Novel Compounds As Potential Alzheimer S Disease Therapeutics And Inhibitors Of The Nlrp3 Inflammasome
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Novel Compounds As Potential Alzheimer S Disease Therapeutics And Inhibitors Of The Nlrp3 Inflammasome
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Author : Jeremy E. Chojnacki
language : en
Publisher:
Release Date : 2014
Novel Compounds As Potential Alzheimer S Disease Therapeutics And Inhibitors Of The Nlrp3 Inflammasome written by Jeremy E. Chojnacki and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014 with categories.
Alzheimer's disease is a devastating neurodegenerative disorder and the leading cause of dementia. The disease manifests via several pathologies including neuroinflammation, oxidative stress, metal ion dyshomeostasis, and cell death. To address the multifaceted nature of this disorder, the design of several diverse compounds, targeting many pathological effects, was generated. First, a series of compounds based on curcumin and diosgenin were synthesized following the bivalent design strategy. Two compounds were discovered to have neuroprotective ability, anti-oxidative function, and anti-A[beta] oligomerization (A[beta]O) properties. A second set of molecules was also designed, wherein a hybrid compound strategy was utilized. Three hybrids were to shown to protect MC65 cells from A[beta]-induced toxicity and to have significant anti-oxidative activity. Mechanistic studies propose that protection is through disruption of interactions between A[beta]Os and partner proteins. Furthermore, one hybrid was also shown to be able to pass the BBB. Lastly, studies of glyburide, an anti-diabetic medication, have shown an off-target anti-inflammatory effect specific for the NLRP3 inflammasome, which has been implicated in AD development. Therefore, a series of glyburide analogs were synthesized and characterized. One analog was able to successfully inhibit the NLRP3 inflammasome and reduce IL-1[beta] expression without affecting blood glucose. In vivo studies demonstrated an ability to prevent or ameliorate adverse inflammation-related outcomes in murine inflammatory models. Altogether, these investigations have yielded three novel series of compounds, all capable of modifying Alzheimer's disease pathology. These results warrant future investigations into the development, optimization, and characterization of these analogs as potential treatments for Alzheimer's disease.
The Development Of Novel Inhibitors Of The Nlrp3 Inflammasome
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Author : Jacob W. Fulp
language : en
Publisher:
Release Date : 2018
The Development Of Novel Inhibitors Of The Nlrp3 Inflammasome written by Jacob W. Fulp and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
Inflammasomes are intracellular multimeric protein complexes that regulate inflammation by controlling the maturation of cytokines, interleukin-1[beta] (IL-1[beta]) and interleukin-18 (IL-18). Additionally, activation of these inflammasome complexes has been implicated in an inflammatory form of death known as proptosis. Of the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLPP3) inflammasome, is the most elucidated. Under physiological conditions, NLRP3-mediated inflammation promotes healing and the elimination of cellular debris and pathogens. However, the dysregulation of IL-1[beta], IL-18 and pyroptosis are instrumental in the development of multiple pathologies. Furthermore, studies suggest that the NLRP3 inflammasome mediates detrimental neuroinflammation and contributes significantly to the development of several neurodegenerative diseases. This includes Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis. Novel NLRP3 inflammasome inhibitors (NLRP3Is) are needed as pharmacological tools to complement ongoing molecular and genetic studies to aid in defining the roles of NLRP3 in neurological diseases. Development of such inhibitors also has significant translational potential. In order to develop novel small molecule inhibitors of the NLRP3 inflammasome, we conducted an in-depth structure-activity-relationship study of a known NLRP3 inhibitor. Two new lead compounds, 54 and 64, were identified. These compounds were potent and selective NLRP3 inhibitors in both in BMDMs and J774A.1 cell-lines. Importantly, a study utilizing mice challenged with LPS demonstrated that both of these compounds have in vivo activity. Collectively, these results strongly encourage further development of new analogs based on this promising chemical scaffold.
Development Of Small Molecule Neuroprotectants
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Author : Ashley Boice
language : en
Publisher:
Release Date : 2018
Development Of Small Molecule Neuroprotectants written by Ashley Boice and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
Neurodegenerative diseases are a class of conditions that lead to progressive atrophy of different parts of the central nervous system (CNS). These diseases lead to devastating clinical outcomes to patients and give rise to an enormous socio-economical burden on society. 1 One commonality among some of the most well-known neurodegenerative disorders, e.g. Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (M.S.), is neuroinflammation. 2−4 Neuroinflammation stems from interactions of the innate immune system with toxins and insults to the central nervous system. In the case of irremovable or chronic insults and toxins, this leads to chronic damaging inflammation that hastens neuronal degeneration and exacerbates disease pathology. 5−6 Recently, inflammasomes of the innate immune system have been indicated in playing essential roles in the observed inflammatory responses. The most studied inflammasome is the nod-like receptor pyrin containing 3 (NLRP3) inflammasome. 7−9 Recently our research group has successfully developed sulfonamide-based small molecule inhibitors of the NLRP3 inflammasome, such as JC-21 and JC-171, as potential therapeutics for AD and MS. Our studies established that JC-21 is a selective inhibitor of the NLRP3 inflammasome. 10−11 Structural modifications led to the development of JC-171 with improved pharmacokinetic properties. More importantly, our studies demonstrated the in vivo activity of JC-171 to effectively ameliorate the experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. 12 Our data also strongly suggested that inhibitors based on this chemical scaffold may directly target the NLRP3 inflammasome.10−12 In this dissertation, we conducted biophysical, biochemical, and modeling studies to further elucidate the mechanistic information of these compounds as inhibitors of the NLRP3 inflammasome. In order to conduct further mechanistic studies, the NLRP3 protein was produced via transfection of HEK 293 cells with a modified plasmid of full-length human NLRP3 protein. 13 Furthermore, LC-MS studies were conducted to confirm the blood-brain barrier penetration (BBB) of JC-171. Our studies established that JC-171 directly binds to the NLRP3 protein. The results also suggested that JC-171 may bind to the NACHT domain of NLRP3 while in a site that is distinct from the ATP binding site. This notion is supported by the fact that our compounds do not interfere with the ATPase activity of NLRP3. Docking studies of JC-171 to the homology model of the NACHT domain of NLRP3 also supported this assertion by showing the interaction of JC-171 with residues that are not overlapping with the ATP binding pocket. BBB penetration studies in combination with LC-MS analysis confirmed that JC-171 shows better BBB penetration when compared to MCC950. Collectively, our results strongly support that our compounds function as NLRP3 inflammasome inhibitors by directly binding to the NLRP3 protein, a novel and distinct mechanism of action when compared to the known inhibitors that target the NLRP3 inflammasome pathway. These results strongly encourage further development of such inhibitors as potential therapeutics for neurodegenerative diseases.
