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Today, 12 Ιουλίου 2016, 4:19:50 μμ
Sulforaphane Treatment of Young Men with Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders that begin in early childhood. They are characterized by differences in behavior and delays in communication and affect at least 1% of children. Observational studies have now confirmed that behaviors of a substantial percentage of children with autism tend to improve with the onset of febrile illness, which might be the downstream effects of altered metabolic pathways involving increased expression of heat shock proteins (HSP) and cellular stress responses. Sulforaphane, a phytochemical derived from a number of cruciferous vegetables, most notably broccoli sprouts, has metabolic effects that in some ways resemble that of fever. This review paper discusses this “fever effect” and the intracellular effects of sulforaphane as well as the results of our recent clinical trial of sulforaphane in young adults with autism. The accompanying review by Liu et al. describes the cellular actions of sulforaphane and potential biomarkers in the study of ASD.
Oxidative Stress Genes, Antioxidants and Coronary Artery Disease in Type 2 Diabetes Mellitus
Today, 12 Ιουλίου 2016, 4:19:51 μμ
The worldwide increasing prevalence of obesity and sedentary lifestyle is the main cause of the rising incidence of T2DM. Due to chronic macrovascular and microvascular complications, T2DM represent a huge socioeconomic burden in the world. Oxidative stress is a key pathogenic mechanism implicated in diabetic coronary artery disease (CAD). Polymorphisms of oxidative stress genes are known to influence oxidative stress levels and are therefore thought to impact CAD pathogenesis. Identifying higher risk groups would be rational, since it would allow better sample selection and thus better results in antioxidant trials. In this review, we summarize the evidence of oxidative stress gene polymorphisms related to the pathogenesis of CAD. Moreover, we provide a review of antioxidants tested in subjects with CAD.
Metabolic Control of Type 2 Diabetes by Targeting the GLUT4 Glucose Transporter: Intervention Approaches
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Type 2 diabetes mellitus (T2DM), the most common form of diabetes, is characterized by insulin resistance in the hepatic and peripheral tissues. Glucose transporter 4 (GLUT4) plays a major role in the pathophysiology of T2DM. Its defective expression or translocation to the peripheral cell plasma membrane in T2DM patients hinders the entrance of glucose into the cell for energy production. In addition to suitable drugs, an appropriate diet and/or exercise can be implemented to target the increase in GLUT4 expression, GLUT4 concentrations and GLUT4 translocation to the cell surface when managing the glucose metabolism of T2DM patients. In this review, we discussed successful intervention strategies that were individually administered or coupled with diet and/or exercise and affected the expression and translocation of GLUT4 in T2DM while reducing the excess glucose load from the blood. Additionally, some potentially good synthetic and natural compounds, which can activate the insulin-independent GLUT4 signaling pathways for the efficient management of T2DM, are highlighted as possible targets or emerging alternative sources for future anti-diabetic drug development.
Editorial (Thematic Issue: New Therapeutic Targets for Autism Spectrum Disorders)
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Recent Advances Using Phosphodiesterase 4 (PDE4) Inhibitors to Treat Inflammatory Disorders: Animal and Clinical Studies
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Phosphodiesterase 4 (PDE4) inhibitors can be effective drugs for treating inflammation in different tissues/organs caused by conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, and Alzheimer’s disease. It has been demonstrated that PDE4 inhibitors used for drug therapy provide some advantages over conventional formulations, including sensitivity to selective inhibitors, unique tissue distribution, and ease of oral administration. To date, the U.S. Food and Drug Administration (USFDA) had approved two PDE4 inhibitors, roflumilast (Daxas®, Daliresp®) and apremilast (Otezla®), for treating respective COPD and plaque psoriasis. Several pharmaceutical companies and academic laboratories continuously develop novel PDE4 inhibitors for clinical application. A concern pertaining to the development of PDE4 inhibitors is the high occurrence rate of side effects such as emesis, nausea, and headache. This review describes recent developments using PDE4 inhibitors for inflammation management. Special attention is paid to the use of PDE4 inhibitors in treating pulmonary and cutaneous inflammation. This review article focuses on issues related to animal and human studies. The action mode of the inhibitors is also addressed.
