Caffeic acid 3,4-dihydroxyphenethyl ester prevents colorectal cancer through inhibition of multiple cancer-promoting signal pathways in 1,2-Dimethylhydrazine/dextran sodium sulphate mouse model.

OBJECTIVE: To elucidate the potential feature and mechanism of the caffeic acid 3,4-dihydroxyphenethyl ester (CADPE) molecule, which can prevent colorectal cancer (CRC) in the 1,2-Dimethylhydrazine (DMH)/dextran sodium sulphate (DSS)-induced mouse model. METHODS: Institute of cancer research (ICR) male mice were injected with 20 mg/kg DMH for a week. After that, 2% DSS was administered in the drinking water for another 7 d. The CADPE treatment was given to the DMH/DSS induced male mice at three different periods until their sacrifice. Histopathological examination was used for observing the CRC development at colonic mucosa. Immunohistochemistry (IHC), blood cells smearing and crypt damage scoring methods were used for investigating the anti-inflammation feature of CADPE related to CRC. The reversing targets searching method was applied with artificial intelligence (AI), computer-aided drug designing (CADD) and Ingenuity Pathway Analysis (IPA) techniques for predicting the potential targets and mechanism of CADPE highly related to CRC. RESULTS: The data indicated that CADPE inhibited CRC tumor development in the colitis-associated DMH/DSS induced mouse model after giving the early treatment. CADPE also impeded the acute inflammation by decreasing the infiltration of neutrophils significantly during the initial stage of CRC development. Finally, our data showed that CADPE prevented CRC by blocking active sites of three pivotal protein targets including epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) in two major cancer development pathways. CONCLUSIONS: CADPE effectively prevented CRC at early stage of tumor germination in the DMH/DSS mouse model highly likely due to its anti-acute inflammation characteristic and the ability of blocking EGFR, ERK and mTOR activities in two highly related CRC developing pathways.

Effects of probiotic supplementation on chronic inflammatory process modulation in colorectal carcinogenesis.

The current study investigated the potential effects of probiotic supplementation on colorectal carcinogenesis chemically induced with 1,2-dimethylhydrazine (DMH) and treated with 5-fluorouracil (5FU)-based chemotherapy in mice. Animals were randomly allocated in five different groups: Control: which not receive any treatment throughout the experimental course; Colitis model group (DMH): treated with DMH; DMH+ 5FU: animals received I.P. (intraperitoneal) dose of chemotherapy on a weekly basis; DMH+PROB: animals received daily administrations (via gavage) of probiotics (Lactobacillus: acidophilus and paracasei, Bifidobacterium lactis and bifidum); and DMH+ PROB+ 5FU: animals received the same treatment as the previous groups. After ten-week treatment, mice's large intestine was collected and subjected to colon length, histopathological, periodic acid-schiff (PAS) staining and immunohistochemistry (TLR2, MyD88, NF-κB, IL-6, TLR4, TRIF, IRF-3, IFN-γ, Ki-67, KRAS, p53, IL-10, and TGF-ß) analyzes. Variance (ANOVA) and Kruskal-Wallis tests were used for statistical analysis, at significance level p 0.05. Probiotics' supplementation has increased the production of Ki-67 cell-proliferation marker, reduced body weight, and colon shortening, as well as modulated the chronic inflammatory process in colorectal carcinogenesis by inhibiting NF-κB expression and mitigating mucin depletion. Thus, these findings lay a basis for guide future studies focused on probiotics' action mechanisms in tumor microenvironment which might have implications in clinical practice.

Combination of vitamin D and probiotics inhibits chemically induced colorectal carcinogenesis in Wistar rats.

