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Aksu M, Kaschke K, Podojil JR, Chiang M, Steckler I, Bruce K, Cogswell AC, Schulz G, Kelly J, Wiseman RL, Miller S, Popko B, Chen Y. AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss. Glia 2025; 73:1241-1257. [PMID: 39928347 PMCID: PMC12014361 DOI: 10.1002/glia.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 01/05/2025] [Accepted: 01/28/2025] [Indexed: 02/11/2025]
Abstract
Inflammation-induced oligodendrocyte death and CNS demyelination are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions of Grp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels of Grp78 as well as Ho-1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.
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Affiliation(s)
- Metin Aksu
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Kevin Kaschke
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Joseph R. Podojil
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - MingYi Chiang
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - Ian Steckler
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Kody Bruce
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Andrew C. Cogswell
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - Gwen Schulz
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
| | - Jeffery Kelly
- The Scripps Research Institute, Department of Chemistry, La Jolla, CA 92037, USA
| | - R. Luke Wiseman
- The Scripps Research Institute, Department of Molecular and Cellular Biology, La Jolla, CA 92037, USA
| | - Stephen Miller
- Northwestern University, Department of Microbiology-Immunology, Chicago, IL 60611, USA
| | - Brian Popko
- Northwestern University, Department of Neurology, Chicago, IL 60611, USA
| | - Yanan Chen
- Loyola University Chicago, Department of Biology, Chicago, IL 60660, USA
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2
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Papadopoulos D, Magliozzi R, Bandiera S, Cimignolo I, Barusolo E, Probert L, Gorgoulis V, Reynolds R, Nicholas R. Accelerated Cellular Senescence in Progressive Multiple Sclerosis: A Histopathological Study. Ann Neurol 2025; 97:1074-1087. [PMID: 39891488 PMCID: PMC12081997 DOI: 10.1002/ana.27195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/29/2024] [Accepted: 01/16/2025] [Indexed: 02/03/2025]
Abstract
OBJECTIVE The neurodegenerative processes driving the build-up of disability in progressive multiple sclerosis (P-MS) have not been fully elucidated. Recent data link cellular senescence (CS) to neurodegeneration. We investigated for evidence of CS in P-MS and sought to determine its pattern. METHODS We used 53BP1, p16, and lipofuscin as markers of CS in white matter lesions (WMLs), normal appearing white matter (NAWM), normal appearing cortical gray matter (NAGM), control white matter (CWM), and control gray matter (CGM) on autopsy material from patient with P-MS and healthy controls. Senescence-associated secretory phenotype (SASP) factors were quantified in cerebrospinal fluid (CSF). RESULTS P16+ cell counts were significantly increased in WMLs and GMLs, compared with NAWM, CWM, NAGM, and CGM and lipofuscin+ cells were significantly increased in WMLs, compared with NAWM and CWM, indicating more abundant CS in demyelinated lesions. The 53BP1+ cells in WMLs were significantly increased compared with NAWM and CWM. The 53BP1+ and p16+ cells were found significantly more abundant in acute active WMLs and GMLs, compared with chronic inactive lesions. Co-localization studies showed evidence of CS in neurons, astrocytes, oligodendrocytes, microglia, and macrophages. Among the quantified CSF SASP factors, IL-6, MIF, and MIP1a levels correlated with 53BP1+ cell counts in NAGM, whereas IL-10 levels correlated with p16+ cell counts in NAWM. P16+ cell counts in WMLs exhibited an inverse correlation with time to requiring a wheelchair and with age at death. INTERPRETATION Our data indicates that CS primarily affects actively demyelinating gray and WMLs. A higher senescent cell load in P-MS is associated with faster disability progression and death. ANN NEUROL 2025;97:1074-1087.
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Affiliation(s)
- Dimitrios Papadopoulos
- School of MedicineEuropean UniversityNicosiaCyprus
- Laboratory of Molecular GeneticsHellenic Pasteur InstituteAthensGreece
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of MedicineNational and Kapodistrian University of AthensAthensGreece
| | - Roberta Magliozzi
- Department of Neurosciences and Biomedicine and MovementThe Multiple Sclerosis Center of University Hospital of VeronaVeronaItaly
- Department of Brain Sciences, Faculty of MedicineImperial College LondonLondonUK
| | - Sara Bandiera
- Department of Brain Sciences, Faculty of MedicineImperial College LondonLondonUK
| | - Ilaria Cimignolo
- Department of Neurosciences and Biomedicine and MovementThe Multiple Sclerosis Center of University Hospital of VeronaVeronaItaly
| | - Elena Barusolo
- Department of Neurosciences and Biomedicine and MovementThe Multiple Sclerosis Center of University Hospital of VeronaVeronaItaly
| | - Lesley Probert
- Laboratory of Molecular GeneticsHellenic Pasteur InstituteAthensGreece
| | - Vassilis Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of MedicineNational and Kapodistrian University of AthensAthensGreece
- Ninewells Hospital and Medical SchoolUniversity of DundeeDundeeUK
- Division of Cancer Sciences, School of Medical Sciences, Faculty of BiologyMedicine and Health, University of ManchesterManchesterUK
| | - Richard Reynolds
- Department of Brain Sciences, Faculty of MedicineImperial College LondonLondonUK
| | - Richard Nicholas
- Department of Brain Sciences, Faculty of MedicineImperial College LondonLondonUK
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Seke M, Stankovic A, Zivkovic M. Capacity of fullerenols to modulate neurodegeneration induced by ferroptosis: Focus on multiple sclerosis. Mult Scler Relat Disord 2025; 97:106378. [PMID: 40088719 DOI: 10.1016/j.msard.2025.106378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/10/2025] [Accepted: 03/05/2025] [Indexed: 03/17/2025]
Abstract
Multiple sclerosis is an inflammatory disease of the central nervous system (CNS), characterized by oligodendrocyte loss and demyelination of axons leading to neurodegeneration and severe neurological disability. Despite the existing drugs that have immunomodulatory effects an adequate therapy that slow down or stop neuronal death has not yet been found. Oxidative stress accompanied by excessive release of iron into the extracellular space, mitochondrial damage and lipid peroxidation are important factors in the controlled cell death named ferroptosis, latterly recognized in MS. As the fullerenols exhibit potent antioxidant activity, recent results imply that they could have protective effects by suppressing ferroptosis. Based on the current knowledge we addressed the main mechanisms of the protective effects of fullerenols in the CNS in relation to ferroptosis. Inhibition of inflammation, iron overload and lipid peroxidation through the signal transduction mechanism of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), chelation of heavy metals and free radical scavenging using fullerenols are proposed as benefitial strategy preventing MS progression. Current review connects ferroptosis molecular targets and important factors of MS progression, with biomedical properties and mechanisms of fullerenols' actions, to propose new treatment strategies that could be addaptobale in other neurodegenerative diseases.
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Affiliation(s)
- Mariana Seke
- Laboratory for Radiobiology and Molecular Genetics, ˮVinčaˮ Institute of Nuclear Sciences -National Institute of The Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, Belgrade 11 000, Serbia
| | - Aleksandra Stankovic
- Laboratory for Radiobiology and Molecular Genetics, ˮVinčaˮ Institute of Nuclear Sciences -National Institute of The Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, Belgrade 11 000, Serbia
| | - Maja Zivkovic
- Laboratory for Radiobiology and Molecular Genetics, ˮVinčaˮ Institute of Nuclear Sciences -National Institute of The Republic of Serbia, University of Belgrade, Mike Petrovica Alasa 12-14, Belgrade 11 000, Serbia.
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4
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Khabazian A, Koopaie M, Khabazian T, Manifar S, Kolahdooz S, Tafakhori A. Evaluation of salivary nitric oxide levels and anxiety in multiple sclerosis patients, with and without Xerostomia: correlation with clinical variables. BMC Oral Health 2025; 25:507. [PMID: 40200257 PMCID: PMC11980173 DOI: 10.1186/s12903-025-05878-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/26/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Xerostomia is a prevalent but often overlooked condition in multiple sclerosis (MS) patients, significantly impacting their quality of life and oral health. This cross-sectional observational study investigates the role of nitric oxide (NO) in the pathophysiology of multiple sclerosis (MS) and explores its association with xerostomia in MS patients. The primary objective was to compare salivary NO concentrations and stress levels between MS patients with and without xerostomia. METHODS MS patients diagnosed by neurologists and MRI were categorized into two groups: those with xerostomia and those without. Unstimulated whole saliva samples were collected using the spitting method, and salivary NO levels were quantified using an enzyme-linked immunosorbent assay (ELISA) kit based on the Griess reaction. Stress levels were assessed using the Beck Anxiety Inventory (BAI) questionnaire. The presence of xerostomia was evaluated through the Xerostomia Inventory (XI) and clinical examinations. RESULTS Salivary NO levels were significantly higher in MS patients without xerostomia (227.47 ng/mL) compared to those with xerostomia (102.37 ng/mL, p < 0.001). Stress levels were also notably higher in MS patients with xerostomia (17.23) versus those without (11.77, p = 0.03). A moderate negative correlation was observed between salivary NO levels and xerostomia (r = 0.44, p < 0.001), indicating that lower NO levels were associated with a higher likelihood of xerostomia. The correlation between stress levels and xerostomia was weaker but still significant (r = 0.28, p = 0.03). Multivariate binary logistic regression analysis identified salivary NO, stress levels, and age as significant predictors of xerostomia in MS patients. The logistic regression model achieved an 80% accuracy in predicting xerostomia based on salivary NO levels and stress. CONCLUSION This study highlights a significant negative correlation between salivary NO levels and xerostomia, suggesting that decreased salivary NO concentrations are associated with an increased risk of xerostomia in MS patients. Additionally, stress levels were positively correlated with xerostomia, indicating a potential link between higher stress and the likelihood of xerostomia in MS patients.
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Affiliation(s)
- Aynaz Khabazian
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Koopaie
- Department of Oral Medicine, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.
| | - Tanaz Khabazian
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheila Manifar
- Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
- Department of Oral Medicine, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajad Kolahdooz
- Universal Scientific Education and Research Network (USERN), Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Tafakhori
- Department of Neurology, School of Medicine, Tehran University of Medical Sciences and Iranian Center of Neurological Research, Tehran, Iran
- Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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5
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Motyer A, Jackson S, Yang B, Harliwong I, Tian W, Shiu WIA, Shao Y, Wang B, McLean C, Barnett M, Kilpatrick TJ, Leslie S, Rubio JP. Neuronal somatic mutations are increased in multiple sclerosis lesions. Nat Neurosci 2025; 28:757-765. [PMID: 40038527 DOI: 10.1038/s41593-025-01895-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 01/09/2025] [Indexed: 03/06/2025]
Abstract
Neuroinflammation underpins neurodegeneration and clinical progression in multiple sclerosis (MS), but knowledge of processes linking these disease mechanisms remains incomplete. Here we investigated somatic single-nucleotide variants (sSNVs) in the genomes of 106 single neurons from post-mortem brain tissue of ten MS cases and 16 controls to determine whether somatic mutagenesis is involved. We observed an increase of 43.9 sSNVs per year in neurons from chronic MS lesions, a 2.5 times faster rate than in neurons from normal-appearing MS and control tissues. This difference was equivalent to 1,291 excess sSNVs in lesion neurons at 70 years of age compared to controls. We performed mutational signature analysis to investigate mechanisms underlying neuronal sSNVs and identified a signature characteristic of lesions with a strong, age-associated contribution to sSNV counts. This research suggests that neuroinflammation is mutagenic in the MS brain, potentially contributing to disease progression.
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Affiliation(s)
- Allan Motyer
- Melbourne Integrative Genomics, The University of Melbourne, Melbourne, Victoria, Australia
- School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Stacey Jackson
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
| | | | | | - Wei Tian
- BGI-Australia, Herston, Queensland, Australia
| | | | | | - Bo Wang
- China National GeneBank, Shenzhen, China
- Shenzhen Key Laboratory of Environmental Microbial Genomics and Application, BGI Research, Shenzhen, China
| | - Catriona McLean
- Department of Anatomical Pathology, Alfred Health, Melbourne, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Michael Barnett
- Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
- Department of Neurology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - Trevor J Kilpatrick
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Stephen Leslie
- Melbourne Integrative Genomics, The University of Melbourne, Melbourne, Victoria, Australia
- School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia
| | - Justin P Rubio
- The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
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6
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Golabi M, Kazemi D, Chadeganipour AS, Fouladseresht H, Sullman MJM, Ghezelbash B, Dastgerdi AY, Eskandari N. The Role of Cobalamin in Multiple Sclerosis: An Update. Inflammation 2025; 48:485-500. [PMID: 38902541 DOI: 10.1007/s10753-024-02075-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/29/2024] [Accepted: 06/03/2024] [Indexed: 06/22/2024]
Abstract
Multiple sclerosis (MS) is a neurodegenerative condition that results in axonal and permanent damage to the central nervous system, necessitating healing owing to autoimmune reactions and persistent neuroinflammation. Antioxidant and anti-inflammatory drugs are essential for the management of oxidative stress and neuroinflammation. Additionally, multivitamin supplementation, particularly vitamin B12 (cobalamin), may be beneficial for neuronal protection. Although there is no documented connection between vitamin B12 deficiency and MS, researchers have explored its potential as a metabolic cause. This review highlights the therapeutic benefits of cobalamin (Cbl) in patients with MS.
