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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 -
Inflammopharmacology Apr 2024Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and...
BACKGROUND
Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and pain. In this scenario, a higher proportion of the proinflammatory macrophage type 1 (M1) than the anti-inflammatory macrophage type 2 (M2) could be highlighted as a hallmark of OA progression. The balance between these two macrophage types emerges as a new therapeutic target in OA. This study aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with systemic dimethyl fumarate (DMF) or local intra-articular monomethyl fumarate (MMF).
RESULTS
DMF via gavage or MMF via intra-articular in the right knee of EOA rats showed improvements in gait parameters and the nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey treatment on the twenty-first day (long-lasting phase). DMF treatment decreased proinflammatory TNF-α while increasing anti-inflammatory IL-10 cytokines from the macerated capsule on the fifth day (inflammatory phase). MMF treatment showed joint capsule mRNA extraction downregulating iNOS and TNF-α gene expression while upregulating IL-10 and MCP-1. However, CD206 was not significant but higher than untreated EOA rats' joints on the seventh day (inflammatory phase).
CONCLUSIONS
Our studies with EOA model induced by MIA suggest a new perspective for human treatment committed with OA based on macrophage polarization as a therapeutic target, switching the proinflammatory profile M1 to the anti-inflammatory profile M2 with DMF systematic or by MMF locally treatment according to the OA severity.
Topics: Humans; Rats; Animals; Interleukin-10; Tumor Necrosis Factor-alpha; Osteoarthritis; Pain; Dimethyl Fumarate; Macrophages; Anti-Inflammatory Agents; Fumarates
PubMed: 38472616
DOI: 10.1007/s10787-024-01443-w -
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 -
Multiple Sclerosis (Houndmills,... Mar 2024After 1.5 years of treatment with dimethyl fumarate (DMF) for multiple sclerosis, preceded 8 years earlier by intravenous (IV) cladribine and 1 year earlier by...
After 1.5 years of treatment with dimethyl fumarate (DMF) for multiple sclerosis, preceded 8 years earlier by intravenous (IV) cladribine and 1 year earlier by natalizumab, our patient developed myelodysplastic syndrome (MDS). The initial manifestation was a severe drop in absolute neutrophil and lymphocyte counts. Repeat bone marrow biopsy demonstrated a new unbalanced translocation (between the chromosome 1 long arm and chromosome 7 short arm). This case report, to our knowledge, is the first linking iatrogenic MDS to DMF and cladribine, while also suggesting caution with immunosuppressants in multiple sclerosis patients.
PubMed: 38459716
DOI: 10.1177/13524585241235539 -
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 -
Molecular Neurobiology Mar 2024Our previous study showed that dimethyl fumarate (DMF) treatment performed within three weeks after intracerebroventricular (ICV) injection of streptozotocin (STZ)...
Our previous study showed that dimethyl fumarate (DMF) treatment performed within three weeks after intracerebroventricular (ICV) injection of streptozotocin (STZ) attenuated spatial memory impairment, hippocampal neurodegeneration, and neuroinflammation in rats. The present study is aimed at verifying the hypothesis that DMF alleviates late effects of STZ (6 months after ICV injection) which reflects advanced stage of the Alzheimer's disease (AD) in human patients. Spatial memory was assessed with Morris water maze (MWM), general brain level of amyloid β (Aβ) and p-tau was measured by western blot, immunofluorescent labelling of active microglia (IBA1), Aβ and p-tau and histological assay of neurodegeneration (Fluoro-Jade C) were performed in hippocampus and cortex. Two-week oral therapy with DMF normalized spatial memory disrupted by STZ but had no influence on general brain level of Aβ and p-tau. However, immunofluorescence showed local reduction of Aβ aggregates number in parietal cortex and p-tau cells in CA2 hippocampal area. Microgliosis was alleviated by DMF in CA1 area and parietal cortex. DMF-treated STZ injected rats showed higher number of Aβ containing microglia than untreated group in CA2 and frontal cortex, which may be the result of increased phagocytic activity in these areas after DMF treatment. STZ-induced neurodegeneration was alleviated by DMF in dentate gyrus and frontal cortex. In conclusion DMF treatment exerts beneficial effect on spatial memory in the rat model of late stage of AD, but weakly influences neuropathological features, as only local reduction in number of Aβ aggregates, p-tau containing cells, neurodegeneration, and microgliosis was found.
PubMed: 38430351
DOI: 10.1007/s12035-024-04024-8