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Background: The intake of high-fructose corn syrup (HFCS) may increase the risk of colorectal cancer (CRC). This study aimed to explore the potential effects and mechanisms of resistant starch (RS) in HFCS-induced colon tumorigenesis., Methods: The azoxymethane/dextran sodium sulfate (AOM/DSS) and Apc Min/+ mice models were used to investigate the roles of HFCS and RS in CRC in vivo. An immunohistochemistry (IHC) staining analysis was used to detect the expression of proliferation-related proteins in tissues. 16S rRNA sequencing for microbial community, gas chromatography for short-chain fatty acids (SCFAs), and mass spectrometry analysis for glycolysis products in the intestines were performed. Furthermore, lactic acid assay kit was used to detect the glycolysis levels in vitro., Results: RS suppressed HFCS-induced colon tumorigenesis through reshaping the microbial community. Mechanistically, the alteration of the microbial community after RS supplement increased the levels of intestinal SCFAs, especially butyrate, leading to the suppression of glycolysis and CRC cell proliferation by downregulating HK2., Conclusions: Our study identified RS as a candidate of protective factors in CRC and may provide a potential target for HFCS-related CRC treatment., (© 2024. The Author(s).)

The human colonic commensal enterotoxigenic Bacteroides fragilis (ETBF) is associated with chronic colitis and colon cancer. ETBF colonization induces colitis via the Bacteroides fragilis toxin (BFT). BFT secreted by ETBF cause colon inflammation via E-cadherin cleavage/NF-κB signaling. ETBF promotes colon tumorigenesis via interleukin 17A (IL-17A)/CXCL-dependent inflammation, but its bioactive therapeutics in ETBF-promoted tumorigenesis remain unexplored. In the current study, we investigated the caffeic acid phenethyl ester (CAPE) in the murine model of ETBF colitis and tumorigenesis. In this study, we observed that CAPE treatment mitigated inflammation induced by ETBF in mice. Additionally, our findings indicate that CAPE treatment offers protective effects against ETBF-enhanced colon tumorigenesis in a mouse model of colitis-associated colon cancer induced by azoxymethane (AOM) and dextran sulfate sodium. Notably, the decrease in colon tumorigenesis following CAPE administration correlates with a reduction in the expression of IL-17A and CXCL1 in the gastrointestinal tract. The molecular mechanism for CAPE-induced protection against ETBF-mediated tumorigenesis is mediated by IL-17A/CXCL1, and by NF-κB activity in intestinal epithelial cells. Our findings indicate that CAPE may serve as a preventive agent against the development of ETBF-induced colitis and colorectal cancer (CRC).

Background/aim: Inflammatory bowel diseases and colorectal cancer are a major cause of morbidity and mortality. Amine oxidase, copper-containing 3 (AOC3) is a critical enzyme in the physiological trafficking of leukocytes and the regulation of inflammation. This study aimed to examine the effects of Aoc3 deficiency in mice models of colitis and colorectal tumorigenesis., Materials and Methods: C57BL/6 and Aoc3 knockout mice were used for Dextran Sodium Sulfate (DSS) induced acute colitis and the Azoxymethane (AOM)/DSS model of inflammation-related colon cancer. We also evaluated the effect of Aoc3 in an Apc mutant mice model of intestinal and colonic tumorigenesis., Results: We observed that Aoc3 deficient mice were more prone to colitis induced by DSS in early phases and their survival was shorter. We also showed that Aoc3 deficient mice developed more tumors both in AOM/DSS and Apc mutant mice models. Furthermore, colonic tumors in the AOM/DSS groups in Aoc3 mutant mice were generally invasive type adenocarcinomas., Conclusion: Aoc3 deficiency promotes colitis and colonic tumorigenesis in mouse models., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant transformation. To investigate acute inflammation, we employed an in vitro model by subjecting Caco-2 cells to various inflammatory stimuli (IL-1β, TNF-α, or LPS) individually or in combination. The successful induction of inflammation was confirmed by robust increases in IL-6 and NO production. Notably, inflamed Caco-2 cells exhibited significantly diminished levels of ABCB1 and ABCG2, while the expression of ABCC2 was upregulated. For chronic inflammation induction in vivo, we employed the well-established AOM/DSS mouse model known for its association with colitis-driven tumorigenesis. Persistent inflammation was effectively monitored throughout the experiment via elevated IL-6 and NO levels. The sequential stages of tumorigenesis were confirmed through Ki-67 immunohistochemistry. Intriguingly, we observed gradual alterations in the expression patterns of the studied drug transporters during stepwise induction, with ABCB1, ABCG2, and ABCC1 showing downregulation and ABCC2 exhibiting upregulation. Immunohistochemistry further revealed dynamic changes in the expression of ABCB1 and ABCC2 during the induction cycles, closely paralleling the gradual increase in Ki-67 expression observed during the development of precancerous lesions. Collectively, our findings underscore the significant impact of inflammation on drug transporter expression, potentially influencing the process of malignant transformation of the colon., (© 2024 Wiley Periodicals LLC.)

Objective: Colorectal cancer, one of the most frequently diagnosed cancers worldwide, has a high mortality rate. Thus, our research aims to examine the preventive effects of diosmin (DIO) alone and in conjunction with the anti-cancer drug irinotecan (camptothecin-11, CPT-11), on 1,2-dimethylhydrazine (DMH)-induced colon cancer (CC) in male Wistar rats., Materials and Methods: Fifty adult male Wistar rats were categorized into five groups. Group I (Normal) received saline 0.9 orally % as a vehicle once a week for 14 weeks. Group II (DMH) received DMH (20 mg/kg/week) orally dissolved in 0.9% saline for 14 weeks and 1% carboxymethylcellulose (CMC) every other day for the final 10 weeks. Group III (DMH+DIO) received DMH orally for 14 weeks and DIO (10 mg/kg, suspended in 1% CMC) every other day for the final 10 weeks. Group IV (DMH+CPT-11) received DMH orally for 14 weeks and intraperitoneal injection of CPT-11 (3 mg/kg) twice a week for the final 10 weeks. Group V (DMH+DIO+CPT-11) orally received DMH for 14 weeks and both DIO and CPT-11., Results: All treated groups showed a significant reduction (p<0.05) in their elevated serum malondialdehyde levels and significant amelioration (p<0.05) of their lowered activities of colon glutathione-S-transferase (GST) and glutathione reductase (GR) as well as serum glutathione level (GSH). In addition, simultaneous treatment with DIO and CPT-11 led to a significant decrease (p<0.05) in the elevated serum levels of carcinoembryonic antigen (CEA) in rats administered with DMH, as well as a reduction in the colon expression levels of the inflammatory mediator (NF-κB), cell proliferator protein (Ki-67), and proapoptotic protein (p53)., Conclusions: These findings suggest DIO, CPT-11, and their combination have anticarcinogenic effects against DMH-induced CC by suppressing oxidative stress, simulating the antioxidant defense system, attenuating the inflammatory effects, and reducing cell proliferation.