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Affiliation(s)
- Marjan Golabi
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Danial Kazemi
- Student Research Committee, Isfahan University of Medical Science, Isfahan, Iran
| | | | - Hamed Fouladseresht
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mark J M Sullman
- Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus
- Department of Social Sciences, University of Nicosia, Nicosia, Cyprus
| | - Behrooz Ghezelbash
- Laboratory Hematology and Blood Banking, School of Allied Medical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ava Yeganegi Dastgerdi
- Department of Cell and Molecular Biology, Falavarjan Branch, Islamic Azad University of Science, Isfahan, Iran
| | - Nahid Eskandari
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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7
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BAŞAR E, BAYINDIR H, KÖMÜRCÜ HF, DİRİK EB, ANLAR Ö, EREL Ö. Comparison of total oxidative state, total antioxidative state, serum paraoxonase activity, and thiol levels before and after 6 months of treatment in patients with multiple sclerosis who have been recently started on new therapy agents. Turk J Med Sci 2025; 55:398-403. [PMID: 40342312 PMCID: PMC12058004 DOI: 10.55730/1300-0144.5983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 04/17/2025] [Accepted: 03/10/2025] [Indexed: 05/11/2025] Open
Abstract
Background/aim The objective of this study was to establish the oxidative stress determiners as a total oxidative state (TOS), total antioxidative state (TAS), paraoxonase (PON) activity, oxidative stress index (OSI), and thiol/disulfide levels before and after 6 months of immunomodulator therapy in patients who were diagnosed according to the revised McDonald Criteria. Materials and methods Thirty-nine patients were included in our study who were diagnosed according to the revised McDonald Criteria, approved to participate in the study, and had been treated in the neurology inpatient clinic or presented in the neurology outpatient clinic of Ankara Yıldırım Beyazıt University Atatürk Training and Research Hospital. Blood samples were collected from patients before treatment and six months after treatment. The venous blood samples of the patients were evaluated for routine biochemical tests, TOS, TAS, PON activity, OSI, and thiol/disulfide levels. Results The oxidative stress parameter levels of blood samples obtained before and after 6 months of the treatment were compared. The blood samples obtained after 6 months of therapy exhibited statistically significant results, including elevated levels of native thiol/total thiol (SH/SH+SS), PON, and TAS (p = 0.001). No significant relation was observed between the duration of disease, sex, used therapy agents, and oxidative stress parameters. Conclusion In this study, we determined that TOS and OSI, which are indicators of oxidative stress, and TAS and PON, which exhibit antioxidative activity, can be employed to evaluate the therapy response. Additionally, we found that immunomodulator therapies can exhibit a protective effect, as evidenced by a reduction in oxidative stress indicators.
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Affiliation(s)
- Emel BAŞAR
- Department of Neurology, Ankara Bilkent City Hospital, Ankara,
Turkiye
| | - Hasan BAYINDIR
- Department of Neurology, Ankara Bilkent City Hospital, Ankara,
Turkiye
| | - Hatice Ferhan KÖMÜRCÜ
- Department of Neurology, University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, İstanbul,
Turkiye
| | - Ebru Bilge DİRİK
- Department of Neurology, Ankara Bilkent City Hospital, Ankara,
Turkiye
| | - Ömer ANLAR
- Department of Neurology, Yüksek İhtisas University Medical School, Ankara,
Turkiye
| | - Özcan EREL
- Department of Clinical Biochemistry, Yıldırım Beyazıt University Medical School, Ankara,
Turkiye
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8
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Zabihi MR, Zangooie A, Piroozkhah M, Harirchian MH, Salehi Z. From Multiple Sclerosis to Organ-Specific Autoimmune Disorders: Insights into the Molecular and Clinical Implications of Comorbidity. Mol Neurobiol 2025; 62:3396-3411. [PMID: 39287744 DOI: 10.1007/s12035-024-04458-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 08/27/2024] [Indexed: 09/19/2024]
Abstract
Multiple sclerosis (MS) is a complex autoimmune disorder that affects the central nervous system. Although the pathological mechanisms of MS have been extensively studied, its association with other autoimmune diseases, known as comorbidities, remains unclear. In this comprehensive review article, we aim to clarify the cellular and molecular relationship between MS and the incidence of organ-specific autoimmune comorbidities by summarizing former studies. We will explore the commonalities and possible differences between the immune response mechanisms in MS and other autoimmune diseases and provide an overview of the current understanding of the pathophysiological processes involved in the co-occurrence of MS and other organ-specific autoimmune comorbidities. Through this review, we aim to contribute to the development of effective therapeutic strategies that can improve the quality of life of MS patients with comorbidities.
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Affiliation(s)
- Mohammad Reza Zabihi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Zangooie
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Mobin Piroozkhah
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Harirchian
- Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Salehi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran.
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Rahdar S, Basir Z, Tabandeh MR, Ghotbeddin Z, Khazaeel K. Betaine alleviates cerebellar endoplasmic reticulum stress and oxidative imbalance in a cuprizone model of multiple sclerosis in rat. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:2651-2664. [PMID: 39249501 DOI: 10.1007/s00210-024-03381-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 08/14/2024] [Indexed: 09/10/2024]
Abstract
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, especially the cerebellum, with numerous physical and mental symptoms. Oxidative stress caused by inflammation can play a role in the occurrence of this disease. Betaine, a natural methyl donor compound, has potent neuroprotective effects. Here, we investigated the effects of betaine on motor behavior, cerebellar histological changes, oxidative stress response, and endoplasmic reticulum stress in a cuprizone (CPZ)-induced multiple sclerosis model in male rats. Twenty Wistar adult male rats were randomly divided into four groups including control, MS, betaine-treated MS, and betaine groups. MS was induced by feeding animals with rodent chow containing 0.5% CPZ for 12 weeks. Betaine was daily administrated as 1% in drinking water for the last 6 weeks. The motor behavioral performance was evaluated by open field, rotarod, and reverse basket tests. Histological analysis of the cerebellum was performed by hematoxylin and eosin (H&E) and Cresyl violet (Nissl) staining. Oxidative stress factors (GSH, GSSG, GPX, GR, and GT) were assessed in the experimental groups and finally, the expression of ERS-associated proteins was measured using western blot analysis. Data showed that treatment with betaine could effectively prevent and reverse the adverse behavioral manifestation compared with the MS group. Betaine treatment protected cerebellar demyelination and neuron and Purkinje cell degeneration against CPZ-induced demyelination. Betaine attenuated the protein levels of ESR-related proteins in the cerebellum of MS rats and similarly increased the level of enzymes related to antioxidants in the cerebellum. Therefore, our results suggest that oral administration of betaine may be used as a novel adjunct therapy against cerebellar dysfunctions in an animal model of MS.
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Affiliation(s)
- Samaneh Rahdar
- Department of Basic Sciences, Division of Histology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Zahra Basir
- Department of Basic Sciences, Division of Histology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Mohammad Reza Tabandeh
- Department of Basic Sciences, Division of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- Stem cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Zohreh Ghotbeddin
- Stem cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- Department of Basic Sciences, Division of Physiology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Kaveh Khazaeel
- Stem cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- Department of Basic Sciences, Division of Anatomy and Embryology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
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10
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Trofin DM, Sardaru DP, Trofin D, Onu I, Tutu A, Onu A, Onită C, Galaction AI, Matei DV. Oxidative Stress in Brain Function. Antioxidants (Basel) 2025; 14:297. [PMID: 40227270 PMCID: PMC11939459 DOI: 10.3390/antiox14030297] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/22/2025] [Accepted: 02/26/2025] [Indexed: 04/15/2025] Open
Abstract
Oxidative stress (OS) is an important factor in the pathophysiology of numerous neurodegenerative disorders, such as Parkinson's disease, multiple sclerosis, cerebrovascular pathology or Alzheimer's disease. OS also significantly influences progression among the various neurodegenerative disorders. The imbalance between the formation of reactive oxygen species (ROS) and the body's capacity to neutralize these toxic byproducts renders the brain susceptible to oxidative injury. Increased amounts of ROS can result in cellular malfunction, apoptosis and neurodegeneration. They also represent a substantial factor in mitochondrial dysfunction, a defining characteristic of neurodegenerative disorders. Comprehending the fundamental mechanisms of OS and its interactions with mitochondrial function, neuroinflammation and cellular protective pathways becomes essential for formulating targeted therapeutics to maintain brain health and reduce the impacts of neurodegeneration. We address recent highlights on the role of OS in brain function in terms of significance for neuronal health and the progression of neurodegenerative disorders.
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Affiliation(s)
- Daniela-Marilena Trofin
- Doctoral School, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania
| | - Dragos-Petrica Sardaru
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania (I.O.); (D.V.M.)
| | - Dan Trofin
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania (I.O.); (D.V.M.)
| | - Ilie Onu
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania (I.O.); (D.V.M.)
| | - Andrei Tutu
- Doctoral School, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania
| | - Ana Onu
- Doctoral School, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania
| | - Cristiana Onită
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania (I.O.); (D.V.M.)
| | - Anca Irina Galaction
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania (I.O.); (D.V.M.)
| | - Daniela Viorelia Matei
- Department of Biomedical Sciences, Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, 700454 Iasi, Romania (I.O.); (D.V.M.)
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11
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Messmer ML, Salapa HE, Popescu BF, Levin MC. RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis. Ann Neurol 2025; 97:313-328. [PMID: 39422285 DOI: 10.1002/ana.27114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 10/01/2024] [Accepted: 10/02/2024] [Indexed: 10/19/2024]
Abstract
OBJECTIVE Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS. METHODS Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration. RESULTS We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1low), MS-A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1high cases. INTERPRETATION hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2025;97:313-328.
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Affiliation(s)
- Miranda L Messmer
- Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK, Canada
- Cameco MS Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Hannah E Salapa
- Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK, Canada
- Cameco MS Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
- Neurology Division, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Bogdan F Popescu
- Cameco MS Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Michael C Levin
- Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK, Canada
- Cameco MS Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
- Neurology Division, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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12
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Jank L, Singh SS, Lee J, Dhukhwa A, Siavoshi F, Joshi D, Minney V, Gupta K, Ghimire S, Deme P, Schoeps VA, Soman K, Ladakis D, Smith M, Borkowski K, Newman J, Baranzini SE, Waubant EL, Fitzgerald KC, Mangalam A, Haughey N, Kornberg M, Chamling X, Calabresi PA, Bhargava P. Restoring the Multiple Sclerosis Associated Imbalance of Gut Indole Metabolites Promotes Remyelination and Suppresses Neuroinflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.10.27.620437. [PMID: 39554063 PMCID: PMC11565924 DOI: 10.1101/2024.10.27.620437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
In multiple sclerosis (MS) the circulating metabolome is dysregulated, with indole lactate (ILA) being one of the most significantly reduced metabolites. We demonstrate that oral supplementation of ILA impacts key MS disease processes in two preclinical models. ILA reduces neuroinflammation by dampening immune cell activation as well as infiltration; and promotes remyelination and in vitro oligodendrocyte differentiation through the aryl hydrocarbon receptor (AhR). Supplementation of ILA, a reductive indole metabolite, restores the gut microbiome's oxidative/reductive metabolic balance by lowering circulating indole acetate (IAA), an oxidative indole metabolite, that blocks remyelination and oligodendrocyte maturation. The ILA-induced reduction in circulating IAA is linked to changes in IAA-producing gut microbiota taxa and pathways that are also dysregulated in MS. Notably, a lower ILA:IAA ratio correlates with worse MS outcomes. Overall, these findings identify ILA as a potential anti-inflammatory remyelinating agent and provide insights into the role of gut dysbiosis-related metabolic alterations in MS progression.
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Affiliation(s)
- Larissa Jank
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Saumitra S. Singh
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Judy Lee
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Asmita Dhukhwa
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Fatemeh Siavoshi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Deepika Joshi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Veronica Minney
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kanak Gupta
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Sudeep Ghimire
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Pragney Deme
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Vinicius A. Schoeps
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
| | - Karthik Soman
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
| | - Dimitrios Ladakis
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthew Smith
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kamil Borkowski
- West Coast Metabolomics Center, University of California Davis, Davis, CA, USA
| | - John Newman
- Obesity and Metabolism Research, Agriculture Research Service, United States Department of Agriculture, Davis, CA, USA
| | - Sergio E. Baranzini
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
| | - Emmanuelle L. Waubant
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA
| | - Kathryn C. Fitzgerald
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ashutosh Mangalam
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Center for the Prevention and Treatment of Visual Loss, Iowa City VA Health Care System, Iowa City, IA, USA
| | - Norman Haughey
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael Kornberg
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xitiz Chamling
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter A. Calabresi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Pavan Bhargava
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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13
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Olesen MA, Villavicencio-Tejo F, Cuevas-Espinoza V, Quintanilla RA. Unknown roles of tau pathology in neurological disorders. Challenges and new perspectives. Ageing Res Rev 2025; 103:102594. [PMID: 39577774 DOI: 10.1016/j.arr.2024.102594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/16/2024] [Accepted: 11/18/2024] [Indexed: 11/24/2024]
Abstract
Aging presents progressive changes that increase the susceptibility of the central nervous system (CNS) to suffer neurological disorders (NDs). Several studies have reported that an aged brain suffering from NDs shows the presence of pathological forms of tau protein, a microtubule accessory protein (MAP) critical for neuronal function. In this context, accumulative evidence has shown a pivotal contribution of pathological forms of tau to Alzheimer's disease (AD) and tauopathies. However, current investigations have implicated tau toxicity in other NDs that affect the central nervous system (CNS), including Parkinson's disease (PD), Huntington's disease (HD), Traumatic brain injury (TBI), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). These diseases are long-term acquired, affecting essential functions such as motor movement, cognition, hearing, and vision. Previous evidence indicated that toxic forms of tau do not have a critical contribution to the genesis or progression of these diseases. However, recent studies have shown that these tau forms contribute to neuronal dysfunction, inflammation, oxidative damage, and mitochondrial impairment events that contribute to the pathogenesis of these NDs. Recent studies have suggested that these neuropathologies could be associated with a prion-like behavior of tau, which induces a pathological dissemination of these toxic protein forms to different brain areas. Moreover, it has been suggested that this toxic propagation of tau from neurons into neighboring cells impairs the function of glial cells, oligodendrocytes, and endothelial cells by affecting metabolic function and mitochondrial health and inducing oxidative damage by tau pathology. Therefore, in this review, we will discuss current evidence demonstrating the critical role of toxic tau forms on NDs not related to AD and how its propagation and induced-bioenergetics failure may contribute to the pathogenic mechanism present in these NDs.