The modulation of inflammatory elements, cell differentiation and proliferation by vitamin D and the role of probiotics in the intestinal microbiota and immunogenic response have sparked interest in the application of both in chemotherapeutics and chemoprevention of colorectal tumors. AIMS: The present study aimed to investigate the effects of isolated and/or combined treatment of vitamin D3 and probiotics on colorectal carcinogenesis. MAIN METHODS: Pre-neoplastic lesions were induced with 1,2-dimethylhydrazine in the colon of Wistar rats, which were treated with probiotics and/or vitamin D in three different approaches (simultaneous, pre-, and post-treatment). We investigated the frequency of aberrant crypt foci (ACF) and aberrant crypt (AC) in the distal colon, fecal microbiome composition, gene and protein expression through immunohistochemical and RT-PCR assays, and general toxicity through water consumption and weight gain monitoring. KEY FINDINGS: Results confirm the systemic safety of treatments, and show a protective effect of vitamin D and probiotics in all approaches studied, as well as in combined treatments, with predominance of different bacterial phyla compared to controls. Treated groups show different levels of Nrf2, GST, COX2, iNOS, ß-catenin and PCNA expression. SIGNIFICANCE: These experimental conditions explore the combination of vitamin D and probiotics supplementation at low doses over pathways involved in distinct stages of colorectal carcinogenesis, with results supporting its application in prevention and long-term strategies.

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.

Ficus dubia latex extract prevent DMH-induced rat early colorectal carcinogenesis through the regulation of xenobiotic metabolism, inflammation, cell proliferation and apoptosis.

Ficus dubia latex is recognized as a remedy in Asian traditional medicine with various therapeutic effects. The present study aimed to determine the preventive action of Ficus dubia latex extract (FDLE) on 1,2-dimethylhydrazine (DMH)-induced rat colorectal carcinogenesis and its mechanisms. The experiment included an initiation model in which rats were orally administered with FDLE daily for 1 week before DMH injection until the end of the experiment, while only after DMH injection until the end in the post-initiation model. The results firstly indicated that FDLE treatment could reduce the level of methylazoxymethanol (MAM) in rat colonic lumen by inhibition of the activities of both phase I xenobiotic metabolizing enzymes in the liver and ß-glucuronidase in the colon, leading to reduced DNA methylation in colonic mucosal cells, related to the number of ACF in the initiation stage. Besides, FDLE modulated the inflammation which could suppress the growth and induce apoptosis of aberrant colonic mucosal cells, leading to retardation of ACF multiplicity. Therefore, FDLE showed the ability to suppress the DMH-induced rat ACF formation and inflammation promoted growth of ACF. In conclusion, FDLE had the potential to prevent carcinogens-induced rat colorectal carcinogenesis in the initiation stage.

Caffeine and Chlorogenic Acid Combination Attenuate Early-Stage Chemically Induced Colon Carcinogenesis in Mice: Involvement of oncomiR miR-21a-5p.

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.

Hesperetin alleviates DMH induced toxicity via suppressing oxidative stress and inflammation in the colon of Wistar rats.

1,2-Dimethylhydrazine (DMH), a colon-specific environmental toxicant is one among the carcinogen responsible for the cause of colon cancer. The present study was designed to evaluate the protective effect of Hesperetin (HST) against colon toxicity induced by DMH in Wistar rats. HST, a flavonoid widely found in citrus fruits possesses several biological activities including anti-microbial, anti-oxidant properties among others. A single dose of DMH (40 mg/kg body weight) was administered subcutaneously on 1st day for induction of colon toxicity followed by oral treatment with HST at a dose of 20 mg/kg bodyweight for 14 consecutive days. DMH administration leads to excessive ROS generation, resulting in an imbalance in redox homeostasis and causing membrane lipid peroxidation, which is also partly due to the decrease in the level of tissue antioxidant machinery. Our result showed HST significantly ameliorates DMH-induced lipid peroxidation and also substantially increases the activity/level of various anti-oxidant proteins (GR, GPx, GST, GSH, and SOD). HST was also found to reduce the expression of inflammatory proteins (TNF-α, IL-6, i-NOS, COX-2, NF-kB-p65), goblet cell disintegration as well as mucin depletion (sulfo and sialomucin) in the colon that was found to be elevated upon administration of DMH. Our histological results further provide confirmation of the protective role of HST against DMH-induced pathological alterations. The results of the present study demonstrate supplementation of HST is beneficial in ameliorating DMH-induced toxicity by suppressing oxidative stress, inflammation, goblet cell disintegration as well mucin depletion in the colon of Wistar rats.

