Search

Colorectal cancer (CRC) is one of the most common malignant tumours worldwide. Diarylheptanoids, secondary metabolites isolated from Zostera marina, are of interest in natural products research due to their biological activities. Zosterabisphenone B (ZBP B) has recently been shown to inhibit the viability of CRC cells. The aim of this study was to investigate the therapeutic potential of ZBP B for targeting human CRC cells. Cell viability was determined using the MTT assay. Flow cytometry and Western blot analyses were used to assess apoptosis and autophagy. A CRC xenograft model was used to evaluate the in vivo effect of ZBP B. No cytotoxic effect on HCEC cells was observed in the in vitro experiments. ZBP B caused morphological changes in HCT116 colon cancer cells due to an increase in early and late apoptotic cell populations. Mechanistically, ZBP B led to an increase in cleaved caspase-3, caspase-8, caspase-9, PARP and BID proteins and a decrease in Bcl-2 and c-Myc proteins. In the xenograft model of CRC, ZBP B led to a reduction in tumour growth. These results indicate that ZBP B exerts a selective cytotoxic effect on CRC cells by affecting apoptotic signalling pathways and reducing tumour growth in mice. Taken together, our results suggest that ZBP B could be a lead compound for the synthesis and development of CRC drugs., (© 2024 John Wiley & Sons Ltd.)

Background and Purpose: Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC)., Experimental Approach: TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8 -/- mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC., Key Results: TRPM8 is overexpressed in colon primary tumours and in CD326 + tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt-Frizzled signalling hyperactivation and adenomatous polyposis coli down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β-catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β-catenin and its target oncogenes such as C-Myc and Cyclin D1., Conclusion and Implications: Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required., Objectives: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS., Search Methods: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews., Selection Criteria: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS., Data Collection and Analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence., Main Results: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female.  The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes • Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I 2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. • Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. • Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes • PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. • HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I 2 = 0%; low-certainty evidence); • SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence); • AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence); • Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence); • Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence)., Authors' Conclusions: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background and Purpose: N-Acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N-acylethanolamines (NAEs) and its pharmacological inhibition has beneficial effects in inflammatory conditions. The knowledge of NAAA in cancer is fragmentary with an unclarified mechanism, whereas its contribution to colorectal cancer (CRC) is unknown to date., Experimental Approach: CRC xenograft and azoxymethane models were used to assess the in vivo effect of NAAA inhibition. Further, the tumour secretome was evaluated by an oncogenic array, CRC cell lines were used for in vitro studies, cell cycle was analysed by cytofluorimetry, NAAA was knocked down with siRNA, human biopsies were obtained from surgically resected CRC patients, gene expression was measured by RT-PCR and NAEs were measured by LC-MS., Key Results: The NAAA inhibitor AM9053 reduced CRC xenograft tumour growth and counteracted tumour development in the azoxymethane model. NAAA inhibition affected the composition of the tumour secretome inhibiting the expression of EGF family members. In CRC cells, AM9053 reduced proliferation with a mechanism mediated by PPAR-α and TRPV1. AM9053 induced cell cycle arrest in the S phase associated with cyclin A2/CDK2 down-regulation. NAAA knock-down mirrored the effects of NAAA inhibition with AM9053. NAAA expression was down-regulated in human CRC tissues, with a consequential augmentation of NAE levels and dysregulation of some of their targets., Conclusion and Implications: Our results show novel data on the functional importance of NAAA in CRC progression and the mechanism involved. We propose that this enzyme is a valid drug target for the treatment of CRC growth and development., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects. We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately. Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability. CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon. By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease., (© 2020 John Wiley & Sons Ltd.)

