Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 7, Issue 3, 2007

Obesity and the metabolic syndrome are becoming one of the biggest health challenges of the 21st century. Cholesterol metabolism is significantly altered in both obesity and metabolic syndrome in that cholesterol synthesis is increased and absorption reduced and this has important implications for the treatment of lipid disorders in both obesity and the metabolic syndrome. In the present review we discuss these changes in detail especially in the context of a more standardized approach for cholesterol reduction like the TARGET LDL trial. Customized care is topical in lipidology as we strive to achieve LDL cholesterol and non-HDL cholesterol targets in every patient.

Cardiovascular disease is the leading cause of death in the United States and developing world. Experimental and clinical studies have demonstrated that a number of interventions including brief periods of ischemia or hypoxia and certain endogenous factors such as opioids, bradykinin, growth factors or pharmacological agents are capable of protecting the heart against post-ischemic contractile dysfunction, arrhythmias and myocardial infarction. This conventional cardioprotection occurs via an autocrine or paracrine action in which these protective factors are released from the heart to act upon itself. Over the last ten years, a growing body of evidence indicates that a brief ischemic insult on one organ releases endogenous factors that protect other organs against a prolonged ischemic insult. This phenomenon, termed remote preconditioning or preconditioning at a distance, implicates an endocrine action, and may involve humoral or neuralendocrine signaling. This review will summarize the endocrine factors identified and implicated in this inter-organ cytoprotection.

Major advances in our understanding of how the mammalian immune system recognises pathogens have evolved from initial observations of fruit-fly developmental mutants. Through this work it has been established that vertebrates possess a specialised ‘early warning system’ in the form of a panel of detectors to rapidly sense and trigger responses to the presence of microbial invaders through detection of so called pathogen-associated molecular patterns (PAMPs). This discovery has led to the search for new agonists and antagonists that can be used, therapeutically, for rational manipulation of the immune response. These efforts have already yielded several exciting new strategies to treat autoimmune, atopic, malignant and infectious disease. This review article provides an overview of the potential impact of these drugs on human medicine.

Conventional treatment of moderate-severe ulcerative colitis (UC) has resulted in only a limited therapeutic benefit. Advancing knowledge of UC pathogenesis and recent advances in biotechnology have led to the development of biological agents that selectively target individual inflammatory pathways. In particular, the role of tumor necrosis factor alpha (TNF-α) in UC pathogenesis has been clarified by serological and immunohistochemical studies in humans and by experimental models. Clinical efficacy of anti-TNF-α therapy with infliximab has been assessed in two large controlled trials, showing a good compromise between therapeutic gain and safety. The aim of this review is to provide an insight into the role of TNF-α and anti-TNF-α therapy in patients with UC and diverticular disease associated colitis.

Biomarkers are generally considered to be plasma measurements of molecules, proteins, or enzymes that provide independent diagnostic and prognostic value by reflecting an underlying disease state or condition. In the case of coronary heart disease, they must reflect the underlying biology of the vessel wall and in particular, the atherosclerotic process and/or its sequelae. The clinical utility of a biomarker depends on its ability to account for a significant proportion of the disease being evaluated; it should be accurate and reliable; provide good sensitivity and specificity; and be available for widespread application. Data are being accumulated on the potential clinical utility of markers of inflammation, hemostasis and thrombosis, phospholipases, proteolysis and oxidative stress. Whereas C-reactive protein (CRP) emerges as a biomarker in the setting of primary prevention, we have recently found that CRP enhances the endothelial expression of metalloproteinases (MMPs). Regardless of the causality, circulating inflammatory markers have the potential to refine prediction of risk of cardiovascular events. However, a recommendation that they should be added to current risk factor scores is premature, since the benefits and costs of screening with any inflammatory marker require careful evaluation. A multimarker approach to estimate cardiovascular risk either by inflammatory markers and cumulative risk markers obtained from non-invasive tests or both may be superior to assessing a single marker.

Regulatory T (Treg) cells show promise for treating autoimmune diseases, but their induction to elevated potency has been problematic when the most optimally derived cells are from diseased animals. To circumvent reliance on auto-antigen reactive Treg cells, stimulation to vaccine antigens (Ags) may offer a viable alternative while maintaining potency to protect against proinflammatory diseases. Our Salmonella vaccine expressing colonization factor Ag I (CFA/I) possesses anti-inflammatory properties, evident by elevated Th2 cell responses, reduced inflammatory cell infiltrates in the Peyer's patches, and an absence of proinflammatory cytokine production by infected macrophages. Given these findings, we hypothesized whether this vaccine would be protective against experimental autoimmune encephalomyelitis (EAE). As such, Salmonella-CFA/I protected in both prophylactic and therapeutic paradigms against proteolipid protein (PLP139-151)-mediated EAE in SJL mice. The protected mice showed significantly reduced clinical disease and subsequent resolution when compared to PBS-treated controls. Histopathological studies showed reduced demyelination and no inflammation of spinal cords when compared to PBS- or Salmonella vector-treated mice. To ascertain whether the observed immune deviation was in part supported by Treg cells, analysis revealed involvement of FoxP3+ CD25+ CD4+ T cells. Adoptive transfer of induced TGF-β+ Treg cells from vaccinated mice showed complete protection against PLP139-151 challenge, but not by naive Treg cells. Partial protection to EAE was also achieved by the adoptive transfer of CD25- CD4+ T cells, suggesting that Th2 cells also contributed. Thus, these data show that Treg cells are induced by oral vaccination with Salmonella-CFA/I contributing to the efficacious treatment of autoimmune disease.

There is increasing evidence to suggest that neuroinflammatory processes contribute to the cascade of events that lead to the progressive neuronal damage observed in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Therefore, treatment regimes aimed at modulating neuroinflammatory processes may act to slow the progression of these debilitating brain disorders. Recently, a group of dietary polyphenols known as flavonoids have been shown to exert neuroprotective effects in vivo and in neuronal cell models. In this review we discuss the evidence relating to the modulation of neuroinflammation by flavonoids. We highlight the evidence which suggests their mechanism of action involves: 1) attenuation of the release of cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α); 2) an inhibitory action against inducible nitric oxide synthase (iNOS) induction and subsequent nitric oxide (NO.) production; 3) inhibition of the activation of NADPH oxidase and subsequent reactive oxygen species generation; 4) a capacity to down-regulate the activity of pro-inflammatory transcription factors such as nuclear factor-κB (NF-κB); and 5) the potential to modulate signalling pathways such as mitogen-activated protein kinase (MAPK) cascade. We also consider the potential of these dietary compounds to represent novel therapeutic agents by considering their metabolism in the body and their ability to access the brain via the blood brain barrier. Finally, we discuss future areas of study which are necessary before dietary flavonoids can be established as therapeutic agents against neuroinflammation.

A number of therapeutic targets have been explored for developing drugs in the treatment of endocrine, metabolic and immune disorders. Continuous efforts and increasing interest have been directed at the search of new targets. Data from the therapeutic target database at http://bidd.nus.edu.sg/group/cjttd/ttd.asp, shows that there are 26, 24, and 22 targets of marketed drugs for the treatment of these three classes of diseases, respectively. The number of targets of investigational agents has reached 98, 124, and 72, respectively. An analysis of these targets, particularly those of recently approved drugs and patented investigational agents, provides useful hint about the general trends of target exploration, with current focus on drug discovery and the difficulties encountered in developing drugs against these targets. Multiple profiles of these targets have been analyzed to probe the sequence, structural, physicochemical and systems-related features contributing to the successful exploration of a target against these diseases.