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It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment. [ABSTRACT FROM AUTHOR]

T cell proliferation and T helper (TH) cells that make IL-17 (TH17 cells) and IFN-γ (TH1 cells) have been shown to be inhibited by 1,25(OH)2D3. Previous work has shown that immune-mediated diseases, where TH1 and TH17 cells are pathogenic, are ameliorated with 1,25(OH)2D3 treatment. Paradoxically, infectious diseases that require TH1 and TH17 responses for host resistance are unaffected by 1,25(OH)2D3 treatment. Resting T cells are not responsive to vitamin D because they do not express the vitamin D receptor (VDR) until late after activation. T cells activated following an infection help clear the infection, and since the antigen is eliminated, vitaminDis not needed to dampen the immune response. Conversely, in immune-mediated disease, there is chronicTcell activation, and in this scenario, vitamin D and 1,25(OH)2D3 are critical for inhibiting T cell proliferation and cytokine production. Vitamin D is a late regulator of T cell function and acts to turn off T cells. This paper will review these data. [ABSTRACT FROM AUTHOR]

This paper presents commentaries on how endoluminal antireflux procedures compare to laparoscopic fundoplication; new endoscopic procedures being studied to treat refractory gastroesophageal reflux disease (GERD); the new Stretta; the relationship between obesity and proton pump inhibitor (PPI) resistance; data concerning acid hypersensitivity and sensory receptors (vallinoid, TRPV1) causing refractory GERD; whether microscopic esophagitis is relevant in determining symptoms of non-erosive reflux disease (NERD); how concomitant functional gastrointestinal disorders affect the PPI response in NERD; the evidence that a functional esophagus is associated with inflammatory bowel syndrome (IBS); the role of GABA agonists in the treatment of refractory GERD; the role of biofeedback and antidepressants in refractory GERD; and endoluminal fundoplication using the EsophyX device. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) are being employed in clinical trials to facilitate engraftment and to treat steroid-resistant acute graft-versus-host disease after hematopoietic stem cell transplantation, as well as to repair tissue damage in inflammatory/degenerative disorders, in particular, in inflammatory bowel diseases (IBDs). When entering the clinical arena, a few potential risks of MSC therapy have to be taken into account: (i) immunogenicity of the cells, (ii) biosafety of medium components, (iii) risk of ectopic tissue formation, and (iv) potential in vitro transformation of the cells during expansion. This paper analyzes the main risks connected with the use of MSCs in cellular therapy approaches, and reports on some of the most intriguing findings on the use of MSCs in the context of regenerative medicine. Experimental studies in animal models and phase I/II clinical trials on the use of MSCs for the treatment of IBDs and other inflammatory/degenerative conditions are reviewed. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) has been identified as an inflammatory bowel disease (IBD) candidate gene. However, the mechanism through which mutations in the PTPN2 gene contribute to the pathogenesis of IBD has not been identified. PTPN2 acts as a negative regulator of signaling induced by the proinflammatory cytokine, interferon-gamma (IFN-γ). IFN-γ is known not only to play an important role in the pathogenesis of Crohn's disease (CD), but also to increase permeability of the intestinal epithelial barrier. We have shown that PTPN2 protects epithelial barrier function by restricting the capacity of IFN-γ to increase epithelial permeability and prevent induction of expression of the pore-forming protein, claudin-2. These data identify an important functional role for PTPN2 as a protector of the intestinal epithelial barrier and provide clues as to how PTPN2 mutations may contribute to the pathophysiology of CD. [ABSTRACT FROM AUTHOR]

The tight junction connects neighboring epithelial or endothelial cells. As a general function, it seals the paracellular pathway and thus prevents back-leakage of just transported solutes and water. However, not all tight junctions are merely tight: some tight junction proteins build their own transport pathways by forming channels selective for small cations, anions, or water. Two families of tight junction proteins have been identified, claudins (27 members in mammals) and tight junction-associated MARVEL proteins ((TAMPs) occludin, tricellulin, and MarvelD3); an additional, structurally different, junction protein is junction adhesion molecule (JAM). Besides classification by genetic or molecular kinship, classification of tight junction proteins has been suggested according to permeability attributes. Recent studies describe specific cis and trans interactions and manifold physiologic regulations of claudins and TAMPs. In many inflammatory and infectious diseases they are found to be altered, for example, causing adversely increased permeability. Currently, attempts are being made to alter the paracellular barrier for therapeutic interventions or for transiently facilitating drug uptake. This overview concludes with a list of open questions and future topics in tight junction research. [ABSTRACT FROM AUTHOR]

Inflammatory muscle diseases are a group of muscle disorders characterized by muscle weakness, fatigue, and an association with malignancy and paraneoplastic syndrome. A diagnosis of idiopathic inflammatory myopathy is suggested by abnormal myometry and rising creatine kinase, but tissue diagnosis is also needed. Magnetic resonance imaging (MRI) helps localize the appropriate site of biopsy, demonstrate the extent of muscle involvement, and monitor the response to therapy. However, the sensitivity of magnetic resonance (MR) is limited, and whole-body imaging is still far from routine. [18F]Fluoro-desoxy-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the ultimate metabolic imaging technique for the management of cancer. It has also been shown to detect inflammatory conditions and tomonitor their response to treatment. The use of FDG PET in screening for underlying malignancies is widely reported and recommended in patients with paraneoplastic syndrome. Unfortunately, only a few reports have been published to show the value of FDG PET in inflammatorymuscle diseases, which as we show herein, deserve further pursuit. [ABSTRACT FROM AUTHOR]