Background: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2009, Issue 3).Tea is one of the most commonly consumed beverages worldwide. Teas from the plant Camellia sinensis can be grouped into green, black and oolong tea, and drinking habits vary cross-culturally. C sinensis contains polyphenols, one subgroup being catechins. Catechins are powerful antioxidants, and laboratory studies have suggested that these compounds may inhibit cancer cell proliferation. Some experimental and nonexperimental epidemiological studies have suggested that green tea may have cancer-preventative effects., Objectives: To assess possible associations between green tea consumption and the risk of cancer incidence and mortality as primary outcomes, and safety data and quality of life as secondary outcomes., Search Methods: We searched eligible studies up to January 2019 in CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and reference lists of previous reviews and included studies., Selection Criteria: We included all epidemiological studies, experimental (i.e. randomised controlled trials (RCTs)) and nonexperimental (non-randomised studies, i.e. observational studies with both cohort and case-control design) that investigated the association of green tea consumption with cancer risk or quality of life, or both., Data Collection and Analysis: Two or more review authors independently applied the study criteria, extracted data and assessed methodological quality of studies. We summarised the results according to diagnosis of cancer type., Main Results: In this review update, we included in total 142 completed studies (11 experimental and 131 nonexperimental) and two ongoing studies. This is an additional 10 experimental and 85 nonexperimental studies from those included in the previous version of the review. Eleven experimental studies allocated a total of 1795 participants to either green tea extract or placebo, all demonstrating an overall high methodological quality based on 'Risk of bias' assessment. For incident prostate cancer, the summary risk ratio (RR) in the green tea-supplemented participants was 0.50 (95% confidence interval (CI) 0.18 to 1.36), based on three studies and involving 201 participants (low-certainty evidence). The summary RR for gynaecological cancer was 1.50 (95% CI 0.41 to 5.48; 2 studies, 1157 participants; low-certainty evidence). No evidence of effect of non-melanoma skin cancer emerged (summary RR 1.00, 95% CI 0.06 to 15.92; 1 study, 1075 participants; low-certainty evidence). In addition, adverse effects of green tea extract intake were reported, including gastrointestinal disorders, elevation of liver enzymes, and, more rarely, insomnia, raised blood pressure and skin/subcutaneous reactions. Consumption of green tea extracts induced a slight improvement in quality of life, compared with placebo, based on three experimental studies. In nonexperimental studies, we included over 1,100,000 participants from 46 cohort studies and 85 case-control studies, which were on average of intermediate to high methodological quality based on Newcastle-Ottawa Scale 'Risk of bias' assessment. When comparing the highest intake of green tea with the lowest, we found a lower overall cancer incidence (summary RR 0.83, 95% CI 0.65 to 1.07), based on three studies, involving 52,479 participants (low-certainty evidence). Conversely, we found no association between green tea consumption and cancer-related mortality (summary RR 0.99, 95% CI 0.91 to 1.07), based on eight studies and 504,366 participants (low-certainty evidence). For most of the site-specific cancers we observed a decreased RR in the highest category of green tea consumption compared with the lowest one. After stratifying the analysis according to study design, we found strongly conflicting results for some cancer sites: oesophageal, prostate and urinary tract cancer, and leukaemia showed an increased RR in cohort studies and a decreased RR or no difference in case-control studies., Authors' Conclusions: Overall, findings from experimental and nonexperimental epidemiological studies yielded inconsistent results, thus providing limited evidence for the beneficial effect of green tea consumption on the overall risk of cancer or on specific cancer sites. Some evidence of a beneficial effect of green tea at some cancer sites emerged from the RCTs and from case-control studies, but their methodological limitations, such as the low number and size of the studies, and the inconsistencies with the results of cohort studies, limit the interpretability of the RR estimates. The studies also indicated the occurrence of several side effects associated with high intakes of green tea. In addition, the majority of included studies were carried out in Asian populations characterised by a high intake of green tea, thus limiting the generalisability of the findings to other populations. Well conducted and adequately powered RCTs would be needed to draw conclusions on the possible beneficial effects of green tea consumption on cancer risk., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The aim of the present work was to examine if hydrogen peroxide treatment of sugar beet fibre that aimed at improving its physicochemical properties would impair its antioxidant potential. Three different sugar beet fibres were obtained from sugar beet - non-treated fibre (NTF) from sugar beet cossettes extracted with sulphurous acid, treated fibre (TF) from NTF treated with hydrogen peroxide in alkaline solution and commercially available Fibrex(®) . The antioxidant activity of extractable and non-extractable fibre fractions in ethanol/water mixture (80:20, v/v) of three fibre samples was estimated. Non-extractable fractions obtained after alkaline treatment of investigated fibres were much higher in phenolic compounds and possessed higher antioxidant potential than extractable fractions. Ferulic acid was proven to be the dominant phenolic acid. Regarding both extractable and non-extractable fractions, Fibrex(®) had the highest antioxidant activity in chemical tests, while NTF was superior in comparison with TF. Based on the results of Caco-2 cells-based test, all non-extractable fractions possessed potential for reactive oxygen species inhibition. Regarding the extractable fractions, only the TF manifested this effect.Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background and Purpose: Palmitoylethanolamide (PEA) acts via several targets, including cannabinoid CB1 and CB2 receptors, transient receptor potential vanilloid type-1 (TRPV1) ion channels, peroxisome proliferator-activated receptor alpha (PPAR α) and orphan G protein-coupled receptor 55 (GRR55), all involved in the control of intestinal inflammation. Here, we investigated the effect of PEA in a murine model of colitis., Experimental Approach: Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters and by histology; intestinal permeability by a fluorescent method; colonic cell proliferation by immunohistochemistry; PEA and endocannabinoid levels by liquid chromatography mass spectrometry; receptor and enzyme mRNA expression by quantitative RT-PCR., Key Results: DNBS administration caused inflammatory damage, increased colonic levels of PEA and endocannabinoids, down-regulation of mRNA for TRPV1 and GPR55 but no changes in mRNA for CB1 , CB2 and PPARα. Exogenous PEA (i.p. and/or p.o., 1 mg·kg(-1) ) attenuated inflammation and intestinal permeability, stimulated colonic cell proliferation, and increased colonic TRPV1 and CB1 receptor expression. The anti-inflammatory effect of PEA was attenuated or abolished by CB2 receptor, GPR55 or PPARα antagonists and further increased by the TRPV1 antagonist capsazepine., Conclusions and Implications: PEA improves murine experimental colitis, the effect being mediated by CB2 receptors, GPR55 and PPARα, and modulated by TRPV1 channels., (© 2014 The British Pharmacological Society.)