A Systematic Review of Plant-Derived Natural Compounds for Anxiety Disorders
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn results in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers. </p><p> The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. </p><p> Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms include interaction with γ-aminobutyric acid (GABA)<sub>A</sub> receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)<sub>1A</sub> and 5-HT<sub>2A/C</sub> receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors. Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NOcGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity. </p><p> Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects. Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plantderived natural agents. </p><p>
Personalized Treatment of Obsessive-Compulsive Disorder: Radiology, EEG, Pharmacogenetics and Biochemistry
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Background: Obsessive-compulsive disorder (OCD) is a common mental illness and a ubiquitous cause of disability. Approximately half of the patients with OCD only partially respond or do not respond at all to current ways of treatment. Even patients responding to treatment usually need high doses of medication and/or intense psychotherapy for a long time. It is obvious that therapeutic approaches to OCD need improving. In this article, we review the modalities of personalized medicine in OCD. </p><p> Methods: We conducted a search in PubMed (until June 2015) and Scopus (until June 2015) by using the following terms: “obsessive-compulsive disorder,” “personalized medicine,” “response prediction,” “pharmacogenetics,” “therapeutic drug monitoring,” “EEG,” “neuroimaging” and “serotonin.” The literature about neuroimaging including radiological techniques (positron emission tomography, single-photon emission tomography, functional and morphometric magnetic resonance imaging and magnetic resonance spectroscopy) and electroencephalography, therapeutic drug monitoring (measuring the plasma levels of drugs), pharmacogenetics (genes encoding cytochrome P450 enzymes, serotonin transporter, serotonin receptors, norepinephrine transporter, dopamine receptors, brain-derived neurotrophic factor [BDNF] and catechol-O-methyltransferase) and biochemistry (whole blood serotonin levels and neuroendocrine challenge tests) is investigated. </p><p> Results: Pre-treatment changes in glucose metabolism shown by radiological instruments might be related to response to medication. Increased alpha in EEG is predictive of good response whereas increased theta forecasts a poor response. BDNF, serotonin receptors and glutamatergic and serotonergic transmission have been found to be somewhat related to treatment response in OCD. Few studies on whole blood serotonin levels and hormone response to challenge with a serotonergic medication in patients seem to have a predictive value in OCD treatment. </p><p> Conclusion: Although the studies to elaborate a personalized treatment of OCD have produced some promising results, much more work is required to provide clinician with a reliable decision tree. </p><p>
Communication from Tubular Epithelial Cells to Podocytes through Sirt1 and Nicotinic Acid Metabolism
Today, 12 Ιουλίου 2016, 4:19:51 μμ
We have recently published that tubular epithelial cells affect the podocyte epigenome though nicotinic acid metabolism in diabetic nephropathy (DN), and we have named this relationship “proximal tubule–podocyte communication”. In this review, we describe this novel mechanism in the early stage of DN, focusing on the function of renal tubular Sirt1 and Sirt1-related nicotinic acid metabolism. Mainly, we discuss the following three findings. First, we described the details of proximal tubule–podocyte communication. Second, we explained how Sirt1 regulates albuminuria via epigenetic mechanisms. This means that repeated high glucose stress triggers the initial changes in proximal tubules, which lead to the epigenetically irreversible glomerular damages. However, proximal tubular Sirt1 overexpression can rescue these changes. Our previous data indicated that the decrease in Sirt1 expression in proximal tubules caused the reduction in glomerular Sirt1 and the subsequent increase in glomerular Claudin-1. It seemed plausible that some humoral mediator is released from proximal tubules, migrates to podocytes and glomeruli, and affects Sirt1 expression in podocytes. Third, we mentioned a mediator connecting this communication, nicotinamide mononucleotide (NMN). We suggest the potential of Sirt1 or NMN as not only a therapeutic target but also as a prognostic marker of very early stage DN.
