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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 -
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 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 -
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 -
BioMed Research International 2022Cancer is one of the leading causes of death worldwide, and natural agents have shown some promise in fighting it. Thus, the present study tried to evaluate the healing...
Cancer is one of the leading causes of death worldwide, and natural agents have shown some promise in fighting it. Thus, the present study tried to evaluate the healing potential of an equal combination of olive and sesame extract (MOS) against the colorectal cancerous lesions that were induced by dimethylhydrazine (DMH) in male rats and also compare the anticarcinogenic potential of the MOS and vitamin E with each other. Therefore, the mixture of equal olive and sesame extract (MOS) was used as the main treatment, alongside vitamin E as a parallel treatment. This study examined the red blood cell (RBC) and white blood cell (WBC) levels, biochemical indices, lactate dehydrogenase (LDH), C-reactive protein (CRP), total protein (TP), creatine kinase (CPK), albumin, and the colon tissue pathology, as well as the level of protein expression of the adenomatous polyposis coli (APC), proliferating cell nuclear antigen (PCNA), carcinoembryonic antigen (CEA), and platelet-derived growth factor (PDGF). Also, the tissue stress markers including total antioxidant capacity (TAC), malondialdehyde (MDA), and superoxide dismutase (SOD) were analyzed. Overall, the results represented a significant reduction in the congestion, mitotic index, inflammation, and cell destruction in the MOS group compared to the DMH group. In terms of the oxidative stress level, a significant increase was observed in the DMH group in comparison with the DMH-MOS group ( < 0.05), and the MOS significantly increased TAC level ( < 0.05). Furthermore, the DMH+MOS-exposed group exhibited a significantly lower expression of the PCNA, CEA, and PDGF proteins than those of the DMH group. Overall, the MOS showed that it can effectively prevent DMH-induced colon lesions. This mixture, as a strong antioxidant agent, can be clinically applied for preventing and treating colorectal cancer, the effectiveness of which is higher than that of vitamin E.
Topics: Animals; Male; Rats; 1,2-Dimethylhydrazine; Antioxidants; C-Reactive Protein; Carcinoembryonic Antigen; Colorectal Neoplasms; Creatine Kinase; Lactate Dehydrogenases; Malondialdehyde; Olea; Platelet-Derived Growth Factor; Proliferating Cell Nuclear Antigen; Rats, Wistar; Sesamum; Superoxide Dismutase; Vitamin E
PubMed: 36262974
DOI: 10.1155/2022/5440773 -
International Journal of Molecular... Apr 2018Resistant starch is as common soluble fiber that escapes digestion in the small intestine and can regulate intestinal function, metabolism of blood glucose and lipids,...
Resistant starch is as common soluble fiber that escapes digestion in the small intestine and can regulate intestinal function, metabolism of blood glucose and lipids, and may prevent tumorigenesis of gastrointestinal cancer. Epidemiology and other evidence have suggested that resistant starch may prevent colon cancer development. The aim of the current study was to explore the ameliorative effects and potential mechanisms of resistant starch in the tumorigenesis of colon tumors induced by dimethylhydrazine in C57BL/6 mice. Western blot analysis, ELISA, microscopy, immunofluorescence and immunohistochemistry were used to analyze the efficacy of resistant starch on the metabolic balance in the colon and tumorigenesis of colon tumors. The results demonstrated that a diet containing resistant starch decreased the animal body weight and reduced free ammonia, pH and short chain fatty acids in feces compared with mice that received a standard diet. Resistant starch reduced the incidence of colon tumors and suppressed the expression of carcinogenesis‑associated proteins, including heat shock protein 25, protein kinase C‑d and gastrointestinal glutathione peroxidase in colon epithelial cells compared with standard starch and control groups. Colon tumor cells proliferation and dedifferentiation were significantly decreased by a resistant starch diet. The results also demonstrated that resistant starch increased the apoptosis of colon tumor cells through regulation of apoptosis‑associated gene expression levels in colon tumor cells. Oxidative stress and endoplasmic reticulum stress were upregulated, and elevation eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor‑4 and secretase‑β expression levels were increased in the resistant starch diet group. Additionally, the activity of eIF2α and PERK were increased in colon tumor cells from mice that had received resistant starch. Increasing DNA damage‑inducible transcript 3 protein (CHOP), binding immunoglobulin protein (BIP) and caspase‑12 expression levels upregulated by resistant starch diet may contribute to the resistant starch‑induced apoptosis of colon tumor cells induced by 1,2‑dimethylhydrazine. In vitro assays demonstrated that knockdown of eIF2α inhibited apoptosis of colon tumor cells isolated from mice fed with resistant starch, which also downregulated CHOP, BIP and caspase‑3 expression levels compared with controls. Furthermore, long‑term survival of experimental mice was prolonged by the resistant starch diet compared with the standard diet group. In conclusion, the results indicate that resistant starch in the diet may prevent carcinogenesis of colon epithelial cells, mediated by enhancing apoptosis through an endoplasmic reticulum stress‑mediated mitochondrial apoptosis pathway.
