Current Pharmaceutical Design - Volume 17, Issue 16, 2011

There is little doubt that the pathogenesis of gastrointestinal disorders, diagnosis as well as the therapy is a pertinent scientific focus and one of the largest and most intriguing areas in medicine. Likewise, it has been generally accepted that most of the therapy and understanding of pathophysiology in the gastrointestinal tract is well and should be validated in clinical practice. Therefore, there is still an open door for one or more new ways. Hopefully, the most recent findings may provide a new insight into future developments. In this, I hope, in scope of Emerging Drugs in Gastrointestinal Tract, these papers may contribute a new view that may likely improve the future understanding of pathogenesis and therapy in gastrointestinal tract. In this issue, Yanaka (Faculty of Pharmaceutical Sciences, Tokyo University of Science, Japan) reviewed cellular mechanisms by which the nrf2-keap1 system contributes to induction of a variety of antioxidant enzymes during exposure to oxidative stress and introduced the beneficial effects of sulforaphane, an isothiocyanate family, rich in broccoli sprouts, on the gastric mucosa through such mechanisms [1]. Brzozowski and collaborators (Jagiellonian University Medical College, Cracow, Poland and Thuringia-Clinic, Saalfeld, Germany) reviewed COX-2 derived products, “lipoxins” in the mechanism of gastric mucosal defense. Aspirin-triggered lipoxin synthesis via COX-2 plays also an important role in gastric adaptation during chronic aspirin administration, in addition to the mechanism of injury,gastroprotection and healing of acute and chronic gastric ulcers in the gut [2]. Chen and Zhao (Norwegian University of Science and Technology, Trondheim, Norway)reviewed gut-bone axis, based on the various factors affecting bone mass, an issue that may be particularly important. They examined critically the influence of; acid, serotonin, lowdensity lipoprotein receptor-related protein5, etc, affecting bone mass. They concluded that evidence still could not completely prove a close relationship between these factors and bone mass [3]. Historically, the phenomenon of “cytoprotection” caused a big impact to many GI investigators, like “an epoch-making finding”, and although caused major impacts on GI research & development, the current clinic did not gain adequate advantage. In this, Mozsik (University of Pecs, Hungary) extensively reviewed gastrointestinal cytoprotection (at the level of isolated cells, animal experiments, healthy human beings and patients with different gastrointestinal disorders), including the historic lookback, reviewing the huge range of agents supposed to be involved in cytoprotection [4]. Wood (The Ohio State University College of Medicine Columbus, Ohio, USA)focused on chronic functional abdominal and pelvic pain syndromes. Within the scope of Visceral Pain: Spinal Afferents, Enteric Mast Cells, Enteric Nervous System and Stress, Wood reviews and expands the understanding of visceral hypersensitivity and functional abdominal pain of intestinal origin in relation to the enteric nervous system, spinal sensory neurons and enteric mast cells [5]. Until recently, fat was considered a relatively inactive tissue serving only as a depot for the storage of excess lipid around the body. Over the last decade, however, several studies have established fat as a metabolically active endocrine organ able to affect human pathophysiology at multiple levels. Karagainides and collaborators (David Geffen School of Medicine at the University of California Los Angeles, USA) reviewed the potential pathways by which changes in fat physiology may affect the development and progress of intestinal pathological conditions such as inflammatory bowel disease, and especially discussed the central role of neuropeptides in the pathogenesis and course of inflammatory bowel disease, via adipose tissue associated responses as well as the potential crosstalk between obesity-associated fat tissue and neuropeptides [6]. The role of constitutive and inducible antibacterial peptides has been investigated thoroughly over the recent years; especially in the gastrointestinal tract, where the balance between luminal bacteria and antibacterial peptides is crucial. Wong and collaborators (The Chinese University of Hong Kong, Shatin, Hong Kong, China) focused on and emphasized the role of defensins and cathelicidins, two of the most popular mammalian antibacterial peptides (produced by neutrophils and epithelial cells and are highly expressed during infection), in gastrointestinal inflammation and cancers as well as other physiological processes such as cell proliferation, wound healing and so on. In addition, they also proposed that the dysregulation of their expressions could be used as a biomarker for early diagnosis, especially for H. pylori-related diseases as well as cancers in the gastrointestinal tract [7].....

