Endocannabinoid and Cannabinoid-Like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study

Aims

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS) was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients.

Methods

AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D) and constipation-predominant (IBS-C) patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls.

Results

Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C.

Conclusion

IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.     

Peripheral receptor populations involved in the regulation of gastrointestinal motility and the pharmacological actions of metoclopramide-like drugs

This minireview is concerned with a re-examination of the locus of action and the possible peripheral mechanisms involved in the gastrointestinal (GI) stimulant effects of metoclopramide. Such a re-evaluation is opportune given the increasing use of this drug in the therapy of certain GI tract disorders. To provide an orientation on this subject the location in the GI tract and function of several relevant receptor types have been reviewed. In the past metoclopramide has been reported to enhance contractions of a variety of GI preparations to electrical stimulation, acetylcholine, carbachol and ganglion stimulants, to inhibit responses to alpha 2-adrenoreceptor agonists and 5-hydroxytryptamine, as well as blocking those to dopamine. Also in such preparations metoclopramide facilitates the release of acetylcholine to transmural stimulation. One important question is whether this effect is mediated via a specific prejunctional receptor. In this respect 2 suggestions have been made. Firstly that the drug may act as a preferential, prejunctional muscarinic antagonist thus inhibiting the negative feedback inhibition of acetylcholine release and secondly that metoclopramide may be a prejunctional agonist (partial) at 5-hydroxy-tryptamine receptors. Although the latter possibility appears most tenable at present, the involvement of a specific receptor remains to be confirmed. The important finding that dopamine receptors are probably not involved in the local stimulant effects of metoclopramide has important implications for future research orientated towards the discovery of a new generation of GI drugs lacking the side effects associated with central dopamine receptor blockade. Several compounds (cinitapride, BRL 20627A and cisapride) are now in the early stages of clinical evaluation.     

Ghrelin as a target for gastrointestinal motility disorders

The therapeutic potential of ghrelin and synthetic ghrelin receptor (GRLN-R) agonists for the treatment of gastrointestinal (GI) motility disorders is based on their ability to stimulate coordinated patterns of propulsive GI motility. This review focuses on the latest findings that support the therapeutic potential of GRLN-R agonists for the treatment of GI motility disorders. The review highlights the preclinical and clinical prokinetic effects of ghrelin and a series of novel ghrelin mimetics to exert prokinetic effects on the GI tract. We build upon a series of excellent reviews to critically discuss the evidence that supports the potential of GRLN-R agonists to normalize GI motility in patients with GI hypomotility disorders such as gastroparesis, post-operative ileus (POI), idiopathic chronic constipation and functional bowel disorders.     

Role of Interstitial Cells of Cajal and their relationship with the enteric nervous system.

The term 'Interstitial cells of Cajal' (ICC) designates several groups of mesenchymal cells present along the gastro-intestinal tract (GI), in close association with smooth muscle cells and elements of the enteric nervous system (ENS). For years, transmission electron microscopy (TEM) has been the only reliable tool to study ICC. Whilst TEM remains the golden standard for identification of ICC, the observation that the tyrosine kinase receptor c-kit plays a crucial role in their development recently resulted in numerous immunohistochemical studies and also led to a better characterization of their roles. ICC form extensive networks of electrically coupled cells and certain groups of ICC are currently regarded as the source of the spontaneous slow waves of the gut musculature (pacemaker cells). Other ICC appear to be involved in the transduction of the relaxation of smooth muscle triggered by nitric oxide. Abnormal distribution of ICC has been reported in several human diseases and abnormal functioning of ICC might actually be involved in many disorders of GI transit. This review addresses (1) the morphology and relationships of ICC along the GI tract in man and mouse, mainly based on data from immunohistochemistry and confocal microscopy, (2) the emerging role of ICC in the pathophysiology of human diseases, like infantile hypertrophic pyloric stenosis (a common disorder with a dysfunction of the pyloric sphincter), Hirschsprung's disease (aganglion-osis coli) and intestinal pseudo-obstruction, (3) developmental issues, (4) recent reports suggesting a possible link between ICC and gastrointestinal stromal tumors.     

