Current Molecular Medicine - Volume 11, Issue 9, 2011

Biochemical processes within a cell or an organism are usually instigated by molecular interaction and/or recognition events. Therefore, understanding the molecular biology and genetics of a disease is vital in designing the newer generation of molecularly targeted agents. Knowledge regarding the molecular basis of disease pathogenesis, genetic and epigenetic changes with disease progression, dysregulation of key cellular pathways for cell survival and proliferation, needs to be considered in the successful design and development of new agents for the treatment of the various stages of a disease, with the ultimate goal of cure. Manipulating living systems at the molecular level requires profound knowledge of the variability of small molecule effects that probe a particular cellular response. The successful discovery and design of molecular medicine is highly dependent upon the creative interplay of many scientific disciplines. Selection of articles in this issue provides a glimpse of the breadth and extent of fascinating research that is being conducted in the pursuit of developing effective medicines. In their article Dr. S. Chandrasekaran and colleague review Sirtuin (Sir2) proteins, the key regulators of numerous cellular processes which have been implicated in diverse physiological processes ranging from aging to cancer to neurological dysfunctions. Authors give an account of the efforts in understanding biology of these targets and development of chemical modulators of Sir2. Dr. Rigano and team nicely describe the role of oxidative stress in Beta2-Glycoproteins and thereby potential effect on the phenotypic and functional role of innate immune cells. While, Dr. Ferlini et al. discuss the rationale for connecting expression of Class III β-tubulin (TUBB3) linked to drug resistance as a complex survival mechanism activated by micro-environmental conditions such as poor nutrient supply and hypoxia. The Catechol-o-methyltranferase (COMT) is one of the major modulators of prefrontal dopamine function and has emerged as an important determinant of schizophrenia associated cognative dysfunction and response to antipsychotics. Diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia have been the focus of article by Dr. Ritushree Kukreti. The interest in G-quadruplexes, has grown rapidly. Dr. Shrikant Kukreti enumerates on their structural diversity and specific recognition rendering them as important drug target which can also act as gene regulatory elements. Dr. Cimino and team outline the importance of hormetic properties of plant antioxidants which could be employed in health promoting dietary interventions for neurodegenerative diseases and cancer. Similarly, oxidative stress has been implicated in the pathogenesis of various diseases such as diabetes and coronary artery diseases its main modifiable risk factor is the abnormal level of lipids and/or lipoproteins in the blood. Dr. Pallottini et al. give an update on the antioxidants with ability to affect 3-hydroxy-3-methylglutaryl coenzyme A reductase in short or long term, and therefore, could potentially provide additional approach in the management of hypercholesterolemia. It is my honor to serve as the guest editor of this special issue and I thank the Editor-in-Chief, Dr. David Li for inviting me, Dr. Luciano Saso for assisting in the process, and of course, the authors, for accepting my invitation to write and whose articles made this outstanding special issue possible.

Sirtuin (Sir2) proteins being key regulators of numerous cellular processes have been, over the recent past, the subject of intense study. Sirs have been implicated in diverse physiological processes ranging from aging and cancer to neurological dysfunctions. Studies on Sir2s using tools of genetics, molecular biology, biochemistry and structural biology have provided significant insight into the diverse functions of this class of deacetylases. This apart, medicinal chemistry approaches have enabled the discovery of modulators (both activators and inhibitors) of Sir2 activity of diverse chemical structures and properties. The availability of these small molecule modulators of Sir2 activity not only has pharmacological significance but also opens up the possibility of exploiting chemical genetic approaches in understanding the role of this multi-functional enzyme in cellular processes.

Beta2-glycoprotein I (β2-GPI), an abundant 50 kDa plasma glycoprotein, is the most common target for antiphospholipid antibodies (aPLs). These autoantibodies are associated with thrombotic events in patients with anti-phospholipid antibody syndrome (APS) and systemic lupus erythematosus (SLE) and are proatherogenic. β2-GPI can also stimulate a vigorous adaptive cellular immune response in these patients. Although much is known about β2-GPI as a cofactor in autoimmune diseases, crucial information is still lacking to clarify why this abundant self plasma protein is the target of autoimmune responses. Throughout the years, a remarkable number of theories have been proposed to explain how the immune system recognises self. On the basis of a large variety of epidemiological, clinical and experimental evidence, it has been suggested that an unfortunate interplay of genetic susceptibility and environmental factors may play an important role in generating an abnormal immune response. Among the environmental factors, oxidative stress is one of the major events causing protein structural modifications, thus inducing the appearance of neo/cryptic epitopes of β2-GPI able to activate the immune system. In particular, oxidized β2-GPI is able to induce phenotypic and functional maturation of dendritic cells which represent the link between innate and adaptive immunity. Chronic activation of autoimmune reactions against this self protein modified by oxidative events may contribute to local and systemic inflammation, thus sustaining endothelial dysfunction in patients with APS, SLE and cardiovascular diseases. The role of oxidative stress in β2-GPI-mediated immune response is described in the light of our research experience and of relevant literature emerging in the field.

