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Cellular and molecular mechanisms of motor neuron death in amyotrophic lateral sclerosis

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193769 Year: Pages: 190 DOI: 10.3389/978-2-88919-376-9 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2015-11-19 16:29:12
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Abstract

Amyotrophic lateral sclerosis (ALS), which was described since 1869 by Jean Martin Charcot, is a devastating neurodegenerative disease characterized by the selective and progressive loss of upper and lower motor neurons of the cerebral cortex, brainstem and the spinal cord. The cognitive process is not affected and is not merely the result of aging because may occur at young ages. The only known cause of the disease is associated with genetic mutations, mainly in the gene encoding superoxide dismutase 1 (familial ALS), whereas there is no known cause of the sporadic form of ALS (SALS), which comprises >90% of cases. Both ALS types develop similar histopathological and clinical characteristics, and there is no treatment or prevention of the disease. Because effective treatments for ALS, as for other neurodegenerative diseases, can only result from the knowledge of their cellular and molecular pathophysiological mechanisms, research on such mechanisms is essential. Although progress in neurochemical, physiological and clinical investigations in the last decades has identified several mechanisms that seem to be involved in the cell death process, such as glutamate-mediated excitotoxicity, alterations of inhibitory circuits, inflammatory events, axonal transport deficits, oxidative stress, mitochondrial dysfunction and energy failure, the understanding of the origin and temporal progress of the disease is still incomplete and insufficient. Clearly, there is a need of further experimental models and approaches to discern the importance of such mechanisms and to discover the factors that determine the selective death of motor neurons characteristic of ALS, in contrast to other neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Whereas studies in vitro in cell cultures, tissue slices or organotypic preparations can give useful information regarding cellular and molecular mechanisms, the experiments in living animal models obviously reflect more closely the situation in the human disease, provided that the symptoms and their development during time mimics as close as possible those of the human disease. It is necessary to correlate the experimental findings in vitro with those in vivo, as well as those obtained in genetic models with those in non-genetic models, aiming at designing and testing therapeutic strategies based on the results obtained.

The Role of Mitochondria, Oxidative Stress and Altered Calcium Homeostasis in Amyotrophic Lateral Sclerosis: From Current Developments in the Laboratory to Clinical Treatments

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889451463 Year: Pages: 336 DOI: 10.3389/978-2-88945-146-3 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2017-07-06 13:27:36
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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, devastating and fatal disease characterized by selective loss of upper and lower motor neurons of the cerebral cortex, brainstem, spinal cord and muscle atrophy. In spite of many years of research, the pathogenesis of ALS is still not well understood. ALS is a multifaceted genetic disease, in which genetic susceptibility to motor neuron death interacts with environmental factors and there is still no cure for this deleterious disease. At present, there is only one FDA approved drug, Riluzole which according to past studies only modestly slows the progression of the disease, and improves survival by up to three months. The suffering of the ALS patients, and their families is enormous and the economic burden is colossal. There is therefore a pressing need for new therapies. Different molecular pathways and pathological mechanisms have been implicated in ALS. According to past studies, altered calcium homeostasis, abnormal mitochondrial function, protein misfolding, axonal transport defects, excessive production of extracellular superoxide radicals, glutamate-mediated excitotoxicity, inflammatory events, and activation of oxidative stress pathways within the mitochondria and endoplasmic reticulum can act as major contributor that eventually leads to loss of connection between muscle and nerve ultimately resulting to ALS. However, the detailed molecular and cellular pathophysiological mechanisms and origin and temporal progression of the disease still remained elusive. Ongoing research and future advances will likely advance our improve understanding about various involved pathological mechanism ultimately leading to discoveries of new therapeutic cures. Importantly, clinical biomarkers of disease onset and progression are thus also urgently needed to support the development of the new therapeutic agents and novel preventive and curative strategies. Effective translation from pre-clinical to clinical studies will further require extensive knowledge regarding drug activity, bioavailability and efficacy in both the pre-clinical and clinical setting, and proof of biological activity in the target tissue. During the last decades, the development of new therapeutic molecules, advance neuroimaging tools, patient derived induced stem cells and new precision medicine approaches to study ALS has significantly improved our understanding of disease. In particular, new genetic tools, neuroimaging methods, cellular probes, biomarker study and molecular techniques that achieve high spatiotemporal resolution have revealed new details about the disease onset and its progression. In our effort to provide the interested reader, clinician and researchers a comprehensive summaries and new findings in this field of ALS research, hereby we have created this electronic book which comprises of twenty seven chapters having various reviews, perspective and original research articles. All these chapters and articles in this book not only summarize the cutting-edge techniques, approaches, cell and animal models to study ALS but also provide unprecedented coverage of the current developments and new hypothesis emerging in ALS research. Some examples are novel genetic and cell culture based models, mitochondria-mediated therapy, oxidative stress and ROS mechanism, development of stem cells and mechanism-based therapies as well as novel biomarkers for designing and testing effective therapeutic strategies that can benefit ALS patients who are at the earlier stages in the disease. I am extremely grateful to all the contributors to this book and want to thank them for their phenomenal efforts. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, devastating and fatal disease characterized by selective loss of upper and lower motor neurons of the cerebral cortex, brainstem, spinal cord and muscle atrophy. In spite of many years of research, the pathogenesis of ALS is still not well understood. ALS is a multifaceted genetic disease, in which genetic susceptibility to motor neuron death interacts with environmental factors and there is still no cure for this deleterious disease. At present, there is only one FDA approved drug, Riluzole which according to past studies only modestly slows the progression of the disease, and improves survival by up to three months. The suffering of the ALS patients, and their families is enormous and the economic burden is colossal. There is therefore a pressing need for new therapies. Different molecular pathways and pathological mechanisms have been implicated in ALS. According to past studies, altered calcium homeostasis, abnormal mitochondrial function, protein misfolding, axonal transport defects, excessive production of extracellular superoxide radicals, glutamate-mediated excitotoxicity, inflammatory events, and activation of oxidative stress pathways within the mitochondria and endoplasmic reticulum can act as major contributor that eventually leads to loss of connection between muscle and nerve ultimately resulting to ALS. However, the detailed molecular and cellular pathophysiological mechanisms and origin and temporal progression of the disease still remained elusive. Ongoing research and future advances will likely advance our improve understanding about various involved pathological mechanism ultimately leading to discoveries of new therapeutic cures. Importantly, clinical biomarkers of disease onset and progression are thus also urgently needed to support the development of the new therapeutic agents and novel preventive and curative strategies. Effective translation from pre-clinical to clinical studies will further require extensive knowledge regarding drug activity, bioavailability and efficacy in both the pre-clinical and clinical setting, and proof of biological activity in the target tissue. During the last decades, the development of new therapeutic molecules, advance neuroimaging tools, patient derived induced stem cells and new precision medicine approaches to study ALS has significantly improved our understanding of disease. In particular, new genetic tools, neuroimaging methods, cellular probes, biomarker study and molecular techniques that achieve high spatiotemporal resolution have revealed new details about the disease onset and its progression. In our effort to provide the interested reader, clinician and researchers a comprehensive summaries and new findings in this field of ALS research, hereby we have created this electronic book which comprises of twenty seven chapters having various reviews, perspective and original research articles. All these chapters and articles in this book not only summarize the cutting-edge techniques, approaches, cell and animal models to study ALS but also provide unprecedented coverage of the current developments and new hypothesis emerging in ALS research. Some examples are novel genetic and cell culture based models, mitochondria-mediated therapy, oxidative stress and ROS mechanism, development of stem cells and mechanism-based therapies as well as novel biomarkers for designing and testing effective therapeutic strategies that can benefit ALS patients who are at the earlier stages in the disease. I am extremely grateful to all the contributors to this book and want to thank them for their phenomenal efforts.

