Current Molecular Medicine (v.11, #2)
microRNAs in Stroke Pathogenesis by J.R. Tan, Y.X. Koo, P. Kaur, F. Liu, A. Armugam, P.T.-H. Wong, K. Jeyaseelan (76-92).
Stroke is one of the leading causes of death and disability worldwide. There are two major types of stroke: cerebral ischemia caused by obstruction of blood vessels in the brain and haemorrhagic stroke that is triggered by the disruption of blood vessels. Thrombolytic therapy involving recombinant tissue plasminogen activator (rtPA) has been shown to be beneficial only when used within 4.5 hours of onset of acute ischemic stroke. rtPA treatment beyond this time window has been found to be unsuitable and usually resulting in haemorrhagic transformation. Stroke is a multifactorial disease that forms a possible end state for majority of patients suffering from diabetes, atherosclerosis and hypertension which are known risk factors. Although the biochemistry of stroke and related diseases is quite well understood, the knowledge on the molecular mechanisms underlying these diseases is still at its infancy. microRNAs that form a unique class of endogenous riboregulators of gene function, offer tremendous potential in unraveling the mechanisms underlying stroke pathogenesis. microRNA expression also reflects the response of individuals to drugs and therapy. Several microRNAs and their target genes, known to be involved in endothelial dysfunction, dysregulation of neurovascular integrity, edema formation, pro-apoptosis, inflammation and extra-cellular matrix remodeling contribute to the critical processes in the pathogenesis of stroke. In this review, we will also be discussing the role of microRNAs as possible diagnostic and prognostic biomarkers as well as potential therapeutic targets in stroke pathogenesis.
Practical Aspects of microRNA Target Prediction by T.M. Witkos, E. Koscianska, W.J. Krzyzosiak (93-109).
microRNAs (miRNAs) are endogenous non-coding RNAs that control gene expression at theposttranscriptional level. These small regulatory molecules play a key role in the majority of biologicalprocesses and their expression is also tightly regulated. Both the deregulation of genes controlled by miRNAsand the altered miRNA expression have been linked to many disorders, including cancer, cardiovascular,metabolic and neurodegenerative diseases. Therefore, it is of particular interest to reliably predict potentialmiRNA targets which might be involved in these diseases. However, interactions between miRNAs and theirtargets are complex and very often there are numerous putative miRNA recognition sites in mRNAs. ManymiRNA targets have been computationally predicted but only a limited number of these were experimentallyvalidated. Although a variety of miRNA target prediction algorithms are available, results of their application areoften inconsistent. Hence, finding a functional miRNA target is still a challenging task. In this review, currentlyavailable and frequently used computational tools for miRNA target prediction, i.e., PicTar, TargetScan,DIANA-microT, miRanda, rna22 and PITA are outlined and various practical aspects of miRNA target analysisare extensively discussed. Moreover, the performance of three algorithms (PicTar, TargetScan and DIANAmicroT)is both demonstrated and evaluated by performing an in-depth analysis of miRNA interactions withmRNAs derived from genes triggering hereditary neurological disorders known as trinucleotide repeatexpansion diseases (TREDs), such as Huntington's disease (HD), a number of spinocerebellar ataxias (SCAs),and myotonic dystrophy type 1 (DM1).
Decorin Biology, Expression, Function and Therapy in the Cornea by R.R. Mohan, J.C.K.Tovey, R. Gupta, A. Sharma, A. Tandon (110-128).
Decorin is a small leucine-rich proteoglycan (SLRP) that plays a vital role in many important cellularprocesses in several tissues including the cornea. A normal constituent of the corneal stroma, decorin is alsofound in the majority of connective tissues and is related structurally to other small proteoglycans. It interactswith various growth factors such as epidermal growth factor (EGF) and transforming growth factor beta (TGFβ)to regulate processes like collagen fibrillogenesis, extracellular matrix (ECM) compilation, and cell-cycleprogression. Studies have linked decorin dysregulation to delayed tissue healing in patients with variousdiseases including cancer. In the cornea, decorin is involved in the regulation of transparency, a key functionfor normal vision. It has been reported that mutations in the decorin gene are associated with congenitalstromal dystrophy, a disease that leads to corneal opacity and visual abnormalities. Decorin also antagonizesTGFβ in the cornea, a central regulatory cytokine in corneal wound healing. Following corneal injury, increasedTGFβ levels induce keratocyte transdifferentiation to myofibroblasts and, subsequently, fibrosis (scarring) inthe cornea. We recently reported that decorin overexpression in corneal fibroblasts blocks TGFβ-drivenmyofibroblast transformation and fibrosis development in the cornea in vitro suggesting that decorin genetherapy can be used for the treatment of corneal scarring in vivo.