Helicobacter pylori infection induces oxidative stress on gastric mucosa, thereby causing mucosal damage, retarding mucosal repair, and eventually inducing gastric cancer. Cells can survive against chronic oxidative stress by enhancing activities of antioxidant enzymes, thereby protecting cells from DNA damage. Recent studies have clearly shown that the genes encoding nrf2 (NF-E2 p45- related factor-2) and keap1 (Kelch-like ECH-associated protein 1) play an important role in the induction of antioxidant enzymes against oxidative stress. In this paper, we will first describe the cellular mechanisms by which the nrf2-keap1 system contributes to induction of a variety of antioxidant enzymes during exposure to oxidative stress. Secondly, we will also mention beneficial effects of a natural compound sulforaphane, an isothiocyanate family, rich in broccoli sprouts, on gastric mucosa. Sulforaphane stimulates nrf2 gene-dependent antioxidant enzyme activities, thereby protecting cells from oxidative injury. Finally, we will show our data on the effect of sulforaphane, a natural chemical compound rich in broccoli sprouts, on protection and repair of gastric mucosa against oxidative stress, and antiinflammatory effects on gastric mucosa during H. pylori infection, which appears to be closely related to chemoprotection against gastric cancer induced by H. pylori-infection.

Previous studies revealed that prostaglandins contribute to the mechanism of maintenance of gastrointestinal integrity and mediate various physiological aspects of mucosal defense. The suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after administration of various NSAID including aspirin (ASA). A worldwide use of ASA is now accepted due to its remarkable analgesic, antipyretic and anti-thrombotic prophylactics against myocardial infarct and coronary disorders despite the fact that the use of NSAIDs is associated with the risk of gastrointestinal bleedings, haemorrhagic lesions and ulcerations. It has become clear that other mediators besides prostaglandins can similarly act to protect the gastrointestinal mucosa of experimental animals and humans from injury induced by ASA. For instance, nitric oxide (NO) released from vascular epithelium, epithelial cells of gastrointestinal tract and sensory nerves can influence many of the same components of mucosal defense as do prostaglandins. This review was designed to provide an updated overview based on the experimental and clinical evidence on the involvement COX-2 derived products, lipoxins in the mechanism of gastric defense, gastroprotection and gastric adaptation to ASA. Lipoxins were recently considered as another group of lipid mediators that can protect the stomach similarly as NO-donors known to exert protective influence on the stomach from the injury under condition where the mucosal prostaglandin levels are suppressed. The new class of NO-releasing NSAIDs, including NO-aspirin or NO-naproxen, represent a very promising approach to reducing the toxicity of their parent NSAIDs. Aspirin-triggered lipoxin (ATL) synthesis, via COX-2, acts to reduce the severity of damage induced by this NSAID. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Evidence presented in this review documents that ATL also play in important role in gastric adaptation during chronic ASA administration. Suppression of COX-2 activity by selective COX-2 inhibitors such as rofecoxib or celecoxib was shown to abolish the production of ATL and to diminish the gastric tolerability of ASA and gastric adaptation developed in response to repetitive administration of this NSAID. Synthetic analogues of lipoxins as well as newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAIDs ingestion.

Recently, reports published in Nature Medicine and Cell have suggested the existence of a gut-bone axis based on studies of gene knockout mice. First, impaired gastric acid secretion was claimed to negatively affect calcium homeostasis and bone mass; which was based on the bone phenotype of cholecystokinin-B (or 2) receptor knockout mice. However, also histidine decarboxylase knockout mice suffered from impaired gastric acid secretion, while exhibiting a very different bone phenotype. This argues against the view that lack of gastric acid causes bone loss. Second, circulating serotonin was claimed to inhibit bone formation. This claim was based on the observation that mice deficient in low-density lipoprotein receptor-related protein 5 (Lrp5) exhibited bone loss coupled with accelerated serotonin synthesis. Lrp5 was claimed to control bone formation by a link involving duodenal serotonin synthesis. However, the accelerated serotonin synthesis in Lrp5 knockouts occurred after the onset of bone loss, a sequence of events that does not suggest a causal relationship between elevated serotonin in blood and bone loss. Moreover, pharmacological inhibition of serotonin synthesis prevented bone loss following ovariectomy in wild-type mice and rats, an observation that does not support the existence of Lrp5 pathway in the serotonin- bone axis.

