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.

Anticarcinogenic activity of methanol extract of Melastoma malabathricum leaves is attributed to the presence of phenolics compounds and the activation of endogenous antioxidant system / Actividad anticancerígena del extracto metanólico de hojas de Melastoma malabathricum atribuida a la presencia de compuestos fenólicos y a la activación del sistema antioxidante endógeno

Melastoma malabathricum (M. malabathricum) extracts have been reported to exert various pharmacological activities including antioxidants, anti-inflammatory and antiproliferative activities. The objective of the present study was to determine the anticarcinogenic activity of its methanol extract (MEMM) against the azoxymethane (AOM)-induced early colon carcinogenesis in rats. Rats were randomly assigned to five groups (n=6) namely normal control, negative control, and treatment (50, 250 or 500 mg/kg of MEMM) groups. Colon tissues were harvested for histopathological analysis and endogenous antioxidant system determination. MEMM was also subjected to HPLC analysis. Findings showed that MEMM significantly (p<0.05) reversed the AOM-induced carcinogenicity by: i) reducing the formation of aberrant crypt foci (ACF) in colon tissues, and; ii) enhancing the endogenous antioxidant activity (catalase, superoxide dismutase and glutathione peroxidase). Moreover, various phenolics has been identified in MEMM. In conclusion, MEMM exerts the in vivo anticarcinogenic activity via the activation of endogenous antioxidant system and synergistic action of phenolics.

Se ha informado que los extractos de Melastoma malabathricum (M. malabathricum) ejercen diversas actividades farmacológicas, incluidas actividades antioxidantes, antiinflamatorias y antiproliferativas. El objetivo del presente estudio fue determinar la actividad anticancerígena de su extracto de metanol (MEMM) contra la carcinogénesis de colon temprana inducida por azoximetano (AOM) en ratas. Las ratas se asignaron al azar a cinco grupos (n=6), a saber, los grupos de control normal, control negativo y tratamiento (50, 250 o 500 mg/kg de MEMM). Tejidos de colon fueron recolectados para análisis histopatológico y determinación del sistema antioxidante endógeno. MEMM también se sometió a análisis de HPLC. Los hallazgos mostraron que MEMM invirtió significativamente (p<0.05) la carcinogenicidad inducida por AOM al: i) reducir la formación de focos de criptas aberrantes (ACF) en los tejidos del colon, y; ii) potenciar la actividad antioxidante endógena (catalasa, superóxido dismutasa y glutatión peroxidasa). Además, se han identificado varios fenólicos en MEMM. En conclusión, MEMM ejerce la actividad anticancerígena in vivo mediante la activación del sistema antioxidante endógeno y la acción sinérgica de los fenólicos.

Antitumor and hepatoprotective effect of Cuscuta reflexa Roxb. in a murine model of colon cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Cuscuta reflexa Roxb. (C. reflexa) is a well-known traditional herbal plant, with numerous inherent therapeutic potentials including anticancer, antitumor, antibacterial, analgesic, anthelmintic, laxative and others. Moreover, the anticancer and antitumor potentials of this herb are ongoing with several trails, thus an attempt was made to assess the anticancer and hepatoprotective potentials of traditional C. reflexa herbs. METHOD: The dried ethanolic extract of C. reflexa was tested for acute oral toxicity in the treated animals subsequently their behavioral, neurological, and autonomic profiles changes were observed. The preliminary anti-cancer effects of extracts against 1, 2- Dimethyl hydrazine (DMH) induced animals were assessed through barium enema X-ray, colonoscopy, and Aberrant crypt foci (ACF) studies. The blood samples of the animals (treated and untreated) were collected and their in-vitro histological parameters were evaluated by the experienced technician. RESULTS: It was observed that C. reflexa significantly reduced Disease activity indexing (DAI) level and ACF counting, as well as demonstrated similar activity as of the standard drug 5-Fluorouracil (5-FU). Histopathological results revealed that the apoptotic bodies decreased in the DMH-induced group (group II) during cancer progression while in 5-FU treated (group III) and C. reflexa treated (group IV and V) animals the apoptotic bodies were increased. Inversely, the mitotic bodies increased in group II animals and reduced in group III, IV, and V animals. In the colonic section, DMH-induced cancer assay exhibited significant effects on the levels of hemoglobin, Packed cell volume (PCV), Red blood cell (RBC) counts, Mean corpuscular hemoglobin concentration (MCHC), Mean corpuscular volume (MCV), and Mean cell hemoglobin (MCH), and was found to be less in group II animals whereas administration of C. reflexa efficiently recovered back the loss probably by healing the colon damage/depletion of cancer progression. Moreover, compared to the group II animals, the neutrophil count was within the normal range in C. reflexa administered group. CONCLUSIONS: In the present study, the major hematological parameters significantly increased within DMH treated animals and exhibited extensive damage in the hepatic regions. Moreover, the histopathological findings demonstrated that the C. reflexa extracts potentially reduced the cell proliferation, with no toxicity. The C. reflexa extracts exhibited impending anti-cancer activity as well as protected the hepatic cells and thus could be potentially used in the management of colon or colorectal cancer and hepatic impairments.