Background and Purpose: Palmitoylethanolamide (PEA), a naturally occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, such as cannabinoid CB1 and CB2 receptors, TRPV1 channels and PPARα. Here, we investigated the effect of PEA in a mouse model of functional accelerated transit which persists after the resolution of colonic inflammation (post-inflammatory irritable bowel syndrome)., Experimental Approach: Intestinal inflammation was induced by intracolonic administration of oil of mustard (OM). Mice were tested for motility and biochemical and molecular biology changes 4 weeks later. PEA, oleoylethanolamide and endocannabinoid levels were measured by liquid chromatography-mass spectrometry and receptor and enzyme mRNA expression by qRT-PCR., Key Results: OM induced transient colitis and a functional post-inflammatory increase in upper gastrointestinal transit, associated with increased intestinal anandamide (but not 2-arachidonoylglycerol, PEA or oleoylethanolamide) levels and down-regulation of mRNA for TRPV1 channels. Exogenous PEA inhibited the OM-induced increase in transit and tended to increase anandamide levels. Palmitic acid had a weaker effect on transit. Inhibition of transit by PEA was blocked by rimonabant (CB1 receptor antagonist), further increased by 5'-iodoresiniferatoxin (TRPV1 antagonist) and not significantly modified by the PPARα antagonist GW6471., Conclusions and Implications: Intestinal endocannabinoids and TRPV1 channel were dysregulated in a functional model of accelerated transit exhibiting aspects of post-inflammatory irritable bowel syndrome. PEA counteracted the accelerated transit, the effect being mediated by CB1 receptors (possibly via increased anandamide levels) and modulated by TRPV1 channels., (© 2014 The British Pharmacological Society.)

