Kynurenines with Neuroactive and Redox Properties: Relevance to Aging and Brain Diseases

The kynurenine pathway (KP) is the main route of tryptophan degradation whose final product is NAD+. The metabolism of tryptophan can be altered in ageing and with neurodegenerative process, leading to decreased biosynthesis of nicotinamide. This fact is very relevant considering that tryptophan is the major source of body stores of the nicotinamide-containing NAD+coenzymes, which is involved in almost all the bioenergetic and biosynthetic metabolism. Recently, it has been proposed that endogenous tryptophan and its metabolites can interact and/or produce reactive oxygen species in tissues and cells. This subject is of great importance due to the fact that oxidative stress, alterations in KP metabolites, energetic deficit, cell death, and inflammatory events may converge each other to enter into a feedback cycle where each one depends on the other to exert synergistic actions among them. It is worth mentioning that all these factors have been described in aging and in neurodegenerative processes; however, has so far no one established any direct link between alterations in KP and these factors. In this review, we describe each kynurenine remarking their redox properties, their effects in experimental models, their alterations in the aging process.

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Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

Cells ◽

10.3390/cells10030686 ◽

2021 ◽

Vol 10 (3) ◽

pp. 686

Author(s):

Maria Concetta Geloso ◽

Nadia D’Ambrosi

Keyword(s):

Multiple Sclerosis ◽

Neuronal Death ◽

Environmental Changes ◽

Experimental Models ◽

Synaptic Dysfunction ◽

Synapse Elimination ◽

Neurodegenerative Process ◽

Immune Mediated ◽

Wide Range ◽

Demyelinating Lesions

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.

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Stiffness and Aging in Cardiovascular Diseases: The Dangerous Relationship between Force and Senescence

International Journal of Molecular Sciences ◽

10.3390/ijms22073404 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3404

Author(s):

Silvia Ferrari ◽

Maurizio Pesce

Keyword(s):

Risk Factors ◽

Aging Process ◽

Tissue Structure ◽

Biological Aging ◽

Ros Production ◽

Oxygen Species ◽

Chromatin Modifications ◽

Gradual Decline ◽

Cycle Arrest ◽

Inflammatory Activation

Biological aging is a process associated with a gradual decline in tissues’ homeostasis based on the progressive inability of the cells to self-renew. Cellular senescence is one of the hallmarks of the aging process, characterized by an irreversible cell cycle arrest due to reactive oxygen species (ROS) production, telomeres shortening, chronic inflammatory activation, and chromatin modifications. In this review, we will describe the effects of senescence on tissue structure, extracellular matrix (ECM) organization, and nucleus architecture, and see how these changes affect (are affected by) mechano-transduction. In our view, this is essential for a deeper understanding of the progressive pathological evolution of the cardiovascular system and its relationship with the detrimental effects of risk factors, known to act at an epigenetic level.

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The in vitro effect of kynurenic acid on the rainbow trout (Oncorhynchus mykiss) leukocyte and splenocyte activity

Polish Journal of Veterinary Sciences ◽

10.2478/pjvs-2014-0065 ◽

2014 ◽

Vol 17 (3) ◽

pp. 453-458 ◽

Cited By ~ 4

Author(s):

J. Małaczewska ◽

A. K. Siwicki ◽

R. Wójcik ◽

W. a. Turski ◽

E. Kaczorek

Keyword(s):

Rainbow Trout ◽

Immune Cells ◽

Kynurenic Acid ◽

Kynurenine Pathway ◽

Phagocytic Cells ◽

Mitogenic Response ◽

Tryptophan Degradation ◽

Selective Ligand ◽

Vitro Effect

Abstract Kynurenic acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for kynurenic acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells. The objective of this study has been to determine the effect of different concentrations of kynurenic acid (12.5 μM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of kynurenic acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 μM and 25 μM) seems indicative of endogenous kynurenic acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA.

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Gaseous neurotransmitter nitric oxide: Its role in experimental models of epilepsy

Archives of Biological Sciences ◽

10.2298/abs1203207h ◽

2012 ◽

Vol 64 (3) ◽

pp. 1207-1216 ◽

Cited By ~ 6

Author(s):

D. Hrncic ◽

Aleksandra Rasic-Markovic ◽

Jelica Bjekic-Macut ◽

Veselinka Susic ◽

D. Mladenovic ◽

...

