Direct Identification of O─O Bond Formation Through Three-Step Oxidation During Water Splitting by Operando Soft X-ray Absorption Spectroscopy.

Anionic redox allows the direct formation of O─O bonds from lattice oxygens and provides higher catalytic in the oxygen evolution reaction (OER) than does the conventional metal ion mechanism. While previous theories have predicted and experiments have suggested the possible O─O bond, it has not yet been directly observed in the OER process. In this study, operando soft X-ray absorption spectroscopy (sXAS) at the O K-edge and the operando Raman spectra is performed on layered double CoFe hydroxides (LDHs) after intercalation with [Cr(C2O4)3]3-, and revealed a three-step oxidation process, staring from Co2+ to Co3+, further to Co4+ (3d6L), and ultimately leading to the formation of O─O bonds and O2 evolution above a threshold voltage (1.4 V). In contrast, a gradual oxidation of Fe is observed in CoFe LDHs. The OER activity exhibits a significant enhancement, with the overpotential decreasing from 300 to 248 mV at 10 mA cm-2, following the intercalation of [Cr(C2O4)3]3- into CoFe LDHs, underscoring a crucial role of anionic redox in facilitating water splitting.

IL-1ß mediates Candida tropicalis-induced immunosuppressive function of MDSCs to foster colorectal cancer.

BACKGROUND: There is increasing evidence that gut fungi dysbiosis plays a crucial role in the development and progression of colorectal cancer (CRC). It has been reported that gut fungi exacerbate the severity of CRC by regulating tumor immunity. Our previous studies have shown that the opportunistic pathogenic fungal pathogen, Candida tropicalis (C. tropicalis) promotes CRC progression by enhancing the immunosuppressive function of MDSCs and activating the NLRP3 inflammasome of MDSCs. However, the relationship between IL-1ß produced by NLRP3 inflammasome activation and the immunosuppressive function of MDSCs enhanced by C. tropicalis in CRC remains unclear. METHODS: The TCGA database was used to analyze the relationship between IL-1ß and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1ß in human CRC tissues was detected by immunofluorescence staining. The proteomic analysis was performed on the culture supernatant of C. tropicalis-stimulated MDSCs. The experiments of supplementing and blocking IL-1ß as well as inhibiting the NLRP3 inflammasome activation were conducted. A mouse colon cancer xenograft model was established by using MC38 colon cancer cell line. RESULTS: Analysis of CRC clinical samples showed that the high expression of IL-1ß was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1ß was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1ß further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1ß axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1ß secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer. CONCLUSIONS: C. tropicalis promotes excessive secretion of IL-1ß from MDSCs via the NLRP3 inflammasome. IL-1ß further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1ß secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.

Metastatic Early-Onset Colon Cancer With BRCA2 Mutation Presenting With a Large Obstructing Pelvic Mass and Causing Acute Liver Failure and Acute Hypoxic Respiratory Failure.

Colorectal cancer (CRC) still constitutes a significant healthcare burden. Although its overall incidence is reducing, the incidence of early-onset CRC is increasing. There is uncertainty about the association between CRC and BRCA2 mutations and also, even though most cancers metastasize to the liver, acute liver failure (ALF) from metastatic cancer and specifically CRC is uncommon. This is a case of a young patient with BRCA2 mutation who presented with a large obstructing CRC with extensive metastatic burden to the liver, causing a fatal ALF. This case shows the growing number of ALFs associated with metastatic disease and suggests a possible association between BRCA2 mutation and CRC. This association needs more research to establish.

E3 ubiquitin ligases and deubiquitinases in colorectal cancer: Emerging molecular insights and therapeutic opportunities.

Colorectal cancer (CRC) presents ongoing challenges due to limited treatment effectiveness and a discouraging prognosis, underscoring the need for ground-breaking therapeutic approaches. This review delves into the pivotal role of E3 ubiquitin ligases and deubiquitinases (DUBs), underscoring their role as crucial regulators for tumor suppression and oncogenesis in CRC. We spotlight the diverse impact of E3 ligases and DUBs on CRC's biological processes and their remarkable versatility. We closely examine their specific influence on vital signaling pathways, particularly Wnt/ß-catenin and NF-κB. Understanding these regulatory mechanisms is crucial for unravelling the complexities of CRC progression. Importantly, we explore the untapped potential of E3 ligases and DUBs as novel CRC treatment targets, discussing aspects that may guide more effective therapeutic strategies. In conclusion, our concise review illuminates the E3 ubiquitin ligases and deubiquitinases pivotal role in CRC, offering insights to inspire innovative approaches for transforming the treatment landscape in CRC.

