Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 8, Issue 3, 2009

Welcome to the 2009 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (HOT TOPIC) Vol. 8, No. 3. The theme we have chosen for this volume is Microbiota, innate immune, and anti-inflammation. We attempt to highlight the current state-of-the-art relevant to innate immunity regulation and inflammation, functions of the anti-inflammatory bacterial proteins, application of the probiotics in digestive diseases, and evolution of the non-steroidal anti-inflamamtory drugs (NSAIDs). In particular, Sahni features the current understanding of pathogenic rickettsiae infection, host response, and apoptotic death mechanisms. This review summarizes critical roles for infection-induced oxidative stress, nuclear factor-kappa B, and p38 MAP kinase pathways in the regulation of innate immune responses and in preventing apoptosis during infection. Sun discusses the mechanisms of the bacterial proteins in inhibiting inflammation in the host cells. The anti-inflammatory roles of the bacterial proteins and the research progress on the bacterial protein structures are highlighted. Insights in the antiinflammatory mechanisms of the bacterial proteins will provide promising opportunities for therapeutical intervention. It is clear that bacteria in the colon, and perhaps in the small intestine, are significant players in the development of GI diseases, such as inflammatory bowel diseases (IBD) and necrotizing enterocolitis (NEC). Bacterial activation of the innate immune system can have both inflammatory as well as protective healing roles in the intestine. Gibson et al. review on the current state of knowledge underlying the bacteria's role for innate immunity in the gastrointestinal tract, and discuss the strengths and weaknesses of the chemical and infectious models used in these studies. In addition, they discuss preliminary evidence that exaggerated microbial activation of the innate immune system may cause the fibrotic responses that develop in some patients with IBD. Claud focuses on bacterial colonization patterns, intestinal barrier function, and inflammatory responses of immature enterocytes leading to a unique vulnerability of the preterm gut in NEC. In addition the possible therapeutic potential of factors in human milk and probiotic bacteria is discussed.

Spotted fever rickettsioses due to Rickettsia rickettsii and R. conorii and epidemic typhus caused by R. prowazekii have been known to humankind since the beginning of the 20th century. Alarmingly, new species/subspecies of arthropod-borne rickettsiae are still being recognized and described as globally emerging pathogens. The genus Rickettsia includes obligate intracellular α-proteobacteria with affinity to infect vascular endothelium of small and medium-sized blood vessels in humans. Endothelial cells, key immunoreactive cells involved in host defense and inflammation, are intimately involved in the manifestations of rickettsial infections. The present review features the current understanding of cell signaling, host response, and apoptotic death mechanisms during in vitro infection of cultured human umbilical vein endothelial cells or endothelial-like cell lines with pathogenic rickettsiae and summarizes critical roles for infectioninduced oxidative stress, nuclear factor-kappa B, and p38 MAP kinase pathways in the regulation of innate immune responses and in preventing apoptosis early during infection to ensure host cell survival for rickettsial replication/spread. However, in the context of emerging concept of ‘endothelial heterogeneity’, the existing knowledge pertaining to the interactions of these unique intracellular pathogens with endothelial cells of different vascular beds remains in its infancy. A complete definition of signaling interactions between organ-specific host endothelial cells and strains of varying virulence and further detailed characterization of direct in vivo models of disseminated vascular infection represent major steps in advancing our depth of understanding of rickettsial pathogenesis, which should allow the development of novel antiinflammatory strategies to combat the pathologic sequelae of debilitating human rickettsioses.

Bacteria use multiple strategies to bypass the inflammatory responses in order to survive in the host cells. In this review, we discuss the mechanism of the bacerial proteins in inhibiting inflammation. We highlight the antiinflammatory roles of the type three secretion proteins including Salmonella AvrA, Enteropathogenic Escherichia coli Cif, and Yersinia YopJ, Staphylococcus aureus extracellular adherence protein, and Chlamydia proteins. We also discuss the research progress on the structures of these anti-inflammatory bacterial proteins. The current therapeutic methods for diseases, such as inflammatory bowel diseases, sclerosis, lack influence on the course of chronic inflammation and infection. Therefore, based on the molecular mechanism of the anti-inflammatory bacterial proteins and their 3-Dimension structure, we can design new peptides or non-peptidic molecules that serve as anti-inflammatory drugs without the possible side effect of promoting bacterial infection.

