scholarly journals Redox Homeostasis and Prospects for Therapeutic Targeting in Neurodegenerative Disorders

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Musbau Adewumi Akanji ◽  
Damilare Emmanuel Rotimi ◽  
Tobiloba Christiana Elebiyo ◽  
Oluwakemi Josephine Awakan ◽  
Oluyomi Stephen Adeyemi
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Redox Homeostasis ◽  
Reactive Species ◽  
Cellular Damage ◽  
Cellular Mechanisms ◽  
Cellular Redox ◽  
Redox Imbalance ◽  
Cellular Processes ◽  
The Brain

Reactive species, such as those of oxygen, nitrogen, and sulfur, are considered part of normal cellular metabolism and play significant roles that can impact several signaling processes in ways that lead to either cellular sustenance, protection, or damage. Cellular redox processes involve a balance in the production of reactive species (RS) and their removal because redox imbalance may facilitate oxidative damage. Physiologically, redox homeostasis is essential for the maintenance of many cellular processes. RS may serve as signaling molecules or cause oxidative cellular damage depending on the delicate equilibrium between RS production and their efficient removal through the use of enzymatic or nonenzymatic cellular mechanisms. Moreover, accumulating evidence suggests that redox imbalance plays a significant role in the progression of several neurodegenerative diseases. For example, studies have shown that redox imbalance in the brain mediates neurodegeneration and alters normal cytoprotective responses to stress. Therefore, this review describes redox homeostasis in neurodegenerative diseases with a focus on Alzheimer’s and Parkinson’s disease. A clearer understanding of the redox-regulated processes in neurodegenerative disorders may afford opportunities for newer therapeutic strategies.

scholarly journals Cerebral sterile inflammation in neurodegenerative diseases

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Kento Otani ◽  
Takashi Shichita
Keyword(s):  
Immune Responses ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Therapeutic Agents ◽  
Sterile Inflammation ◽  
Cellular Damage ◽  
Cellular Mechanisms ◽  
Abnormal Accumulation ◽  
The Brain ◽  
Lateral Sclerosis

AbstractTherapeutic strategies for regulating neuroinflammation are expected in the development of novel therapeutic agents to prevent the progression of central nervous system (CNS) pathologies. An understanding of the detailed molecular and cellular mechanisms of neuroinflammation in each CNS disease is necessary for the development of therapeutics. Since the brain is a sterile organ, neuroinflammation in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) is triggered by cerebral cellular damage or the abnormal accumulation of inflammatogenic molecules in CNS tissue through the activation of innate and acquired immunity. Inflammation and CNS pathologies worsen each other through various cellular and molecular mechanisms, such as oxidative stress or the accumulation of inflammatogenic molecules induced in the damaged CNS tissue. In this review, we summarize the recent evidence regarding sterile immune responses in neurodegenerative diseases.

scholarly journals Mitochondria and Reactive Oxygen Species Contribute to Neurogenic Hypertension

Physiology ◽  
2017 ◽  
Vol 32 (4) ◽  
pp. 308-321 ◽  
Author(s):  
Samuel H.H. Chan ◽  
Julie Y.H. Chan
Keyword(s):  
Redox Homeostasis ◽  
Neural Mechanism ◽  
High Energy ◽  
Primary Role ◽  
Brain Areas ◽  
Neurogenic Hypertension ◽  
Cellular Redox ◽  
Cellular Processes ◽  
Future Challenges ◽  
The Brain

Beyond its primary role as fuel generators, mitochondria are engaged in a variety of cellular processes, including redox homeostasis. Mitochondrial dysfunction, therefore, may have a profound impact on high-energy-demanding organs such as the brain. Here, we review the roles of mitochondrial biogenesis and bioenergetics, and their associated signaling in cellular redox homeostasis, and illustrate their contributions to the oxidative stress-related neural mechanism of hypertension, focusing on specific brain areas that are involved in the generation or modulation of sympathetic outflows to the cardiovascular system. We also highlight future challenges of research on mitochondrial physiology and pathophysiology.

