Irritable bowel syndrome (IBS) is a spectrum of disorders characterized by abdominal discomfort and pain, associated with altered bowel habits. Though gut motility, secretion and sensation may be ...altered in patients with IBS, the pathophysiology of this condition remains to be fully understood. The endocannabinoid system is involved in the regulation of numerous gastrointestinal functions including motility, sensation and secretion under both physiological and pathophysiological conditions. Activation of cannabinoid (CB)1 and CB2 receptors under various circumstances reduces motility, limits secretion and decreases hypersensitivity in the gut. Drugs that alter the levels of endocannabinoids in the gut also reduce motility and attenuate inflammation. In this review, we discuss the role of the endocannabinoid system in gastrointestinal physiology. We go on to consider the involvement of the endocannabinoid system in the context of symptoms associated with IBS and a possible role of this system in the pathophysiology and treatment of IBS.
Summary
Background Recent studies suggest a role for the endocannabinoid system, including fatty acid amide hydrolase (FAAH), in intestinal inflammation.
Aim To analyse FAAH expression and the FAAH ...385 C/A (p.Pro129Thr; rs324420) single nucleotide polymorphism (SNP) in‐patients with Crohn’s disease (CD) and ulcerative colitis (UC).
Patients and methods Genomic DNA from 1008 individuals (CD: n = 435; UC: n = 167; controls: n = 406) was analysed for the FAAH 385 C/A SNP. We determined FAAH mRNA expression by quantitative PCR in CD and UC lesions as well as in intestinal epithelial cells (IECs).
Results There were no significant differences regarding the frequency of this SNP in the three study groups (CD, UC, controls). However, CD patients homozygous for the FAAH p.Pro129Thr polymorphism were more likely to develop a severe disease phenotype associated with fistulas (P = 0.03, OR 3.12, 95% CI 1.08–8.98) and extra‐intestinal manifestations (P = 0.005, OR 4.29, CI 1.49–12.35). In UC, homozygous carriers had an earlier disease onset than wild‐type carriers (P = 0.01). FAAH mRNA expression correlated with IL‐8 mRNA expression in CD lesions (r = 0.53). However, pro‐inflammatory stimuli did not significantly increase FAAH mRNA expression in IECs.
Conclusion The FAAH p.Pro129Thr polymorphism may modulate the CD phenotype.
Background Cannabinoid (CB) receptors are involved in the regulation of gastrointestinal (GI) motility under physiological and pathophysiological conditions. We aimed to characterize the possible ...influence of CB1 and CB2 receptors on motility impairment in a model of septic ileus.
Methods Lipopolysaccharide (LPS) injections were used to mimic pathophysiological features of septic ileus. Spontaneous jejunal myoelectrical activity was measured in rats in vivo, and upper GI transit was measured in vivo by gavaging of a charcoal marker into the stomach of mice, in absence or presence of LPS, and CB1 and CB2 receptor agonists and antagonists. Tumour necrosis factor (TNF)‐α and interleukin (IL)‐6 levels were measured using enzyme‐linked immunosorbent assay. Histology was performed with haematoxylin–eosin staining.
Key Results Lipopolysaccharide treatment significantly reduced amplitude and frequency of myoelectric spiking activity and GI transit in vivo in a dose‐dependent manner. TNF‐α and IL‐6 were increased in LPS‐treated animals and histology showed oedema and cell infiltration. Both, the CB1 agonist HU210 and the CB2 agonist JWH133 reduced myoelectrical activity whereas the CB1 antagonist AM251 caused an increase of myoelectrical activity. Pretreatment with AM251 or AM630 prevented against LPS‐induced reduction of myoelectrical activity, and also against the delay of GI transit during septic ileus in vivo.
Conclusions & Inferences The LPS model of septic ileus impairs jejunal myoelectrical activity and delays GI transit in vivo. Antagonists at the CB1 receptor or the CB2 receptor prevent the delay of GI transit and thus may be powerful tools in the future treatment of septic ileus.
Background Cannabinoid receptors are involved in visceral pain perception and control of intestinal motility in vivo. The underlying mechanisms are not well characterized. We aimed to determine ...whether the cannabinoid‐1 (CB1) receptor modulates intestinal afferent nerve discharge and the peristaltic reflex.
