Interleukin-22 protects intestinal stem cells against genotoxic stress.

Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

Design and evaluation of a colon cancer mobile application.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer and the second cause of cancer-related deaths in the world. Despite the infrastructure and the availability of organized screening programs, participation in their screening programs is less than the set goals. Considering the importance of informing the society about the prevention and early detection of colorectal cancer symptoms and the positive impact of mobile health technologies, the present research was conducted with the aim of designing and evaluating a colon cancer mobile application. METHODS: The present research was conducted in two phases: software design and evaluation. In the first phase, the software was prepared using the cascade method. First, all the educational content related to colorectal cancer was collected through an expert panel with the participation of 10 specialists. Then the software was evaluated with alpha and beta testing, and the initial version was approved by users in terms of simplicity and usability. In the second phase, a parallel clinical randomized trial study was conducted with the aim of investigating the effect of a colon cancer mobile application on the early detection of colorectal cancer. In this stage, 204 volunteers participated; inclusion criteria were age 18-85 years, owning a smartphone and the ability to read and write. Participants were randomized into control and intervention groups. The intervention group was educated with the colon cancer application for education about colorectal cancer, and the control group was educated with a pamphlet. After education, both groups were screened for colorectal cancer symptoms, and the results were compared. RESULTS: In the software evaluation phase, the application was used by 204 users. In this stage, 84 (41.2%) women and 120 (58.8%) men, with an average (Standard Deviation) age of 47.53 (13.68) participated. Participants were randomized in two groups, 103 people with an average (Standard Deviation) age of 47.62 (14.65) in intervention group and 101 people with an average (Standard Deviation) age of 47.44 (12.70) in control group. There were no significant differences between the demographic characteristics of age, gender, marriage, occupation, instruction level, digestive disease history, cancer history, cancer risk factors, and family history of cancer between the two groups (P > 0.05). The Mann-Whitney U test indicated that there is a significant difference between the two groups of participants in self-assessment, willingness to do the screening, and the results of the assessment of colorectal cancer (P < 0.05). CONCLUSION: The results of the research indicated the positive impact of the Colon Cancer Application on the abilities of the users of self-assessment of colon cancer. Therefore, based on the findings, it can be concluded that the use of the colon cancer mobile application is effective for colon cancer prevention and self-care. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials ( https://irct.behdasht.gov.ir ) on 13/2/2024, with the IRCT ID: IRCT20210131050189N9.

Protective Role of Spermidine in Colitis and Colon Carcinogenesis.

BACKGROUND & AIMS: Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis. METHODS: SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed. RESULTS: SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd. CONCLUSIONS: Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.

GPR109a: the missing link between microbiome and good health?

A complex partnership between the host and the vast intestinal microbial ecosystem serves numerous biological activities including nutrition, immunity, and barrier function. In this issue of Immunity, Singh et al. (2014) demonstrate that microbial-derived butyrate mediated its protective activity against inflammation and colorectal cancer through GPR109a signaling.

Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis.

Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing T cells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 in colonic epithelium. Consequently, Niacr1(-/-) mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon.

Pre-diagnostic intake of vitamin D and incidence of colorectal cancer by anatomical subsites: the Norwegian Women and Cancer Cohort Study (NOWAC).

According to the World Cancer Research Fund International, vitamin D might decrease the risk of colorectal cancer (CRC). However, less is known about the association with cancers in different subsites of the colon and in the rectum. The aim of this study was to examine associations between pre-diagnostic intake of vitamin D and risk of CRC by anatomical subsites. Data from 95 416 participants in the Norwegian Women and Cancer Cohort Study was included, and vitamin D intake was estimated from two repeated FFQ. Associations between vitamin D intake and incidence of CRC were assessed using multivariable Cox regression. During follow-up, there were 1774 incident cases of CRC. A small but borderline significant inverse association was found for a 5-µg increase in vitamin D intake and risk of CRC (hazard ratio (HR) = 0·97; 95 % CI 0·93, 1·01) and colon cancer (HR = 0·96; 95 % CI 0·91, 1·01). High (≥ 20 µg) compared with low (< 10 µg) vitamin D intake was associated with 17 % borderline significant reduced risk of CRC (HR = 0·83; 95 % CI 0·68, 1·02). Medium (10-19 µg) v. low intake (< 10 µg) was associated with 27 % reduced risk of proximal colon cancer (HR = 0·73; 95 % CI 0·57, 0·94). No significant associations were observed between vitamin D intake and risk of distal colon or rectal cancer. Our study indicates that vitamin D may be differently associated with subsites of the colon. The association between vitamin D intake and proximal colon cancer is novel.

