Current Pharmaceutical Design - Volume 15, Issue 18, 2009

Inflammatory bowel disease (IBD) is a chronic relapsing disorder associated with uncontrolled inflammation within the gastrointestinal tract, which has been shown to predispose patients to the development of colorectal cancer later in life. The pathogenesis of IBD is complex, but the current model favors a dysregulated cytokine network that is triggered by intestinal microbiota in a genetically-susceptible host. Interestingly, a germ free rodent model was reported not to cause cytokine dysregulation and intestinal inflammation. Therefore, microbiota and cytokines are both considered as theoretical targets for therapeutic approaches in IBD. This special issue of Current Pharmaceutical Design focuses on the role of microbiota and cytokines in IBD. Furthermore, therapeutic approaches targeting these two factors are also discussed including functional food and the pharmacological and non-pharmacological treatment modalities. First of all, Possemiers S, et al. provided a brief overview on the importance of the indigenous microbial community and its enormous metabolic potential, microbe-microbe interactions, mechanisms of host-bacterium cross-talk and discussed the onset of obesity, a specific disease state in which intestinal microbiota play a role [1]. Andoh A, et al. provided a review focusing on new insights into the role of commensal microbiota in gut health and disease, and presented recent advances in molecular approaches to the imbalance of intestinal microbiota in IBD [2]. Kanauchi O, et al. introduced the therapeutic impact of manipulating microbiota in IBD [3]. This review shows that the administration of selected prebiotics, probiotics and synbiotics may improve the clinical outcome of patients with IBD as a target for new forms of functional food. In addition, they describe the possibility of preventive treatment of IBD-associated colon cancer by using special prebiotics because of their physiologic characteristics and lack of obvious toxicity.

The human intestine is colonized by a complex microbial ecosystem, which could be considered as a separate organ within the human host, having a coding capacity which exceeds the liver by a factor 100. On the one hand, this extensive microbiome is closely involved in the first-pass metabolism and bioavailability of food and drug compounds. Understanding to which extent each individual’s gut microbiota affects the bioavailability and response to orally administered drugs is therefore a first important challenge towards novel drug development strategies. On the other hand, as our microbiota is directly or indirectly involved in the onset of a number of disease states, a new generation of therapeutics may be developed that affect the structure and functioning of the intestinal microbiota and interfere with their specific cross-talk with the human host. Ultimately, the intestinal microbiota may even be used as a biomarker for impending diseases inside or outside the gastrointestinal tract and for the evaluation of responses to specific therapeutic interventions. This review will therefore highlight the importance of the indigenous microbial community and its enormous metabolic potential, microbe-microbe interactions, mechanisms of host-bacterium cross-talk and will discuss the onset of obesity, a specific disease state in which the role of intestinal bacteria becomes more and more apparent. Understanding the importance of the intestinal ecosystem in these phenomena may open the door for new strategies which target the management of the intestinal microbiome into the desired direction and therefore to a completely new type of nutrition research and pharmaceutical design.

Inflammatory bowel diseases [IBD], ulcerative colitis [UC] and Crohn’s disease [CD], are chronic intestinal disorders of unknown etiology. UC and CD are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria in genetically susceptible individuals. As one of critical factors involved in pathogenesis of IBD, relative imbalance of aggressive and protective bacterial species, termed dysbiosis, has been reported by various literatures. Since early days of microbiology, representatives of microbial species [over 400 species] have been isolated from human gastrointestinal tract, and analyses of dysbiosis in IBD were mainly dependent on culture techniques. However, recent molecular ecological studies based on ribosomal RNA [rRNA] sequences have revealed that cultivation has been able only to access a small fraction of the microbial diversity within the gastrointestinal tract. These techniques enable characterization and quantification of the microbiota. Clone libraries enable identification of the composition of the microbiota. Microbial community structure can be analyzed via fingerprinting techniques, and dot blot hybridization or fluorescent in situ hybridization can analyze abundance of particular taxa. Recent report shows a systematic framework of the microbial diversity in the human gut of more than 1000 different species-level phylogenetic types [phylotypes]. This review focuses on recent advances in the molecular ecological approaches for studying the gut microbiota in IBD.

