scholarly journals The First Dose of Fingolimod Affects Circulating Extracellular Vesicles in Multiple Sclerosis Patients

2018 ◽  
Vol 19 (8) ◽  
pp. 2448 ◽  
Author(s):  
Matías Sáenz-Cuesta ◽  
Ainhoa Alberro ◽  
Maider Muñoz-Culla ◽  
Iñaki Osorio-Querejeta ◽  
Marta Fernandez-Mercado ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Extracellular Vesicles ◽  
Regulatory Function ◽  
Target Cells ◽  
Novel Biomarkers ◽  
Membrane Bound ◽  
Multiple Sclerosis Patients ◽  
Immunomodulatory Therapies ◽  
Ms Pathogenesis ◽  
Potential Use

Extracellular vesicles (EVs) are membrane-bound particles involved in intercellular communication. They carry proteins, lipids, and nucleotides such as microRNAs (miRNAs) from the secreting cell that can modulate target cells. We and others have previously described the presence of EVs in peripheral blood of multiple sclerosis (MS) patients and postulated them as novel biomarkers. However, their immune function in MS pathogenesis and the effect during the onset of new immunomodulatory therapies on EVs remain elusive. Here, we isolated plasma EVs from fingolimod-treated MS patients in order to assess whether EVs are affected by the first dose of the treatment. We quantified EVs, analyzed their miRNA cargo, and checked their immune regulatory function. Results showed an elevated EV concentration with a dramatic change in their miRNA cargo 5 h after the first dose of fingolimod. Besides, EVs obtained prior to fingolimod treatment showed an increased immune regulatory activity compared to EVs obtained 5 h post-treatment. This work suggests that EVs are implicated in the mechanism of action of immunomodulatory treatments from the initial hours and opens a new avenue to explore a potential use of EVs for early treatment monitoring.

scholarly journals Extracellular Vesicles as Biological Shuttles for Targeted Therapies

2019 ◽  
Vol 20 (8) ◽  
pp. 1848 ◽  
Author(s):  
Stefania Raimondo ◽  
Gianluca Giavaresi ◽  
Aurelio Lorico ◽  
Riccardo Alessandro
Keyword(s):  
Extracellular Vesicles ◽  
Therapeutic Agents ◽  
Bioactive Molecules ◽  
Target Cells ◽  
Special Focus ◽  
Pathological Conditions ◽  
Critical Issues ◽  
Membrane Bound ◽  
And Function ◽  
Potential Use

The development of effective nanosystems for drug delivery represents a key challenge for the improvement of most current anticancer therapies. Recent progress in the understanding of structure and function of extracellular vesicles (EVs)—specialized membrane-bound nanocarriers for intercellular communication—suggests that they might also serve as optimal delivery systems of therapeutics. In addition to carrying proteins, lipids, DNA and different forms of RNAs, EVs can be engineered to deliver specific bioactive molecules to target cells. Exploitation of their molecular composition and physical properties, together with improvement in bio-techniques to modify their content are critical issues to target them to specific cells/tissues/organs. Here, we will discuss the current developments in the field of animal and plant-derived EVs toward their potential use for delivery of therapeutic agents in different pathological conditions, with a special focus on cancer.

scholarly journals Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis

2020 ◽  
Vol 21 (19) ◽  
pp. 7336
Author(s):  
Ettore Dolcetti ◽  
Antonio Bruno ◽  
Livia Guadalupi ◽  
Francesca Romana Rizzo ◽  
Alessandra Musella ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Extracellular Vesicles ◽  
Target Cells ◽  
Autoimmune Encephalomyelitis ◽  
Alternative Mode ◽  
Intensive Investigation ◽  
Neuronal Functions ◽  
Ms Pathogenesis ◽  
Experimental Autoimmune

