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The administration of a ketogenic diet (KD) has been considered therapeutic in subjects with irritable bowel syndrome (IBS). This study aimed to investigate the molecular mechanisms by which a low-carbohydrate diet, such as KD, can improve gastrointestinal symptoms and functions in an animal model of IBS by evaluating possible changes in intestinal tissue expression of endocannabinoid receptors. In rats fed a KD, we detected a significant restoration of cell damage to the intestinal crypt base, a histological feature of IBS condition, and upregulation of CB1 and CB2 receptors. The diet also affected glucose metabolism and intestinal membrane permeability, with an overexpression of the glucose transporter GLUT1 and tight junction proteins in treated rats. The present data suggest that CB receptors represent one of the molecular pathways through which the KD works and support possible cannabinoid-mediated protection at the intestinal level in the IBS rats after dietary treatment.

Background/aim: The expression of cannabinoid receptor-1 (CB1-R) seems to be modulated by bioactive natural components such as the flavonoid quercetin. The aim of this study was to determine in an animal model of induced-colon cancer, whether quercetin inhibits colon carcinogenesis through changes in the expression of CB1-R., Materials and Methods: C57BL/6J male mice were randomly assigned to standard diet or experimental diet supplemented with 0.5% quercetin. Azoxymethane (AOM) (10 mg/kg body weight) or saline solution (PBS) was intraperitoneally injected, once weekly for 6 weeks., Results: The diet supplemented with quercetin induced CB1-R gene expression and protein, inhibiting the protein levels of STAT3 and p-STAT3 (both mediators of cell proliferation). Dietary quercetin also caused a significant increase in Bax/Bcl2 ratio protein expression., Conclusion: The anti-proliferative and pro-apoptotic effects of quercetin in AOM-treated mice are mediated by induction of the protein and gene expression levels of CB1-R., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Mediterranean diet components, such as olive oil and ω-3 polyunsaturated fatty acids (ω-3 PUFAs), can arrest cell growth and promote cell apoptosis. Recently, olive oil has been demonstrated to modulate type-1 cannabinoid ( CB1 ) receptor gene expression in both human colon cancer cells and rat colon. The aim of this study was to investigate a possible link between olive oil and ω-3 PUFAs effects and CB1 receptor expression in both intestinal and adipose tissue of Apc Min/+ mice. To confirm the role for the CB1 receptor as a negative modulator of cell proliferation in human colon cancer, CB1 receptor gene expression was also detected in tumor tissue and in surrounding normal mucosa of patients with colorectal cancer (CRC). Dietary ω-3 PUFAs significantly inhibited intestinal polyp growth in mice, correlating with CB1 receptor gene and protein expression induction. CB1 receptor gene up-regulation was also detected in adipose tissue, suggesting a close communication between cancer cells and the surrounding environment. Tissue CB1 receptor induction was associated with a concurrent inactivation of the Wnt/β-catenin pathway. Moreover, there was a significant reduction in CB1 receptor gene expression levels in cancer tissue compared to normal surrounding mucosa of patients with CRC, confirming that in cancer the "protective" action of the CB1 receptor is lost.

Quercetin, the major constituent of flavonoid and widely present in fruits and vegetables, is an attractive compound for cancer prevention due to its beneficial anti proliferative effects, showing a crucial role in the regulation of apoptosis and cell cycle signaling. In vitro studies have demonstrated that quercetin specifically influences colon cancer cell proliferation. Our experiments, using human colon adenocarcinoma cells, confirmed the anti proliferative effect of quercetin and gave intriguing new insight in to the knowledge of the mechanisms involved. We observed a significant increase in the expression of the endocannabinoids receptor (CB1-R) after quercetin treatment. CB1-R can be considered an estrogen responsive receptor and quercetin, having a structure similar to that of the estrogens, can interact with CB1-R leading to the regulation of cell growth. In order to clarify the contribution of the CB1-R to the quercetin action, we investigated some of the principal molecular pathways that are inhibited or activated by this natural compound. In particular we detected the inhibition of the major survival signals like the PI3K/Akt/mTOR and an induction of the pro apoptotic JNK/JUN pathways. Interestingly, the metabolism of β-catenin was modified by flavonoid both directly and through activated CB1-R. In all the experiments done, the quercetin action has proven to be reinforced by anandamide (Met-F-AEA), a CB1-R agonist, and partially counteracted by SR141716, a CB1-R antagonist. These findings open new perspectives for anticancer therapeutic strategies., (© 2015 Wiley Periodicals, Inc.)

