Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 12, Issue 1, 2012

It is my great honor to introduce new wind from Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (IEMAMC) as an exciting forum for exchanging thoughts and experiences about basic and clinical research to solve the problems in Immunology, Endocrine & Metabolism. IEMAMC aims to cover all the latest and outstanding developments in the medicinal chemistry and rational drug design for the discovery of new immunology, endocrine & metabolic agents. This area is now rapidly growing due to the tremendous increase in the population of the diabetes and obesity. Each issue contains a series of timely in-depth reviews and original research articles written by leaders in the field covering a range of current topics in immunology, endocrine & metabolic medicinal chemistry. In this age, IEMAMC would offer new cutting edge in this field. The aim of IEMAMC is to report rapidly new theories, methods and techniques for prevention, diagnosis, and treatment in the field of immunology, endocrinology and metabolism. IEMAMC covers the topics concerning diabetes, atherosclerosis, obesity, endocrinology, hypertension, cardiovascular and cerebrovascular diseases, clinical aspects and trials for diabetes, hypertension, endocrine, metabolic disorders, and others. The mission of IEMAMC is to foster excellence in immunology, endocrinology and metabolism research, for the prevention of cardiovascular diseases and stroke. If you have not yet submitted to IEMAMC, now is the time to join. Together with the excellent Editorial Board Members, I look forward to serving the readers of IEMAMC and to working with you over the next few years so that the objectives of the missions of IEMAMC will be successfully achieved. So, if you want to share any new idea, any basic research, any clinical experiences in immunology, endocrinology and metabolism, IEMAMC is happy to provide a space to you!

Recently, the secretory - endocrine, paracrine and autocrine - phenotype of adipose tissue, consisting of adipocytes, stromovascular cells and immune cells, has increasingly been recognized. In humans, adipose tissue is partitioned into two large depots (subcutaneous and visceral) and many small depots associated with heart, blood vessels, major lymph nodes, pancreas, prostate gland, ovaries. Accordingly, two major subfields of adipobiology have emerged, adipoendocrinology (studying the endocrine activity of adipose tissue) and adipoparacrinology (studying the paracrine activity of adipose tissue). Traditional concept of the pathogenesis of atherosclerosis focuses on intimal surface, where endothelial dysfunction expressed by an “inside-out” inflammatory process triggers the formation of atherosclerotic plaque. The present short review highlights evidence for the possible role of dysfunctional paracrine activity of epicardial adipose tissue and of periadventitial adipose tissue in an “outside-in” pathway in the development of coronary and peripheral atherosclerosis, respectively. Such a paradigm may have various therapeutic applications including in coronary artery bypass surgery.

Introduction: Hemolysis and rhabdomyolysis may result from prolonged physical activity such as long distance running and marathon. Aim: The aim of this study was to assess the extent of cell damages after 42 km and 180 km of running, and to elucidate possible mechanisms of the membrane damage. The aim of this study was also to examine the effect of a simple dietary supplementation of antioxidative substances such as vitamin E, selenium and zinc. Method: A 41-year-old female schoolteacher ran continuously for 24 hours, achieving a total running distance of about 180 km. A group of well trained marathon athletes, 60 men and 10 women with a median age of 36 years, participated in the Beito Marathon in Norway. A smaller group of less trained people, 19 men and 4 women was also followed during the same marathon. Results: The hemolysis associated with marathon involved the apparent release of less than 250 mg hemoglobin per liter into plasma, whereas the 180 km run appeared to induce at least 20 times more hemolysis. The maximum values of released muscle enzymes after 180 km (CK 20.000 U/l), were several orders of magnitude higher than after marathon (CK 416 U/l). Furthermore, the prolonged physical exercise evoked a substantial inflammatory response. Discussion: Mechanical factors alone may cause cell damage, but we hypothesized a contributory role of cellular formation of free oxygen radicals. Moderate doses of vitamin E and selenium given to well trained marathon runners appeared to exert only negligible protective effects, either because the initiating membrane lesion is not directly related to oxidative stress, or because the training itself represented a much stronger antioxidant protection. However, the extensive membrane damages observed in the ultra marathon phase (42 to 182 km) may be accelerated by a collapse of endogenous antioxidants. Thus, although glutathione (GSH) peroxidase appears to operate adequately for several hours of exercise in well trained individuals, it is tempting to presume an ongoing GSH depletion in the 42-to-182 km phase. Conclusion: Systematic training and a balanced diet prior to long distance running and marathon may protect the body from organ disturbances in marathoners and ultra marathoners.

Blood vessels play a pivotal role in transporting nutrients and removing wastes. New vessel formation from pre-existing blood vessels, termed angiogenesis, is observed under physiological conditions such as embryonic development, wound healing, and during female reproductive cycle. Thus, angiogenesis allows organisms to maintain normal and adaptive functions. However, robust angiogenesis has been linked to pathological processes. Due to its fundamental impact on normal and disease development, angiogenesis is attracting the interests of both scientists and clinicians. This review will highlight the advances of pathological angiogenesis and potential therapeutic approaches. In particular, we will focus on an emerging signaling pathway, Rho-associated coiled-coil forming kinase (ROCK), which has been implicated in pathological angiogenesis.

