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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 -
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 -
Experimental Physiology Sep 2020What is the central question of this study? What are the alleviative effects of the combination of exercise training and quercetin supplementation on colorectal...
Combination of quercetin and exercise training attenuates depression in rats with 1,2-dimethylhydrazine-induced colorectal cancer: Possible involvement of inflammation and BDNF signalling.
NEW FINDINGS
What is the central question of this study? What are the alleviative effects of the combination of exercise training and quercetin supplementation on colorectal cancer-related depression in rats with 1,2-dimethylhydrazine-induced colorectal cancer and what is the corresponding signalling pathway? What is the main finding and its importance? We showed that the combination of exercise training and quercetin supplementation resulted in a significant decrease in tumour incidence and improvement in depressive-like behaviours through modulation of the BDNF/TrKβ/β-catenin axis in the prefrontal cortex.
ABSTRACT
In addition to physical problems, depression is considered to be one of the most important challenges for patients with various types of cancers, particularly colorectal cancer. Inflammation and upregulation of brain neurotrophic factors are two major links between cancer and depression. In this study, we aimed to evaluate the alleviative effects of quercetin and exercise training on depressive-like behaviours in rats with 1,2-dimethylhydrazine (DMH)-induced colorectal cancer and to investigate the underlying mechanisms. Animals were assigned into the following five groups: (i) control group; (ii) DMH (20 mg kg s.c., once a week for 10 weeks); (iii) DMH for 10 weeks, followed by quercetin (50 mg kg p.o., once per week) for 12 weeks; (iv) DMH for 10 weeks, followed by exercise training for 12 weeks; and (v) DMH for 10 weeks, followed by quercetin and exercise training for 12 weeks. The DMH-treated rats showed an increase in depressive-like behaviours in both open field and forced swimming tests. Histopathological examination revealed neural damage and reduced Nissl bodies in the prefrontal cortex. In addition, administration of DMH increased inflammatory cytokines in the serum, prefrontal cortex and tumour tissues and decreased the expression levels of brain-derived neurotrophic factor (BDNF), tyrosine kinase β receptor (TrKβ) and β-catenin in the cortex. In contrast, treatment with quercetin and exercise training effectively alleviated all the above-mentioned DMH-associated behavioural, biochemical and histopathological alterations without changing its anti-tumour activity. Taken together, our results show that the combination of quercetin and exercise training exerts potent anti-tumour and anti-depressive effects through suppression of inflammation and upregulation of the BDNF/TrKβ/β-catenin axis in the prefrontal cortex.
Topics: 1,2-Dimethylhydrazine; Animals; Brain-Derived Neurotrophic Factor; Colorectal Neoplasms; Cytokines; Depression; Male; Physical Conditioning, Animal; Prefrontal Cortex; Quercetin; Rats; Rats, Wistar; Receptor, trkB; Signal Transduction; beta Catenin
PubMed: 32681548
DOI: 10.1113/EP088605 -
Molecules (Basel, Switzerland) May 2021This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon...
This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon carcinogenesis in rats. VA did not induce the formation of hepatic glutathione -transferase placental form (GST-P) positive foci and colonic aberrant crypt foci, demonstrating no carcinogenic activity. VA (75 mg kg body weight) could significantly reduce the number and areas of hepatic GST-P positive foci when administered before carcinogen injections, but no such effect was seen when it was administered after carcinogen injection. No protection was seen in the colon when VA was treated before or after carcinogen injection. Immunohistochemical studies demonstrated the decreased expression of proliferating cell nuclear antigen and the induction of apoptosis. Mechanistic studies showed that VA significantly induced the expression of and genes, which are associated with the detoxification system. Likewise, the antiproliferative effect was noticed by the reduction of expression. The apoptotic activity may be due to the upregulation of and levels and downregulation of the level. These data suggest that VA exhibited significant protection against diethylnitrosamine- and 1,2-dimethylhydrazine-induced hepatocarcinogenesis, which might be related to the induction of the detoxifying enzyme, the reduction of proliferation and the induction of apoptosis.
Topics: 1,2-Dimethylhydrazine; Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Carcinogenesis; Cell Proliferation; Diethylnitrosamine; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Male; Organ Size; Protective Agents; Rats, Wistar; Vanillic Acid; Rats
PubMed: 34063148
DOI: 10.3390/molecules26092718 -
International Journal of Molecular... Sep 2021Colon cancer is accompanied by a decrease of epithelial barrier properties, which are determined by tight junction (TJ) proteins between adjacent epithelial cells. The...
Colon cancer is accompanied by a decrease of epithelial barrier properties, which are determined by tight junction (TJ) proteins between adjacent epithelial cells. The aim of the current study was to analyze the expression of TJ proteins in a rat model of 1,2-dimethylhydrazine (DMH)-induced colorectal cancer, as well as the barrier properties and TJ protein expression of IPEC-J2 cell monolayers after incubation with DMH. Transepithelial electrical resistance and paracellular permeability for sodium fluorescein of IPEC-J2 were examined by an epithelial volt/ohm meter and spectrophotometry. The expression and localization of TJ proteins were analyzed by immunoblotting and immunohistochemistry. In the colonic tumors of rats with DMH-induced carcinogenesis, the expression of claudin-3 and -4 was significantly increased compared to controls. The transepithelial electrical resistance of IPEC-J2 cells increased, while paracellular permeability for sodium fluorescein decreased, accompanied by an increased expression of claudin-4. The increase of claudin-4 in rat colon after chronic DMH exposure was consistent with the acute effect of DMH on IPEC-J2 cells, which may indicate an essential role of this protein in colorectal cancer development.
Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Cell Line; Claudins; Colonic Neoplasms; Electric Impedance; Intestinal Mucosa; Male; Permeability; Rats; Rats, Wistar; Swine; Tight Junction Proteins
PubMed: 34638619
DOI: 10.3390/ijms221910278