Current Medicinal Chemistry - Volume 14, Issue 25, 2007

Discrete chemical modifications of the chromatin (DNA and primarily histones) can regulate gene expression or repression and can be transmitted to the descent (cells or organisms) thanks to an epigenetic memory. These modifications involve histone posttranslational modifications, DNA methylation at CpG islands and small nuclear RNAs processes. They play fundamental roles in cell proliferation and differentiation. These two processes are crucial in particular during embryonic development, X chromosome inactivation in females, genomic imprinting, gene bookmarking, cell reprogramming, position effect and silencing of retroviral elements. While, only one major DNA modification is known, more than 150 post-translation modifications of histones have been reported, including methylations, acetylations, ubiquitinations, SUMOylations and phosphorylations. How these modifications are inherited from mother cells to daughter cells or from an organism to its descent remains a major scientific challenge. We propose here a macro-molecular complex, called ECREM for “Epigenetic Code REplication Machinery”, as being involved in the inheritance of the epigenetic code. The composition of ECREM may vary in a spatio-temporal manner according to the chromatin state, the cell phenotype and the development stage. We describe the members of ECREM, responsible for the epigenetic code inheritance, i.e., enzymes involved in DNA methylation and histone post-translational modifications. Some of them, such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs) and histone deacetylases (HDACS including sirtuins), have been found to be deregulated in several types of pathologies and are already targeted by inhibitors. ECREM, thus, appears to be an interesting complex to be investigated in order to find new drugs for cancer, metabolic, neuro-degenerative and inflammatory diseases therapy.

Epigenetics is a postmeiotic modification of gene expression that is independent of the primary DNA sequence. DNA methylation, methylated DNA binding proteins, and histone modification-related enzymes are associated with epigenetics. Abnormalities in DNA methylation of CpG islands which are important for gene expression control, affect gene expression, which may influence carcinogenesis, aging, and other diseases. Aberrant DNA methylation occurs with aging, inflammation, viral infection, and carcinogenesis. DNA methylation can be evaluated for molecular analysis for diagnosis of early cancer. It is also important for laboratory diagnosis by using classic and authentic laboratory tests because the tests can be affected by epigenetics-controlled gene expression. It is also related to the effectiveness of therapeutic agents affecting DNA methylation and histone deacetylation, and the strategy in search of genetic abnormality for epigenetic as well as genetic error.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of antialzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the developement of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group - dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT3 receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.

The γ-aminobutyric acid type A (GABAA) receptors are the major inhibitory neuronal receptors in the mammalian brain. Their activation by GABA opens the intrinsic ion channel, enabling chloride flux into the cell with subsequent hyperpolarization. Several GABAA receptor subunit isoforms have been cloned, the major isoform containing α, β, and γ subunits, and a regional heterogeneity associated with distinct physiological effects has been suggested. As a variety of allosteric ligands can modulate GABA-gated conductance changes through binding to distinct sites, the development of subtype-selective ligands may lead to the selective treatment of GABA system- associated pathology. In particular, the best characterized binding site is the benzodiazepine site (BzR), localized at the α/γ subunit interface, in which the α subunit is the main determinant of BzR ligand action selectivity. The α1-containing BzR have been proposed to be responsible for the sedative action; the α2 and/or the α3 subtypes have been suggested to mediate the anxiolytic activity and the myorelaxation effects, and the α5 subtype has been associated with cognition processes. The discovery of α-selective subtype ligands may help in the specific treatment of anxiety, sleep disorders, convulsions and memory deficits with fewer side effects. Selectivity may be achieved by two approaches: selective affinity or selective efficacy. Selective affinity needs a compound to bind with a higher affinity to one receptor subtype compared with another, whereas subtype-selective efficacy relies on a compound binding to all subtypes, but having different efficacies at various subtypes. The status of BzR ligands, subdivided on the basis of their main chemical structural features, is reviewed in relation to structure-activity relationships which determine their affinity or efficacy selectivity for a certain BzR subtype.

