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Malaria Journal Oct 2020Cerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from...
BACKGROUND
Cerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes. A potentially protective role of the nuclear factor E2-related factor 2 (NRF2) pathway, which serves as a therapeutic target in brain microvascular diseases and central nervous system (CNS) inflammatory diseases such as multiple sclerosis was tested to protect endothelial cells in an in vitro culture system subjected to tumour necrosis factor (TNF) or infected red blood cell exposure. NRF2 is a transcription factor that mediates anti-oxidant and anti-inflammatory responses.
METHODS
To accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NFκB. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined.
RESULTS
Transcriptional profiling demonstrates that DMF upregulates the NRF2-Mediated Oxidative Stress Response, ErbB4 Signaling Pathway, Peroxisome Proliferator-activated Receptor (PPAR) Signaling and downregulates iNOS Signaling and the Neuroinflammation Signaling Pathway on TNF activated HBMVEC. The parasite lines derived from eight paediatric CM patients demonstrated increased binding to TNF activated HBMVEC and varied in their binding and activation of HBMVEC. Overall DMF reduced both TNF and CM derived parasite activation of HBMVEC.
CONCLUSIONS
These findings provide evidence that targeting the NRF2 pathway in TNF and parasite activated HBMVEC mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.
Topics: Anti-Inflammatory Agents; Antioxidants; Brain; Child; Child, Preschool; Dimethyl Fumarate; Endothelial Cells; Humans; Infant; Malaria, Cerebral; Malaria, Falciparum; Plasmodium falciparum; Tumor Necrosis Factor-alpha
PubMed: 33087130
DOI: 10.1186/s12936-020-03447-7 -
Neurotherapeutics : the Journal of the... Sep 2023In the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for... (Meta-Analysis)
Meta-Analysis
In the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for relapsing-remitting multiple sclerosis, namely, dimethyl fumarate (DMF) and teriflunomide (TRF). We searched scientific databases to identify real-world studies reporting a direct comparison of DMF versus TRF. We fitted inverse-variance weighted meta-analyses with random effects models to estimate the risk ratio (RR) of relapse, confirmed disability worsening (CDW), and treatment discontinuation. Quantitative synthesis was accomplished on 14 articles yielding 11,889 and 8133 patients treated with DMF and TRF, respectively, with a follow-up ranging from 1 to 2.8 years. DMF was slightly more effective than TRF in reducing the short-term relapse risk (RR = 0.92, p = 0.01). Meta-regression analyses showed that such between-arm difference tends to fade in studies including younger patients and a higher proportion of treatment-naïve subjects. There was no difference between DMF and TRF on the short-term risk of CDW (RR = 0.99, p = 0.69). The risk of treatment discontinuation was similar across the two oral drugs (RR = 1.02, p = 0.63), but it became slightly higher with DMF than with TRF (RR = 1.07, p = 0.007) after removing one study with a potential publication bias that altered the final pooled result, as also confirmed by a leave-one-out sensitivity analysis. Discontinuation due to side effects and adverse events was reported more frequently with DMF than with TRF. Our findings suggest that DMF is associated with a lower risk of relapses than TRF, with more nuanced differences in younger naïve patients. On the other hand, TRF is associated with a lower risk of treatment discontinuation for side effects and adverse events.