Arthrospira (Spirulina) platensis feeding reduces the early stage of chemically induced rat colon carcinogenesis.

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.

The Potential Chemopreventive Effect of Andrographis paniculata on 1,2-Dimethylhydrazine and High-Fat-Diet-Induced Colorectal Cancer in Sprague Dawley Rats.

Colorectal cancer (CRC) is responsible for a notable rise in the overall mortality rate. Obesity is found to be one of the main factors behind CRC development. Andrographis paniculata is a herbaceous plant famous for its medicinal properties, particularly in Southeast Asia for its anti-cancer properties. This study examines the chemopreventive impact of A. paniculata ethanolic extract (APEE) against a high-fat diet and 1,2-dimethylhydrazine-induced colon cancer in Sprague Dawley rats. Sprague Dawley rats were administered 1,2-dimethylhydrazine (40 mg/kg, i.p. once a week for 10 weeks) and a high-fat diet (HFD) for 20 weeks to induce colorectal cancer. APEE was administered at 125 mg/kg, 250 mg/kg, and 500 mg/kg for 20 weeks. At the end of the experiment, blood serum and organs were collected. DMH/HFD-induced rats had abnormal crypts and more aberrant crypt foci (ACF). APEE at a dose of 500 mg/kg improved the dysplastic state of the colon tissue and caused a 32% reduction in the total ACF. HFD increased adipocyte cell size, while 500 mg/kg APEE reduced it. HFD and DMH/HFD rats had elevated serum insulin and leptin levels. Moreover, UHPLC-QTOF-MS analysis revealed that APEE was rich in anti-cancer phytochemicals. This finding suggests that APEE has anti-cancer potential against HFD/DMH-induced CRC and anti-adipogenic and anti-obesity properties.

A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice.

Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug-drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil but exhibited an almost 20-fold reduced EC50 for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention.

The Protective Role of Urtica dioica Seed Extract Against Azoxymethane-Induced Colon Carcinogenesis in Rats.

The aim of this study was to investigate the protective role of Urtica dioica seed (UDS) extract against azoxymethane (AOM)-induced colon carcinogenesis in rats. Thirty-two male Wistar albino rats were divided into four groups: Control, AOM, AOM + UDS, and UDS. The AOM and AOM + UDS groups were induced by AOM (15 mg/kg body weight) subcutaneously once a week for 10 weeks. AOM + UDS and UDS groups additionally received fed with pellets included 30 ml/kg UDS extract. At the end of the trial, blood and colon tissue samples were taken from the rats following necropsy. The gross and histopathological findings revealed that the administration of UDS extract significantly decreased lesions including aberrant cript foci, adenoma, and adenocarcinoma formation both numerically and dimensionally. Immunohistochemically, slight CEA and COX-2, strong Caspase-3 immune-expressions were detected in the group AOM + UDS compared to AOM group. Biochemical examinations indicated that a markedly increase in the malondialdehyde and fluctuated antioxidant defense system constituents levels such as reduced glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase were restored in AOM + UDS group. These results reveal that the UDS may act as a chemopreventive dietary agent, inducing apoptosis, resulting in a significant reduction of colon carcinogenesis.

Effect of Hesperidin against Induced Colon Cancer in Rats: Impact of Smad4 and Activin A Signaling Pathway.