Activin A regulates growth of gastro‐intestinal epithelial cells by mediating epithelial‐mesenchymal interaction

The importance of epithelial–mesenchymal interaction on the development of gastro‐intestinal (GI) organs has been repeatedly reported, but its molecular mechanism has not been fully understood though several factors including hepatocyte growth factor and endothelin‐3 have been shown to mediate it. Activins have been demonstrated to play important roles in the regulation of organogenesis in vertebrates, but their roles in the regulation of growth and differentiation of GI organs remain to be solved. In the present study, we examined expression of activins in developing rat GI tract, and found that inhibin bA encoding activin A was specifically expressed by GI mesenchymes, while inhibin bB encoding activin B was expressed by both epithelial and mesenchymal components. We then examined the effect of activin A on the growth of fetal rat GI epithelial cells in primary culture. We found that activin A inhibited the growth of forestomach and glandular stomach epithelial cells while it stimulated the growth of colonic epithelial cells. These results suggest that activin A secreted from GI mesenchymes region‐specifically regulates the growth of attaching epithelial cells. We thus conclude that activin A mediates epithelial‐mesenchymal interaction in the developing GI tract.     

Reactive oxygen species responsive nanoplatforms as smart drug delivery systems for gastrointestinal tract targeting

The pharmacological therapy for gastrointestinal (GI) diseases, such as inflammatory bowel diseases, continues to present challenges in targeting efficacy. The need for maximal local drug exposure at the inflamed regions of the GI tract has led research to focus on a disease-targeted drug delivery approach. Smart nanomaterials responsive to the reactive oxygen species (ROS) concentrated in the inflamed areas, can be formulated into nanoplatforms to selectively release the active compounds, avoiding unspecific drug delivery to healthy tissues and limiting systemic absorption. Recent developments of ROS-responsive nanoplatforms include combination with other materials to obtain multi-responsive systems and modifications/derivatization to increase the interactions with biological tissues, cell uptake and targeting. This review describes the applications of ROS-responsive nanosystems for on-demand drug delivery to the GI tract.     

Saffron (Crocus sativus) in the treatment of gastrointestinal cancers: Current findings and potential mechanisms of action

Gastrointestinal (GI) cancers are major causes of cancer-related mortality worldwide and include malignancies of the GI tract such as the stomach, liver, pancreas, small intestine, colon, and rectum. Promising and selective anticancer effects of pharmacologically active components of saffron (Crocus sativus L.) have been shown in preclinical in vitro and in vivo studies. Saffron and its active components including crocin, crocetin, and safranal exert their anticancer effects through different mechanisms, including induction of apoptosis, influence on the cell cycle, and regulation of host immune response and anti-inflammatory activities. This review summarizes the recent literature on the chemopreventive properties of saffron in GI cancers to have a better understanding of the potential underlying mechanisms and hence the appropriate management of these malignancies.     

Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA‐mutant GISTs

PDGFRA mutations in the gastrointestinal (GI) tract can cause GI stromal tumour (GIST) and inflammatory fibroid polyp (IFP). Hitherto no cell type has been identified as a physiological counterpart of the latter, while interstitial Cajal cells (ICC) are considered the precursor of the former. However, ICC hyperplasia (ICCH), which strongly supports the ICC role in GIST pathogenesis, has been identified in germline KIT‐mutant settings but not in PDGFRA‐mutant ones, challenging the precursor role of ICC for PDGFRA‐driven GISTs. Telocytes are a recently described interstitial cell type, CD34+/PDGFRA+. Formerly considered fibroblasts, they are found in many organs, including the GI tract where they are thought to be involved in neurotransmission. Alongside IFPs and gastric GISTs, GI wall “fibrosis” has been reported in germline PDGFRA‐mutants. Taking the opportunity offered by its presence in a germline PDGFRA‐mutant individual, we demonstrate that this lesion is sustained by hyperplastic telocytes, constituting the PDGFRA‐mutant counterpart of germline KIT mutation‐associated ICCH. Moreover, our findings support a pathogenetic relationship between telocyte hyperplasia and both IFPs and PDGFRA‐mutant GISTs. We propose the term “telocytoma” for defining IFP, as it conveys both the pathogenetic (neoplastic) and histotypic (“telocytary”) essence of this tumour, unlike IFP, which rather evokes an inflammatory‐hyperplastic lesion.     

