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Inflammopharmacology Apr 2024Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal...
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal degeneration and functional impairments. No efficient therapy is available at present to combat such insults, and hence, novel safe and effective alternatives for MS therapy are extremely required. Rutin (RUT) is a flavonoid that exhibits antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. The present study evaluated the potential beneficial effects of two doses of RUT in a model of pattern-III lesion of MS, in comparison to the conventional standard drug; dimethyl fumarate (DMF). Demyelination was induced in in male adult C57BL/6 mice by dietary 0.2% (w/w) cuprizone (CPZ) feeding for 6 consecutive weeks. Treated groups received either oral RUT (50 or 100 mg/kg) or DMF (15 mg/kg), along with CPZ feeding, for 6 consecutive weeks. Mice were then tested for behavioral changes, followed by biochemical analyses and histological examinations of the corpus callosum (CC). Results revealed that CPZ caused motor dysfunction, demyelination, and glial activation in demyelinated lesions, as well as significant oxidative stress, and proinflammatory cytokine elevation. Six weeks of RUT treatment significantly improved locomotor activity and motor coordination. Moreover, RUT considerably improved remyelination in the CC of CPZ + RUT-treated mice, as revealed by luxol fast blue staining and transmission electron microscopy. Rutin also significantly attenuated CPZ-induced oxidative stress and inflammation in the CC of tested animals. The effect of RUT100 was obviously more marked than either that of DMF, regarding most of the tested parameters, or even its smaller tested dose. In silico docking revealed that RUT binds tightly within NF-κB at the binding site of the protein-DNA complex, with a good negative score of -6.79 kcal/mol. Also, RUT-Kelch-like ECH-associated protein 1 (Keap1) model clarifies the possible inhibition of Keap1-Nrf2 protein-protein interaction. Findings of the current study provide evidence for the protective effect of RUT in CPZ-induced demyelination and behavioral dysfunction in mice, possibly by modulating NF-κB and Nrf2 signaling pathways. The present study may be one of the first to indicate a pro-remyelinating effect for RUT, which might represent a potential additive benefit in treating MS.
Topics: Male; Animals; Mice; Multiple Sclerosis; Cuprizone; Kelch-Like ECH-Associated Protein 1; Demyelinating Diseases; Neuroprotective Agents; NF-kappa B; Rutin; NF-E2-Related Factor 2; Neurodegenerative Diseases; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38512652
DOI: 10.1007/s10787-024-01442-x -
Bioactive Materials Jun 2024Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport....
Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the -terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.
PubMed: 38496034
DOI: 10.1016/j.bioactmat.2024.02.022 -
Cell Death & Disease Mar 2024Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors,...
Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways downstream of these receptors lead to NF-κB activation, thus protecting leukemic cells from apoptosis. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug used to treat patients with multiple sclerosis and psoriasis in which it blocks aberrant NF-κB pathways and impacts the NRF2 antioxidant circuit. Our in vitro analysis demonstrated that increasing concentrations of DMF reduce ATP levels and lead to the apoptosis of CLL cells, including cell lines, splenocytes from Eµ-TCL1-transgenic mice, and primary leukemic cells isolated from the peripheral blood of patients. DMF showed a synergistic effect in association with BTK inhibitors in CLL cells. DMF reduced glutathione levels and activated the NRF2 pathway; gene expression analysis suggested that DMF downregulated pathways related to NFKB and inflammation. In primary leukemic cells, DMF disrupted the TLR signaling pathways induced by CpG by reducing the mRNA expression of NFKBIZ, IL6, IL10 and TNFα. Our data suggest that DMF targets a vulnerability of CLL cells linked to their inflammatory pathways, without impacting healthy donor peripheral blood mononuclear cells.
Topics: Mice; Animals; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Dimethyl Fumarate; NF-kappa B; Leukocytes, Mononuclear; NF-E2-Related Factor 2; Apoptosis; Mice, Transgenic
PubMed: 38494482
DOI: 10.1038/s41419-024-06602-z -
International Immunopharmacology Apr 2024Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of...
