Journal of Clinical Medicine

Editorial

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4 pages, 175 KiB

Open AccessEditorial

Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications

by Andrea Tarozzi

J. Clin. Med. 2020, 9(4), 1223; https://doi.org/10.3390/jcm9041223 - 24 Apr 2020

Cited by 14 | Viewed by 3470

Abstract

Oxidative stress plays an important role in the pathogenesis of several different neurodegenerative diseases (NDDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) [...] Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

Research

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19 pages, 1502 KiB

Open AccessArticle

Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels in A Transgenic Murine Model of Alzheimer’s Disease

by Sarah Beggiato, Maria Cristina Tomasini, Tommaso Cassano and Luca Ferraro

J. Clin. Med. 2020, 9(2), 428; https://doi.org/10.3390/jcm9020428 - 5 Feb 2020

Cited by 29 | Viewed by 4775

Abstract

N-palmitoylethanolamide (PEA) is a lipid mediator belonging to the class of the N-acylethanolamine. Products containing PEA, also in ultramicronized formulation (um-PEA), are already licensed for use in humans for its analgesic and anti-inflammatory properties, and demonstrated high safety and tolerability. Preclinical studies indicate [...] Read more.

N-palmitoylethanolamide (PEA) is a lipid mediator belonging to the class of the N-acylethanolamine. Products containing PEA, also in ultramicronized formulation (um-PEA), are already licensed for use in humans for its analgesic and anti-inflammatory properties, and demonstrated high safety and tolerability. Preclinical studies indicate that PEA, especially in the ultramicronized form, could be a potential therapeutic agent for Alzheimer’s disease (AD). In this study, we evaluated the neuroprotective and antioxidant effects of chronic (three months) um-PEA administration in an animal model of AD (3×Tg-AD mice). For translation purposes, the compound has been orally administered. Cognitive performance as well as biochemical markers [(interleukin-16 (IL-16) and tumor necrosis factor-α (TNF-α)] levels, reactive oxygen species (ROS) production, synaptophysin and glutamate levels) have been evaluated at the end of um-PEA treatment. The results indicate that orally administered um-PEA was adsorbed and distributed in the mice brain. The chronic treatment with um-PEA (100 mg/kg/day for three months) rescued cognitive deficit, restrained neuroinflammation and oxidative stress, and reduced the increase in hippocampal glutamate levels observed in 3×Tg-AD mice. Overall, these data reinforce the concept that um-PEA exerts beneficial effects in 3×Tg-AD mice. The fact that PEA is already licensed for the use in humans strongly supports its rapid translation in clinical practice. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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11 pages, 1777 KiB

Open AccessArticle

Oxidative Stress and Inflammation Interdependence in Multiple Sclerosis

by Rodica Padureanu, Carmen Valeria Albu, Radu Razvan Mititelu, Manuela Violeta Bacanoiu, Anca Oana Docea, Daniela Calina, Vlad Padureanu, Gabriela Olaru, Raluca Elena Sandu, Ramona Denise Malin and Ana-Maria Buga

J. Clin. Med. 2019, 8(11), 1815; https://doi.org/10.3390/jcm8111815 - 1 Nov 2019

Cited by 85 | Viewed by 5984

Abstract

The study aims to explore the oxidative status related to inflammation in peripheral blood of stable relapsing-remitting multiple sclerosis (MS) patients with low disability. In this study, 31 people were included and divided into two groups: an MS group in which 16 relapsing-remitting [...] Read more.

The study aims to explore the oxidative status related to inflammation in peripheral blood of stable relapsing-remitting multiple sclerosis (MS) patients with low disability. In this study, 31 people were included and divided into two groups: an MS group in which 16 relapsing-remitting MS patients with a low disability level (age 38.9 ± 7.08, EDSS median 2.5) were included and a control group that contains 15 healthy volunteers of similar age to the MS group. Thiobarbituric acid reactive substances (TBARS), protein carbonyl level (PCO), total antioxidant capacity (TAC) as oxidative stress markers, neutrophil/lymphocyte ratio (NLR), and erythrocyte sedimentation rate (ESR) were analyzed in the peripheral blood sample of the healthy and the MS patients to establish the oxidative stress/inflammatory level using conventional plasma markers. In this study, we showed that the pro-inflammatory status of the relapse-remitting stage of diseases can be easily and accurately appreciated by NLR. An increased NLR is associated with a decreased antioxidant capacity, even in the early stage of neuronal damage. Oxidative stress associated with inflammation aggravates the functional outcome, potentiates neuronal damage, and can accelerate the progression of the disease. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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23 pages, 6309 KiB