Phaseolin, a Protein from the Seed of Phaseolus vulgaris, Has Antioxidant, Antigenotoxic, and Chemopreventive Properties.

The present report was designed to determine the antioxidant and antigenotoxic effects of phaseolin (isolated from Phaseolus vulgaris) against mouse colon and liver damage induced by azoxymethane (AOM) and its colon chemopreventive effect. Eight groups with 12 mice each were utilized for an eight-week experiment: the control group was intragastrically (ig) administered 0.9% saline solution; the positive control group was intraperitoneally (ip) injected with 7.5 mg/kg AOM twice a week (weeks three and four of the experiment); three groups were ig administered each day with phaseolin (40, 200, and 400 mg/kg); and three groups were ig administered phaseolin daily (40, 200, and 400 mg/kg) plus 7.5 mg/kg AOM twice a week in weeks three and four of the experiment. The results showed that phaseolin did not produce oxidative stress, DNA damage, or aberrant crypts; in contrast, 100% inhibition of lipoperoxidation, protein oxidation, and nitrites induction generated by AOM was found in both organs, and DPPH radical capture occurred. The two highest phaseolin doses reduced DNA damage induced by AOM in both organs by more than 90% and reduced the AOM-induced aberrant crypts by 84%. Therefore, our study demonstrated the strong in vivo antioxidant, antigenotoxic, and chemopreventive potential of phaseolin.

The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis.

Despite that colorectal cancer (CRC) is a severe global health problem, effective chemopreventive strategies against CRC are still lacking. Huang-qin tea (HQT), a healthy herbal tea, is prepared from the aerial parts of Scutellaria baicalensis Georgi and has been consumed in China for thousands of years. HQT contains abundant flavonoids, which display potent anticancer effects, but no research studies have investigated the cancer-preventive effects of HQT on CRC in vivo. Here, we found that HQT inhibits azoxymethane-induced aberrant crypt foci (ACF) formation in a preneoplastic colonic ACF rat model. The essential role of the gut microbiota in the chemopreventive effect of HQT on CRC in a pseudo-germ-free rat model was confirmed. Besides, HQT modulates inflammatory cytokine expression by significantly decreasing IL-1ß, IL-6, IL-10, and TNF-α expression, and elevating IFN-γ production. 16S rDNA sequencing analysis indicated that HQT regulated the gut microbiota by increasing the abundance of beneficial bacteria (Lachnoclostridium, Alistipes, Roseburia, and Lactococcus) and reducing the levels of Bacteroides, Parasutterella, and unidentified_Clostridiales. Fecal metabolomics showed that HQT modulated the AOM-induced metabolomic disorder, and these altered metabolites were almost involved in the lipid metabolic pathways. The Spearman correlation analysis revealed a correlation between the gut microbiota and fecal metabolites. Collectively, these results suggested that HQT exerted beneficial effects on host health by inhibiting inflammation, and by regulating the gut microbiota profile and certain metabolic pathways. In conclusion, HQT inhibits AOM-induced ACF formation by modulating the gut microbiota composition and improving metabolomic disorders, indicating the potential of HQT as a functional beverage candidate for the prevention and treatment of CRC.

Effects of Dietary Ethanol Extracts from Sake Rice and Sake Lees on Intestinal Impairment in Mice.