Class III β-tubulin (TUBB3) is a prominent mechanism of drug resistance expressed in a variety of solid tumors and particularly in lung and ovarian cancer. In the classical view, TUBB3 expression and drug resistance have been linked, and together they have been associated with a perturbation in microtubule dynamics. In keeping with this observation, TUBB3 was associated with drug resistance only when chemotherapy included a taxane in its chemical composition. In this review, we demonstrate that the classical supposition about TUBB3 is not correct, and that instead TUBB3 expression is linked to drug resistance as a complex survival mechanism activated by microenvironmental conditions such as poor nutrient supply and hypoxia.

Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia.

Structural multitude of nucleic acids serves basis for its multiple merits and applications. During structural transitions, significant to perform respective cellular functions, these DNA forms can vary from the single stranded to multi-stranded species. Hence, beyond the image of a monotonous DNA double-helix, there is now increasing interest in other polymorphic/ multi-stranded forms, the roles they may play in vivo and their potential use in therapeutics. Distinct guanine-rich nucleic acid sequences readily form a structurally diverse four-stranded architecture called G-quadruplexes. In addition to their presence at physical ends of chromosomes called telomeres, occurrence of these structural motifs in the upstream promoter regions of a number of genes, oncogenes and near transcription start sites, highlights that G-quadruplexes are involved in regulation of gene expression. Cancer cells typically possess shorter telomeres and have telomerase activity greatly exceeding that of normal cells. These differences create an opportunity to use anticancer therapies targeting telomerase and telomeres. The ability of small molecules to interact with and presumably stabilize Gquadruplex structures as a means of inhibiting telomerase has been a major drug design effort. Ligands, capable of interacting with four-stranded G-quadruplex have been generated. The discovery of proteins including transcription factors, recognizing G-quadruplexes, and conferring stabilization or unfolding them in biological systems, again makes G-quadruplexes, biologically pertinent structures. This review is an attempt to summarize the rapidly evolving literature exploring the amazing polymorphism of G-quadruplexes, and understanding their structure-specific-recognition and biological relevance, keeping in mind that G-tetraplexes are not only important drug targets, but may also act as gene regulatory elements. A pertinent detail of the challenges towards the rational design of structure-specific novel drugs has also been discussed.

Many plant antioxidants, intaken through the daily diet or plant-derived dietary supplements, have been shown able to prevent free radical-related diseases by counteracting cell oxidative stress. However, it is now considered that the in vivo beneficial effects of these phytochemicals are unlikely to be explained just by their antioxidant capability. Several plant antioxidants exhibit hormetic properties, by acting as ‘low-dose stressors’ that may prepare cells to resist more severe stress. In fact, low doses of these phytochemicals activate cell signaling pathways (being the most prominent examples the modulation of the Nrf2/Keap1 pathway, the NF-κB pathway and the Sirtuin-FOXO pathway) but high doses are cytotoxic. Herein we review the adaptive responses induced by the most known plant hormetic antioxidants, which are sulforaphane, resveratrol, curcumin, flavonoids, green tea catechins and diallylsulphides, as well as the molecular mechanisms involved in such responses. Furthermore, this review outlines that the hormetic properties of these bioactive plant antioxidants might be successfully employed for realizing health-promoting dietary interventions especially in the field of neurodegenerative diseases and cancer.

Oxidative stress has recently been implicated in the pathogenesis of various diseases such as diabetes and coronary artery disease whose main modifiable risk factor is the abnormal level of lipids and/or lipoproteins in the blood. Thus, the maintenance of cholesterol homeostasis together with the reduction of intracellular reactive oxygen species content could partially prevent the occurrence of atherosclerotic phenomena. Owing to the ability exerted by some antioxidants to modulate the activity and/or the protein levels of 3- hydroxy-3-methylglutaryl coenzyme A reductase (the rate-limiting enzyme of cholesterol biosynthetic pathway), their use as additional approach to the management of hypercholesterolemia should be taken into account. Here we provide an up-dated overview of the antioxidants whose ability to affect 3-hydroxy-3-methylglutaryl coenzyme A reductase either in the short- or in the long-term regulations has been reported.