Open AccessArticle

Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment

by Ashfaq Ahmad, Tahir Ali, Shafiq Ur Rehman and Myeong Ok Kim

J. Clin. Med. 2019, 8(6), 850; https://doi.org/10.3390/jcm8060850 - 14 Jun 2019

Cited by 56 | Viewed by 7490

Abstract

Phytomedicine based natural flavonoids have potent antioxidant, anti-inflammatory, and neuroprotective activities against neurodegenerative diseases. The aim of the present study is to investigate the potent neuroprotective and antioxidant potential effects of fisetin (natural flavonoid) against central nervous system (CNS)-insult, lipopolysaccharide (LPS)-induced reactive oxygen [...] Read more.

Phytomedicine based natural flavonoids have potent antioxidant, anti-inflammatory, and neuroprotective activities against neurodegenerative diseases. The aim of the present study is to investigate the potent neuroprotective and antioxidant potential effects of fisetin (natural flavonoid) against central nervous system (CNS)-insult, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS), neuroinflammation, neurodegeneration, and synaptic/memory deficits in adult mice. The mice were injected intraperitoneally (i.p.) with LPS (250 μg/kg/day for 1 week) and a fisetin dosage regimen (20 mg/kg/day i.p. for 2 weeks, 1 week pre-treated to LPS and 1 week co-treated with LPS). Behavioral tests, and biochemical and immunofluorescence assays were applied. Our results revealed that fisetin markedly abrogated the LPS-induced elevated ROS/oxidative stress and activated phosphorylated c-JUN N-terminal Kinase (p-JNK) in the adult mouse hippocampus. Fisetin significantly alleviated LPS-induced activated gliosis. Moreover, fisetin treatment inhibited LPS-induced activation of the inflammatory Toll-like Receptors (TLR4)/cluster of differentiation 14 (CD14)/phospho-nuclear factor kappa (NF-κB) signaling and attenuated other inflammatory mediators (tumor necrosis factor-α (TNF-α), interleukin-1 β (IL1-β), and cyclooxygenase (COX-2). Furthermore, immunoblotting and immunohistochemical results revealed that fisetin significantly reversed LPS-induced apoptotic neurodegeneration. Fisetin improved the hippocampal-dependent synaptic and memory functions in LPS-treated adult mice. In summary, our results strongly recommend that fisetin, a natural potent antioxidant, and neuroprotective phytomedicine, represents a promising, valuable, and therapeutic candidate for the prevention and treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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23 pages, 7502 KiB

Open AccessArticle

Salivary Redox Biomarkers in Different Stages of Dementia Severity

by Anna Klimiuk, Mateusz Maciejczyk, Magdalena Choromańska, Katarzyna Fejfer, Napoleon Waszkiewicz and Anna Zalewska

J. Clin. Med. 2019, 8(6), 840; https://doi.org/10.3390/jcm8060840 - 12 Jun 2019

Cited by 59 | Viewed by 3933

Abstract

This study is the first to evaluate oxidative stress biomarkers in saliva/blood of patients with varying degrees of dementia progression. The study included 50 healthy controls and 50 dementia patients divided into two groups: those with mild and moderate dementia (MMSE 11–23) and [...] Read more.

This study is the first to evaluate oxidative stress biomarkers in saliva/blood of patients with varying degrees of dementia progression. The study included 50 healthy controls and 50 dementia patients divided into two groups: those with mild and moderate dementia (MMSE 11–23) and patients suffering from severe dementia (MMSE 0–10). Cognitive functions of the subjects were assessed using the Mini Mental State Examination (MMSE). Enzymatic and non-enzymatic antioxidants, oxidative damage products and protein glycoxidative modifications were determined in non-stimulated (NWS) and stimulated (SWS) saliva as well as erythrocyte/plasma samples. Generally, in dementia patients, we observed the depletion of antioxidant defences leading to oxidative and glycoxidative damage in NWS, SWS and blood samples. Both salivary and blood oxidative stress increased with the severity of the disease, and correlated with a decrease of cognitive functions. Interestingly, in dementia patients, reduced glutathione (GSH) in NWS correlated not only with the severity of dementia, but also with GSH concentration in the plasma. In receiver operating characteristic (ROC) analysis, we have demonstrated that salivary GSH clearly distinguishes patients with severe dementia from those suffering from mild or moderate dementia (area under the curve (AUC) = 1). Therefore, salivary GSH can be used as a non-invasive biomarker of cognitive impairment. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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15 pages, 1754 KiB

