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Microglial Polarization in the Pathogenesis and Therapeutics of Neurodegenerative Diseases

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889455256 Year: Pages: 327 DOI: 10.3389/978-2-88945-525-6 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2019-01-23 14:53:42
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Abstract

Microglia-mediated neuroinflammation is one of the shared prominent hallmarks among various forms of neurodegeneration. Depending on the milieu in which microglia become activated, the polarization of microglia shows to be heterogeneous with diverse functional phenotypes that range from pro-inflammatory phenotypes to immunosuppressive phenotypes. Therefore, targeting microglial polarization holds great promise for the treatment of neurodegeneration.This eBook focuses on the potential mechanisms of microglial polarization that are critically associated with a broad spectrum of neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Traumatic brain injury (TBI), glaucomatous neurodegeneration and prion diseases. This topic also involves the therapeutic targeting of microglial polarization by nutritional and pharmacological modulators. Moreover, this topic describes advanced technologies employed for studying microglia. Age-related changes in microglia functions are also discussed.Overall, this eBook provides comprehensive understandings of microglial polarization in the course of neurodegeneration, linking with aging-related microglial alterations and technologies developed for microglial studies. Hopefully, it will also give comprehensive insights into various aspects of therapeutic treatment for neurodegeneration, through targeting microglial polarization.

M1/M2 Macrophages: The Arginine Fork in the Road to Health and Disease

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194995 Year: Pages: 280 DOI: 10.3389/978-2-88919-499-5 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-03 13:02:24
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Abstract

Macrophages have unique and diverse functions necessary for survival. And, in humans (and other species), they are the most abundant leukocytes in tissues. The Innate functions of macrophages that are best known are their unusual ability to either "Kill" or "Repair". Since killing is a destructive process and repair is a constructive process, it was stupefying how one cell could exhibit these 2 polar – opposite functions. However, in the late 1980’s, it was shown that macrophages have a unique ability to enzymatically metabolize Arginine to Nitric Oxide (NO, a gaseous non – specific killer molecule) or to Ornithine (a precursor of polyamines and collagen for repair). The dual Arginine metabolic capacity of macrophages provided a functional explanation for their ability to kill or repair. Macrophages predominantly producing NO are called M1 and those producing Ornithine are called M2. M1 and M2 – dominant responses occur in lower vertebrates, and in T cell deficient vertebrates being directly driven by Damage and Pathogen Associated Molecular Patterns (DAMP and PAMP). Thus, M1 and M2 are Innate responses that protect the host without Adaptive Immunity. In turn, M1/M2 is supplanting previous models in which T cells were necessary to "activate" or "alternatively activate" macrophages (the Th1/Th2 paradigm). M1 and M2 macrophages were named such because of the additional key findings that these macrophages stimulate Th1 and Th2 – like responses, respectively. So, in addition to their unique ability to kill or repair, macrophages also govern Adaptive Immunity. All of the foregoing would be less important if M1 or M2 – dominant responses were not observed in disease. But, they are. The best example to date is the predominance of M2 macrophages in human tumors where they act like wound repair macrophages and actively promote growth. More generally, humans have become M2 – dominant because sanitation, antibiotics and vaccines have lessened M1 responses. And, M2 dominance seems the cause of ever - increasing allergies in developed countries. Obesity represents a new and different circumstance. Surfeit energy (e.g., lipoproteins) causes monocytes to become M1 dominant in the vessel walls causing plaques. Because M1 or M2 dominant responses are clearly causative in many modern diseases, there is great potential in developing the means to selectively stimulate (or inhibit) either M1 or M2 responses to kill or repair, or to stimulate Th1 or Th2 responses, depending on the circumstance. The contributions here are meant to describe diseases of M1 or M2 dominance, and promising new methodologies to modulate the fungible metabolic machinery of macrophages for better health.

