancer specific survival. TAK1 signalling may be an important pathway to investigate underlying mechanisms for recurrence in microsatellite-stable colorectal cancer.

Colorectal cancer (CRC) remains a significant global health challenge, with barriers to effective prevention and treatment including tumor recurrence, chemoresistance, and limited overall survival rates. Anthocyanins, known for their strong anti-cancer properties, have shown promise in preventing and suppressing various cancers, including CRC. However, natural sources of anthocyanins often fail to provide sufficient quantities needed for therapeutic effects. Bioengineered crops, particularly anthocyanin-enriched tomatoes, offer a viable solution to enhance anthocyanin content. Given its large-scale production and consumption, tomatoes present an ideal target for bioengineering efforts aimed at increasing dietary anthocyanin intake. This review provides an overview of anthocyanins and their health benefits, elucidating the mechanisms by which anthocyanins modulate the transcription factors involved in CRC development. It also examines case studies demonstrating the successful bioengineering of tomatoes to boost anthocyanin levels. Furthermore, the review discusses the effects of anthocyanin extracts from bioengineered tomatoes on CRC prevention, highlighting their role in altering metabolic pathways and reducing tumor-related inflammation. Finally, this review addresses the challenges associated with bioengineering tomatoes and proposes future research directions to optimize anthocyanin enrichment in tomatoes.

Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.

Colon cancer is the third most common cancer worldwide, with high mortality. Adverse side effects and chemoresistance of the first-line chemotherapy 5-fluorouracil (5-FU) have promoted the widespread use of combination therapies. Thymoquinone (TQ) is a natural compound with potent antioxidant activity. Loading antioxidants into nano delivery systems has been a major advance in enhancing their bioavailability to improve clinical application. Hence, this study aimed to prepare the optimal TQ-loaded calcium carbonate nanoparticles (TQ-CaCO3 NPs) and investigate their therapeutic potential and underlying molecular mechanisms of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Firstly, we developed purely aragonite CaCO3 NPs with a facile mechanical ball-milling method. The pH-sensitive and biocompatible TQ-CaCO3 NPs with sustained release properties were prepared using the optimal synthesized method (a high-speed homogenizer). The in vitro study revealed that the combination of TQ-CaCO3 NPs (15 μM) and 5-FU (7.5 μM) inhibited CT26 cell proliferation and migration, induced cell apoptosis and cell cycle arrest in the G0/G1 phase, and suppressed the CT26 spheroid growth, exhibiting a synergistic effect. Finally, network pharmacology and molecular docking results indicated the potential targets and crucial signaling pathways of TQ-CaCO3 NPs in combination with 5-FU against colon cancer. Therefore, TQ-CaCO3 NPs combined with 5-FU could enhance the anti-colon cancer effects of 5-FU with broader therapeutic targets, warranting further application for colon cancer treatment.

Colorectal cancer (CRC) continues to be a significant contributor to global morbidity and mortality. Emerging evidence indicates that disturbances in gut microbial composition, the formation of reactive oxygen species (ROS), and the resulting inflammation can lead to DNA damage, driving the pathogenesis and progression of CRC. Notably, bacterial metabolites can either protect against or contribute to oxidative stress by modulating the activity of antioxidant enzymes and influencing signaling pathways that govern ROS-induced inflammation. Additionally, microbiota byproducts, when supplemented through probiotics, can affect tumor microenvironments to enhance treatment efficacy and selectively mediate the ROS-induced destruction of CRC cells. This review aims to discuss the mechanisms by which taxonomical shifts in gut microbiota and related metabolites such as short-chain fatty acids, secondary bile acids, and trimethylamine-N-oxide influence ROS concentrations to safeguard or promote the onset of inflammation-mediated CRC. Additionally, we focus on the role of probiotic species in modulating ROS-mediated signaling pathways that influence both oxidative status and inflammation, such as Nrf2-Keap1, NF-κB, and NLRP3 to mitigate carcinogenesis. Overall, a deeper understanding of the role of gut microbiota on oxidative stress may aid in delaying or preventing the onset of CRC and offer new avenues for adjunct, CRC-specific therapeutic interventions such as cancer immunotherapy.