Open AccessArticle

Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

by Matteo Bordoni, Orietta Pansarasa, Michela Dell’Orco, Valeria Crippa, Stella Gagliardi, Daisy Sproviero, Stefano Bernuzzi, Luca Diamanti, Mauro Ceroni, Gabriella Tedeschi, Angelo Poletti and Cristina Cereda

J. Clin. Med. 2019, 8(5), 729; https://doi.org/10.3390/jcm8050729 - 22 May 2019

Cited by 29 | Viewed by 5439

Abstract

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its [...] Read more.

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its consequent aggregation. We found an increase in DNA damage in patients PBMCs characterized by a high level of aggregated SOD1, while we found no DNA damage in PBMCs with normal soluble SOD1. We found an activation of ataxia-telangiectasia-mutated (ATM)/Chk2 and ATM and Rad3-related (ATR)/Chk1 DNA damage response pathways, which lead to phosphorylation of SOD1. Moreover, data showed that phosphorylation allows SOD1 to shift from the cytoplasm to the nucleus, protecting DNA from oxidative damage. Such pathway was finally confirmed in our cellular model. Our data lead us to suppose that in a sub-group of patients this physiologic pathway is non-functional, leading to an accumulation of DNA damage that causes the death of particularly susceptible cells, like motor neurons. In conclusion, during oxidative stress SOD1 is phosphorylated by Chk2 leading to its translocation in the nuclear compartment, in which SOD1 protects DNA from oxidative damage. This pathway, inefficient in sALS patients, could represent an innovative therapeutic target. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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19 pages, 12274 KiB

Open AccessArticle

Caffeine Modulates Cadmium-Induced Oxidative Stress, Neuroinflammation, and Cognitive Impairments by Regulating Nrf-2/HO-1 In Vivo and In Vitro

by Amjad Khan, Muhammad Ikram, Tahir Muhammad, Junsung Park and Myeong Ok Kim

J. Clin. Med. 2019, 8(5), 680; https://doi.org/10.3390/jcm8050680 - 14 May 2019

Cited by 116 | Viewed by 7271

Abstract

Cadmium (Cd), a nonbiodegradable heavy metal and one of the most neurotoxic environmental and industrial pollutants, promotes disturbances in major organs and tissues following both acute and chronic exposure. In this study, we assessed the neuroprotective potential of caffeine (30 mg/kg) against Cd [...] Read more.

Cadmium (Cd), a nonbiodegradable heavy metal and one of the most neurotoxic environmental and industrial pollutants, promotes disturbances in major organs and tissues following both acute and chronic exposure. In this study, we assessed the neuroprotective potential of caffeine (30 mg/kg) against Cd (5 mg/kg)-induced oxidative stress-mediated neuroinflammation, neuronal apoptosis, and cognitive deficits in male C57BL/6N mice in vivo and in HT-22 and BV-2 cell lines in vitro. Interestingly, our findings indicate that caffeine markedly reduced reactive oxygen species (ROS) and lipid peroxidation (LPO) levels and enhanced the expression of nuclear factor-2 erythroid-2 (Nrf-2) and hemeoxygenase-1 (HO-1), which act as endogenous antioxidant regulators. Also, 8-dihydro-8-oxoguanine (8-OXO-G) expression was considerably reduced in the caffeine-treated group as compared to the Cd-treated group. Similarly, caffeine ameliorated Cd-mediated glial activation by reducing the expression of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), and other inflammatory mediators in the cortical and hippocampal regions of the mouse brain. Moreover, caffeine markedly attenuated Cd-induced neuronal loss, synaptic dysfunction, and learning and cognitive deficits. Of note, nuclear factor-2 erythroid-2 (Nrf-2) gene silencing and nuclear factor-κB (NF-κB) inhibition studies revealed that caffeine exerted neuroprotection via regulation of Nrf-2- and NF-κB-dependent mechanisms in the HT-22 and BV-2 cell lines, respectively. On the whole, these findings reveal that caffeine rescues Cd-induced oxidative stress-mediated neuroinflammation, neurodegeneration, and memory impairment. The present study suggests that caffeine might be a potential antioxidant and neuroprotective agent against Cd-induced neurodegeneration. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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19 pages, 3702 KiB