Disease modifying therapies (DMTs) used for treating people with relapsing-remitting multiple sclerosis (pwRRMS) target the immune system by different mechanisms of action. However, there is a lack of a comprehensive assessment of their effects on the immune system in comparison to treatment-naïve pwRRMS. Herein, we evaluated the numbers of circulating B cells, CD4 and CD8 T cells, regulatory T cells (Tregs), natural killer (NK) cells and NKT cells, and their subsets, in pwRRMS who were treatment-naïve or treated with different DMTs. Compared to treatment-naïve pwRRMS, common and divergent effects on immune system cells were observed on pwRRMS treated with different DMTs, with no consistent pattern across all therapies in any of the cell populations analysed. PwRRMS treated with fingolimod, dimethyl fumarate (DMF), or alemtuzumab have reduced numbers of CD4 and CD8 T cells, as well as Treg subsets, with fingolimod causing the most pronounced decrease in T cell subsets. In contrast, teriflunomide and interferon (IFN) β have minimal impact on T cells, and natalizumab marginally increases the number of memory T cells in the blood. The effect of DMTs on the B cell, NKT and NK cell subsets is highly variable with alemtuzumab inducing a strong increase in the number of the most immature NK cells and its subsets. This study comprehensively evaluates the magnitude of the effect of different DMTs on blood immune cells providing a better understanding of therapy outcome. Furthermore, the lack of a discernible pattern in the effects of DMTs on blood immune cells suggests that multiple immune cells can independently modulate the disease.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Fingolimod Hydrochloride; Immunosuppressive Agents; Alemtuzumab; Multiple Sclerosis; CD8-Positive T-Lymphocytes
PubMed: 38461632
DOI: 10.1016/j.intimp.2024.111826 -
Neurological Research and Practice Mar 2024In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort...
Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study.
INTRODUCTION
In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients.
METHODS
ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed.
PERSPECTIVE
Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.
PubMed: 38449051
DOI: 10.1186/s42466-024-00310-x -
PloS One 2024The 5-item Medication Adherence Report Scale (MARS-5) is a reliable and valid questionnaire for evaluating adherence in patients with asthma, hypertension, and diabetes....
The 5-item Medication Adherence Report Scale (MARS-5) is a reliable and valid questionnaire for evaluating adherence in patients with asthma, hypertension, and diabetes. Validity has not been determined in multiple sclerosis (MS). We aimed to establish criterion validity and reliability of the MARS-5 in persons with MS (PwMS). Our prospective study included PwMS on dimethyl fumarate (DMF). PwMS self-completed the MARS-5 on the same day before baseline and follow-up brain magnetic resonance imaging (MRI) 3 and 9 months after treatment initiation and were graded as highly and medium adherent upon the 24-cut-off score, established by receiver operator curve analysis. Health outcomes were represented by relapse occurrence from the 1st DMF dispense till follow-up brain MRI and radiological progression (new T2 MRI lesions and quantitative analysis) between baseline and follow-up MRI. Criterion validity was established by association with the Proportion of Days Covered (PDC), new T2 MRI lesions, and Beliefs in Medicines questionnaire (BMQ). The reliability evaluation included internal consistency and the test-retest method. We included 40 PwMS (age 37.6 ± 9.9 years, 75% women), 34 were treatment-naive. No relapses were seen during the follow-up period but quantitative MRI analysis showed new T2 lesions in 6 PwMS. The mean (SD) MARS-5 score was 23.1 (2.5), with 24 PwMS graded as highly adherent. The higher MARS-5 score was associated with higher PDC (b = 0.027, P<0.001, 95% CI: (0.0134-0.0403)) and lower medication concerns (b = -1.25, P<0.001, 95% CI: (-1.93-(-0,579)). Lower adherence was associated with increased number (P = 0.00148) and total volume of new T2 MRI lesions (P = 0.00149). The questionnaire showed acceptable internal consistency (Cronbach α = 0.72) and moderate test-retest reliability (r = 0.62, P < 0.0001, 95% CI: 0.33-0.79). The MARS-5 was found to be valid and reliable for estimating medication adherence and predicting medication concerns in persons with MS.
Topics: Humans; Female; Adult; Middle Aged; Male; Multiple Sclerosis; Prospective Studies; Psychometrics; Reproducibility of Results; Dimethyl Fumarate; Medication Adherence
PubMed: 38437197
DOI: 10.1371/journal.pone.0294116 -
Sultan Qaboos University Medical Journal Feb 2024Dimethyl fumarate (DMF) is known to cause lymphopenia when used to treat patients with multiple sclerosis (MS). However, research on DMF therapy in the Arab world,...
OBJECTIVES
Dimethyl fumarate (DMF) is known to cause lymphopenia when used to treat patients with multiple sclerosis (MS). However, research on DMF therapy in the Arab world, especially in Oman, is scarce. This study aimed to analyse the prevalence of lymphopenia among Omani patients with MS and their reasons for discontinuing DMF therapy.
METHODS
In this retrospective study, the medical records of Omani patients with MS who were treated using DMF at two tertiary hospitals in Muscat, Oman, from February 2017 to February 2023 were reviewed. Their demographic, clinical and laboratory data were retrieved and analysed. Absolute lymphocyte count values at baseline and at the last follow-up, as well as the reasons for discontinuing DMF therapy, were collected. Descriptive and inferential statistical techniques were used for data analysis. Binary-logistic regression analysis was used to identify the risk factors for DMF-induced lymphopenia.
