Current Medicinal Chemistry - Volume 15, Issue 13, 2008

Fusion of a mammalian sperm cell with an oocyte will lead to the formation of a new organism. As this new organism develops, the cells that construct the organism gradually lose developmental competence and become differentiated, a process which is in part mediated via epigenetic modifications. These mechanisms include DNA methylation, histone tail modifications and association with Polycomb and Trithorax proteins. Several cells within the organism must however maintain or regain developmental competence while they are highly specialized. These are the primordial germ cells that form the gametes; the oocytes and sperm cells. In this review different epigenetic modifying mechanisms will be discussed as they occur in developing embryos. In addition, aspects of nuclear reprogramming that are likely to occur via removal of epigenetic modifications are important, and several epigenetic removal mechanisms are indeed also active in developing germ cells. In vivo, a pluripotent cell has the capacity to form gametes, but in vitro terminal gametogenesis has proven to be difficult. Although development of pluripotent cells to cells with the characteristics of early germ cells has been unequivocally demonstrated, creating the correct culture milieu that enables further maturation of these cells has as yet been futile.

A number of nuclear and mitochondrial mutations have been implicated in non-syndromic hearing loss. Among them, various mutations of mitochondrial SerUCN-tRNA and 12S rRNA genes have been found to be associated with deafness; the A7445G mitochondrial DNA (mtDNA) in this group is unique, simultaneously affecting two different mitochondrial genes, encoding the SerUCN-tRNA and the first subunit of cytochrome oxidase. Besides the hearing loss, it is mainly associated with palmoplantar keratoderma, though; different phenotypic associations have been reported. The current paper reviews the available PubMed reports on the A7445G mtDNA mutation, with special attention to the phenotypic variations. Further, a Hungarian family with the A7445G mutation is reported, in which analysis of both the affected and the non-affected members revealed the mutation in both homo- and heteroplasmic forms, independently of the hearing status of the subjects, a phenomenon previously not reported in other pedigrees. The female lineage represented a rare variant of the U4b haplogroup.

Histone deacetylase (HDAC) inhibition as a therapeutic regimen in motor neuron diseases (MND) is generating intense interest in both the scientific and medical areas, with a number of potent compounds having demonstrated good safety profiles and hints of clinical activity on animal models. In this review, we discuss recent developments in dissecting the mechanism of action of HDAC inhibitors (HDACi) as a new group of mechanism-based drugs for motor neuron diseases, together with current progress in understanding their clinical application. We also discuss how the use of HDACi on animal models with motor neuron defects has allowed critical advances in the understanding of the pathophysiology of motor neuron diseases. The use of HDACi and possible mechanisms of action will be reviewed in three MND, i.e. amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA), diseases among which clinical trials with HDACi are currently perfomed (ALS, SMA).

Epigenetic mechanisms affecting chromatin structure contribute to regulate gene expression and assure the inheritance of information, which are essential for the proper expression of key regulatory genes in healthy cells, tissues and organs. In the medical field, an increasing body of evidence indicates that altered gene expression or de-regulated gene function lead to disease. Cancer cells also suffer a profound change in the genomic methylation patterns and chromatin status. Aberrant DNA methylation patterns, changes in chromatin structure and in gene expression are common in all kind of tumor types. However, studies on leukemias have provided paradigmatic examples for the functional implications of the epigenetic alterations in cancer development and progression as well as their relevance for therapeutical targeting.

This article comments on the role of the most important biochemical markers that are already applied in clinical practice or are still under research, in Acute Coronary Syndromes (ACS). Cardiac troponin (cTn) is established as the ‘gold standard’ in the diagnosis of ACS. C-reactive protein (CRP) and especially high-sensitivity CRP (hs-CRP) are considered to be the most useful inflammatory markers for clinical practice in the setting of acute coronary syndrome. Brain-type natriuretic peptide (BNP) and the amino terminal fragment of the prohormone BNP (NT-proBNP) appear to provide prognostic information in individuals admitted for acute coronary syndromes. Microalbuminuria in nondiabetics appears to be a signal from the kidney that the vasculature, particularly the endothelium, is not functioning properly. Increased plasma levels of cystatin C, neopterin, myeloperoxidase, and pregnancy associated protein are associated with adverse cardiovascular outcomes, cardiovascular and noncardiovascular death, and possibly cerebrovascular disease. Furthermore, recent evidence suggests that serum levels of CD40-CD40L pathway exert important roles in progression, and outcome of acute coronary syndrome. In the future further, studies are necessary to elucidate the exact role of the new biochemical markers in ACS.

Chemotactic cytokines, or chemokines, are a large family of small proteins, which are distinguished from other cytokines in that they are the only members of the cytokine family that act on G-protein coupled receptor superfamily. This minireview tries to answer the title question by structure/function analysis of chemokines, cytokines, and their receptors. We also consider secretion of chemokines/ cytokines in health and disease as well as expression of their receptors both in immune system and brain. Our analysis suggests that cytokine and chemokine receptors may share similar architecture with Toll-like receptors. Such similarity hints a similar way of their functioning as molecular switches controlled by protein-protein interactions. Hence, we pay attention to the related receptor-receptor associations and evolutionary conserved leucine-rich motifs.