Open AccessArticle

Indoxyl Sulfate Induces Apoptosis through Oxidative Stress and Mitogen-Activated Protein Kinase Signaling Pathway Inhibition in Human Astrocytes

by Yi-Ting Lin, Ping-Hsun Wu, Yi-Chun Tsai, Ya-Ling Hsu, Han Ying Wang, Mei-Chuan Kuo, Po-Lin Kuo and Shang-Jyh Hwang

J. Clin. Med. 2019, 8(2), 191; https://doi.org/10.3390/jcm8020191 - 5 Feb 2019

Cited by 46 | Viewed by 6408

Abstract

Uremic toxins accumulated in chronic kidney disease (CKD) increases the risk of cognitive impairment. Indoxyl sulfate (IS) is a well-known protein-bound uremic toxin that is correlated with several systemic diseases, but no studies on human brain cells are available. We investigated the effect [...] Read more.

Uremic toxins accumulated in chronic kidney disease (CKD) increases the risk of cognitive impairment. Indoxyl sulfate (IS) is a well-known protein-bound uremic toxin that is correlated with several systemic diseases, but no studies on human brain cells are available. We investigated the effect of IS on primary human astrocytes through next-generation sequencing and cell experiment confirmation to explore the mechanism of IS-associated brain damage. Total RNAs extracted from IS-treated and control astrocytes were evaluated by performing functional and pathway enrichment analysis. The toxicities of IS in the astrocytes were investigated in terms of cell viability through flow cytometry; the signal pathway was then investigated through immunoblotting. IS stimulated the release of reactive oxygen species, increased nuclear factor (erythroid-derived 2)-like 2 levels, and reduced mitochondrial membrane potential. IS triggered astrocyte apoptosis by inhibiting the mitogen-activated protein kinase (MAPK) pathway, including extracellular-signal-regulated kinase (ERK), MAPK/ERK kinase, c-Jun N-terminal kinase, and p38. The decreased ERK phosphorylation was mediated by the upregulated dual-specificity phosphatase 1, 5, 8, and 16. In conclusion, IS can induce neurotoxicity in patients with CKD and the pathogenesis involves cell apoptosis through oxidative stress induction and MAPK pathway inhibition in human astrocytes. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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19 pages, 3709 KiB

Open AccessArticle

Elevated Serum Melatonin under Constant Darkness Enhances Neural Repair in Spinal Cord Injury through Regulation of Circadian Clock Proteins Expression

by Yunkyung Hong, Yunho Jin, Kanghui Park, Jeonghyun Choi, Hyunbon Kang, Sang-Rae Lee and Yonggeun Hong

J. Clin. Med. 2019, 8(2), 135; https://doi.org/10.3390/jcm8020135 - 23 Jan 2019

Cited by 14 | Viewed by 3882

Abstract

We investigated the effects of environmental lighting conditions regulating endogenous melatonin production on neural repair, following experimental spinal cord injury (SCI). Rats were divided into three groups randomly: the SCI + L/D (12/12-h light/dark), SCI + LL (24-h constant light), and SCI + [...] Read more.

We investigated the effects of environmental lighting conditions regulating endogenous melatonin production on neural repair, following experimental spinal cord injury (SCI). Rats were divided into three groups randomly: the SCI + L/D (12/12-h light/dark), SCI + LL (24-h constant light), and SCI + DD (24-h constant dark) groups. Controlled light/dark cycle was pre-applied 2 weeks before induction of spinal cord injury. There was a significant increase in motor recovery as well as body weight from postoperative day (POD) 7 under constant darkness. However, spontaneous elevation of endogenous melatonin in cerebrospinal fluid was seen at POD 3 in all of the SCI rats, which was enhanced in SCI + DD group. Augmented melatonin concentration under constant dark condition resulted in facilitation of neuronal differentiation as well as inhibition of primary cell death. In the rostrocaudal region, elevated endogenous melatonin concentration promoted neural remodeling in acute phase including oligodendrogenesis, excitatory synaptic formation, and axonal outgrowth. The changes were mediated via NAS-TrkB-AKT/ERK signal transduction co-regulated by the circadian clock mechanism, leading to rapid motor recovery. In contrast, exposure to constant light exacerbated the inflammatory responses and neuroglial loss. These results suggest that light/dark control in the acute phase might be a considerable environmental factor for a favorable prognosis after SCI. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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Review