Oxidative Stress in Polycystic Ovary Syndrome
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Backgrouund: Polycystic ovary syndrome is a multifaceted disorder with a pathogenetic pathway that is not fully understood yet. Apart from hormonal derangements, insulin signaling defects and adipose tissue dysfunction, oxidative stress, defined as an imbalance derived from excessive formation of oxidants in the presence of limited antioxidants defenses, has been actively implicated in the etiology of the syndrome. Methods: This review focuses on understanding the putative role of oxidative stress in the pathophysiology of PCOS and analyzing its interconnection with the rest etiologic parameters and its contribution to the reproductive and metabolic manifestations of the syndrome. Results: Although underlying mechanisms have not been fully elucidated yet, it becomes evident that oxidative stress holds a respectable share in the pathogenesis of PCOS. In fact, PCOS can be considered as a purely oxidative state, where the body antioxidants cannot outweigh the excessive production of free radicals. Conclusion: Oxidative stress, in conjunction with the rest etiologic mechanisms of PCOS and the cardinal contribution of environmental factors, leads to an adverse redox status that stigmatizes the natural process of the syndrome.
Effects of Yokukansan, a Japanese Kampo Medicine for Symptoms Associated Autism Spectrum Disorder
Today, 12 Ιουλίου 2016, 4:19:51 μμ
A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients’ behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.
The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders.
Competitive Interaction Between Plasma Omega-3 Fatty Acids and Arachidonic Acid is Related to Down-Regulation of A Signaling Mediator
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Autism spectrum disorders (ASD) may be attributed to altered composition of polyunsaturated fatty acids. We examined the relationships between the plasma ratios of docosahexaenoic acid (DHA)/arachidonic acid (AA) and eicosapentaenoic acid (EPA)/AA, and biomarkers of AA-related signaling mediators, i.e., ceruloplasmin, transferrin and superoxide dismutase, with the behavioral symptoms of 30 individuals with ASD (mean age, 13.0 years old) and 20 age- and gender-matched normal controls (mean age, 13.6 years old). Behavioral symptoms were assessed using the Aberrant Behavior Checklists (ABC). The ASD group had significantly higher plasma DHA/AA and EPA/AA ratios, as well as ABC scores, compared to the control group. The plasma ceruloplasmin levels in the ASD group were significantly reduced compared to those in the control group. Multiple linear regression demonstrated that plasma DHA/AA ratio was a fitting model for distinguishing the ASD group from the control group. These findings suggested that increased plasma DHA/AA ratio may be related to lower plasma levels of ceruloplasmin, which may contribute to the pathophysiology of behavioral symptoms in 30 individuals with ASD.
Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Background: Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11-q13 region with three main genetic subtypes. These include paternal 15q11-q13 deletion (about 70% of cases), maternal uniparental disomy 15 or both 15s from the mother (20-30% of cases), and defects in the imprinting center (1-3%) which controls the expression of imprinted genes in this chromosome region. Clinical manifestations include infantile hypotonia with a poor suck resulting in failure to thrive, short stature, small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies, hyperphagia and excessive weight gain with obesity and cognitive and behavioral problems including obsessive compulsions, tantrums and self-injury. The phenotype is likely related to hypothalamic dysfunction. </p><p> Objective: Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS requiring accurate diagnosis, appropriate medical management and treatment; the major objective of our report. </p><p> Methods and Results: An extensive review of the literature was undertaken including genetics, clinical and behavioral aspects, and updated health-related information addressing the importance of early diagnosis and treatment of individuals with Prader-Willi syndrome. A searchable, bulleted and formatted list of topics related to this obesity syndrome was provided utilizing a Table of Contents approach for the clinical practitioner. </p><p> Conclusions: Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections that are pertinent in the context of clinical practice. Finally, frequently asked questions by clinicians, families and other interested participants will be addressed. </p><p>
Population Studies of Association Between Lithium and Risk of Neurodegenerative Disorders
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Background: Lithium shows neuroprotective and neurotrophic effects in vitro and in vivo. Due to its involvement in hippocampal neurogenesis and the interaction with beta-amyloid and neurofibrillary tangle metabolism it has been hypothesized that lithium could have the potential to influence the development of dementia. Method: Using the PubMed database and cross-reference search strategies our aim was to specifically identify population (cohort or case-control) studies investigating the association between lithium and dementia. Results: Data from large cohort studies suggest an association between lithium treatment and dementia risk reduction or reduced dementia severity. Studies with smaller sample sizes yield more variable findings. Conclusions: Lithium may reduce the risk of dementia among middle-aged and older people. Beneficial lithium effects are possibly limited to specific types of neurodegenerative processes.