Our clinical observations proved that the duodenal ulcer in patients healed without any inhibition of gastric acid secretion (1965), and the healing rates of atropine vs. cimetidine vs. Carbenoxolone were equal and superior to that of placebo in randomized, prospective and multiclinical study of DU patients (1978). The phenomenon of gastric cytoprotection was defined by Andre Robert in rats (1979). The essential point of this phenomenon is that the prostaglandins prevent the chemical-induced gastric mucosal damage without affecting gastric acid secretion, this being originally suggested as a reaction specific to prostaglandins. Since then gastrointestinal cytoprotection has been shown with various agents (anticholinergic agents, H2RA, growth factors, body protecting compound, BPC) and retinoids in animals; the latter differing from the actions of vitamin A. In examining the various components of gastrointestinal cytoprotection , different studies have performed in isolated cells, stable cell lines, animal experiments, healthy human subjects, in patients chronic gastric and duodenal ulcers, and with different gastrointestinal disorders. Our attention has focused on the effects of cytoprotective agents on cellular viability, mitochondrial and DNA damage, oxygen free radicals, natural antioxidant systems, mucosal biochemistry, vascular events, gastrointestinal mucosal protection as well as in their prevention of different human diseases. This paper gives an overview on the different approaches for the exploring gastrointestinal cytoprotection (at the level of isolated cells, animal experiments, healthy human beings and patients with different gastrointestinal disorders). It has been indicated that the gastric cytoprotection exists in animals , human healthy subjects, patients with different gastrointestinal disorders. The our observations in patients with duodenal ulcer healed without any changes of gastric acid secretion, there were no significant differences between the cimetidine vs. atropine (as antisecterory agents) or vs. Carbenoxolone vs. retinoid (as cytoprotective compounds) treatment. Also we indicated the presence of intact vagal nerve basically necessary for development of gastrointestinal cytoprotection and for capsaicin-sensitive vagal nerve induced mucosal protection (1982).

This review aims to examine current basic and clinical concepts, the results of which are expanding our understanding of visceral hypersensitivity and functional abdominal pain of intestinal origin in relation to the enteric nervous system (ENS), spinal sensory neurons and enteric mast cells. Advances in this sphere are translating to improved insight into chronic functional abdominal and pelvic pain syndromes in general.

Until recently, fat was considered a relatively inactive tissue serving only as a depot for the storage of excess lipid around the body. Over the last decade, however, several studies have established fat as a metabolically active endocrine organ able to affect human pathophysiology at multiple levels. During this time adipose tissue has been shown to produce a number of hormones and inflammatory mediators collectively termed as adipokines. These molecules have been shown to be involved in the etiology of a number of inflammation- associated pathological conditions ranging from atherosclerosis and hypertension to diabetes and cancer. Despite the close physical association of abdominal fat and the intestine in the visceral cavity and the significant paracrine functions now attributed to adipose tissue, very little is known on the potential interactions between these tissues as they may relate to intestinal homeostasis. Considering the dramatic alterations in mesenteric fat depot size and placement during at least one intestinal disease, Crohn's disease, the potential involvement of fat tissue in the development as well as the progression of this and other pathological conditions should be considered. In this review we discuss the latest knowledge on neuropeptide-adipose tissue communication and the potential changes such interaction may induce in intra-abdominal fat tissue physiology. Finally we will discuss evidence on the potential pathways by which such changes in fat physiology may affect the development and progress of intestinal pathological conditions such as inflammatory bowel disease.

Defensins and cathelicidins are small cationic peptides produced by neutrophils and epithelial cells. They are highly expressed during infection. The role of constitutive and inducible antibacterial peptides has been extensively studied over the recent years; especially in the gastrointestinal (GI) tract, where the balance between the luminal bacteria and antibacterial peptides is crucial in the maintenance of a healthy GI tract. There are reports showing that the expressions of defensins and cathelicidins in the gut are dysregulated in various disease states. They could participate in the development of different disorders ranging from inflammation to cancer. Experimental findings showed that supplementation with animal cathelicidin promoted gastric ulcer healing in rats and suppressed tumorigenesis of gastric cancer in mice. Mouse cathelicidin could alleviate murine colitis by preserving mucus content and suppression of apoptosis. Other clinical applications for these antibacterial peptides are awaiting for further studies.