Protective effect of methanol extract of latex of Calotropis procera in an experimental model of colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant, Calotropis procera, has been used for treating various gastrointestinal disorders and cancer. Some of these medicinal properties have been attributed to the latex produced by the plant. AIM OF THE STUDY: To evaluate the efficacy of methanol extract of air-dried latex (MeDL) of C. procera in the rat model of colorectal cancer (CRC). MATERIALS AND METHODS: CRC was induced in the rats by 1,2-dimethylhydrazine (DMH) and the effect of MeDL was evaluated at two doses (50 and 150 mg/kg). MeDL and reference drug aspirin (60 mg/kg) were administered orally starting from 1 h before injecting DMH till 8 weeks after the second dose of DMH. The study also included experimental and normal control groups. Microscopic analysis was carried out to determine the count for aberrant crypt foci (ACF) and histology score whereas enzyme-linked immunosorbent assay and immunohistochemical analyses were performed for markers of carcinogenesis and angiogenesis. Other parameters that were evaluated include deoxyribonucleic acid (DNA) fragmentation, laddering, Bcl2 and Bax immunoreactivity, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity. RESULTS: Subcutaneous injection of DMH induced pre-neoplastic changes in the colon of rats with the appearance of ACF with multiple crypts (1-3, 4-6 or >6). In the experimental control group, total ACF count was 3.49 ± 0.23/cm of the colon length and the median histology score was 2.0 for architectural abnormalities, 2.0 for dilatation of crypts and 1.5 for hyperplasia/dysplasia against 1.0 for all the characteristics in normal rats. Oral administration of MeDL similar to aspirin, led to a reduction in ACF count and histology score of CRC concomitant with a decrease in the levels of markers of carcinogenesis - ß-catenin and proliferating cell nuclear antigen (PCNA); markers of angiogenesis - matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF), and an increase in apoptotic DNA fragmentation. CONCLUSION: MeDL confers protection in the rat model of CRC and the study suggests its therapeutic potential in this condition.

Protective effect of Callistemon citrinus on oxidative stress in rats with 1,2-dimethylhydrazine-induced colon cancer.

Callistemon citrinus has terpenes effective in inducing antioxidant enzymes, an important mechanism involved in cancer chemoprevention. This study investigated the chemopreventive efficacy of herbal preparation of C. citrinus leaves against the oxidative stress produced during the colorectal cancer (CRC) in male Wistar rats. The amelioration of toxicity in a model of CRC induced with 1,2-dimethylhydrazine (DMH) was determined by assessing antioxidant enzymes, phase II enzymes activities and lipid peroxidation (LPO) products after 22 weeks of treatment. C. citrinus was administered at a daily oral dose of 250 mg/kg. The activities in proximal, middle and distal colon, liver, kidney and heart were determined. C. citrinus showed a strong antioxidant activity that correlated with the high content of phenolics and terpenoids. DMH treated animals showed a decrease of the enzymes activity in most tissues and the level of reduced glutathione (GSH). Conversely, the levels of lipid peroxidation products were increased. Macroscopic examination revealed the protective effect of C. citrinus in damaged organs caused by DMH. Moreover, histopathological examination of the liver displayed normal structure in the C. citrinus-treated group, unlike the DMH-treated group. C. citrinus supplementation significantly maintained or increased the antioxidant enzyme activities, whereas lipid peroxidation products levels were reduced to values similar to the level of control group. The ability of C. citrinus to induce the antioxidant system reduced the damage of oxidative stress, which makes this plant a good candidate to be used as a prevention agent in treatment of diseases such as colorectal cancer.

Ellagitannins from jabuticaba (Myrciaria jaboticaba) seeds attenuated inflammation, oxidative stress, aberrant crypt foci, and modulated gut microbiota in rats with 1,2 dimethyl hydrazine-induced colon carcinogenesis.