scholarly journals Cellular Mechanisms of Melatonin: Insight from Neurodegenerative Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1158 ◽  
Author(s):  
Dongmei Chen ◽  
Tao Zhang ◽  
Tae Ho Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cellular Mechanisms ◽  
Wide Range ◽  
Public Health Challenge ◽  
Cumulative Evidence ◽  
The Brain ◽  
Lateral Sclerosis

Neurodegenerative diseases are the second most common cause of death and characterized by progressive impairments in movement or mental functioning in the central or peripheral nervous system. The prevention of neurodegenerative disorders has become an emerging public health challenge for our society. Melatonin, a pineal hormone, has various physiological functions in the brain, including regulating circadian rhythms, clearing free radicals, inhibiting biomolecular oxidation, and suppressing neuroinflammation. Cumulative evidence indicates that melatonin has a wide range of neuroprotective roles by regulating pathophysiological mechanisms and signaling pathways. Moreover, melatonin levels are decreased in patients with neurodegenerative diseases. In this review, we summarize current knowledge on the regulation, molecular mechanisms and biological functions of melatonin in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis. We also discuss the clinical application of melatonin in neurodegenerative disorders. This information will lead to a better understanding of the regulation of melatonin in the brain and provide therapeutic options for the treatment of various neurodegenerative diseases.

scholarly journals A Destruction Model of the Vascular and Lymphatic Systems in the Emergence of Psychiatric Symptoms

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 34
Author(s):  
Kohei Segawa ◽  
Yukari Blumenthal ◽  
Yuki Yamawaki ◽  
Gen Ohtsuki
Keyword(s):  
Neurodegenerative Diseases ◽  
Lymphatic System ◽  
Psychiatric Symptoms ◽  
Neurological Diseases ◽  
Immune Surveillance ◽  
Brain Network ◽  
Cellular Mechanisms ◽  
Postmortem Brains ◽  
New Interpretation ◽  
The Brain

The lymphatic system is important for antigen presentation and immune surveillance. The lymphatic system in the brain was originally introduced by Giovanni Mascagni in 1787, while the rediscovery of it by Jonathan Kipnis and Kari Kustaa Alitalo now opens the door for a new interpretation of neurological diseases and therapeutic applications. The glymphatic system for the exchanges of cerebrospinal fluid (CSF) and interstitial fluid (ISF) is associated with the blood-brain barrier (BBB), which is involved in the maintenance of immune privilege and homeostasis in the brain. Recent notions from studies of postmortem brains and clinical studies of neurodegenerative diseases, infection, and cerebral hemorrhage, implied that the breakdown of those barrier systems and infiltration of activated immune cells disrupt the function of both neurons and glia in the parenchyma (e.g., modulation of neurophysiological properties and maturation of myelination), which causes the abnormality in the functional connectivity of the entire brain network. Due to the vulnerability, such dysfunction may occur in developing brains as well as in senile or neurodegenerative diseases and may raise the risk of emergence of psychosis symptoms. Here, we introduce this hypothesis with a series of studies and cellular mechanisms.

scholarly journals Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

2020 ◽  
Author(s):  
Carla Umansky ◽  
Agustín Morellato ◽  
Marco Scheidegger ◽  
Matthias Rieckher ◽  
Manuela R. Martinefski ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Redox Homeostasis ◽  
Thiol Group ◽  
Cellular Damage ◽  
Repair Pathway ◽  
Cellular Redox ◽  
Redox Active ◽  
Development And Aging

AbstractFormaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

scholarly journals S-Adenosylmethionine Deficiency and Brain Accumulation of S-Adenosylhomocysteine in Thioacetamide-Induced Acute Liver Failure

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2135
Author(s):  
Anna Maria Czarnecka ◽  
Wojciech Hilgier ◽  
Magdalena Zielińska
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Redox Homeostasis ◽  
Cerebral Function ◽  
Total Glutathione ◽  
Cellular Redox ◽  
Therapeutic Value ◽  
Transsulfuration Pathway ◽  
Subsequent Hydrolysis ◽  
The Brain