Endoplasmic reticulum proteostasis impairment in aging

Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one‐third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.     

Neuropeptidases regulating gonadal function

The generation and metabolism of bioactive peptides involves a series of highly ordered proteolytic events. This post-translational processing can occur either within the cell, at the cell surface or after secretion. In the central nervous system a number of extracellular peptidases have been implicated in the regulated processing of peptides, particularly in the regulation of neuroendocrine function. The aim of this study has been to identify the peptidases involved in the metabolism of gonadotropin-releasing hormone (GnRH) and to characterize the factors and the mechanisms by which the activity of these peptidases are regulated. We have shown that both prolylendopeptidase and the thimet oligopeptidase EC 3.4. 24.15 are involved in GnRH metabolism and that both oestrogen and thiol-based reductants could be involved in the physiological regulation of their activities.     

Plant amine oxidases “on the move”: An update

Amine oxidases (AOs) catalyse the oxidative de-amination of polyamines, ubiquitous polycationic compounds involved in important events of cell life. They include the copper-containing amine oxidases (CuAOs; EC 1.4.3.6) and the flavin-containing polyamine oxidases (PAOs; EC 1.5.3.11). The main physiological role of these moonlighting proteins has been linked to compartment-specific H₂O₂ synthesis in different phases of development and differentiation as well as in the course of defence mechanisms against pathogens and abiotic stress. Moreover, several studies evidenced a correlation of AO expression levels with physiological stages characterized by intense metabolism, such as cell division or organ formation, thus leaving open the hypothesis that AOs may have also a role in the regulation of cell cycle through the modulation of polyamine cellular content. This update will deal with recent reports on the involvement of CuAOs and PAOs in abiotic (salt) stress, wound-healing and host–pathogen interactions.     

Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131

Aims

The 28 amino acid hormone ghrelin, the natural ligand for the growth hormone secretagogue, or ghrelin receptor (GHR), has diverse physiological functions, including a possible role as a gastrointestinal prokinetic. The synthetic ghrelin mimetic RM-131 is in Phase II clinical trials for treatment of diabetic gastroparesis and other gastrointestinal (GI) disorders. We aimed to determine the relative potency of RM-131, when compared to other GI ghrelin mimetics, to predict efficacy and determine the role of RM-131 in models of inflammatory bowel disease.

Main methods

We evaluated and compared ghrelin, RM-131 and other synthetic ghrelin mimetics for their prokinetic potency in models of gastrointestinal disorders in the rat and we evaluated the endocrine (rats and dogs) and anti-inflammatory effects (mice) of the ghrelin mimetic RM-131.

Key findings

The pentapeptide RM-131 increased gastric emptying in rodent models of ileus. RM-131 is about 100-fold more potent than human ghrelin and is 600 to 1800-fold more potent, when compared to several investigational ghrelin mimetics tested in clinical trials. RM-131 has anti-inflammatory effects and significantly increases survival and reduces macroscopic markers of tissue damage in a TNBS model of inflammatory bowel disease. RM-131 treatment shows a transient increase in growth hormone levels in Beagle dogs and rats, returning to baseline upon chronic treatment. Significant effects on glucose and insulin are not observed in chronic studies.

Significance

RM-131's potency, efficacy and endocrine profile, are promising attributes for the treatment of diverse functional gastrointestinal disorders in humans.     

Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism

Transmethylation reactions utilize S-adenosylmethionine (SAM) as a methyl donor and are central to the regulation of many biological processes: more than fifty SAM-dependent methyltransferases methylate a broad spectrum of cellular compounds including DNA, histones, phospholipids and other small molecules. Common to all SAM-dependent transmethylation reactions is the release of the potent inhibitor S-adenosylhomocysteine (SAH) as a by-product. SAH is reversibly hydrolyzed to adenosine and homocysteine by SAH hydrolase. Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. However, a major unanswered question is if homocysteine is causally involved in disease pathogenesis or simply a passive and indirect indicator of a more complex mechanism. A chronic elevation in homocysteine levels results in a parallel increase in intracellular or plasma SAH, which is a more sensitive biomarker of cardiovascular disease than homocysteine and suggests that SAH is a critical pathological factor in homocysteine-associated disorders. Previous reports indicate that supplementation with folate and B vitamins efficiently lowers homocysteine levels but not plasma SAH levels, which possibly explains the failure of homocysteine-lowering vitamins to reduce vascular events in several recent clinical intervention studies. Furthermore, more studies are focusing on the role and mechanisms of SAH in different chronic diseases related to hyperhomocysteinemia, such as cardiovascular disease, kidney disease, diabetes, and obesity. This review summarizes the current role of SAH in cardiovascular disease and its effect on several related risk factors. It also explores possible the mechanisms, such as epigenetics and oxidative stress, of SAH.This article is part of a Directed Issue entitled: Epigenetic dynamics in development and disease.     

Expanding role for the apelin/APJ system in physiopathology

Apelin is a bioactive peptide known as the ligand of the G protein-coupled receptor APJ. Diverse active apelin peptides exist under the form of 13, 17 or 36 amino acids, originated from a common 77-amino-acid precursor. Both apelin and APJ mRNA are widely expressed in several rodent and human tissues and have functional effects in both the central nervous system and peripheral tissues. Apelin has been shown to be involved in the regulation of cardiovascular functions, fluid homeostasis, vessel formation and cell proliferation. More recently, apelin has been described as an adipocyte-secreted factor (adipokine), up-regulated in obesity. By acting as circulating hormone or paracrine factor, adipokines are involved in physiological regulations (fat depot development, energy storage, metabolism or eating behavior) or in the promotion of obesity-associated disorders (type 2 diabetes and cardiovascular dysfunctions). In this regard, expression of apelin gene in adipose tissue is increased by insulin and TNFalpha. This review will consider the main roles of apelin in physiopathology with particular attention on its role in energy balance regulation and in obesity-associated disorders.     

The role of HSP27 in the development of drug resistance of gastrointestinal malignancies: Current status and perspectives

Heat-shock protein 27 (HSP27) is a chaperone molecule that plays a critical role in the refolding and activity of several proteins responsible for cancer cell drug toxicity. Upregulation of HSP27 is associated with decreased drug sensitivity as well as poorer survival in gastrointestinal (GI) malignancies. It is, therefore, possible that HSP27 may be of value in the assessment of prognostic and therapeutic efficacy in the treatment of GI cancers. Pharmacological and biological inhibitors of HSP27 enhance tumor cell chemosensitivity. This review summarizes the potential role of HSP27 in chemotherapy drug resistance and the therapeutic potential of HSP27 inhibitors as a novel strategy in the treatment of GI cancers.     

肥胖与神经调节

机体的能量获取和能量消耗,在一定时期内,是处于一种相对平衡的状态;获取的能量等于消耗的能量,在这一调节中,神经系统起有重要的作用,如果获取的能量（进食）大于消耗的能量,将产生肥胖,由于很多疾病与肥胖的产生有密切的关系,因此,对能量平衡调节的研究越来越受到重视。本文简要总结了近年来这方面的研究进展,内容包括：（１）饱感的产生与进食的终止;（２）机体脂肪储存信号与进食的调节;（３）与进食有关的中枢;（４）下丘脑中传递与进食有关信息的一级和二级神经元;（５）与临床的关系。     