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27 pages, 467 KiB

Open AccessReview

Salivary Redox Biomarkers in Selected Neurodegenerative Diseases

by Mateusz Maciejczyk, Anna Zalewska and Karolina Gerreth

J. Clin. Med. 2020, 9(2), 497; https://doi.org/10.3390/jcm9020497 - 12 Feb 2020

Cited by 49 | Viewed by 5663

Abstract

Neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are disorders, which cause irreversible and progressive deterioration of the central nervous system. The pathophysiology of NDDs is still not fully explained; nevertheless, oxidative stress is considered as a critical mediator [...] Read more.

Neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are disorders, which cause irreversible and progressive deterioration of the central nervous system. The pathophysiology of NDDs is still not fully explained; nevertheless, oxidative stress is considered as a critical mediator of cerebral degeneration, brain inflammation, as well as neuronal apoptosis. Therefore, it is not surprising that redox biomarkers are increasingly used in the diagnosis of neurodegenerative diseases. As saliva is a very easy to obtain bioliquid, it seems promising to use this biomaterial in the diagnosis of NDDs. Saliva collection is easy, cheap, stress-free, and non-infectious, and it does not require the help of a specialised medical personnel. Additionally, the concentrations of many salivary redox biomarkers correlate with their content in blood serum as well as the degree of disease progression, which makes them non-invasive indicators of NDDs. This paper reviews the latest knowledge concerning the use of salivary redox biomarkers in the diagnosis and prognosis of selected neurodegenerative diseases. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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10 pages, 549 KiB

Open AccessReview

Back to The Fusion: Mitofusin-2 in Alzheimer’s Disease

by Giulia Sita, Patrizia Hrelia, Agnese Graziosi and Fabiana Morroni

J. Clin. Med. 2020, 9(1), 126; https://doi.org/10.3390/jcm9010126 - 2 Jan 2020

Cited by 18 | Viewed by 3823

Abstract

Mitochondria are dynamic organelles that undergo constant fission and fusion. Mitochondria dysfunction underlies several human disorders, including Alzheimer’s disease (AD). Preservation of mitochondrial dynamics is fundamental for regulating the organelle’s functions. Several proteins participate in the regulation of mitochondrial morphology and networks, and [...] Read more.

Mitochondria are dynamic organelles that undergo constant fission and fusion. Mitochondria dysfunction underlies several human disorders, including Alzheimer’s disease (AD). Preservation of mitochondrial dynamics is fundamental for regulating the organelle’s functions. Several proteins participate in the regulation of mitochondrial morphology and networks, and among these, Mitofusin 2 (Mfn2) has been extensively studied. This review focuses on the role of Mfn2 in mitochondrial dynamics and in the crosstalk between mitochondria and the endoplasmic reticulum, in particular in AD. Understanding how this protein may be related to AD pathogenesis will provide essential information for the development of therapies for diseases linked to disturbed mitochondrial dynamics, as in AD. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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32 pages, 1349 KiB

Open AccessReview

Reformulating Pro-Oxidant Microglia in Neurodegeneration

by Juan García-Revilla, Isabel M. Alonso-Bellido, Miguel A. Burguillos, Antonio J. Herrera, Ana M. Espinosa-Oliva, Rocío Ruiz, Luis Cruz-Hernández, Irene García-Domínguez, María A. Roca-Ceballos, Marti Santiago, José A. Rodríguez-Gómez, Manuel Sarmiento Soto, Rocío M. de Pablos and José L. Venero

J. Clin. Med. 2019, 8(10), 1719; https://doi.org/10.3390/jcm8101719 - 17 Oct 2019

Cited by 50 | Viewed by 7690

Abstract

In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state’s [...] Read more.

