Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 8, Issue 3, 2008

Celiac disease is a digestive disease, considered as an autoimmune disorder, that damages the small intestine and interferes with absorption of nutrients. Individuals affected by celiac disease cannot tolerate a protein called gluten, present in wheat, rye, and barley, but also in other common products such as stamp and envelope adhesive, medicines, and vitamins. Celiac disease is a genetic condition that is triggered—or becomes active for the first time—after surgery, pregnancy, childbirth, viral infection, or severe emotional stress. Symptoms may occur in the digestive system, or in other parts of the body. Diagnosis involves blood tests and a biopsy of the small intestine. Recent findings estimate that about 2 million people in the United States have celiac disease, or about 1 in 133 people, as in Europe. Recent studies have shown that it may be more common in Africa, South America, and Asia than previously believed. The only treatment for celiac disease is to follow a gluten-free diet. Various other approaches are being studied that would reduce the need of dieting. One of those promising new approaches involves treating celiac patients with AT-1001, a paracellular permeability inhibitor, and with R-spondin1, a recombinant, secreted protein that early animal studies have shown to act as a highly specific stimulator of the gastrointestinal (GI) epithelial cells .

Cannabinoids have been reported to alter the activities of immune cells in vitro and in vivo. These compounds may serve as ideal agents for adjunct treatment of pathological processes that have a neuroinflammatory component. As highly lipophilic molecules, they readily access the brain. Furthermore, they have relatively low toxicity and can be engineered to selectively target cannabinoid receptors. To date, two cannabinoid receptors have been identified, characterized and designated CB1 and CB2. CB1 appears to be constitutively expressed within the CNS while CB2 apparently is induced during inflammation. The inducible nature of expression of CB2 extends to microglia, the resident macrophages of the brain that play a critical role during early stages of inflammation in that compartment. Thus, the cannabinoid-cannabinoid receptor system may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, HIV encephalitis, closed head injury, and granulomatous amebic encephalitis.

The genome-based study of human disease has been developing rapidly with the completion of the human genome project and the remarkable progress of technology. The genetic variation information associated with disease will certainly enable us to discover potential drug targets and to develop personalized medicine. Chronic kidney disease (CKD) is now recognized as a public health problem because its prevalence is increasing all over the world. No treatment can reverse the progression of CKD to end-stage renal disease (ESRD), which requires enormous medical resources. Moreover, CKD is known to be a strong risk factor for cardiovascular disease. In this review, we summarize the genetic studies that have reported a number of disease susceptibility genes and loci for CKD and ESRD. Earlier investigations, mostly by linkage analysis and association analysis with candidate gene approaches, have demonstrated that genetic factors play a crucial role in CKD and ESRD. However, the findings have contributed little great impacts related to drug discovery and diagnostic tool development in kidney diseases: further investigations are necessary to confirm the previously identified susceptibility genes. Recent technological advances will enable us to perform genome-wide association analysis, discover new disease susceptibility genes, and establish novel treatment strategies based on genomic information related to kidney disease.

Maintaining health requires a dynamic balance between the influence of pro-inflammatory and antiinflammatory mediators. While inflammation serves an important protective role against infection, unrestrained inflammation is acutely lethal and unresolved inflammation contributes to a broad range of chronic disorders. Immunotherapy with cytokines themselves or cytokine antagonists faces strict limitations due to efficacy, safety and cost. More successful treatment of the pro-inflammatory component of chronic disorders may emerge from strategies designed to reset the balance between pro and anti-inflammatory cytokines through physiological regulatory pathways. One emerging avenue for this approach is exploitation of the link between the cell surface protein CD36 and the anti-inflammatory cytokine interleukin- 10 (IL-10). Agents that increase CD36 expression and agents that directly bind to CD36 have anti-inflammatory properties that may directly relate to induction of IL-10. The immunosuppressive effects of apoptotic cells were first reported more than a decade ago and have since been tested in animal models and several clinical trials. A recent publication demonstrates that induction of IL-10 by apoptotic cells is largely dependent upon the interaction between apoptotic cells and CD36, the receptor on monocytes and macrophages for apoptotic cells. This provides a direct mechanistic link between CD36 engagement and IL-10 induction, opening up new possibilities for using CD36 ligands, agents that increase CD36 expression or a combination of both to modulate inflammation and treat, or even prevent, an important set of chronic disorders.