Flavonoids are widely distributed secondary metabolites and currently consumed in large amounts in the daily diet. In this article, some of the most recent developments in flavonoid - and related polyphenolic compounds - pharmacology are discussed, with particular emphasis on very recent data, most of which are published in Phytotherapy Research, which highlight new aspects in flavonoid anti-inflammatory, antilipidemic, antihyperglycemic, antiviral, hepatoprotective, gastric antiulcer, cardioprotective, neuroprotective, antioxidant and anticancer actions. These updated data confirm the well-established diverse beneficial pharmacological actions and might support the perspective for a therapeutic use., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background and Purpose: Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states., Experimental Approach: Inflammation was induced in the mouse small intestine by croton oil. Endocannabinoid (anandamide and 2-arachidonoyl glycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry; TRPA1 and cannabinoid receptors were analysed by quantitative RT-PCR; upper gastrointestinal transit, colonic propulsion and whole gut transit were evaluated in vivo; contractility was evaluated in vitro by stimulating the isolated ileum, in an organ bath, with ACh or electrical field stimulation (EFS)., Key Results: Croton oil administration was associated with decreased levels of anandamide (but not 2-arachidonoyl glycerol) and palmitoylethanolamide, up-regulation of TRPA1 and CB₁ receptors and down-regulation of CB₂ receptors. Ex vivo CBC did not change endocannabinoid levels, but it altered the mRNA expression of TRPA1 and cannabinoid receptors. In vivo, CBC did not affect motility in control mice, but normalized croton oil-induced hypermotility. In vitro, CBC reduced preferentially EFS- versus ACh-induced contractions. Both in vitro and in vivo, the inhibitory effect of CBC was not modified by cannabinoid or TRPA1 receptor antagonists., Conclusion and Implications: CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background and Purpose: Allyl isothiocyanate (AITC, mustard oil), a constituent of many common cruciferous vegetables (Brassicaceae), activates transient receptor potential of ankyrin type-1 (TRPA1) channels, claimed to regulate gastrointestinal contractility. In this study, we have investigated the effect of AITC on intestinal motility., Experimental Approach: Effects of AITC were investigated in vivo on upper gastrointestinal transit in mice and in mouse isolated ileum [contractions induced by electrical field stimulation (EFS), acetylcholine and spontaneous contractility]. The contractor activity of AITC was studied in mouse isolated colon. The ability of TRPA1 channel antagonists to block AITC-induced elevation of intracellular Ca(2+) [Ca(2+)](i) was assessed in HEK293 cells transfected with rat TRPA1 channels., Key Results: AITC increased [Ca(2+)](i) in HEK293 cells, reduced ileal contractility (acetylcholine-, EFS-induced contractions and spontaneous contractility), but contracted the isolated colon. Gentamicin and camphor (non-selective TRPA1 channel antagonists), HC-030031 and AP18 (selective TRPA1 channel agonists) inhibited AITC-induced effects in HEK293 cells but not in the ileum or colon. AITC-induced contractions were reduced by tetrodotoxin and strongly reduced by nifedipine, cyclopiazonic acid and ryanodine. In vivo, AITC reduced (following i.p. administration) or increased (following intragastric administration) upper gastrointestinal transit in mice These effects were not affected by HC-030031., Conclusion and Implications: AITC, depending, in vitro, on the regions of gut examined and, in vivo, on the route of administration, exerted both stimulatory and inhibitory effects on intestinal motility, which were not sensitive to TRPA1 channel antagonists. The proposition that TRPA1 channels are the primary targets for AITC to induce contraction should be revised., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Background and Purpose: Endocannabinoids in tissues controlling energy homeostasis are altered in obesity, thus contributing to metabolic disorders. Here we evaluate endocannabinoid dysregulation in the small intestine of mice with diet-induced obesity (DIO) and in peripheral tissues of Zucker and lean rats following food deprivation and re-feeding., Experimental Approach: Intestinal transit, evaluated using rhodamine-B-labelled dextran, and small intestinal endocannabinoid levels, measured by liquid chromatography mass spectrometry, were measured in mice fed normal or high-fat diets (HFDs). Endocannabinoid levels were measured also in various tissues of lean and Zucker rats fed ad libitum or following overnight food deprivation with and without subsequent re-feeding., Key Results: After 8 weeks of HFD, baseline intestinal transit was increased in DIO mice and enhanced by cannabinoid CB(1) receptor antagonism less efficaciously than in lean mice. Small intestinal anandamide and 2-arachidonoylglycerol levels were reduced and increased respectively. In Zucker rats, endocannabinoids levels were higher in the pancreas, liver and duodenum, and lower in the subcutaneous adipose tissue. Food deprivation increased endocannabinoid levels in the duodenum and liver of both rat strains, in the pancreas of lean rats and in adipose tissues of Zucker rats., Conclusions and Implications: Reduced anandamide levels might account for increased intestinal motility in DIO mice. Regulation of endocannabinoid levels in rat peripheral tissues, induced by food deprivation and re-feeding, might participate in food intake and energy processing and was altered in Zucker rats. These data, together with previous observations, provide further evidence for dysregulation of peripheral endocannabinoids in obesity.