Glucosylceramide (GlcCer), a major sphingolipid in plants and fungi, is known to have food functions, such as preventing intestinal impairment and enhancing the moisture content of skin. This study investigated the influence of fermentation on the composition and function of lipophilic components containing GlcCer in plant-based foods; we compared the effects of ethanol extracts from sake rice (SR) and sake lees (SL) on colon impairment in mice. GlcCer and ceramide (Cer) levels in SL were much higher than those in SR, and GlcCer in SL contained 9-methyl-trans-4,trans-8-sphingadienine as a fungi-specific sphingoid base. 1,2-dimethylhydrazine (DMH) treatment markedly increased the formation of aberrant crypt foci (ACF) and the levels of TNF-α and lipid oxidation in mice colons. However, dietary SR or SL significantly suppressed these DMH-induced changes, and SR demonstrated stronger effects than SL. In addition, dietary SR or SL suppressed the expression of apoptotic and anti-apoptotic proteins induced by DMH treatment. This study suggests that SR or SL intake could reduce colon ACF formation via the suppression of inflammation and oxidation-induced cell cycle disturbances. When compared to SR, the weaked effects of SL rich in GlcCer may be the result of the changes in sphingolipid composition (sphingoid base and Cer) and differences in the concentration of other bioactive compounds produced or digested during fermentation.

Epigallocatechin gallate inhibits dimethylhydrazine-induced colorectal cancer in rats.

BACKGROUND: Epigallocatechin gallate (EGCG) is a polyhydroxy phenolic compound extracted from tea and its antitumor effect has received widespread attention. We explored the inhibitory effect of EGCG on dimethylhydrazine (DMH)-induced colorectal cancer (CRC) using a rat model, predicted the interaction between EGCG and CRC target genes using a database, and explained the EGCG associated target pathways and mechanisms in CRC. AIM: To understand the inhibitory mechanisms of EGCG on CRC cell proliferation and identify its pharmacological targets by network pharmacology analysis. METHODS: DMH (40 mg/kg, s.c., twice weekly for eight weeks) was used to induce CRC in rats. After model establishment, the rats were administered with EGCG (50, 100, or 200 mg/kg, p.o., once daily for eight weeks) and killed 12 and 20 wk after the start of the experiment. Formation of aberrant crypt foci and tumor was studied by histological analysis. Using network pharmacology analysis, candidate and collective targets of EGCG and CRC were identified, and Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the pathways altered by EGCG. RESULTS: At week 12, high-dose EGCG treatment significantly reduced the tumor formation rate, total number of tumors, cancerous and non-cancerous tumors, tumor volume, ascites formation, and aberrant crypt foci count. At week 20, all three doses of EGCG were effective. Seventy-eight collective targets of EGCG and CRC were identified, of which 28 genes were dysregulated in CRC. Kyoto Encyclopedia of Genes and Genomes and GO analyses showed that the dysregulated genes were enriched in hsa05210 (CRC), hsa04115 (p53 signaling pathway), and hsa04151 (PI3K-Akt signaling pathway), GO:0043124 (negative regulation of I-kappaB kinase/NF-kappaB signaling pathway), GO:0043409 (negative regulation of mitogen-activated protein kinase cascade), and GO:2001244 (positive regulation of intrinsic apoptotic signaling pathway) respectively. CONCLUSION: EGCG inhibits the formation of DMH-induced CRC by regulating key pathways involved in tumorigenesis.

Resistant starch supplementation increases crypt cell proliferative state in the rectal mucosa of older healthy participants.

There is strong evidence that foods containing dietary fibre protect against colorectal cancer, resulting at least in part from its anti-proliferative properties. This study aimed to investigate the effects of supplementation with two non-digestible carbohydrates, resistant starch (RS) and polydextrose (PD), on crypt cell proliferative state (CCPS) in the macroscopically normal rectal mucosa of healthy individuals. We also investigated relationships between expression of regulators of apoptosis and of the cell cycle on markers of CCPS. Seventy-five healthy participants were supplemented with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design in a randomised, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study). CCPS was assessed, and the expression of regulators of the cell cycle and of apoptosis was measured by quantitative PCR in rectal mucosal biopsies. SCFA concentrations were quantified in faecal samples collected pre- and post-intervention. Supplementation with RS increased the total number of mitotic cells within the crypt by 60 % (P = 0·001) compared with placebo. This effect was limited to older participants (aged ≥50 years). No other differences were observed for the treatments with PD or RS as compared with their respective controls. PD did not influence any of the measured variables. RS, however, increased cell proliferation in the crypts of the macroscopically-normal rectum of older adults. Our findings suggest that the effects of RS on CCPS are not only dose, type of RS and health status-specific but are also influenced by age.