Background: Cannabinoid type 1 receptor (CB1-R) is a key mediator in the control of food intake and is linked to obesity., Aim: To evaluate the relationship between CB1-R gene polymorphism and dietary macronutrient intake in elderly subjects., Methods: This study included 118 subjects (60 males, 58 females) from a population survey carried out in southern Italy in 1992-1993 who were older than 65 years and previously characterized for CB1-R polymorphism (75 with GG wild-type genotype, 41 with heterozygous polymorphic allele AG, and 2 with genotype AA). All subjects completed a validated semi-quantitative food frequency questionnaire. Statistical methods included multiple logistic regression to model macronutrient intake to genotype, controlling for potential confounders., Results: When controlled for age, gender, and body mass index, the intake of dietary cholesterol and saturated fats corrected for calories was inversely associated with the CB1-R 1359 G/A polymorphism, while the intake of starchy carbohydrates was directly associated with this polymorphism., Conclusion: In our unselected elderly population, the 1359 G/A polymorphism is linked with a specific macronutrient intake. This could be explained by the role of the cannabinoid system as a determinant of food intake and eating behavior., (Copyright © 2012 S. Karger AG, Basel.)

Rimonabant (SR141716), a highly selective cannabinoid receptor antagonist, exerts along with its anti-obesity action, pleiotropic functions affecting a broad range of diseases, from obesity-related co-morbidities to drug dependence and cancer. Several studies suggested an anti-tumour activity of rimonabant in several in vitro and in vivo models. In this study, we compared the anti-proliferative effect of SR141716 in the human colon cancer cell line DLD-1 with oxaliplatin, one of the cytotoxic drugs currently used in the treatment of colorectal cancer. We show that SR141716 inhibits DLD-1 cell proliferation similarly to oxaliplatin and if administered in combination SR141716 potentiated the inhibitory effect caused by oxaliplatin. Assessment of drug interaction was performed calculating combination index that showed a strong synergistic effect between the two drugs added to cells in combination. Our findings suggest that the combined synergic effect of SR141716 and oxaliplatin improves the blocking of colon cancer cell proliferation. Therefore, this combination merits further explorations in preclinical and clinical settings.

Objective: Cannabinoids are a class of compounds that have the ability to activate two specific receptor subtypes, the cannabinoid CB1 and CB2 receptors. CB1 receptor is a G-protein-coupled receptor that is linked to the signal transduction pathways. The cumulative effects of this receptor have important implications in the control of cell survival and cell death having the potential to regulate tumor cell growth. In this connection, interest has been focused on factors such as sex steroid hormones, which regulate CB1 receptor expression. The aim of this study was to investigate the effects of 17beta-estradiol exposure on the CB1 receptor gene and its protein expression in human primary tumor colon cancer cell lines, such as DLD-1, HT-29 and one lymph node metastatic cell line, SW620., Material and Methods: CB1 gene expression was determined using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in DLD-1, HT-29 and SW620 cells treated at different times and doses of 17beta-estradiol exposure. CB 1 protein expression was detected by Western immunoblot., Results: 17beta-estradiol induced CB1 gene expression in all the human colon cancer cells studied. The early induction of CB1 receptor mRNA in DLD-1 and SW620 cells was mediated by the estrogen receptor because the pure estrogen antagonist, ICI 182,780, was able to counteract this effect. Estrogenic induction of the CB1 receptor was also detectable at protein level in all cell types tested., Conclusions: The CB1 receptor can be considered an estrogen-responsive gene in DLD-1, HT-29 and SW620 cells. Up-regulation of CB1 expression by 17beta-estradiol is a further mechanism of estrogens to control colon cancer proliferation.

Context: Endocannabinoids control food intake via both central and peripheral mechanisms, and cannabinoid type-1 receptor (CB1) modulates lipogenesis in primary adipocyte cell cultures and in animal models of obesity., Objectives: We aimed to evaluate, at the population level, the frequency of a genetic polymorphism of CB1 and to study its correlation with body mass index., Design, Setting and Participants: Healthy subjects from a population survey carried out in southern Italy examined in 1992-1993 and older than 65 years (n=419, M=237, F=182) were divided into quintiles by body mass index (BMI). Two hundred and ten subjects were randomly sampled from the first, third and fifth quintile of BMI (BMI, respectively: 16.2-23.8=normal, 26.7-28.4=overweight, 31.6-49.7=obese) to reach a total of 70 per quintile. Their serum and white cells from the biological bank were used to measure the genotype and the blood variables for the study., Measurements: Anthropometric parameters, blood pressure, serum glucose and lipid levels were measured with standard methods; genotyping for the CB1 1359G/A polymorphism was performed using multiplex PCR. Statistical methods included chi2 for trend, binomial and multinomial multiple logistic regression to model BMI on the genotype, controlling for potential confounders., Results: We found a clear trend of increasing relative frequency of the CB1 wild-type genotype with the increase of BMI (P=0.03) and, using a multiple logistic regression model, wild-type genotype, female gender, age, glycaemia and triglycerides were directly associated with both overweight (third quintile of BMI) and obesity (fifth quintile of BMI)., Conclusions: Although performed in a limited number of subjects, our results show that the presence of the CB1 polymorphic allele was significantly associated with a lower BMI.