Topics: Humans; Dimethyl Fumarate; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Recurrence
PubMed: 37528262
DOI: 10.1007/s13311-023-01416-x -
Frontiers in Medicine 2022Psoriasis vulgaris is a chronic inflammatory skin disease characterized by well-demarcated scaly plaques. Oxidative stress plays a crucial role in the psoriasis... (Review)
Review
Psoriasis vulgaris is a chronic inflammatory skin disease characterized by well-demarcated scaly plaques. Oxidative stress plays a crucial role in the psoriasis pathogenesis and is associated with the disease severity. Dimethyl fumarate modulates the activity of the pro-inflammatory transcription factors. This is responsible for the downregulation of inflammatory cytokines and an overall shift from a pro-inflammatory to an anti-inflammatory/regulatory response. Both steps are necessary for the amelioration of psoriatic inflammation, although additional mechanisms have been proposed. Several studies reported a long-term effectiveness and safety of dimethyl fumarate monotherapy in patients with moderate-to-severe psoriasis. Furthermore, psoriasis is a chronic disease often associated to metabolic comorbidities, as obesity, diabetes, and cardiovascular diseases, in which glutathione-S transferase deregulation is present. Glutathione-S transferase is involved in the antioxidant system. An increase of its activity in psoriatic epidermis in comparison with the uninvolved and normal epidermal biopsies has been reported. Dimethyl fumarate depletes glutathione-S transferase by formation of covalently linked conjugates. This review investigates the anti-inflammatory role of dimethyl fumarate in oxidative stress and its effect by reducing oxidative stress. The glutathione-S transferase regulation is helpful in treating psoriasis, with an anti-inflammatory effect on the keratinocytes hyperproliferation, and in modulation of metabolic comorbidities.
PubMed: 35211489
DOI: 10.3389/fmed.2022.760852 -
Multiple Sclerosis Journal -... 2022Comparing real-world effectiveness and tolerability of therapies for relapsing-remitting multiple sclerosis is increasingly important, though average treatment effects...
Overall and patient-level comparative effectiveness of dimethyl fumarate and fingolimod: A precision medicine application to the Observatoire Français de la Sclérose en Plaques registry.
BACKGROUND
Comparing real-world effectiveness and tolerability of therapies for relapsing-remitting multiple sclerosis is increasingly important, though average treatment effects fail to capture possible treatment effect heterogeneity. With the clinical course of the disease being highly heterogeneous across patients, precision medicine methods enable treatment response heterogeneity investigations.
OBJECTIVE
To compare real-world effectiveness and discontinuation profiles between dimethyl fumarate and fingolimod while investigating treatment effect heterogeneity with precision medicine methods.
METHODS
Adults initiating dimethyl fumarate or fingolimod as a second-line therapy were selected from a French registry. The primary outcome was annualized relapse rate at 12 months. Seven secondary outcomes relative to discontinuation and disease progression were considered. A precision medicine framework was used to characterize treatment effect heterogeneity.
RESULTS
Annualized relapse rates at 12 months were similar for dimethyl fumarate and fingolimod. The odd of treatment persistence was 47% lower for patients treated with dimethyl fumarate relative to those treated with fingolimod (odds ratio: 0.53, 95% confidence interval: 0.39, 0.70). None of the five precision medicine scoring approaches identified treatment heterogeneity.
CONCLUSION
These findings substantiated the similar effectiveness and different discontinuation profiles for dimethyl fumarate and fingolimod as a second-line therapy for relapsing-remitting multiple sclerosis, with no significant effect heterogeneity observed.
PubMed: 35959484
DOI: 10.1177/20552173221116591 -
European Journal of Medicinal Chemistry Jan 2024The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS)... (Review)
Review
The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS) damage in various cells and organs. It has garnered significant attention as a potential therapeutic target for neurodegenerative diseases (NDD). Although progress has been achieved in strategies to regulate the Keap1-Nrf2 pathway, the availability of Nrf2 activators applicable to NDD is currently limited. Currently, the FDA has approved the Nrf2 activators dimethyl fumarate (DMF) and Omaveloxolone (Omav) as novel first-line oral drugs for the treatment of patients with relapsing forms of multiple sclerosis and Friedreich's ataxia. A promising alternative approach involves the direct inhibition of Keap1-Nrf2 protein-protein interactions (PPI), which offers numerous advantages over the use of electrophilic Nrf2 activators, primarily in avoiding off-target effects. This review examines the compelling evidence supporting the beneficial role of Nrf2 in NDD and explores the potential of Keap1 inhibitors and Keap1-Nrf2 PPI inhibitors as therapeutic agents, with the aim to provide further insights into the development of inhibitors targeting this pathway for the treatment of NDD.