Ethnopharmacological Relevance: Colitis is an important risk factor for the occurrence of colorectal cancer (CRC), and the colonization of Fusobacterium nucleatum (Fn) in the intestines accelerates this transformation process. Banxia Xiexin Decoction (BXD), originating from Shanghanlun, is a classic prescription for treating gastrointestinal diseases. Current researches indicate that BXD can effectively delay the colitis-to-cancer transition, but it is still unclear whether it can inhibit Fn colonization to achieve this delaying effect., Aim of Study: This study explored the effect and mechanism of BXD in inhibiting Fn intestinal colonization to delay colitis-to-cancer transition., Materials and Methods: We constructed a mouse model of colitis-to-cancer transition by regularly gavaging Fn combined with azoxymethane (AOM)/dextran sodium sulfate (DSS), and administered BXD by gavage. We monitored the body weight of mice, measured the length and weight of their colons, and calculated the disease activity index (DAI) score. The growth status of colon tumors was observed by hematoxylin and eosin (H&E) staining, and the changes in gut microbiota in each group of mice were detected by 16S rDNA analysis. Immunohistochemistry was used to detect the expression of E-cadherin and β-catenin in colon tissues, and immunofluorescence was used to observe the infiltration of M2 macrophages in colon tissues. In cell experiments, we established a co-culture model of Fn and colon cancer cells and intervened with BXD-containing serum. Malignant behaviors such as cell proliferation, invasion, and migration were detected, as well as changes in their cell cycle. We examined the protein levels of E-cadherin, β-catenin, Axin2, and Cyclin D1 in each group were detected by Western blot. We used US1 strain (fadA-) as a control and observed the effects of BXD-containing serum on Fn attachment and invasion of colon cancer cells through attachment and invasion experiments., Results: BXD can inhibit the colitis-to-cancer transition in mice infected with Fn, reduce crypt structure damage, improve gut microbiota dysbiosis, upregulate E-cadherin and decrease β-catenin expression, and reduce infiltration of M2 macrophages, thus inhibiting the process of colitis-to-cancer transition. Cell experiments revealed that BXD-containing serum can inhibit the proliferation, migration, and invasion of colon cancer cells infected with Fn and regulate their cell cycle. More importantly, we found that BXD-containing serum can inhibit the binding of Fn's FadA adhesin to E-cadherin, reduce Fn's attachment and invasion of colon cancer cells, thereby downregulating the E-cadherin/β-catenin signaling pathway., Conclusions: These findings show that BXD can inhibit Fn colonization by interfering with the binding of FadA to E-cadherin, reducing the activation of the E-cadherin/β-catenin signaling pathway, and ultimately delaying colitis-to-cancer transition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In adult male C57BL/6 mice with high (HR) and low (LR) resistance to hypoxia, morphological features of colon tumors and blood parameters were evaluated 70 days after intraperitoneal injection of azoxymethane and subsequent consumption of 3 cycles of dextran sulfate sodium. On macroscopic analysis, tumors were found in the distal colon in 35% (7 of 20 animals) of HR and 31% (4 of 13 animals) of LR animals. Microscopic analysis of the distal colon revealed tumors in 75% (15 of 20 animals) of HR and 69% (9 of 13 animals) of LR mice. The tumors were presented by areas of glandular intraepithelial neoplasia and adenocarcinomas; the incidence and the area of the tumors did not differ in groups of HR and LR mice. The number of neuroendocrine and goblet cells in the distal colon mucosa in the areas of tumors was similar in the compared groups. However, in both HR and LR mice of the experimental groups, the content of goblet cells in tumors was lower and the content of endocrine cells was higher than in the corresponding control groups. In the peripheral blood, the erythrocyte count and hemoglobin content decreased in HR and LR mice of the experimental groups; the relative number of monocytes increased only in HR mice and the absolute number of lymphocytes and monocytes decreased in LR mice. Thus, 70 days after azoxymethane administration and dextran sulfate sodium consumption, the tumors in mice were presented by glandular intraepithelial neoplasia and adenocarcinomas, and their incidence and area did not differ between animals with different tolerance to hypoxia., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Pectins are a class of soluble polysaccharides that can have anticancer properties through several mechanisms. This study aimed to characterize the molecular structure of water-soluble fractions (WSF) derived from ripe and unripe papayas and assess their biological effects in two models: the 3D colon cancer spheroids to measure cell viability and cytotoxicity, and the in vivo model to investigate the inhibition of preneoplastic lesions in rats. WSF yield was slightly higher in ripe papaya, and both samples mainly consisted of pectin. Both pectins inhibited the growth of colon cancer HT29 and HCT116 spheroids. Unripe pectin disturbed HT29/NIH3T3 spheroid formation, decreased HCT116 spheroid viability, and increased spheroid cytotoxicity. Ripe pectin had a more substantial effect on the reduction of spheroid viability for HT29 spheroids. Furthermore, in vivo experiments on a rat model revealed a decrease in aberrant crypt foci (ACF) formation for both pectins and increased apoptosis in colonocytes for ripe papaya pectins. The results suggest potential anticancer properties of papaya pectin, with ripe pectin showing a higher potency., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Regorafenib is the first multikinase inhibitor for treating metastatic colorectal cancer (mCRC). Proteinuria is a frequently encountered adverse effect, regardless of prior administration of vascular endothelial growth factor inhibitors. Herein, we aimed to assess the impact of baseline preexisting proteinuria on regorafenib-induced problematic proteinuria during real-world mCRC therapy. Patients with mCRC receiving regorafenib (n = 100) were retrospectively assessed and divided into control and preexisting proteinuria (baseline grade of 1-2) groups. The primary endpoint was the development of grade ≥ 2 (grade ≥ 3 in case of baseline grade 2 patients) proteinuria. Propensity score-matching was performed to confirm the robustness of primary analyses. Defined proteinuria occurred in 30.7 and 57.9% of patients in the control and preexisting proteinuria groups, respectively, with significant differences in the all-patient population (P = 0.01). The preexisting proteinuria group exhibited significant defined proteinuria development within 7 days of regorafenib initiation, grade ≥ 3 symptoms, and treatment suspension owing to proteinuria. Similar results were obtained in the propensity score-matched population. According to multivariate logistic regression analysis, baseline proteinuria was a singular risk factor for defined proteinuria development (adjusted odds ratio; 3.76, 95% confidence interval; 1.45-9.75, P = 0.007). Collectively, our study revealed that patients with preexisting proteinuria develop regorafenib-induced proteinuria degradation., (© 2024. The Author(s).)

Background/aim: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC., Patients and Methods: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29)., Results: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999)., Conclusion: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To investigate the risk factors for gastrointestinal perforation in metastatic colorectal cancer patients receiving bevacizumab., Methods: We retrospectively reviewed 217 patients with metastatic colorectal cancer receiving bevacizumab to investigate the risk factors for gastrointestinal perforation. Three patients occurred intestinal perforation after receiving bevacizumab. We analyzed the clinical characteristics of three patients with intestinal perforation., Results: All patients receiving bevacizumab. Three of 217 patients occurred intestinal perforation after receiving bevacizumab. Patient no. 1 was 70 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab. Patient no. 2 was 59 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation after receiving bevacizumab, and recovered smoothly after symptomatic treatment. Patient no. 3 was 60 years old, female, having history of intestinal obstruction. The patient occurred intestinal perforation and ultimately died after receiving bevacizumab., Conclusions: Patients with advanced colorectal cancer receiving bevacizumab are at risk of gastrointestinal perforation. The patient's age, gender and history of bowel obstruction may be associated with gastrointestinal perforation., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Cadmium (Cd) is a prevalent heavy metal contaminant that can cause centrosome amplification (CA) and cancer. Since CA can initiate tumorigenesis, it is plausible that cadmium initiates tumorigenesis via CA. The present study investigated the signaling pathways underlying CA by Cd. Our findings confirmed that sub-toxic concentrations of Cd could induce CA in the HCT116 colon cancer cells, and revealed that reactive oxygen species (ROS), GCLM, CCDC85C and PLK4 were the signaling molecules that formed a pathway of ROS-GCLM-CCDC85C-PLK4. Cd not only increased the protein levels of CCDC85C and PLK4, but also promoted their distribution to the centrosomes. Molecular docking analysis revealed that CCDC85C and PLK4 had the binding potential. Indeed, antibodies against CCDC85C and PLK4 were able to pull down PLK4 and CCDC85C, respectively. Knockdown of CCDC85C decreased the Cd-promoted centrosomal distribution of PLK4. Similarly, knockdown of PLK4 reduced the centrosomal distribution of CCDC85C. Our results suggest that Cd activates ROS-GCLM pathway that triggers the expression of and binding between CCDC85C and PLK4, and promotes the translocation of CCDC85C-PLK4 complex to the centrosomes, which eventually leads to CA., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Herbal medicine is one of the most common fields explored for combating colon cancers, and Pimpinella anisum L. seeds (PAS) have been utilized widely as medicinal agents because of their increased essential oil (trans-anethole) contents. In this essence, our study investigates the toxic effect and chemoprotective potentials of PAS against azoxymethane (AOM)-induced colon cancer in rats. The toxicity trial for PAS conducted by clustering fifteen rats into three groups (five rats each): A, normal control had 10% Tween 20; B, ingested with 2 g/kg PAS; and C, supplemented with 4 g/kg PAS. The in vivo cancer trial was performed by using 30 rats (Sprague-Dawley) that were randomly adapted in five steel cages (six rats each): group A, normal controls received two subcutaneous injections of normal saline 0.09% and ingested orally 10% Tween 20; groups B-E, rats received two injections of 15 mg/kg of azoxymethane (AOM) subcutaneously in 2 weeks and treated orally with 10% Tween 20 (group B) or intraperitoneal injection of 5-fluorouracil (35 mg/kg) (group C), or orally given 200 mg/kg PAS (group D) and 400 mg/kg PAS (group E) for 8 weeks. After the scarification of rats, the colon tissues were dissected for gross and histopathological evaluations. The acute toxicity trial showed the absence of any toxic signs in rats even after 14 days of ingesting 4 g/kg of PAS. The chemoprotective experiment revealed significant inhibitory potentials (65.93%) of PAS (400 mg/kg) against aberrant crypto foci incidence that could be correlated with its positive modulation of the immunohistochemically proteins represented by a significant up-regulation of the Bax protein and a decrease of the Bcl-2 protein expressions in colon tissues. Furthermore, PAS-treated rats had notably lower oxidative stress in colon tissues evidenced by decreased MDA levels and increased antiradical defense enzymes (SOD, CAT, and GPx). The outcomes suggest 400 mg/kg PAS as a viable additive for the development of potential pharmaceuticals against colorectal cancer., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Colorectal cancer, which is the third leading cause of cancer-related deaths worldwide, is a multistep disease, featuring preneoplastic aberrant crypt foci (ACF) as the early morphological manifestation. The roles of hemichannel-forming transmembrane Pannexin 1 (Panx1) protein have not been investigated in the context of colon carcinogenesis yet, although it has contrasting roles in other cancer types. Thus, this study was conducted to examine the effects of Panx1 knockout (Panx1 -/- ) on the early events of chemically induced colon carcinogenesis in mouse. Wild type (WT) and Panx1 -/- female C57BL6J mice were submitted to a chemically induced model of colon carcinogenesis by receiving six intraperitoneal administrations of 1,2-dimethylhydrazine (DMH) carcinogen. Animals were euthanized 8 h (week 7) or 30 weeks (week 37) after the last DMH administration in order to evaluate sub-acute colon toxicity outcomes or the burden of ACF, respectively. At week 7, Panx1 genetic ablation increased DMH-induced genotoxicity in peripheral blood cells, malondialdehyde levels in the colon, and apoptosis (cleaved caspase-3) in colonic crypts. Of note, at week 37, Panx1 -/- animals showed an increase in aberrant crypts (AC), ACF mean number, and ACF multiplicity (AC per ACF) by 56%, 57% and 20%, respectively. In essence, our findings indicate that Panx1 genetic ablation promotes preneoplastic ACF development during chemically induced mouse colon carcinogenesis, and a protective role of Panx1 is postulated., (© 2023 Company of the International Journal of Experimental Pathology (CIJEP).)