The Role of mGlu Receptors in Hippocampal Plasticity Deficits in Neurological and Psychiatric Disorders: Implications for Allosteric Modulators as Novel Therapeutic Strategies
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Long-term potentiation (LTP) and long-term depression (LTD) are two distinct forms of synaptic plasticity that have been extensively characterized at the Schaffer collateral-CA1 (SCCA1) synapse and the mossy fiber (MF)-CA3 synapse within the hippocampus, and are postulated to be the molecular underpinning for several cognitive functions. Deficits in LTP and LTD have been implicated in the pathophysiology of several neurological and psychiatric disorders. Therefore, there has been a large effort focused on developing an understanding of the mechanisms underlying these forms of plasticity and novel therapeutic strategies that improve or rescue these plasticity deficits. Among many other targets, the metabotropic glutamate (mGlu) receptors show promise as novel therapeutic candidates for the treatment of these disorders. Among the eight distinct mGlu receptor subtypes (mGlu<sub>1-8</sub>), the mGlu<sub>1,2,3,5,7</sub> subtypes are expressed throughout the hippocampus and have been shown to play important roles in the regulation of synaptic plasticity in this brain area. However, development of therapeutic agents that target these mGlu receptors has been hampered by a lack of subtype-selective compounds. Recently, discovery of allosteric modulators of mGlu receptors has provided novel ligands that are highly selective for individual mGlu receptor subtypes. The mGlu receptors modulate the multiple forms of synaptic plasticity at both SC-CA1 and MF synapses and allosteric modulators of mGlu receptors have emerged as potential therapeutic agents that may rescue plasticity deficits and improve cognitive function in patients suffering from multiple neurological and psychiatric disorders.
Lysosomal Acid Phosphatase Biosynthesis and Dysfunction: A Mini Review Focused on Lysosomal Enzyme Dysfunction in Brain
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Lysosomes are membrane-bound organelles that are responsible for degrading and recycling macromolecules. Lysosomal dysfunction occurs in enzymatic and non-enzymatic deficiencies, which result in abnormal accumulation of materials. Although lysosomal storage disorders affect different organs, the central nervous system is the most vulnerable. Evidence shows the role of lysosomal dysfunction in different neurodegenerative diseases, such as Niemann–Pick Type C disease, juvenile neuronal ceroid lipofuscinosis, Alzheimer’s disease and Parkinson’s disease. Lysosomal enzymes such as lysosomal acid phosphatase 2 (Acp2) play a critical role in mannose-6-phosphate removal and Acp2 controls molecular and cellular functions in the brain during development and adulthood. Acp2 is essential in cerebellar development, and mutations in this gene cause severe cerebellar neurodevelopmental and neurodegenerative disorders. In this mini-review, we highlight lysosomal dysfunctions in the pathogenesis of neurodevelopmental and/or neurodegenerative diseases with special attention to Acp2 dysfunction.
Smell and Taste Disorders Resulting from Cancer and Chemotherapy
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Malnutrition is common in both adult and pediatric patients undergoing treatment for cancer. Patients commonly attribute difficulties maintaining food intake to an altered taste developed during treatment. This review summarizes what is known about taste and smell dysfunction in patients with undergoing chemotherapy as their main treatment modality. Self-reported taste and smell alterations are prevalent in upwards of 86% of cancer patients. There is some evidence for decreased taste sensitivity in cancer patients when assessed using common gustatory tests. In some patients, taste and smell alterations may continue well after their cancer treatment has been completed. Such disorders can increase distress, reduce appetite and contribute towards poor nutritional status in cancer patients. There remain no effective interventions for improving the appetite or nutritional intake of patients with cancer experiencing taste and smell changes. There is a lack of consistency in assessment methodologies for measuring taste and smell changes in cancer patients and we therefore recommend that future work use well-established methods. Research should also take into account the role of food hedonics, food flavor and texture in assessing the association between taste dysfunction, poor oral intake and malnutrition in cancer patients. Both adult and child cancer patients should be counselled on the potential impact taste and smell dysfunction can have on their appetite and oral intake.