Topics: Humans; NF-E2-Related Factor 2; Kelch-Like ECH-Associated Protein 1; Neurodegenerative Diseases; Oxidative Stress; Dimethyl Fumarate
PubMed: 38043492
DOI: 10.1016/j.ejmech.2023.115998 -
Multiple Sclerosis and Related Disorders Jul 2022Infections in people with multiple sclerosis (PwMS) may have a detrimental effect on disease progression, risk of hospitalization, and healthcare resource utilization...
BACKGROUND
Infections in people with multiple sclerosis (PwMS) may have a detrimental effect on disease progression, risk of hospitalization, and healthcare resource utilization (HRU). The infection risk and HRU costs may vary between disease-modifying therapies (DMTs); however, the individual risks and differences associated with DMTs are not well characterized. Some DMTs may increase the risk for infections in PwMS; however, previous studies have reported an intact humoral immune response in dimethyl fumarate (DMF)-treated patients. The objective was to compare infection-related HRU and healthcare costs (HCCs) between PwMS treated with DMF or ocrelizumab (OCR).
METHODS
Eligible patients were identified from the Optum US claims database between April 2017 and September 2020 (DMF n = 1429; OCR n = 3170). Patients were followed from index date to first occurrence of: (1) end of study, (2) end of insurance eligibility, (3) discontinuation of index DMT, or (4) switch from index DMT to another DMT. Outcomes were annualized rate of infection encounters (defined as infection encounters [n] during follow-up window / days followed [n] × 365); annualized infection-related HCCs (defined as aggregated costs of infection encounters during follow-up window / days followed [n] × 365); location-specific infections, and overall infection-related events. Propensity score matching (PSM) 1:1 method was used; PS was calculated via logistic regression for probability of DMF treatment conditional on demographics and comorbidities. Mean differences (MD) were reported for infection encounter measures.
RESULTS
After PSM, DMF and OCR cohorts (n = 1094 in each cohort) were balanced based on baseline characteristics (standardized MD of adjusted baseline characteristics <0.1). Mean (standard deviation) follow-up was 296 (244) days for DMF patients and 297 (243) for OCR patients. DMF patients experienced lower annualized rates of overall infection encounters vs OCR patients (MD -0.51 [95% confidence interval (CI): -0.92 to -0.11], p = 0.01). When stratified by type of infection encounter, DMF patients experienced significantly lower annualized rates of outpatient (MD [95% CI]: -0.44 [-0.80 to -0.08], p = 0.02) and inpatient/hospitalization infection encounters (-0.08 [-0.14 to -0.02], p<0.01) vs OCR patients. A trend towards a shorter duration of infection-related hospitalization in the DMF vs the OCR group was observed (MD [95% CI]: -2.20 [-4.73 to 0.26] days, p = 0.08). The most common infection types in both DMT groups were urinary tract infections, sepsis, and pneumonia. DMF patients experienced lower annualized infection-related HCCs (MD [95% CI]: -$3642 [-$6380 to -$904], p < 0.01) vs OCR patients, which were driven largely by infection-related hospitalization costs (-$3639 [-$6019 to -$1259], p < 0.01).
CONCLUSION
DMF-treated patients PS-matched with OCR patients experienced lower annualized rates of infection encounters and lower infection-related HCCs.
Topics: Antibodies, Monoclonal, Humanized; Dimethyl Fumarate; Health Care Costs; Humans; Multiple Sclerosis; Retrospective Studies
PubMed: 35700674
DOI: 10.1016/j.msard.2022.103921 -
Inflammation Feb 2023This study aimed to clarify the nephroprotective effect of dimethyl fumarate (DMF) against Di (2-ethylhexyl) phthalate (DEHP)-induced nephrotoxicity in both in vitro and...