RESULTS
A total of 64 Omani patients with MS were included in this study. The majority of the study participants (n = 40; 63%) were female. All included patients started DMF therapy at the mean age of 33 ± 7.7 years. After administration of DMF, 14 (21.9%) patients developed grades 1-3 of lymphopenia. The DMF therapy was discontinued for 23 (36.0%) patients, mainly in response to adverse events or confirmed pregnancy. Female gender was the only significant predictor of DMF-induced lymphopenia ( = 0.037).
CONCLUSIONS
Most Omani patients with MS had mild lymphopenia (grades 1-2). Early adverse events and pregnancy were the main reasons provided for discontinuing DMF therapy.
Topics: Pregnancy; Humans; Female; Male; Adult; Dimethyl Fumarate; Multiple Sclerosis; Retrospective Studies; Lymphopenia; Arab World
PubMed: 38434464
DOI: 10.18295/squmj.9.2023.051 -
Heliyon Mar 2024To explore the current status and trends of disease-modifying therapies (DMTs) for multiple sclerosis through bibliometric and visual analyses of the related literature. (Review)
Review
OBJECTIVE
To explore the current status and trends of disease-modifying therapies (DMTs) for multiple sclerosis through bibliometric and visual analyses of the related literature.
METHODS
Relevant literature from the Web of Science Core Collection from 2017 to 2022 was retrieved, and a bibliometric analysis was performed using CiteSpace 6.1. R2. Thesoftware was used to generate visual graphs of the author, institution, country, keyword co-occurrence, and literature co-citation network.
RESULTS
A total of 1719 manuscripts were retrieved, including 1397 original studies and 322 reviews. In the past five years, Patti F and the University of London were the authors and institutions generating the largest number of publications, respectively, and there was active collaboration between authors and institutions. The United States was the largest contributor to the relevant literature, and the high-frequency keywords in the field of multiple sclerosis disease-modifying therapies in the past five years mainly included multiple sclerosis, disease-modifying therapy, double-blind, disability, natalizumab, effectiveness, fingolimod, glatiramer acetate, and dimethyl fumarate.
CONCLUSIONS
Current research hotspots and trends in DMTs in multiple sclerosis focus on the effectiveness of different DMTs drugs in treating patients with MS and how to optimise treatment strategies. In the context of the COVID-19 pandemic, the correlation between MS and COVID-19 infection and the method to manage and address the adverse effects of DMTs on multiple sclerosis patients is also future research trends.
PubMed: 38434405
DOI: 10.1016/j.heliyon.2024.e26173 -
Advanced Science (Weinheim,... May 2024Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the...
Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra-conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory-polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein-based conduits. Moreover, the NGC can gradually regulate the intra-conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.
Topics: Animals; Nerve Regeneration; Rats; Peripheral Nerve Injuries; Fibroins; Disease Models, Animal; Rats, Sprague-Dawley; Schwann Cells; Guided Tissue Regeneration; Inflammation; Tissue Scaffolds; Sciatic Nerve
PubMed: 38430538
DOI: 10.1002/advs.202302988 -
Journal of Neurology Jun 2024To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with... (Observational Study)
Observational Study Comparative Study
OBJECTIVES
To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with relapsing-remitting multiple sclerosis (RRMS).
MATERIALS AND METHODS
The EIT cohort started with alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR), or ozanimod (OZA); whereas, the ESC cohort was escalated from dimethylfumarate (DMF) or teriflunomide (TERI) to AZM, CLAD, FTY, NTZ, OCR, or OZA within the Austrian MS Treatment Registry. Patients had to stay on therapy for at least 3 months and up to 16 years. The EIT cohort included 743 and the ESC cohort 227 RRMS patients. We used multinomial propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for the bias of this non-randomized registry study.
RESULTS
Estimated mean annualized relapse rates (ARR) were 0.09 for EIT and 0.4 for ESC patients. The incidence rate ratio (IRR) in the GLM model for relapses showed a decreased relapse probability of 78% for the EIT versus ESC cohort [IRR = 0.22, 95% CI (0.16-0.30), p < 0.001]. Analyzing the time to the first relapse by Cox regression, a hazard ratio (HR) of 0.17 [95% CI (0.13-0.22), p < 0.001] revealed a decreased risk of 83% for the EIT group. Regarding sustained Expanded Disability Status Scale (EDSS) progression for 12 weeks, a HR of 0.55 [95% CI (0.40-0.76), p < 0.001] showed a decreased probability of 45% for the EIT cohort.
CONCLUSIONS
ESC treatment after DMF and TERI revealed a higher relapse and EDSS progression probability compared to EIT in Austrian RRMS patients. Therefore, an early intensive treatment should be started in patients with an active or highly active disease course.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Male; Austria; Female; Adult; Immunosuppressive Agents; Registries; Cohort Studies; Middle Aged; Immunologic Factors; Dimethyl Fumarate; Toluidines
PubMed: 38430270
DOI: 10.1007/s00415-024-12256-w