Since dietary factors are thought to be responsible for high colon cancer risk, we investigated the chemopreventive effect of jabuticaba seed extract (LJE) by administering yogurt with or without LJE against 1,2 dimethyl hydrazine (DMH)-induced colon carcinogenesis in rats. Results showed that LJE contained a total phenolic content of 57.16 g/100 g of seed extract in which 7.67 and 10.09 g/100 g represented total flavonoids and ellagitannins, respectively. LJE protected DNA and human LDL against induced in vitro oxidation, which was associated with the ellagitannin content and with the free-radical scavenging and reducing capacities. LJE alone had a non-clastogenicity/aneugenicity property, but in combination with cisplatin, it enhanced the chromosome aberrations in cancer cells. In colon cancer-induced rats, yogurt with or without LJE caused a reduction in pro-inflammatory parameters, decreased the RNA expression of antiapoptotic cytokines and increased the expression of proapoptotic cytokines. Moreover, LJE attenuated colon cancer initiation and progression by decreasing aberrant crypt foci and LJE recovered the gut microbiome. Together, this evidence suggests that LJE provides chemopreventive protection against colon cancer development by reducing inflammation and increasing proapoptotic pathways.

Elucidation of underlying molecular mechanism of 5-Fluorouracil chemoresistance and its restoration using fish oil in experimental colon carcinoma.

Latest strategies for cancer treatment primarily focus on the use of chemosensitizers to enhance therapeutic outcome. N-3 PUFAs have emerged as the strongest candidate for the prevention of colorectal cancer (CRC). Our previous studies have demonstrated that fish oil (FO) rich in n-3 PUFAs not only increased therapeutic potential of 5-Fluorouracil(5-FU) in colon cancer but also ameliorated its toxicity. Henceforth, the present study is designed to elucidate mechanistic insights of FO as a chemosensitizer to circumvent drug resistance in experimental colon carcinoma. The colon cancer was induced by 1,2-dimethylhydrazine(DMH)/dextran sulfate sodium(DSS) in male Balb/c mice and these animals were treated with 5-FU(12.5 mg/kg b.w.), FO(0.2 ml), or 5-FU + FO(12.5 mg/kg b.w + 0.2 ml) orally for 14 days. The molecular mechanism of overcoming 5-FU resistance using FO in colon cancer was delineated by estimating expression of cancer stem cell markers using flowcytometric method and drug transporters by immunohistochemistry and immunoblotting. Additionally, distribution profile of 5-FU and its cytotoxic metabolite, 5-FdUMP at target(colon), and non-target sites (serum, kidney, liver, spleen) was assessed using high-performance liquid chromatography(HPLC) method. The observations revealed that expression of CSCs markers was remarkably reduced after using fish oil along with 5-FU in carcinogen-treated animals. Interestingly, the use of FO alongwith 5-FU also significantly declined the expression of drug transporters (ABCB1,ABCC5) and consequently resulted in an increased cellular uptake of 5-FU and its metabolite, 5-FdUMP at target site (colon). It could be possibly associated with change in permeability of cell membrane owing to the alteration in membrane fluidity. The present study revealed the mechanistic insights of FO as a MDR revertant which successfully restored 5-FU-mediated chemoresistance in experimental colon carcinoma.

Methanolic Extract of Muntingia Calabura L. Mitigates 1,2-Dimethyl Hydrazine Induced Colon Carcinogenesis in Wistar Rats.

OBJECTIVE: The present study aimed to evaluate the efficacy of methanolic extract of Muntingia calabura L. leaves (MEMC) in ameliorating oxidative stress and inflammation associated with 1,2-dimethyl hydrazine (DMH) induced colon cancer. METHODS: The antioxidant enzymes, oxidative stress markers, liver and renal toxicity markers were evaluated. Histopathological examination of colon tissues was carried out with the aid of alcian blue stain and Hematoxylin and Eosin stain. RESULTS: MEMC supplementation at doses of 100 and 200 mg/kg body weight of rats causes the antioxidant enzymic levels to retain near to its normal range. Meanwhile the oxidative stress markers, which showed an elevation from its normal level upon DMH administration, gets significantly reduced on MEMC treatment. Histopathological observation also revealed that the severity of colorectal cancer was reduced by the supplementation of MEMC. CONCLUSION: The findings from the present study showed that MEMC can exert a potential role to ameliorate the oxidative stress and inflammation associated with colorectal cancer.

