-
International Journal of Molecular... Aug 2022In this study, transethosomes were investigated as potential delivery systems for dimethyl fumarate. A formulative study was performed investigating the effect of the...
In this study, transethosomes were investigated as potential delivery systems for dimethyl fumarate. A formulative study was performed investigating the effect of the composition of transethosomes on the morphology and size of vesicles, as well as drug entrapment capacity, using cryogenic transmission electron microscopy, photon correlation spectroscopy, and HPLC. The stability of vesicles was evaluated, both for size increase and capability to control the drug degradation. Drug release kinetics and permeability profiles were evaluated in vitro using Franz cells, associated with different synthetic membranes. The in vitro viability, as well as the capacity to improve wound healing, were evaluated in human keratinocytes. Transmission electron microscopy enabled the evaluation of transethosome uptake and intracellular fate. Based on the obtained results, a transethosome gel was further formulated for the cutaneous application of dimethyl fumarate, the safety of which was evaluated in vivo with a patch test. It was found that the phosphatidylcholine concentration affected vesicle size and lamellarity, influencing the capacity to control dimethyl fumarate's chemical stability and release kinetics. Indeed, phosphatidylcholine 2.7% / led to multivesicular vesicles with 344 nm mean size, controlling the drug's chemical stability for at least 90 days. Conversely, phosphatidylcholine 0.9% / resulted in 130 nm sized unilamellar vesicles, which maintained 55% of the drug over 3 months. These latest kinds of transethosomes were able to improve wound healing in vitro and were easily internalised by keratinocytes. The selected transethosome gel, loading 25 mg/mL dimethyl fumarate, was not irritant after cutaneous application under occlusion, suggesting its possible suitability in the treatment of wounds caused by diabetes mellitus or peripheral vascular diseases.
Topics: Administration, Cutaneous; Dimethyl Fumarate; Drug Delivery Systems; Humans; Liposomes; Phosphatidylcholines; Skin; Skin Absorption
PubMed: 35955900
DOI: 10.3390/ijms23158756 -
Pesticide Biochemistry and Physiology Feb 2023Paraquat (PQ) is the most important cationic bipyridyl herbicide in the agricultural industry, which is very toxic to humans and animals and causes disruption in many...
Paraquat (PQ) is the most important cationic bipyridyl herbicide in the agricultural industry, which is very toxic to humans and animals and causes disruption in many organs, mainly in the lungs. Dimethyl fumarate (DMF) is an immune-modulating drug used in the treatment of multiple sclerosis and psoriasis shows antioxidant, anti-inflammatory, and antifibrotic effects. In this study, the ameliorative effects of DMF (10, 30 and 100 mg/kg, orally) on PQ (30 mg/kg) model of lung damage were evaluated in male mice. DMF was given daily for 7 days and PQ was administrated in the fourth day in a single dose. On the eighth day, the animals were sacrificed, and their lung tissue were removed. The results indicated that DMF can ameliorate PQ-induced the significant increase in lung index, hydroxyproline, as well as TBARS, TGF-β, NF-κB and decrease in the amount of total thiol, catalase, glutathione peroxidase, superoxide dismutase, Nrf-2, and INF-γ. The histopathological results confirmed indicated findings. The results showed that the protective effect of DMF on PQ-induced toxicity is mediated through antioxidant, anti-inflammatory and antifibrotic activities.
Topics: Humans; Mice; Animals; Paraquat; Antioxidants; Dimethyl Fumarate; Lung; Oxidative Stress; Fibrosis; Inflammation
PubMed: 36740344
DOI: 10.1016/j.pestbp.2023.105336 -
International Immunopharmacology Feb 2023We aimed to investigate the therapeutic role of dimethyl fumarate (DMF) in fungal keratitis.
PURPOSE
We aimed to investigate the therapeutic role of dimethyl fumarate (DMF) in fungal keratitis.