Background: Acute liver failure (ALF) impairs cerebral function and induces hepatic encephalopathy (HE) due to the accumulation of neurotoxic and neuroactive substances in the brain. Cerebral oxidative stress (OS), under control of the glutathione-based defense system, contributes to the HE pathogenesis. Glutathione synthesis is regulated by cysteine synthesized from homocysteine via the transsulfuration pathway present in the brain. The transsulfuration-transmethylation interdependence is controlled by a methyl group donor, S-adenosylmethionine (AdoMet) conversion to S-adenosylhomocysteine (AdoHcy), whose removal by subsequent hydrolysis to homocysteine counteract AdoHcy accumulation-induced OS and excitotoxicity. Methods: Rats received three consecutive intraperitoneal injections of thioacetamide (TAA) at 24 h intervals. We measured AdoMet and AdoHcy concentrations by HPLC-FD, glutathione (GSH/GSSG) ratio (Quantification kit). Results: AdoMet/AdoHcy ratio was reduced in the brain but not in the liver. The total glutathione level and GSH/GSSG ratio, decreased in TAA rats, were restored by AdoMet treatment. Conclusion: Data indicate that disturbance of redox homeostasis caused by AdoHcy in the TAA rat brain may represent a deleterious mechanism of brain damage in HE. The correction of the GSH/GSSG ratio following AdoMet administration indicates its therapeutic value in maintaining cellular redox potential in the cerebral cortex of ALF rats.

scholarly journals Glutathione in the Brain

2021 ◽  
Vol 22 (9) ◽  
pp. 5010
Author(s):  
Koji Aoyama
Keyword(s):  
Neurodegenerative Diseases ◽  
Regulatory Mechanism ◽  
Excitatory Amino Acid ◽  
Redox Homeostasis ◽  
Disease Onset ◽  
Glutamate Transporter ◽  
Antioxidant Defense System ◽  
Common Finding ◽  
Potential Therapeutic Application ◽  
The Brain

Glutathione (GSH) is the most abundant non-protein thiol, and plays crucial roles in the antioxidant defense system and the maintenance of redox homeostasis in neurons. GSH depletion in the brain is a common finding in patients with neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and can cause neurodegeneration prior to disease onset. Excitatory amino acid carrier 1 (EAAC1), a sodium-dependent glutamate/cysteine transporter that is selectively present in neurons, plays a central role in the regulation of neuronal GSH production. The expression of EAAC1 is posttranslationally controlled by the glutamate transporter-associated protein 3–18 (GTRAP3-18) or miR-96-5p in neurons. The regulatory mechanism of neuronal GSH production mediated by EAAC1 may be a new target in therapeutic strategies for these neurodegenerative diseases. This review describes the regulatory mechanism of neuronal GSH production and its potential therapeutic application in the treatment of neurodegenerative diseases.

scholarly journals Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar Maurya ◽  
Neetu Bhattacharya ◽  
Suman Mishra ◽  
Amit Bhattacharya ◽  
Pratibha Banerjee ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Neuroprotective Effect ◽  
Inhibitory Effect ◽  
Dual Function ◽  
Redox Imbalance ◽  
The Brain

Microglia, a type of innate immune cell of the brain, regulates neurogenesis, immunological surveillance, redox imbalance, cognitive and behavioral changes under normal and pathological conditions like Alzheimer’s, Parkinson’s, Multiple sclerosis and traumatic brain injury. Microglia produces a wide variety of cytokines to maintain homeostasis. It also participates in synaptic pruning and regulation of neurons overproduction by phagocytosis of neural precursor cells. The phenotypes of microglia are regulated by the local microenvironment of neurons and astrocytes via interaction with both soluble and membrane-bound mediators. In case of neuron degeneration as observed in acute or chronic neurodegenerative diseases, microglia gets released from the inhibitory effect of neurons and astrocytes, showing activated phenotype either of its dual function. Microglia shows neuroprotective effect by secreting growths factors to heal neurons and clears cell debris through phagocytosis in case of a moderate stimulus. But the same microglia starts releasing pro-inflammatory cytokines like TNF-α, IFN-γ, reactive oxygen species (ROS), and nitric oxide (NO), increasing neuroinflammation and redox imbalance in the brain under chronic signals. Therefore, pharmacological targeting of microglia would be a promising strategy in the regulation of neuroinflammation, redox imbalance and oxidative stress in neurodegenerative diseases. Some studies present potentials of natural products like curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane to suppress activation of microglia. These natural products have also been proposed as effective therapeutics to regulate the progression of neurodegenerative diseases. The present review article intends to explain the molecular mechanisms and functions of microglia and molecular dynamics of microglia specific genes and proteins like Iba1 and Tmem119 in neurodegeneration. The possible interventions by curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane on microglia specific protein Iba1 suggest possibility of natural products mediated regulation of microglia phenotypes and its functions to control redox imbalance and neuroinflammation in management of Alzheimer’s, Parkinson’s and Multiple Sclerosis for microglia-mediated therapeutics.