Inflammatory bowel diseases (IBD) are thought to occur because of impaired mucosal integrity that allows enteric bacteria to leak out of the intestine, triggering maladaptive intestinal inflammation. While the exact pathogenesis of IBD is unclear, studies have recently demonstrated that bacterial activation of innate receptors not only causes inflammation, but may also play an important role in modulating intestinal epithelial barrier function, as well as intestinal epithelial cell proliferation and repair. These mucosal homeostatic mechanisms are essential in limiting as well as repairing mucosal damage. Therefore bacterial activation of the innate immune system can have both inflammatory as well as protective healing roles in the intestine. Strikingly, these findings suggest that dysregulation of these processes could be responsible for both the barrier dysfunction as well as the heightened inflammatory tone that characterize IBD. In this review we explore the current state of knowledge underlying this novel role for innate immunity in the gastrointestinal tract, and discuss the strengths and weaknesses of the chemical and infectious models used in these studies. In addition, we discuss preliminary evidence that exaggerated microbial activation of the innate immune system may cause the fibrotic responses that develop in some patients with IBD.

Neonatal necrotizing enterocolitis is a devastating inflammatory bowel disease of premature infants. The pathogenesis remains incompletely understood and there is no specific treatment. Efforts are ongoing to understand aspects of intestinal immaturity which contribute to susceptibility to this disease. This review focuses on bacterial colonization patterns, intestinal barrier function, and inflammatory responses of immature enterocytes leading to a unique vulnerability of the preterm gut. In addition the possible therapeutic potential of factors in human milk and probiotic bacteria is discussed.

Our intestinal microbiota serve many roles vital to the normal daily function of the human gastrointestinal tract. Many probiotics are derived from our intestinal bacteria, and have been shown to provide clinical benefit in a variety of gastrointestinal conditions. Current evidence indicates that probiotic effects are strain-specific, they do not act through the same mechanisms, and nor are all probiotics indicated for the same health conditions. However, they do share several common features in that they exert anti-inflammatory effects, they employ different strategies to antagonize competing microorganisms, and they induce cytoprotective changes in the host either through enhancement of barrier function, or through the upregulation of cytoprotective host proteins. In this review we focus on a few selected probiotics - a bacterial mixture (VSL#3), a Gram-negative probiotic (E. coli Nissle 1917), two Gram-positive probiotic bacteria (LGG, L.reuteri), and a yeast probiotic (S. boulardii) - for which sound clinical and mechanistic data is available. Safety of probiotic formulations is also discussed.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve pain and symptoms of arthritis and soft tissue inflammation. The gastrointestinal (GI) adverse effects such as gastric and duodenal ulcers and their complications are the major limitations to the prescription of these drugs. As many as 25% of chronic NSAID users develop peptic ulcer disease among which 2%-4% bleed or perforate. Hence, the emphasis has always been on developing novel NSAIDs without GI toxicity. Selective cyclooxygenase (COX)-2 inhibitors (coxibs) elicit less clinically significant GI damage and bleeding than conventional NSAIDs, but there are concerns about the cardiovascular safety of these drugs. New treatment modalities such as Nitric Oxide (NO) releasing NSAIDs, dual COX/5-lipooxygenase (5-LOX) inhibitors and selective inhibition of terminal Prostaglandin synthases may be superior to coxibs in terms of reducing toxicity and increasing potency and efficacy. The advent of new mediators (lipoxins, Hydrogen Sulfide) may offer new key targets for safer NSAIDs. Several Phosphatidylcholine (PC)-NSAIDs, which were found to have increased analgesic and antiinflammatory activity with significantly less gastric and intestinal damage in animal models, are now in the advanced clinical trial. The R-enantiomers of NSAIDs, which may be helpful in chemoprevention of cancer and Alzheimer's disease, generally exhibit greatly reduced GI toxicity. The evolution of these different novel NSAIDs may provide new modalities of anti-inflammatory therapies with greatly reduced GI toxicity.