Dysplastic Aberrant Crypt Foci: Biomarkers of Early Colorectal Neoplasia and Response to Preventive Intervention.

The discovery of aberrant crypt foci (ACF) more than three decades ago not only enhanced our understanding of how colorectal tumors form, but provided new opportunities to detect lesions prior to adenoma development and intervene in the colorectal carcinogenesis process even earlier. Because not all ACF progress to neoplasia, it is important to stratify these lesions based on the presence of dysplasia and establish early detection methods and interventions that specifically target dysplastic ACF (microadenomas). Significant progress has been made in characterizing the morphology and genetics of dysplastic ACF in both preclinical models and humans. Image-based methods have been established and new techniques that utilize bioactivatable probes and capture histologic abnormalities in vivo are emerging for lesion detection. Successful identification of agents that target dysplastic ACF holds great promise for intervening even earlier in the carcinogenesis process to maximize tumor inhibition. Future preclinical and clinical prevention studies should give significant attention to assessing the utility of dysplastic ACF as the earliest identifiable biomarker of colorectal neoplasia and response to therapy.See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention.

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.

Preventive Effect of an Infusion of the Aqueous Extract of Chaya Leaves (Cnidoscolus aconitifolius) in an Aberrant Crypt Foci Rat Model Induced by Azoxymethane and Dextran Sulfate Sodium.

Aberrant crypt foci (ACF) is the precursor lesion of colorectal carcinogenesis (CRC), one of the most common malignancies in the world. Many studies have reported that people with higher phytochemical intake are at a reduced risk of developing ACF. One example of the botanical potential of preventive plant products is Cnidoscolus aconitifolius (CA), commonly known as Chaya. This study evaluated the phenolic profile of CA and the effects of the daily consumption of CA leaf infusion on the formation of ACF, histopathological lesions, and molecular biomarkers after azoxymethane (AOM) and dextran sulfate sodium (DSS) induced premalignant colon lesions in rats treated with for 16 and 32 weeks. The phenolic composition of the CA infusion was identified by reversed phase-high performance liquid chromatography-diode array detection (RP-HPCC-DAD). After sacrifice, a 4 cm segment was collected from the distal part of the colon and stained with methylene blue to look for ACF. Furthermore, 4 µm of colon, liver, and kidney was collected and stained with hematoxylin and eosin for histopathological analysis, along with 7 µm of colon for immunohistochemistry analysis. Eleven phenolic compounds were identified in the infusions, and ACF formation was reduced by 29.5% at the subchronic and by 64.6% at chronic stages. Lesions on kidney, liver, and colon tissue were also reduced. Our data suggest that CA treatment has preventive effects against AOM-/DSS-induced premalignant colon lesions in colon rats at the promotion level, inhibiting the cell proliferation of early neoplastic lesions and colonic inflammation through the decrease of ß-catenin by 41.8% at the subchronic stage and 29% at the chronic stage, along with a 46.2% reduction of cyclooxygenase 2 (COX-2) at long term, despite a high expression of NF-κB (30.3% at the subchronic stage and 22.8% at the chronic stage).

Extraction of Lipophilic Fraction from Polished Rice Improves Its Ameliorative Effect on Intestinal Impairment.

Glucosylceramide (GlcCer), a major sphingolipid in plants and fungi, is known to have food functions such as preventing intestinal impairment and enhancing the moisture content of skin. However, there is little information about functions of GlcCer in food sources as most of the studies on GlcCer functions are done using purified GlcCer. This study was performed to investigate the effects of GlcCer contained in food on intestinal impairment; polished rice flour (RF) and this ethanol extract (RE) were used as sources of GlcCer, and these were evaluated by studying the formation of aberrant crypt foci (ACF) in 1,2-dimethylhydrazine (DMH)-treated mice, which is a model of colon cancer. Mice were fed with either a control diet, a RF diet where RF replaces cornstarch (150 g/kg), or a plus RE diet (0.5 g/kg; RE was extracted from the same amount of RF present in the RF diet). The amount of GlcCer was similar in both the RF and RE diets (3.0 and 2.7 mg/kg, respectively). DMH treatment induced the formation of ACF and the production of inflammation-related cytokines. Both dietary RF and RE suppressed ACF formation and RE, in particular, showed a significant suppressive effect. Dietary RE inhibited the production of almost all of the inflammation-related cytokines studied, while RF suppressed only a few of these cytokines. The present study suggests that the lipophilic fraction including GlcCer, present in polished rice has protective effects against intestinal impairment, but it requires extraction since digestion alone is not enough to elicit its complete protective action.