Small conductance Ca2+-activated K+ (SKCa) channels comprise an important subclass of K+ channels. Selective blockade of SKCa channels may find application in the therapy of myotonic muscular dystrophy, gastrointestinal dysmotilities, memory disorders, narcolepsy, and alcohol abuse. In the cyclophanes described herein the two 4-aminoquinolinium groups are joined at the ring N atoms (linker L) and at the exocyclic N atoms (linker A). When both the spacer A and L have only one benzene ring, the blocking potency changes dramatically with simple structural variations in the linkers. One of these smaller cyclophanes having A = benzene-1,4- diylbis(methylene) and L = benzene-1,3-diylbis(methylene) shows activity in the low nanomolar range. Furthermore, the results with the present series add significantly to the structure-activity knowledge in the field, since they incorporate the first example of molecules in which the activity depends critically on the nature of the linkers joining the two quinolinium (Q) groups. Later on, a novel series of bisquinolinium bis-alkylene cyclophanes was described. The biological results of the present series add support to the suggestion that the linkers of the two Q groups do not form direct interactions with the channel protein but comprise a molecular support for the two Q groups. Two important structural features of the pharmacophore for SKCa channel blockade have been identified. These are (1) an optimum distance of ca. 5.8 Å between the centroids of the pyridinium rings of the two quinolinium groups, and (2) a preference for conformations having the Q groups in a synperiplanar orientation.

The liver plays a key role in glucose homeostasis, lipid and energy metabolism. Its function is primarily controlled by the anabolic hormone insulin and its counterparts glucagon, catecholamines and glucocorticoids. Dysregulation of this homeostatic system is a major cause for development of the metabolic syndrome and type 2 diabetes mellitus. The features of the underlying dynamic molecular network that coordinates systemic nutrient homeostasis are less clear. But recently, considerable progress has been made in elucidating molecular pathways and potential factors involved in the regulation of energy and lipid metabolism and affected in diabetic states. In this review we will focus on important stations in the complex network of molecules that control the balance between glucose production, glucose utilization and regulation of lipid metabolism. Special attention will be paid to the insulin receptor substrate (IRS) proteins with the two major isoforms IRS-1 and IRS-2 as a critical node in hepatic insulin signalling. IRS proteins act as docking molecules to connect tyrosine kinase receptor activation to essential downstream kinase cascades, including activation of the PI-3 kinase or MAPK cascade. IRS-1 and IRS-2 are complementary key players in the regulation of hepatic insulin signalling and expression of genes involved in gluconeogenesis, glycogen synthesis and lipid metabolism. The function of IRS proteins is regulated by their expression levels and posttranslational modifications. This regulation within the dynamic molecular network that coordinates systemic nutrient homeostasis will be outlined in detail under the following conditions: after feeding, during fasting and during exercise. Dysfunction of IRS proteins initially leads to post-prandial hyperglycemia, increased hepatic glucose production, and dysregulated lipid synthesis and is discussed as major pathophysiological mechanism for the development of insulin resistance and type 2 diabetes mellitus. Understanding the molecular regulation and the pathophysiological modifications of IRS proteins is crucial in order to identify new sites for potential intervention to treat or prevent hepatic insulin resistance and type 2 diabetes mellitus.

Phellinus Linteus (Berkeley & M. A. Curtis) Teng (PL) is a medicinal mushroom that has been practiced in oriental countries for centuries to prevent ailments as diverse as gastroenteric dysfunction, diarrhea, haemorrhage and cancers. In an effort to translate the Asian traditional medicines into western-accepted therapies, scientists have demonstrated that the extracts from fruit-bodies or mycelium of PL not only stimulate the hormonal and cell-mediated immune function and quench the inflammatory reactions caused by a variety of stimuli, but also suppress the tumor growth and metastasis. Mounting evidence from different research groups has shown that PL induces apoptosis in a host of murine and human carcinomas without causing any measurable toxic effects to their normal counterparts. Recently, research has been focused on the anti-tumor effect of PL, and in particular, on its ability to enhance some conventional chemotherapeutic drugs. These studies suggest PL to be a promising candidate as an alternative anticancer agent or a synergizer for existing antitumor drugs. Hereinafter, we summarize the present progress in elucidating the mechanisms underlying the potency of PL and its anti-tumor function. The fractionation and identification of the biologically active components from PL are also briefly introduced.

Protein aggregation correlates with the development of several deleterious human disorders such as Alzheimer's disease, Parkinson's disease, prion-associated transmissible spongiform encephalopathies and type II diabetes. The polypeptides involved in these disorders may be globular proteins with a defined 3D-structure or natively unfolded proteins in their soluble conformations. In either case, proteins associated with these pathogeneses all aggregate into amyloid fibrils sharing a common structure, in which β-strands of polypeptide chains are perpendicular to the fibril axis. Because of the prominence of amyloid deposits in many of these diseases, much effort has gone into elucidating the structural basis of protein aggregation. A number of recent experimental and theoretical studies have significantly increased our understanding of the process. On the one hand, solid-state NMR, X-ray crystallography and single molecule methods have provided us with the first high-resolution 3D structures of amyloids, showing that they exhibit conformational plasticity and are able to adopt different stable tertiary folds. On the other hand, several computational approaches have identified regions prone to aggregation in disease-linked polypeptides, predicted the differential aggregation propensities of their genetic variants and simulated the early, crucial steps in protein self-assembly. This review summarizes these findings and their therapeutic relevance, as by uncovering specific structural or sequential targets they may provide us with a means to tackle the debilitating diseases linked to protein aggregation.