Untapped Potential of Disordered Proteins in Current Druggable Human Proteome
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Current efforts in design and characterization of drugs often rely on the structure of their protein targets. However, a large fraction of proteins lack unique 3-D structures and exist as highly dynamic structural ensembles. These intrinsically disordered proteins are involved in pathogenesis of various human diseases and are highly abundant in eukaryotes. Based on a comprehensive analysis of the current druggable human proteome covering 12 drug classes and 18 major classes of drug targets we show a significant bias toward high structural coverage and low abundance of intrinsic disorder. We review reasons for this bias including widespread use of the structural information in various stages of drug development and characterization process and difficulty with attaining structures for the intrinsically disordered proteins. We also discuss future of intrinsically disordered proteins as drug targets. Given the overall high disorder content of the human proteome and current bias of the druggable human proteome toward structural proteins, it is inevitable that disordered proteins will have to raise up on the list of prospective drug targets. The protein disorder-assisted drug design can draw from current rational drug design techniques and would also need novel approaches that no longer rely on a unique protein structure.
Omega-3 Fatty Acids in the Management of Epilepsy
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids (PUFAs) with multiple double bonds. Linolenic and alpha-linolenic acids are omega-6 and omega-3 PUFAs, precursors for the synthesis of long-chain PUFAs (LC-PUFAs), such as arachidonic acid (omega-6 PUFA), and eicosapentaenoic and docosahexaenoic acids (omega-3 PUFAs). The three most important omega-3 fatty acids are alpha-linolenic, eicosapentaenoic and docosahexaenoic acids, which cannot be synthesized in enough amounts by the body, and therefore they must be supplied by the diet. Omega-3 fatty acids are essential for the correct functioning of the organism and participate in many physiological processes in the brain. Epilepsy is a common and heterogeneous chronic brain disorder characterized by recurrent epileptic seizures leading to neuropsychiatric disabilities. The prevalence of epilepsy is high achieving about 1% of the general population. There is evidence suggesting that omega-3 fatty acids may have neuroprotective and anticonvulsant effects and, accordingly, may have a potential use in the treatment of epilepsy. In the present review, the potential use of omega-3 fatty acids in the treatment of epilepsy, and the possible proposed mechanisms of action are discussed. The present article summarizes the recent knowledge of the potential protective role of dietary omega-3 fatty acids in epilepsy.
Impact of Splicing Factor Mutations on Pre-mRNA Splicing in the Myelodysplastic Syndromes
Today, 12 Ιουλίου 2016, 4:19:51 μμ
Splicing is an essential cellular process which is carried out by the spliceosome in order to remove the introns and join the exons present in pre-mRNA transcripts. A variety of spliceosomal mutations have been recently identified in the myelodysplastic syndromes (MDS), a heterogeneous group of hematopoietic stem cell malignancies, revealing a new leukemogenic pathway involving spliceosomal dysfunction. Splicing factor genes are the most frequently mutated genes found in MDS, with mutations occurring in more than half of all patients. The high mutation frequency in different components of the spliceosome in MDS indicates that aberrant splicing may be a common consequence of these mutations in this disorder. RNA sequencing studies using MDS patient bone marrow cells and different mouse models have identified several downstream targets of the splicing factor mutations. Aberrant splicing of these target genes may contribute to MDS pathogenesis, however functional studies are required in order to fully determine the effects of the aberrant isoforms on disease phenotype. Splicing inhibitors are currently being developed and may be used as therapeutic agents to target aberrant pre-mRNA splicing in MDS and other cancers with splicing factor mutations. The mouse models expressing splicing factor mutations may prove particularly valuable for pre-clinical testing of these drugs.
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