Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 12, Issue 3, 2012

Both osteoporosis and high blood pressure are major diseases in the recent aging society and may share the same background genetically and environmentally. Although several antihypertensive drugs, thiazides, beta (β)-blockers and angiotensin converting enzyme (ACE) inhibitors, are reported to decrease the risk of bone fractures, calcium channel blockers (CCBs), which are widely used as first line drugs, have not shown significant effects. As treatments to prevent aging- related diseases simultaneously are desirable, a simple approach to identify drugs effective for both diseases is essential. In this study, we screened various antihypertensive drugs with a focus on osteoclast function of acid secretion, bone resorption and reactive oxygen species (ROS) activity. Extracellular acidification in the resorption lacunae of osteoclasts was identified by acridine orange staining under a fluorescence microscope. Low pH of activated osteoclasts was identified as red to orange waves, while neutral pH of resting osteoclasts was identified as yellow to green waves. These phenomena were well correlated with the findings of excavated pit areas formed on the synthetic bone surface by active or resting stage osteoclasts, respectively. It was shown that benidipine, cilnidipine, olmesartan and calvedilol strongly attenuated acid secretion of osteoclasts, azelnidipine moderately, and hydrochlorothiazide mildly reduced the secretion, while amlodipine and telmisartan did not. Overall, screening drugs by osteoclast acidification by fluoresence microscopy might be a useful approach for evaluating the action of drugs on bone metabolism.

Cardiovascular disease (CVD) is the principal cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD promotes hypertension and dyslipidemia. Diabetes causes diabetic nephropathy, leading to the progression of renal failure. These traditional cardiovascular risk factors can promote CVD development. In addition, inflammatory mediators such as cytokines, chemokines, adhesion molecules, fibroblast growth factor 23, homocysteine, or reactive oxygen species are often elevated and the renin–angiotensin system, endothelin, and the sympathetic nervous system are frequently activated in patients with CKD, accelerating atherosclerosis and/or left ventricular hypertrophy. Mineral dysregulation accompanied by reduction of vitamin D, hyperphosphatemia, and hyperparathyroidism in CKD patients promotes vascular calcification associated with end-stage renal disease. Accelerated atherosclerosis then leads to increased prevalence of coronary artery disease, peripheral arterial disease, arterial stiffness, left ventricular hypertrophy, and cerebrovascular disease. On the other hand, renal dysfunction can result from diminished renal perfusion secondary to low cardiac output in left ventricular failure, peripheral arterial disease, and atherosclerosis and increased renal vasoconstriction mediated by neurohormonal and autonomic activation. Thus, traditional and non-traditional cardiovascular risk factors serve as cardiovascular and kidney risk factors. Consequently, kidney and cardiovascular dysfunction bidirectionally promote chronic renal failure and congestive heart failure. Whether differences in CVD in CKD patients suggest preventative or therapeutic strategies unique to this population remains unclear. Randomized controlled clinical trials must confirm the effectiveness of current pharmacological and interventional therapies modifying traditional and novel cardiovascular risk factors in patients at each stage of CKD, with or without unique co-morbidities.

It is well-known that the drug discovery and development process is lengthy, expensive and prone to failure. This high failure rate is a significant factor in the pharma industry's productivity problems, subsequent mergers and downsizing. Starting from the selection of a novel target in the discovery stage, through the multiple stages of development to regulatory approval, the overall probability of success is less than 1%. Given the time and resources needed to investigate a novel biological mechanism, i.e. one that has not been tested in humans before, success rates as low as these yield an unsustainable business model. In the face of a negative return-on-investment for new chemical entity drug discovery and development and constricted healthcare budgets that demand improved drugs to warrant reimbursement, an alternative approach must be identified to provide patients with new and better therapies as well as sustain the industry. The therapy of type II diabetes and obesity is currently based on seven approved drug classes encompassing both small molecule chemicals (metformin, sulfonylureas, glitazones, DPP-IV inhibitors, pancreatic lipase inhibitors) and (unmodified or modified) proteins (insulin and analogues, glucagon-like polypeptide-I and analogues). Clearly, this repertoire does not meet the requirements for the individualized treatment of metabolic diseases with estimated 2000 to 3000 susceptibility and protective genes and even higher numbers of underlying polymorphisms and combinations thereof, that is thought to form the basis for personalised therapy in the future. As a consequence, novel strategies for the identification of targets that can be addressed by the oral delivery as well as tissue and intracellular targeting of therapeutic proteins and nucleic acids are required. The identified and validated targets emerging will hopefully enable the future development of personalised polypharmacy based on multiple and individual combinations of susceptibility gene products that contribute to the common complex metabolic diseases.