Background: Tea is one of the most commonly consumed beverages worldwide. Teas from the plant Camellia sinensis can be grouped into green, black and oolong tea. Cross-culturally tea drinking habits vary. Camellia sinensis contains the active ingredient polyphenol, which has a subgroup known as catechins. Catechins are powerful antioxidants. It has been suggested that green tea polyphenol may inhibit cell proliferation and observational studies have suggested that green tea may have cancer-preventative effects., Objectives: To critically assess any associations between green tea consumption and the risk of cancer incidence and mortality., Search Strategy: We searched eligible studies up to January 2009 in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Amed, CancerLit, Psych INFO and Phytobase and reference lists of previous reviews and included studies., Selection Criteria: We included all prospective, controlled interventional studies and observational studies, which either assessed the associations between green tea consumption and risk of cancer incidence or that reported on cancer mortality., Data Collection and Analysis: At least two review authors independently applied the study criteria, extracted data and assessed methodological quality of studies. Due to the nature of included studies, which were mainly epidemiological, results were summarised descriptively according to cancer diagnosis., Main Results: Fifty-one studies with more than 1.6 million participants were included. Twenty-seven of them were case-control studies, 23 cohort studies and one randomised controlled trial (RCT).Twenty-seven studies tried to establish an association between green tea consumption and cancer of the digestive tract, mainly of the upper gastrointestinal tract, five with breast cancer, five with prostate cancer, three with lung cancer, two with ovarian cancer, two with urinary bladder cancer one with oral cancer, three further studies included patients with various cancer diagnoses.The methodological quality was measured with the Newcastle-Ottawa scale (NOS). The 9 nested case-control studies within prospective cohorts were of high methodological quality, 13 of medium, and 1 of low. One retrospective case-control study was of high methodological quality and 21 of medium and 5 of low.Results from studies assessing associations between green tea and risk of digestive tract cancer incidence were highly contradictory. There was limited evidence that green tea could reduce the incidence of liver cancer. The evidence for esophageal, gastric, colon, rectum, and pancreatic cancer was conflicting. In prostate cancer, observational studies with higher methodological quality and the only included RCT suggested a decreased risk in men consuming higher quantities green tea or green tea extracts. However, there was limited to moderate evidence that the consumption of green tea reduced the risk of lung cancer, especially in men, and urinary bladder cancer or that it could even increase the risk of the latter. There was moderate to strong evidence that green tea consumption does not decrease the risk of dying from gastric cancer. There was limited moderate to strong evidence for lung, pancreatic and colorectal cancer., Authors' Conclusions: There is insufficient and conflicting evidence to give any firm recommendations regarding green tea consumption for cancer prevention. The results of this review, including its trends of associations, need to be interpreted with caution and their generalisability is questionable, as the majority of included studies were carried out in Asia (n = 47) where the tea drinking culture is pronounced. Desirable green tea intake is 3 to 5 cups per day (up to 1200 ml/day), providing a minimum of 250 mg/day catechins. If not exceeding the daily recommended allowance, those who enjoy a cup of green tea should continue its consumption. Drinking green tea appears to be safe at moderate, regular and habitual use.

