-
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 -
Nature Reviews. Neurology May 2019
Topics: Cohort Studies; Crotonates; Dimethyl Fumarate; Humans; Hydroxybutyrates; Nitriles; Recurrence; Toluidines
PubMed: 30918354
DOI: 10.1038/s41582-019-0177-1 -
International Journal of Molecular... Aug 2022Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and...
Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic target. In the present study, we examined whether dimethyl fumarate (DMF), an NF-κB inhibitor, induces apoptosis in TNBC cells and enhances the apoptosis-inducing effect of paclitaxel and adriamycin. Cell survival was analyzed by the trypan blue assay and apoptosis assay. Protein detection was examined by immunoblotting. The activation of NF-κB p65 was correlated with poor prognosis in patients with TNBC. DMF induced apoptosis in MDA-MB-231 and BT-549 cells at concentrations that were non-cytotoxic to the normal mammary cell line MCF-10A. Furthermore, DMF inhibited NF-κB nuclear translocation and Survivin, XIAP, Bcl-xL, and Bcl-2 expression in MDA-MB-231 and BT-549 cells. Moreover, DMF enhanced the apoptosis-inducing effect of paclitaxel and adriamycin in MDA-MB-231 cells. These findings suggest that DMF may be an effective therapeutic agent for the treatment of TNBC, in which NF-κB is constitutively active. DMF may also be useful as an adjuvant therapy to conventional anticancer drugs.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Dimethyl Fumarate; Doxorubicin; Humans; NF-kappa B; Paclitaxel; Signal Transduction; Triple Negative Breast Neoplasms
PubMed: 35955813
DOI: 10.3390/ijms23158681 -
Journal of Cardiothoracic Surgery Nov 2021Dimethyl fumarate (DMF) has been reported to exert a protective role against diverse lung diseases and cognitive impairment-related diseases. Thus this study aimed to...
OBJECTIVE
Dimethyl fumarate (DMF) has been reported to exert a protective role against diverse lung diseases and cognitive impairment-related diseases. Thus this study aimed to investigate its role on acute lung injury (ALI) and related cognitive impairment in animal model.
METHODS
C57BL/6 mice were divided into four groups: control group, DMF group, ALI group, and ALI + DMF group. For ALI group, the ALI mice model was created by airway injection of LPS (50 μL, 1 μg/μL); for ALI + DMF group, DMF (dissolved in 0.08% methylcellulose) was treated twice a day for 2 days, and on the third day, mice were injected with LPS for ALI modeling. Mice pre-administered with methylcellulose or DMF without LPS injection (PBS instead) were used as the control group and DMF group, respectively. Morris water maze test was performed before any treatment (0 h) and 6 h after LPS-induction (54 h) to evaluate the cognitive impairment of mice. Next, the brain edema and blood brain barrier (BBB) permeability of ALI mice were assessed by brain water content, Evans blue extravasation and FITC-Dextran uptake assays. In addition, the effect of DMF on the numbers of total cells and neutrophils, protein content in BALF were quantified; the inflammatory factors in BALF, serum, and brain tissues were examined by ELISA, qRT-PCR, and Western blot assays. The effect of DMF on the cognitive impairment-related factor HIF-1α level in lung and brain tissues was also examined by Western blot.
RESULTS
DMF reduced the numbers of total cells, neutrophils and protein content in BALF of ALI mice, inhibited the levels of IL-6, TNF-α and IL-1β in BALF, serum and brain tissues of ALI mice. The protein expressions of p-NF-κB/NF-κB and p-IKBα/IKBα was also suppressed by DMF in ALI mice. Morris water maze test showed that DMF alleviated the cognitive impairment in ALI mice by reducing the escape latency and path length. Moreover, DMF lessened the BBB permeability by decreasing cerebral water content, Evans blue extravasation and FITC-Dextran uptake in ALI mice. The HIF-1α levels in lung and brain tissues of ALI mice were also lessened by DMF.
CONCLUSION
In conclusion, DME had the ability to alleviate the lung injury and cerebral cognitive impairment in ALI model mice. This protective effect partly associated with the suppression of inflammation by DMF.
Topics: Acute Lung Injury; Animals; Cognitive Dysfunction; Dimethyl Fumarate; Inflammation; Lung; Mice; Mice, Inbred C57BL
PubMed: 34772431
DOI: 10.1186/s13019-021-01705-6 -
Dermatologic Therapy Sep 2021Dimethyl fumarate (DMF) is a fumaric acid esters derivate approved for plaque psoriasis as first-line systemic therapy. It has been available in Italy since 2017 and an...