Keyword(s):

Nitric Oxide ◽

Experimental Studies ◽

Experimental Models ◽

Initiation And Propagation ◽

Organ Systems ◽

The Central Nervous System ◽

Animal Models Of Epilepsy ◽

Almost All ◽

Gaseous Neurotransmitter ◽

Models Of Epilepsy

Epilepsy is one of the leading neurological disorders and affects 1-2% of the world?s population. Generally, it is a result of an imbalance between excitatory and inhibitory phenomena in the central nervous system (CNS), but the mechanisms of its initiation and propagation still require further investigations. Experimental models represent one of the most powerful tools to better understand the mechanisms of epileptogenesis. Nitric oxide (NO) is gaseous molecule with pleiotropic physiological and pathological effects in almost all organ systems and intriguing biological relevance, especially in the CNS where it acts as a gaseous neurotransmitter. The role of NO in the generation of epilepsy is highly contradictory, since there is evidence of its anticonvulsive, as well as proconvulsive properties. Therefore, we will discuss in this review the involvement of NO-mediated signaling pathways in the mechanisms of epileptogenesis, taking into account the findings revealed in experimental studies on animal models of epilepsy.

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Microglia Regulate Neuronal Circuits in Homeostatic and High-Fat Diet-Induced Inflammatory Conditions

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.722028 ◽

2021 ◽

Vol 15 ◽

Author(s):

Xiao-Lan Wang ◽

Lianjian Li

Keyword(s):

High Fat Diet ◽

Microglial Activation ◽

Current Knowledge ◽

Brain Diseases ◽

High Fat ◽

Synaptic Remodeling ◽

Inflammatory Conditions ◽

Cellular Debris ◽

Neuronal Connections ◽

Almost All

Microglia are brain resident macrophages, which actively survey the surrounding microenvironment and promote tissue homeostasis under physiological conditions. During this process, microglia participate in synaptic remodeling, neurogenesis, elimination of unwanted neurons and cellular debris. The complex interplay between microglia and neurons drives the formation of functional neuronal connections and maintains an optimal neural network. However, activation of microglia induced by chronic inflammation increases synaptic phagocytosis and leads to neuronal impairment or death. Microglial dysfunction is implicated in almost all brain diseases and leads to long-lasting functional deficiency, such as hippocampus-related cognitive decline and hypothalamus-associated energy imbalance (i.e., obesity). High-fat diet (HFD) consumption triggers mediobasal hypothalamic microglial activation and inflammation. Moreover, HFD-induced inflammation results in cognitive deficits by triggering hippocampal microglial activation. Here, we have summarized the current knowledge of microglial characteristics and biological functions and also reviewed the molecular mechanism of microglia in shaping neural circuitries mainly related to cognition and energy balance in homeostatic and diet-induced inflammatory conditions.

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P.3.06 Tryptophan degradation in psychosis: simultaneous measurement of tryptophan and kynurenine pathway metabolites by HPLC

European Neuropsychopharmacology ◽

10.1016/s0924-977x(08)70077-4 ◽

2008 ◽

Vol 18 ◽

pp. s67-s68

Author(s):

G. Clarke ◽

S. Barry ◽

P. Scully ◽

J.F. Cryan ◽

T.G. Dinan

Keyword(s):

Simultaneous Measurement ◽

Kynurenine Pathway ◽

Tryptophan Degradation

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Exploring the Potentials of Antioxidants in Retarding Ageing

Examining the Development, Regulation, and Consumption of Functional Foods - Advances in Environmental Engineering and Green Technologies ◽

10.4018/978-1-5225-0607-2.ch008 ◽

2017 ◽

pp. 166-195 ◽

Cited By ~ 1

Author(s):