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.

Chemopreventive efficacy zingerone (4-[4-hydroxy-3-methylphenyl] butan-2-one) in experimental colon carcinogenesis in Wistar rats.

Colorectal cancer is one of the most common cancers worldwide. Development of naturally occurring inexpensive and safe alternatives can be effective in suppressing colon related proliferations. Zingerone (4-[4-hydroxy-3-methylphenyl] butan-2-one), a polyphenolic alkanone of ginger, has massive pharmacological properties and thus can be used as promising candidate against various ailments. In the current study, we aimed at demonstrating the protective effect of zingerone against experimental colon carcinogenesis and elucidating its possible mechanism by studying inflammatory and Nrf-2 signaling cascade. Four groups of animals (I-IV) were made with six animals each. Group I (control) was given normal saline orally. Group II was given 1,2-dimethylhydrazine (DMH) at the dose rate of 20 mg/kg body weight. Group III and IV were treated with DMH at the dose rate of 20 mg/kg body weight and also received oral treatment of zingerone at a dose rate of 50 and 100 mg/kg body weight, respectively, for first 5 weeks and animals were euthanized after 16 weeks. Our results reveal that DMH treated rats exhibited elevated ROS and MDA levels, increased activity of cytochrome P450 2E1 and serum marker enzyme carcinoembreyonic antigen (CEA), increased no of aberrant crypts of foci (ACF), and elevated expression of inflammatory and proliferative proteins. Nrf-2 was downregulated by DMH treatment. Treatment with zingerone to DMH treated rats, resulted in alterations in the activity of the cytochrome P450 2E1 and CEA. In addition, immunostaining of NF-kB-p65, COX-2, iNOS, and PCNA, Ki-67 was suppressed by zingerone. Furthermore, zingerone administration also attenuated the level of IL-6 and TNF-α and it also helps in preserving mucous layer. Thus, zingerone could be considered as a good chemopreventive agent in experimental model of colon carcinogenesis. Further studies are required to study other pathways involved in colon carcinogenesis and their modulation buy zingerone.

Effects of Watermelon Powder and l-arginine Supplementation on Azoxymethane-Induced Colon Carcinogenesis in Rats.

Diets high in fruits and vegetables may help prevent colorectal cancer (CRC). Watermelon consumption may reduce CRC risk due to its concentration of l-citrulline and its role in endothelial nitric oxide (NO) production. Research suggests that increased NO levels have tumoricidal effects. The purpose of this study was to determine the effects of watermelon powder supplementation on aberrant crypt foci (ACF) formation, precancerous lesions, and expression of genes associated with colon carcinogenesis. Thirty-two male Sprague-Dawley rats were assigned into three groups: control, 0.36% l-arginine, or 0.5% watermelon powder and injected with azoxymethane (15 mg/kg body weight). Both l-arginine and watermelon powder groups exhibited lower total numbers of ACF and high multiplicity ACF (P < 0.01). The watermelon powder group exhibited higher NO levels and lower 8-hydroxyguanosine DNA damage (P < 0.05). Watermelon powder and l-arginine downregulated 8-oxoguanine DNA glycosylase gene expression and upregulated O6-methylguanine DNA methyltransferase gene expression (P < 0.05). Cyclooxgenase-2 gene expression was lower for rats fed with watermelon powder (P < 0.05). These results suggest that watermelon powder or l-arginine supplementation may reduce the risk of colon cancer by suppressing ACF formation through lowering oxidative DNA damage and inflammation, modulating DNA repair enzyme expression, and/or enhancing NO production.