This study aimed to clarify the nephroprotective effect of dimethyl fumarate (DMF) against Di (2-ethylhexyl) phthalate (DEHP)-induced nephrotoxicity in both in vitro and in vivo models. The HEK-293 cells were exposed to different concentrations of DMF plus IC50 concentration of monoethylhexyl phthalate (MEHP) (the main metabolite of DEHP). Then, some of the oxidative stress parameters including ROS, MDA, and GSH, and cytotoxicity (MTT assay) were determined in treated cells. For in vivo evaluation, rats were divided into 7 groups (n = 6 per group). Corn oil group (gavage), DEHP group (200 mg/kg dissolved in corn oil, gavage), DMF (15, 30, and 60 mg/kg, gavage) plus DEHP (200 mg/kg) groups, DMF (60 mg/kg, gavage) alone, and vitamin E (20 mg/kg, intraperitoneal (IP)) plus DEHP (200 mg/kg) group. This treatment continued for 45 days. Then, BUN and creatinine were evaluated by a commercial kit based on the urease enzymatic method and the Jaffe method, respectively. Mitochondrial oxidative stress and mitochondrial dysfunction parameters were evaluated using appropriate reagents, and gene expression of the p65 nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNFα), nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were evaluated by real-time PCR method. High concentrations of DMF significantly increased cell viability, and GSH content and significantly decreased ROS and MDA levels compared with the MEHP group in HEK-293 cells. DMF (60 mg/kg) significantly decreased BUN and creatinine levels compared with the DEHP group. Mitochondrial function and mitochondrial swelling were significantly improved in DMF group (60 mg/kg) compared with the DEHP group. DMF (30 and 60 mg/kg) significantly improved MMP collapse compared with the DEHP group. DMF (30 and 60 mg/kg) significantly decreased ROS levels compared with the DEHP group in isolated kidney mitochondria. DMF (60 mg/kg) significantly decreased MDA levels and significantly increased GSH content compared with DEHP group in isolated kidney mitochondria. The mRNA expression levels of Nrf2 and HO-1 were significantly reduced in the DEHP group compared to the control group and were significantly increased in the DMF group compared to the DEHP group. p65NF-κB and TNFα mRNA expression levels were significantly increased in the DEHP group compared to the control group. However, DMF significantly decreased p65NF-κB and TNFα mRNA expression compared to the DEHP group. DMF can act as a nephroprotective agent against DEHP partly through modulation of oxidative stress, mitochondrial function, and inflammation.
Topics: Rats; Humans; Animals; NF-kappa B; Diethylhexyl Phthalate; Dimethyl Fumarate; NF-E2-Related Factor 2; Reactive Oxygen Species; Heme Oxygenase-1; Corn Oil; Creatinine; HEK293 Cells; Tumor Necrosis Factor-alpha; Oxidative Stress; Signal Transduction; RNA, Messenger
PubMed: 36195817
DOI: 10.1007/s10753-022-01746-6 -
Irish Journal of Medical Science Dec 2022The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and...
OBJECTIVE
The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and volume of lesions. They mediate their effects through reduction of immune reactivation, which may potentially lead to lymphopaenia and increased risk of infections. Previous studies have examined the effects of these therapies on lymphocyte subsets; however, the in vivo effects on circulating lymphocyte proliferation require further elucidation. The aim of this study was to determine the effects of DMF and FTY on T-cell proliferation in patients with MS.
METHOD
We examined T-cell lymphocyte proliferation and lymphocyte subsets in ten patients (five on DMF, five on FTY) before starting DMT and again 4 to 11 months after being maintained on DMT.
RESULTS
In the FTY-treated group, the mean percentage proliferation was significantly lower using both assays (PHA assay mean percentage change - 51.2 ± 25.97, p < 0.05; anti-CD3/CD28 assay mean percentage change - 39.74 ± 27.85, p < 0.05). There was no statistical difference in T-cell lymphocyte proliferation in the DMF-treated group for either assay (PHA, p = 0.316; anti-CD3/CD28, p = 0.373).