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender ( HR =1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments ( HR =0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

Objective: This study aims to investigate the potential of mustard oil-induced reduction in acetylcholine expression as a means to delay the progression of colon cancer within the internal environment., Methods: The study design in this research involved both in vitro cellular experiments and in vivo animal experiments to employ mustard oil to modulate acetylcholine expression levels and evaluate its impact on colon cancer. Cellular experiments involved the introduction of six concentrations of acetylcholine (10-2, 10-3, 10-4, 10-5, 10-6, and 10-7 mol/L) into colon cancer cell cultures to monitor cell proliferation. Animal experiments encompassed the subcutaneous CT26 colon cancer cells implantation into 28 Balb/c mice, divided into experimental and control groups. After tumor establishment, both groups were fed standard diets for two weeks. Serum acetylcholine concentrations were measured from eye blood samples. Additionally, Balb/c mice were inoculated with CT26-derived colon cancer cells and further categorized into experimental and control groups. A total of 14 mice comprised each group, with experimental mice fed mustard oil and control mice fed soybean oil. Post two weeks, serum acetylcholine expression in both groups was assessed. After sacrifice, subcutaneous tumors were excised, and tumor dimensions were measured using a Vernier scale., Results: Acetylcholine concentration augmentation in the culture medium corresponded to gradual cell proliferation escalation, peaking at 10-5 mol/L, exhibiting statistical significance. Comparative analysis revealed significantly elevated relative acetylcholine expression levels in Balb/c mice with tumor-bearing colon cancers compared to normal Balb/c mice. Experimental group mice exhibited substantially lower serum acetylcholine concentrations than control group mice. Mustard oil administration effectively curtailed acetylcholine expression in normal Balb/c mice, consequently retarding tumor growth. These findings underscore mustard oil's potential to diminish serum acetylcholine expression, thereby delaying colon cancer progression., Conclusions: This study suggests that mustard oil's modulation of acetylcholine expression within the internal environment holds the potential for impeding colon cancer growth.

Background and Aim: There is an increased risk of colon cancer associated with inflammatory bowel disease (IBD). Dietary fibers (DFs) naturally present in vegetables and whole grains offer numerous beneficial effects on intestinal health. However, the effects of refined DFs on intestinal health remain unclear. Therefore, we elucidated the impact of the refined DF inulin on colonic inflammation and tumorigenesis., Methods: Four-week-old wild-type (WT) mice were fed diets containing insoluble DF cellulose (control) or refined DF inulin for 4 weeks. A subgroup of mice was then switched to drinking water containing dextran sulfate sodium (DSS, 1.4% wt/vol) for colitis induction. In another subgroup of mice, colitis-associated colorectal cancer (CRC) was initiated with three 7-day alternate cycles of DSS following an initial dose of mutagenic substance azoxymethane (AOM; 7.5 mg/kg body weight; i.p.). Post 7 weeks of AOM treatment, mice were euthanized and examined for CRC development., Results: Mice consuming inulin-containing diet exhibited severe colitis upon DSS administration, as evidenced by more body weight loss, rectal bleeding, and increased colonic inflammation than the DSS-treated control group. Correspondingly, histological analysis revealed extensive disruption of colon architecture and massive infiltration of immune cells in the inulin-fed group. We next examined the effect of inulin on CRC development. Surprisingly, significant mortality (~50%) was observed in the inulin-fed but not in the control group during the DSS cycle. Consequently, the remaining inulin-fed mice, which completed the study exhibited extensive colon tumorigenesis. Immunohistochemical characterization showed comparatively high expression of the cell proliferation marker Ki67 and activation of the Wnt signaling in tumor sections obtained from the inulin-fed group. Gut microbiota and metabolite analysis revealed expansion of succinate producers and elevated cecal succinate in inulin-fed mice. Human colorectal carcinoma cells (HCT116) proliferated more rapidly when supplemented with succinate in an inflamed environment, suggesting that elevated luminal succinate may contribute to tumorigenesis., Conclusions: Our study uncovers that supplementation of diet with refined inulin induces abnormal succinate accumulation in the intestinal lumen, which in part contributes to promoting colon inflammation and tumorigenesis., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

This study researched the mineral composition of Korean washed-dehydrated solar salt (WDS) without bittern. It also evaluated the anticancer effects of doenjang (WDSD) prepared using WDS on azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer in C57BL/6 mice. The mineral composition of WDS showed lower Mg (11.71 ± 1.89 g/kg) and S (9.77 ± 2.88 g/kg) contents, and it was confirmed that mice in the WDSD group (AOM/DSS+WDSD) displayed significantly lower weight loss, colon length reduction, and tumor formation compared with the control (Con) group. In addition, pathologically, it was confirmed that the extent of epithelial cell damage and inflammation in the colon tissue of the WDSD group was restored to a state similar to that of the Nor group. Besides, WDSD regulated the protein expression of apoptosis (Bcl-2-associated X protein [Bax], B cell lymphoma-2 [Bcl-2], B cell lymphoma-extra large [Bcl-xL], and caspase 9, caspase 3), and p53, p21, and proinflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]- α ), thereby inducing the apoptosis and cell cycle arrest of cancer cells and suppressing inflammation. In addition, the intestinal microbiota of the mice treated with WDSD were more diverse, with an abundance of Bifidobacterium , a lactic acid bacterium beneficial to colon health, was also a greater presence of Faecalibaculum , which showed antitumor effects. These results indicate that solar salts and their different processing methods affect their functional health-promoting properties. In addition, the inhibitory effect on colon cancer was further enhanced when doenjang was prepared with WDS with low Mg and S content.

Colon cancer is one of the most common types of cancer worldwide, and its incidence is increasing. Despite advances in medical science, the treatment of colon cancer still poses a significant challenge. This study aimed to investigate the potential protective effects of Adiantum pedatum (AP) extract and/or piceatannol on colon cancer induced via phenylhydrazine (PHZ) in terms of the antioxidant and apoptotic pathways and histopathologic changes in the colons of male albino rats. The rats were randomly divided into eight groups: control, AP extract, piceatannol (P), PHZ, PHZ and AP treatments, PHZ and P treatments, PHZ and both AP and P, and PHZ and prophylaxis with both AP and P. The results demonstrated that PHZ induced oxidative damage, apoptosis, and histopathological changes compared to the control group. However, the administration of AP or P or AP + P as therapy or prophylaxis significantly ameliorated these changes and upregulated the colonic mir-145 and mRNA expression of P53 and PDCD-4 while downregulating the colonic mRNA expression of PI3K, AKT, c-Myc, CK-20, SOX-2, OCT-4, and NanoG compared to the PHZ group. These findings suggest that the candidate drugs may exert their anti-cancer effects through multiple mechanisms, including antioxidant and apoptotic activities.