Interstitial cell network volume is reduced in the terminal bowel of ageing mice

Ageing is associated with impaired neuromuscular function of the terminal gastrointestinal (GI) tract, which can result in chronic constipation, faecal impaction and incontinence. Interstitial cells of cajal (ICC) play an important role in regulation of intestinal smooth muscle contraction. However, changes in ICC volume with age in the terminal GI tract (the anal canal including the anal sphincter region and rectum) have not been studied. Here, the distribution, morphology and network volume of ICC in the terminal GI tract of 3‐ to 4‐month‐old and 26‐ to 28‐month‐old C57BL/6 mice were investigated. ICC were identified by immunofluorescence labelling of wholemount preparations with an antibody against c‐Kit. ICC network volume was measured by software‐based 3D volume rendering of confocal Z stacks. A significant reduction in ICC network volume per unit volume of muscle was measured in aged animals. No age‐associated change in ICC morphology was detected. The thickness of the circular muscle layer of the anal sphincter region and rectum increased with age, while that in the distal colon decreased. These results suggest that ageing is associated with a reduction in the network volume of ICC in the terminal GI tract, which may influence the normal function of these regions.     

Role of the Endocannabinoid System in Management of Patients with Type 2 Diabetes Mellitus and Cardiovascular Risk Factors

ObjectiveTo review the role of the endogenous cannabinoid system (ECS) in the peripheral and central regulation of food intake, appetite, and energy storage and discuss the potential for the ECS to be an important target for lowering cardiovascular risk.MethodsMaterials used for this article were identified through a MEDLINE search of the pertinent literature (1975 to present), including English-language randomized controlled, prospective, cohort, review, and observational studies. We summarize the available experimental and clinical data.ResultsThe ECS is composed of two 7-transmembrane G protein-coupled cannabinoid receptor subtypes, CB₁ and CB₂, endogenous cannabinoid ligands (anandamide and 2-arachidonoylglycerol), and the enzymes that synthesize and break down the ligands. Understanding the role of the ECS in central and peripheral metabolic processes related to the regulation of food intake and energy balance as well as the endocrine role of excess adipose tissue, particularly visceral adipose tissue, and its promotion of global cardiometabolic risk has led to the development of pharmacologic agents with potential for blockade of CB₁ receptors. In several studies, rimonabant (20 mg daily) demonstrated a favorable effect on various risk factors for cardiovascular disease, including dyslipidemia, abdominal obesity, insulin resistance, blood pressure, and measures of inflammation.ConclusionThe ECS has been shown to have a key role in the regulation of energy balance, and modulation of this system may affect multiple cardiometabolic risk factors. Clinical studies involving pharmacologic blockade of CB₁ receptors in overweight patients with and without type 2 diabetes have demonstrated effective weight loss and improvements in several risk factors for cardiovascular disease. (Endocr Pract. 2007;13:790-804)     

Endocannabinoid lipids and mediated system: implications for alcoholism and neuropsychiatric disorders

Several natural lipids have emerged as candidate modulators of central nervous system (CNS) functions. Fatty acid amides and their coupled signaling pathways are known to regulate several physiological and behavioral processes. Recent studies from our laboratory and others also have implicated endogenous marijuana-like brain constituents, endocannabinoids (ECs), and cannabinoid-1 (CB1) receptors in the neural circuitry that mediate drug addiction and neuropsychiatric disorders. Neuroadaptation to chronic ethanol (EtOH) has been shown to involve changes in the EC system. These changes include alterations in the synthesis of EC, their precursors, as well as density and coupling efficacy of CB1 receptors. The evidence for the participation of the EC system in the pathophysiology of various neuropsychiatric disorders is just beginning to evolve. It is of great interest to explore the components of EC system in different areas of the CNS for further understanding of its role in health and disease. This article presents a comprehensive overview of the currently available literature pertaining to the role of the EC system in alcoholism, schizophrenia, depression and/or suicide.