SCOPE: To evaluate the chemopreventive efficacy of hesperidin (Hsd) in 1,2-dimethylhydrazine (DMH)-induced colorectal cancer (CRC) and demonstrate its role in mothers against decapentaplegic homolog 4(Smad4) and activin A signaling pathways. METHODS AND RESULTS: A CRC rat model was established by DMH exposure, and the animals were randomly divided into five groups: Control group, Hsd, DMH, DMH + Hsd, and DMH followed by Hsd. The resected colon was subjected to macroscopic, microscopic, molecular, histopathological, and immunohistochemical examination. Activin A, Smad4, malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), and superoxide dismutase (SOD) levels in tissues were also measured. The DMH group exhibited a significant increase in the gene and protein expression of activin A as well as MDA and NO levels in tissues. There was a significant reduction in the gene and protein expression of Smad4 as well as GSH and SOD levels in tissues. Administration of Hsd significantly upregulated Smad4 and activin A gene expressions in both the DMH + Hsd and DMH followed by Hsd groups. Moreover, Hsd improved the antioxidant status of the former two groups. CONCLUSION: This study demonstrated the chemopreventive effect of Hsd against CRC by modulating Smad4 and activin A signaling in vivo. Further studies are needed to demonstrate its clinical value and explore its possible role in advanced malignancy.

The Wnt-ß-Catenin-IL-10 Signaling Axis in Intestinal APCs Protects Mice from Colitis-Associated Colon Cancer in Response to Gut Microbiota.

Loss of immune tolerance to gut microflora is inextricably linked to chronic intestinal inflammation and colitis-associated colorectal cancer (CAC). The LRP5/6 signaling cascade in APCs contributes to immune homeostasis in the gut, but whether this pathway in APCs protects against CAC is not known. In the current study, using a mouse model of CAC, we show that the LRP5/6-ß-catenin-IL-10 signaling axis in intestinal CD11c+ APCs protects mice from CAC by regulating the expression of tumor-promoting inflammatory factors in response to commensal flora. Genetic deletion of LRP5/6 in CD11c+ APCs in mice (LRP5/6ΔCD11c) resulted in enhanced susceptibility to CAC. This is due to a microbiota-dependent increased expression of proinflammatory factors and decreased expression of the immunosuppressive cytokine IL-10. This condition could be improved in LRP5/6ΔCD11c mice by depleting the gut flora, indicating the importance of LRP5/6 in mediating immune tolerance to the gut flora. Moreover, mechanistic studies show that LRP5/6 suppresses the expression of tumor-promoting inflammatory factors in CD11c+ APCs via the ß-catenin-IL-10 axis. Accordingly, conditional activation of ß-catenin specifically in CD11c+ APCs or in vivo administration of IL-10 protected LRP5/6ΔCD11c mice from CAC by suppressing the expression of inflammatory factors. In summary, in this study, we identify a key role for the LRP5/6-ß-catenin-IL-10 signaling pathway in intestinal APCs in resolving chronic intestinal inflammation and protecting against CAC in response to the commensal flora.

Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

Human α-defensin 5 suppressed colon cancer growth by targeting PI3K pathway.

Defensins are highly conserved antimicrobial peptides, which ubiquitously expressed in different species. In addition to the functions in host defense, their aberrant expression have also been documented in cancerous tissue including breast cancer, lung caner and renal carcinoma etc. Whereas, roles of Defensin Alpha 5 (DEFA5) in colon cancer has not been explored. Bioinformatic analysis was used to study the expression of DEFA5 and its correlation with clinical outcomes; Western blot, qPCR, Co-immunoprecipitation, xenograft models were used to the study the molecular mechanism. Decreased expression of DEFA5 at protein level was observed in colon tissues. Colon cancer cell lines proliferation and colony formation capacity were significantly suppressed by DEFA5 overexpression. Moreover, in vivo tumor growth in nude mice was also suppressed by DEFA5 overexpression, suggesting a tumor suppressor role of DEFA5 in colon cancer. Mechanistically, DEFA5 directly binds to the subunits of PI3K complex, thus attenuates the downstream signaling transduction, leads to delayed cell growth and metastasis. Collectively, we concluded that DEFA5 showed an inhibitory effect in colon cancer cell growth and may serve as a potential tumor suppressor in colon cancer.