Polyphenols are plant metabolites with potential anti-inflammatory and anti-proliferative effects, which may be advantageous for disorders like colorectal cancer (CRC). Despite promising in vitro and in vivo evidence, human clinical trials have yielded mixed results. The present study aimed to evaluate the clinical evidence of polyphenols for CRC prevention or treatment. A systematic review was performed according to PRISMA. Based on a PROSPERO registered protocol (CRD42024560044), online databases (PubMed and COCHRANE) were utilized for the literature search. A total of 100 studies articles were initially identified. After reviewing, 12 studies with a low risk of bias were selected, examining the effect of a variety of compounds. Curcumin demonstrated promise in various trials, mainly decreasing inflammatory cytokines, though results varied, and it did not lower intestinal adenomas or improve outcomes after chemotherapy. Neither epigallocatechin gallate nor artepillin C reduced the incidence of adenomas. Finally, fisetin seemed to improve the inflammatory status of patients under chemotherapy (5-fluorouracil). In summary, although certain polyphenols appear to exert some effect, their role in the prevention or treatment of CRC is inconclusive, and more clinical studies under more controlled conditions are needed.

Inflammatory bowel diseases (IBD) remain challenging in terms of understanding their causes and in terms of diagnosing, treating, and monitoring patients. Modern diagnosis combines biomarkers, imaging, and endoscopic methods. Common biomarkers like CRP and fecal calprotectin, while invaluable tools, have limitations and are not entirely specific to IBD. The limitations of existing markers and the invasiveness of endoscopic procedures highlight the need to discover and implement new markers. With an ideal biomarker, we could predict the risk of disease development, as well as the possibility of response to a particular therapy, which would be significant in elucidating the pathogenesis of the disease. Recent research in the fields of machine learning, proteomics, epigenetics, and gut microbiota provides further insight into the pathogenesis of the disease and is also revealing new biomarkers. New markers, such as BAFF, PGE-MUM, oncostatin M, microRNA panels, αvβ6 antibody, and S100A12 from stool, are increasingly being identified, with αvβ6 antibody and oncostatin M being potentially close to being presented into clinical practice. However, the specificity of certain markers still remains problematic. Furthermore, the use of expensive and less accessible technology for detecting new markers, such as microRNAs, represents a limitation for widespread use in clinical practice. Nevertheless, the need for non-invasive, comprehensive markers is becoming increasingly important regarding the complexity of treatment and overall management of IBD.

Ferroptosis induces significant changes in mitochondrial morphology, including membrane condensation, volume reduction, cristae alteration, and outer membrane rupture, affecting mitochondrial function and cellular fate. Recent reports have described the intrinsic cellular iron metabolism and its intricate connection to ferroptosis, a significant kind of cell death characterized by iron dependence and oxidative stress regulation. Furthermore, updated molecular insights have elucidated the significance of mitochondria in ferroptosis and its implications in various cancers. In the context of cancer therapy, understanding the dual role of anastasis and ferroptosis in chemoresistance is crucial. Targeting the molecular pathways involved in anastasis may enhance the efficacy of ferroptosis inducers, providing a synergistic approach to overcome chemoresistance. Research into how DNA damage response (DDR) proteins, metabolic changes, and redox states interact during anastasis and ferroptosis can offer new insights into designing combinatorial therapeutic regimens against several cancers associated with stemness. These treatments could potentially inhibit anastasis while simultaneously inducing ferroptosis, thereby reducing the likelihood of cancer cells evading death and developing resistance to chemotherapy. The objective of this study is to explore the intricate interplay between anastasis, ferroptosis, EMT and chemoresistance, and immunotherapeutics to better understand their collective impact on cancer therapy outcomes. We searched public research databases including google scholar, PubMed, relemed, and the national library of medicine related to this topic. In this review, we discussed the interplay between the tricarboxylic acid cycle and glycolysis implicated in modulating ferroptosis, adding complexity to its regulatory mechanisms. Additionally, the regulatory role of reactive oxygen species (ROS) and the electron transport chain (ETC) in ferroptosis has garnered significant attention. Lipid metabolism, particularly involving GPX4 and System Xc- plays a significant role in both the progression of ferroptosis and cancer. There is a need to investigate the intricate interplay between anastasis, ferroptosis, and chemoresistance to better understand cancer therapy clinical outcomes. Integrating anastasis, and ferroptosis into strategies targeting chemoresistance and exploring its potential synergy with immunotherapy represent promising avenues for advancing chemoresistant cancer treatment. Understanding the intricate interplay among mitochondria, anastasis, ROS, and ferroptosis is vital in oncology, potentially revolutionizing personalized cancer treatment and drug development.