Postoperative gastric ileus develops after abdominal surgery and if prolonged leads to longer hospitalization times. Besides discomfort for the patient such as abdominal bloating and pain, this condition is associated with a great increase in healthcare costs. In order to develop new and effective treatment strategies to alleviate the ileus, a good understanding of the pathophysiological underlying mechanisms is necessary. Postoperative gastric ileus consists of two phases, a first neural/humoral phase and a second inflammatory phase. The present review will focus on the role of the orexigenic and prokinetic hormone ghrelin in the development of postoperative ileus. Although ghrelin and ghrelin mimetics have been used during the recent years in pre-clinical and a first clinical trial to alleviate symptoms of postoperative ileus, the regulation of this hormone under conditions of abdominal surgery has just recently begun to be explored. Growing evidence indicates that postoperative restoration of ghrelin signaling leads to an orexigenic effect whereas the gastroprokinetic actions seem to require supraphysiological doses. Since the expression of ghrelin-O-acyltransferase (GOAT), the only ghrelin acylating enzyme, is reduced after abdominal surgery, the stimulation of GOAT signaling may also be a new promising approach to restore levels of acyl ghrelin under these conditions and a potential useful addition to ghrelin mimetics.

The finding that somatostatin (SST) or its analogue, octreotide caused a dose-dependent reduction in exocrine pancreatic secretions triggered their research as therapeutic options for acute pancreatitis (AP), a life-threatening illness. However, the accumulative clinical trials of SST or octreotide in AP treatment present the controversial results. The insufficient secretory capacity of acinar cells in AP patients also queries the validity of traditional assumption on the effects of SST and octreotide. This reviewer updates the current pharmacological concepts of SST and octreotide in treatment of AP and the clinical strategies of their application. The impressive inhibitive effects on the massive inflammatory injury via the several signal pathways make SST as an important anti-inflammatory peptide. Furthermore, endocrine SST may decrease the sphincter tone of Oddi (SO) by its potential role on the neurocrine of SST in SO. Therefore, it should be rational that exogenous supplement of SST or octreotide for AP patients due to the plasma level of SST during AP is usually lower than that of normal. In accordance with these findings, the optimal stage of SST or octreotide administration, application in high risk population, the cost-effective dosage or duration as well as the design of suitable clinical outcomes would be the interesting topics of translational medical research for both basic scientists and clinicians.

Alendronate, a nitrogen containing bisphosphonate (BPP), when given p.o., decreases the transmucosal potential difference by direct irritating action, resulting in non-hemorrhagic lesions in both the corpus and antrum of fasted rats, and after re-feeding produces large ulcers in the antrum with increased vascular permeability and submucosal edema. The pathogenesis of these ulcers may be explained by the impairment of the mucosal anti-oxidative system and does not involve acid digestion as well as a deficiency of prostaglandins (PGs). Alendronate, although does not affect cyclooxygenase/ PGE2 production in the ulcerated mucosa, but impairs the healing of gastric ulcers in rats, and this effect may be related to the down-regulation of vascular endothelial growth factor and basic fibroblast growth factor (bFGF), the important growth factors for the vascularization/granulation as well as the suppression of the stimulatory action of epidermal growth factor on the epithelial proliferation/migration. Rebamipide, a mucosal protective and antiulcer drug, does not affect the direct irritating action of alendronate in the gastric mucosa but prevents the alendronate-induced antral ulceration, probably due to anti-oxidative and anti-inflammatory actions. In addition, this agent also antagonizes the healing impairment action of alendronate by counteracting the down-regulation of bFGF expression in the ulcerated mucosa. It is assumed that rebamipide is a promising drug that can be used as a prophylactic against the adverse effects of BPPs in the stomach.

Stable gastric pentadecapeptide BPC 157 is an anti-ulcer peptidergic agent, safe in inflammatory bowel disease clinical trials (GEPPPGKPADDAGLV, M.W. 1419, PL 14736) and wound healing, stable in human gastric juice and has no reported toxicity. We focused on BPC 157 as a therapy in peridontitis, esophagus, stomach, duodenum, intestine, liver and pancreas lesions. Particularly, it has a prominent effect on alcohol-lesions (i.e., acute, chronic) and NSAIDs-lesions (interestingly, BPC 157 both prevents and reverses adjuvant arthritis). In rat esophagitis and failed function of both lower esophageal sphincter (LES) and pyloric sphincters (PS), BPC 157 increased pressure in both sphincters till normal and reduced esophagitis. However, in healthy rats, it may decrease (PS) or increase (LES) the pressure in sphincters. It has strong angiogenic potential, it acts protectively on endothelium, prevents and reverses thrombus formation after abdominal aorta anastomosis, affects many central disturbances (i.e., dopamine and 5-HT system), the NO-system (either Larginine and L-NAME effects), endothelin, acts as a free radical scavenger (counteracting CCl4-, paracetamol-, diclofenac-injuries) and exhibits neuroprotective properties. BPC 157 successfully heals the intestinal anastomosis, gastrocutaneous, duodenocutaneous and colocutaneous fistulas in rats, as well as interacting with the NO-system. Interestingly, the fistula closure was achieved even when the BPC 157 therapy was postponed for one month. In short-bowel syndrome escalating throughout 4 weeks, the constant weight gain above preoperative values started immediately with peroral and parental BPC 157 therapy and the villus height, crypth depth and muscle thickness (inner (circular) muscular layer) additionally increased. Thus, BPC 157 may improve gastrointestinal tract therapy.