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Affiliation(s)
- Margrethe A Olesen
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile
| | - Francisca Villavicencio-Tejo
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile
| | - Víctor Cuevas-Espinoza
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile
| | - Rodrigo A Quintanilla
- Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile.
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14
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Salekzamani S, Pakkhesal S, Babaei M, Mirzaaghazadeh E, Mosaddeghi-Heris R, Talebi M, Sanaie S, Naseri A. Coenzyme Q10 supplementation in multiple sclerosis; A systematic review. Mult Scler Relat Disord 2025; 93:106212. [PMID: 39667129 DOI: 10.1016/j.msard.2024.106212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 12/02/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND AND AIMS Multiple Sclerosis (MS) is a chronic and progressive inflammatory disease of the central nervous system (CNS). Oxidative stress is a crucial mediator in multiple conditions, including the MS. Coenzyme Q10 (CoQ10) is a potent antioxidant, present in enzyme complexes of mitochondria, and involved in oxidative phosphorylation to produce adenosine triphosphate (ATP). The objective of this systematic review was to investigate the outcomes of CoQ10 supplementation in oxidative stress, inflammatory, and clinical status of patients with MS. METHODS Following the Cochrane and PRISMA methods, a comprehensive search was conducted in PubMed, Scopus, Embase, and Web of Science databases, and clinical studies that reported the outcomes of CoQ10 supplementation in MS patients, are included. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (RoB2). RESULTS The initial search yielded 237 articles, of which eight reports from six studies (total n = 195), including three RCTs, two semi-experimental studies, and one retrospective analysis were included. The effects of 2-3 months of CoQ10 supplementation on inflammatory factors, antioxidant enzyme system, and lipid peroxidation remain controversial in 200mg/day dose; however, 500mg/day of CoQ10 supplement can improve oxidative stress and inflammation, along with depression and fatigue amelioration in MS patients. DISCUSSION This study concludes that CoQ10 might exert dose-dependent beneficial effects on ameliorating oxidative stress and inflammation in MS, and also sheds light on its possible utility in relieving clinical symptoms of MS; however, limitations of the evidence such as the small number of included studies, suggested future studies for clinical recommendations. FUNDING AND REGISTRATION The research protocol was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences (grant number: 71910). This study was registered in International prospective register of systematic reviews (PROSPERO ID: CRD42023461877).
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Affiliation(s)
- Shabnam Salekzamani
- Department of Nutrition, Faculty of Health and Nutrition, Bushehr University of Medical Sciences, Bushehr, Iran.
| | - Sina Pakkhesal
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mohammad Babaei
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ehsan Mirzaaghazadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Reza Mosaddeghi-Heris
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mahnaz Talebi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Sarvin Sanaie
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Amirreza Naseri
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran; Tabriz USERN Office, Universal Scientific Education and Research Network (USERN), Tabriz, Iran.
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15
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Maupin EA, Adams KL. Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis. J Neurochem 2025; 169:e16301. [PMID: 39831743 PMCID: PMC11745082 DOI: 10.1111/jnc.16301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/16/2024] [Accepted: 12/19/2024] [Indexed: 01/22/2025]
Abstract
Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, the irreversible state of cell cycle arrest, is the main driver of aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Cellular senescence in the central nervous system of MS patients has recently gained attention, with several studies providing evidence that demyelination induces cellular senescence, with common hallmarks of p16INK4A and p21 expression, oxidative stress, and senescence-associated secreted factors. Here we discuss the current evidence of cellular senescence in animal models of MS and different glial populations in the central nervous system, highlighting the major gaps in the field that still remain. As premature senescence in MS may exacerbate demyelination and inflammation, resulting in inhibition of myelin repair, it is critical to increase understanding of cellular senescence in vivo, the functional effects of senescence on glial cells, and the impact of removing senescent cells on remyelination and MS. This emerging field holds promise for opening new avenues of treatment for MS patients.
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Affiliation(s)
- Elizabeth A. Maupin
- Department of Biological SciencesUniversity of Notre DameNotre DameIndianaUSA
| | - Katrina L. Adams
- Department of Biological SciencesUniversity of Notre DameNotre DameIndianaUSA
- The Center for Stem Cells and Regenerative MedicineUniversity of Notre DameNotre DameIndianaUSA
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16
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Sharma T, Mehan S, Tiwari A, Khan Z, Gupta GD, Narula AS. Targeting Oligodendrocyte Dynamics and Remyelination: Emerging Therapies and Personalized Approaches in Multiple Sclerosis Management. Curr Neurovasc Res 2025; 21:359-417. [PMID: 39219420 DOI: 10.2174/0115672026336440240822063430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 01/01/1970] [Accepted: 07/12/2024] [Indexed: 09/04/2024]
Abstract
Multiple sclerosis (MS) is a progressive autoimmune condition that primarily affects young people and is characterized by demyelination and neurodegeneration of the central nervous system (CNS). This in-depth review explores the complex involvement of oligodendrocytes, the primary myelin- producing cells in the CNS, in the pathophysiology of MS. It discusses the biochemical processes and signalling pathways required for oligodendrocytes to function and remain alive, as well as how they might fail and cause demyelination to occur. We investigate developing therapeutic options that target remyelination, a fundamental component of MS treatment. Remyelination approaches promote the survival and differentiation of oligodendrocyte precursor cells (OPCs), restoring myelin sheaths. This improves nerve fibre function and may prevent MS from worsening. We examine crucial parameters influencing remyelination success, such as OPC density, ageing, and signalling pathway regulation (e.g., Retinoid X receptor, LINGO-1, Notch). The review also examines existing neuroprotective and antiinflammatory medications being studied to see if they can assist oligodendrocytes in surviving and reducing the severity of MS symptoms. The review focuses on medicines that target the myelin metabolism in oligodendrocytes. Altering oligodendrocyte metabolism has been linked to reversing demyelination and improving MS patient outcomes through various mechanisms. We also explore potential breakthroughs, including innovative antisense technologies, deep brain stimulation, and the impact of gut health and exercise on MS development. The article discusses the possibility of personalized medicine in MS therapy, emphasizing the importance of specific medicines based on individual molecular profiles. The study emphasizes the need for reliable biomarkers and improved imaging tools for monitoring disease progression and therapy response. Finally, this review focuses on the importance of oligodendrocytes in MS and the potential for remyelination therapy. It also underlines the importance of continued research to develop more effective treatment regimens, taking into account the complexities of MS pathology and the different factors that influence disease progression and treatment.
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Affiliation(s)
- Tarun Sharma
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Aarti Tiwari
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | | | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC 27516, USA
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17
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Zhao X, Hu X, Wang W, Lu S. Macrophages dying from ferroptosis promote microglia-mediated inflammatory responses during spinal cord injury. Int Immunopharmacol 2024; 143:113281. [PMID: 39357207 DOI: 10.1016/j.intimp.2024.113281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/15/2024] [Accepted: 09/26/2024] [Indexed: 10/04/2024]
Abstract
The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1β, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1β and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.
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Affiliation(s)
- Xuan Zhao
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Xinli Hu
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Beijing, China
| | - Wei Wang
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Beijing, China.
| | - Shibao Lu
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Beijing, China.
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18
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Shriwash N, Aiman A, Singh P, Basir SF, Shamsi A, Shahid M, Dohare R, Islam A. Understanding the role of potential biomarkers in attenuating multiple sclerosis progression via multiomics and network-based approach. PLoS One 2024; 19:e0314428. [PMID: 39700118 DOI: 10.1371/journal.pone.0314428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 11/10/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Multiple sclerosis (MS) is a complex neurological disorder marked by neuroinflammation and demyelination. Understanding its molecular basis is vital for developing effective treatments. This study aims to elucidate the molecular progression of MS using multiomics and network-based approach. METHODS We procured differentially expressed genes in MS patients and healthy controls by accessing mRNA dataset from a publicly accessible database. The DEGs were subjected to a non-trait weighted gene co-expression network (WGCN) for hub DEGs identification. These hub DEGs were utilized for enrichment, protein-protein interaction network (PPIN), and feed-forward loop (FFL) analyses. RESULTS We identified 880 MS-associated DEGs. WGCN revealed a total of 122 hub DEGs of which most significant pathway, gene ontology (GO)-biological process (BP), GO-molecular function (MF) and GO-cellular compartment (CC) terms were assembly and cell surface presentation of N-methyl-D-aspartate (NMDA) receptors, regulation of catabolic process, NAD(P)H oxidase H2O2 forming activity, postsynaptic recycling endosome. The intersection of top 10 significant pathways, GO-BP, GO-MF, GO-CC terms, and PPIN top cluster genests identified STAT3 and CREB1 as key biomarkers. Based on essential centrality measures, CREB1 was retained as the final biomarker. Highest-order subnetwork FFL motif comprised one TF (KLF7), one miRNA (miR-328-3p), and one mRNA (CREB1) based on essential centrality measures. CONCLUSIONS This study provides insights into the roles of potential biomarkers in MS progression and offers a system-level view of its molecular landscape. Further experimental validation is needed to confirm these biomarkers' significance, which will lead to early diagnostic and therapeutic advancements.
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Affiliation(s)
- Nitesh Shriwash
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Okhla, New Delhi, India
| | - Ayesha Aiman
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Okhla, New Delhi, India
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, Okhla, New Delhi, India
| | - Prithvi Singh
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Okhla, New Delhi, India
| | - Seemi Farhat Basir
- Department of Biosciences, Faculty of Natural Sciences, Jamia Millia Islamia, Okhla, New Delhi, India
| | - Anas Shamsi
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Mohammad Shahid
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Ravins Dohare
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Okhla, New Delhi, India
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Okhla, New Delhi, India
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19
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Smith Z, Cheli VT, Angeliu CG, Wang C, Denaroso GE, Tumuluri SG, Corral J, Garbarini K, Paez PM. Ferritin loss in astrocytes reduces spinal cord oxidative stress and demyelination in the experimental autoimmune encephalomyelitis (EAE) model. Glia 2024; 72:2327-2343. [PMID: 39228110 PMCID: PMC11930306 DOI: 10.1002/glia.24616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/12/2024] [Accepted: 08/24/2024] [Indexed: 09/05/2024]
Abstract
Demyelinating diseases such as multiple sclerosis (MS) cause myelin degradation and oligodendrocyte death, resulting in the release of toxic iron and iron-induced oxidative stress. Astrocytes have a large capacity for iron transport and storage, however the role of astrocytic iron homeostasis in demyelinating disorders is not completely understood. Here we investigate whether astrocytic iron metabolism modulates neuroinflammation, oligodendrocyte survival, and oxidative stress following demyelination. To this aim, we conditionally knock out ferritin in astrocytes and induce experimental autoimmune encephalomyelitis (EAE), an autoimmune-mediated model of demyelination. Ferritin ablation in astrocytes reduced the severity of disease in both the acute and chronic phases. The day of onset, peak disease severity, and cumulative clinical score were all significantly reduced in ferritin KO animals. This corresponded to better performance on the rotarod and increased mobility in ferritin KO mice. Furthermore, the spinal cord of ferritin KO mice display decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes. Correspondingly, the size of demyelinated lesions, iron accumulation, and oxidative stress were attenuated in the CNS of ferritin KO subjects, particularly in white matter regions of the spinal cord. Thus, deleting ferritin in astrocytes reduced neuroinflammation, oxidative stress, and myelin deterioration in EAE animals. Collectively, these findings suggest that iron storage in astrocytes is a potential therapeutic target to lessen CNS inflammation and myelin loss in autoimmune demyelinating diseases.