The role of the lymphatic circulation to actively remove fluid, cells, proteins, and other particles from the interstitium to prevent mounting edema is well appreciated, but whether and how this function is compromised during inflammation has been scarcely investigated. We discuss here the mechanisms of lymphatic pumping and their modulation in inflammatory conditions or by inflammatory mediators in the context of inflammatory bowel disease (IBD), an ensemble of disorders typically described with abnormal or dysfunctional intestinal or mesenteric lymphatic vessels. We report our findings showing impaired mesenteric lymphatic contractile activity in an animal model of intestinal inflammation that recapitulates some features of IBD and suggests a role for prostanoids in this dysfunction. With the knowledge that prostaglandin E2 and prostacyclin are implicated in IBD pathogenesis and induce a potent inhibition of lymphatic pumping, we established the pharmacological profile for these prostaglandin receptors in mesenteric lymphatic vessels and their respective role in pumping inhibition. Inhibition of mesenteric lymphatic pumping during inflammation may be a cause of edema, compromised immune response, and granuloma associated with IBD. [ABSTRACT FROM AUTHOR]

Clinical observations suggest that the sites of initial inflammation in ileal Crohn's disease (CD) are the lymphoid follicles, where the aphtoid lesions originate from small erosions of the follicle-associated epithelium (FAE). Lymphoid follicles and Peyer's patches (PPs) consist of a number of B-cell follicles with intervening T cell areas. The T cell follicular area is also populated by dendritic cells (DCs) and macrophages. A single layer of epithelial cells covering each follicle forms a dome between the surrounding villi. This FAE differs from normal villus epithelium in several ways that make the epithelial cells of the FAE more exposed to the luminal contents, more accessible to antigens, and in closer contact with the immune system. The most prominent feature is the presence of specialized M cells, which are optimized for antigen adherence and transport. M cells play an important role in the surveillance of the intestinal lumen, but also provide a route of entry for various pathogens. In this article we review the current knowledge on the epithelial phenotype of the human FAE, and changes of the FAE and M cells in intestinal inflammation, leading to a hypothesis of the role of the FAE and M cells in the pathogenesis of CD. [ABSTRACT FROM AUTHOR]

There is currently a growing appreciation for the role of the enteric flora in health and disease. In the past years overwhelming evidence has accumulated for the role of commensal gut bacteria in the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Both entities are mainly located in areas with high bacterial concentrations. Reduction of the enteric bacterial concentration by antibiotics, lavage, or surgical bypass results in a mitigation of symptoms, while experimental colitis models depend on the presence of the bacterial flora and the NOD2/CARD15-mutation results in inefficient clearance of invasive bacteria. Those findings helped to bring the concept of probiotic therapy to the forefront, a therapy that had been known for millennia, but had been disregarded by the scientific world. Probiotics are meanwhile established in the maintenance therapy of ulcerative colitis and chronic recurrent or refractory pouchitis. Promising data exist for the primary prevention of pouchitis. Probiotic research at the intersection of gastroenterology, immunology and microbiology is highly dynamic in both the basic and the clinical field. Further understanding of the complex molecular mechanisms leading to the effectiveness of probiotics will also spur the development of more successful probiotic formulations. [ABSTRACT FROM AUTHOR]

The transcription factor, nuclear factor-κB (NF-κB), is a dominant regulator of the expression of hundreds of genes, many of which play important roles in the regulation of inflammation and programmed cell death (apoptosis). Since the discovery of NF-κB in the mid 1980s, this transcription factor has been the subject of intense investigation. Excess or inappropriate activation of NF-κB has been observed in human inflammatory bowel disease and in a host of other inflammatory diseases and type of cancer. Functional studies in animals have shed light on the role of NF-κB in broader pathophysiological contexts. From such studies, it has become quite clear that NF-κB plays unique and distinct functions in different cell types. Because of the importance of NF-κB in signaling inflammation, and in inhibiting programmed cell death, many pharmaceutical companies are developing small-molecule inhibitors of this pathway. In this article, we evaluate the relative pros and cons of blocking NF-κB as a therapeutic approach for inflammatory bowel disease. On the basis of the results of studies in animals that have primarily used genetic approaches to inhibit NF-κB activity, we suggest that there are certain niche indications for blocking NF-κB in inflammatory bowel disease that offer particular promise. [ABSTRACT FROM AUTHOR]

Current treatment of inflammatory bowel disease is rather effective through it is only working in symptomatic fashion. Most recombinant “biologicals” have not been an overwhelming success. Infliximab has shown clinically relevant efficacy and is used in patients not responding to the standards. Alternatives such as modulating the bacterial-epithelial interaction, tightening of the mucosal barrier and maybe even immunostimulation should be studied since most recent finding on etiology and pathophysiology point to a disturbed barrier with consequent abnormal bacterial epithelial interaction as the main problem in the IBD syndrome. We still need to learn much but we should not focus only on immunosuppressive systems. [ABSTRACT FROM AUTHOR]