Background and Purpose: Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut., Experimental Approach: Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays., Key Results: Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake., Conclusions and Implications: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.

Clinical studies suggest that the Ayurvedic plant Boswellia serrata may be effective in reducing diarrhoea in patients with inflammatory bowel disease. In the present study, we evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhoea in rodents. BSE depressed electrically-, acetylcholine-, and barium chloride-induced contractions in the isolated guinea-pig ileum, being more potent in inhibiting the contractions induced by acetylcholine and barium chloride. The inhibitory effect of BSE on acetylcholine-induced contractions was reduced by the L-type Ca(2+) channel blockers verapamil and nifedipine, but not by the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid, by the phosphodiesterase type IV inhibitor rolipram or by the lipoxygenase inhibitor zileuton. 3-acetyl-11-keto-beta-boswellic acid, one of the main active ingredients of B. serrata, inhibited acetylcholine-induced contractions. BSE inhibited upper gastrointestinal transit in croton oil-treated mice as well as castor oil-induced diarrhoea. However, BSE did not affect intestinal motility in control mice, both in the small and in the large intestine. It is concluded that BSE directly inhibits intestinal motility with a mechanism involving L-type Ca(2+) channels. BSE prevents diarrhoea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results could explain, at least in part, the clinical efficacy of this Ayurvedic remedy in reducing diarrhoea in patients with inflammatory bowel disease.

Bacopa monniera L. (family Scrophulariaceae) (BM) is an Ayurvedic medicine, clinically used for memory enhancing, epilepsy, insomnia and as a mild sedative. In this work, the free radical scavenging capacity of a methanol extract of BM and the effect on DNA cleavage induced by H2O2 UV-photolysis was investigated. In addition, we examined whether this plant extract is capable of reducing the hydrogen peroxide-induced cytotoxicity and DNA damage in human non-immortalized fibroblasts. It showed a dose-dependent free radical scavenging capacity and a protective effect on DNA cleavage. These results were confirmed by a significant protective effect on H2O2-induced cytoxicity and DNA damage in human non-immortalized fibroblasts. The antioxidant capacity of BM may explain, at least in part, the reported antistress, immunomodulatory, cognition-facilitating, antiinflammatory and antiaging effects produced by it in experimental animals and in clinical situations and may justify further investigation of its other beneficial properties. Moreover, this experimental evidence suggests that because of its antioxidant activity, this Ayurvedic drug may be useful in the treatment of human pathologies in which free radical production plays a key role., (Copyright 2003 John Wiley & Sons, Ltd.)

1. The aim of this study was to evaluate whether caffeic acid phenethyl ester (CAPE), an active component of propolis, was able to reduce neointimal formation in a model of endothelial injury of rat carotid artery (balloon angioplasty). Furthermore, we investigated the relationship between neointima formation and nuclear factor-kappaB (NF-kappaB) activation and we correlated NF-kappaB activation to the expression of inducible isoform of cyclo-oxygenase (COX-2) in injured carotids. 2. In control group a significant proliferation of neointima was observed 14 days after balloon angioplasty, which was correlated to an increase of NF-kappaB/DNA binding activity as well as p50/p65 nuclear levels compared to those observed in the carotids from sham-operated rats. Furthermore, NF-kappaB activation was correlated to increased COX-2, but not beta-actin, protein expression. 3. Treatment of rats for 14 days with CAPE (3, 10, 30 mg x kg(-1)) caused a significant inhibition of all the parameters assayed, except beta-actin protein expression. 4. These results indicate that treatment with CAPE may lead to a reduction of neointima formation by inhibiting NF-kappaB activation and suggest that this agent may have therapeutic relevance for the prevention of human restenosis.