Objective: The primary endpoint of the present study was to assess the potential therapeutic effects of three different mouthwashes for alleviation and treatment of oral complications (OCs). The secondary endpoint was to assess patients' perceptions and daily functional activities after therapy of OCs in patients with colon cancer receiving 5-fluorouracil (5-FU)-based chemotherapy regimens., Methods: A prospective, randomised controlled study carried out on 90 patients with colon cancer eligible for 5-FU-based chemotherapy regimens at the oncology centre, Istanbul, Turkey. Patients were randomly randomised into three groups (30 patients in each group) and received a single mouthwash. The first group (group A) received benzydamine at a dose of 15 mL; the second group (group B) received sodium bicarbonate at a dose of 1.2-2.4 g in 240 mL of water; and the third group (group C) received glutamine suspension 10 g. Patients were assessed for the occurrence of oral complications based on the WHO scale for oral mucosa evaluation and National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Oral pain was assessed using a visual analogue scale alongside assessment of patients' perceptions and daily functional activities based on the Rotterdam Symptom Checklist., Results: A total of 119 oral complications were reported, including mouth dryness (n=56, 47.1%), oral mucositis (n=31, 26.1%) and oral pain (n=32, 26.8%). At the end of the study, patients of group A and group B significantly suffered from mouth dryness (p=0.0001), oral mucositis (p=0.029) and oral pain (p=0.039) compared with patients in group C. Although there was no significant change, group C patients showed a slight improvement in psychological discomfort, activity levels and quality of life at the end of the study., Conclusion: The present study showed that benzydamine and sodium bicarbonate mouthwashes were significantly less effective for the alleviation and treatment of oral complications compared with glutamine among patients with colon cancer receiving 5-FU-based chemotherapy regimens., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

1,2-Dimethylhydrazine (DMH) is a plant toxicant that enters the food web through the diet. It is biotransformed into azoxymethane, a colon carcinogen, during the first hepatic passage. In mice, this study assessed the role of glutamate dehydrogenase (GDH), a key glutaminolysis enzyme in DMH-induced colorectal cancer (CRC). Colon samples were taken from mice given 6 or 15 weekly doses of 20 mg/kg DMH and serially sacrificed. Repeated DMH doses induced early aberrant crypt foci that evolved into irreversible adenocarcinomas over 24 weeks, along with an increase in GDH and lactate dehydrogenase activities (+ 122%, + 238%, P < 0.001), indicating a switch to aerobic glycolysis and glutaminolysis. Transcriptional downregulation of the endogenous GDH inhibitor, sirtuin4, and two redox regulators, mitochondrial sestrin2 and nuclear factor (erythroid derivative 2)-like 2 (- 26% and - 22%, P < 0, 05; and - 30%, P < 0.01), exacerbated mitochondrial stress by boosting mitochondrial superoxide dismutase activity (+ 240% (P < 0.001) while depressing catalase activity and GSH levels (- 57% and - 60%, P < 0.001). In vitro, allosteric GDH inhibition by 50 µM epigallocatechin gallate decreased human carcinoma (HCT-116) cells' viability, clonogenicity, and migration (- 43% and - 57%, P < 0.001, 41%, P < 0.05), while stimulating ROS release (+ 57%, P < 0.001). Dimethylfumarate (DMF), a linear electrophile and mitochondrial fumarate analog, rebalanced ROS levels (- 34%, P < 0.05) and improved GDH activity, cell viability, and tumorogenic capacity (+ 20%, 20%, P < 0.001; and 33%, P < 0.05). Thus, the pathological remodeling of colon mucosa is supported by metabolic reprogramming bypassing uncoupled mitochondria. DMF highlights the critical role of electrophile response elements in modulating redox mithormesis and redox homeostasis during CRC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Colon cancer was the second leading cause of cancer-related death in 2019. We herein investigated the effects of acertannin containing Acer species on azoxymethane (AOM)/dextran sulfate sodium (DDS)-induced colon cancer growth and changes in the colonic levels of interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1, IL-10, and programmed cell death-1 (PD-1). Colorectal carcinogenesis was induced by an intraperitoneal injection of AOM (10 mg/kg) on days 0 and 27. Mice were given 1% (w/v) DSS drinking water ad libitum on days 7-14, 32-33, and 35-38. Acertannin (30 and 100 mg/kg) was orally administered on days 1-16, discontinued for 11 days (days 16-26), and then administered again on days 27-41. The colonic levels of cytokines, a chemokine, and PD-1 were measured using the respective ELISA kits. The number and area of tumors in mice treated with acertannin (100 mg/kg) decreased by 53.9 and 63.1%, respectively. Furthermore, the colonic levels of IL-1β, MCP-1, IL-10, and PD-1 showed reductions of 57.3, 62.9, 62.8, and 100%, respectively, while the numbers of cyclooxygenase-2 (COX-2)-, thymocyte selection-associated high mobility group box proteins (TOX)/TOX2-, PD-1-, and signal transducer and activator of transcription 3 (STAT3) phosphorylation-positive numbers decreased by 79.6, 77.9, 93.8, and 100%, respectively. In conclusion, the inhibitory effects of acertannin on AOM/DSS-induced colon tumor growth appear to be associated with reductions in the colonic levels of IL-1β, MCP-1, IL-10, and PD-1 through the down-regulated expression of COX-2 and TOX/TOX2 in the tumor microenvironment., Competing Interests: Declaration of competing interest The authors declare that this research was conducted in the absence of any commercial or financial relationships that may be construed as a potential conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Despite being shown to be effective for chemoprevention of colorectal cancer, aspirin has limitations including adverse effects and inability to block colitis-associated colon cancer (CAC). γ-Tocopherol (γT), a vitamin E form, has been reported to mitigate experimental colitis and CAC, prolong the anti-inflammatory activity of aspirin and alleviate aspirin-induced adverse effect. We therefore hypothesize that combining γT and aspirin is better than either compound singly for suppressing CAC. This hypothesis was tested in the murine azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model and with human HCT116 colon cancer cells. Compared to the control, combining aspirin (250 ppm) and γT (500 ppm) but not either compound alone significantly reduced AOM/DSS-induced tumor area and multiplicity of large-size tumors by 60% and 50%, respectively. Meanwhile, γT mitigated aspirin-promoted inflammation and stomach lesions in mice. Moreover, the combination appeared to cause favorable changes of gut microbiota compared to the control and synergistically suppressed the growth of HCT116 cells. Our study demonstrates that combining aspirin and γT improves anticancer effects and counteracts side effects compared to aspirin and may therefore be a novel combinatory chemopreventive agent against CAC., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Colon cancer was the second leading cause of cancer-related deaths in Japan in 2019. The effects of geniposide isolated from Gardenia jasminoides fructus (Rubiaceae) on the azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced growth of colon tumors and changes in interleukin (IL)-1 β, monocyte chemoattractant protein (MCP)-1, IL-10, and programmed cell death-1 (PD-1) levels in the colon were investigated. The intraperitoneal administration of AOM (10 mg/kg) on days 0 and 27 induced colorectal carcinogenesis. Free access to 1% (w/v) DSS drinking water was given to mice on days 7-15, 32-33, and 35-38. Geniposide (30 and 100 mg/kg) was orally administered on days 1-16, discontinued for 11 days (days 16 to 26), and then administered again on days 27-41. Colonic levels of cytokines, chemokine, and PD-1 were measured using by enzyme-linked immunosorbent assay (ELISA). Increases in colorectal tumor numbers and areas were significantly inhibited by geniposide. In addition, geniposide (100 mg/kg) reduced colonic levels of IL-1 β, MCP-1, PD-1 and IL-10 by 67.4, 57.2, 100%, and 100% respectively. Cyclooxygenase (COX)-2- and thymocyte selection high mobility group box proteins (TOX/TOX2)-positive cell numbers were significantly reduced by geniposide. Geniposide (30 and 100 mg/kg) decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) expressions in immunohistochemical analysis by 64.2 and 98.2%, respectively. Thus, the inhibitory effects of geniposide on colon tumor growth may be associated with reductions in the colonic levels of IL-1 β, MCP-1, IL-10, and PD-1 via the down-regulated expression of COX-2 and TOX/TOX2 through the inhibition of Phospho-STAT3 expression (in vivo and in vitro)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [I (Yoshiyuki Kimura) declare that this research was conducted in the absence of any commercial or financial relationships that may be construed as a potential conflict of interest]., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Colon carcinoma stands as the most familiar malignancy throughout across the globe. Raptinal induce apoptosis through the alteration of cellular events. Thus, in the present investigation, the anticancer activity of raptinal counter to 1,2-dimethylhydrazine (DMH) persuaded colon carcinoma has been evaluated through both in vivo and in vitro systems., Materials and Methods: The pharmacophore analysis demonstrated the binding efficacy of raptinal with the apoptotic proteins. The chemotherapeutic activity of raptinal was examined through HT-29 human colorectal cancer (CRC) cell line as well as DMH persuaded CRC in the rat model. The cytotoxicity analysis, flow cytometry, and DAPI analysis have been carried out on HT-29 cell line through in vitro assessment. The colon carcinoma has been induced through DMH administration and subsequently Dextran sulfate sodium treatment in male Wistar rats. After 18 weeks of raptinal treatment, the colon tissues have been investigated for aberrant crypt foci (ACF) count, antioxidant status, histology, immunohistochemical assessment, and apoptotic analysis., Results: The raptinal therapy on HT-29 cells demonstrated a substantial % of early apoptosis followed by G0 and G1 phase arrest, which subsequently led to apoptosis. Furthermore, it inhibits ACF development with improved colonic abrasions and structural integrity of colonic mucosa with increased levels of antioxidants, proapoptotic biomarkers including p53, caspase-3, Bax and downstream effects of Bcl-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 mutation., Conclusions: These findings indicate the raptinal effectively reduces colon cancer by inducing apoptosis through p53/Bcl2/Bax/caspase-3 pathway and suppressing IL-6, TNF-mediated chronic inflammation in the colon cancer microenvironment., Competing Interests: None