Keywords

macrophage --- innate immunity --- M1 --- M2 --- wound --- Cancer --- Infection --- Atherosclerosis

Polyamine Metabolism in Disease and Polyamine-Targeted Therapies

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ISBN: 9783039211524 9783039211531 Year: Pages: 240 DOI: 10.3390/books978-3-03921-153-1 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Science (General) --- Biology
Added to DOAB on : 2019-12-09 11:49:15
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Abstract

Polyamines are ubiquitous polycations essential for all cellular life. The most common polyamines in eukaryotes, spermine, spermidine, and putrescine, exist in millimolar intracellular concentrations that are tightly regulated through biosynthesis, catabolism, and transport. Polyamines interact with, and regulate, negatively charged macromolecules, including nucleic acids, proteins, and ion channels. Accordingly, alterations in polyamine metabolism affect cellular proliferation and survival through changes in gene expression and transcription, translation, autophagy, oxidative stress, and apoptosis. Dysregulation of these multifaceted polyamine functions contribute to multiple disease processes, thus their metabolism and function have been targeted for preventive or therapeutic intervention. The correlation between elevated polyamine levels and cancer is well established, and ornithine decarboxylase, the rate-limiting biosynthetic enzyme in the production of putrescine, is a bona fide transcriptional target of the Myc oncogene. Furthermore, induced polyamine catabolism contributes to carcinogenesis that is associated with certain forms of chronic infection and/or inflammation through the production of reactive oxygen species. These and other characteristics specific to cancer cells have led to the development of polyamine-based agents and inhibitors aimed at exploiting the polyamine metabolic pathway for chemotherapeutic and chemopreventive benefit. In addition to cancer, polyamines are involved in the pathologies of neurodegenerative diseases including Alzheimer’s and Parkinson’s, parasitic and infectious diseases, wound healing, ischemia/reperfusion injuries, and certain age-related conditions, as polyamines are known to decrease with age. As in cancer, polyamine-based therapies for these conditions are an area of active investigation. With recent advances in immunotherapy, interest has increased regarding polyamine-associated modulation of immune responses, as well as potential immunoregulation of polyamine metabolism, the results of which could have relevance to multiple disease processes. The goal of this Special Issue of Medical Sciences is to present the most recent advances in polyamine research as it relates to health, disease, and/or therapy.

Keywords

polyamine transport inhibitor --- Drosophila imaginal discs --- difluoromethylorthinine --- DFMO --- polyamine --- cancer --- metabolism --- difluoromethylornithine --- polyamine transport inhibitor --- pancreatic ductal adenocarcinoma --- curcumin --- diferuloylmethane --- ornithine decarboxylase --- polyamine --- NF-?B --- chemoprevention --- carcinogenesis --- polyphenol --- ornithine decarboxylase --- polyamines --- untranslated region --- polyamines --- ?-difluoromethylornithine --- polyamine transport system --- melanoma --- mutant BRAF --- spermine --- spermidine --- putrescine --- polyamine metabolism --- mast cells --- eosinophils --- neutrophils --- M2 macrophages --- airway smooth muscle cells --- Streptococcus pneumoniae --- polyamines --- pneumococcal pneumonia --- proteomics --- capsule --- complementation --- metabolism --- cadaverine --- polyamines --- ornithine decarboxylase --- difluoromethylornithine --- eflornithine --- DFMO --- African sleeping sickness --- hirsutism --- colorectal cancer --- neuroblastoma --- aging --- atrophy --- autophagy --- oxidative stress --- polyamines --- skeletal muscle --- spermidine --- spermine oxidase --- transgenic mouse --- immunity --- T-lymphocytes --- B-lymphocytes --- tumor immunity --- metabolism --- epigenetics --- autoimmunity --- polyamines --- ornithine decarboxylase --- polyamine analogs --- spermidine/spermine N1-acetyl transferase --- spermine oxidase --- bis(ethyl)polyamine analogs --- breast cancer --- MCF-7 cells --- transgenic mice --- polyamines --- MYC --- protein synthesis in cancer --- neuroblastoma --- protein expression --- antizyme 1 --- ornithine decarboxylase --- CRISPR --- human embryonic kidney 293 (HEK293) --- cell differentiation --- DFMO --- ornithine decarboxylase --- osteosarcoma --- polyamines --- polyamines --- polyamine metabolism --- antizyme --- antizyme inhibitors --- ornithine decarboxylase --- Snyder-Robinson Syndrome --- spermine synthase --- X-linked intellectual disability --- polyamine transport --- spermidine --- spermine --- transglutaminase

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