Improving Colon Cancer Prevention in Poland. A Long Way Off.

The aim of this study was to analyse knowledge on colon cancer prevention among patients of primary care and identify their sources of information. The questionnaire study was conducted among patients of 36 primary healthcare clinics in Poland between September 2018 and February 2019. Patients were interviewed separately by trained researchers. Over 39% of the primary health patients declared that their knowledge about colon cancer prevention is unsatisfactory. Information about colon cancer prevention varied according to sex, age and BMI. Men declared lower level of knowledge than women: 46% of men thought it was unsatisfactory compared with 36% of women (p = 0.003). Preventive recommendations were more often provided to patients over 60 years old (p < 0.01). Overweight and obese patients were more likely to receive recommendations on diet (p < 0.001) and physical activity (p < 0.001) than patients with normal weight. The most common source of information on colon cancer prevention was Internet (68%) and medical doctors (60%). There is a need for developing colon cancer prevention policy. Crucial aspect includes educational programs aimed at improving patient's knowledge and involving medical staff. The policymakers should pay greater attention to cancer prevention policies and medical staff involved in prevention to quality of communication to make sure patients thoroughly understand information they are provided.

Epidemiology and Mechanisms of the Increasing Incidence of Colon and Rectal Cancers in Young Adults.

In contrast to the decreasing incidence of colorectal cancer (CRC) in older populations, the incidence has nearly doubled in younger adults since the early 1990s. Approximately 1 in 10 new diagnoses of CRC are now made in individuals 50 years or younger. Patients' risk of CRC has been calculated largely by age and family history, yet 3 of 4 patients with early-onset CRC have no family history of the disease. Rapidly increasing incidence rates in younger people could result from generational differences in diet, environmental exposures, and lifestyle factors. We review epidemiologic trends in CRC, data on genetic and nongenetic risk factors, and new approaches for determining CRC risk. These may identify individuals likely to benefit from early screening and specialized surveillance.

Medication use and risk of proximal colon cancer: a systematic review of prospective studies with narrative synthesis and meta-analysis.

PURPOSE: Evidence of differences in the etiology of, and poorer survival from, proximal colon compared to the distal colorectum, necessitates research into its risk factors. This systematic review summarizes the evidence on medication use and proximal colon cancer risk. METHODS: MEDLINE and EMBASE were searched for prospective studies investigating nine medication groups, namely non-steroidal anti-inflammatory drugs (NSAIDs), exogenous hormones, i.e., hormone replacement therapy (HRT) or oral contraceptives (OCs), statins, proton pump inhibitors, anti-hypertensives, metformin (an antidiabetic), antidiarrheals or laxatives, and the risk of proximal colon cancer. Narrative synthesis and meta-analyses, using random effects models to estimate risk ratios (RRs) and 95% confidence intervals (CIs), were conducted. RESULTS: Twenty nine publications investigating NSAIDs (n = 13), exogenous hormones [HRT (n = 9) or OCs (n = 4)] statins (n = 5), anti-hypertensives (n = 1), and metformin (n = 1) were included. Summary RRs reported a protective effect of aspirin use (RR 0.80, 95% CI 0.73-0.89) but no associations between HRT (RR 0.92, 95% CI 0.83-1.02), OC (RR 1.06, 95% CI 0.98-1.14) or statin use (RR 0.94, 95% CI 0.67-1.31), and proximal colon cancer incidence compared to never/non-use. One study on metformin and one on anti-hypertensives reported no association. Sources of between-study heterogeneity included study design, period of exposure ascertainment, exposure source, and exposure comparison, but this exploration was hindered by the small numbers of studies. CONCLUSION: Despite some studies on NSAID or HRT use, evidence on the impact of a range of medications on proximal colon cancer risk is limited. This highlights the need for more research to inform chemoprevention strategies.

Fatty acid metabolism and colon cancer protection by dietary methyl donor restriction.