METHODS
Human corneal epithelial cells (HCECs) and mouse models of fungal keratitis were used in this study. The antifungal effect of DMF on Aspergillus fumigatus (A. fumigatus) was confirmed by examining the minimum inhibitory concentration (MIC), biofilm formation, conidial adherence and corneal fungal loads. Slit-lamp photography, haematoxylin and eosin staining and immunostaining were used to assess the severity of corneal impairment. RT-PCR, western blot, ELISA, immunohistochemistry and immunostaining were performed to examine the effects of DMF on the expression of the inflammatory mediators during fungal infection.
RESULTS
In vitro, DMF limited A. fumigatus growth, biofilm formation, and conidial adherence and reduced the mRNA levels of AldA, GlkA, GAPDH, HxkA, PgkA, Sdh2, GelA and ChsF in A. fumigatus. In vivo, DMF effectively decreased corneal fungal loads. DMF attenuated corneal inflammatory impairment by suppressing inflammatory cell accumulation and downregulating cytokine expression. DMF notably downregulated the high expression of NLRP3, cleaved GSDMD, cleaved caspase-1, mature IL-1β and mature IL-18 induced by fungi. The production of Nrf2 and HO-1 could be further increased by DMF in infected HCECs. Nrf2 siRNA pretreatment counteracted DMF-mediated downregulation of the expression of the active forms of IL-18, IL-1β, caspase-1 and GSDMD.
CONCLUSION
DMF limits fungal growth by suppressing biofilm formation, conidial adherence and respiratory metabolism. It also exerts an anti-inflammatory effect on fungal keratitis by inhibiting pyroptosis, which could be regulated by Nrf2. Our results suggest that DMF plays a therapeutic role in fungal keratitis.
Topics: Mice; Animals; Humans; Dimethyl Fumarate; Interleukin-18; Aspergillosis; Pyroptosis; NF-E2-Related Factor 2; Keratitis; Aspergillus fumigatus; Eye Infections, Fungal; Caspase 1; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36641891
DOI: 10.1016/j.intimp.2023.109721 -
Journal of Neurology Mar 2021Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple...
BACKGROUND
Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple sclerosis (RRMS).
OBJECTIVE
To compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.
METHODS
We identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.
RESULTS
Of the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8-1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6-1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6-1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.
CONCLUSION
Dimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.
Topics: Dimethyl Fumarate; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 32974794
DOI: 10.1007/s00415-020-10226-6 -
Neurology(R) Neuroimmunology &... Sep 2023Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVE
Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20 T cells and the effect of dimethyl fumarate on CD20 T cells in PPMS.
METHODS
The main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20 T cells and ELISA measurements of myelin basic protein and neurofilament light chain in untreated patients with PPMS and patients treated for 48 weeks with dimethyl fumarate or placebo. MRI measures included new and enlarging T2-weighted lesions over 48 weeks and lesion, normal-appearing white matter, cortical, and thalamic volume.
RESULTS
Assessing CD20 T cells in patients with PPMS and controls showed an increased percentage of CD20 T cells in the blood of untreated patients and a strong enrichment in the CSF. In addition, a higher frequency of CD8CD20 T cells in the CSF correlated with a higher concentration of myelin basic protein and T2-weighted lesion volume and with a lower normal-appearing white matter and thalamus volume. Furthermore, CD8CD20 T cells were associated with the development of new T2 lesions. After 48 weeks of treatment with dimethyl fumarate, total T cells in CSF were reduced; however, CD20 T cells were unaffected.
DISCUSSION
This study shows an association between intrathecal CD8CD20 T cells, white matter injury, and thalamic atrophy in PPMS, suggesting a role of CD8CD20 T cells in the immunopathogenesis of PPMS. The results also suggest that limited efficacy of dimethyl fumarate in PPMS may, at least partly, be a consequence of failure to suppress CD8CD20 T cells in CSF.