The Inflammasome
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Author : Christine M. De Nardo
language : en
Publisher: Humana
Release Date : 2013-07-13
The Inflammasome written by Christine M. De Nardo and has been published by Humana this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013-07-13 with Medical categories.
This Methods in Molecular Biology book offers methods for studying inflammasome function, including generation of inflammasome stimuli, monitoring of caspase-1 activity and processing, activation of IL-1β cytokines, plus lab protocols, material lists and tips.
Pre Clinical Models
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Author : Paul C. Guest
language : en
Publisher: Humana Press
Release Date : 2019-02-04
Pre Clinical Models written by Paul C. Guest and has been published by Humana Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019-02-04 with Medical categories.
This volume details reviews and protocols on the development and analysis of both cellular and animal-based pre-clinical models in a number of medical areas, including metabolic disorders, longevity, cancer, heart disease and psychiatric disorders. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Pre-Clinical Models: Techniques and Protocols aims to provide methods that describe the context of specific disease or therapeutic areas.
Novel Therapeutic Mechanisms Targeting Neuro Immune Regulation Of Neurological Disorders
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Author : Xin Luo
language : en
Publisher: Frontiers Media SA
Release Date : 2023-01-04
Novel Therapeutic Mechanisms Targeting Neuro Immune Regulation Of Neurological Disorders written by Xin Luo and has been published by Frontiers Media SA this book supported file pdf, txt, epub, kindle and other format this book has been release on 2023-01-04 with Science categories.
Motor Neuron Disease In Adults
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Author : Mark B. Bromberg
language : en
Publisher: Contemporary Neurology
Release Date : 2014-10-28
Motor Neuron Disease In Adults written by Mark B. Bromberg and has been published by Contemporary Neurology this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014-10-28 with Medical categories.
'Motor Neuron Disease in Adults' reviews new information from 1998 as it applies to all aspects of motor neuron disease. Articles included use evidence-based methods to ensure that the new information is solid and advances the topic. The book can be used by anyone who provides any type of care to ALS patients.
Translocator Protein Tspo
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Author : Giovanni Natile
language : en
Publisher: MDPI
Release Date : 2018-03-05
Translocator Protein Tspo written by Giovanni Natile and has been published by MDPI this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018-03-05 with Electronic books categories.
This book is a printed edition of the Special Issue "Translocator Protein (TSPO)" that was published in IJMS
Neuroprotection
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Author : Matilde Otero-Losada
language : en
Publisher: BoD – Books on Demand
Release Date : 2020-11-26
Neuroprotection written by Matilde Otero-Losada and has been published by BoD – Books on Demand this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020-11-26 with Medical categories.
Neurological disease affects nearly 25%–30% of the world’s population, exerting enormous financial strain on the healthcare system. Estimated current costs are around $800 annual billion, and this number is expected to increase exponentially as the global population ages. As such, new and alternative neuroprotective strategies are urgently needed. This book examines some of the most promising approaches in neuroprotection as well as discusses current goals and prospects. Organized into three sections, chapters cover such topics as the use of cannabinoids, medicinal plants, and essential oils in Alzheimer’s and Parkinson’s; protein misfolding and the neuroprotective potential of vitamin E in cerebral ischemia; and potential new neurological treatments and their mechanisms of action.
Molecular Neurology
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Author : Stephen Waxman
language : en
Publisher: Elsevier
Release Date : 2010-07-26
Molecular Neurology written by Stephen Waxman and has been published by Elsevier this book supported file pdf, txt, epub, kindle and other format this book has been release on 2010-07-26 with Medical categories.
Why a book on molecular neurology? Molecular neuroscience is advancing at a spectacular rate. As it does so, it is revealing important clues to the pathogenesis and pathophysiology of neurological diseases, and to the therapeutic targets that they present. Medicines work by targeting molecules. The more specific the targeting, the more specific the actions, and the fewer the side effects. Molecular Neurology highlights, for graduate and MD-PhD students, research fellows and research-oriented clinical fellows, and researchers in the neurosciences and other biomedical sciences, the principles underlying molecular medicine as related to neurology. Written by internationally recognized experts, this well-illustrated and well-referenced book presents the most up-to-date principles and disease examples relevant to molecular neurology, and reviews the concepts, strategies, and latest progress in this field. This book will interest anyone studying the molecular basis of neurology, or developing new therapies in neurology. Describes the newest molecular aspects of neurological disorders Provides an introduction to neurological disorders for basic scientists Updates clinicians and clinical researchers on the most recent developments