Dimethyl fumarate (DMF) is a fumaric acid esters derivate approved for plaque psoriasis as first-line systemic therapy. It has been available in Italy since 2017 and an increasing number of patients are treated with this drug. To evaluate DMF effectiveness, side effects and drug survival in a dermatological real-life setting. We performed a retrospective multi-center study in five dermatologic clinics in Emilia-Romagna, Northern Italy, which included all consecutive patients affected by moderate-severe psoriasis treated with DMF. We assessed effectiveness (in terms of PASI50 and PASI75 in an intention to treat observation) and safety (occurrence of side effects) of DMF and their association with demographic and disease characteristics, mean daily dose taken and treatment discontinuation. We included 103 patients, 78 (75.72%) had at least one comorbidity including 19 (18.44%) with a history of cancer; the mean treatment duration was 23.61 ± 17.99 weeks (min 4, max 130) and the mean daily dose was 262.13 ± 190.94 mg. Twenty-four patients (23.30%) reached PASI75 at week 12, while a further 18 patients (17.47%) reached it at week 26. Side effects occurred in 63 patients (61.16%), the most frequent were diarrhea, epigastric discomfort, nausea, and flushing. Sixteen patients (15.53%) showed an alteration of laboratory tests. In some cases side effects were transitory, while in 53 patients (51.45%) they led to cessation of therapy. The median daily dose showed a direct association with PASI50 achievement and an indirect association with treatment discontinuation. Our study shows the peculiarities of DMF in a real-world setting: effectiveness is often reached after 12 weeks of treatment and side effects could limit the continuation of the therapy but, at the same time, DMF has no major contraindications and, due to the wide range of dosage, it can allow both to manage side effects and to personalize the prescription for each patient.
Topics: Dermatologic Agents; Dimethyl Fumarate; Fumarates; Humans; Psoriasis; Retrospective Studies; Treatment Outcome
PubMed: 34291547
DOI: 10.1111/dth.15066 -
Multiple Sclerosis (Houndmills,... Oct 2019
Topics: Dimethyl Fumarate; Humans; Immunosenescence; Leukoencephalopathy, Progressive Multifocal; Lymphopenia; Multiple Sclerosis; Natalizumab
PubMed: 31436127
DOI: 10.1177/1352458519872897 -
Inflammopharmacology Apr 2021Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor...
BACKGROUND
Chronic cerebral hypoperfusion (CCH) induced oxidative stress and inflammation is known to be implicated in the pathogenesis of vascular dementia. The nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a potential therapeutic target for neuroprotection. In the present study, we investigated the beneficial effects of dimethyl fumarate (DMF), an Nrf2 activator in an experimental model of vascular dementia.
METHODS
Permanent occlusion of the bilateral common carotid arteries (2-VO) was performed to induce CCH in adult male Sprague-Dawley rats. DMF (15, 30, and 60 mg/kg) was administered for 4 weeks. Cognitive performance was assessed using the Morris water maze (MWM) and novel object (NOR) tests. After behavior tests, various oxidative and inflammatory markers were assessed in the hippocampus.
RESULTS
The obtained results indicate that treatment with DMF significantly improved 2 VO-induced cognitive deficits. DMF decreased MDA (p < 0.001), protein carbonyl (PCO) contents (p < 0.001), and acetylcholinesterase (p < 0.01) activities, and inhibited inflammatory markers (TNF-α, IL-1β, NF-κβ, and COX-2) levels. Furthermore, our results showed that DMF augmented GSH (p < 0.001) levels and SOD (p < 0.05), CAT, and GSH-Px (p < 0.001) activities in the hippocampus. Nrf2 (p < 0.05) and its downstream targets HO-1 levels (p < 0.01) and NQO1 (p < 0.05) levels were also up-regulated after DMF treatment.
CONCLUSION
Taken together, the results demonstrate that DMF could serve as a promising neuroprotective agent for treating vascular dementia.
Topics: Animals; Brain Ischemia; Cognition Disorders; Dementia, Vascular; Dimethyl Fumarate; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Inflammation; Male; Maze Learning; NF-E2-Related Factor 2; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 33459879
DOI: 10.1007/s10787-020-00785-5 -
European Journal of Neurology Jan 2021Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing-remitting multiple sclerosis (RRMS) patients. The relationship between this... (Observational Study)
Observational Study
BACKGROUND AND PURPOSE
Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing-remitting multiple sclerosis (RRMS) patients. The relationship between this reduction and DMF effectiveness is controversial. The objective was to investigate if the decrease in absolute lymphocyte count (ALC) from baseline during DMF treatment is associated with clinical and magnetic resonance imaging (MRI) disease activity. A secondary aim was to evaluate ALC variations over time in a real-life cohort of DMF-treated patients.