Colorectal cancer (CRC) is a common and deadly tumor. FK506-binding protein 5 (FKBP5) is associated with some cancers, but the role of FKBP5 in CRC is not clear. The present study aimed to reveal the relationship between FKBP5 and CRC and to uncover the roles of FK506 in CRC. In total, 96 CRC patients were recruited. Survival analysis was conducted using the Kaplan-Meier method and COX regression analyses. Bioinformatics analyses were performed to explore the functions of FKBP5. The mechanisms of FKBP5 and the roles of FK506 in CRC progression were clarified by immunohistochemistry, MTS, scratch assay, transwell and flow cytometric analyses via in vitro and in vivo experiments. FKBP5 was overexpressed in 77 cancer tissues compared to that in matched normal tissues, and the overall survival rate of these patients was relatively shorter. Bioinformatics analyses showed that FKBP5 regulates proliferation, invasion, migration, epithelial-mesenchymal transition and nuclear factor-kappa B (NF-κB) signaling. The upregulation or downregulation of FKBP5 dramatically increases or decreases the proliferation, invasion and migration abilities of CRC cells. The expression of NF-κB, inhibitor B kinase α, matrix metalloproteinase-2 and metalloproteinase-9 positively correlated with FKBP5. FK506 inhibits the progression of CRC via the FKBP5/NF-κB signaling pathway. Our study identified a regulatory role for FKBP5 in CRC progression. Therefore, targeting FKBP5 may provide a novel treatment approach for CRC. FK506 can inhibit the progression of CRC by restraining the FKBP5/NF-κB signaling pathway and is expected to become a new drug for the treatment of CRC.

The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway's overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKβ, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKβ inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC.

Colorectal cancer (CRC) ranks as the third most prevalent malignancy worldwide. Despite the gradual expansion of therapeutic options for CRC, its clinical management remains a formidable challenge. And, because of the current dearth of technical means for early CRC screening, most patients are diagnosed at an advanced stage. Therefore, it is imperative to develop novel diagnostic and therapeutic tools for this disease. N6-methyladenosine (m6A), the predominant RNA modification in eukaryotes, can be recognized by m6A-specific methylated reading proteins to modulate gene expression. Studies have revealed that CRC disrupts m6A homeostasis through various mechanisms, thereby sustaining aberrant signal transduction and promoting its own progression. Consequently, m6A-based diagnostic and therapeutic strategies have garnered widespread attention. Although utilizing m6A as a biomarker and drug target has demonstrated promising feasibility, existing observations primarily stem from preclinical models; henceforth necessitating further investigation and resolution of numerous outstanding issues.

Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since tumor development and chronic inflammation are linked, sharing common signaling pathways. At least 20% of breast and colorectal cancers are associated with chronic inflammation triggered by infections, irritants, or autoimmune diseases. Obesity, chronic inflammation, and cancer interconnection underscore the importance of population-based interventions in maintaining healthy body weight, to disrupt this axis. Given that the dietary inflammatory index is correlated with an increased risk of cancer, adopting an anti-inflammatory diet supplemented with nutraceuticals may be useful for cancer prevention. Natural products and their derivatives offer promising antitumor activity with favorable adverse effect profiles; however, the development of natural bioactive drugs is challenging due to their variability and complexity, requiring rigorous research processes. It has been shown that combining anti-inflammatory products, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins, with plant-derived products demonstrate clinical utility as accessible adjuvants to traditional therapeutic approaches, with known safety profiles. Pharmacological approaches targeting multiple proteins involved in inflammation and cancer pathogenesis emerge as a particularly promising option. Given the systemic and multifactorial nature of inflammation, comprehensive strategies are essential for long term success in cancer therapy. To gain insights into carcinogenic phenomena and discover diagnostic or clinically relevant biomarkers, is pivotal to understand genetic variability, environmental exposure, dietary habits, and TME composition, to establish therapeutic approaches based on molecular and genetic analysis. Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type compounds as potential therapeutic targets or biomarkers requires further investigation. This review aims to elucidate the role of specific etiological agents and mediators contributing to persistent inflammatory reactions in tumor development. It explores potential therapeutic strategies for cancer treatment, emphasizing the urgent need for cost-effective approaches to address cancer-associated inflammation.

This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T-cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 blockade-based immunotherapy. In conclusion, the facilitated NFKB2-STAT2/PD-L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.

Toll-like receptors (TLRs) are implicated in the pathogenesis and progression of inflammation-associated cancers, except their role in regulating innate immunity. Specifically, a berrant expression of TLR6 has been observed in colorectal cancers (CRC). However, the effect of abnormal TLR6 expression on CRC remians unclear. Therefore, the present study evaluated TLR6 expression in CRC, its effect on CRC proliferation, and its underlying mechanism.