It is well established that intestinal microbiota play an important role in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Various methods of altering the composition of intestinal microbiota have been examined. Recent evidence suggests that the administration of select prebiotics, probiotics and synbiotics may improve the clinical outcome of patients with IBD. In addition, IBD patients are well known to carry a higher risk of developing colorectal cancer due to chronic inflammation. Therefore, probiotics and/or prebiotics may be appropriate treatments for prophylactic use due to their physiologic characteristics and lack of obvious toxicity. This review summarizes the current experimental and clinical knowledge about the role of intestinal microbiota in IBD, the prevention of carcinogenesis related to IBD, and its importance as a target for new forms of neutraceutical therapy.

Inflammatory bowel disease (IBD) is a chronic relapsing-remitting condition that afflicts millions of people throughout the world and impairs their daily functions and quality of life. While the aetiology of IBD is not understood well, it appears to be driven by inflammatory cytokines such as tumor necrosis factor (TNF)-α. Hence, there is a strong interest in agents that can block the generation or actions of inflammatory cytokines. Curcumin is a bioactive substance present in the rhizomes of the herb “Curcuma longa” which has been used for centuries in Asia, both in traditional medicine and in cooking as turmeric which gives food an exotic natural yellow color. Further, in recent years, a large number of research papers have reported intriguing pharmacologic effects associated with curcumin. These include inhibitory effects on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-α, interferon γ (IFN-γ), inducible nitric oxide synthase (iNOS), and the transcriptional nuclear factor kappa B (NF-κB), in addition to a strong anti-oxidant effect. NF-κB is a key factor in the upregulation of inflammatory cytokines that have a high profile in inflammatory diseases, suggesting that curcumin could be a novel therapeutic agent for patients with IBD. Therefore, in recent years, the efficacy of curcumin has been investigated in several experimental models of IBD. The results indicate striking suppression of induced IBD colitis and changes in cytokine profiles, from the pro-inflammatory Th1 to the anti-inflammatory Th2 type. In human IBD, up to now, only one open study has achieved encouraging results. In this study, patients were given curcumin (360mg/dose) 3 or 4 times/day for three months. Further, curcumin significantly reduced clinical relapse in patients with quiescent IBD. The inhibitory effects of curcumin on major inflammatory mechanisms like COX-2, LOX, TNF-α, IFN-γ, NF-κB and its unrivalled safety profile suggest that it has bright prospects in the treatment of IBD. However, randomized controlled clinical investigations in large cohorts of patients are needed to fully evaluate the clinical potential of curcumin.

The complex pathogenesis of inflammatory bowel disease (IBD) and inflammation induced colon cancer involves a wide range of mediators including cytokines. Recent investigations underline the fundamental role of interleukin- 6 (IL-6) signaling in the development and maintenance of IBD and for the progression of this inflammation to colon cancer. The molecular mechanisms of this pathway, the source of the cytokine and the identity of target cells in the intestine are incompletely understood. It is known that the circulating and intestinal levels of IL-6 as well as the soluble IL-6 receptor (sIL-6R) are increased in patients with IBD. Remarkably, mucosal T cells of IBD patients are extremely resistant to apoptosis and a large fraction of these cells express membrane-bound gp130 but not the IL-6R. Increasing evidence suggests that the development and perpetuation of IBD relies on IL-6 synthesized by T-cells and myeloid cells and on increased formation of IL-6/sIL-6R complexes interacting with membrane-bound gp130 on T-cells, a process called IL-6 trans-signaling. Recent investigations suggested a protective role of IL-6 mediated STAT3 signaling in intestinal epithelial cells. Here we review these pro- and anti-inflammatory properties of IL-6 in IBD and inflammation induced colon cancer and we will summarize the consequences of these new results for the prospects of IL-6 targeted therapeutic strategies for the treatment of chronic inflammatory diseases such as IBD.