Colorectal cancer (CRC) ranks third among fatal diseases afflicting mankind globally due to the shortage of primary detection methods and appropriate choice of drugs. Moreover, current treatments such as chemo drugs and radiotherapies create adverse effects and lead to drug resistance. In this context, recent advances in nanomedicine offer novel clinical solutions for colon cancer therapy. The current study denotes the therapeutic roles of biogenic Abutilon indicum silver and gold nanoparticles (AIAgNPs and AIAuNPs) against a 1, 2-dimethyl hydrazine (DMH)-induced CRC in Wistar rats. Following treatment of nanoparticles (NPs), the CRC rats showed great localization of AIAgNPs and AIAuNPs in colon tumors shown by ICP-OES, indicating their bioavailability. The AIAgNPs and AIAuNPs significantly enhanced cellular antioxidant enzyme levels including catalase, SOD, GSH, GPx and reduced lipid peroxidation (LPO) compared to the standard drug paclitaxel. AIAgNPs and AIAuNPs revealed significant protection against metastasis compared to paclitaxel shown in the histopathological study. The important CRC signaling molecules of the Wnt pathway, the β-catenin and Tcf-4 levels were significantly downregulated in AIAgNPs and AIAuNPs treated CRC rats compared to paclitaxel. Furthermore, the expression levels of cleaved apoptotic caspase-9, -8, and - 3 and lamins were significantly upregulated in AIAgNPs and AIAuNPs treated CRC rats compared to paclitaxel. This preclinical study provides substantial insights into the anti-colon cancer roles of biogenic NPs and gives an idea for targeting different cancers., Competing Interests: Declaration of competing interest The authors declare that, there were no conflicts of interest associated with this publication., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Napabucasin is an investigational, orally administered reactive oxygen species generator bioactivated by intracellular antioxidant NAD(P)H:quinone oxidoreductase 1 that has been evaluated in various solid tumors, including metastatic colorectal cancer (mCRC). Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is hypothesized to predict response in napabucasin-treated patients with mCRC., Patient and Methods: In the multi-center, open-label, phase III CanStem303C (NCT02753127) study, adults with histologically confirmed mCRC that progressed on first-line fluoropyrimidine plus oxaliplatin ± bevacizumab were randomized to twice-daily napabucasin plus FOLFIRI (napabucasin) or FOLFIRI alone (control). The primary endpoint was overall survival (OS) in the general study population and in patients with pSTAT3-positive tumors (biomarker-positive)., Results: In the general study population (napabucasin, n = 624; control, n = 629), median OS was 14.3 months for napabucasin and 13.8 months for control (hazard ratio [HR], 0.976, one-sided P = .74). Overall, 44% of patients were biomarker-positive (napabucasin, n = 275; control, n = 272). In the biomarker-positive population, median OS was 13.2 months for napabucasin and 12.1 months for control (HR, 0.969; one-sided P > .99). In the control arm, median OS was shorter for biomarker-positive versus biomarker negative patients (12.1 vs. 18.5 months; HR, 1.518; nominal 2-sided P = .0002). The most common treatment-emergent adverse events (TEAEs) were diarrhea (napabucasin, 84.6%; control, 53.9%), nausea (60.5%, 50.5%), vomiting (41.2%, 29.3%), and abdominal pain (41.0%, 25.2%). Grade ≥3 TEAEs occurred in 73.8% of napabucasin-treated and 66.7% of control-treated patients, most commonly diarrhea (21.2%, 7.0%), neutrophil count decreased (13.7%, 19.2%), and neutropenia (13.3%, 15.2%). Safety was similar in biomarker-positive patients., Conclusion: In patients with previously treated mCRC, adding napabucasin to FOLFIRI did not improve OS. Results from the control arm indicate that pSTAT3 is an adverse prognostic factor in mCRC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cytidine deaminase (CDA) catalyzes the deamination of cytidine (C) and deoxycytidine (dC) to uridine and deoxyuridine, respectively. We recently showed that CDA deficiency leads to genomic instability, a hallmark of cancers. We therefore investigated whether constitutive CDA inactivation conferred a predisposition to cancer development. We developed a novel mouse model of Cda deficiency by generating Cda-knockout mice. Cda +/+ and Cda -/- mice did not differ in lifetime phenotypic or behavioral characteristics, or in the frequency or type of spontaneous cancers. However, the frequency of chemically induced tumors in the colon was significantly lower in Cda -/- mice. An analysis of primary kidney cells from Cda -/- mice revealed an excess of C and dC associated with significantly higher frequencies of sister chromatid exchange and ultrafine anaphase bridges and lower Parp-1 activity than in Cda +/+ cells. Our results suggest that, despite inducing genetic instability, an absence of Cda limits the number of chemically induced tumors. These results raise questions about whether a decrease in basal Parp-1 activity can protect against inflammation-driven tumorigenesis; we discuss our findings in light of published data for the Parp-1-deficient mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Colorectal cancer is the third most diagnosed cancer worldwide and linked to dietary/lifestyle factors. Arthrospira ( Spirulina) platensis (AP) contains bioactive compounds with beneficial effects in vivo / in vitro . We evaluated the effects of AP feeding against 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male Sprague Dawley rats were given subcutaneous injections of DMH (4 × 40 mg/kg body weight) (G1-G3) or vehicle (G4-G5) twice a week (weeks 3-4). During weeks 1-4, animals were fed a diet containing 1 % (G2) or 2 % (G3-G4) AP powder (w/w). After this period, all groups received a balanced diet until week 12. Some animals were euthanised after the last DMH injection (week 4) for histological, immunohistochemical (Ki-67, γ -H2AX and caspase-3) and molecular analyses (real time-PCR for 91 genes), while other animals were euthanised at week 12 for preneoplastic aberrant crypt foci (ACF) analysis. Both AP treatments (G2-G3) significantly decreased the DMH-induced increase in γ -H2AX (DNA damage) and caspase 3 (DNA damage-induced cell death) in colonic crypts at week 4. In addition, Cyp2e1 (Drug metabolism), Notch1 , Notch2 and Jag1 genes (Notch pathway) and Atm, Wee1, Chek2, Mgmt, Ogg1 and Xrcc6 genes (DNA repair) were also down-regulated by 2 % AP feeding (G3) at week 4. A significant reduction in ACF development was observed in both AP-treated groups (G2-G3) at week 12. In conclusion, findings indicate that AP feeding reduced acute colonic damage after DMH, resulting in fewer preneoplastic lesions. Our study provided mechanistic insights on dietary AP-preventive effects against early colon carcinogenesis.

Background: Distinct sets of microbes contribute to colorectal cancer (CRC) initiation and progression. Some occur due to the evolving intestinal environment but may not contribute to disease. In contrast, others may play an important role at particular times during the tumorigenic process. Here, we describe changes in the microbiota and host over the course of azoxymethane (AOM)-induced tumorigenesis., Methods: Mice were administered AOM or PBS and were euthanised 8, 12, 24 and 48 weeks later. Samples were analysed using 16S rRNA gene sequencing, UPLC-MS and qRT-PCR., Results: The microbiota and bile acid profile showed distinct changes at each timepoint. The inflammatory response became apparent at weeks 12 and 24. Moreover, significant correlations between individual taxa, cytokines and bile acids were detected. One co-abundance group (CAG) differed significantly between PBS- and AOM-treated mice at week 24. Correlation analysis also revealed significant associations between CAGs, bile acids and the bile acid transporter, ASBT. Aberrant crypt foci and adenomas were first detectable at weeks 24 and 48, respectively., Conclusion: The observed changes precede host hyperplastic transformation and may represent early therapeutic targets for the prevention or management of CRC at specific timepoints in the tumorigenic process., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The aim: To study pro- and antioxidant systems indicators in rats with chemically induced colon carcinogenesis on the background of the reishi mushrooms dry extract use., Patients and Methods: Materials and methods: The study was performed on 120 white male rats. Chronic oncogenic intoxication was modeled by administering 1,2-dimethyl¬hydrazine (DMH) hydrochloride for 30 weeks (1 time per week). A dry extract from the reishi mushrooms was administered intragastrically daily at a dose of 100 mg/kg of the animal's body weight. Blood and liver samples were taken for research monthly. The state of the pro- and antioxidant systems was studied by the content of oxidative modification of proteins products, superoxide dismutase and catalase activity, contents of reduced glutathione and ceruloplasmin., Results: Results: An increase in the activity of free radical oxidation processes after DMH-induced colon carcinogenesis in rats is evidenced by a decrease in the super-oxide dismutase activity, catalase activity, content of reduced glutathione, an increase in the content of ceruloplasmin and products of oxidative modification of proteins in the blood serum and liver of animals. The effectiveness of the dry extract of reishi mushrooms and its positive effect on the state of pro- and antioxidant systems was experimentally proved., Conclusion: Conclusions: The use of the dry extract of reishi mushrooms under conditions of DMH-induced colon carcinogenesis in rats led to normalization of the anti¬oxidant protection system state and the reduction of oxidative stress.