Topics: Animals; Apoptosis; Body Weight; Carcinogenesis; Cell Line; Colon; Colonic Neoplasms; Diet; Dietary Fiber; Dimethylhydrazines; Endoplasmic Reticulum Stress; Mice, Inbred C57BL; Mitochondria; Signal Transduction; Starch; Tumor Cells, Cultured
PubMed: 29393371
DOI: 10.3892/ijmm.2018.3423 -
Oxidative Medicine and Cellular... 2022This study was conducted among 60 rats, and groups consist of control, three separate groups for RJ, dimethylhydrazine (DMH), and vitamin E, and two separate treated...
METHODS
This study was conducted among 60 rats, and groups consist of control, three separate groups for RJ, dimethylhydrazine (DMH), and vitamin E, and two separate treated groups with DMH + RJ and DMH + vitamin E. Additionally, the cytotoxicity of royal jelly was examined on HT-29 cell line. . Based on the assessment using MTT assay, the LC50 of royal jelly was 1.781 mg/ml, and the highest cytotoxicity was observed at 25 mg/ml concentration after 48 hours. Meanwhile, in the study, after the 13th week, compared to the DMH group, the rats exposed to DMH + royal jelly experienced a significant less oxidative stress ( < 0.05) and a significantly greater total antioxidant capacity (TAC) level ( < 0.05). The expression of proliferating cell nuclear antigen (PCNA), platelet-derived growth factor (PDGF), and carcinoembryonic antigen (CEA) proteins significantly decreased among the animals receiving DMH + royal jelly compared to the DMH group. The pathological examinations revealed less congestion, necrosis, inflammation, and cell proliferation in the colon tissue of the RJ-treated group than that of the DMH group. Overall, the biochemical indices were better in the treatment groups in comparison with the DMH group.
CONCLUSION
The results represented the clinical usability of royal jelly, as a substance with anticancer properties, to prevent and treat colorectal cancer. This issue is related to its effective antioxidant potential, which even exhibits more effectiveness than the vitamin E, which is known as a strong antioxidant.
Topics: Animals; Rats; 1,2-Dimethylhydrazine; Antineoplastic Agents; Antioxidants; Colonic Neoplasms; Colorectal Neoplasms; Fatty Acids; Rats, Wistar; Vitamin E
PubMed: 35910834
DOI: 10.1155/2022/9506026 -
BioMed Research International 2022Propolis is a natural compound with anticarcinogenic properties. The present study aimed to compare the inhibitory effect of ethanolic extract of propolis (EEP) and...
Propolis is a natural compound with anticarcinogenic properties. The present study aimed to compare the inhibitory effect of ethanolic extract of propolis (EEP) and vitamin E on dimethylhydrazine-induced colon lesions in rats. In this study, 60 rats were randomly categorized into six 10-member groups. After 13 weeks, blood and colon tissue were sampled to examine some factors. The parameters included red (RBC) and white (WBC) blood cell profile, lactate dehydrogenase (LDH), C-reactive protein (CRP), total protein (TP), creatine kinase (CPK), and albumin, as well as the extent of colon histological lesions, protein expression (adenomatous polyposis coli (APC), proliferating cell nuclear antigen (PCNA), carcinoembryonic antigen (CEA), and platelet-derived growth factor (PDGF)), and oxidative stress markers (total antioxidant capacity (TAC), malondialdehyde (MDA), and superoxide dismutase (SOD)) in colon tissue. A significant decrease was observed in congestion, mitotic index, inflammation, and cell destruction in colon tissue in dimethylhydrazine group in comparison with the control group ( < 0.05). The EEP exposed rats exhibited a significant lower oxidative stress than the DMH group ( < 0.05). Furthermore, the extract significantly affected TAC level ( < 0.05). While the expression level of APC rose substantially in the EEP-treated group compared to the DMH group, the level of PCNA, CEA, and PDGF proteins significantly reduced. It seems that the EEP can efficiently prevent DMH-induced colonic lesions. Furthermore, its effectiveness is more than the vitamin E, which is a strong antioxidant.