METHODS
Demographic, laboratory, clinical and MRI data were collected in this observational multicentre study, conducted on RRMS patients treated with DMF for at least 6 months. Multivariate Cox models were performed to evaluate the impact of 6-month ALC drop on time to no evidence of disease activity (NEDA-3) status loss. NEDA-3 is defined as absence of clinical relapses, MRI disease activity and confirmed disability progression.
RESULTS
In all, 476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed up to 5-year follow-up. A greater lymphocyte decrease was associated with a lower risk of NEDA-3 status loss (hazard ratio 0.87, P = 0.01). A worse outcome in patients with lower ALC drop (<11.5%), compared with higher tertiles (11.5%-40.5% and >40.5%), was observed (P = 0.008). The nadir of ALC drop (-33.6%) and 35% of grade III lymphopaenia cases occurred after 12 months of treatment.
CONCLUSION
A higher lymphocyte count drop at 6 months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.
Topics: Dimethyl Fumarate; Female; Humans; Immunosuppressive Agents; Lymphocyte Count; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 32931130
DOI: 10.1111/ene.14538 -
British Journal of Clinical Pharmacology Oct 2021Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA ) and induce flushing. It is not known whether HCA mediates other adverse drug...
AIM
Dimethyl fumarate and nicotinic acid activate the hydroxy-carboxylic acid receptor 2 (HCA ) and induce flushing. It is not known whether HCA mediates other adverse drug reactions (ADRs) to these two substances. This study aims to compare ADRs associated with dimethyl fumarate and nicotinic acid, and to discuss whether they are HCA -mediated.
METHODS
We identified spontaneous reports of suspected ADRs to dimethyl fumarate and nicotinic acid in the European Adverse Drug Reaction Database (EudraVigilance). These reports were analysed at different hierarchical levels of the Medical Dictionary for Regulatory Activities (MedDRA). In addition, we screened murine organs for HCA expression.
RESULTS
Similarities in the ADR profile of dimethyl fumarate and nicotinic acid included "gastrointestinal signs and symptoms" (odds ratio [OR] 0.8 [0.6-1.1]), "hepatobiliary investigations" (OR 1.3 [0.7-2.5]) and "anxiety disorders and symptoms" (OR 0.9 [0.3-2.2]) in High Level Group Terms; "diarrhoea (excluding infective)" (OR 1.2 [0.7-1.8]) and "liver function analyses" (OR 1.3 [0.7-2.6]) in High Level Terms; and "diarrhoea" (OR 1.2 [0.7-2.0]) and "vomiting" (OR 0.9 [0.4-1.7]) in Preferred Terms. In analogy, HCA was expressed in the gastrointestinal tract, liver and central nervous system (CNS) of murine organs. A discrepant ADR profile was seen for "lymphopenia" (n = 777) at the preferred term level (only reported for dimethyl fumarate) and "blood glucose increased" (more often reported for nicotinic acid; OR 0.1 [0.0-0.5]).
CONCLUSION
The gastrointestinal ADRs common to both substances may be mediated by HCA . Other ADRs not common to both substances are compound or indication-specific reactions and likely do not involve HCA .
Topics: Adverse Drug Reaction Reporting Systems; Animals; Databases, Factual; Dimethyl Fumarate; Drug-Related Side Effects and Adverse Reactions; Humans; Mice; Niacin
PubMed: 33605454
DOI: 10.1111/bcp.14787 -
Dermatologic Therapy Nov 2020Alopecia areata is an autoimmune condition leading to non-scarring hair loss. Clinically, several presentations ranging from single or few small patches to complete hair...
Alopecia areata is an autoimmune condition leading to non-scarring hair loss. Clinically, several presentations ranging from single or few small patches to complete hair loss are documented. The management of alopecia areata is challenging and all available treatments do not ensure a long-term remission to assess the safety and efficacy of systemic dimethyl fumarate in alopecia areata patients not responding to other systemic treatments. After obtaining informed consent, we administered off-label dimethyl fumarate to 10 adult patients with alopecia areata, for a period ranging from 4 to 37 weeks. Medical information for each patient and the severity of alopecia tool (SALT) score before and after dimethyl fumarate administration were recorded. During the treatment, 50% of patients (5 patients out of 10) had a slight improvement of hair regrowth; it was mainly as partial hair regrowth (ranging from 8% to 32%) and only one patient (10%) achieved > 50% terminal hair regrowth. Authors conclude that dimethyl fumarate is not advisable as a treatment of alopecia areata, also considering the risk of fumaric acid esters toxicity.
Topics: Adult; Alopecia Areata; Dimethyl Fumarate; Hair; Humans
PubMed: 32888223
DOI: 10.1111/dth.14158