Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 12, Issue 4, 2012

The metabolic syndrome is characterized by visceral obesity, insulin resistance, Type 2 diabetes, dyslipidemia and hypertension. These risk factors and diseases are also associated with cortisol hyperactivity, such as in Cushing’s syndrome. Therefore, increased cortisol activity may be considered to be a pathogenetic mechanism also for the metabolic syndrome, despite cortisol levels within reference values. In one study thirty women, 49-65 yrs old, with visceral obesity, insulin resistance and Type 2 diabetes were treated with ketoconazole 400 mg daily, in order to down-regulate cortisol activity, in a 3-month randomized, double-blind, placebo-controlled trial. In another study, a modified release formulation of ketoconazole was administered to 72 men and women in a 3-month randomized, double-blind, placebo-controlled trial at three different centers. In a third study, an enantiomer of ketoconazole was evaluated in 36 patients with Type 2 diabetes who were studied for 14 days. All three studies demonstrated that a down-regulation of cortisol secretion can favorably affect most of the multiple risk factors associated with the metabolic syndrome such as improvements in insulin resistance, glucose homeostasis, total cholesterol, blood pressure and hepatic steatosis. The last study also indicated a decrease in CRP, which has been reported to be elevated in metabolic syndrome/insulin resistance.

Neovascularization, which may play a pivotal role in physiological and pathological conditions such as rheumatoid arthritis (RA), is a complex process involving endothelial cell division, selective degradation of vascular basement membranes and the surrounding extracellular matrix, and endothelial cell migration. The involvement of several endogenous molecules has been suggested based on the ability of these molecules to regulate the proliferation of endothelial cells. There are a number of factors that regulate angiogenic and angiostatic functions and may be crucial in promoting neovascularization, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietins and members of the chemokine family, such as CXCL8 and CXCL10. This review discusses the expression and regulation of angiogenic and angiostatic cytokines in the context of chronic inflammatory arthritis, such as RA.

Manipulating the action of the Cholesteryl Ester Transfer Protein -CETP- and transforming the human lipid phenotype into one resembling the mouse lipid phenotype, in order to reduce susceptibility to atherosclerosis, is a hypothesis based on at least three lines of scientific evidence summarized within the introduction of this article. The following aspects related to the pharmacological manipulation of the CETP are discussed within the present article: a) CETP as a controversial protein involved in heterotypic and homotypic transport of neutral lipids between different lipoproteins; b) CETP as a protein involved in atherogenic dyslipidemia associated with the insulin resistance syndrome and c) pharmacological manipulation of the CETP by using "second generation" drugs -dalcetrapib, anacetrapib and evacetrapib- focusing on the results of Phase IIb and Phase III studies published up to May 2012 . The article concludes with a review of the strengths, weaknesses, opportunities and current controversy on the HDL-centric versus LDL-centric theories.

Atherosclerosis is the major cause of morbidity and mortality worldwide. Endothelial dysfunction is central to the pathogenesis of atherosclerosis, initiating a triad of lipid accumulation in the vessel wall, a co-existent inflammatory response and proliferation of smooth muscle cells. It has also been implicated in the precipitation of acute ischaemia, and the determination of the extent of injury following such complications. Healthy endothelium regulates numerous blood vessel functions, including vascular tone, cell adhesiveness, and coagulation through the production of mediators. The best characterised of these are the vasodilators, nitric oxide (NO), prostacyclin, and endothelium derived hyperpolarising factor, and the vasoconstrictors thromboxane and endothelin. The endothelium itself may also be maintained by bone-marrow derived endothelial progenitor cells (EPC) which are mobilised in response to vascular injury and have angiogenic and proliferative properties. Understanding of the biology of the endothelium in atherosclerosis has led to new treatments and more may follow. Work is ongoing into NO bioavailability, prostacyclin agonists, endothelin and thromboxane antagonists, novel antiinflammatory and anti-oxidative agents as well as means of harnessing the properties of EPCs. It is hoped that this research will yield clinically useful approaches that will retard the progression of atherosclerosis and reduce the incidence or consequences of acute complications.