Minu Kesheri ◽

Swarna Kanchan ◽

Rajeshwar P. Sinha

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Growth And Development ◽

Aging Process ◽

Reactive Oxygen ◽

Normal Growth ◽

Antioxidant Defenses ◽

Oxygen Species ◽

Biotic Stresses ◽

Living Organisms

In retrospect to the rise in the occurrence of ageing related disorders and the everlasting desire to overcome ageing, exploring the causes, mechanisms and therapies to curb ageing becomes relevant. Reactive Oxygen Species (ROS) are commonly generated during normal growth and development. However abiotic and biotic stresses enhance the level of ROS which in turn pose the threat of oxidative stress. Ability to perceive ROS and to speedily commence antioxidant defenses is crucial for the survival as well as longevity of living cells. Therefore living organisms are bestowed with antioxidants to combat the damages caused by oxidative stress. This chapter aims to elucidate an overview of the process of ageing, generation and enhancement of reactive oxygen species, damages incurred by oxidative stress, its amelioration strategies, therapeutic and biotechnological potentials of antioxidants and various sources of bioactive compounds significant in retardation of aging process.

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Regulation of Vascular Calcification by Reactive Oxygen Species

Antioxidants ◽

10.3390/antiox9100963 ◽

2020 ◽

Vol 9 (10) ◽

pp. 963 ◽

Cited By ~ 1

Author(s):

Andrea Tóth ◽

Enikő Balogh ◽

Viktória Jeney

Keyword(s):

Reactive Oxygen Species ◽

Signal Transduction ◽

Vascular Calcification ◽

Reactive Oxygen ◽

Experimental Models ◽

Signal Transduction Pathways ◽

Ros Production ◽

Oxygen Species ◽

Protective Mechanisms ◽

Phenotype Switch

Vascular calcification is the deposition of hydroxyapatite crystals in the medial or intimal layers of arteries that is usually associated with other pathological conditions including but not limited to chronic kidney disease, atherosclerosis and diabetes. Calcification is an active, cell-regulated process involving the phenotype transition of vascular smooth muscle cells (VSMCs) from contractile to osteoblast/chondrocyte-like cells. Diverse triggers and signal transduction pathways have been identified behind vascular calcification. In this review, we focus on the role of reactive oxygen species (ROS) in the osteochondrogenic phenotype switch of VSMCs and subsequent calcification. Vascular calcification is associated with elevated ROS production. Excessive ROS contribute to the activation of certain osteochondrogenic signal transduction pathways, thereby accelerating osteochondrogenic transdifferentiation of VSMCs. Inhibition of ROS production and ROS scavengers and activation of endogenous protective mechanisms are promising therapeutic approaches in the prevention of osteochondrogenic transdifferentiation of VSMCs and subsequent vascular calcification. The present review discusses the formation and actions of excess ROS in different experimental models of calcification, and the potential of ROS-lowering strategies in the prevention of this deleterious condition.

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Antifibrotic Activity of Acylated and Unacylated Ghrelin

International Journal of Endocrinology ◽

10.1155/2015/385682 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Elia Angelino ◽

Simone Reano ◽

Michele Ferrara ◽

Emanuela Agosti ◽

Andrea Graziani ◽

...

Keyword(s):

Growth Hormone ◽

Extracellular Matrix ◽

Tissue Injury ◽

Biological Activities ◽

Experimental Models ◽

Major Health ◽

Unacylated Ghrelin ◽

Ghrelin Gene ◽

Almost All ◽

Major Health Issue

Fibrosis can affect almost all tissues and organs, it often represents the terminal stage of chronic diseases, and it is regarded as a major health issue for which efficient therapies are needed. Tissue injury, by inducing necrosis/apoptosis, triggers inflammatory response that, in turn, promotes fibroblast activation and pathological deposition of extracellular matrix. Acylated and unacylated ghrelin are the main products of the ghrelin gene. The acylated form, through its receptor GHSR-1a, stimulates appetite and growth hormone (GH) release. Although unacylated ghrelin does not bind or activate GHSR-1a, it shares with the acylated form several biological activities. Ghrelin peptides exhibit anti-inflammatory, antioxidative, and antiapoptotic activities, suggesting that they might represent an efficient approach to prevent or reduce fibrosis. The aim of this review is to summarize the available evidence regarding the effects of acylated and unacylated ghrelin on different pathologies and experimental models in which fibrosis is a predominant characteristic.

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