The expression of TLR6 in CRC was assessed using data from TCGA, GTEx, and HPA datasets and immunohistochemical assays of tumor tissues from patients with CRC. In human CRC cell lines, TLR6 signaling was activated using the TLR6 agonist Pam2CSK4 and was blocked using antiTLR6-IgG; subsequently, cell growth, migration, invasion, cell cycle, and apoptosis were compared in CRC cells. The levels of the anti-apoptotic protein Bcl-2 and the apoptotic protein Bax were identified using western blotting. In addition, the effect of TLR6 knockdown by shRNAs in CRC cells was observed both in vitro and in vivo. Nuclear factor κB (NF-κB) level was evaluated using immunofluorescence and western bolt.

TLR6 expression was significantly downregulated in CRC tissues. The activation of TLR6 by Pam2CSK4 (100 pg/mL to 10 ng/mL) inhibited the proliferation of CRC cells. Compared with blocking TLR6 signaling using antiTLR6-IgG, activating TLR6 signaling significantly inhibited CRC cell growth, migration, and invasion as well as decreased the proportion of cells in the S and G2/M phases and promoted apoptosis. Furthermore, the knockdown of TLR6 by shRNA promoted the biological activity of CRC cells both in vitro and in vivo. Moreover, the activation of TLR6 signaling by Pam2CSK4 significantly downregulated NF-κB and Bcl-2 levels but upregulated Bax levels.

The findings of this study demonstrate that TLR6 may play a inhibitive role in CRC tumorigenesis by suppressing the activity of NF-κB signaling.

The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.

The DNA repair gene PARP1 and NF-κB signalling pathway affect the metastasis of breast cancer by influencing the drug resistance of cancer cells. Therefore, this study focused on the value of the DNA repair gene PARP1 and NF-κB pathway proteins in predicting the postoperative metastasis of breast cancer. A nested case‒control study was performed. Immunohistochemical methods were used to detect the expression of these genes in patients. ROC curves were used to analyse the predictive effect of these factors on distant metastasis. The COX model was used to evaluate the effects of PARP1 and TNF-α on distant metastasis. The results showed that the expression levels of PARP1, IKKβ, p50, p65 and TNF-α were significantly increased in the metastasis group (P < 0.001). PARP1 was correlated with IKKβ, p50, p65 and TNF-α proteins (P < 0.001). There was a correlation between IKKβ, p50, p65 and TNF-α proteins (P < 0.001). ROC curve analysis showed that immunohistochemical scores for PARP1 of > 6, IKKβ of > 4, p65 of > 4, p50 of > 2, and TNF-α of > 4 had value in predicting distant metastasis (SePARP1 = 78.35%, SpPARP1 = 79.38%, AUCPARP1 = 0.843; Sep50 = 64.95%, Spp50 = 70.10%, AUCp50 = 0.709; SeTNF-α = 60.82%, SpTNF-α = 69.07%, AUCTNF-α = 0.6884). Cox regression analysis showed that high expression levels of PARP1 and TNF-α were a risk factor for distant metastasis after breast cancer surgery (RRPARP1 = 4.092, 95% CI 2.475-6.766, P < 0.001; RRTNF-α = 1.825, 95% CI 1.189-2.799, P = 0.006). Taken together, PARP1 > 6, p50 > 2, and TNF-α > 4 have a certain value in predicting breast cancer metastasis, and the predictive value is better when they are combined for diagnosis (Secombine = 97.94%, Spcombine = 71.13%).

Colorectal cancer (CRC) is ranked as the second leading cause of mortality worldwide, mainly due to metastasis. Epithelial to mesenchymal transition (EMT) is a complex cellular process that drives CRC metastasis, regulated by changes in EMT-associated gene expression. However, while numerous genes have been identified as EMT regulators through various in vivo and in vitro studies, little is known about the genes that are differentially expressed in CRC tumour tissue and their signalling pathway in regulating EMT. Using an integration of systematic search and bioinformatic analysis, gene expression profiles of CRC tumour tissues were compared to non-tumour adjacent tissues to identify differentially expressed genes (DEGs), followed by performing systematic review on common identified DEGs. Fifty-eight common DEGs were identified from the analysis of 82 tumour tissue samples obtained from four gene expression datasets (NCBI GEO). These DEGS were then systematically searched for their roles in modulating EMT in CRC based on previously published studies. Following this, 10 common DEGs (CXCL1, CXCL8, MMP1, MMP3, MMP7, TACSTD2, VIP, HPGD, ABCG2, CLCA4) were included in this study and subsequently subjected to further bioinformatic analysis. Their roles and functions in modulating EMT in CRC were discussed in this review. This study enhances our understanding of the molecular mechanisms underlying EMT and uncovers potential candidate genes and pathways that could be targeted in CRC.