scholarly journals Understanding Cellular Redox Homeostasis: A Challenge for Precision Medicine

2021 ◽  
Vol 23 (1) ◽  
pp. 106
Author(s):  
Verena Tretter ◽  
Beatrix Hochreiter ◽  
Marie Louise Zach ◽  
Katharina Krenn ◽  
Klaus Ulrich Klein
Keyword(s):  
Oxidative Stress ◽  
Precision Medicine ◽  
Redox Homeostasis ◽  
Reactive Species ◽  
Scientific Field ◽  
Redox Systems ◽  
Cellular Redox ◽  
Redox Biology ◽  
Living Organisms ◽  
Large Repertoire

Living organisms use a large repertoire of anabolic and catabolic reactions to maintain their physiological body functions, many of which include oxidation and reduction of substrates. The scientific field of redox biology tries to understand how redox homeostasis is regulated and maintained and which mechanisms are derailed in diverse pathological developments of diseases, where oxidative or reductive stress is an issue. The term “oxidative stress” is defined as an imbalance between the generation of oxidants and the local antioxidative defense. Key mediators of oxidative stress are reactive species derived from oxygen, nitrogen, and sulfur that are signal factors at physiological concentrations but can damage cellular macromolecules when they accumulate. However, therapeutical targeting of oxidative stress in disease has proven more difficult than previously expected. Major reasons for this are the very delicate cellular redox systems that differ in the subcellular compartments with regard to their concentrations and depending on the physiological or pathological status of cells and organelles (i.e., circadian rhythm, cell cycle, metabolic need, disease stadium). As reactive species are used as signaling molecules, non-targeted broad-spectrum antioxidants in many cases will fail their therapeutic aim. Precision medicine is called to remedy the situation.

scholarly journals POTENTIAL USE OF SULFORAPHANE AS A NEUROPROTECTOR

2021 ◽  
pp. 125-136
Author(s):  
S. A. Tsiumpala ◽  
K. M. Starchevska ◽  
V. I. Lushchak
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Old Age ◽  
Neurodegenerative Disorders ◽  
Therapeutic Potential ◽  
The Body ◽  
Biologically Active ◽  
Inflammatory Processes ◽  
The Brain ◽  
Potential Use

Introduction. Under normal conditions, oxidative stress and proinflammatory processes are tightly controlled. However, during neuroinflammation and overproduction of reactive oxygen species (ROS), homeostasis is disrup­ted, which may lead to development of Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders. Inflammatory processes may result in neurodegenerative disorders. Sulforaphane is an isothiocyanate compound which has potential for treatment of neurodegenerative disorders. Its therapeutic potential is based on the ability to activate transcription of genes, that regulate protective cellular mechanisms. The importance of stu­dying sulforaphane as a neuroprotector is based on the fact, that dementias are the seventh leading cause of death glo­bally and actively progress due to aging of human population. In this review, the anti-inflammatory effects of sulforaphane in the brain and its use as a potential neuroprotector in the treatment of neurodegenerative diseases are discussed. The aim of the study – to review available literature sources on the potential use of sulforaphane to prevent or mitigate neuroinflammation. Conclusions. Economic and technological development of mankind and the improvement of the general qua­lity of life leads to prolongation of human life. But, achievements of longevity give new challenges to humanity. In young age and early adulthood, the organisms can relatively easily maintain homeostasis, then in old age intensification of oxidative stress and inflammatory processes can lead to the development of dementias and mental disorders. What should we do now to save clear mind in old age? In this review, sulforaphane is considered to be a potential neuroprotector. Biologically active supplements and drugs containing sulforaphane can weaken up inflammatory processes in the brain and in the body in general, and therefore they can be used for prevention and treatment of neurodegenerative diseases.

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