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Biomedicine & Pharmacotherapy =... Feb 2021Theanine and theobromine are abundantly present in tea and cocoa, respectively. This study was performed to assess the chemopreventive effects of these phytochemicals,... (Comparative Study)
Comparative Study
Theanine and theobromine are abundantly present in tea and cocoa, respectively. This study was performed to assess the chemopreventive effects of these phytochemicals, alone or together, on dimethylhydrazine (DMH)-induced colon cancer. Thirty male Wistar rats were divided into five groups and subcutaneously injected with saline (negative control group) or 30 mg/kg DMH (the other groups) two times/week for 12 weeks. The negative and positive control animals were orally treated with drinking water, and the other groups were gavaged with theanine (400 mg/kg), theobromine (100 mg/kg), or their mixture for two weeks before and throughout the injection period. At the end of the study, the morphological and histopathological features, Ki-67 proliferation marker, and the expression of Akt/mTOR, JAK2/STAT3, MAPK/ERK, and TGF-β/Smad pathways were investigated. Theanine and theobromine, alone or together, reduced the number of cancerous and precancerous lesions, the volume of tumors, the Ki-67 immunostaining, and the expression of Akt/mTOR and JAK2/STAT3 oncogenic pathways. The simultaneous treatment was more effective in the down-regulation of Akt and mTOR compared to either theanine or theobromine alone. Theobromine administration also caused more inhibitory effects on the Ki-67 and Akt/mTOR expression than theanine. Besides, all dietary interventions increased the mRNA and protein expression of Smad2. In conclusion, theanine and theobromine, alone and in combination, inhibited tumorigenesis through down-regulation of the Akt/mTOR and JAK2/STAT3 pathways and an increment of the Smad2 tumor suppressor. The inhibition of the Akt/mTOR pathway was more pronounced by simultaneous treatment.
Topics: Animals; Anticarcinogenic Agents; Cell Proliferation; Colon; Colonic Neoplasms; Dimethylhydrazines; Disease Models, Animal; Glutamates; Janus Kinase 2; Ki-67 Antigen; Male; Proto-Oncogene Proteins c-akt; Rats, Wistar; STAT3 Transcription Factor; Signal Transduction; TOR Serine-Threonine Kinases; Theobromine; Rats
PubMed: 33360052
DOI: 10.1016/j.biopha.2020.111140 -
IARC Monographs on the Evaluation of... 1999
Review
Topics: 1,2-Dimethylhydrazine; Animals; Carcinogens; Humans; Mutagenicity Tests; Mutagens; Neoplasms, Experimental
PubMed: 10476370
DOI: No ID Found -
IARC Monographs on the Evaluation of... 1999
Review
Topics: Animals; Carcinogenicity Tests; Carcinogens; Dimethylhydrazines; Humans; Mutagenicity Tests; Mutagens; Neoplasms, Experimental; Salmonella typhimurium
PubMed: 10476423
DOI: No ID Found -
World Journal of Gastroenterology May 2020Epigallocatechin gallate (EGCG) is a polyhydroxy phenolic compound extracted from tea and its antitumor effect has received widespread attention. We explored the...
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.
Topics: Aberrant Crypt Foci; Animals; Anticarcinogenic Agents; Carcinogenesis; Catechin; Cell Proliferation; Colon; Colorectal Neoplasms; Dimethylhydrazines; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Intestinal Mucosa; Male; Neoplasms, Experimental; Protein Interaction Maps; Rats; Rectum; Signal Transduction
PubMed: 32536775
DOI: 10.3748/wjg.v26.i17.2064 -
Journal of Biomedicine & Biotechnology 2011The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many... (Review)
Review
The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many morphological as well as molecular similarities to human sporadic colorectal cancer (CC), which are summarized and discussed in this paper. In addition, the paper combines present knowledge of morphological and molecular features in the multistep development of CC recognized in the DMH/AOM rat model. This understanding is necessary in order to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH/AOM rat colon carcinogenesis. The DMH/AOM model provides a wide range of options for investigating various initiating and environmental factors, the role of specific dietary and genetic factors, and therapeutic options in CC. The limitations of this model and suggested areas in which more research is required are also discussed.
