International Journal of Molecular Sciences

Research

27 pages, 5102 KiB

Open AccessArticle

The Relevance of Reperfusion Stroke Therapy for miR-9-3p and miR-9-5p Expression in Acute Stroke—A Preliminary Study

by Daria Gendosz de Carrillo, Olga Kocikowska, Małgorzata Rak, Aleksandra Krzan, Sebastian Student, Halina Jędrzejowska-Szypułka, Katarzyna Pawletko and Anetta Lasek-Bal

Int. J. Mol. Sci. 2024, 25(5), 2766; https://doi.org/10.3390/ijms25052766 - 27 Feb 2024

Viewed by 871

Abstract

Reperfusion stroke therapy is a modern treatment that involves thrombolysis and the mechanical removal of thrombus from the extracranial and/or cerebral arteries, thereby increasing penumbra reperfusion. After reperfusion therapy, 46% of patients are able to live independently 3 months after stroke onset. MicroRNAs [...] Read more.

Reperfusion stroke therapy is a modern treatment that involves thrombolysis and the mechanical removal of thrombus from the extracranial and/or cerebral arteries, thereby increasing penumbra reperfusion. After reperfusion therapy, 46% of patients are able to live independently 3 months after stroke onset. MicroRNAs (miRNAs) are essential regulators in the development of cerebral ischemia/reperfusion injury and the efficacy of the applied treatment. The first aim of this study was to examine the change in serum miRNA levels via next-generation sequencing (NGS) 10 days after the onset of acute stroke and reperfusion treatment. Next, the predictive values of the bioinformatics analysis of miRNA gene targets for the assessment of brain ischemic response to reperfusion treatment were explored. Human serum samples were collected from patients on days 1 and 10 after stroke onset and reperfusion treatment. The samples were subjected to NGS and then validated using qRT-PCR. Differentially expressed miRNAs (DEmiRNAs) were used for enrichment analysis. Hsa-miR-9-3p and hsa-miR-9-5p expression were downregulated on day 10 compared to reperfusion treatment on day 1 after stroke. The functional analysis of miRNA target genes revealed a strong association between the identified miRNA and stroke-related biological processes related to neuroregeneration signaling pathways. Hsa-miR-9-3p and hsa-miR-9-5p are potential candidates for the further exploration of reperfusion treatment efficacy in stroke patients. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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21 pages, 4449 KiB

Open AccessArticle

CD163-Mediated Small-Vessel Injury in Alzheimer’s Disease: An Exploration from Neuroimaging to Transcriptomics

by Yuewei Chen, Peiwen Lu, Shengju Wu, Jie Yang, Wanwan Liu, Zhijun Zhang and Qun Xu

Int. J. Mol. Sci. 2024, 25(4), 2293; https://doi.org/10.3390/ijms25042293 - 14 Feb 2024

Cited by 1 | Viewed by 1417

Abstract

Patients with Alzheimer’s disease (AD) often present with imaging features indicative of small-vessel injury, among which, white-matter hyperintensities (WMHs) are the most prevalent. However, the underlying mechanism of the association between AD and small-vessel injury is still obscure. The aim of this study [...] Read more.

Patients with Alzheimer’s disease (AD) often present with imaging features indicative of small-vessel injury, among which, white-matter hyperintensities (WMHs) are the most prevalent. However, the underlying mechanism of the association between AD and small-vessel injury is still obscure. The aim of this study is to investigate the mechanism of small-vessel injury in AD. Differential gene expression analyses were conducted to identify the genes related to WMHs separately in mild cognitive impairment (MCI) and cognitively normal (CN) subjects from the ADNI database. The WMH-related genes identified in patients with MCI were considered to be associated with small-vessel injury in early AD. Functional enrichment analyses and a protein–protein interaction (PPI) network were performed to explore the pathway and hub genes related to the mechanism of small-vessel injury in MCI. Subsequently, the Boruta algorithm and support vector machine recursive feature elimination (SVM-RFE) algorithm were performed to identify feature-selection genes. Finally, the mechanism of small-vessel injury was analyzed in MCI from the immunological perspectives; the relationship of feature-selection genes with various immune cells and neuroimaging indices were also explored. Furthermore, 5×FAD mice were used to demonstrate the genes related to small-vessel injury. The results of the logistic regression analyses suggested that WMHs significantly contributed to MCI, the early stage of AD. A total of 276 genes were determined as WMH-related genes in patients with MCI, while 203 WMH-related genes were obtained in CN patients. Among them, only 15 genes overlapped and were thus identified as the crosstalk genes. By employing the Boruta and SVM-RFE algorithms, CD163, ALDH3B1, MIR22HG, DTX2, FOLR2, ALDH2, and ZNF23 were recognized as the feature-selection genes linked to small-vessel injury in MCI. After considering the results from the PPI network, CD163 was finally determined as the critical WMH-related gene in MCI. The expression of CD163 was correlated with fractional anisotropy (FA) values in regions that are vulnerable to small-vessel injury in AD. The immunostaining and RT-qPCR results from the verifying experiments demonstrated that the indicators of small-vessel injury presented in the cortical tissue of 5×FAD mice and related to the upregulation of CD163 expression. CD163 may be the most pivotal candidates related to small-vessel injury in early AD. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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13 pages, 2980 KiB