Topics: Animals; Rats; Adenomatous Polyposis Coli; Antioxidants; Ascomycota; Carcinoembryonic Antigen; Dimethylhydrazines; Ethanol; Plant Extracts; Proliferating Cell Nuclear Antigen; Propolis; Rats, Wistar; Vitamin E
PubMed: 35782078
DOI: 10.1155/2022/8497562 -
International Journal of Molecular... Aug 2017The role of deficiency of oxoguanine glycosylase 1 () homolog, a repair enzyme of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the...
The role of deficiency of oxoguanine glycosylase 1 () homolog, a repair enzyme of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J background carrying a mutant allele of the gene () and wild type (Ogg1) mice were administered N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), N-bis (2-hydroxypropyl) nitrosamine (DHPN) and 1,2-dimethylhydrazine dihydrochloride (DMH) (DMBDD) to induce carcinogenesis in multiple organs, and observed up to 34 weeks. Significant increase of lung adenocarcinomas incidence was observed in DMBDD-treated male mice, but not in DMBDD-administered animals. Furthermore, incidences of lung adenomas were significantly elevated in both males and females as compared with respective control and DMBDD-treated groups. Incidence of total liver tumors (hepatocellular adenomas, hemangiomas and hemangiosarcomas) was significantly higher in the DMBDD-administered males and females. In addition, in DMBDD-treated male mice, incidences of colon adenomas and total colon tumors showed a trend and a significant increase, respectively, along with significant rise in incidence of simple hyperplasia of the urinary bladder, and a trend to increase for renal tubules hyperplasia in the kidney. Furthermore, incidence of squamous cell hyperplasia in the forestomach of DMBDD-treated male mice was significantly higher than that of males. Incidence of small intestine adenomas in DMBDD groups showed a trend for increase, as compared to the wild type mice. The current results demonstrated increased susceptibility of mutant mice to the multiorgan carcinogenesis induced by DMBDD. The present bioassay could become a useful tool to examine the influence of various targets on mouse carcinogenesis.
Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Butylhydroxybutylnitrosamine; Carcinogenesis; Carcinogens; Carcinoma, Hepatocellular; DNA Glycosylases; Diethylnitrosamine; Female; Liver Neoplasms; Lung Neoplasms; Male; Methylnitrosourea; Mice, Inbred C57BL; Mice, Knockout; Mutation; Nitrosamines
PubMed: 28820464
DOI: 10.3390/ijms18081801 -
The Turkish Journal of Gastroenterology... Jul 2018The aim of this study was to investigate the influence of a synbiotic preparation (a mixture of six probiotics and a prebiotic) on aberrant crypt foci (ACF) formation,...
BACKGROUND/AIMS
The aim of this study was to investigate the influence of a synbiotic preparation (a mixture of six probiotics and a prebiotic) on aberrant crypt foci (ACF) formation, dysplasia, inflammation, and colitis-like lesions in experimental colon cancer in rats.
MATERIALS AND METHODS
Sixty male rats were categorized into three groups of 20 animals each. Group A was administered 1,2-dimethylydrazine, 15 mg/kg body weight (BW), once a week for 2 weeks. Group B was administered 1,2-dimethylydrazine at the same dose plus synbiotic, started after the second dose of carcinogen and lasted for 5 weeks. Group C was administered synbiotic plus carcinogen from the beginning of the experiment and lasted for 7 weeks. Animals were killed at the end of week 7.
RESULTS
At the end of the experiment, the animals that received carcinogen plus the synbiotic had 100%, whereas the animals that received only carcinogen has 70% survival. Animals of groups B and C had significantly lower percentage of inflammation, colitis-like lesions, and ACF dysplasia than animals of group A, whereas those of group C had the least pathological lesions.
CONCLUSION
Synbiotics seem to protect against the appearance of preneoplastic colon lesions in rats. The results of this experimental study suggest that treatment with a synbiotic preparation exerts significant antimutagenic properties against the development of preneoplastic lesions in rats.
Topics: 1,2-Dimethylhydrazine; Animals; Anticarcinogenic Agents; Carcinogens; Colon; Colonic Neoplasms; Male; Precancerous Conditions; Rats; Synbiotics
PubMed: 30249566
DOI: 10.5152/tjg.2018.17469