In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state’s proinflammatory M1 (classical activation) and immunosuppressive M2 (alternative activation). Molecular signatures of DAM and proinflammatory microglia (highly pro-oxidant) have shown clear differences, yet a partial overlapping gene profile is evident between both phenotypes. The switch activation of homeostatic microglia into reactive microglia relies on the selective activation of key surface receptors involved in the maintenance of brain homeostasis (a.k.a. pattern recognition receptors, PRRs). Two relevant PRRs are toll-like receptors (TLRs) and triggering receptors expressed on myeloid cells-2 (TREM2), whose selective activation is believed to generate either a proinflammatory or a DAM phenotype, respectively. However, the recent identification of endogenous disease-related ligands, which bind to and activate both TLRs and TREM2, anticipates the existence of rather complex microglia responses. Examples of potential endogenous dual ligands include amyloid β, galectin-3, and apolipoprotein E. These pleiotropic ligands induce a microglia polarization that is more complicated than initially expected, suggesting the possibility that different microglia subtypes may coexist. This review highlights the main microglia polarization states under disease conditions and their leading role orchestrating oxidative stress. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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11 pages, 465 KiB

Open AccessReview

DJ-1 in Parkinson’s Disease: Clinical Insights and Therapeutic Perspectives

by Mariaelena Repici and Flaviano Giorgini

J. Clin. Med. 2019, 8(9), 1377; https://doi.org/10.3390/jcm8091377 - 3 Sep 2019

Cited by 130 | Viewed by 8619

Abstract

Mutations in the protein DJ-1 cause autosomal recessive forms of Parkinson’s disease (PD) and oxidized DJ-1 is found in the brains of idiopathic PD individuals. While several functions have been ascribed to DJ-1 (most notably protection from oxidative stress), its contribution to PD [...] Read more.

Mutations in the protein DJ-1 cause autosomal recessive forms of Parkinson’s disease (PD) and oxidized DJ-1 is found in the brains of idiopathic PD individuals. While several functions have been ascribed to DJ-1 (most notably protection from oxidative stress), its contribution to PD pathogenesis is not yet clear. Here we provide an overview of the clinical research to date on DJ-1 and the current state of knowledge regarding DJ-1 characterization in the human brain. The relevance of DJ-1 as a PD biomarker is also discussed, as are studies exploring DJ-1 as a possible therapeutic target for PD and neurodegeneration. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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16 pages, 1451 KiB

Open AccessReview

Emerging Roles of Sestrins in Neurodegenerative Diseases: Counteracting Oxidative Stress and Beyond

by Shang-Der Chen, Jenq-Lin Yang, Tsu-Kung Lin and Ding-I Yang

J. Clin. Med. 2019, 8(7), 1001; https://doi.org/10.3390/jcm8071001 - 9 Jul 2019

Cited by 44 | Viewed by 6395

Abstract

Low levels of reactive oxygen species (ROS) are critical for the operation of regular neuronal function. However, heightened oxidative stress with increased contents of oxidation markers in DNA, lipids, and proteins with compromised antioxidant capacity may play a harmful role in the brain [...] Read more.

Low levels of reactive oxygen species (ROS) are critical for the operation of regular neuronal function. However, heightened oxidative stress with increased contents of oxidation markers in DNA, lipids, and proteins with compromised antioxidant capacity may play a harmful role in the brain and may be implicated in the pathophysiology of neurodegenerative diseases. Sestrins, a family of evolutionarily-conserved stress-inducible proteins, are actively regulated by assorted stresses, such as DNA damage, hypoxia, and oxidative stress. Three highly homologous genes that encode sestrin1, sestrin2, and sestrin3 proteins exist in the genomes of vertebrates. Under stressful conditions, sestrins are activated with versatile functions to cope with different types of stimuli. A growing body of evidence suggests that sestrins, especially sestrin2, can counteract oxidative stress, lessen mammalian/mechanistic target of rapamycin (mTOR) expression, and promote cell survival, thereby playing a critical role in aging-related disorders including neurodegeneration. Strategies capable of augmenting sestrin expression may; thus, facilitate cell adaptation to stressful conditions or environments through stimulation of antioxidant response and autophagy process, which may carry clinical significance in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Oxidative Stress in Neurodegenerative Diseases: From Preclinical Studies to Clinical Applications)

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