The Many Faces of Glutathione Transferase Pi by O. Vasieva (129-139).
Glutathione transferase Pi (GST-pi, GSTP) is known to strongly affect human susceptibility toseveral cancers, asthma and neurodegenerative disorders. As with other glutathione transferases, it catalysesthe addition of reduced glutathione to electrophilic species, and it is important in metabolite detoxification. Italso was shown to bind proteins and compounds containing iron and nitric oxide. Some of these interactionshave developed in the course of evolution into regulatory pathways that back up the GST's most ancientcatalytic functions and provide precise and diverse responses to chemical and redox stresses. An aim of thisreview is to summarise recent knowledge on GSTP's complementary functions in crosstalking pathways ofconventional glutathione transfer, nitric oxide and lipid metabolism and ASK1-dependent stress response. Thisreview will describe how these complex interactions affect regulation of cell respiration, biosynthesis of lungsurfactant, organism's immunity and circadian rhythms. Integration of the data leads to a new interpretation ofthe role of GSTP in normal human physiology, pathology and an organism's susceptibility to diseases.
Pathobiology and Prevention of Cancer Chemotherapy-Induced Bone Growth Arrest, Bone Loss, and Osteonecrosis by C. Fan, B.K. Foster, W.H. Wallace, C.J. Xian (140-151).
Cancer chemotherapy has been recognized as one severe risk factor that influences bone growthand bone mass accumulation during childhood and adolescence. This article reviews on the importance of thisclinical issue, current understanding of the underlying mechanisms for the skeletal defects and potentialpreventative strategies. Both clinical and basic studies that appeared from 1990 to 2010 were reviewed forbone defects (growth arrest, bone loss, osteonecrosis, and/or fractures) caused by paediatric cancerchemotherapy. As chemotherapy has become more intensive and achieved greater success in treatingpaediatric malignancies, skeletal complications such as bone growth arrest, low bone mass, osteonecrosis,and fractures during and/or after chemotherapy have become a problem for some cancer patients andsurvivors particularly those that have received high dose glucocorticoids and methotrexate. Whilechemotherapy-induced skeletal defects are likely multi-factorial, recent studies suggest that differentchemotherapeutic agents can directly impair the activity of the growth plate and metaphysis (the two majorcomponents of the bone growth unit) through different mechanisms, and can alter bone modeling/remodelingprocesses via their actions on bone formation cells (osteoblasts), bone resorption cells (osteoclasts) and bone-maintenance- cells (osteocytes). Intensive use of multi-agent chemotherapy can cause growth arrest, lowbone mass, fractures, and/or osteonecrosis in some paediatric patients. While there are currently no specificstrategies for protecting bone growth during childhood cancer chemotherapy, regular BMD monitoring andexercise are have been recommended, and possible adjuvant treatments could include calcium/vitamin D,antioxidants, bisphosphonates, resveratrol, and/or folinic acid.
Regulatory Functions of Ubiquitin in Diverse DNA Damage Responses by C.H.M.A. Ramaekers, B.G. Wouters (152-169).
In recent years there has been intense investigation and rapid progress in our understanding of thecellular responses to various types of endogenous and exogenous DNA damage that ensure genetic stability.These studies have identified numerous roles for ubiquitylation, the post-translational modification of proteinswith single ubiquitin or poly-ubiquitin chains. Initially discovered for its role in targeting proteins for degradationin the proteasome, ubiquitylation functions in a variety of regulatory roles to co-ordinate the recruitment andactivity of a large number of protein complexes required for recovery from DNA damage. This includes theidentification of essential DNA damage response genes that encode proteins directly involved in theubiquitylation process itself, proteins that are targets for ubiquitylation, proteins that contain ubiquitin bindingdomains, as well as proteins involved in the de-ubiquitylation process. This review will focus on the regulatoryfunctions of ubiquitylation in three distinct DNA damage responses that involve ubiquitin modification ofproliferating cell nuclear antigen (PCNA) in DNA damage tolerance, the core histone H2A and its variant H2AXin double strand break repair (DSBR) and the Fanconi anaemia (FA) proteins FANCD2 and FANCI in cross linkrepair.