Recently it has been reported that the tumor adjacent colon tissues of 1,2-dymethylhydrazine induced (DMH)-rats revealed a high paracellular permeability. We hypothesized that the changes might be induced by cytokines. Colorectal cancer is accompanied by an increase in tumor necrosis factor alpha (TNFα) and interleukin 10 (IL10) that exert opposite regulatory effects on barrier properties of the colon, which is characterized by morphological and functional segmental heterogeneity. The aim of this study was to analyze the level of TNFα and IL10 in the colon segments of DMH-rats and to investigate their effects on barrier properties of the proximal and distal parts of the colon in healthy rats. Enzyme immunoassay analysis showed decreased TNFα in tumors in the distal part of the colon and increased IL10 in proximal tumors and in non-tumor tissues. Four-hour intraluminal exposure of the colon of healthy rats with cytokines showed reduced colon barrier function dependent on the cytokine: TNFα decreased it mainly in the distal part of the colon, whereas IL10 decreased it only in the proximal part. Western blot analysis revealed a more pronounced influence of IL10 on tight junction (TJ) proteins expression by down-regulation of the TJ proteins claudin-1, -2 and -4, and up-regulation of occludin only in the proximal part of the colon. These data may indicate a selective role of the cytokines in regulation of the barrier properties of the colon and a prominent role of IL10 in carcinogenesis in its proximal part.

Colorectal adenoma appears as benign lesions and is a precursor of colorectal adenocarcinoma. The effect of 6-Shogaol (6-[S]), a bioactive agent from ginger, in early colonic adenoma growth is unknown. As a result, this study examines the effect of 6-[S] in a mouse colorectal adenoma model induced by Azoxymethane (AOM) and dextran sulfate sodium (DSS). Adult male mice served as control in Group 1. Group 2 was treated orally with 6-[S] extract (20 mg/kg BW). Group 3 was exposed to AOM (25 mg/kg BW, ip) and one cycle of DSS (2.5%) in drinking water alone while Group 4 was co-treated with 6-[S] for twenty-one (21) days. The body weight gain, organ weight and length, oxidative stress indices, inflammatory markers and histological examination were estimated. Our findings show that 6-[S] co-treatment reversed AOM/DSS-induced elevation in colon weight, colon length, nitric oxide (NO), myeloperoxidase (MPO), hydrogen peroxidase (H 2 O 2 ), and tumor necrosis factor-alpha (TNF-α). However, the antioxidant enzyme activities measured namely catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and glutathione-S-transferase were significantly increased in 6-[S] treated mice. Taken together, the protective effect of 6-[S] on oxidative burden, inflammation, and histological aberration observed in the colon of the AOM/DSS model of adenoma growth in mice is mediated primarily owing to its anti-inflammatory and anti-oxidative properties. Thus, this study reveals 6-[S] as a useful agent in the possible clinical intervention of colorectal adenoma. PRACTICAL APPLICATIONS: Certain spices have been reported to have numerous phytochemicals with numerous medicinal purposes. However, no studies have been conducted to investigate the role of 6-[S], a phytochemical found in ginger, in the treatment of colorectal adenoma. The study's findings show that 6-[S] is protective in early colonic cancer development, as it manages colorectal adenoma cancer models of AOM/DSS. As a result, 6-[S]'s ability to reduce oxidative stress and inflammation in the colon may be a potential nutritional therapeutic adjuvant for colorectal adenoma., (© 2022 Wiley Periodicals LLC.)

As colorectal cancer (CRC) is largely due to modifiable lifestyle habits, the awareness on its risk factors is highly important. Dietary fatty acids have been linked to CRC risk. We explored the association between dietary trans fatty acids (TFAs) intake and CRC risk. We analyzed 865 CRC cases (434 in colon and 404 in rectum) and 3206 controls of the IROPICAN study, with data collected by trained interviewers using validated questionnaires. TFAs intake (industrial and ruminant types) was categorized into quartiles. Multivariate logistic regression models were built to calculate the odds ratios (OR) for the association between CRC and TFAs. We observed a positive association between industrial TFAs and colon cancer (OR for highest vs lowest quartile [OR Q4vsQ1 ] = 1.28, 95% confidence interval 1.07-1.54). A higher association was observed between industrial TFAs and CRC, occurring after 50 years of age. In addition, elaidic acid was associated with an increased risk of colon (OR Q4vsQ1 = 1.58, 1.24-2.02) and specifically of proximal colon cancer (OR Q4vsQ1 = 2.12, 1.40-3.20), as well as of rectum cancer (OR Q4vsQ1 = 1.40, 1.07-1.83). An inverse association was observed between ruminant TFAs intake and colon cancer risk (OR Q4vsQ1 = 0.80, 0.67-0.97). Industrial TFAs, such as semisolid/solid hydrogenated oils, may increase the risk of CRC, especially colon and proximal colon cancer. In contrast, ruminant TFAs do not appear to be associated with CRC. Awareness programs and regulatory actions regarding hydrogenated oils are warranted, given their high consumption through ultra-processed foods in more developed and less developed countries.

In recent decades there has been a dramatic increase in the incidence and prevalence of inflammatory bowel disease (IBD), a chronic inflammatory disease of the intestinal tissues and a major risk factor of developing colon cancer. While accumulating evidence supports that the rapid increase of IBD is mainly caused by exposure to environmental risk factors, the identities of the risk factors, as well as the mechanisms connecting environmental exposure with IBD, remain largely unknown. Triclosan (TCS) and triclocarban (TCC) are high-volume chemicals that are used as antimicrobial ingredients in consumer and industrial products. They are ubiquitous contaminants in the environment and are frequently detected in human populations. Recent studies showed that exposure to TCS/TCC, at human exposure-relevant doses, increases the severity of colitis and exacerbates colon tumorigenesis in mice, suggesting that they could be risk factors of IBD and associated diseases. The gut toxicities of these compounds require the presence of gut microbiota, since they fail to induce colonic inflammation in mice lacking the microbiota. Regarding the functional roles of the microbiota involved, gut commensal microbes and specific microbial β-glucuronidase (GUS) enzymes mediate colonic metabolism of TCS, leading to metabolic reactivation of TCS in the colon and contributing to its subsequent gut toxicity. Overall, these results support that these commonly used compounds could be environmental risk factors of IBD and associated diseases through gut microbiota-dependent mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Multiple animal models have been developed to investigate the pathogenesis of colorectal cancer and to evaluate potential treatments. One model system uses azoxymethane, a metabolite of cycasin, alone and in conjunction with dextran sodium sulfate to induce colon cancer in rodents. Azoxymethane is metabolized by hepatic P450 enzymes and can also be eliminated through the kidneys. In this study, C57BL/6J mice were fed either standard or high-fat diet and then all mice received azoxymethane at 10 mg/kg body weight twice a week for 6 wk. Shortly after the end of treatment, high mortality occurred in mice in the high-fat diet group. Postmortem examination revealed hepatic and renal pathology in mice on both diets. Histologic changes in liver included hepatocytomegaly with nuclear pleomorphism and bile duct hyperplasia accompanied by mixed inflammatory-cell infiltrates. Changes in the kidneys ranged from basophilia of tubular epithelium to tubular atrophy. The results indicate that further optimization of this model is needed when feeding a high-fat diet and giving multiple azoxymethane doses to induce colon cancer in C57BL/6J mice.

Colorectal cancer (CRC) is the third most common malignancy worldwide and the second most deadly cancer. Scientists have projected that by 2040, the prevalence will reach up to 3.2 million new cases annually due to population aging, disadvantageous diet transformations, and elevated exposure to risk factors. In the past decades, the five-year survival rate in colorectal cancer has significantly increased to 65% due to the development of an early endoscopic diagnosis and new chemotherapeutic approaches. Fluoropyrimidines, such as 5-fluorouracil or capecitabine, are commonly used to treat CRC. One of the most fundamental mechanisms of 5-FU is based on the inhibition of thymidylate synthase. This action is responsible for the therapeutic, but also toxic, effects of the drug. In this short review, we discuss the possible effects of vitamin D activity on colorectal cancer cells in relation to fluoropyrimidines. PubMed, Embase, and Web of Science databases were searched up to January 2022 for studies on vitamin D and 5-fluorouracil interaction mechanisms. Original studies, case reports, and review articles were included. Vitamin D or its analogs target multiple biochemical pathways and modulate numerous pathophysiological mechanisms in the course of colon cancer, including those related to the pharmacological sites of fluoropyrimidines. However, the available data concerning vitamin D-fluoropyrimidine pharmacological interactions are limited, especially regarding patients suffering from colon cancer and being treated with fluoropyrimidines.s.