An Unusual Tumor: Squamous Cell Carcinoma of the Colon in Lynch Syndrome.

Primary squamous cell carcinoma of the colon and rectum is a rare malignancy. Most of the anatomical sites that are reported to be affected include the esophagus and anal canal. This report highlights the case of a 54-year-old male with a known history of Lynch syndrome and a previous diagnosis of colon cancer who was found to have a recurrence of malignancy affecting this unlikely area. The treatment strategies for this colorectal squamous cell carcinoma have not been thoroughly explored, so this report aims to highlight effective interventions, including surgical resection and neoadjuvant chemotherapy and radiation. There is a poor prognosis associated with this condition, as it does not typically present until the late stages; however, in this particular instance, early detection leads to improved outcomes.

A nomogram for predicting colorectal cancer liver metastasis using circulating tumor cells from the first drainage vein.

PURPOSE: To use circulating tumor cells (CTC) from the first drainage vein (FDV) of the primary lesion and other clinically relevant parameters to construct a nomogram for predicting liver metastasis in colorectal cancer (CRC) patients, and to provide a theoretical basis for clinical diagnosis and treatment. METHODS: Information from 343 CRC patients was collected and a database was established. Multivariate logistic analysis was used to identify independent factors for colorectal cancer liver metastasis(mCRC) and nomograms were constructed. Receiver operating characteristic curves(ROC), calibration plots, and decision curve analysis (DCA) were used to assess discrimination, agreement with actual risk, and the clinical utility of the prediction model, respectively. RESULT: CTC levels in FDV were significantly higher in patients with liver metastasis than in those without liver metastasis. Logistic multivariate analysis showed that vascular invasion, T stage, carcinoembryonic antigen (CEA), CA19-9, and CTC could be used as predictors to construct nomograms. The nomograms showed good discriminatory ability in predicting mCRC, with area under the curve (AUC) values of 0.871 [95 % CI: 0.817-0.924) and 0.891 (95 % CI: 0.817-0.964) for the training and validation sets, respectively.] The calibration curves of both the training and validation sets showed that the model was effective in predicting the probability of mCRC. DCA was used to evaluate this predictive model and showed good net clinical benefit. CONCLUSION: We developed and validated a nomogram model based on the combination of CTC in the FDV with other clinical parameters to better predict the occurrence of mCRC.

Unraveling the ncRNA landscape that governs colorectal cancer: A roadmap to personalized therapeutics.

Colorectal cancer (CRC) being one of the most common malignancies, has a significant death rate, especially when detected at an advanced stage. In most cases, the fundamental aetiology of CRC remains unclear despite the identification of several environmental and intrinsic risk factors. Numerous investigations, particularly in the last ten years, have indicated the involvement of epigenetic variables in this type of cancer. The development, progression, and metastasis of CRC are influenced by long non-coding RNAs (lncRNAs), which are significant players in the epigenetic pathways. LncRNAs are implicated in diverse pathological processes in CRC, such as liver metastasis, epithelial to mesenchymal transition (EMT), inflammation, and chemo-/radioresistance. It has recently been determined that CRC cells and tissues exhibit dysregulation of tens of oncogenic and tumor suppressor lncRNAs. Serum samples from CRC patients exhibit dysregulated expressions of several of these transcripts, offering a non-invasive method of detecting this kind of cancer. In this review, we outlined the typical paradigms of the deregulated lncRNA which exert significant role in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the role of lncRNAs as innovative targets for CRC prognosis and treatment.

SIPA1 promotes epithelial-mesenchymal transition in colorectal cancer through STAT3 activation.