CONCLUSIONS
This pilot study suggests that the T-lymphocytes of patients on FTY have an abnormal proliferation response as well as being reduced in the circulation.
Topics: Humans; Fingolimod Hydrochloride; Dimethyl Fumarate; Multiple Sclerosis; CD28 Antigens; Pilot Projects; Immunosuppressive Agents; Treatment Outcome; Lymphocytes; Cell Proliferation
PubMed: 35028898
DOI: 10.1007/s11845-021-02913-8 -
International Immunopharmacology Oct 2023The ferroptosis of neurons is an important pathological mechanism of spinal cord ischemia reperfusion injury (SCIRI). Previous studies showed that synoviolin 1 (SYVN1)...
BACKGROUND
The ferroptosis of neurons is an important pathological mechanism of spinal cord ischemia reperfusion injury (SCIRI). Previous studies showed that synoviolin 1 (SYVN1) is a good prognostic marker of neurodegenerative diseases, but its mechanism is still unclear. This study aims to explore the role of SYVN1 in the ferroptosis of neurons and to clarify its internal mechanism.
METHODS
Rat primary spinal cord neurons were treated with oxygen-glucose deprivation (OGD) for 1, 4 or 8 h, and then cell viability, ROS and MDA levels, glutathione peroxidase (GSH-Px) activity, and the expression of ferroptosis-related proteins GPX4, FTH1 and PTGS2 were detected. OGD/R-induced neurons were transfected with pcDNA-SYVN1 or si-HMGB1, and then cell functions were detected. Transmission electron microscope (TEM) was used to detect cell ferroptosis. The interplay between SYVN1 and high mobility group box 1 (HMGB1) was confirmed with Co-immunoprecipitation (Co-IP) assay. The stability of HMGB1 was measured by ubiquitination assay. Also, cells were treated with pcDNA-SYVN1 or together with ubiquitination inhibitor MG132, as well as treated with pcDNA-SYVN1 and pcDNA-HMGB1 or together with NRF2 activator dimethyl fumarate (DMF), and then Western blotting was used to detect the expression of HMGB1, nuclear NRF2 and HO-1 proteins. In addition, SD rats were occluded left common carotid artery and aortic arch to establish a SCIRI rat model. And rats were injected intrathecal with adenovirus-mediated SYVN1 overexpression vector (Ad-SYVN1, 2 μL, virus titer 5 × 10 transduction unit [TU]/mL) to overexpress SYVN1. The motion function of rats was quantified using the Basso Rat Scale (BMS) for Locomotion. The ferroptosis and the number of neurons in the spinal cord tissue of rats were detected.
RESULTS
SYVN1 overexpression inhibited ferroptosis of SCIRI rats and OGD/R-treated primary spinal cord neurons, and down-regulated the expression of HMGB1. In terms of mechanism, the binding of SYVN1 and HMGB1 promoted the ubiquitination and degradation of HMGB1, and negatively regulated the expression of HMGB1. Moreover, under OGD/R conditions, MG132 treatment or HMGB1 overexpression eliminated the inhibitory effect of SYVN1 overexpression on the ferroptosis of neurons and the activation of the NRF2/HO-1 pathway, and DMF treatment abolished the inhibition of HMGB1 overexpression on the NRF2/HO-1 pathway. Finally, in vivo experiments showed that SYVN1 overexpression could alleviate the spinal cord ischemia-reperfusion injury in rats by down-regulating HMGB1 and promoting the activation of the NRF2/HO-1 pathway.
CONCLUSION
SYVN1 regulates ferroptosis through the HMGB1/NRF2/HO-1 axis to prevent spinal cord ischemia-reperfusion injury.
Topics: Animals; Rats; Dimethyl Fumarate; Ferroptosis; Glucose; HMGB1 Protein; NF-E2-Related Factor 2; Rats, Sprague-Dawley; Spinal Cord Ischemia
PubMed: 37591122
DOI: 10.1016/j.intimp.2023.110802 -
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