In developed countries, cancer has replaced infectious diseases as a major cause of death. Currently, efforts in the immunoprevention of cancer are beginning to resemble those presented by the prevention of infectious diseases by immunization a century ago. Breast cancer is the most frequent type of tumor in women and is the second leading cause of death by this illness, among them. Moreover, cancer incidence will grow during next years. Some findings in autoimmunity related to breast cancer in animal models have been important to clarify mechanisms that potentiate tumor growth. Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in the neoplastic microenvironment where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Generally, antigens involved in autoimmune response in breast cancer are modified self-proteins or over-expressed normal proteins that induce autoantibodies (autoAbs) formation, which exhibit tumor promoting actions. Very frequently muscarinic acetylcholine receptors (mAChR) are up-regulated in different types of tumors appearing in different animal species. mAChR have the ability to act as autoantigens for tumor bearers. This article will review recent results concerning to the ability of mAChR expressed in transformed breast cells to trigger autoAbs formation either in experimental models or in breast cancer patients. We will also discuss the action of these antibodies as agonists of mAChR.

Diabetes is characterized by impaired insulin production by pancreatic beta cells. Metabolic testing in clinical settings does not adequately reflect beta cell mass (BCM), which is a target of multiple therapies under development. Thus, reliable imaging agents are needed for monitoring changes in beta cells during diabetes development and therapy. Various imaging modalities such as PET/CT, SPECT, MRI and PET-MRI have been investigated for in vivo imaging of pancreas. Application of these modalities for beta cell imaging is hampered by lack of beta cell specific imaging probes. Proteomics, systems biology, antibody library screening and phage display screening have been employed to find a suitable target on beta cell surface in order to design the probes for imaging functional beta cell mass. We expect that in the near future these methods will eventually lead to discovery of suitable marker(s) for beta cell paving the way for development of imaging probes for clinical settings.

One of the key roles of the immune system is the identification of potentially dangerous pathogens or tumour cells, and raising a wide range of mechanisms to eliminate them from the organism. One of these mechanisms is activation and expansion of antigen-specific cytotoxic T cells, after recognition of antigenic peptides on the surface of antigen presenting cells such as dendritic cells (DCs). However, DCs also process and present autoantigens. Therefore, antigen presentation has to occur in the appropriate context to either trigger immune responses or establish immunological tolerance. This is achieved by co-stimulation of T cells during antigen presentation. Co-stimulation consists of the simultaneous binding of ligand-receptor molecules at the immunological synapse which will determine the type and extent of T cell responses. In addition, the type of cytokines/chemokines present during antigen presentation will influence the polarisation of T cell responses, whether they lead to tolerance, antibody responses or cytotoxicity. In this review, we will focus on approaches manipulating co-stimulation during antigen presentation, and the role of cytokine stimulation on effective T cell responses. More specifically, we will address the experimental strategies to interfere with negative co-stimulation such as that mediated by PD-L1 (Programmed cell death 1 ligand 1) / PD-1 (Programmed death 1) to enhance anti-tumour immunity.

Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and is independently associated with poor cardiovascular outcomes. However, the direct relationship between serum ADMA level and the extent of subclinical coronary atherosclerotic plaque has never been investigated. In total, 130 consecutive asymptomatic Taiwanese subjects (mean age, 55.6±10 years), who received a health screening evaluation, were enrolled. Coronary plaque detected by computed tomography coronary angiography (CTCA) was observed in 85 (65.4%) of 130 individuals. Patients with coronary plaque had a higher ADMA level (1.16±1.15 μmol/L vs. 0.42 ± 0.33 μmol /L, p<0.001). The Receiver Operating Characteristic (ROC) curve analysis and further statistics revealed that individuals with an elevated ADMA level (≥0.6 μmol /L) had an increased prevalence of any plaque type, including calcified and noncalcified plaque (83% vs 39% P<0.001). Further multivariable logistic regression analysis after adjusting for conventional risk factors demonstrated that elevated ADMA (≥ 0.6 μmol /L, 76.5% sensitivity and 68.9% specificity) could independently predict the presence of coronary plaque (Odds ratio: 9.040; 95% confidence interval, 3.16 to 25.86, p<0.001). Our study demonstrated that an elevated ADMA level is associated with an increased prevalence of coronary plaque. Longitudinal studies may determine whether the excess risk observed in persons with elevated ADMA may be mediated, at least in part, by an increased burden of coronary atherosclerotic plaque.