Colorectal cancer (CRC) is the third leading cancer type worldwide and accounts for the second highest rate of cancer-related mortality. Liver metastasis significantly contributes to the mortality associated with CRC, but the fundamental mechanisms behind it remain unclear. Signal-induced proliferation-associated protein 1 (SIPA1), a GTPase activating protein, has been shown to promote metastasis in breast cancer. In this study, our objective was to explore the role of SIPA1 in regulating epithelial-mesenchymal transition (EMT) in CRC. The analysis of The Cancer Genome Atlas (TCGA) database revealed that the expression level of SIPA1 mRNA was notably upregulated and exhibited a positively correlated with EMT and STAT3 signaling pathways in CRC. Knockdown of SIPA1 impairs CRC cell proliferation and migration. Further studies on the reliance of SIPA1 on STAT3 signaling for EMT regulation have shown that SIPA1 stimulates the activation of STAT3, resulting in its nuclear translocation. The co-treatment of overexpressed SIPA1 with the STAT3 inhibitor STTITA has shown that SIPA1 regulates the expression of EMT-related markers through STAT3. Our study indicate that SIPA1 promotes CRC metastasis by activating the STAT3 signaling pathway, underscoring the potential of SIPA1 as a therapeutic target for metastatic CRC patients.

The Role of Dietary Vitamins and Antioxidants in Preventing Colorectal Cancer: A Systematic Review.

The role of dietary vitamins and antioxidants in preventing colorectal cancer (CRC) is a significant area of research within nutritional oncology. However, the relationship between these nutrients and CRC prevention is complex and influenced by factors such as dosage, timing, and individual health status. This review aims to comprehensively analyze and synthesize the existing scientific literature on the potential role of dietary vitamins and antioxidants in preventing CRC. A comprehensive literature review was conducted by searching electronic databases to identify studies examining the prospected impacts of dietary vitamins and antioxidants on the prevention of CRC. According to the outcomes of this review, this research review shows a complex link between vitamins and CRC. While some vitamins such as B2, B6, and D seemed helpful, others such as A and E had mixed results. Vitamin C deficiency was even linked to worse outcomes in cancer patients. Overall, the studies suggest focusing on a balanced diet rich in various vitamins rather than relying solely on individual supplements to prevent CRC. On the other hand, the results of our review suggest that the relationship between antioxidant intake and CRC is more intricate than previously thought. Data from this review indicates that taking specific antioxidant supplements such as selenium and vitamin E does not seem to offer the same protection. This suggests that a balanced diet with a variety of antioxidants is more helpful than focusing on single supplements. While we did not observe a direct association, future studies could investigate how different types and combinations of antioxidants might influence CRC development. In conclusion, the present systematic review highlights the need for more research on the relationship between vitamins, antioxidants, and CRC. We need to understand how these nutrients affect both the survival of people with CRC and the prevention of the disease. This will help us determine the best ways to use vitamins and antioxidants in CRC management and prevention.

Prognostic Value of Insulin Growth Factor-Like Receptor 1 (IGFLR1) in Stage II and III Colorectal Cancer and Its Association with Immune Cell Infiltration.

IGFLR1 is a novel biomarker, and some evidences suggested that is involved in the immune microenvironment of CRC. Here, we explored the expression of IGFLR1 and its association with the prognosis as well as immune cell infiltration in CRC, with the aim to provide a basis for further studies on IGFLR1. Immunohistochemical staining for IGFLR1, TIM-3, FOXP3, CD4, CD8, and PD-1 was performed in eligible tissues to analyze the expression of IGFLR1 and its association with prognosis and immune cell infiltration. Then, we screened colon cancer samples from TCGA and grouped patients according to IGFLR1-related genes. We also evaluated the co-expression and immune-related pathways of IGFLR1 to identify the potential mechanism of it in CRC. When P < 0.05, the results were considered statistically significant. IGFLR1 and IGFLR1-related genes were associated with the prognosis and immune cell infiltration (P < 0.05). In stage II and III CRC tissue and normal tissue, we found (1) IGFLR1 was expressed in both the cell membrane and cytoplasm and which was differentially expressed between cancer tissue and normal tissue. IGFLR1 expression was associated with the expression of FOXP3, CD8, and gender but was not associated with microsatellite instability. (2) IGFLR1 was an independent prognostic factor and patients with high IGFLR1 had a better prognosis. (3) A model including IGFLR1, FOXP3, PD-1, and CD4 showed good prognostic stratification ability. (4) There was a significant interaction between IGFLR1 and GATA3, and IGFLR1 had a significant co-expression with related factors in the INFR pathway. IGFLR1 has emerged as a new molecule related to disease prognosis and immune cell infiltration in CRC patients and showed a good ability to predict the prognosis of patients.

Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion.

The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). The pathobiont Fusobacterium nucleatum influences the anti-tumor functions of CRC-infiltrating iNKT cells. However, the impact of other bacteria associated with CRC, like Porphyromonas gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumor microenvironment. Mechanistically, in vivo and in vitro experiments showed that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery through increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing the upregulation of CHI3L1 in iNKT cells, thus impairing their cytotoxic functions and promoting host tumor immune evasion.

Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via regulating lipidome metabolic reprogramming.

BACKGROUND: The failure of proper recognition of the intricate nature of pathophysiology in colorectal cancer (CRC) has a substantial effect on the progress of developing novel medications and targeted therapy approaches. Imbalances in the processes of lipid oxidation and biosynthesis of fatty acids are significant risk factors for the development of CRC. Therapeutic intervention that specifically targets the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream response element, in response to lipid metabolism, has been found to promote the growth of tumors and has shown significant clinical advantages in cancer patients. METHODS: Clinical CRC samples and extensive in vitro and in vivo experiments were carried out to determine the role of ZDHHC6 and its downstream targets via a series of biochemical assays, molecular analysis approaches and lipid metabolomics assay, etc. RESULTS: To study the effect of ZDHHC6 on the progression of CRC and identify whether ZDHHC6 is a palmitoyltransferase that regulates fatty acid synthesis, which directly palmitoylates and stabilizes PPARγ, and this stabilization in turn activates the ACLY transcription-related metabolic pathway. In this study, we demonstrate that PPARγ undergoes palmitoylation in its DNA binding domain (DBD) section. This lipid-related modification enhances the stability of PPARγ protein by preventing its destabilization. As a result, palmitoylated PPARγ inhibits its degradation induced by the lysosome and facilitates its translocation into the nucleus. In addition, we have identified zinc finger-aspartate-histidine-cysteine 6 (ZDHHC6) as a crucial controller of fatty acid biosynthesis. ZDHHC6 directly interacts with and adds palmitoyl groups to stabilize PPARγ at the Cys-313 site within the DBD domain of PPARγ. Consequently, this palmitoylation leads to an increase in the expression of ATP citrate lyase (ACLY). Furthermore, our findings reveals that ZDHHC6 actively stimulates the production of fatty acids and plays a role in the development of colorectal cancer. However, we have observed a significant reduction in the cancer-causing effects when the expression of ZDHHC6 is inhibited in in vivo trials. Significantly, in CRC, there is a strong positive correlation between the high expression of ZDHHC6 and the expression of PPARγ. Moreover, this high expression of ZDHHC6 is connected with the severity of CRC and is indicative of a poor prognosis. CONCLUSIONS: We have discovered a mechanism in which lipid biosynthesis is controlled by ZDHHC6 and includes the signaling of PPARγ-ACLY in the advancement of CRC. This finding provides a justification for targeting lipid synthesis by blocking ZDHHC6 as a potential therapeutic approach.

Consensus clustering and development of a risk signature based on trajectory differential genes of cancer-associated fibroblast subpopulations in colorectal cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a crucial role in the progression of colorectal cancer (CRC). However, the impact of CAF subpopulation trajectory differentiation on CRC remains unclear. METHODS: In this study, we first explored the trajectory differences of CAFs subpopulations using bulk and integrated single-cell sequencing data, and then performed consensus clustering of CRC samples based on the trajectory differential genes of CAFs subpopulations. Subsequently, we analyzed the heterogeneity of CRC subtypes using bioinformatics. Finally, we constructed relevant prognostic signature using machine learning and validated them using spatial transcriptomic data. RESULTS: Based on the differential genes of CAFs subpopulation trajectory differentiation, we identified two CRC subtypes (C1 and C2) in this study. Compared to C1, C2 exhibited worse prognosis, higher immune evasion microenvironment and high CAF characteristics. C1 was primarily associated with metabolism, while C2 was primarily associated with cell metastasis and immune regulation. By combining 101 combinations of 10 machine learning algorithms, we developed a High-CAF risk signatures (HCAFRS) based on the C2 characteristic gene. HCAFRS was an independent prognostic factor for CRC and, when combined with clinical parameters, significantly predicted the overall survival of CRC patients. HCAFRS was closely associated with epithelial-mesenchymal transition, angiogenesis, and hypoxia. Furthermore, the risk score of HCAFRS was mainly derived from CAFs and was validated in the spatial transcriptomic data. CONCLUSION: In conclusion, HCAFRS has the potential to serve as a promising prognostic indicator for CRC, improving the quality of life for CRC patients.