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Affiliation(s)
- Z Smith
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - V T Cheli
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - C G Angeliu
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - C Wang
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - G E Denaroso
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - S G Tumuluri
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - J Corral
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - K Garbarini
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
| | - P M Paez
- Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, Institute for Myelin and Glia Exploration, The State University of New York, University at Buffalo, Buffalo, New York, USA
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20
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Evangelista BG, Giardini AC, Hösch NG, Sant'Anna MB, Martins BB, Neto BS, Chacur M, Pagano RL, Picolo G, Zambelli VO. Aldehyde dehydrogenase-2 deficiency aggravates neuroinflammation, nociception, and motor impairment in a mouse model of multiple sclerosis. Free Radic Biol Med 2024; 225:767-775. [PMID: 39481766 DOI: 10.1016/j.freeradbiomed.2024.10.305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/15/2024] [Accepted: 10/28/2024] [Indexed: 11/02/2024]
Abstract
Aldehyde dehydrogenase-2 deficiency (ALDH2∗2) found in 36 % of Han Chinese, affects approximately 8 % of the world population. ALDH2 is a mitochondrial key enzyme in detoxifying reactive aldehydes to less reactive forms. Studies demonstrate a potential link between ALDH2∗2 mutation and neurodegenerative diseases. Multiple sclerosis (MS) is an incurable and disabling neurodegenerative autoimmune disease that induces motor, and cognitive impairment, and hypersensitivity, including chronic pain. Accumulating evidence suggests that reactive aldehydes, such as 4-hydroxynonenal (4-HNE), contribute to MS pathogenesis. Here, using knock-in mice carrying the inactivating point mutation in ALDH2, identical to the mutation found in Han Chinese, we showed that the impairment in ALDH2 activity heightens motor disabilities, and hypernociception induced by experimental autoimmune encephalomyelitis (EAE). The deleterious clinical signs are followed by glial cell activation in the spinal cord and increased 4-HNE levels in the spinal cord and serum. Importantly, the pharmacological ALDH2 activation by Alda-1 ameliorates EAE-induced hypernociception and motor impairment in both wild-type and ALDH2∗2KI mice. Reduced hypernociception was associated with less early growth response protein 1 (EGR1), neuronal and glial activation, and reactive aldehyde accumulation in the spinal cord and serum. Taken together, our data suggest that the mitochondrial enzyme ALDH2 plays a role in regulating clinical, cellular, and molecular responses associated with EAE. This indicates that ALDH2 could serve as a molecular target for MS control, with ALDH2 activators, like Alda-1 as potential neuroprotective candidates. Furthermore, ALDH2∗2 carriers may be at increased risk of developing more accentuated MS symptoms.
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MESH Headings
- Animals
- Aldehyde Dehydrogenase, Mitochondrial/genetics
- Aldehyde Dehydrogenase, Mitochondrial/metabolism
- Mice
- Multiple Sclerosis/genetics
- Multiple Sclerosis/pathology
- Multiple Sclerosis/metabolism
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Disease Models, Animal
- Aldehydes/metabolism
- Nociception
- Neuroinflammatory Diseases/metabolism
- Neuroinflammatory Diseases/pathology
- Neuroinflammatory Diseases/genetics
- Neuroinflammatory Diseases/etiology
- Spinal Cord/metabolism
- Spinal Cord/pathology
- Benzamides/pharmacology
- Gene Knock-In Techniques
- Humans
- Mice, Inbred C57BL
- Female
- Benzodioxoles/pharmacology
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Affiliation(s)
- Bianca G Evangelista
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil
| | - Aline C Giardini
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil
| | - Natália G Hösch
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil
| | - Morena B Sant'Anna
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil
| | - Bárbara B Martins
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil
| | - Beatriz S Neto
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil
| | - Marucia Chacur
- Department of Anatomy, University of São Paulo, São Paulo, SP, Brazil
| | - Rosana L Pagano
- Laboratory of Neuroscience, Hospital Sírio-Libanês, São Paulo, SP, 01308-060, Brazil
| | - Gisele Picolo
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil
| | - Vanessa O Zambelli
- Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, 05503-900, Brazil.
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21
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Damiza-Detmer A, Pawełczyk M, Głąbiński A. Protective Role of High-Density Lipoprotein in Multiple Sclerosis. Antioxidants (Basel) 2024; 13:1276. [PMID: 39594418 PMCID: PMC11591269 DOI: 10.3390/antiox13111276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 10/18/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
Multiple sclerosis (MS) is a chronic, progressive demyelinating disease with a most likely autoimmune background and a neurodegenerative component. Besides the demyelinating process caused by autoreactive antibodies, an increased permeability in the blood-brain barrier (BBB) also plays a key role. Recently, there has been growing interest in assessing lipid profile alterations in patients with MS. As a result of myelin destruction, there is an increase in the level of cholesterol released from cells, which in turn causes disruptions in lipid metabolism homeostasis both in the central nervous system (CNS) and peripheral tissues. Currently, there is a growing body of evidence suggesting a protective role of HDL in MS through its effect on the BBB by decreasing its permeability. This follows from the impact of HDL on the endothelium and its anti-inflammatory effect, mostly by interacting with adhesion molecules like vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin. HDL, through its action via sphingosine-1-phosphate, exerts an inhibitory effect on leukocyte migration, and its antioxidant properties contribute to the improvement of the BBB function. In this review, we want to summarize these studies and focus on HDL as a mediator of the anti-inflammatory response in MS.
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Affiliation(s)
- Agnieszka Damiza-Detmer
- Department of Neurology and Stroke, Medical University of Lodz, ul. Zeromskiego 113, 90-549 Lodz, Poland (A.G.)
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22
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Navarrete-Pérez A, Gómez-Melero S, Escribano BM, Galvao-Carmona A, Conde-Gavilán C, Peña-Toledo MÁ, Villarrubia N, Villar LM, Túnez I, Agüera-Morales E, Caballero-Villarraso J. MIND Diet Impact on Multiple Sclerosis Patients: Biochemical Changes after Nutritional Intervention. Int J Mol Sci 2024; 25:10009. [PMID: 39337497 PMCID: PMC11431943 DOI: 10.3390/ijms251810009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 09/11/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
There is substantial evidence supporting the neuroprotective effects of the MIND diet in neurodegenerative diseases like Parkinson's and Alzheimer's. Our aim was to evaluate the impact of a nutritional intervention (NI) with this diet on multiple sclerosis (MS) patients. The study was conducted in two stages. In the first stage, two groups were included: MS patients before the NI (group A) and healthy control subjects (group B). In this stage, groups (A) and (B) were compared (case-control study). In the second stage, group (A) was assessed after the NI, with comparisons made between baseline and final measurements (before-and-after study). In the case-control stage (baseline evaluation), we found significant differences in fatigue scores (p < 0.001), adherence to the MIND diet (p < 0.001), the serum levels of brain-derived neurotrophic factor (BDNF) (p < 0.001), and higher oxidative status in the MS group, with lower levels of reduced glutathione (p < 0.001), reduced/oxidised glutathione ratio (p < 0.001), and elevated levels of lipoperoxidation (p < 0.002) and 8-hydroxy-2'-deoxyguanosine (p < 0.025). The before-and-after intervention stage showed improvements in fatigue scores (p < 0.001) and physical quality-of-life scores (MSQOL-54) (p < 0.022), along with decreases in the serum levels of glial-derived neurotrophic factor (GDNF) (p < 0.041), lipoperoxidation (p < 0.046), and 8-hydroxy-2'-deoxyguanosine (p < 0.05). Consumption of the MIND diet is linked to clinical and biochemical improvement in MS patients.
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Affiliation(s)
- Ainoa Navarrete-Pérez
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
| | - Sara Gómez-Melero
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
| | - Begoña Mª Escribano
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
- Department of Cell Biology, Physiology and Immunology, Faculty of Veterinary Medicine, Universidad of Córdoba, 14071 Córdoba, Spain
| | - Alejandro Galvao-Carmona
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
- Department of Psychology, Universidad Loyola Andalucía, 41704 Sevilla, Spain
| | - Cristina Conde-Gavilán
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
| | - Mª Ángeles Peña-Toledo
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
| | - Noelia Villarrubia
- Immunology Department, Hospital Universitario Ramón y Cajal, Red Española de Esclerosis Múltiple, Red de Enfermedades Inflamatorias, Instituto de Salud Carlos III, IRYCIS, 28034 Madrid, Spain; (N.V.); (L.M.V.)
| | - Luisa Mª Villar
- Immunology Department, Hospital Universitario Ramón y Cajal, Red Española de Esclerosis Múltiple, Red de Enfermedades Inflamatorias, Instituto de Salud Carlos III, IRYCIS, 28034 Madrid, Spain; (N.V.); (L.M.V.)
| | - Isaac Túnez
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
- Department of Biochemistry and Molecular Biology, Universidad of Córdoba, 14071 Córdoba, Spain
| | - Eduardo Agüera-Morales
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
- Neurology Service, Reina Sofia University Hospital, 14004 Córdoba, Spain
| | - Javier Caballero-Villarraso
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), 14004 Córdoba, Spain; (A.N.-P.); (S.G.-M.); (B.M.E.); (A.G.-C.); (C.C.-G.); (M.Á.P.-T.); (I.T.)
- Department of Biochemistry and Molecular Biology, Universidad of Córdoba, 14071 Córdoba, Spain
- Clinical Analyses Service, Reina Sofía University Hospital, 14004 Córdoba, Spain
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23
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Gakh O, Wilkins JM, Guo Y, Popescu BF, Weigand SD, Kalinowska-Lyszczarz A, Lucchinetti CF. Infrared spectral profiling of demyelinating activity in multiple sclerosis brain tissue. Acta Neuropathol Commun 2024; 12:146. [PMID: 39256864 PMCID: PMC11385516 DOI: 10.1186/s40478-024-01854-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 08/25/2024] [Indexed: 09/12/2024] Open
Abstract
Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. The highly dynamic nature of MS lesions has made them difficult to study using traditional histopathology due to the specificity of current stains. This requires numerous stains to track and study demyelinating activity in MS. Thus, we utilized Fourier transform infrared (FTIR) spectroscopy to generate holistic biomolecular profiles of demyelinating activities in MS brain tissue. Multivariate analysis can differentiate MS tissue from controls. Analysis of the absorbance spectra shows profound reductions of lipids, proteins, and phosphate in white matter lesions. Changes in unsaturated lipids and lipid chain length indicate oxidative damage in MS brain tissue. Altered lipid and protein structures suggest changes in MS membrane structure and organization. Unique carbohydrate signatures are seen in MS tissue compared to controls, indicating altered metabolic activities. Cortical lesions had increased olefinic lipid content and abnormal membrane structure in normal appearing MS cortex compared to controls. Our results suggest that FTIR spectroscopy can further our understanding of lesion evolution and disease mechanisms in MS paving the way towards improved diagnosis, prognosis, and development of novel therapeutics.
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Affiliation(s)
- Oleksandr Gakh
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
| | | | - Yong Guo
- Department of Neurology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Bogdan F Popescu
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, S7K 0M7, Canada
- Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, S7K 0M7, Canada
| | - Stephen D Weigand
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
| | - Alicja Kalinowska-Lyszczarz
- Department of Neurology, Division of Neurochemistry and Neuropathology, Poznan University of Medical Sciences, 49 Przybyszewskiego Street, 60-355, Poznan, Poland
| | - Claudia F Lucchinetti
- Department of Neurology, Frank and Charmaine Denius Dean's Chair in Medical Leadership, Dean of Dell Medical School, Senior Vice President Medical Affairs, University of Texas at Austin, Austin, TX, 78712, USA.
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24
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Toubasi AA, Xu J, Eisma JJ, AshShareef S, Gheen C, Vinarsky T, Adapa P, Shah S, Eaton J, Dortch RD, Donahue MJ, Bagnato F. Watershed regions are more susceptible to tissue microstructural injury in multiple sclerosis. Brain Commun 2024; 6:fcae299. [PMID: 39372138 PMCID: PMC11452773 DOI: 10.1093/braincomms/fcae299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 07/22/2024] [Accepted: 09/02/2024] [Indexed: 10/08/2024] Open
Abstract
Histopathologic studies report higher concentrations of multiple sclerosis white matter lesions in watershed areas of the brain, suggesting that areas with relatively lower oxygen levels may be more vulnerable to disease. However, it is unknown at what point in the disease course lesion predilection for watershed territories begins. Accordingly, we studied a cohort of people with newly diagnosed disease and asked whether (1) white matter lesions disproportionally localize to watershed-regions and (2) the degree of microstructural injury in watershed-lesions is more severe. Fifty-four participants, i.e. 38 newly diagnosed people with multiple sclerosis, clinically isolated syndrome or radiologically isolated syndrome, and 16 age- and sex-matched healthy controls underwent brain magnetic resonance imaging. T1-weighted and T2-weighted fluid-attenuated inversion recovery sequences, selective inversion recovery quantitative magnetisation transfer images, and the multi-compartment diffusion imaging with the spherical mean technique were acquired. We computed the macromolecular-to-free pool size ratio, and the apparent axonal volume fraction maps to indirectly estimate myelin and axonal integrity, respectively. We produced a flow territory atlas in each subject's native T2-weighted fluid-attenuated inversion recovery images using a T1-weighted magnetic resonance imaging template in the Montreal Neurological Institute 152 space. Lesion location relative to the watershed, non-watershed and mixed brain vascular territories was annotated. The same process was performed on the T2-weighted fluid-attenuated inversion recovery images of the healthy controls using 294 regions of interest. Generalized linear mixed models for continuous outcomes were used to assess differences in size, pool size ratio and axonal volume fraction between lesions/regions of interests (in healthy controls) situated in different vascular territories. In patients, we assessed 758 T2-lesions and 356 chronic black holes (cBHs). The watershed-territories had higher relative and absolute concentrations of T2-lesions (P≤0.041) and cBHs (P≤0.036) compared to either non-watershed- or mixed-zones. T2-lesions in watershed-areas also had lower pool size ratio relative to T2-lesions in either non-watershed- or mixed-zones (P = 0.039). These results retained significance in the sub-cohort of people without vascular comorbidities and when accounting for periventricular lesions. In healthy controls, axonal volume fraction was higher only in mixed-areas regions of interest compared to non-watershed-ones (P = 0.008). No differences in pool size ratio were seen. We provide in vivo evidence that there is an association between arterial vascularisation of the brain and multiple sclerosis-induced tissue injury as early as the time of disease diagnosis. Our findings underline the importance of oxygen delivery and healthy arterial vascularisation to prevent lesion formation and foster a better outcome in multiple sclerosis.