Estrogen deficiency increases the cardiovascular risks and metabolic dysfunction in postmenopausal women. The potential effects of estrogen are partially related to its direct effects on the vascular wall, stimulating endotheliumderived NO synthesis (eNOS). HMG-CoA reductase inhibitors (statins) may also improve the endothelial function through upregulation of eNOS. In this study, we examined whether the treatment of pitavastatin for a short period (1 week) may improve the endothelial function or glucose metabolism under estrogen deficiency induced by ovariectmy. At 4 weeks after ovariectomy, hyperglycemia and hyperinsulinemia were observed in estrogen deficient mice as assessed by intraperitoneal glucose tolerance test, and endothelial dysfunction was also observed as assessed by the vasodilator response to acetylcholine. At 3 weeks after ovariectomy, we started to administer pitavastatin to ovariectomized mice for 1 week. Although the treatment of pitavastatin for a week did not affect obesity, the treatment of pitavastatin significantly attenutaed hyperglycemia and hyperinsulinemia as well as endothelial dysfunction induced by estrogen deficiency. These results demonstrated that treatment of pitavastatin rapidly improved glucose metabolism and endothelial function under estrogen deficiency.

The relevance of anti-human leucocyte antigen (anti-HLA) antibodies in the outcome of organ transplantation has been recognized in the past 40 years. Detection of these antibodies in sensitized recipients plays a pivotal role in this issue. Flow cytometry analysis is one of the choice cell-based techniques together with the pioneer complementdependent cytotoxicity crossmatch. Here, we discuss the advantages and limits of these cell-based assays and their use in the clinical laboratory of immunology of transplantation. Moreover, we compared this approach to other beads-based detection assays introduced more recently in the laboratory practice.

Background: Nuclear factor–kappa B (NF-κB) plays a pivotal role in vascular remodeling after percutaneous coronary intervention (PCI) with a stent implantation. Methods and Results: This is the first clinical report to demonstrate the effect of NF-κB decoy oligodeoxynucleotide (ODN) on the prevention of restenosis after an eight-year observation period. We revealed that decoy ODN treatment suppressed neointimal formation in comparison to that without ODN transfected stent lesion in the same artery. Conclusion: We showed the long-term usefulness of NF-κB decoy ODN transfer after PCI.

In the mammalian testis, the irreversible conversion of androgens into estrogens is catalyzed by the cytochrome P450 aromatase, a microsomal enzymatic complex encoded by a unique gene (Cyp19) in humans which contained 18 exons, 9 of them being translated. In addition that gene includes 12 non-coding exons I, located in the 5' end and controlled by tissue-specific promoters that are spliced alternatively onto a common site in exon II. However, a unique protein of 55 kDa is produced in human beings. In most of mammals studied so far, at least in rodents, all testicular cells except peritubular cells contain aromatase which is therefore constitutively expressed and very precisely controlled (in terms of expression and enzyme activity) according to somatic and germ cell origin (both estrogen receptors ERα and ERβ) as well as GPER (or GPR30), a seven transmembrane receptor which was concerned in these rapid effect of estrogens. In man, our data obtained from both ejaculated spermatozoa and immature gem cells demonstrate the presence of a biologically active aromatase ; moreover estrogen receptors (ER alpha and ER beta) are also present. All together according to the widespread localisation of aromatase and estrogen receptors in testicular cells, our review clearly shows that besides gonadotrophins and androgens, estrogens produced locally, should be considered as physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

Introduction: The association between metabolic syndrome and cortisol levels has previously been discussed and recent studies have also shown that down-regulation of cortisol improves metabolic and circulatory risk factors in obese patients with the metabolic syndrome. Aim: The primary objectives were to establish the effect of modified-release formulation of ketoconazole, a substance known to inhibit cortisol secretion, on insulin resistance and to establish a suitable dose for further investigation. The secondary objectives were to confirm improvement in other parameters related to metabolic syndrome such as HbA1c, blood pressure, liver enzymes, serum lipids, fasting blood glucose, and 24-hour urinary microalbuminuria. Method: Seventy-two overweight and viscerally obese male and female patients aged 18 to 75 year were included in a randomized, double-blind, placebo-controlled, 3-month study, with a 4 weeks safety follow-up period. They were randomized to receive 200 mg and 400 mg of the modified-release formulation of ketoconazole and placebo with 24 patients in each group. Entry criteria included a diagnosis of type 2 diabetes for at least one year prior to study entry, HbA1c levels ≥ 6.7%, fasting plasma insulin ≥ 15mU/L (ref: ≤ 10mU/L), visceral obesity withwaist to hip ratio of ≥ 0.93 for males and ≥ 0.88 for females, and the presence or history of two or more of the following: hypertension, dyslipidemia and microalbuminuria. Results: Administration of 400mg of the modified-release formulation of ketoconazole improved HbA1c levels, fasting blood glucose and total cholesterol compared to placebo with less consistent effects at 200mg of the modified-release formulation of ketoconazole. Additionally, reductions in systolic and diastolic blood pressure were found, and the study showed reductions in urinary microalbuminuria. Urinary cortisol decreased without signs of cortisol deficiency as measured with the standardized ACTH test. We found small mean increases from baseline in glucose disposal rate (GDR). Conclusion: This study with modified-release ketoconazole, showed improvements in several parameters of the metabolic syndrome, but did not meet the primary efficacy endpoint of improvement in insulin resistance most likely due to the short study period.