Extracellular vesicles (EVs) represent a new reality for many physiological and pathological functions as an alternative mode of intercellular communication. This is due to their capacity to interact with distant recipient cells, usually involving delivery of the EVs contents into the target cells. Intensive investigation has targeted the role of EVs in different pathological conditions, including multiple sclerosis (MS). MS is a chronic inflammatory and neurodegenerative disease of the nervous system, one of the main causes of neurological disability in young adults. The fine interplay between the immune and nervous systems is profoundly altered in this disease, and EVs seems to have a relevant impact on MS pathogenesis. Here, we provide an overview of both clinical and preclinical studies showing that EVs released from blood–brain barrier (BBB) endothelial cells, platelets, leukocytes, myeloid cells, astrocytes, and oligodendrocytes are involved in the pathogenesis of MS and of its rodent model experimental autoimmune encephalomyelitis (EAE). Most of the information points to an impact of EVs on BBB damage, on spreading pro-inflammatory signals, and altering neuronal functions, but EVs reparative function of brain damage deserves attention. Finally, we will describe recent advances about EVs as potential therapeutic targets and tools for therapeutic intervention in MS.

scholarly journals Extracellular vesicles (exosomes and ectosomes) play key roles in the pathology of brain diseases

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Jacopo Meldolesi
Keyword(s):  
Multiple Sclerosis ◽  
Extracellular Vesicles ◽  
Brain Diseases ◽  
Target Cells ◽  
Surface Binding ◽  
Cells Of Origin ◽  
Relapsing Remitting ◽  
And Function ◽  
The Brain

AbstractLast century, neurons and glial cells were mostly believed to play distinct functions, relevant for the brain. Progressively, however, it became clear that neurons, astrocytes and microglia co-operate intensely with each other by release/binding of signaling factors, direct surface binding and generation/release of extracellular vesicles, the exosomes and ectosomes, called together vesicles in this abstract. The present review is focused on these vesicles, fundamental in various brain diseases. Their properties are extraordinary. The specificity of their membrane governs their fusion with distinct target cells, variable depending on the state and specificity of their cells of origin and target. Result of vesicle fusion is the discharge of their cargos into the cytoplasm of target cells. Cargos are composed of critical molecules, from proteins (various nature and function) to nucleotides (especially miRNAs), playing critical roles in immune and neurodegenerative diseases. Among immune diseases is multiple sclerosis, affected by extensive dysregulation of co-trafficking neural and glial vesicles, with distinct miRNAs inducing severe or reducing effects. The vesicle-dependent differences between progressive and relapsing-remitting forms of the disease are relevant for clinical developments. In Alzheimer’s disease the vesicles can affect the brain by changing their generation and inducing co-release of effective proteins, such Aβ and tau, from neurons and astrocytes. Specific miRNAs can delay the long-term development of the disease. Upon their traffic through the blood-brainbarrier, vesicles of various origin reach fluids where they are essential for the identification of biomarkers, important for diagnostic and therapeutic innovations, critical for the future of many brain patients.

scholarly journals Neural stem cells traffic functional mitochondria via extracellular vesicles to correct mitochondrial dysfunction in target cells

2020 ◽  
Author(s):  
Luca Peruzzotti-Jametti ◽  
Joshua D. Bernstock ◽  
Giulia Manferrari ◽  
Rebecca Rogall ◽  
Erika Fernandez-Vizarra ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cell ◽  
Mitochondrial Dysfunction ◽  
Extracellular Vesicles ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mononuclear Phagocytes ◽  
Host Cells ◽  
Target Cells ◽  
Therapeutic Effects

AbstractNeural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs).EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs is yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics.Herein we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells.Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs (Mito-EVs) with conserved membrane potential and respiration. We found that the transfer of Mito-EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of Mito-EVs into inflammatory professional phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits.Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via Mito-EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

scholarly journals IL-2 and Mycobacterial Lipoarabinomannan as Targets of Immune Responses in Multiple Sclerosis Patients

2020 ◽  
Vol 8 (4) ◽  
pp. 500 ◽  
Author(s):  
Marco Bo ◽  
Magdalena Niegowska ◽  
Jessica Frau ◽  
GianPietro Sechi ◽  
Giannina Arru ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mycobacterium Avium Subspecies Paratuberculosis ◽  
Interleukin 2 ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Slight Reduction ◽  
Multiple Sclerosis Patients ◽  
The Impact ◽  
Ms Pathogenesis ◽  
Future Practice

Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapies targeting its receptor have been developed; however, a resolution of the disease and side effects are still an issue of concern. The involvement of other factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) and envelope protein derived from human endogenous retrovirus type W (HERV-Wenv), in MS pathogenesis has been recently suggested. Here, we investigated the levels of antibodies (Abs) directed against IL-2 and HERV-Wenv in 108 MS patients, 34 patients affected by neuromyelitis optica spectrum disorder (NMOSD), and 137 healthy controls (HCs). Our results show increased levels of Abs specific to IL-2 and HERV-Wenv-su antigens in MS vs. HCs (p < 0.0001 for IL-2, p = 0.0004 for HERV-Wenv) and significantly decreased levels in NMOSD vs. MS. The assessment of different 12-month-long therapies on Abs against IL-2, HERV-Wenv, and MAP lipoarabinomannan (LAM) demonstrated the strongest effect on anti-LAM Abs (p = 0.018), a slight reduction of anti-IL-2 Abs, and small variations for anti-HERV-Wenv Abs. These results highlight the conclusion that the impact of therapy is more correlated with selected epitopes than with the therapeutic agent. Screening for anti-IL-2 and anti-HERV-Wenv Abs has a potential as additional future practice to distinguish between symptomatically similar MS and NMOSD.

Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies

2001 ◽  
Vol 115 (1-2) ◽  
pp. 192-198 ◽  
Author(s):  
Diego Franciotta ◽  
Gianvito Martino ◽  
Elisabetta Zardini ◽  
Roberto Furlan ◽  
Roberto Bergamaschi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stable Disease ◽  
Csf Levels ◽  
Multiple Sclerosis Patients ◽  
Immunomodulatory Therapies

scholarly journals Neural stem cells traffic functional mitochondria via extracellular vesicles

PLoS Biology ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. e3001166
Author(s):  
Luca Peruzzotti-Jametti ◽  
Joshua D. Bernstock ◽  
Cory M. Willis ◽  
Giulia Manferrari ◽  
Rebecca Rogall ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cell ◽  
Mitochondrial Dysfunction ◽  
Extracellular Vesicles ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mononuclear Phagocytes ◽  
Host Cells ◽  
Target Cells ◽  
Therapeutic Effects

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.

Levocarnitine administration in multiple sclerosis patients with immunosuppressive therapy-induced fatigue

2006 ◽  
Vol 12 (3) ◽  
pp. 321-324 ◽  
Author(s):  
C Lebrun ◽  
H Alchaar ◽  
M Candito ◽  
V Bourg ◽  
M Chatel
Keyword(s):  
Multiple Sclerosis ◽  
Acid Oxidation ◽  
Plasma Carnitine ◽  
Fatigue Syndrome ◽  
Experienced Fatigue ◽  
Multiple Sclerosis Patients ◽  
Disease Modifying Treatment ◽  
Immunomodulatory Therapies ◽  
Prevalent Symptom

Nutritional factors and comedications are among the postulated causes of fatigue, a highly prevalent symptom in the multiple sclerosis (MS) population, with serious impact on patients’ quality of life. Deficiency of carnitine may play a role by reducing energy production through fatty acid oxidation and numerous MS therapies can induce fatigue syndrome. The aim of this prospective open-labelled study was to collect and study serum carnitine levels in MS patients with and without disease-modifying treatment-induced fatigue syndrome. We investigated whether restoration of the carnitine pool might improve treatment-induced fatigue in MS patients. In our study, there was no statistical difference in fatigue frequency between treated and untreated patients ( P=0.5). Matched to age, gender and treatments, carnitine levels were lower for MS treated patients compared to untreated MS patients ( P<0.05) or controls ( P<0.001). Consecutive patients with low plasma carnitine levels who experienced fatigue were substituted. Treatment consisted of oral levocarnitine, 3-6 g daily. All patients achieved normal plasma carnitine levels. For 63% of patients treated with immunosuppressive or immunomodulatory therapies, oral levocarnitine adjunction decreased fatigue intensity, especially in patients treated with cyclophosphamide and interferon beta.

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