Open AccessArticle

Short- and Long-Term Regulation of HuD: A Molecular Switch Mediated by Folic Acid?

by Nicoletta Marchesi, Pasquale Linciano, Lucrezia Irene Maria Campagnoli, Foroogh Fahmideh, Daniela Rossi, Giosuè Costa, Francesca Alessandra Ambrosio, Annalisa Barbieri, Simona Collina and Alessia Pascale

Int. J. Mol. Sci. 2023, 24(15), 12201; https://doi.org/10.3390/ijms241512201 - 30 Jul 2023

Cited by 2 | Viewed by 1451

Abstract

The RNA-binding protein HuD has been shown to play a crucial role in gene regulation in the nervous system and is involved in various neurological and psychiatric diseases. In this study, through the creation of an interaction network on HuD and its potential [...] Read more.

The RNA-binding protein HuD has been shown to play a crucial role in gene regulation in the nervous system and is involved in various neurological and psychiatric diseases. In this study, through the creation of an interaction network on HuD and its potential targets, we identified a strong association between HuD and several diseases of the nervous system. Specifically, we focused on the relationship between HuD and the brain-derived neurotrophic factor (BDNF), whose protein is implicated in several neuronal diseases and is involved in the regulation of neuronal development, survival, and function. To better investigate this relationship and given that we previously demonstrated that folic acid (FA) is able to directly bind HuD itself, we performed in vitro experiments in neuron-like human SH-SY5Y cells in the presence of FA, also known to be a pivotal environmental factor influencing the nervous system development. Our findings show that FA exposure results in a significant increase in both HuD and BDNF transcripts and proteins after 2 and 4 h of treatment, respectively. Similar data were obtained after 2 h of FA incubation followed by 2 h of washout. This increase was no longer detected upon 24 h of FA exposure, probably due to a signaling shutdown mechanism. Indeed, we observed that following 24 h of FA exposure HuD is methylated. These findings indicate that FA regulates BDNF expression via HuD and suggest that FA can behave as an epigenetic modulator of HuD in the nervous system acting via short- and long-term mechanisms. Finally, the present results also highlight the potential of BDNF as a therapeutic target for specific neurological and psychiatric diseases. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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23 pages, 4597 KiB

Open AccessArticle

After Ischemic Stroke, Minocycline Promotes a Protective Response in Neurons via the RNA-Binding Protein HuR, with a Positive Impact on Motor Performance

by Katarzyna Pawletko, Halina Jędrzejowska-Szypułka, Katarzyna Bogus, Alessia Pascale, Foroogh Fahmideh, Nicoletta Marchesi, Aniela Grajoszek, Daria Gendosz de Carrillo and Jarosław Jerzy Barski

Int. J. Mol. Sci. 2023, 24(11), 9446; https://doi.org/10.3390/ijms24119446 - 29 May 2023

Cited by 3 | Viewed by 1731

Abstract

Ischemic stroke is the most common cause of adult disability and one of the leading causes of death worldwide, with a serious socio-economic impact. In the present work, we used a new thromboembolic model, recently developed in our lab, to induce focal cerebral [...] Read more.

Ischemic stroke is the most common cause of adult disability and one of the leading causes of death worldwide, with a serious socio-economic impact. In the present work, we used a new thromboembolic model, recently developed in our lab, to induce focal cerebral ischemic (FCI) stroke in rats without reperfusion. We analyzed selected proteins implicated in the inflammatory response (such as the RNA-binding protein HuR, TNFα, and HSP70) via immunohistochemistry and western blotting techniques. The main goal of the study was to evaluate the beneficial effects of a single administration of minocycline at a low dose (1 mg/kg intravenously administered 10 min after FCI) on the neurons localized in the penumbra area after an ischemic stroke. Furthermore, given the importance of understanding the crosstalk between molecular parameters and motor functions following FCI, motor tests were also performed, such as the Horizontal Runway Elevated test, CatWalk™ XT, and Grip Strength test. Our results indicate that a single administration of a low dose of minocycline increased the viability of neurons and reduced the neurodegeneration caused by ischemia, resulting in a significant reduction in the infarct volume. At the molecular level, minocycline resulted in a reduction in TNFα content coupled with an increase in the levels of both HSP70 and HuR proteins in the penumbra area. Considering that both HSP70 and TNF-α transcripts are targeted by HuR, the obtained results suggest that, following FCI, this RNA-binding protein promotes a protective response by shifting its binding towards HSP70 instead of TNF-α. Most importantly, motor tests showed that reduced inflammation in the brain damaged area after minocycline treatment directly translated into a better motor performance, which is a fundamental outcome when searching for new therapeutic options for clinical practice. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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Review