A New Genetic Signature of Lactate Metabolism-Associated Genes Predicting Clinically Distinctive Features and Tumor Microenvironment in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is characterized by its high malignancy and challenging prognosis. A significant aspect of cancer is metabolic reprogramming, where lactate serves as a crucial metabolite that contributes to the development of cancer and the tumor microenvironment (TME). Current studies have indicated that lactate plays a significant role in the progression of CRC. However, the relationship between lactate and the tumor microenvironment remains understudied, underscoring the potential of lactate as a novel biomarker. METHODS: We sourced transcriptomic data for colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and the Gene Expression Omnibus (GEO) portals, along with the corresponding clinical information. Utilizing univariate Cox regression in conjunction with LASSO regression analysis, we identified genes involved in lactate metabolism that are associated with CRC prognosis. Subsequently, we developed models based on multi-factor Cox regression. To evaluate the correlation between tumor mutational burden (TMB), tumor microenvironment (TME), and lactate scores with patient survival, we conducted gene set enrichment analysis (GSEA) and immunogenic signature analyses. RESULTS: 3 lactate metabolism-related genes (LMRGs) (SLC16A8, GATA1, and PYGL) were used to construct models that categorized patients into 2 subgroups based on their lactate scores. The function of the differential genes between the 2 subgroups was mainly enriched in cell cycle and mRNA division, and the prognosis of patients in the high score subgroup was poor. Furthermore, a significant positive correlation was observed between TMB and LMRGs scores in the high-scoring group (P = 0.003, r2 = 0.12). Lastly, LMRGs also reflected the characteristics of TME, with differences in immune cells and immune checkpoints between the 2 subgroups. CONCLUSIONS: LMRGs may serve as a promising biomarker for predicting prognostic survival in CRC patients and to assess the TME.

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DNA Methylation Biomarkers in Stool Samples: Enhancing Colorectal Cancer Screening Strategies.

Colorectal cancer (CRC) is a significant global health challenge, ranking among the leading causes of cancer-related mortality worldwide. Despite efforts in prevention and early detection, CRC incidence and mortality rates are expected to rise substantially. Traditional screening methods like gFOBT, FIT, flexible sigmoidoscopy, colonoscopy, CTC, and colon capsule have limitations, including false positives/negatives, limited scope, or invasiveness. Recent developments in CRC screening involve DNA methylation biomarkers, showing promise in detecting early-stage CRC and precancerous lesions. Stool-based DNA testing is emerging as a noninvasive and convenient method for detecting CRC-associated DNA methylation alterations, offering potential for earlier detection compared to traditional methods. Several commercial stool-based DNA methylation tests targeting different genes associated with CRC have demonstrated varying sensitivity and specificity, some surpassing traditional screening methods. Challenges remain in optimizing their performance and accessibility. This review discusses how DNA methylation biomarkers could enhance CRC screening, and stool-based DNA methylation tests could revolutionize CRC screening practices, comparing them to the gold standard.

PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer.

Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.

Effect of blood pressure control on the risk of proteinuria during bevacizumab treatment in patients with colorectal cancer: a single-center retrospective cohort study.