Colorectal cancer (CRC), a tumor of the digestive system, is characterized by high malignancy and poor prognosis. Currently, targeted therapy of CRC is far away from satisfying. The molecular mechanisms of regulated cell death (RCD) have been clearly elucidated, which can be intervened by drug or genetic modification. Numerous studies have provided substantial evidence linking these mechanisms to the progression and treatment of CRC. The RCD includes apoptosis, autophagy-dependent cell death (ADCD), ferroptosis, necroptosis, and pyroptosis, and immunogenic cell death, etc, which provide potential targets for anti-cancer treatment. For the last several years, small-molecule compounds targeting RCD have been a well concerned therapeutic strategy for CRC. This present review aims to describe the function of small-molecule compounds in the targeted therapy of CRC via targeting apoptosis, ADCD, ferroptosis, necroptosis, immunogenic dell death and pyroptosis, and their mechanisms. In addition, we prospect the application of newly discovered cuproptosis and disulfidptosis in CRC. Our review may provide references for the targeted therapy of CRC using small-molecule compounds targeting RCD, including the potential targets and candidate compounds.

The prevalence of colorectal cancer is increasing worldwide, and despite advances in treatment, colorectal cancer (CRC) remains in the top three for mortality due to several issues, including drug resistance and low efficiency. There is increasing evidence that baicalin and baicalein, novel small molecule inhibitor extracts of the Chinese herb Scutellaria baicalensis, have better anti-colorectal cancer effects and are less likely to induce drug resistance in cancer cells. The present review article explains the anti-proliferative properties of baicalin and baicalein in the context of against CRC. Additionally, it explores the underlying mechanisms by which these compounds modulate diverse signaling pathways associated with apoptosis, cell proliferation, tumor angiogenesis, invasion, metastasis, and tumor microenvironment. Moreover, this review article highlights the inhibitory effect of colorectal inflammatory-cancer transformation and the near-term therapeutic strategy of using them as adjuvant agents in chemotherapy.

O-linked N-acetylglucosamine (O-GlcNAc) is a unique intracellular post-translational glycosylation at the hydroxyl group of serine or threonine residues in nuclear, cytoplasmic and mitochondrial proteins. The enzyme O-GlcNAc transferase (OGT) is responsible for adding GlcNAc, and anomalies in this process can lead to the development of diseases associated with metabolic imbalance, such as diabetes and cancer. Repurposing approved drugs can be an attractive tool to discover new targets reducing time and costs in the drug design. This work focuses on drug repurposing to OGT targets by virtual screening of FDA-approved drugs through consensus machine learning (ML) models from an imbalanced dataset. We developed a classification model using docking scores and ligand descriptors. The SMOTE approach to resampling the dataset showed excellent statistical values in five of the seven ML algorithms to create models from the training set, with sensitivity, specificity and accuracy over 90% and Matthew's correlation coefficient greater than 0.8. The pose analysis obtained by molecular docking showed only H-bond interaction with the OGT C-Cat domain. The molecular dynamics simulation showed the lack of H-bond interactions with the C- and N-catalytic domains allowed the drug to exit the binding site. Our results showed that the non-steroidal anti-inflammatory celecoxib could be a potentially OGT inhibitor.

Colorectal cancer (CRC) is characterized by a complex tumor inflammatory microenvironment, while angiogenesis and immunosuppression frequently occur concomitantly. However, the exact mechanism that controls angiogenesis and immunosuppression in CRC microenvironment remains unclear. Herein, we found that expression levels of lipid raft protein STOML2 were increased in CRC and were associated with advanced disease stage and poor survival outcomes. Intriguingly, we revealed that STOML2 is essential for CRC tumor inflammatory microenvironment, which induces angiogenesis and facilitates tumor immune escape simultaneously both in vitro and in vivo. Moreover, tumors with STOML2 overexpression showed effective response to anti-angiogenesis treatment and immunotherapy in vivo. Mechanistically, STOML2 regulates CRC proliferation, angiogenesis, and immune escape through activated NF-κB signaling pathway via binding to TRADD protein, resulting in upregulation of CCND1, VEGF, and PD-L1. Furthermore, treatment with NF-κB inhibitor dramatically reversed the ability of proliferation and angiogenesis. Clinically, we also observed a strong positive correlation between STOML2 expression and Ki67, CD31, VEGFC and PD-1 of CD8+T cell expression. Taken together, our results provided novel insights into the role of STOML2 in CRC inflammatory microenvironment, which may present a therapeutic opportunity for CRC.