Polyphenols of jabuticaba [Myrciaria jaboticaba (Vell.) O.Berg] seeds incorporated in a yogurt model exert antioxidant activity and modulate gut microbiota of 1,2-dimethylhydrazine-induced colon cancer in rats.

The chemical composition, antioxidant activity (AA), cytotoxic activity, antihemolytic effects, and enzyme inhibition (EI) of lyophilized jabuticaba (Myrciaria jaboticaba) seed extract (LJE) was studied. The main compounds found were castalagin, vescalagin, procyanidin A2, and ellagic acid. LJE was more toxic to cancer cells than to normal cells, meaning relative toxicological safety. This cytotoxic effect can be attributed to the pro-oxidant effect observed in the reactive oxygen species (ROS) generation assay. LJE inhibited α-amylase, α-glucosidase, and ACE-I activities and protected human erythrocytes from hemolysis. LJE was incorporated into yogurts at different concentrations and the total phenolic content, AA, and EI increased in a dose-dependent manner. LJE-containing yogurt presented 86% sensory acceptance. The yogurt was administered to Wistar rats bearing cancer and it modulated the gut bacterial microbiota, having a prebiotic effect. LJE is a potential functional ingredient for food companies looking for TPC, AA, and prebiotic effect in vivo.

Ethyl acetate fraction of Muntingia calabura L. exerts anti-colorectal cancer potential via regulating apoptotic and inflammatory pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Muntingia calabura L. is a plant with traditional pharmacological relevance. The various plant parts are used by tribal communities for treating gastric ulcers, prostate gland swellings, headache, cold etc. Hence, an attempt was made to evaluate the anti-colorectal cancer potential of ethyl acetate fraction of M. calabura (EFMC). MATERIALS AND METHODS: HR LC-MS analysis was carried out for the identification of compounds present in EFMC. 1,2 Dimethylhydrazine (DMH) induced animal model was used for the evaluation of anti-CRC potential of EFMC. Antioxidant enzyme status, oxidative stress marker status, hepatic and renal function marker level were determined. Evaluation of mRNA level expression of inflammatory and apoptotic genes, hematological and histopathological examinations were also carried out to figure out the extent of colorectal cancer (CRC) and the beneficial role offered by EFMC. RESULTS: HR LC-MS analysis of EFMC revealed the presence of ten pharmacologically active compounds. EFMC treatment made the altered levels of antioxidant enzymes, oxidative stress markers, liver and renal function markers to retain near to its normal range. The hematological and histopathological evaluations also confirmed the anti-CRC effects exhibited by EFMC. EFMC offered a regulatory control over the inflammatory and apoptotic genes thereby mitigating the damaging effects of CRC. CONCLUSION: The present study depicted the presence of therapeutically active compounds exhibiting strong antioxidant, anti-inflammatory and anticancer potential. The beneficial role offered by these compounds could be responsible for the amelioration of DMH induced CRC. Hence, EFMC can be used as an anti-CRC agent in human subjects.

Protective effect of Matricaria chamomilla extract against 1,2-dimethylhydrazine-induced colorectal cancer in mice.

Background Colorectal cancer (CRC) is a major public health problem, with almost 1.8 million newly diagnosed cases and about 881,000 deaths annually. Chamomile (Matricaria chamomilla) is a well-documented medicinal herb that possesses anti-inflammatory and anti-carcinogenic properties. This study aimed to unravel the effect of aqueous chamomile extract against 1,2-dimethylhydrazine(DMH)-induced CRC in mice. Methods Male Balb/c mice received a weekly intraperitoneal injection of DMH (20 mg/kg body weight) for 12 weeks. Chamomile extract (150 mg/kg body weight/5 days/week p.o.) was administered at the initiation and post-initiation stages of carcinogenesis. Polyps count, histopathological analysis, real-time polymerase chain reaction (RT-PCR) analysis of Wnt signaling genes, ELISA of cyclooxygenase-2 (COX-2), and enzyme assay for inducible nitric oxide synthase (iNOS) were performed. Results Chamomile extract modulated the Wnt pathway in colonic tissues, where it significantly downregulated Wnt5a, ß-catenin, T cell factor (Tcf4), lymphoid enhancer factor 1 (Lef1), c-Myc and Cyclin D1 expression levels, while it upregulated adenomatous polyposis coli (APC) and glycogen synthase kinase (GSK3ß) expression levels. This extract significantly reduced COX-2 levels and iNOS activities. Polyps count and histopathological analysis provided supportive evidence for the biochemical and molecular analyses. Conclusions Chamomile can act as a potent dietary chemopreventive agent against DMH-induced CRC.