Aberrant crypt foci are regionally affected by zinc treatment in a 1,2-dimethylhydrazine induced colon carcinogenesis model.

Zinc is a trace element widely known for its marked antioxidant properties. To gain more insight into the site- and time- specific mechanisms by which it induces chemoprevention, this study was elaborated over a pre-cancerous model of colon carcinogenesis. Colon cancer was induced by 1,2-dimethylhydrazine (DMH) in mice (20 mg/kg for 2 weeks) and groups of animals were supplemented with or without zinc sulfate (ZnSO4, 200 mg/L) in drinking water for 4, 10 or 14 weeks. Colon tissues were collected for pathological observation, analyzing aberrant crypt (AC) and aberrant crypt foci (ACF) formations, multiplicity and distribution. Similarly, histological assessment and mucin production, as well as oxidative stress markers estimation was performed for the different groups. Results showed a significant increase in ACF and AC numbers, ACF multiplicity and demonstrated stronger distal occurrence than in the proximal after DHM administration. Histopathological analysis presented marked structural alterations and mucin loss in the distal than the proximal colons. A significant increase in myeloperoxidase (MPO), nitric oxide (NO), L-ornithine and malondialdehyde (MDA) levels was observed followed by a significant decrease in antioxidant markers (superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH)). Oral ZnSO4 supplementation (continuous or partial) induced significant decrease in ACF, AC numbers and multiplicity, restored histological architecture and mucin production, and a significant decrease in proinflammatory markers while it reduced antioxidants to normal levels. From this study, insight was obtained on the use of ZnSO4 as a chemopreventive agent and shed light on its potential, as a supplement in nutraceutical approaches.

Naringenin (4,5,7-trihydroxyflavanone) suppresses the development of precancerous lesions via controlling hyperproliferation and inflammation in the colon of Wistar rats.

Colon cancer is a world-wide health problem and one of the most dangerous type of cancer, affecting both men and women. Naringenin (4, 5, 7-trihydroxyflavanone) is one of the major flavone glycoside present in citrus fruits. Naringenin has long been used in Chinese's traditional medicine because of its exceptional pharmacological properties and non-toxic nature. In the present study, we investigated the chemopreventive potential of Naringenin against 1,2-dimethyhydrazine (DMH)-induced precancerous lesions, that is, aberrant crypt foci (ACF) and mucin depleted foci (MDF), and its role in regulating the oxidative stress, inflammation and hyperproliferation, in the colon of Wistar rats. Animals were divided into five groups. In groups 3-5, Naringenin was administered at the dose of 50 mg/kg b. wt. orally while in groups 2-4, DMH was administered subcutaneously in the groin at the dose of 20 mg/kg b. wt. once a week for first 5 weeks and animals were euthanized after 10 weeks. Administration of Naringenin ameliorated the development of DMH-induced lipid peroxidation, ROS formation, precancerous lesions (ACF and MDF) and it also reduced the infiltration of mast cells, suppressed the immunostaining of NF-κB-p65, COX-2, i-NOS PCNA and Ki 67 Naringenin treatment significantly attenuated the level of TNF-α and it also prevented the depletion of the mucous layer. Our findings suggest that Naringenin has strong chemopreventive potential against DMH-induced colon carcinogenesis but further studies are warranted to elucidate the precise mechanism of action of Naringenin.

Effect of Spirogyra neglecta on the early stages of 1, 2-dimethylhydrazine-induced colon carcinogenesis in rats.

This study focused on the chemopreventive effects of Spirogyra neglecta extract (SNE) and dried S. neglecta mixed diet on the early stages of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. Male Wistar rats were injected with DMH to initiate aberrant crypt foci (ACF) formation. In the initiation stage, SNE significantly decreased the number of ACF in the colon of DMH-treated rats. Rats that received a low dose of SNE showed enhanced activity of several detoxifying and antioxidant enzymes. In the postinitiation stage, a low dose of SNE significantly decreased the number of ACF in the colon of DMH-treated rats. It significantly reduced the number of proliferating cell nuclear antigen-positive cells and increased the number of apoptotic cells in colonic crypts. S. neglecta thus inhibited the development of the early stages of DMH-induced colon carcinogenesis in rats by modulation of xenobiotic metabolizing enzymes and inhibition of cell proliferation as well as induction of apoptosis.