An array of investigations has revealed that macrophage migration inhibitory factor (MIF) plays an important role in the exacerbation of a wide range of inflammatory diseases. For the past two decades, we have extensively studied MIF's pathophysiological roles in human diseases, and have accumulated evidence elucidating its molecular mechanisms in the pathogenesis of immune disorders and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel diseases (IBD). In a study of IBD, we demonstrated for the first time that anti-MIF antibody suppressed the degree of dextran- sulfate sodium (DSS)-induced colitis, indicating its potential therapeutic use for IBD patients. Following that report, a number of researchers, including us, clarified that MIF was profoundly involved in various gastrointestinal disorders, such as hepatitis and pancreatitis. We recently revealed that a MIF-deficient mouse was resistant to a challenge of DSS, and showed few clinical and pathological signs. Currently, we are developing new therapeutic approaches targeting MIF in inflammatory disorders, particularly IBD. We here overview MIF's pathophysiological function, mainly in IBD, and introduce two therapeutic approaches, anti-MIF antibody treatment and MIF-antisense therapy, via a drug delivery system using 1,3-β glucan.

Inflammatory bowel disease (IBD) is frequently associated with the infiltration of a large number of leukocytes into the bowel mucosa. Therefore, the removal of circulating leukocytes may be an attractive approach for the treatment of IBD. Leukocytapheresis with Cellsorba, a column of polyethylenephtarate fibers that captures monocytes, granulocytes, and lymphocytes, has been used to treat IBD, particularly ulcerative colitis, in Japan. The objective of this paper is to provide an overview of current knowledge regarding the mechanisms of action, available clinical data, and possible future perspectives for the use of LCAP with Cellsorba in the management of IBD. Leukocytapheresis appears to remove or inactivate inflammatory cells, to reset immunity by modulating immune system components like cytokines, and to repair the intestinal mucosa by mobilizing mesenchymal progenitors. Although the majority of clinical studies had an open-label design and enrolled only a small number of patients, leukocytapheresis has been demonstrated to exert clinical efficacy with an excellent safety profile. Although leukocytapheresis with Cellsorba appears very promising, its future in the treatment of IBD requires further evaluation.

Since the first case of acquired immunodeficiency syndrome (AIDS) was reported in 1981, AIDS has always been a global health threat and the leading cause of deaths due to the rapid emergence of drug-resistance and unwanted metabolic side effects. Every day in 2007 an estimated 6850 people were newly infected with human immunodeficiency virus (HIV). Over the past 28 years the rapid worldwide spread of AIDS has prompted an intense research effort to discover compounds that could effectively inhibit HIV. The development of new, selective and safe inhibitors for the treatment of HIV, therefore, still remains a high priority for medical research. To the best of our knowledge, the indole derivatives have been considered as one class of promising HIV-1 inhibitors, such as delavirdine approved by the Food and Drug Administration (FDA) in 1997 for use in combination with other antiretrovirals in adults with HIV infection. In this review we focus on the synthesis and anti-HIV-1 activity of indole derivatives, in the meantime, the structure-activity relationship (SAR) for some derivatives are also surveyed. It will pave the way for the design of indole derivatives as anti- HIV-1 drugs in the future.

This article reviews evidence that hyperpolarization-activated, cation nonselective (HCN) channels, the molecular basis of the Ih current, potentially represent valid targets for novel analgesic agents. Ih is a prominent current in many peripheral sensory nerves, with highest current density typically found in large diameter neurons. Recent data suggest that Ih may represent a valid target for the treatment of spontaneous pain and allodynia associated with nerve injury. The majority of available electrophysiological and molecular evidence suggests that fast activating, weakly cyclic adenosine monophosphate (cAMP) sensitive HCN1-based channels may make a significant contribution to Ih, especially in large diameter, mechanosensitive fibers, where the Ih current appears to support abnormal spontaneous firing after nerve injury. In contrast, HCN4 channels seem to play the predominant role in cardiac pacemaker tissue. These observations raise the possibility that HCN1 selective blockers may inhibit pain associated with nerve injury without dramatic effects on heart rate. Development of novel HCN blocking analgesics presents a number of significant technical challenges. Although a number of HCN blockers are available, such as ZD-7288, ivabradine, and others, these drugs inhibit all HCN isoforms with the same potency. As a result, these compounds have powerful effects on heart rate, severely limiting their utility for non-cardiac indications such as pain. Selectivity challenges, mechanisms of compound interaction with the channel, and assay methods are described in detail.