PURPOSE: Pre-existing hypertension is reportedly a major risk factor for bevacizumab-induced proteinuria. However, few studies have focused on the effects of blood pressure (BP) control on proteinuria during bevacizumab treatment. We report a retrospective study of the association between poor BP control and the risk of developing proteinuria in patients with colorectal cancer (CRC). METHODS: Data for CRC patients who received bevacizumab between April 2015 and March 2022 were retrospectively collected. Patients were categorized into two groups based on average systolic blood pressure (SBP) during treatment: normal SBP (< 140 mmHg) and high SBP (≥ 140 mmHg). To evaluate the association between average SBP and grade ≥ 2 proteinuria, we used a 3 month landmark analysis and a Cox regression model. RESULTS: Of the 279 patients analyzed, 109 had high SBP and 170 had normal SBP. The cumulative incidence of grade ≥ 2 and severe proteinuria was significantly higher in the high compared to the normal SBP group (p < 0.001 and p = 0.028, respectively). Landmark analysis indicated significant differences in proteinuria between patients with and without high average SBP during the first 3 months of treatment (p = 0.002 and p = 0.015, respectively). Multivariate analysis showed that average SBP ≥ 140 mmHg was a significant independent risk factor for proteinuria (p = 0.008). CONCLUSION: Landmark analysis showed that BP status during the first 3 months of bevacizumab treatment influences the risk of subsequent proteinuria. Therefore, timely diagnosis and stricter BP control are recommended for at least the first 3 months to avoid severe proteinuria.

Insights into the Anticancer Mechanisms Modulated by Gamma and Delta Tocotrienols in Colorectal Cancers.

Colorectal cancer (CRC) is a growing concern all over the world. There has been a concerted effort to identify natural bioactive compounds that can be used to prevent or overcome this condition. Tocotrienols (T3s) are a naturally occurring form of vitamin E known for various therapeutic effects, such as anticancer, antioxidant, neuroprotective, and anti-inflammatory activities. The literature evidence suggests that two T3 analogues, ie, gamma (γ)- and delta (δ)-T3, can modulate cancers via several cancer-related signaling pathways. The aim of this review was to compile and analyze the existing literature on the diverse anticancer mechanisms of γT3 and δT3 exhibited in CRC cells, to showcase the anticancer potential of T3s. Medline was searched for research articles on anticancer effects of γT3 and δT3 in CRC published in the past 2 decades. A total of 38 articles (26 cell-based, 9 animal studies, 2 randomized clinical trials, and 1 scoping review) that report anticancer effects of γT3 and δT3 in CRC were identified. The findings reported in those articles indicate that γT3 and δT3 inhibit the proliferation of CRC cells, induce cell cycle arrest and apoptosis, suppress metastasis, and produce synergistic anticancer effects when combined with well-established anticancer agents. There is preliminary evidence that shows that T3s affect telomerase functions and support anticancer immune responses. γT3 and δT3 have the potential for development as anticancer agents.

Microbiota and plasticity of antigen-presenting ILC3s: impact on antitumor immune response.

Growing evidence highlights the pivotal role of RORγt-innate lymphoid cells (ILCs) in the establishment of antitumor immune response and in enhancing tumor sensitivity to immunotherapy. Noteworthy, type 3 ILCs (ILC3s) have been recently acknowledged as an important class of antigen-presenting cells (APCs) in the context of host-microorganism interactions shaping the adaptive immune response in the intestinal mucosa. Although a broad range of mouse models has led to significant progress in untangling the role of ILC3s as APCs, the outcome of major histocompatibility complex (MHC)-dependent ILC-T cell crosstalk in colorectal cancer (CRC) remains underexplored in human. Moreover, expression of MHCII is confined to ILC3 subset, endowed with lymphoid tissue-inducing properties, that adopts tissue-specific fates and functions. Intestinal microbiota could dictate the plasticity of antigen-presenting ILC3s and we here summarize our current understanding of the functions of these cells in both mouse and human CRC discussing the role of microbiota as a key modulator of their tumor-suppressive activity.

Exploring the molecular mechanisms and therapeutic potential of SMAD4 in colorectal cancer.

Colorectal Cancer (CRC) is the third most common cancer worldwide, and the occurrence and development of CRC are influenced by the molecular biology characteristics of CRC, especially alterations in key signaling pathways. The transforming growth factor-ß (TGF-ß) plays a crucial role in cellular growth, differentiation, migration, and apoptosis, with SMAD4 protein serving as a key transcription factor in the TGF-ß signaling pathway, thus playing a significant role in the onset and progression of CRC. CRC is one of the malignancies with a high mortality rate worldwide. Despite significant research progress in recent years, especially regarding the role of SMAD4, its dual role in the early and late stages of tumor progression has promoted further discussion on its complexity as a therapeutic target, highlighting the urgent need for a deeper analysis of its role in CRC. This review aims to explore the function of SMAD4 protein in CRC and its potential as a therapeutic target.