Endocannabinoids like anandamide and 2-arachidonoylglycerol bind and activate type-1 (CB1R) and type-2 (CB2R) cannabinoid receptors, two inhibitory G protein-coupled receptors (GPCRs) that are localized in the central nervous system and in peripheral tissues. The biological actions of these lipids are controlled through not yet fully characterized cellular mechanisms that regulate the release of endocannabinoids from membrane precursors, their uptake by cells, and their intracellular disposal. The transport of anadamide through the plasma membrane is saturable and energy-independent, and might occur through a putative anandamide membrane transporter. Altogether anandamide and 2-arachidonoylglycerol, their congeners and the proteins that bind, transport, synthesize and hydrolyze these lipids, form the “endocannabinoid system”. Accumulating evidence shows that CB1R (but not CB2R) binding and signaling, as well as anandamide transport, are under the control of lipid rafts (LRs), plasma membrane subdomains which modulate the activity of a number of GPCRs. Here we summarize the main features of the endocannabinoid system and LRs, in order to put the functional and structural effects of LRs on CB receptors, AEA transport and endocannabinoid signaling in a better focus. We outline the structural determinants that might explain the differential sensitivity of cannabic receptors towards raft integrity, and propose a general model to explain the dependence of endocannabinoid system on LRs. Finally, we also discuss the possible exploitation of LRs-targeted drugs as novel therapeutics for the treatment of endocannabinoid system-related pathologies.

Several lines of defense maintain the surface integrity of the delicate airway epithelium which is regularly subjected to severe trauma. These defense mechanisms include protection by the mucus layer, rapid repair by restitution (cell migration) and regeneration via proliferation and differentiation. Luminal surveillance peptides such as epidermal growth factor (EGF) and trefoil factor family (TFF) peptides support synergistically these processes. TFFs are well known particularly for their key role in mucosal restitution and there is an increasing body of evidence that TFFs also support mucosal differentiation processes. Mucus overproduction during inflammatory and obstructive airway diseases is a partial consequence of an increase in the number of goblet cells due to cell division (goblet cell hyperplasia) or differentiation (goblet cell metaplasia). Particularly the latter process reflects the plasticity of the airway epithelium and causes intense airway remodeling. Goblet cells are derived, at least in part, from Clara cells, which trans-differentiate from a serous into a mucous phenotype. This process is critically dependent upon IL-13. In a recent report (Kouznetsova et al. AJRCMB 36:286-297, 2007) using a murine asthma model it was shown that trans-differentiating Clara cells specifically express Tff1 which is stored in a specific subset of secretory granules. This points to a role for Tff1 as an autocrine factor for the trans-differentiation of Clara cells toward goblet cells. Such a role of TFFs for differentiation processes of the airways is supported by another recent study (LeSimple et al. AJRCMB 36:296-303, 2007) where induction of TFF3 synthesis was shown with differentiation in in vivo humanized tracheal xenograft and in vitro air-liquid interface culture models. Furthermore, exogenous TFF3 promoted differentiation of ciliated cells in an EGF receptor-dependent manner. Taken together, both studies imply that TFFs may play key roles for various differentiation processes of the airways and they could be promising novel targets in order to treat severe chronic and acute airway diseases.

Carbon monoxide (CO), which is classically thought of as a toxic molecule and cellular asphyxiate, has become increasingly recognized as an important molecule in the physiological regulation of multiple organ systems and in the restoration of homeostasis in pathophysiological states. CO has long been utilized as a tool in chemistry and physiology secondary to its ability to bind to heme proteins. Additionally, CO is produced endogenously in the breakdown of heme by heme oxygenase enzymes. Here we review the biological chemistry of CO and highlight some of the anti-inflammatory biological effects of the heme oxygenase/CO system.

Apatite-related calcium phosphate, the main component of biological hard tissue, has good biocompatibility and is an economical material. Methods for the synthesis of apatite materials including hydroxyapatite (HAp) have previously been established. Therefore, for many years, apatite materials have been utilized as substitute materials for bone in orthopedic and dental fields. Such types of conventional substitute materials, which are implanted in the human body, should ostensibly be chemically stable to maintain their quality over time. However, recent advances in tissue engineering have altered this concept. Physicians and researchers now seek to identify materials that alter their properties temporally and spatially to achieve ideal tissue regeneration. In order to use apatite materials for tissue engineering and as drug delivery systems, the materials require both a high affinity for cells, tissues and/or functional molecules (e.g. growth factors and genes) and controllable bioabsorbability. To achieve these properties, various physicochemical modifications of apatite materials have been attempted. In addition, fabrication desiring three-dimensional structures (e.g. size, morphology and porosity) of apatite materials for implant sites could be one of the crucial techniques used to obtain ideal prognoses. In this review, the latest research trends relating to the techniques for the fabrication and modification of apatite materials are introduced.