INTRODUCTION: A methyl donor depleted (MDD) diet dramatically suppresses intestinal tumor development in Apc-mutant mice, but the mechanism of this prevention is not entirely clear. OBJECTIVES: We sought to gain insight into the mechanisms of cancer suppression by the MDD diet and to identify biomarkers of cancer risk reduction. METHODS: A plasma metabolomic analysis was performed on ApcΔ14/+ mice maintained on either a methyl donor sufficient (MDS) diet or the protective MDD diet. A group of MDS animals was also pair-fed with the MDD mice to normalize caloric intake, and another group was shifted from an MDD to MDS diet to determine the durability of the metabolic changes. RESULTS: In addition to the anticipated changes in folate one-carbon metabolites, plasma metabolites related to fatty acid metabolism were generally decreased by the MDD diet, including carnitine, acylcarnitines, and fatty acids. Some fatty acid selectivity was observed; the levels of cancer-promoting arachidonic acid and 2-hydroxyglutarate were decreased by the MDD diet, whereas eicosapentaenoic acid (EPA) levels were increased. Machine-learning elastic net analysis revealed a positive association between the fatty acid-related compounds azelate and 7-hydroxycholesterol and tumor development, and a negative correlation with succinate and ß-sitosterol. CONCLUSION: Methyl donor restriction causes dramatic changes in systemic fatty acid metabolism. Regulating fatty acid metabolism through methyl donor restriction favorably effects fatty acid profiles to achieve cancer protection.

Chemopreventive efficacy of juniper berry oil (Juniperus communis L.) on azoxymethane-induced colon carcinogenesis in rat.

The aim of this study was to investigate the chemopreventive effects of juniper berry (JB) oil on azoxymethane (AOM)-induced colon cancer in rats. Thirty-two male Wistar albino rats were allocated into four groups: Control, AOM, AOM + JB, and JB groups. Whereas the control group was fed with standard pellet feed, the AOM and AOM + JB groups were administered of AOM (15 mg/kg body weight) subcutaneously once every 2 weeks for 10 weeks. AOM + JB and JB groups additionally received JB oil (100 µl/kg) orally. At the end of the 16-week experimental period, blood and tissue samples were obtained from the rats following necropsy. The macroscopic findings showed that the application of JB oil significantly decreased adenoma and adenocarcinoma formation both numerically and dimensionally. Immunohistochemically, CEA, COX-2, and Ki-67 immune-expressions decreased, and the immune-expression of caspase-3 increased in AOM + JB treated rats. Additionally, JB oil supplementation ameliorated antioxidant defense systems and lipid peroxidation within the colon tissue of AOM + JB treated rats. These results reveal that the JB oil acted as a chemopreventive dietary agent, inhibiting cell proliferation and COX-2 expression and inducing apoptosis, resulting in a significant reduction in colon tumor formation.

Probing the chemoprevention potential of the antidepressant fluoxetine combined with epigallocatechin gallate or kaempferol in rats with induced early stage colon carcinogenesis.

The enhanced chemopreventive action against 1,2 Dimethylhydrazine (DMH)-induced preneoplastic lesion in rats could be achieved via simultaneous administration of the antidepressant fluoxetine (FLX) with two natural polyphenolic compounds viz., kaempferol (KMP) and/or epigallocatechin-gallate (EGCG). The obtained results revealed that single FLX pre-treatment possess a significant apoptotic effect by increasing the activity of serum and colon tissue caspase 3. It also attenuated the DMH driven increase in, colon tissue MDA, NO, PCNA and COX-2 expression as well as serum and colon tissue ß-catenin, with a decrease in the multiplicity of ACF and number of MPLs. The combination of FLX with either KMP or EGCG improved the antioxidant, anti-inflammatory and antiproliferating activities but with higher apoptotic activity in case of KMP. Eventually, histopathological assessment of colon tissues exposed that while sole pre-treatment can improve DMH-induced hyperplasia with only moderate inflammatory infiltration, tissues from the combined pre-treatment regimens groups exhibited almost a normal colonic architecture with slight submucosal edema. The study proved that single FLX administration prior to DMH exerts a chemopreventive effect and that the investigated combined pre-treatment regimens demonstrated more potent chemopreventive and antiproliferative actions.