Jump to: Research, Other

19 pages, 3074 KiB

Open AccessReview

Targeting Vascular Impairment, Neuroinflammation, and Oxidative Stress Dynamics with Whole-Body Cryotherapy in Multiple Sclerosis Treatment

by Angela Dziedzic, Karina Maciak, Elżbieta Dorota Miller, Michał Starosta and Joanna Saluk

Int. J. Mol. Sci. 2024, 25(7), 3858; https://doi.org/10.3390/ijms25073858 - 29 Mar 2024

Cited by 2 | Viewed by 1022

Abstract

Multiple sclerosis (MS), traditionally perceived as a neurodegenerative disease, exhibits significant vascular alternations, including blood–brain barrier (BBB) disruption, which may predispose patients to increased cardiovascular risks. This vascular dysfunction is intricately linked with the infiltration of immune cells into the central nervous system [...] Read more.

Multiple sclerosis (MS), traditionally perceived as a neurodegenerative disease, exhibits significant vascular alternations, including blood–brain barrier (BBB) disruption, which may predispose patients to increased cardiovascular risks. This vascular dysfunction is intricately linked with the infiltration of immune cells into the central nervous system (CNS), which plays a significant role in perpetuating neuroinflammation. Additionally, oxidative stress serves not only as a byproduct of inflammatory processes but also as an active contributor to neural damage. The synthesis of these multifaceted aspects highlights the importance of understanding their cumulative impact on MS progression. This review reveals that the triad of vascular damage, chronic inflammation, and oxidative imbalance may be considered interdependent processes that exacerbate each other, underscoring the need for holistic and multi-targeted therapeutic approaches in MS management. There is a necessity for reevaluating MS treatment strategies to encompass these overlapping pathologies, offering insights for future research and potential therapeutic interventions. Whole-body cryotherapy (WBCT) emerges as one of the potential avenues for holistic MS management approaches which may alleviate the triad of MS progression factors in multiple ways. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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22 pages, 1477 KiB

Open AccessReview

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)

by Yizhou Hu, Feng Zhang, Milos Ikonomovic and Tuo Yang

Int. J. Mol. Sci. 2024, 25(7), 3833; https://doi.org/10.3390/ijms25073833 - 29 Mar 2024

Cited by 1 | Viewed by 1109

Abstract

Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is [...] Read more.

Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is enriched in the cerebral vasculature and has diverse roles in metabolic balance, mitochondrial stabilization, redox balance, and anti-inflammation. In this review, we first briefly introduce cerebrovascular aging in VCID and the NRF2 pathway. We then extensively discuss the effects of NRF2 activation in cerebrovascular components such as endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. Finally, we summarize the clinical potential of NRF2 activators in VCID. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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22 pages, 1260 KiB

Open AccessReview

New Insights into Oxidative Stress and Inflammatory Response in Neurodegenerative Diseases

by Eveljn Scarian, Camilla Viola, Francesca Dragoni, Rosalinda Di Gerlando, Bartolo Rizzo, Luca Diamanti, Stella Gagliardi, Matteo Bordoni and Orietta Pansarasa

Int. J. Mol. Sci. 2024, 25(5), 2698; https://doi.org/10.3390/ijms25052698 - 26 Feb 2024

Cited by 6 | Viewed by 1824

Abstract

Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. [...] Read more.

Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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20 pages, 1391 KiB

Open AccessReview

Inhibition of Galectins and the P2X7 Purinergic Receptor as a Therapeutic Approach in the Neurovascular Inflammation of Diabetic Retinopathy

by Caterina Claudia Lepre, Marina Russo, Maria Consiglia Trotta, Francesco Petrillo, Fabiana Anna D’Agostino, Gennaro Gaudino, Giovanbattista D’Amico, Maria Rosaria Campitiello, Erminia Crisci, Maddalena Nicoletti, Carlo Gesualdo, Francesca Simonelli, Michele D’Amico, Anca Hermenean and Settimio Rossi

Int. J. Mol. Sci. 2023, 24(11), 9721; https://doi.org/10.3390/ijms24119721 - 3 Jun 2023

Cited by 3 | Viewed by 1678

Abstract

Diabetic retinopathy (DR) is the most frequent microvascular retinal complication of diabetic patients, contributing to loss of vision. Recently, retinal neuroinflammation and neurodegeneration have emerged as key players in DR progression, and therefore, this review examines the neuroinflammatory molecular basis of DR. We [...] Read more.