Methods Rats were anesthetized and intestinal segments were removed. Afferent nerve discharge from a mesenteric nerve was investigated in vitro in the presence of the CB1 antagonist SR 141716A or the CB1 agonist WIN 55212‐2. The myenteric peristaltic reflex was induced by electrical field stimulation and influence of SR 141716A or WIN 55212‐2 was recorded.
Key Results Afferent nerve discharge to the algesic mediator bradykinin was reduced to 11 ± 5.1 imp s−1 following pretreatment with SR 141716A and unchanged after WIN 55212‐2 compared to 63 ± 15.4 imp s−1 in controls. At maximum distension pressure (80 cmH2O) during ramp distension, 92 ± 12.4 imp s−1 were reached following SR 141716A compared to 260 ± 13.2 in vehicle controls and 227 ± 15.4 in WIN 55212‐2 pretreated animals. In contrast, afferent discharge to 5‐HT (500 μmol L−1) was increased to 75 ± 24.6 imp s−1 following WIN 55212‐2 compared to 18 ± 5.9 imp s−1 in controls, whereas SR 141716A had no effect. Ascending neuronal contractions were dose‐dependently attenuated in the presence of SR 141716A and latency of these contractions was reduced. WIN 55212‐2 had opposite effects that were abolished by SR 141716A.
Conclusions & Inferences Activation of the CB1 receptor differentially alters afferent intestinal nerve sensitivity to bradykinin, 5‐HT, and noxious mechanical distension, while it strengthens ascending neuronal contractions. Further studies are needed to determine the physiological relevance of these observations.
•Development of a robust hybrid stochastic optimisation algorithm using BA and GA.•Genetic operator implementation in the global search of the BA.•Implementation of on the Single Machine scheduling ...problem.•Evaluation of the proposed algorithm by comparing the other well-known algorithms.
This paper presents a hybrid Genetic-Bees Algorithm based optimised solution for the single machine scheduling problem. The enhancement of the Bees Algorithm (BA) is conducted using the Genetic Algorithm’s (GA’s) operators during the global search stage. The proposed enhancement aims to increase the global search capability of the BA gradually with new additions. Although the BA has very successful implementations on various type of optimisation problems, it has found that the algorithm suffers from weak global search ability which increases the computational complexities on NP-hard type optimisation problems e.g. combinatorial/permutational type optimisation problems. This weakness occurs due to using a simple global random search operation during the search process. To reinforce the global search process in the BA, the proposed enhancement is utilised to increase exploration capability by expanding the number of fittest solutions through the genetical variations of promising solutions. The hybridisation process is realised by including two strategies into the basic BA, named as “reinforced global search” and “jumping function” strategies. The reinforced global search strategy is the first stage of the hybridisation process and contains the mutation operator of the GA. The second strategy, jumping function strategy, consists of four GA operators as single point crossover, multipoint crossover, mutation and randomisation. To demonstrate the strength of the proposed solution, several experiments were carried out on 280 well-known single machine benchmark instances, and the results are presented by comparing to other well-known heuristic algorithms. According to the experiments, the proposed enhancements provides better capability to basic BA to jump from local minima, and GBA performed better compared to BA in terms of convergence and the quality of results. The convergence time reduced about 60% with about 30% better results for highly constrained jobs.
This study presents 37 new antioxidant coumarin derivatives and strategies for structural modification to improve their antioxidant activities, the main ferric-reducing antioxidant power (FRAP) assay ...used to evaluate their antioxidant properties and the generation of validated quantitative structure-activity (antioxidant activity) relationship (QSAR) models. In an attempt to generate QSAR models, structures of all coumarin derivatives in the data set were fully optimized by semi-empirical PM6 method using SPARTAN 10 software. Descriptors were calculated by DRAGON 6.0 software. Multiple linear regression (MLR) models were developed with different training/test set combinations using QSARINS 2.2.1 software. Robustness, reliability and predictive power of the models were tested by internal and external validations. Applicability domain of the best two-descriptor model (n
TR
= 30; r
2
= 0.924; RMSE
TR
= 0.213; n
TEST
= 7; r
2
ext
= 0.887; RMSE
ext
= 0.255; CCC
ext
= 0.939) was determined. Descriptors appeared in the model revealed that complexity, H-bond donor and lipophilic character are important parameters in describing the antioxidant activity. Apart from the compounds in the data set, we also designed 31 new antioxidant coumarin derivatives and predicted their antioxidant activity using the best two-descriptor model. Most of these compounds are promising antioxidants
A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon ...beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month.
CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient ...mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1(-/-) mice, TRPV1(-/-) mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory junction potentials (IJP) of circular smooth muscle cells were evaluated at different time points. Additionally a histological colitis severity score was evaluated in CB1(+/+) and CB1(-/-) mice 24 h after DNBS. Inflammation caused spontaneous atropine insensitive rhythmic action potentials in CB1(-/-) and TRPV1(-/-) mice but not in wild-type animals. This indicates that membrane stability is disturbed, which in turn indicates a lack of protective mechanisms. Focal electrical neuronal stimulation of the myenteric plexus induced IJP in the smooth muscle cells. Twenty-four hours after initiation of inflammation, the duration of the IJP is prolonged in all animals, indicating disturbances within neuromuscular interaction. In CB1(-/-) mice, it is interesting that the duration of IJP was significantly extended, as compared to CB1(+/+) mice pointing toward missing protective mechanisms in the CB1(-/-) mice. Inflammatory insults in the mouse colon induce reproducible changes in the electrophysiological properties and such changes correlate with duration of colitis. In mutants, these electrophysiological changes display different patterns, suggesting the lack of protective properties for neuromuscular interactions and membrane stability.
We investigated the effects of Oenothera biennis L. and Hypericum perforatum L. extracts on brain tissue histopathology, myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), total ...antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) in mice with experimental autoimmune encephalomyelitis (EAE). Forty-seven C57BL/6J mice were divided into the following groups: multiple sclerosis (MS), control (healthy mice), MS + H. perforatum treated (MS + HP), MS + O. biennis treated (MS + OB). All groups except the control group were immunized by EAE methods. Two weeks after the immunization, the mice in the MS + HP group were fed normal food containing 18 − 21 g/kg H. perforatum extract, the mice in MS + OB group were fed normal food containing 18 − 21 g/kg O. biennis extract, and the mice in control and MS groups were fed normal food for six weeks. Brain tissue samples were collected from all mice for histopathological and biochemical analysis. Clinical signs of the disease were scored using functional systems scores (FSS) daily. The H. perforatum and O. biennis extracts ameliorated the increased brain tissue MOG and MBP values for animals with MS. H. perforatum and O. biennis extract decreased the TOS and OSI values for brain tissue and increased TAS levels in brain tissue of animals with MS. In addition, H. perforatum and O. biennis extracts decreased the clinical signs at the end of the experiment compared to the beginning of extract administration. We found that myelin was lost in MS group vs. control group. H. perforatum and O. biennis extract treatments decreased the amount of myelin loss in the MS + HP and MS + OB groups. We also observed amyloid deposition on vascular walls, in the cytoplasm of the neurons and in the intercellular space in the MS group. O. biennis and H. perforatum treated groups exhibited neither abnormal amyloid deposition nor obvious cell infiltration. The beneficial effects of O. biennis and H. perforatum for attenuating myelin loss and amyloid deposition suggest their therapeutic utility for treatment of MS.
This paper focuses on improvements to the Bees Algorithm (BA) with slope angle computation and Hill Climbing Algorithm (SACHCA) during the local search process. First, the SAC was employed to ...determine the inclination of the current sites. Second, according to the slope angle, the HCA was utilised to guide the algorithm to converge to the local optima. This enabled the global optimum of the given problem to be found faster and more precisely by focusing on finding the available local optima first before turning the attention on the global optimum. The proposed enhancements to the BA have been tested on continuous-type benchmark functions and compared with other optimisation techniques. The results show that the proposed algorithm performed better than other algorithms on most of the benchmark functions. The enhanced BA performs better than the basic BA, in particular on higher dimensional and complex optimisation problems. Finally, the proposed algorithm has been used to solve the single machine scheduling problem and the results show that the proposed SAC and HCA-BA outperformed the basic BA in almost all the considered instances, in particular when the complexity of the problem increases.
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