Immune mechanism of the body plays an important role in arresting neoplastic growth and in controlling infectious diseases. The innate immunity, adaptive immunity comprising of cellular and humoral immunity have distinct roles in fighting against cancer and infectious diseases. The role of neutrophils, monocytes-macrophages, T helper (Th)-1 and Th-2 lymphocytes, B-lymphocytes and cytokines in arresting neoplastic growth and in combating infections and the complex interrelationship among themselves and with neuro-endocrine network in the body has gained much impetus with the discovery of number of receptors and binding surfaces on these cells. The increased incidence of neoplastic and infectious diseases seen in the elderly is attributed primarily to decreased immune function of the body, and termed as immunosenescence. Alteration in circadian rhythmicity of various subsets of lymphocyte population has been documented in the elderly. Similarly recent studies on cancer patients reveal that there exists two distinct types of lymphocytes with some cells exhibiting acrophase during morning and others in the night and circadian variation of lymphocyte population in cancer patients suggest impaired integration of nervous, endocrine and immune responses in neoplastic disease. Seasonal outbreak of some infectious diseases seen in some parts of the world has supported the photoperiodic regulation of immune function with enhancement during short photoperiods and inhibition during long photoperiods. Although the evidences for this are largely derived from animal studies, its application to human studies is still in a preliminary stage. However, the neurohormone melatonin which was shown to have an immunomodulatory role may stimulate immune mechanisms and in this way, melatonin could be a very useful resource for inhibiting neoplastic growth. Melatonin stimulates natural killer cells which are known to attack and destroy cancerous cells by their immunosurveillance mechanism. In addition, Th-1 cells, B-lymphocytes, release of cytokines from immunoregulatory cells are influenced by melatonin. The synthesis of melatonin by lymphocytes and thymus supports an immunomodulatory role for melatonin and its application in the control of infectious and neoplastic diseases.

Coxiella burnetii is the intracellular bacterium responsible for Q fever and is classified as a category B potential biological weapon. Primary infection by C. burnetii is often asymptomatic or mild and is accompanied by spontaneous recovery. In patients with valve lesions or immunosuppressed patients, including pregnant women, the infection may become chronic. C. burnetii survives and replicates within myeloid cells by subverting receptor-mediated phagocytosis and preventing phagosome maturation. Here, we summarize the existing knowledge regarding the host response to C. burnetii; we also discuss the mechanisms used by C. burnetii to survive within macrophages as well as the defective immune response that characterizes chronic Q fever.

Ursolic acid (UA), a triterpenoid compound found in plants, is used in both the human diet and in medicinal herbs and possesses a wide range of benefits, including antioxidative and anti-inflammatory effects. Additionally, UA may inhibit lipid absorption in pancreatic cells and enhance lipolysis in adipocytes. Oxidized LDL (oxLDL) acts as a major mediator of endothelium dysfunction, which mediates atherogenesis. Until now, we have not known what role UA plays in the absorption of oxidized LDL in vascular endothelial cells. Regardless of whether UA affects oxLDL uptake mediated by specific oxLDL receptors (such as lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), scavenger receptor expressed by endothelial cells (SREC), and scavenger receptor B1 (SR-B1)), it is unclear if UA acts on endothelial cells. However, high-mobility group box 1 (HMGB1) is known to accumulate in atherosclerotic lesions and mediates vascular inflammation, although the mechanisms are not understood. Therefore, in this study, human coronary artery endothelial cells (HCAECs) were used in vitro and hypercholesterolemic mice were used in vivo to investigate the effects and mechanisms of HMGB1 and UA on oxLDL uptake. The results demonstrated that HMGB1 enhances oxLDL uptake through induction of LOX-1 in HCAECs and hypercholesterolemic mice. In vitro data showed that exposing HMGB1- stimulated HCAECs to UA decreased the LOX-1-mediated absorption of oxLDL through a cyclooxygenase (COX)-2- related nitric oxide (NO) signaling pathway. Similarly, UA administration decreased LOX-1, but not SREC and SR-B1 expression, in HMGB1-treated hypercholesterolemic mice. These findings suggest that UA may be a potential therapeutic agent for hypercholesterolemia-induced atherosclerosis.