Colorectal cancer was inducted in Wister rats using titanium dioxide nanoparticles (TiO 2 NPs) and dimethylhydrazine (DMH) and treatment using 5-fluorouracil (5-FU) and curcumin (CUR), individually and following a synergistic approach. Compatibility studies are evaluated by using FT-IR spectra analysis, and Vero cell lines as well as HCT-116 cell lines are used for evaluating the synergistic approach. It was then followed by induction of colorectal cancer in rats for 70 days and treatment using 5-FU and CUR with pectin coating (individually and in combination) for 28 days. The reports state that 5-FU and CUR combination was found to be compatible. The synergistic effect was evaluated for1:1, 1:2, 1:4, and 2:1 ratio of 5-FU:CUR, where 1:4 ratio shows a CI 50 value of 0.853, selected further for the animal studies. The 1:4 ratio of 5-FU and CUR (50:200) shows to be effective for the treatment of colorectal cancer within 28 days, proven using histopathology report, bodyweight analysis, and hematological reports. 5-FU and CUR (1:4) ratio with pectin coating was proven effective for the treatment of colorectal cancer induced by TiO 2 NPs with DMH and was found to produce a synergistic effect., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Contrary to many reports that antiplatelet agents inhibit cancer growth and metastasis, new solid tumors have been reported in patients receiving long-term antiplatelet therapy. We investigated the effects of these agents directly on cancer cells in the absence of platelets to mimic the effects of long-term therapy. When four antiplatelet agents (aspirin, clopidogrel, prasugrel, and ticagrelor) were administered to colon cancer cells, cancer cell proliferation was inhibited similarly to a previous study. However, surprisingly, when cells were treated with a purinergic P2Y12 inhibitor (purinergic antiplatelet agent), the motility of the cancer cells was significantly increased. Therefore, gene expression profiles were identified to investigate the effect of P2Y12 inhibitors on cell mobility, and Serpin family 1 (SERPINE1) was identified as a common gene associated with cell migration and cell death in three groups. Antiplatelet treatment increased the level of SERPINE1 in cancer cells and also promoted the secretion of SERPINE1 into the medium. Increased SERPINE1 was found to induce MMP1 and, thus, increase cell motility. In addition, an increase in SERPINE1 was confirmed using the serum of patients who received these antiplatelet drugs. With these results, we propose that SERPINE1 could be used as a new target gene to prevent the onset and metastasis of cancer in patients with long-term antiplatelet therapy.

Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro . In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper., (Copyright © 2022 Jue Wang et al.)

Bisphenol A (BPA) is a high-production-volume industrial chemical. Despite recent research conducted on its carcinogenicity, its role in the development of colon cancer (CC) has been rarely studied. This study aims to evaluate the effects of BPA on the migration and invasion of CC cells. First, we clinically verified that patients with CC exhibit higher serum BPA level than healthy donors. Subsequently, different CC cell lines were exposed to a series of BPA concentrations, and the migration and invasion of cells were detected by the wound healing test and transwell assay. Finally, N-acetyl-L-cysteine (NAC) and siHIF-1α intervention was used to explore the effects of ROS and HIF-1α on cell migration and invasion, respectively. The results demonstrated that the occurrence of BPA-induced migration and invasion were dependent on the dose and time and was most pronounced in DLD1 cells. ROS production was jointly driven by NADPH oxidase (NOX) and mitochondrial electron-transport chain (ETC). Furthermore, the intervention of NAC and siHIF-1α blocked the HIF-1α/VEGF/PI3K/AKT axis and inhibited cell migration and invasion. In conclusion, our results suggest that BPA exposure promotes the excessive production of ROS induced by NOX and ETC, which in turn activates the HIF-1α/VEGF/PI3K/AKT axis to promote the migration and invasion of CC cells. This study provides new insights into the carcinogenic effects of BPA on CC and warns people to pay attention to environmental pollution and the harm caused to human health by low-dose BPA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xia, Guo, Zhang, Song, Zhao, Cui and Liu.)

Centrosome amplification (CA) refers to a numerical increase in centrosomes resulting in cells with more than two centrosomes. CA has been shown to initiate tumorigenesis and increase the invasive potential of cancer cells in genetically modified experimental models. Hexavalent chromium is a recognized carcinogen that causes CA and tumorigenesis as well as promotes cancer metastasis. Thus, CA appears to be a biological link between chromium and cancer. In the present study, we investigated how chromium triggers CA. Our results showed that a subtoxic concentration of chromium-induced CA in HCT116 colon cancer cells, resulted in the production of reactive oxygen species (ROS), activated ATF6 without causing endoplasmic reticulum stress, and upregulated the protein level of PLK4. Inhibition of ROS production, ATF6 activation, or PLK4 upregulation attenuated CA. Inhibition of ROS using N-acetyl-l-cysteine (NAC) inhibited chromium-induced activation of ATF6 and upregulation of PLK4. ATF6-specific siRNA knocked down the protein level and activation of ATF6, and upregulated PLK4, with no effect on ROS production. Knockdown of PLK4 protein had no effect on chromium-induced ROS production or activation of ATF6. In conclusion, our results suggest that hexavalent chromium induces CA via the ROS-ATF6-PLK4 pathway and provides molecular targets for inhibiting chromium-mediated CA, which may be useful for the assessment of CA in chromium-promoted tumorigenesis and cancer cell metastasis., (© 2022 International Federation for Cell Biology.)

Colorectal cancer (CRC) can be either prevented or alleviated using conventional drugs combined with natural treatments. Andean berry (AB, Vaccinium meridionale Sw.) is an underutilized berry with promising anti-inflammatory and antiproliferative effects that could be used to alleviate CRC markers in combination with Aspirin, a well-known CRC preventive drug. This research aimed to evaluate the impact of Aspirin, AB juice (ABJ), and their mixture on colorectal cancer in vitro and in vivo. The treatments (ABJ: 0, 10, 20, and 30 % v/v; Aspirin: 0, 10, 15, and 20 mM; and their combination) were assessed on SW480 cells to test their antiproliferative and pro-apoptotic effect. To evaluate their chemopreventive and chemoprotective effect in vivo, azoxymethane (AOM, 15 mg/kg BW) was used as a chemical inductor of early-stage colon cancer. Balb/c mice (8 weeks' age) were randomly assigned to five groups (n = 6 mice/group): control (no treatment), positive control (AOM-treated mice), AOM + Aspirin (20 mM: 25 mg/kg BW), AOM + ABJ (30 % v/v), and AOM + Aspirin + ABJ (Aspirin: 25 mg/kg BW; ABJ: 30 % v/v). ABJ contained phenolic compounds such as 3,4-dihydroxybenzoic and gallic acids, morin, and rutin. The mixture showed a strongest antiproliferative effect than their counterparts (+10.39-46.23 %). Except for Aspirin (20 mM), the cells were not able to proliferate based on the cloning efficiency test. The mixture was the most effective treatment arresting the cell cycle and increasing G2/M cell population (p < 0.01). Aspirin and ABJ showed mainly intrinsic and extrinsic-mediated apoptotic processes, while the mixture decreased most pro-apoptotic (cytochrome C, DR4, DR5, TNFRSF1A, Bax, and Bad) and anti-apoptotic proteins (Hsp70, Hsp32, and XIAP) compared to the untreated cells. In silico simulations highlighted the interaction between rutin and catalase as the strongest affinity (-10.30 Kcal/mol). ABJ and the mixture decreased aberrant crypt foci in vivo compared to AOM-only treated mice and protected the colonic and liver architecture, this was latter used as a secondary indicator of AOM-metabolic activity. The chemopreventive approach was more effective, related to a prior regulation of cancer-protective mechanisms in vivo, alleviating the AOM-induced damage. The results indicated that Aspirin and ABJ mixtures exhibit antiproliferative and pro-apoptotic effects in SW480 cells inducing mechanisms linked to extrinsic (TNF and TRAIL-mediated apoptosis) and intrinsic (Bax and cytochrome C modulation) pathways. At in vivo levels, the treatments displayed defensive effects against the AOM-induced damage as observed by macroscopic measurements. However, more in vitro, and in vivo approaches are required to completely fulfill the pro-apoptotic, anti-proliferative, and chemopreventive/chemoprotective effects of ABJ., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Colorectal cancer (CRC) is one of most common cancers worldwide, with high rates of mortality. Epidemiological findings demonstrate that coffee consumption reduces the risk of developing CRC by ~13%. In general, in vivo and in vitro findings demonstrate the antiproliferative, antioxidant and proapoptotic effects of brewed coffee or major bioavailable coffee compounds. Thus, it was assessed whether caffeine (CAF) and/or chlorogenic acid (CGA) attenuates the early-stage of chemically induced mouse colon carcinogenesis. Male Swiss mice were submitted to a 1,2-dimethylhydrazine/deoxycholic acid (DMH/DCA)-induced colon carcinogenesis model. These animals received CAF (50 mg/kg), CGA (25 mg/kg) or CAF+CGA (50 + 25 mg/kg) intragastrically for five times/week for ten weeks. CAF+CGA had the most pronounced effects on decreasing epithelial cell proliferation (Ki-67) and increasing apoptosis (cleaved caspase-3) in colonic crypts. This treatment also decreased the levels of proinflammatory cytokines IL-6, IL-17 and TNF-α, and downregulated the oncomiR miR-21a-5p in the colon. Accordingly, the analysis of miR-21a-5p targets demonstrated the genes involved in the negative regulation of proliferation and inflammation, and the positive regulation of apoptosis. Ultimately, CAF+CGA attenuated preneoplastic aberrant crypt foci (ACF) development. Our findings suggest that a combination of coffee compounds reduces early-stage colon carcinogenesis by the modulation of miR-21a-5p expression, highlighting the importance of coffee intake to prevent CRC.