Phytogenic agents have traditionally been used by herbalists and indigenous healers for the prevention and treatment of peptic ulcer. This article reviews the anti-acid/anti-peptic, gastro-protective and/or anti-ulcer properties of the most commonly employed herbal medicines and their identified active constituents. Botanical compounds with anti-ulcer activity include flavonoids (i.e. quercetin, naringin, silymarin, anthocyanosides, sophoradin derivatives) saponins (i.e. from Panax japonicus and Kochia scoparia), tannins (i.e. from Linderae umbellatae), gums and mucilages (i.e. gum guar and myrrh). Among herbal drugs, liquorice, aloe gel and capsicum (chilli) have been used extensively and their clinical efficacy documented. Also, ethnomedical systems employ several plant extracts for the treatment of peptic ulcer. Despite progress in conventional chemistry and pharmacology in producing effective drugs, the plant kingdom might provide a useful source of new anti-ulcer compounds for development as pharmaceutical entities or, alternatively, as simple dietary adjuncts to existing therapies.

We have evaluated the effect of cannabinoid drugs, administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.) on upper gastrointestinal transit in control and in croton oil-treated mice. The cannabinoid agonists, WIN 55,212-2 (2-239 nmol mouse(-1)) and cannabinol (24-4027 nmol mouse(-1)), decreased while the CB(1) antagonist SR141716A (2-539 nmol mouse(-1)) increased transit in control mice. WIN 55,212-2, cannabinol and SR141716A had lower ED(50) values when administered i.c.v., than when administered i.p. The CB(2) antagonist SR144528 (52 nmol mouse(-1), i.p.) was without effect. During croton oil (0.01 ml mouse(-1), p.o.)-induced diarrhoea, the ED(50) values of i.p. -injected WIN 55,212-2 and cannabinol (but not SR141716A) were significantly decreased (compared to control mice). However, the ED(50) values of WIN 55,212-2 were similar after i.p. or i.c.v. administration. The inhibitory effects of WIN 55,212-2 and cannabinol were counteracted by SR141716A (16 nmol mouse(-1), i.p.) but not by SR144528 (52 nmol mouse(-1), i.p.) both in control and croton-oil treated mice. Ganglionic blockade with hexamethonium (69 nmol mouse(-1), i.p.) did not modify the inhibitory effect of i.p. -injected cannabinoid agonists either in control or in croton-oil treated mice. The lower ED(50) values of cannabinoid drugs after i.c.v. administration suggest a central (CB(1)) site of action. However, a peripheral site of action is suggested by the lack of effect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism.

1. The effect of cannabinoid drugs has been investigated on cholinergic and non-adrenergic non-cholinergic (NANC) contractile responses to the circular smooth muscle of guinea-pig ileum elicited by electrical field stimulation (EFS). 2. The cannabinoid receptor agonist WIN 55,212-2 (1-1000 nM) and the putative endogenous ligand anandamide (0.1-100 microM) both produced a concentration-dependent inhibition of the cholinergic (9-57% and 1-51% inhibition) and NANC (9 55% and 2-57% inhibition) contractile responses. WIN 55,212-2 and anandamide did not modify the contractions produced by exogenous acetylcholine or substance P. 3. Apamin (30 nM), a blocker of Ca2+-activated K+ channels, reduced the inhibitory effect of WIN 55,212-2 on cholinergic, but not NANC, contractile response. NG-nitro-L-arginine methyl ester (100 microM), an inhibitor of nitric oxide synthase, or naloxone (1 microM), an opioid receptors antagonist, did not modify the inhibitory effect of WIN 55,212-2 on both cholinergic and NANC contractions. 4. The inhibitory effects of WIN 55,212-2 and anandamide on both cholinergic and NANC contractile response was competitively antagonized by the cannabinoid CB1 receptor antagonist SR 141716A (10-1000 nM). 5. In absence of other drugs, SR 141716A (1-1000 nM) enhanced cholinergic (1-45% increase) and NANC (2-38% increase) contractile responses elicited by electrical stimulation, but did not modify the contractions produced by acetylcholine or substance P. 6. It is concluded that activation of prejunctional cannabinoid CB1 receptors produces inhibition of cholinergic and NANC excitatory responses in the guinea-pig circular muscle. The inhibition of cholinergic (but not NANC) transmission involves activation of apamin-sensitive K+ channels. In addition, an endogenous cannabinoid ligand could inhibit cholinergic and NANC transmission in the guinea-pig ileal circular muscle.