Quercetin attenuated oxidative DNA damage through NRF2 signaling pathway in rats with DMH induced colon carcinogenesis.

Accumulating recent studies have demonstrated the preventive and therapeutic effects of polyphonic compounds such as quercetin in colorectal cancer. Therefore, we aimed to evaluate the underlying mechanisms for positive effects of quercetin in rats with 1,2-dimethylhydrazine (DMH)- induced colorectal cancer. For this purpose, male Wistar rats were classified as 6 groups, including group 1 without any intervention, group 2 as quercetin received rats (50 mg/kg), groups 3 as DMH received rats (20 mg/kg) group 4-6 DMH and quercetin received rats. DNA damage, DNA repair, the expression levels and activities of enzymic antioxidants, non-enzymic antioxidants, and NRF2/Keap1 signaling were evaluated in colon tissues of all groups. Our results showed significant suppression of DNA damage and induction of DNA repair in DMH + Quercetin groups, particularly in entire-period in comparison to other groups (p < .05). The expression levels and activities of enzymic and non-enzymic antioxidants were increased in DMH + Quercetin groups (p < .05). Lipid and protein peroxidation were significantly suppressed in DMH + Quercetin groups (p < .05). In addition, quercetin also modulated NRF2/Keap1 signaling and its targets, detoxifying enzymes in DMH + Quercetin groups. Our finding demonstrated that quercetin supplementation effectively reversed DMH-mediated oxidative stress and DNA damage through targeting NRF2/Keap1 signaling pathway.

Juçara (Euterpe edulis Mart.) Supplementation Reduces Aberrant Crypt Foci and Increases SOD1 Expression in the Colorectal Mucosa of Carcinogenesis-Induced Rats.

Antioxidants present in food can act as a protective factor against the development of colorectal cancer (CRC) by reducing the development of aberrant crypt foci (ACF). This study aimed to analyze the effects of supplementation with juçara fruit pulp on the number of ACF and the SOD1 expression in an experimental model of CRC. Colorectal carcinogenesis was induced with 1,2-dimethylhydrazine (DMH) in 16 young female rats (Rattus norvegicus) given a diet supplemented with either juçara fruit pulp (DMH+/juçara+) or control (DMH+/juçara-). Five animals were used as a negative control (DMH-/juçara-). The (DMH+/juçara+) group received 14 days of supplementation (100 ml/animal/day) at 2-day intervals for 1 month. The number of ACF, area of positive staining for SOD1, and SOD1 expression score were evaluated. The (DMH+/juçara+) group presented a lower number of ACF, ACF > 3 crypts, and greater SOD1 expression in the colorectal mucosa. Based on the reduction in the number of lesions and possible positive impact on antioxidant enzymes, juçara fruit pulp appears to support the prevention of CRC, opening new possibilities for its use in dietary supplementation, as well as in the development of products and medications for the prevention and treatment of CRC.

Dietary hemin promotes colonic preneoplastic lesions and DNA damage but not tumor development in a medium-term model of colon carcinogenesis in rats.