Previous studies have reported that dietary sphingomyelin could inhibit early stages of colon cancer. Lactic acid-producing bacteria have also been associated with an amelioration of cancer symptoms. However, little is known about the potential beneficial effects of the combined administration of both sphingomyelin and lactic acid-producing bacteria. This article analyzes the effect of a diet supplemented with a combination of the probiotics Lacticaseibacillus casei and Bifidobacterium bifidum (10 8  CFU/ml) and sphingomyelin (0.05%) on mice with 1,2-dimethylhydrazine (DMH)-induced colon cancer. Thirty-six BALB/c mice were divided into 3 groups: one healthy group (group C) and two groups with DMH-induced cancer, one fed a standard diet (group D) and the other fed a diet supplemented with sphingomyelin and probiotics (DS). The number of aberrant crypt foci, marker of colon cancer development, was lower in the DS. The dietary supplementation with the synbiotic reversed the cancer-induced impairment of galactose uptake in enterocyte brush-border-membrane vesicles. These results confirm the beneficial effects of the synbiotic on the intestinal physiology of colon cancer mice and contribute to the understanding of the possible mechanisms involved., (© 2022. The Author(s).)

Background: Colorectal cancer was the second leading cause of mortality in 2019 and the number of new colorectal cancer cases was the highest in 2018 and 2019 in Japan., Purpose: The present study investigated the inhibitory effects of 2(S)-2',5,6',7-tetrahydroxyflavanone and 2 (R), 3(R)-2',3,5,6'-7-pentahydroxyflavanone on the incidence and growth of tumors in azoxymethane (AOM) plus dextran sulfate sodium (DSS)-treated mice., Methods: The intraperitoneal administration of AOM (10 mg/kg) on day 0 induced colorectal carcinogenesis. Mice were given free and unlimited access to drinking water containing 1.5% (w/v) DSS on days 5 - 8, 30 - 33, and 56 - 57. They were orally administered tetra- and penta-hydroxyflavanones (10 and 30 mg/kg) for 10, 11, and 14 days followed by discontinuation intervals of 20 and 15 days. Cytokine, chemokine, programmed cell death-1 (PD-1), cyclooxygenase (COX)-2, and thymocyte selection-associated high mobility group box protein (TOX)/TOX2 expression levels were measured using their respective ELISA kits and an immunohistochemical analysis., Results: The number and area of tumors decreased by 60.6 and 72.9% in mice administered 10 mg/kg tetra- and pentahydroxyflavanones, respectively, with reductions of 95.0 and 87.0% in Ki-67-positive cells, 91.7 and 92.7% in COX-2-postive cells, and 83.1 and 93.8% in TOX/TOX2-positive cells, respectively, in the colon. On the other hand, two tera- and pentahydroxyflavanone had no effect on p53 (a tumor suppressor by cell cycle arrest and apoptosis)-positive cells. The administration of 10 mg/kg tetra- and pentahydroxyflavanones to AOM/DSS-treated mice also resulted in decreases of 59.5 and 42.5% in IL-10 levels and 58.1 and 93.9% in PD-1 levels, respectively, in the colon., Conclusion: The inhibitory effects of tetra- and pentahydroxyflavanones on the growth of colon tumors in AOM/DSS-treated mice appear to be associated with decreases in the colon levels of IL-10 and PD-1 through the down-regulated expression of COX-2 and CD8 + T-cell exhaustion by TOX/TOX2 in the tumor microenvironment., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Fusobacterium nucleatum ( F. nucleatum ) has long been known to cause opportunistic infections and has recently been implicated in colorectal cancer (CRC), which has attracted broad attention. However, the mechanism by which it is involved in CRC development is not fully understood., Aim: To explore its potential causative role in CRC development, we evaluated the colon pathology, mucosa barrier, colon microbiota and host transcriptome profile after F. nucleatum infection in an azoxymethane/dextran sulfate sodium salt (AOM/DSS) mouse model., Methods: Three groups of mice were compared to reveal the differences, i.e. , the control, AOM/DSS-induced CRC and AOM/DSS-FUSO infection groups., Results: Both the AOM/DSS and AOM/DSS-FUSO groups exhibited a significantly reduced body weight and increased tumor numbers than the control group, and AOM/DSS mice with F. nucleatum infection showed the highest tumor formation ratio among the three groups. Moreover, the colon pathology was the most serious in the AOM/DSS-FUSO group. We found that the structure of the colon microbiota changed considerably after F. nucleatum infection; striking differences in mucosal microbial population patterns were observed between the AOM/DSS-FUSO and AOM/DSS groups, and inflammation-inducing bacteria were enriched in the mucosal microbiota in the AOM/DSS-FUSO group. By comparing intestinal transcriptomics data from AOM vs AOM/DSS-FUSO mice, we showed that transcriptional activity was strongly affected by dysbiosis of the gut microbiota. The most microbiota-sensitive genes were oncogenes in the intestine, and the cyclic adenosine monophosphate signaling pathway, neuroactive ligand-receptor interaction, PPAR signaling pathway, retinol metabolism, mineral absorption and drug metabolism were highly enriched in the AOM/DSS-FUSO group. Additionally, we showed that microbial dysbiosis driven by F. nucleatum infection enriched eight taxa belonging to Proteobacteria , which correlates with increased expression of oncogenic genes., Conclusion: Our study demonstrated that F. nucleatum infection altered the colon mucosal microbiota by enriching pathogens related to the development of CRC, providing new insights into the role of F. nucleatum in the oncogenic microbial environment of the colon., Competing Interests: Conflict-of-interest statement: The authors declare no competing interests., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

In our previous research, Lactiplantibacillus plantarum-12 alleviated inflammation in dextran sodium sulfate (DSS)-induced mice by regulating intestinal microbiota and preventing colon shortening (p < 0.05). The purpose of the present study was to evaluate whether L. plantarum-12 could ameliorate the colon cancer symptoms of azoxymethane (AOM)/DSS-treated C57BL/6 mice. The results showed that L. plantarum-12 alleviated colonic shortening (from 7.43 ± 0.15 to 8.23 ± 0.25) and weight loss (from 25.92 ± 0.21 to 27.75 ± 0.88) in AOM/DSS-treated mice. L. plantarum-12 oral administration down-regulated pro-inflammatory factors TNF-α (from 350.41 ± 15.80 to 247.72 ± 21.91), IL-8 (from 322.19 ± 11.83 to 226.08 ± 22.06), and IL-1β (111.43 ± 8.14 to 56.90 ± 2.70) levels and up-regulated anti-inflammatory factor IL-10 (from 126.08 ± 24.92 to 275.89 ± 21.87) level of AOM/DSS-treated mice. L. plantarum-12 oral administration restored the intestinal microbiota dysbiosis of the AOM/DSS treated mice by up-regulating beneficial Muribaculaceae, Lactobacillaceae, and Bifidobacteriaceae levels and down-regulating pathogenic Proteobacteria, Desulfovibrionaceae, and Erysipelotrichaceae levels. As a result, the fecal metabolites of the AOM/DSS-treated mice were altered, including xanthosine, uridine, 3,4-methylenesebacic acid, 3-hydroxytetradecanedioic acid, 4-hydroxyhexanoylglycine, beta-leucine, and glycitein, by L. plantarum-12 oral administration. Furthermore, L. plantarum-12 oral administration significantly ameliorated the colon injury of the AOM/DSS-treated mice by enhancing colonic tight junction protein level and promoting tumor cells death via down-regulating PCNA (proliferating cell nuclear antigen) and up-regulating pro-apoptotic Bax. (p < 0.05). Taken together, L. plantarum-12 oral administration could ameliorate the colon cancer burden and inflammation of AOM-DSS-treated C57BL/6 mice through regulating the intestinal microbiota, manipulating fecal metabolites, enhancing colon barrier function, and inhibiting NF-κB signaling. These results suggest that L. plantarum-12 might be an excellent probiotic candidate for the prevention of colon cancer.