Topics: 1,2-Dimethylhydrazine; Animals; Azoxymethane; Biomarkers, Tumor; Colonic Neoplasms; Humans; Precancerous Conditions; Rats; Terminology as Topic
PubMed: 21253581
DOI: 10.1155/2011/473964 -
The Journal of Nutrition Dec 2005Observational epidemiology supports the hypothesis that variation in diet and other lifestyle exposures accounts for a large part of the variation in incidence of... (Review)
Review
Observational epidemiology supports the hypothesis that variation in diet and other lifestyle exposures accounts for a large part of the variation in incidence of colorectal cancer (CRC). Physical inactivity is associated strongly with enhanced CRC risk, but no human intervention studies have shown causality. This paper reviews data from all available studies of the effects of exercise interventions on intestinal neoplasia using rat and mouse models. All 5 published studies of effects of increased physical activity (both forced and voluntary) using carcinogen-treated rat models show strong protection against CRC by greater physical activity. In contrast, there is little convincing evidence of reduced intestinal neoplasia after increased physical activity in the 3 published studies using Apc(Min) mice (which develop multiple intestinal polyps spontaneously) although the nature and amounts of physical activity imposed in rats and mice were similar. Major differences in protocol between the 2 groups of studies are that the rat studies were much longer (at least 20 wk and in most cases 38 wk compared with < or =9 wk for the mouse studies) and the primary endpoint was colorectal carcinoma (rats) rather than small bowel adenomas (mice). The epidemiological evidence for protection against adenoma formation by increased physical activity is weaker than that for carcinoma. The limited evidence available suggests that, compared with rats, mice may show a greater compensation for energy expenditure in exercise through reduction in nonexercise physical activity, thus ameliorating effects. The resulting smaller effects on body weight and body fatness may limit changes in intestinal neoplasia in Apc(Min) mice.
Topics: 1,2-Dimethylhydrazine; Animals; Azoxymethane; Body Mass Index; Body Weight; Carcinogens; Colorectal Neoplasms; Diet; Male; Mice; Motor Activity; Rats; Rats, Inbred F344; Rats, Sprague-Dawley
PubMed: 16317161
DOI: 10.1093/jn/135.12.3002S -
Journal of Oleo Science Jul 2022In many developed countries, colorectal cancer is a leading cause of morbidity and mortality and its etiology is familiar to be a grouping of nutritional and...
In many developed countries, colorectal cancer is a leading cause of morbidity and mortality and its etiology is familiar to be a grouping of nutritional and environmental factors, less physical activity and hereditary factors. Lycoperoside H (LH) is a steroidal alkaloid saponin commonly found in the tomato and exhibited the various pharmacological effects. The aim of the current study was to scrutinized the anticancer effect of LH against 1,2‑Dimethyl Hydrazine (DMH) induced colorectal cancer (CRC) in rats. Subcutaneous injection of DMH (20 mg/kg) was used for induction the CRC and rats were received the oral administration of LH (10, 20 and 40 mg/kg) for 16 weeks. At the end of the investigation, the tumor incidence, weight, and body weight were calculated. Antioxidant enzymes (phase I and II), inflammatory cytokines, lipids and inflammatory markers were all examined. DMH induced rats exhibited the increased tumor incidence, reduced body weight and LH treatment significantly (p < 0.001) suppressed the tumor incidence, and enhanced the body weight. LH treatment significantly (p < 0.001) boosted the level of SOD, GPx, GSH, CAT and suppressed the MDA level. LH treatment suppressed the level cytochrome b5 (Cyto b5), cytochrome P450 (Cyto P450) and boosted the level of glutathione S‑transferase (GST), uridine diphosphoglucuronyltransferase (UDP‑GT) in the liver and colon tissue. LH also decreased the level of cytokines includes interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α); inflammatory mediators like Inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin (PGE2) and nuclear factor kappa B (NF-κB) in the hepatic and colon tissue. We can conclude that LH revealed the anticancer effect against the DMH induced CRC via suppression of inflammation and oxidative stress.