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Affiliation(s)
- Ahmad A Toubasi
- Neuorimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA
| | - Junzhong Xu
- Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Sciences, VUMC, Nashville, TN 37232, USA
| | - Jarrod J Eisma
- Neuorimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA
| | - Salma AshShareef
- Neuorimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA
- Department of Life and Physical Sciences, Fisk University, Nashville, TN 37208, USA
| | - Caroline Gheen
- Neuorimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA
| | - Taegan Vinarsky
- Neuorimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA
| | - Pragnya Adapa
- Neuorimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA
- College of Arts and Sciences, Vanderbilt University, Nashville, TN 37240, USA
| | - Shailee Shah
- Neuroimmunology Division, Department of Neurology, VUMC, Nashville, TN 37232, USA
| | - James Eaton
- Neuroimmunology Division, Department of Neurology, VUMC, Nashville, TN 37232, USA
- Cognitive Division, Department of Neurology, VUMC, Nashville, TN 37232, USA
| | - Richard D Dortch
- Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Manus J Donahue
- Cognitive Division, Department of Neurology, VUMC, Nashville, TN 37232, USA
- Department of Psychiatry and Behavioral Science, VUMC, Nashville, TN 37232, USA
| | - Francesca Bagnato
- Neuorimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA
- Department of Neurology, TN Valley Healthcare System, Nashville Veterans Affairs Medical Center, Nashville, TN 37212, USA
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25
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Emamnejad R, Pagnin M, Petratos S. The iron maiden: Oligodendroglial metabolic dysfunction in multiple sclerosis and mitochondrial signaling. Neurosci Biobehav Rev 2024; 164:105788. [PMID: 38950685 DOI: 10.1016/j.neubiorev.2024.105788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/06/2024] [Accepted: 06/24/2024] [Indexed: 07/03/2024]
Abstract
Multiple sclerosis (MS) is an autoimmune disease, governed by oligodendrocyte (OL) dystrophy and central nervous system (CNS) demyelination manifesting variable neurological impairments. Mitochondrial mechanisms may drive myelin biogenesis maintaining the axo-glial unit according to dynamic requisite demands imposed by the axons they ensheath. The promotion of OL maturation and myelination by actively transporting thyroid hormone (TH) into the CNS and thereby facilitating key transcriptional and metabolic pathways that regulate myelin biogenesis is fundamental to sustain the profound energy demands at each axo-glial interface. Deficits in regulatory functions exerted through TH for these physiological roles to be orchestrated by mature OLs, can occur in genetic and acquired myelin disorders, whereby mitochondrial efficiency and eventual dysfunction can lead to profound oligodendrocytopathy, demyelination and neurodegenerative sequelae. TH-dependent transcriptional and metabolic pathways can be dysregulated during acute and chronic MS lesion activity depriving OLs from critical acetyl-CoA biochemical mechanisms governing myelin lipid biosynthesis and at the same time altering the generation of iron metabolism that may drive ferroptotic mechanisms, leading to advancing neurodegeneration.
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Affiliation(s)
- Rahimeh Emamnejad
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia.
| | - Maurice Pagnin
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia.
| | - Steven Petratos
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia.
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26
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Vaghasiya J, Jha A, Basu S, Bagan A, Jengsuksavat SK, Ravandi A, Pascoe CD, Halayko AJ. Neutralizing Oxidized Phosphatidylcholine Reduces Airway Inflammation and Hyperreactivity in a Murine Model of Allergic Asthma. BIOLOGY 2024; 13:627. [PMID: 39194564 DOI: 10.3390/biology13080627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/12/2024] [Accepted: 08/15/2024] [Indexed: 08/29/2024]
Abstract
Oxidative stress is associated with asthma pathobiology. We reported that oxidized phosphatidylcholines (OxPCs) are mediators of oxidative stress and accumulate in the lung in response to allergen challenge. The current study begins to unravel mechanisms for OxPC accumulation in the lung, providing the first insights about how OxPCs underpin allergic airway pathophysiology, and pre-clinical testing of selective neutralization of OxPCs in a murine model of allergic asthma. We hypothesized that intranasal delivery of E06, a natural IgM antibody that neutralizes the biological activity of OxPCs, can ameliorate allergen-induced airway inflammation and airway hyperresponsiveness. Adult BALB/c mice were intranasally (i.n.) challenged with house dust mite (HDM) (25 μg/mouse, 2 weeks). Some animals also received E06 monoclonal antibody (mAb) (10 µg) i.n. 1 hr before each HDM challenge. HDM challenge reduced mRNA for anti-oxidant genes (SOD1, SOD2, HO-1, and NFE2L2) in the lung by several orders of magnitude (p < 0.05). Concomitantly, total immune cell number in bronchoalveolar lavage fluid (BALF) increased significantly (p < 0.001). E06 mAb treatment prevented allergen-induced BALF immune cell number by 43% (p < 0.01). This included a significant blockade of eosinophils (by 48%, p < 0.001), neutrophils (by 80%, p < 0.001), macrophages (by 80%, p < 0.05), and CD4 (by 30%, p < 0.05) and CD8 (by 42%, p < 0.01) lymphocytes. E06 effects correlated with a significant reduction in TNF (by 64%, p < 0.001) and IL-1β (by 75%, p < 0.05) and a trend to diminish accumulation of other cytokines (e.g., IL-4, -10, and -33, and IFN-γ). E06 mAb treatment also inhibited HDM exposure-induced increases in total respiratory resistance and small airway resistance by 24% and 26%, respectively. In conclusion, prophylactic treatment with an OxPC-neutralizing antibody significantly limits allergen-induced airway inflammation and airway hyperresponsiveness, suggesting that OxPCs are important mediators of oxidative stress-associated allergic lung pathophysiology.
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Affiliation(s)
- Jignesh Vaghasiya
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Aruni Jha
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Sujata Basu
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Alaina Bagan
- Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Siwon K Jengsuksavat
- Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Amir Ravandi
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Christopher D Pascoe
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Andrew J Halayko
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Biology of Breathing Group, Children's Research Hospital of Manitoba, Winnipeg, MB R3E 3P4, Canada
- Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P4, Canada
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27
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Nheu D, Petratos S. How does Nogo-A signalling influence mitochondrial function during multiple sclerosis pathogenesis? Neurosci Biobehav Rev 2024; 163:105767. [PMID: 38885889 DOI: 10.1016/j.neubiorev.2024.105767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 05/30/2024] [Accepted: 06/08/2024] [Indexed: 06/20/2024]
Abstract
Multiple sclerosis (MS) is a severe neurological disorder that involves inflammation in the brain, spinal cord and optic nerve with key disabling neuropathological outcomes being axonal damage and demyelination. When degeneration of the axo-glial union occurs, a consequence of inflammatory damage to central nervous system (CNS) myelin, dystrophy and death can lead to large membranous structures from dead oligodendrocytes and degenerative myelin deposited in the extracellular milieu. For the first time, this review covers mitochondrial mechanisms that may be operative during MS-related neurodegenerative changes directly activated during accumulating extracellular deposits of myelin associated inhibitory factors (MAIFs), that include the potent inhibitor of neurite outgrowth, Nogo-A. Axonal damage may occur when Nogo-A binds to and signals through its cognate receptor, NgR1, a multimeric complex, to initially stall axonal transport and limit the delivery of important growth-dependent cargo and subcellular organelles such as mitochondria for metabolic efficiency at sites of axo-glial disintegration as a consequence of inflammation. Metabolic efficiency in axons fails during active demyelination and progressive neurodegeneration, preceded by stalled transport of functional mitochondria to fuel axo-glial integrity.
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Affiliation(s)
- Danica Nheu
- Department of Neuroscience, School of Translational Medicine, Monash University, Prahran, VIC 3004, Australia
| | - Steven Petratos
- Department of Neuroscience, School of Translational Medicine, Monash University, Prahran, VIC 3004, Australia.
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Wang Z, Xu J, Mo L, Zhan R, Zhang J, Liu L, Jiang J, Zhang Y, Bai Y. The Application Potential of the Regulation of Tregs Function by Irisin in the Prevention and Treatment of Immune-Related Diseases. Drug Des Devel Ther 2024; 18:3005-3023. [PMID: 39050796 PMCID: PMC11268596 DOI: 10.2147/dddt.s465713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Irisin is a muscle factor induced by exercise, generated through the proteolytic cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC-5). Numerous studies have shown that irisin plays a significant role in regulating glucose and lipid metabolism, inhibiting oxidative stress, reducing systemic inflammatory responses, and providing neuroprotection. Additionally, irisin can exert immunomodulatory functions by regulating regulatory T cells (Tregs). Tregs are a highly differentiated subset of mature T cells that play a key role in maintaining self-immune homeostasis and are closely related to infections, inflammation, immune-related diseases, and tumors. Irisin exerts persistent positive effects on Treg cell functions through various mechanisms, including regulating Treg cell differentiation and proliferation, improving their function, modulating the balance of immune cells, increasing the production of anti-inflammatory cytokines, and enhancing metabolic functions, thereby helping to maintain immune homeostasis and prevent immune-related diseases. As an important myokine, irisin interacts with receptors on the cell membrane, activating multiple intracellular signaling pathways to regulate cell metabolism, proliferation, and function. Although the specific receptor for irisin has not been fully identified, integrins are considered potential receptors. Irisin activates various signaling pathways, including AMPK, MAPK, and PI3K/Akt, through integrin receptors, thereby exerting multiple biological effects. These research findings provide important clues for understanding the mechanisms of irisin's action and theoretical basis for its potential applications in metabolic diseases and immunomodulation. This article reviews the relationship between irisin and Tregs, as well as the research progress of irisin in immune-related diseases such as multiple sclerosis, myasthenia gravis, acquired immune deficiency syndrome, type 1 diabetes, sepsis, and rheumatoid arthritis. Studies have revealed that irisin plays an important role in immune regulation by improving the function of Tregs, suggesting its potential application value in the treatment of immune-related diseases.
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Affiliation(s)
- Zhengjiang Wang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jiaqi Xu
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Liqun Mo
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Renshu Zhan
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jin Zhang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Li Liu
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Yingying Zhang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Yiping Bai
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
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Lee S, Martinez-Valbuena I, Lang AE, Kovacs GG. Cellular iron deposition patterns predict clinical subtypes of multiple system atrophy. Neurobiol Dis 2024; 197:106535. [PMID: 38761956 DOI: 10.1016/j.nbd.2024.106535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/30/2024] [Accepted: 05/14/2024] [Indexed: 05/20/2024] Open
Abstract
BACKGROUND Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. Therefore, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology. METHODS Iron burden in subcortical and brainstem regions were histologically mapped in human post-mortem brains of 4 MSA-parkinsonian (MSA-P), 4 MSA-cerebellar (MSA-C), and 1 MSA case with both parkinsonian and cerebellar features. We then performed the first cell type-specific evaluation of pathological iron deposition in α-synuclein-affected and -unaffected cells of the globus pallidus, putamen, and the substantia nigra, regions of highest iron concentration, using a combination of iron staining with immunolabelling. Selective regional and cellular vulnerability patterns of iron deposition were compared between disease subtypes. In 7 MSA cases, expression of key iron- and closely related oxygen-homeostatic genes were examined. RESULTS MSA-P and MSA-C showed different patterns of regional iron burden across the pathology-related systems. We identified subcortical microglia to predominantly accumulate iron, which was more distinct in MSA-P. MSA-C showed relatively heterogenous iron accumulation, with greater or similar deposition in astroglia. Iron deposition was also found outside cellular bodies. Cellular iron burden associated with oligodendrocytic, and not neuronal, α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen homeostatic genes, rather than of cellular iron. Importantly, hierarchal cluster analysis revealed the pattern of cellular vulnerability to iron accumulation, distinctly to α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes. CONCLUSIONS Our comprehensive evaluation of iron deposition in MSA brains identified distinct regional, and for the first time, cellular distribution of iron deposition in MSA-P and MSA-C and revealed cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes. Our findings suggest distinct iron-related pathomechanisms in MSA clinical subtypes that are therefore not a consequence of a uniform down-stream pathway to α-synuclein pathology, and inform current efforts in iron chelation therapies at the disease and cellular-specific levels.
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Affiliation(s)
- Seojin Lee
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 0S8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Ivan Martinez-Valbuena
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 0S8, Canada; Krembil Brain Institute, University Health Network, Toronto, Ontario M5T 0S8, Canada
| | - Anthony E Lang
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 0S8, Canada; Edmond J. Safra Program in Parkinson's Disease, Rossy Program for PSP Research and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada; Krembil Brain Institute, University Health Network, Toronto, Ontario M5T 0S8, Canada
| | - Gabor G Kovacs
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 0S8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Edmond J. Safra Program in Parkinson's Disease, Rossy Program for PSP Research and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada; Krembil Brain Institute, University Health Network, Toronto, Ontario M5T 0S8, Canada; Laboratory Medicine Program, University Health Network, Toronto, Ontario M5G 2C4, Canada.