Red and processed meat consumption has been strongly related to increase the risk of colorectal cancer (CRC), although its impact is largely unknown. Hemin, an iron-containing porphyrin, is acknowledged as a putative factor of red and processed meat pro-carcinogenic effects. The aim of this study was to investigate the effects of high dietary hemin on the promotion/progression stages of 1,2-dimethylhydrazine (1,2-DMH)-induced colon carcinogenesis. Twenty-four Wistar male rats were given four subcutaneous 1,2-DMH injections and received either balanced diet or balanced diet supplemented with hemin 0.5 mmol/kg for 23 weeks. Colon specimens were analyzed for aberrant crypt foci (ACF) and tumor development. Dietary hemin significantly increased ACF number and fecal water cytotoxicity/genotoxicity in Caco-2 cells when compared to 1,2-DMH control group. However, tumor incidence, multiplicity and cell proliferation did not differ between 1,2-DMH + hemin and 1,2-DMH control group. Gene expression analysis of 91 target-genes revealed that only three genes (Figf, Pik3r5 and Tgfbr2) were down-regulated in the tumors from hemin-fed rats compared to those from 1,2-DMH control group. Therefore, the findings of this study show that high hemin intake promotes mainly DNA damage and ACF development and but does not change the number nor incidence of colon tumors induced by 1,2-DMH in male rats.

Reduction of Preneoplastic Lesions Induced by 1,2-Dimethylhydrazine in Rat Colon by Maslinic Acid, a Pentacyclic Triterpene from Olea europaea L.

Maslinic acid triggers compelling antiproliferative and pro-apoptotic effects in different human cancer cell lines. Hence, the chemopreventive activity was investigated on early stages of carcinogenesis induced by 1,2-dimethylhydrazine (DMH) which is a model that mimics human sporadic colorectal cancer. Male Sprague-Dawley rats were orally administered either maslinic acid at 5, 10 or 25 mg/kg dissolved in (2-hydroxypropyl)-ß-cyclodextrin 20% (w/v) or the solvent for 49 days. After one week of treatment, animals received three weekly intraperitoneal injections of DMH at the dose of 20 mg/kg. Maslinic acid reduced the preneoplastic biomarkers, aberrant crypt foci (ACF) and mucin-depleted foci (MDF), already at 5 mg/kg in a 15% and 27%, respectively. The decline was significant at 25 mg/kg with decreases of 33% and 51%, respectively. Correlation analysis showed a significant association between the concentrations of maslinic acid found in the colon and the reduction of ACF (r = 0.999, P = 0.019) and MDF (r = 0.997, P = 0.049). The present findings demonstrate that maslinic acid induced an inhibition of the initiation stages of carcinogenesis. The assessment of this pentacyclic triterpene at the colon sheds light for designing diets with foods rich in maslinic acid to exert a chemopreventive activity in colorectal cancer.

Chemopreventive effect of Callistemon citrinus (Curtis) Skeels against colon cancer induced by 1,2-dimethylhydrazine in rats.

PURPOSE: Callistemon citrinus (Curtis) Skeels is a shrub native of Australia. In spite of containing an important number of bioactive compounds (1,8-cineole, limonene and α-terpineol) recognized as a potential chemotherapeutic agents, it is only used as an ornamental plant in Mexico. This study investigated the chemopreventive effect of C. citrinus leaves extract on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. METHODS: Twenty-four rats were divided into 3 groups of eight rats. Group 1 served as negative control, groups 2 and 3 were given subcutaneous injections of DMH (65 mg/kg b.w.) twice a week the first 2 weeks, and then one the third week. In addition, group 3 was administrated with leaves extracts (250 mg/kg b.w., orally daily) during the 22 weeks of the experiment. Animals were killed and the presence of colon tumors and aberrant crypt foci (ACF) were scored for number and distribution pattern along the colon. The activity of two-phase II enzymes quinone reductase (QR) and glutathione S-transferase (GST) was determined in the liver and three segments of the colon: proximal, middle and distal. RESULTS: The results show that rats feed with C. citrinus leaves extract significantly reduced the size of tumors, the number of ACF and the crypt multiplicity. Additionally, C. citrinus leaves extract increased or maintained the activity of QR and GST in the different tissues as compared with DHM-treated group (p > 0.05). CONCLUSION: This study demonstrates that Callistemon citrinus extract could have a chemopreventive effect against colon carcinogenesis.