Topics: Animals; Rats; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colorectal Neoplasms; Cytokines; Glycosides; Oxidative Stress; Rats, Wistar; Steroids; 1,2-Dimethylhydrazine
PubMed: 35691840
DOI: 10.5650/jos.ess22003 -
Report on Carcinogens : Carcinogen... 2011
Topics: 1,2-Dimethylhydrazine; Alkylating Agents; Animals; Carcinogenicity Tests; Carcinogens, Environmental; Environmental Exposure; Government Regulation; Guidelines as Topic; Humans; Mice; Molecular Structure; Occupational Exposure
PubMed: 21860472
DOI: No ID Found -
FEBS Open Bio Dec 2019Colorectal cancer (CRC) is the third most common tumor worldwide, and recent epidemiological studies have indicated that obesity contributes to the morbidity and...
Colorectal cancer (CRC) is the third most common tumor worldwide, and recent epidemiological studies have indicated that obesity contributes to the morbidity and mortality of CRC. Furthermore, obesity-related adipokines have been shown to be closely related to the incidence of CRC, but the underlying mechanisms are unclear. Here, we investigated the effects of high-fat diet-induced adipokines and cytokines on the development of CRC in vitro and in vivo. For the in vivo assays, we divided 2-week-old C57BL/6J-ApcMin/J male mice into three groups: normal-fat diet (ND), high-fat and high-sugar feed (HFHS), and high-fat and low-sugar feed (HFLS). After 1 week, all mice were injected with 20 mg·kg 1,2-dimethylhydrazine once weekly for 10 consecutive weeks. Body weight, liver weight, epididymal fat weight and blood glucose levels were greatly increased in HFHS and HFLS groups compared with the ND group, and the expression levels of some adipokines and cytokines were obviously higher in HFHS or HFLS mice compared with ND mice. For the in vitro assays, HCT116 CRC cells were treated with sera of ND, HFHS or HFLS groups, or serum-free media as a negative control. We observed that sera derived from HFHS or HFLS mice that contain excess adipokines and cytokines promoted the proliferation, migration and invasion of HCT116 cells compared with the ND sera-conditioned medium or serum-free medium group. Therefore, high-fat diet-induced adipokines and cytokines may promote the progression of CRC in vivo and in vitro.
Topics: Adipokines; Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Cytokines; Diet, High-Fat; Dimethylhydrazines; Disease Progression; Male; Mice; Neoplasm Invasiveness; Obesity; beta-Glucans
PubMed: 31665829
DOI: 10.1002/2211-5463.12751 -
Canadian Journal of Physiology and... Jan 2012This study was performed to determine the chemopreventive and antioxidant status of multivitamin and mineral (0.01% in drinking water, ad libitum) supplements in...
Multivitamin and mineral supplementation in 1,2-dimethylhydrazine induced experimental colon carcinogenesis and evaluation of free radical status, antioxidant potential, and incidence of ACF.
This study was performed to determine the chemopreventive and antioxidant status of multivitamin and mineral (0.01% in drinking water, ad libitum) supplements in 1,2-dimethylhydrazine (DMH)-induced experimental colon carcinogenesis. Experimental colon carcinogenesis was induced in male albino Wistar rats by injecting DMH (20 mg·(kg body mass)(-1)) once weekly for 15 consecutive weeks, and administering a multivitamin supplement in 3 regimes (initiation, post-initiation, and entire experimental period) for 32 weeks. We studied lipid peroxidation products (thiobarbituric acid reactive substances, lipid hydroperoxides, conjugated dienes) in the circulation and in the tissues, antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and non-enzymatic antioxidant-reduced glutathione) of the tissues, aberrant crypt foci (ACF), and histopathological alterations. DMH-induced rats had an increase in lipid peroxidation products and a lower antioxidant status compared with control animals. Multivitamin and mineral supplementation during the initiation, post-initiation, and the entire study period significantly decreased the levels of lipid peroxidation products in circulation and colonic tissues, significantly elevated the activities of the antioxidant enzymes and reduced glutathione to near normalcy in DMH-induced rats. The incidence of ACF was reduced by [corrected] 84.1% in rats supplemented with multivitamin and minerals for the entire study and prevented the colonic tissue from histopathological alterations induced by DMH.
Topics: 1,2-Dimethylhydrazine; Aberrant Crypt Foci; Animals; Anticarcinogenic Agents; Antioxidants; Colonic Neoplasms; Drug Administration Schedule; Drug Combinations; Drug Screening Assays, Antitumor; Free Radical Scavengers; Lipid Peroxidation; Male; Organic Chemicals; Rats; Rats, Wistar
PubMed: 22185381
DOI: 10.1139/y11-100