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Bahar R, Darabi S, Norouzian M, Roustaei S, Torkamani-Dordshaikh S, Hasanzadeh M, Vakili K, Fathi M, Khodagholi F, Kaveh N, Jahanbaz S, Moghaddam MH, Abbaszadeh HA, Aliaghaei A. Neuroprotective effect of human cord blood-derived extracellular vesicles by improved neuromuscular function and reduced gliosis in a rat model of Huntington's disease. J Chem Neuroanat 2024; 138:102419. [PMID: 38609056 DOI: 10.1016/j.jchemneu.2024.102419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 04/09/2024] [Accepted: 04/09/2024] [Indexed: 04/14/2024]
Abstract
Huntington's disease (HD) is a hereditary condition characterized by the gradual deterioration of nerve cells in the striatum. Recent scientific investigations have revealed the promising potential of Extracellular vesicles (EVs) as a therapy to mitigate inflammation and enhance motor function. This study aimed to examine the impact of administering EVs derived from human umbilical cord blood (HUCB) on the motor abilities and inflammation levels in a rat model of HD. After ultracentrifugation to prepare EVs from HUCB to determine the nature of the obtained contents, the expression of CD markers 81 and 9, the average size and also the morphology of its particles were investigated by DLS and Transmission electron microscopy (TEM). Then, in order to induce the HD model, 3-nitropropionic acid (3-NP) neurotoxin was injected intraperitoneal into the rats, after treatment by HUCB-EVs, rotarod, electromyogram (EMG) and the open field tests were performed on the rats. Finally, after rat sacrifice and the striatum was removed, Hematoxylin and eosin staining (H&E), stereology, immunohistochemistry, antioxidant tests, and western blot were performed. Our results showed that the contents of the HUCB-EVs express the CD9 and CD81 markers and have spherical shapes. In addition, the injection of HUCB-EVs improved motor and neuromuscular function, reduced gliosis, increased antioxidant activity and inflammatory factor, and partially prevented the decrease of neurons. The findings generally show that HUCB-EVs have neuroprotective effects and reduce neuroinflammation from the toxic effects of 3-NP, which can be beneficial for the recovery of HD.
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Affiliation(s)
- Reza Bahar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahram Darabi
- Cellular and Molecular Research Center, Research Institute for Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohsen Norouzian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Roustaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shayesteh Torkamani-Dordshaikh
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maral Hasanzadeh
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Vakili
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Kaveh
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shima Jahanbaz
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Hassani Moghaddam
- Department of Anatomical Sciences, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Hojjat-Allah Abbaszadeh
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abbas Aliaghaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Bsteh G, Dal Bianco A, Zrzavy T, Berger T. Novel and Emerging Treatments to Target Pathophysiological Mechanisms in Various Phenotypes of Multiple Sclerosis. Pharmacol Rev 2024; 76:564-578. [PMID: 38719481 DOI: 10.1124/pharmrev.124.001073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/22/2024] [Accepted: 04/29/2024] [Indexed: 06/16/2024] Open
Abstract
The objective is to comprehensively review novel pharmacotherapies used in multiple sclerosis (MS) and the possibilities they may carry for therapeutic improvement. Specifically, we discuss pathophysiological mechanisms worth targeting in MS, ranging from well known targets, such as autoinflammation and demyelination, to more novel and advanced targets, such as neuroaxonal damage and repair. To set the stage, a brief overview of clinical MS phenotypes is provided, followed by a comprehensive recapitulation of both clinical and paraclinical outcomes available to assess the effectiveness of treatments in achieving these targets. Finally, we discuss various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials. SIGNIFICANCE STATEMENT: This comprehensive review discusses pathophysiological mechanisms worth targeting in multiple sclerosis. Various promising novel and emerging treatments, including their respective hypothesized modes of action and currently available evidence from clinical trials, are reviewed.
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Affiliation(s)
- Gabriel Bsteh
- Department of Neurology (G.B., A.D.B., T.Z., T.B.) and Comprehensive Center for Clinical Neurosciences & Mental Health (G.B., A.D.B., T.Z., T.B.), Medical University of Vienna, Vienna, Austria
| | - Assunta Dal Bianco
- Department of Neurology (G.B., A.D.B., T.Z., T.B.) and Comprehensive Center for Clinical Neurosciences & Mental Health (G.B., A.D.B., T.Z., T.B.), Medical University of Vienna, Vienna, Austria
| | - Tobias Zrzavy
- Department of Neurology (G.B., A.D.B., T.Z., T.B.) and Comprehensive Center for Clinical Neurosciences & Mental Health (G.B., A.D.B., T.Z., T.B.), Medical University of Vienna, Vienna, Austria
| | - Thomas Berger
- Department of Neurology (G.B., A.D.B., T.Z., T.B.) and Comprehensive Center for Clinical Neurosciences & Mental Health (G.B., A.D.B., T.Z., T.B.), Medical University of Vienna, Vienna, Austria
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Chen K, Li C, Zhao B, Shang H. Albumin and multiple sclerosis: a prospective study from UK Biobank. Front Immunol 2024; 15:1415160. [PMID: 38915402 PMCID: PMC11194376 DOI: 10.3389/fimmu.2024.1415160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 05/30/2024] [Indexed: 06/26/2024] Open
Abstract
Background Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. While previous studies have indicated that albumin, the primary protein in human plasma, may exert influence on the inflammatory process and confer beneficial effects in neurodegenerative disorders, its role in the context of MS has been underexplored. Here, we aimed to explore the link between albumin and the risk of MS. Methods Employing data from the UK Biobank, we investigated the association between baseline levels of serum and urine albumin and the risk of MS using Cox proportional hazards regression analysis. Results A higher baseline level of serum albumin was associated with a lower risk of incident MS (HR=0.94, 95% CI: 0.91-0.98, P=7.66E-04). Subgroup analysis revealed a more pronounced effect in females, as well as participants with younger ages, less smoking and deficient levels of vitamin D. Conversely, no association was identified between baseline microalbuminuria level and risk of incident MS. Conclusion Higher serum albumin level at baseline is linked to a reduced risk of MS. These results contribute to an enhanced understanding of albumin's role in MS, propose the potential use of albumin as a biomarker for MS, and have implications for the design of therapeutic interventions targeting albumin in clinical trials.
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Affiliation(s)
- Ke Chen
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Neurology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Chunyu Li
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bi Zhao
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Huifang Shang
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Jiménez-Jiménez FJ, Alonso-Navarro H, Salgado-Cámara P, García-Martín E, Agúndez JAG. Oxidative Stress Markers in Multiple Sclerosis. Int J Mol Sci 2024; 25:6289. [PMID: 38927996 PMCID: PMC11203935 DOI: 10.3390/ijms25126289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/10/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
The pathogenesis of multiple sclerosis (MS) is not completely understood, but genetic factors, autoimmunity, inflammation, demyelination, and neurodegeneration seem to play a significant role. Data from analyses of central nervous system autopsy material from patients diagnosed with multiple sclerosis, as well as from studies in the main experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), suggest the possibility of a role of oxidative stress as well. In this narrative review, we summarize the main data from studies reported on oxidative stress markers in patients diagnosed with MS and in experimental models of MS (mainly EAE), and case-control association studies on the possible association of candidate genes related to oxidative stress with risk for MS. Most studies have shown an increase in markers of oxidative stress, a decrease in antioxidant substances, or both, with cerebrospinal fluid and serum/plasma malonyl-dialdehyde being the most reliable markers. This topic requires further prospective, multicenter studies with a long-term follow-up period involving a large number of patients with MS and controls.
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Affiliation(s)
- Félix Javier Jiménez-Jiménez
- Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, E-28500 Madrid, Spain; (H.A.-N.); (P.S.-C.)
| | - Hortensia Alonso-Navarro
- Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, E-28500 Madrid, Spain; (H.A.-N.); (P.S.-C.)
| | - Paula Salgado-Cámara
- Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, E-28500 Madrid, Spain; (H.A.-N.); (P.S.-C.)
| | - Elena García-Martín
- University Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, E-10071 Cáceres, Spain; (E.G.-M.); (J.A.G.A.)
| | - José A. G. Agúndez
- University Institute of Molecular Pathology Biomarkers, Universidad de Extremadura, E-10071 Cáceres, Spain; (E.G.-M.); (J.A.G.A.)
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Li X, Luo M, Xu H, Jia L, Liang Y, Xu Q, Wang Y. CAP2 contributes to Parkinson's disease diagnosed by neutrophil extracellular trap-related immune activity. Front Immunol 2024; 15:1377409. [PMID: 38846945 PMCID: PMC11153744 DOI: 10.3389/fimmu.2024.1377409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 04/29/2024] [Indexed: 06/09/2024] Open
Abstract
Introduction Neutrophil extracellular traps (NETs) constitute a crucial element of the immune system, and dysfunction in immune responses is implicated in the susceptibility and progression of Parkinson's disease (PD). Nevertheless, the mechanism connecting PD and NETs remains unclear. This study aims to uncover potential NETs-related immune biomarkers and elucidate their role in PD pathogenesis. Methods Through differential gene analysis of PD and NETs in GSE7621 datasets, we identified two PD subtypes and explored potential biological pathways. Subsequently, using ClusterWGCNA, we pinpointed pertinent genes and developed clinical diagnostic models. We then optimized the chosen model and evaluated its association with immune infiltration. Validation was conducted using the GSE20163 dataset. Screening the single-cell dataset GSE132758 revealed cell populations associated with the identified gene. Results Our findings identified XGB as the optimal diagnostic model, with CAP2 identified as a pivotal gene. The risk model effectively predicted overall diagnosis rates, demonstrating a robust correlation between infiltrating immune cells and genes related to the XGB model. Discussion In conclusions, we identified PD subtypes and diagnostic genes associated with NETs, highlighting CAP2 as a pivotal gene. These findings have significant implications for understanding potential molecular mechanisms and treatments for PD.
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Affiliation(s)
| | | | | | | | | | | | - Yonghui Wang
- Rehabilitation Center, Qilu Hospital of Shandong University, Jinan, China
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35
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Xu M, Wang H, Ren S, Wang B, Yang W, Lv L, Sha X, Li W, Wang Y. Identification of crucial inflammaging related risk factors in multiple sclerosis. Front Mol Neurosci 2024; 17:1398665. [PMID: 38836117 PMCID: PMC11148336 DOI: 10.3389/fnmol.2024.1398665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 04/30/2024] [Indexed: 06/06/2024] Open
Abstract
Background Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelinating lesions in the central nervous system. Studies have shown that the inflammation is vital to both the onset and progression of MS, where aging plays a key role in it. However, the potential mechanisms on how aging-related inflammation (inflammaging) promotes MS have not been fully understood. Therefore, there is an urgent need to integrate the underlying mechanisms between inflammaging and MS, where meaningful prediction models are needed. Methods First, both aging and disease models were developed using machine learning methods, respectively. Then, an integrated inflammaging model was used to identify relative risk factors, by identifying essential "aging-inflammation-disease" triples. Finally, a series of bioinformatics analyses (including network analysis, enrichment analysis, sensitivity analysis, and pan-cancer analysis) were further used to explore the potential mechanisms between inflammaging and MS. Results A series of risk factors were identified, such as the protein homeostasis, cellular homeostasis, neurodevelopment and energy metabolism. The inflammaging indices were further validated in different cancer types. Therefore, various risk factors were integrated, and even both the theories of inflammaging and immunosenescence were further confirmed. Conclusion In conclusion, our study systematically investigated the potential relationships between inflammaging and MS through a series of computational approaches, and could present a novel thought for other aging-related diseases.
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Affiliation(s)
- Mengchu Xu
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Huize Wang
- Department of Nursing, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Siwei Ren
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Bing Wang
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Wenyan Yang
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Ling Lv
- Department of Thorax, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xianzheng Sha
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
| | - Wenya Li
- Department of Thorax, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yin Wang
- Department of Biomedical Engineering, School of Intelligent Sciences, China Medical University, Shenyang, Liaoning, China
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Tang Y, Wu X, Li J, Li Y, Xu X, Li G, Zhang P, Qin C, Wu LJ, Tang Z, Tian DS. The Emerging Role of Microglial Hv1 as a Target for Immunomodulation in Myelin Repair. Aging Dis 2024; 15:1176-1203. [PMID: 38029392 PMCID: PMC11081154 DOI: 10.14336/ad.2023.1107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 11/07/2023] [Indexed: 12/01/2023] Open
Abstract
In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.
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Affiliation(s)
- Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xuan Wu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jiarui Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yuanwei Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xiaoxiao Xu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Gaigai Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Chuan Qin
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Long-Jun Wu
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Dai-Shi Tian
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Qin P, Sun Y, Li L. Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review). Int J Mol Med 2024; 53:47. [PMID: 38577947 PMCID: PMC10999227 DOI: 10.3892/ijmm.2024.5371] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 03/14/2024] [Indexed: 04/06/2024] Open
Abstract
Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators of neuroinflammation. In addition to providing energy to cells, mitochondria also participate in the immunoinflammatory response of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis and epilepsy, by regulating processes such as cell death and inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, mitochondrial dynamics and calcium homeostasis imbalance may serve as underlying regulatory mechanisms for these diseases. Therefore, investigating mechanisms related to mitochondrial dysfunction may result in therapeutic strategies against chronic neuroinflammation and neurodegeneration. The present review summarizes the mechanisms of mitochondria in chronic neuroinflammatory diseases and the current treatment approaches that target mitochondrial dysfunction in these diseases.