Diabetic retinopathy (DR) is the most frequent microvascular retinal complication of diabetic patients, contributing to loss of vision. Recently, retinal neuroinflammation and neurodegeneration have emerged as key players in DR progression, and therefore, this review examines the neuroinflammatory molecular basis of DR. We focus on four important aspects of retinal neuroinflammation: (i) the exacerbation of endoplasmic reticulum (ER) stress; (ii) the activation of the NLRP3 inflammasome; (iii) the role of galectins; and (iv) the activation of purinergic 2X7 receptor (P2X7R). Moreover, this review proposes the selective inhibition of galectins and the P2X7R as a potential pharmacological approach to prevent the progression of DR. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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Other

Jump to: Research, Review

8 pages, 965 KiB

Open AccessCase Report

Tako-Tsubo Syndrome in Amyotrophic Lateral Sclerosis: Single-Center Case Series and Brief Literature Review

by Giovanni Napoli, Martina Rubin, Gianni Cutillo, Paride Schito, Tommaso Russo, Angelo Quattrini, Massimo Filippi and Nilo Riva

Int. J. Mol. Sci. 2023, 24(15), 12096; https://doi.org/10.3390/ijms241512096 - 28 Jul 2023

Cited by 1 | Viewed by 1556

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with variable phenotypic expressions which has been associated with autonomic dysfunction. The cardiovascular system seems to be affected especially in the context of bulbar involvement. We describe four new cases of Tako-Tsubo syndrome (TTS) in [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with variable phenotypic expressions which has been associated with autonomic dysfunction. The cardiovascular system seems to be affected especially in the context of bulbar involvement. We describe four new cases of Tako-Tsubo syndrome (TTS) in ALS patients with an appraisal of the literature. We present a late-stage ALS patient with prominent bulbar involvement that presented TTS during hospitalization. We then retrospectively identify three additional ALS–TTS cases reporting relevant clinical findings. TTS cardiomyopathy has been observed in different acute neurological conditions, and the co-occurrence of ALS and TTS has already been reported. Cardiovascular autonomic dysfunctions have been described in ALS, especially in the context of an advanced diseases and with bulbar involvement. Noradrenergic hyperfunction linked to sympathetic denervation and ventilatory deficits coupled in different instances with a trigger event could play a synergistic role in the development of TTS in ALS. Sympathetic hyperfunctioning and ventilatory deficits in conjunction with cardiac autonomic nerves impairment may play a role in the development of TTS in a context of ALS. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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39 pages, 4092 KiB

Open AccessHypothesis

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

by Mirco Masi, Fabrizio Biundo, André Fiou, Marco Racchi, Alessia Pascale and Erica Buoso

Int. J. Mol. Sci. 2023, 24(7), 6639; https://doi.org/10.3390/ijms24076639 - 2 Apr 2023

Cited by 1 | Viewed by 2317

Abstract

Amyloid Precursor Protein (APP) and its cleavage processes have been widely investigated in the past, in particular in the context of Alzheimer’s Disease (AD). Evidence of an increased expression of APP and its amyloidogenic-related cleavage enzymes, β-secretase 1 (BACE1) and γ-secretase, [...] Read more.

Amyloid Precursor Protein (APP) and its cleavage processes have been widely investigated in the past, in particular in the context of Alzheimer’s Disease (AD). Evidence of an increased expression of APP and its amyloidogenic-related cleavage enzymes, β-secretase 1 (BACE1) and γ-secretase, at the hit axon terminals following Traumatic Brain Injury (TBI), firstly suggested a correlation between TBI and AD. Indeed, mild and severe TBI have been recognised as influential risk factors for different neurodegenerative diseases, including AD. In the present work, we describe the state of the art of APP proteolytic processing, underlining the different roles of its cleavage fragments in both physiological and pathological contexts. Considering the neuroprotective role of the soluble APP alpha (sAPPα) fragment, we hypothesised that sAPPα could modulate the expression of genes of interest for AD and TBI. Hence, we present preliminary experiments addressing sAPPα-mediated regulation of BACE1, Isthmin 2 (ISM2), Tetraspanin-3 (TSPAN3) and the Vascular Endothelial Growth Factor (VEGFA), each discussed from a biological and pharmacological point of view in AD and TBI. We finally propose a neuroprotective interaction network, in which the Receptor for Activated C Kinase 1 (RACK1) and the signalling cascade of PKCβII/nELAV/VEGF play hub roles, suggesting that vasculogenic-targeting therapies could be a feasible approach for vascular-related brain injuries typical of AD and TBI. Full article

(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)

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