Gastrointestinal (GI) ulcers are essentially internal wounds that resist normal healing processes. Since their pathogenesis is poorly understood, and the etiologic (e.g., gastric acid, aspirin-like drugs, stress) and aggravating factors (e.g., H. pylori) are not well characterized, the remaining therapeutic option is to accelerate healing. Superficial mucosal lesions, i.e., erosions usually heal by epithelial regeneration and restitution, but when ulcers involve the muscularis propria, smooth muscle cells do not divide/regenerate. These deep lesions are filled by granulation tissue, i.e., angiogenesis followed by proliferation of connective tissue fibroblasts that deposit collagen over which adjacent surviving and dividing epithelial cells migrate to complete the healing. Our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate ulcer healing in the GI tract. Indeed, daily treatment of rats with bFGF, PDGF or VEGF markedly improved the healing of cysteamine-induced chronic duodenal ulcers, without any reduction in gastric acid secretion. These results were reproduced by a single dose of gene therapy with adenoviral vectors encoding PDGF or VEGF genes. The molar potency of angiogenic growth factors was 2-7 million times better than the antiulcerogenic effect of antisecretory H2 antagonists. Since histologically & pathologically gastroduodenal ulcers look similar to ulcers in the lower GI tract, we also predicted that the healing of experimental ulcerative colitis might be also improved by these angiogenic growth factors. Rectal enemas containing bFGF or PDGF indeed accelerated the healing of chemically induced ulcerative colitis in rats. VEGF, also known as VPF (vascular permeability factor), however, had no effect or slightly aggravated the colonic lesions. Injection of anti-VEGF neutralizing antibodies, however, counteracted the increased vascular permeability in the early stages of experimental ulcerative colitis and subsequently decreased the number of inflammatory cells in colonic ulcers in rats, resulting in significantly improved healing in the lower GI tract lesions. Thus, the three angiogenic growth factors tested exerted beneficial effect on gastroduodenal ulcers, and rectal enemas with bFGF or PDGF also accelerated the healing of experimental ulcerative colitis. Surprisingly, we achieved the latter effect with anti-VEGF antibodies, most likely because of the pro-inflammatory actions of VEGF in the pathogenesis of ulcerative colitis.

Inflammatory bowel disease (IBD): ulcerative colitis (UC) and Crohn disease (CD) are characterized by recurrent inflammation and ulceration of intestinal and/or colonic mucosa and an inappropriate and delayed healing. Current therapies with, e.g., anti-TNFα antibody (infliximab) and other anti-inflammatory drugs (e.g., mesalamine) do not induce sustained remission, complete healing or prevent recurrence of UC. Although the pathogenesis of UC is not fully understood, pathologic angiogenesis has been postulated as a critical pathogenic component in UC. Recent studies demonstrated that the poor healing, chronic inflammation in colon of UC could be the result of microvascular dysfunction and endothelial barrier defect, resulting in sustained tissue hypoperfusion and ischemia in the colon. Previously, regeneration of injured endothelium and neovascularization were believed to rely solely on the migration and proliferation of neighboring endothelial cells from existing blood vessels. However, accumulating evidence shows that additional mechanisms may exist, and may be mediated by the circulating pool of bone marrow-derived endothelial progenitor cells (BMD-EPC). Furthermore, stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 have been demonstrated to play an important role in the “homing” of BMD-EPC to injured sites and neovascularization in tissue repair. Recent studies by others and us showed reduced BMD-EPC levels in the circulation of IBD patients and rats with experimental UC. However, the potential therapeutic effect of BMD-EPC on neovascularization and colonic mucosal repair in UC has not been elucidated. In this review, we discussed the possibility that impaired contribution of BMD-EPC (i.e., decreased release of BMD-EPC from bone marrow to circulation and/or blocked/impaired homing of BMD-EPC to colonic lesions) may be a critical component of mechanisms in the incomplete/delayed healing of UC, and may offer a novel form of cell therapy for IBD.