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Affiliation(s)
- Pei Qin
- Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, P.R. China
| | - Ye Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, P.R. China
| | - Liya Li
- Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116000, P.R. China
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Rahimi K, Nourishirazi A, Delaviz H, Ghotbeddin Z. Antinociceptive effects of gamma-linolenic acid in the formalin test in the rats. Ann Med Surg (Lond) 2024; 86:2677-2683. [PMID: 38694379 PMCID: PMC11060212 DOI: 10.1097/ms9.0000000000002001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/13/2024] [Indexed: 05/04/2024] Open
Abstract
Background Gamma-linolenic acid (GLA) is found in animals and plants that play a role in brain function and metabolism. Objective This study aimed to investigate the analgesic effects of GLA on peripheral formalin injection. Methods Wistar rats were randomly assigned to four groups: Sham, formalin, formalin/GLA 100 mg/kg, and formalin/GLA 150 mg/kg. The Formalin test was utilized to create a pain model. A tissue sample was prepared from the spinal cords of rats to measure oxidative stress parameters and pro-inflammatory cytokines. Furthermore, the authors analyzed the expression of c-Fos protein in the spinal cords. Results Our findings demonstrate that GLA has a reliable pain-relieving effect in the formalin test. GLA 100 increased superoxide dismutase (SOD) (P<0.05), glutathione (GSH) (P<0.001), and catalase (CAT) (P<0.05), and decreased the levels of c-Fos (P<0.001), interleukin-1 beta (IL-1β) (P<0.001), tumour necrosis factor-alpha (TNF-α) (P<0.001), and malondialdehyde (MDA) (P<0.001) in the spinal cord. Also GLA 150 increased SOD (P<0.05), GSH (P<0.001), and CAT (P<0.05) and decreased the levels of c-Fos (P<0.001), IL-1β (P<0.001), TNF-α (P<0.001), and MDA (P<0.001) in the spinal cord. Conclusion The findings have validated the antinociceptive impact of GLA and hinted towards its immunomodulatory influence in the formalin test.
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Affiliation(s)
- Kaveh Rahimi
- Department of Basic Sciences, Faculty of Veterinary Medicine
| | | | | | - Zohreh Ghotbeddin
- Department of Basic Sciences, Faculty of Veterinary Medicine
- Stem Cell and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran
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Muzio L, Perego J. CNS Resident Innate Immune Cells: Guardians of CNS Homeostasis. Int J Mol Sci 2024; 25:4865. [PMID: 38732082 PMCID: PMC11084235 DOI: 10.3390/ijms25094865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/22/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Although the CNS has been considered for a long time an immune-privileged organ, it is now well known that both the parenchyma and non-parenchymal tissue (meninges, perivascular space, and choroid plexus) are richly populated in resident immune cells. The advent of more powerful tools for multiplex immunophenotyping, such as single-cell RNA sequencing technique and upscale multiparametric flow and mass spectrometry, helped in discriminating between resident and infiltrating cells and, above all, the different spectrum of phenotypes distinguishing border-associated macrophages. Here, we focus our attention on resident innate immune players and their primary role in both CNS homeostasis and pathological neuroinflammation and neurodegeneration, two key interconnected aspects of the immunopathology of multiple sclerosis.
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Affiliation(s)
- Luca Muzio
- Neuroimmunology Lab, IRCCS San Raffaele Scientific Institute, Institute of Experimental Neurology, 20133 Milan, Italy;
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Sanabria-Castro A, Alape-Girón A, Flores-Díaz M, Echeverri-McCandless A, Parajeles-Vindas A. Oxidative stress involvement in the molecular pathogenesis and progression of multiple sclerosis: a literature review. Rev Neurosci 2024; 35:355-371. [PMID: 38163257 DOI: 10.1515/revneuro-2023-0091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 11/26/2023] [Indexed: 01/03/2024]
Abstract
Multiple sclerosis (MS) is an autoimmune debilitating disease of the central nervous system caused by a mosaic of interactions between genetic predisposition and environmental factors. The pathological hallmarks of MS are chronic inflammation, demyelination, and neurodegeneration. Oxidative stress, a state of imbalance between the production of reactive species and antioxidant defense mechanisms, is considered one of the key contributors in the pathophysiology of MS. This review is a comprehensive overview of the cellular and molecular mechanisms by which oxidant species contribute to the initiation and progression of MS including mitochondrial dysfunction, disruption of various signaling pathways, and autoimmune response activation. The detrimental effects of oxidative stress on neurons, oligodendrocytes, and astrocytes, as well as the role of oxidants in promoting and perpetuating inflammation, demyelination, and axonal damage, are discussed. Finally, this review also points out the therapeutic potential of various synthetic antioxidants that must be evaluated in clinical trials in patients with MS.
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Affiliation(s)
- Alfredo Sanabria-Castro
- Unidad de Investigación, Hospital San Juan de Dios, Caja Costarricense de Seguro Social, San José, 10103, Costa Rica
- Departamento de Farmacología, Toxicología y Farmacodependencia, Facultad de Farmacia, Universidad de Costa Rica, San Pedro de Montes de Oca, 11501, Costa Rica
| | - Alberto Alape-Girón
- Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, Dulce Nombre Vázquez de Coronado, 11103, Costa Rica
| | - Marietta Flores-Díaz
- Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, Dulce Nombre Vázquez de Coronado, 11103, Costa Rica
| | - Ann Echeverri-McCandless
- Unidad de Investigación, Hospital San Juan de Dios, Caja Costarricense de Seguro Social, San José, 10103, Costa Rica
| | - Alexander Parajeles-Vindas
- Servicio de Neurología, Hospital San Juan de Dios, Caja Costarricense de Seguro Social, San José, 10103, Costa Rica
- Servicio de Neurología, Hospital Clínica Bíblica, San José, 10104, Costa Rica
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Chapman TW, Kamen Y, Piedra ET, Hill RA. Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination. J Neurosci 2024; 44:e1794232024. [PMID: 38395617 PMCID: PMC10977033 DOI: 10.1523/jneurosci.1794-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
Myelinating oligodendrocytes die in human disease and early in aging. Despite this, the mechanisms that underly oligodendrocyte death are not resolved and it is also not clear whether these mechanisms change as oligodendrocyte lineage cells are undergoing differentiation and maturation. Here, we used a combination of intravital imaging, single-cell ablation, and cuprizone-mediated demyelination, in both female and male mice, to discover that oligodendrocyte maturation dictates the dynamics and mechanisms of cell death. After single-cell phototoxic damage, oligodendrocyte precursor cells underwent programmed cell death within hours, differentiating oligodendrocytes died over several days, while mature oligodendrocytes took weeks to die. Importantly cells at each maturation stage all eventually died but did so with drastically different temporal dynamics and morphological features. Consistent with this, cuprizone treatment initiated a caspase-3-dependent form of rapid cell death in differentiating oligodendrocytes, while mature oligodendrocytes never activated this executioner caspase. Instead, mature oligodendrocytes exhibited delayed cell death which was marked by DNA damage and disruption in poly-ADP-ribose subcellular localization. Thus, oligodendrocyte maturation plays a key role in determining the mechanism of death a cell undergoes in response to the same insult. This means that oligodendrocyte maturation is important to consider when designing strategies for preventing cell death and preserving myelin while also enhancing the survival of new oligodendrocytes in demyelinating conditions.
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Affiliation(s)
- Timothy W Chapman
- Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755
| | - Yasmine Kamen
- Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755
| | - Enrique T Piedra
- Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755
| | - Robert A Hill
- Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755
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Abstract
Prolonged or excessive exposure to oxidized phospholipids (OxPLs) generates chronic inflammation. OxPLs are present in atherosclerotic lesions and can be detected in plasma on apolipoprotein B (apoB)-containing lipoproteins. When initially conceptualized, OxPL-apoB measurement in plasma was expected to reflect the concentration of minimally oxidized LDL, but, surprisingly, it correlated more strongly with plasma lipoprotein(a) (Lp(a)) levels. Indeed, experimental and clinical studies show that Lp(a) particles carry the largest fraction of OxPLs among apoB-containing lipoproteins. Plasma OxPL-apoB levels provide diagnostic information on the presence and extent of atherosclerosis and improve the prognostication of peripheral artery disease and first and recurrent myocardial infarction and stroke. The addition of OxPL-apoB measurements to traditional cardiovascular risk factors improves risk reclassification, particularly in patients in intermediate risk categories, for whom improving decision-making is most impactful. Moreover, plasma OxPL-apoB levels predict cardiovascular events with similar or greater accuracy than plasma Lp(a) levels, probably because this measurement reflects both the genetics of elevated Lp(a) levels and the generalized or localized oxidation that modifies apoB-containing lipoproteins and leads to inflammation. Plasma OxPL-apoB levels are reduced by Lp(a)-lowering therapy with antisense oligonucleotides and by lipoprotein apheresis, niacin therapy and bariatric surgery. In this Review, we discuss the role of role OxPLs in the pathophysiology of atherosclerosis and Lp(a) atherogenicity, and the use of OxPL-apoB measurement for improving prognosis, risk reclassification and therapeutic interventions.
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Affiliation(s)
- Sotirios Tsimikas
- Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA, USA.
| | - Joseph L Witztum
- Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA
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van den Bosch AMR, van der Poel M, Fransen NL, Vincenten MCJ, Bobeldijk AM, Jongejan A, Engelenburg HJ, Moerland PD, Smolders J, Huitinga I, Hamann J. Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation. Nat Commun 2024; 15:1667. [PMID: 38396116 PMCID: PMC10891081 DOI: 10.1038/s41467-024-46068-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Microglia nodules (HLA-DR+ cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.
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Affiliation(s)
- Aletta M R van den Bosch
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
| | - Marlijn van der Poel
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
| | - Nina L Fransen
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
| | - Maria C J Vincenten
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
| | - Anneleen M Bobeldijk
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
| | - Aldo Jongejan
- Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Hendrik J Engelenburg
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
| | - Perry D Moerland
- Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Joost Smolders
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
- MS Center ErasMS, Department of Neurology and Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Inge Huitinga
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
- Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
| | - Jörg Hamann
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
- Department of Experimental Immunology, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Center, Amsterdam, The Netherlands.
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Amiri H, Javid H, Hashemi SF, Reihani A, Esparham A, Hashemy SI. The protective effects of hesperidin as an antioxidant against quinolinic acid-induced toxicity on oligodendroglia cells: An in vitro study. Mult Scler Relat Disord 2024; 82:105401. [PMID: 38154346 DOI: 10.1016/j.msard.2023.105401] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 12/13/2023] [Accepted: 12/21/2023] [Indexed: 12/30/2023]
Abstract
INTRODUCTION Multiple sclerosis (MS) is a complex central nervous system disorder, marked by neurodegenerative and inflammatory processes, where overproduction of reactive oxygen species (ROS) is a key factor in demyelination and neurodegeneration. The current study aims to investigate the effect of hesperidin and Quinolinic acid (QA) on ROS and antioxidant levels, and cell viability of OLN-93 cells. METHODS OLN-93 cell lines were treated with hesperidin and QA. OLN-93 cells were cultured in Dulbecco's modified Eagle's medium under controlled conditions. Cell viability assays were performed using resazurin to assess the toxicity of hesperidin and QA. Additionally, ROS levels were measured using DCFDA, and malondialdehyde (MDA) levels were determined to evaluate oxidative stress. Superoxide dismutase (SOD) activity and cell viability were assessed by trypan blue staining after exposure to hesperidin and QA. RESULTS The results of the current study showed that co-administration of 8 mM QA with 50, 100, and 200 μM hesperidin significantly reduced both ROS and MDA levels, demonstrating a substantial attenuation in comparison to the elevated ROS and MDA levels induced by 8 mM QA (p-value < 0.01). Furthermore, 8 mM QA + 50, 100, and 200 μM hesperidin significantly increased SOD levels compared with QA alone (p-value < 0.01). In addition, treatment of OLN cells with 8 mM QA + 50, 100, and 200 μM hesperidin led to higher cell viability compared to QA alone (p value <0.0001). CONCLUSION The current study demonstrated the antioxidant effect of hesperidin on OLN-93 cells suggesting new insights into the clinical application of hesperidin as an effective treatment for patients with MS. Future in vivo studies, focusing on cellular mechanisms are recommended.
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Affiliation(s)
- Hamed Amiri
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Fatemeh Hashemi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirali Reihani
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Esparham
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Al-kuraishy HM, Jabir MS, Al-Gareeb AI, Saad HM, Batiha GES, Klionsky DJ. The beneficial role of autophagy in multiple sclerosis: Yes or No? Autophagy 2024; 20:259-274. [PMID: 37712858 PMCID: PMC10813579 DOI: 10.1080/15548627.2023.2259281] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/16/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system (CNS) due to an increase of abnormal peripherally auto-reactive T lymphocytes which elicit autoimmunity. The main pathophysiology of MS is myelin sheath damage by immune cells and a defect in the generation of myelin by oligodendrocytes. Macroautophagy/autophagy is a critical degradation process that eliminates dysfunctional or superfluous cellular components. Autophagy has the property of a double-edged sword in MS in that it may have both beneficial and detrimental effects on MS neuropathology. Therefore, this review illustrates the protective and harmful effects of autophagy with regard to this disease. Autophagy prevents the progression of MS by reducing oxidative stress and inflammatory disorders. In contrast, over-activated autophagy is associated with the progression of MS neuropathology and in this case the use of autophagy inhibitors may alleviate the pathogenesis of MS. Furthermore, autophagy provokes the activation of different immune and supporting cells that play an intricate role in the pathogenesis of MS. Autophagy functions in the modulation of MS neuropathology by regulating cell proliferation related to demyelination and remyelination. Autophagy enhances remyelination by increasing the activity of oligodendrocytes, and astrocytes. However, autophagy induces demyelination by activating microglia and T cells. In conclusion, specific autophagic activators of oligodendrocytes, and astrocytes, and specific autophagic inhibitors of dendritic cells (DCs), microglia and T cells induce protective effects against the pathogenesis of MS.Abbreviations: ALS: amyotrophic lateral sclerosis; APCs: antigen-presenting cells; BBB: blood-brain barrier; CSF: cerebrospinal fluid; CNS: central nervous system; DCs: dendritic cells; EAE: experimental autoimmune encephalomyelitis; ER: endoplasmic reticulum; LAP: LC3-associated phagocytosis; MS: multiple sclerosis; NCA: non-canonical autophagy; OCBs: oligoclonal bands; PBMCs: peripheral blood mononuclear cells; PD: Parkinson disease; ROS: reactive oxygen species; UPR: unfolded protein response.