Topics: Humans; Case-Control Studies; CD8-Positive T-Lymphocytes; Dimethyl Fumarate; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Myelin Basic Protein; T-Lymphocytes
PubMed: 37369602
DOI: 10.1212/NXI.0000000000200140 -
Acta Dermato-venereologica Feb 2020Pemphigoid diseases are organ-specific autoimmune diseases of the skin and/or mucous membranes. They are caused by autoantibodies targeting adhesion molecules located at... (Review)
Review
Pemphigoid diseases are organ-specific autoimmune diseases of the skin and/or mucous membranes. They are caused by autoantibodies targeting adhesion molecules located at the dermal-epidermal junction. While the diagnostics of pemphigoid diseases and insights into their pathogenesis have improved significantly, the development of novel treatments that are effective and safe remains an unmet medical need. However, numerous pre-clinical studies and early clinical trials have recently been launched. This review summarizes some pathways leading to drug development in pemphigoid diseases, namely: (i) hypothesis-driven drug development; (ii) omics-based drug development; (iii) drug repurposing; (iv) screening-based drug development; and (v) drug development based on careful clinical observations. Ultimately, it is hoped that this will lead to personalized and curative treatments.
Topics: Autoantibodies; Autoimmune Diseases; Cell Adhesion Molecules; Dimethyl Fumarate; Doxycycline; Drug Development; Epidermolysis Bullosa Acquisita; Female; Forecasting; Humans; Male; Molecular Targeted Therapy; Pemphigoid, Bullous; Protein-Tyrosine Kinases; Skin Diseases, Vesiculobullous; Translational Research, Biomedical
PubMed: 32039458
DOI: 10.2340/00015555-3400 -
Annals of Neurology May 2022Treatment with dimethyl fumarate (DMF) leads to lymphopenia and infectious complications in a subset of patients with multiple sclerosis (MS). Here, we aimed to reveal... (Observational Study)
Observational Study
Treatment with dimethyl fumarate (DMF) leads to lymphopenia and infectious complications in a subset of patients with multiple sclerosis (MS). Here, we aimed to reveal immune markers of DMF-associated lymphopenia. This prospective observational study longitudinally assessed 31 individuals with MS by single-cell mass cytometry before and after 12 and 48 weeks of DMF therapy. Employing a neural network-based representation learning approach, we identified a CCR4-expressing T helper cell population negatively associated with relevant lymphopenia. CCR4-expressing T helper cells represent a candidate prognostic biomarker for the development of relevant lymphopenia in patients undergoing DMF treatment. ANN NEUROL 2022;91:676-681.
Topics: Dimethyl Fumarate; Humans; Immunosuppressive Agents; Lymphopenia; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Prospective Studies
PubMed: 35170072
DOI: 10.1002/ana.26328 -
Journal of Neuroinflammation Feb 2024Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor...
BACKGROUND
Neuroinflammation substantially contributes to the pathology of Alzheimer's disease (AD), the most common form of dementia. Studies have reported that nuclear factor erythroid 2-related factor 2 (Nrf2) attenuates neuroinflammation in the mouse models of neurodegenerative diseases, however, the detailed mechanism remains unclear.
METHODS
The effects of dimethyl fumarate (DMF), a clinically used drug to activate the Nrf2 pathway, on neuroinflammation were analyzed in primary astrocytes and App (App-KI) mice. The cognitive function and behavior of DMF-administrated App-KI mice were evaluated. For the gene expression analysis, microglia and astrocytes were directly isolated from the mouse cerebral cortex by magnetic-activated cell sorting, followed by quantitative PCR.
RESULTS
DMF treatment activated some Nrf2 target genes and inhibited the expression of proinflammatory markers in primary astrocytes. Moreover, chronic oral administration of DMF attenuated neuroinflammation, particularly in astrocytes, and reversed cognitive dysfunction presumably by activating the Nrf2-dependent pathway in App-KI mice. Furthermore, DMF administration inhibited the expression of STAT3/C3 and C3 receptor in astrocytes and microglia isolated from App-KI mice, respectively, suggesting that the astrocyte-microglia crosstalk is involved in neuroinflammation in mice with AD.