Regulatory microRNA

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ISBN: 9783038977681 9783038977698 Year: Pages: 348 DOI: 10.3390/books978-3-03897-769-8 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Science (General) --- Biology --- Genetics
Added to DOAB on : 2019-04-25 16:37:17
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Abstract

This book includes updated information about microRNA regulation, for example, in the fields of circular RNAs, multiomics analysis, biomarkers and oncogenes. The variety of topics included in this book reaffirms the extent to which microRNA regulation affects biological processes. Although microRNAs are not translated to proteins, their importance for biological processes is not less than proteins. An understanding of their roles in various biological processes is critical to understanding gene function in these biological processes. Although non-coding RNAs other than microRNAs have recently come under investigation, microRNA still remains the front runner as the subject of genetic and biological studies. In reading the collection of papers, readers can grasp the most updated information regarding microRNA regulation, which will continue to be an important topic in genetics and biology.

Keywords

tensor decomposition --- miRNA transfection --- sequence-nonspecific off-target regulation --- extracellular vesicles --- cancer --- therapeutics --- miRNA --- virus --- host --- Cross-Kingdom --- target prediction --- microRNAs --- autophagy --- mitophagy --- cardiac diseases --- biomarker --- calf --- Ileum --- miRNA-mRNA integration --- miRNA sequencing --- growth --- development --- microRNA --- myelodysplastic syndromes --- acute myeloid leukemia --- azacitidine --- 14q32 --- MEG3 --- autophagy regulator --- transcriptional factor --- non-coding RNA --- regulatory network --- RWR algorithm --- circular RNA --- circFGFR2 --- FGFR2 --- miR-133a-5p --- miR-29b-1-5p --- skeletal muscle --- proliferation --- differentiation --- breast cancer --- CAFs --- estrogens --- GPER --- miR-338-3p --- c-Fos --- Cyclin D1 --- amyotrophic lateral sclerosis (ALS) --- biomarker --- microRNA --- cerebrospinal fluid (CSF) --- muscle biopsy --- circulating miRNAs --- RNA interference --- small interfering RNA --- microRNA --- oncolytic virotherapy --- conditionally replicating adenovirus (CRAd) --- biomarker --- gene --- microRNA --- parkinson’s disease --- miRNA --- bioinformatic analysis --- ischemic stroke --- miRNA-gene target interaction --- network --- biomarker --- diagnosis --- prognosis --- microRNAs --- epigenetic biomarker --- sepsis --- inflammation --- Teleostei --- embryogenesis --- tissue-enriched miRNAs --- post-transcriptional gene regulation --- miRNA expression and regulation --- passenger miRNA --- biomarker --- vascular injury --- smooth muscle cells --- porcine vein graft and stent models --- bone angiogenesis --- osteogenesis --- angiogenic-osteogenic coupling --- microRNAs --- bone regeneration --- bone formation --- bone tissue-engineering --- angiomiRs --- osteomiRs --- hypoxamiRs --- circular RNA --- circHIPK3 --- microRNA --- miR-30a-3p --- skeletal muscle --- proliferation --- differentiation

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