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Affiliation(s)
- Hayder M. Al-kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Iraq, Baghdad
| | - Majid S. Jabir
- Department of Applied Science, University of Technology, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Iraq, Baghdad
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, El Beheira, Egypt
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Hamedani SG, Pourmasoumi M, Zarifi SH, Askari G, Jamialahmadi T, Bagherniya M, Sahebkar A. Therapeutic effects of saffron and its components on neurodegenerative diseases. Heliyon 2024; 10:e24334. [PMID: 38298664 PMCID: PMC10827773 DOI: 10.1016/j.heliyon.2024.e24334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 02/02/2024] Open
Abstract
Due to an increase in the number of older people in recent years, neurodegenerative diseases as the most important age-related neurological disorders are considered as a great threat to human health. The treatment strategies for these disorders are symptomatic and there is no known definitive treatment; however, recently, several studies have investigated the effectiveness of some herbs and their components in limiting the progression and treatment of neurodegenerative disorders. In this study, we searched Medline (via PubMed), Scopus, Science Direct, and Google Scholar databases. The keywords used in the search were: saffron [title/abstract] or (saffron compound [title/abstract]) and (neurological disorders [title/abstract]), publication date range (2010-2023), and language (English). After applying inclusion and exclusion criteria, 30 articles remained. Of the 30 articles included in the study, six studies on the treatment of neurodegenerative disorders by saffron and its components were in the clinical trial phase, and 24 studies were in the preclinical phase. Saffron and its compounds can play an important role in inhibiting neuroinflammation and excitotoxic pathways, modulating autophagy and apoptosis, attenuating oxidative damage, and activating defensive antioxidant enzymes, resulting in neuroprotection against neurodegenerative diseases. Therefore, this study aimed to review the studies on the effects of saffron and its compounds on the treatment of neurodegenerative diseases.
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Affiliation(s)
- Sahar Golpour- Hamedani
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of medical science, Iran
| | - Makan Pourmasoumi
- Gastrointestinal & Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Gholamreza Askari
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tannaz Jamialahmadi
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Bagherniya
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Mustafa AM, Shaheen AM, Zaki HF, Rabie MA. Nicorandil and carvedilol mitigates motor deficits in experimental autoimmune encephalomyelitis-induced multiple sclerosis: Role of TLR4/TRAF6/MAPK/NF-κB signalling cascade. Int Immunopharmacol 2024; 127:111387. [PMID: 38134593 DOI: 10.1016/j.intimp.2023.111387] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/27/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023]
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating neurodegenerative disease that negatively affects neurotransmission. It can be pathologically mimicked by experimental autoimmune encephalomyelitis (EAE) animal model. ATP-sensitive potassium channels (KATP) plays a crucial role in the control of neuronal damage, however their role in MS are still obscure. Additionally, Carvedilol showed a promising neuroprotective activity against several neurological disorders. Therefore, the present study aimed to investigate the potential neuroprotective effect of KATP channel opener (nicorandil) as well as α and β adrenoceptor antagonist (Carvedilol) against EAE induced neurodegeneration in mice. Mice was treated with nicorandil (6 mg/kg/day; p.o.) and carvedilol (10 mg/kg/day; p.o.) for 14 days. Nicorandil and carvedilol showed improvement in clinical scoring, behaviour and motor coordination as established by histopathological investigation and immunohistochemical detection of MBP. Furthermore, both treatments downregulated the protein expression of TLR4/ MYD88/TRAF6 signalling cascade with downstream inhibition of (pT183/Y185)-JNK/p38 (pT180/Y182)-MAPK axis leading to reduction of neuroinflammatory status, as witnessed by reduction of NF-κB, TNF-α, IL-1β and IL-6 contents. Moreover, nicorandil and carvedilol attenuated oxidative damage by increasing Nrf2 content and SOD activity together with reduction of MDA content. In addition, an immunomodulating effect via inhibiting the gene expression of CD4, TGF-β, and IL-17 as well as TGF-β, IL-17, and IL-23 contents along with anti-apoptotic effect by decreasing Bax protein expression and Caspase-3 content and increasing Bcl-2 protein expression was observed with nicorandil and carvedilol treatments. In conclusion, nicorandil and carvedilol exerted a neuroprotective activity against EAE induced neuronal loss via inhibition of TLR4/MYD88/TRAF6/JNK/p38-MAPK axis besides antioxidant and anti-apoptotic effects.
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Affiliation(s)
- Aya M Mustafa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Aya M Shaheen
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Hala F Zaki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mostafa A Rabie
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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Cadenas-Garrido P, Schonvandt-Alarcos A, Herrera-Quintana L, Vázquez-Lorente H, Santamaría-Quiles A, Ruiz de Francisco J, Moya-Escudero M, Martín-Oliva D, Martín-Guerrero SM, Rodríguez-Santana C, Aragón-Vela J, Plaza-Diaz J. Using Redox Proteomics to Gain New Insights into Neurodegenerative Disease and Protein Modification. Antioxidants (Basel) 2024; 13:127. [PMID: 38275652 PMCID: PMC10812581 DOI: 10.3390/antiox13010127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/16/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
Antioxidant defenses in biological systems ensure redox homeostasis, regulating baseline levels of reactive oxygen and nitrogen species (ROS and RNS). Oxidative stress (OS), characterized by a lack of antioxidant defenses or an elevation in ROS and RNS, may cause a modification of biomolecules, ROS being primarily absorbed by proteins. As a result of both genome and environment interactions, proteomics provides complete information about a cell's proteome, which changes continuously. Besides measuring protein expression levels, proteomics can also be used to identify protein modifications, localizations, the effects of added agents, and the interactions between proteins. Several oxidative processes are frequently used to modify proteins post-translationally, including carbonylation, oxidation of amino acid side chains, glycation, or lipid peroxidation, which produces highly reactive alkenals. Reactive alkenals, such as 4-hydroxy-2-nonenal, are added to cysteine (Cys), lysine (Lys), or histidine (His) residues by a Michael addition, and tyrosine (Tyr) residues are nitrated and Cys residues are nitrosylated by a Michael addition. Oxidative and nitrosative stress have been implicated in many neurodegenerative diseases as a result of oxidative damage to the brain, which may be especially vulnerable due to the large consumption of dioxygen. Therefore, the current methods applied for the detection, identification, and quantification in redox proteomics are of great interest. This review describes the main protein modifications classified as chemical reactions. Finally, we discuss the importance of redox proteomics to health and describe the analytical methods used in redox proteomics.
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Affiliation(s)
- Paula Cadenas-Garrido
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Ailén Schonvandt-Alarcos
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Lourdes Herrera-Quintana
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.); (C.R.-S.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Héctor Vázquez-Lorente
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.); (C.R.-S.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Alicia Santamaría-Quiles
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Jon Ruiz de Francisco
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - Marina Moya-Escudero
- Research and Advances in Molecular and Cellular Immunology, Center of Biomedical Research, University of Granada, Avda, del Conocimiento s/n, 18016 Armilla, Spain; (P.C.-G.); (A.S.-A.); (A.S.-Q.); (J.R.d.F.); (M.M.-E.)
| | - David Martín-Oliva
- Department of Cell Biology, Faculty of Science, University of Granada, 18071 Granada, Spain;
| | - Sandra M. Martín-Guerrero
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 9RT, UK
| | - César Rodríguez-Santana
- Department of Physiology, Schools of Pharmacy and Medicine, University of Granada, 18071 Granada, Spain; (L.H.-Q.); (H.V.-L.); (C.R.-S.)
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, 18016 Granada, Spain
| | - Jerónimo Aragón-Vela
- Department of Health Sciences, Area of Physiology, Building B3, Campus s/n “Las Lagunillas”, University of Jaén, 23071 Jaén, Spain
| | - Julio Plaza-Diaz
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria IBS, Complejo Hospitalario Universitario de Granada, 18071 Granada, Spain
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Motegi H, Kufukihara K, Kitagawa S, Sekiguchi K, Hata J, Fujiwara H, Jinzaki M, Okano H, Nakamura M, Iguchi Y, Nakahara J. Non-lesional white matter changes depicted by q-space diffusional MRI correlate with clinical disabilities in multiple sclerosis. J Neurol Sci 2024; 456:122851. [PMID: 38181653 DOI: 10.1016/j.jns.2023.122851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 11/20/2023] [Accepted: 12/17/2023] [Indexed: 01/07/2024]
Abstract
BACKGROUND We previously developed an optimized q-space diffusional MRI technique (normalized leptokurtic diffusion [NLD] map) to delineate the demyelinated lesions of multiple sclerosis (MS) patients. Herein, we evaluated the utility of NLD maps to discern the white matter abnormalities in normal-appearing white matter (NAWM) and the abnormalities' possible associations with physical and cognitive disabilities in MS. METHODS We conducted a retrospective observational study of MS patients treated at our hospital (Jan. 2012 to Dec. 2022). Clinical and MRI data were collected; Processing Speed Test (PST) data were obtained when possible. For a quantitative analysis of the NLD maps, we calculated the NLD index as GVROI/GVREF, where GV is a mean grayscale value in the regions of interest (ROIs) and the reference area (REF; cerebrospinal fluid). RESULTS One hundred-one individuals with MS were included. The lower corpus callosum and non-lesional WM NLD index were associated with worse Expanded Disability Status Scale (EDSS) and PST scores. The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly reduced in progressive MS compared to relapsing-remitting MS. We categorized MS severity as moderate/severe (EDSS score ≥ 4 points) and mild (EDSS score < 4 points). The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly lower in the moderate/severe MS group compared to the mild MS group. CONCLUSION The NLD map revealed abnormalities in the non-lesional white matter, providing valuable insights for evaluating manifestations in MS patients.
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Affiliation(s)
- Haruhiko Motegi
- Department of Neurology, Keio University School of Medicine, Tokyo, Japan; Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan.
| | - Kenji Kufukihara
- Department of Neurology, Keio University School of Medicine, Tokyo, Japan; Department of Neurology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
| | - Satoshi Kitagawa
- Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
| | - Koji Sekiguchi
- Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
| | - Junichi Hata
- Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan; Department of Physiology, Keio University School of Medicine, Tokyo, Japan; Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Wako, Japan.
| | - Hirokazu Fujiwara
- Center of Preventive Medicine, Keio University School of Medicine, Tokyo, Japan.
| | - Masahiro Jinzaki
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan; Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Wako, Japan.
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.
| | - Yasuyuki Iguchi
- Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan.
| | - Jin Nakahara
- Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
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Alavi O, Alizadeh A, Dehghani F, Alipour H, Tanideh N. Anti-inflammatory Effects of Umbilical Cord Mesenchymal Stem Cell and Autologous Conditioned Serum on Oligodendrocyte, Astrocyte, and Microglial Specific Gene in Cuprizone Animal Model. Curr Stem Cell Res Ther 2024; 19:71-82. [PMID: 36852798 DOI: 10.2174/1574888x18666230228102731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 11/23/2022] [Accepted: 12/29/2022] [Indexed: 03/01/2023]
Abstract
BACKGROUND Inflammation, myelin loss, astrocytosis, and microgliosis are pathological signs of the autoimmune and demyelinating disease known as multiple sclerosis (MS). Axonal and neuronal degenerations have basic molecular pathways. The remyelination process can be influenced by the secretome of mesenchymal stem cells due to their capacity for immunomodulation, differentiation, and neuroprotection. Microglial cells are divided into two subgroups: M1 and M2 phenotypes. A crucial component of the microglial function is the colony stimulating factor 1 receptor (CSF1R). We aimed to evaluate the immunomodulating effects of secretome and conditioned serum on the microglial phenotypes and improvement of demyelination in a cuprizone model of MS. METHODS The study used 48 male C57BL/6 mice, which were randomly distributed into 6 subgroups (n = 8), i.e., control, cuprizone, MSC (confluency 40% and 80%) secretome group, and blood derived conditioned serum (autologous and humanized). The animals were fed with 0.2% cuprizone diet for 12 weeks. Supplements were injected into the lateral tail vein using a 27-gauge needle every 3 days 500 μl per injection. RESULTS At 14 days after transplantation, animals from each group were sacrificed and analyzed by Real time PCR. The results showed that the administration of MSC secretome can efficiently reduce expression of pro-inflammatory cytokines (IL-1, IL6 and TNF-α) in the corpus callosum; also, conditioned serum downregulated IL-1. Moreover, the oligodendrocyte-specific gene was upregulated by secretome and conditioned serum treatment. Also, the expression of microglial- specific gene was reduced after treatment. CONCLUSION These findings demonstrated that the secretome isolated from MSCs used as a therapy decreased and increased the M1 and M2 levels, respectively, to control neuroinflammation in CPZ mice. In conclusion, the current study showed the viability of devising a method to prepare suitable MSCs and secreted factor to cure neurodegenerative diseases, as well as the capability of regulating MSC secretome patterns by manipulating the cell density.
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Affiliation(s)
- Omid Alavi
- Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Aliakbar Alizadeh
- Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farzaneh Dehghani
- Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Alipour
- Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nader Tanideh
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iranaz Iran
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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