The human extracellular Ca2+-sensing receptor (CaR) plays a key role in the regulation of serum calcium and parathyroid hormone. This large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites. Positive allosteric modulators of the CaR, which increase CaR activation and thereby decrease secretion of parathyroid hormone, are potential for the treatment of primary and secondary hyperparathyroidism. Conversely, negative allosteric modulators of the CaR, which decrease the receptor activation and thereby stimulate endogenous parathyroid hormone secretion, are potential for the treatment of osteoporosis and autosomal dominant hypocalcemia. Significant progress has been made in recent years in screening for allosteric modulators selectively targeting the CaR and identification of receptor residues important for allosteric modulation.

Metabolic syndrome (MetS) can be considered a pheno-physiological cluster of metabolically interrelated risk factors for diabetes mellitus and cardiovascular disease. MetS has emerged as a result of complex interactions among environmental stresses and MetS gene networks and their products. In this review we summarize trends in MetS definitions, their associated controversies and possibilities for their refinement. The National Cholesterol Education Program MetS definition with its improvements by the American Heart Association and NHLBI Conference has the potential to become the primary clinical definition of MetS. For the first time, by reviewing a large body of literature, we construct MetS gene networks in humans and in rodents. These MetS gene networks can serve as a budding platform to develop new hypotheses regarding the genetic mechanisms underlying MetS. We also extend the notion of MetS to mouse models. New and improved molecular genomics and proteomic tools have been developed in parallel with the MetS epidemic which in conjunction with improved and novel computational statistical methods have magnified the genetic resolution of MetS analyses. Our results justify the existence of MetS as a meaningful syndrome and suggest that a better understanding of its etiology can benefit the health of human kind.

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily. Engaging of BMPs to BMP receptors on the cell surface leads to activation of the receptor kinase activity, which phosphorylates Smad1/5/8. Smad1, 5, or 8, with Smad4, forms a complex, which is translocated to the nucleus, where it binds to the consensus DNA sequence to regulate the transcription of BMP target genes. BMP-Smad signaling regulates stem cell renewal, cell proliferation, differentiation, migration, and apoptosis, and controls embryo development and postnatal tissue homoeostasis. Both human and mouse genetic studies have demonstrated that BMPs play positive roles in postnatal bone homeostasis including osteoblast expansion, differentiation, and bone formation. Defects in BMP-Smad signaling cause bone-related disorders such as osteoporosis, a disease that affects hundreds of millions of people. In addition, BMP-Smad signaling has been shown to play an important role in tumorigenesis. Mounting evidence indicates that in many tissues, BMP-Smad signaling has a tumor-suppressing activity and that BMPs can repress tumor growth. These findings suggest that BMP-Smad pathway can be a potential target not only for osteoporosis therapy but also for cancer therapy.

The endocannabinoid system (ECS) consists of two receptors (CB1 and CB2), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS has deep phylogenetic roots and regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways (e.g., ghrelin, leptin, orexin, adiponectin, endogenous opioids, and corticotropin-releasing hormone). Obesity leads to excessive endocannabinoid production by adipocytes, which drives CB1 in a feed-forward dysfunction. Phylogenetic research suggests the genes for endocannabinoid enzymes, especially DAGLα and NAPE-PLD, may harbor mildly deleterious alleles that express disease-related phenotypes. Several CB1 inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB1 blockade induces various adverse effects. Alternatives to systemic blockade include CB1 partial agonists, pleiotropic drugs, peripherally restricted antagonists, allosteric antagonists, and endocannabinoid ligand modulation. The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.