CONCLUSION
The activation of astrocytic Nrf2 signaling confers neuroprotection in mice with AD by controlling neuroinflammation, particularly by regulating astrocytic C3-STAT3 signaling. Furthermore, our study has implications for the repositioning of DMF as a drug for AD treatment.
Topics: Mice; Animals; Alzheimer Disease; Dimethyl Fumarate; Mice, Transgenic; Neuroinflammatory Diseases; NF-E2-Related Factor 2; Cognitive Dysfunction; Disease Models, Animal
PubMed: 38383481
DOI: 10.1186/s12974-024-03046-2 -
Journal of Neuroinflammation Apr 2024Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU)...
BACKGROUND
Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking.
METHODS
To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF.
RESULTS
Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells.
CONCLUSIONS
DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.
Topics: Dimethyl Fumarate; Uveitis; Autoimmune Diseases; Single-Cell Gene Expression Analysis; Disease Models, Animal; Animals; Mice; Female; Mice, Inbred C57BL; Receptors, CXCR4; Proto-Oncogene Proteins c-pim-1; Transcription, Genetic; T-Lymphocyte Subsets; Atlases as Topic; Immunosuppressive Agents; Anti-Inflammatory Agents, Non-Steroidal; Retina; Lymph Nodes
PubMed: 38684986
DOI: 10.1186/s12974-024-03096-6 -
Farmacia Hospitalaria : Organo Oficial... Dec 2020Dimethyl fumarate is a medication approved for the treatment of relapsing-remitting multiple sclerosis. The purpose of the study was to evaluate the safety and... (Observational Study)
Observational Study
OBJECTIVE
Dimethyl fumarate is a medication approved for the treatment of relapsing-remitting multiple sclerosis. The purpose of the study was to evaluate the safety and persistence of dimethyl fumarate in clinical practice and analyze the occurrence of lymphopenia is patients treated with dimethyl fumarate over a period of at least 6 months.
METHOD
This is a retrospective longitudinal observational study carried out between August 2015 and March 2019. The study cohort was made up of patients who had been treated with dimethyl fumarate for at least 6 months. Lymphocyte counts were recorded at different points of time (pre-treatment, at 3, 6, 12 months, and at the end of the study period). The evolution of lymphopenia was evaluated by means of a logistic regression statistical model. An analysis was performed of the relationship between a decreased lymphocyte count over the first 6 months of treatment and the development, by the end of the study, of grade II-III lymphopenia necessitating discontinuation of dimethyl fumarate. Other safety indicators were also evaluated including adverse events and interruptions or discontinuations of treatment. Persistence was determined by measuring the time to discontinuation of treatment.
RESULTS
The study included a total of 55 patients, of whom 80% were female. The most common adverse events were lymphopenia (27), rubefaction (16), digestive symptoms (11), fatigue (9), headache (3) and sleep disturbances (2). Eleven subjects interrupted/discontinued their treatment during the study period; reasons were as follows: pregnancy (2), personal decision (2), John Cunningham virus infection (1), allergy to the drug (2), and lymphopenia (4). Median duration of treatment was 23 months (4-43 months). A statistically significant association was found between a lower lymphocyte count over the first 6 months of treatment and the development of severe lymphopenia by the end of the study [OR = 1.34 (0.35-2.60); 95% CI (p = 0.001)].
CONCLUSIONS
The adverse events observed in the present study are in line with those reported in previous analyses. Lymphopenia was the most common adverse event. The persistence of the medication was similar to that found in pivotal trials. The significant association found between a decreased lymphocyte count over the first 6 months of treatment and the development of severe lymphopenia by the end of the study suggests a connection between both variables, which could be instrumental in being able to predict and even prevent the occurrence of such lymphopenias.
Topics: Dimethyl Fumarate; Female; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Retrospective Studies; Sclerosis
PubMed: 33709887
DOI: 10.7399/fh.11567