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Advanced Science (Weinheim,... Apr 2024Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen...
Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4 resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C monocyte infiltration, MerTk macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.
Topics: Animals; Humans; Male; Mice; Acetaminophen; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Gasdermins; Liver Failure; Mice, Inbred C57BL; Mice, Knockout; Pyroptosis
PubMed: 38417117
DOI: 10.1002/advs.202305715 -
Therapeutic Advances in Neurological... 2024Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy...
BACKGROUND
Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance.
OBJECTIVES
Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate).
DESIGN
This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD.
METHODS
This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW).
RESULTS
After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070-0.092) for natalizumab patients and 0.191 (0.178-0.205) for BRACETD patients ( < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42-0.65); < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients.
CONCLUSION
Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.
PubMed: 38414723
DOI: 10.1177/17562864231221331 -
Journal of Alzheimer's Disease Reports 2024Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial...
BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration.
OBJECTIVE
To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models.
METHODS
The neuroprotective effect of DMF was explored in and PD models. MTT assay was performed to determine the DMF dose followed by JC-1 assay to study its mitoprotective effect in MPP exposed SHSY5Y cells. For the study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP iodide+DMF 15 mg/kg), Mid Dose (MPP iodide+DMF 30 mg/kg), and High Dose (MPP iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR.
RESULTS
DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group.
CONCLUSIONS
DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD.
PubMed: 38405353
DOI: 10.3233/ADR-230128 -
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 -
Archives of Toxicology Apr 2024Dimethyl fumarate (DMF) is an old drug used for psoriasis treatment that has recently been repurposed to treat relapse-remitting multiple sclerosis, mostly due to its...
Dimethyl fumarate (DMF) is an old drug used for psoriasis treatment that has recently been repurposed to treat relapse-remitting multiple sclerosis, mostly due to its neuro- and immunomodulatory actions. However, mining of a pharmacovigilance database recently ranked DMF as the second pharmaceutical most associated with cognitive adverse events. To our best knowledge, the signaling mechanisms underlying its therapeutic and neurotoxic outcomes remain mostly undisclosed. This work thus represents the first-hand assessment of DMF-induced metabolic changes in undifferentiated SH-SY5Y human neuroblastoma cells, through an untargeted metabolomic approach using gas chromatography-mass spectrometry (GC-MS). The endometabolome was analyzed following 24 h and 96 h of exposure to two pharmacologically relevant DMF concentrations (0.1 and 10 μM). None of these conditions significantly reduced metabolic activity (MTT reduction assay). Our data showed that 24 h-exposure to DMF at both concentrations tested mainly affected metabolic pathways involved in mitochondrial activity (e.g., citric acid cycle, de novo triacylglycerol biosynthesis), and the synthesis of catecholamines and serotonin by changing the levels of their respective precursors, namely phenylalanine (0.68-fold decrease for 10 μM DMF vs vehicle), and tryptophan (1.36-fold increase for 0.1 μM DMF vs vehicle). Interestingly, taurine, whose levels can be modulated via Nrf2 signaling (DMF's primary target), emerged as a key mediator of DMF's neuronal action, displaying a 3.86-fold increase and 0.27-fold decrease for 10 μM DMF at 24 h and 96 h, respectively. A 96 h-exposure to DMF seemed to mainly trigger pathways associated with glucose production (e.g., gluconeogenesis, glucose-alanine cycle, malate-aspartate shuttle), possibly related to the metabolism of DMF into monomethyl fumarate and its further conversion into glucose via activation of the citric acid cycle. Overall, our data contribute to improving the understanding of the events associated with neuronal exposure to DMF.
Topics: Humans; Dimethyl Fumarate; NF-E2-Related Factor 2; Neuroblastoma; Neurons; Glucose
PubMed: 38368281
DOI: 10.1007/s00204-024-03683-9 -
Biology of Sex Differences Feb 2024Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as...
BACKGROUND
Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signalling during inflammation, is dysregulated in many chronic inflammatory disorders; however, its role in depression and the associated sex differences have yet to be explored. Here, we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles.
METHODS
Male and female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Sex differences in hippocampal (HIP) microglial activation and gene expression response were also evaluated.
RESULTS
DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, and DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Last, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, most of the differentially expressed genes in males normalized by DMF were related to antioxidant, inflammatory or immune responses.
CONCLUSIONS
Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression.
Topics: Animals; Female; Male; Rats; Antidepressive Agents; Antioxidants; Depression; Depressive Disorder, Major; Dimethyl Fumarate; NF-E2-Related Factor 2
PubMed: 38350966
DOI: 10.1186/s13293-024-00589-0 -
Molecules (Basel, Switzerland) Jan 2024The pyrrolidine nitroxides with four bulky alkyl substituents adjacent to the N-O∙ group demonstrate very high resistance to reduction with biogenic antioxidants and...
The pyrrolidine nitroxides with four bulky alkyl substituents adjacent to the N-O∙ group demonstrate very high resistance to reduction with biogenic antioxidants and enzymatic systems. This makes them valuable molecular tools for studying the structure and functions of biomolecules directly in a living cell and for functional EPR and NMR tomography in vivo. The first example of highly strained pyrrolidine nitroxides with both ethyl and -butyl groups at each of the α-carbon atoms of the nitroxide moiety with -configuration of the -butyl groups was prepared using a three-component domino reaction of -leucine and 2,2-dimethylpentan-3-one with dimethyl fumarate with subsequent conversion of the resulting strained pyrrolidine into 1-pyrroline-1-oxide and addition of EtLi. The nitroxide has demonstrated unexpectedly fast reduction with ascorbate, the rate constant = (2.0 ± 0.1) × 10 Ms. This effect was explained by destabilization of the planar nitroxide moiety due to repulsion with the two neighboring -butyl groups to each other.
PubMed: 38338344
DOI: 10.3390/molecules29030599 -
Neurology Mar 2024Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline-week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS).
METHODS
In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mg QD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (∼30 mm) over time. SELs were identified by MRI and assessed by the Jacobian determinant of the nonlinear deformation from baseline to week 48. SEL volume analysis, stratified by baseline T2 lesion volume tertiles, was based on week 48/end-of-treatment status (completers/non-completers). Treatment effect was analyzed using the stratified Hodges-Lehmann estimate of shift in distribution and stratified Wilcoxon rank-sum test. Comparisons of evobrutinib and DMF vs placebo/evobrutinib 25 mg QD were made. Subgroup analyses used pooled treatment groups (evobrutinib high dose [75 mg QD/BID] vs low dose [placebo/evobrutinib 25 mg QD]).
RESULTS
The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remitting MS). Mean (SD) SEL volume was 2,099 (2,981.0) mm with evobrutinib 75 mg BID vs 2,681 (3,624.2) mm with placebo/evobrutinib 25 mg QD. Median number of SELs/patient ranged from 7 to 11 across treatments. SEL volume decreased with increasing evobrutinib dose vs placebo/evobrutinib 25 mg QD, and no difference with DMF vs placebo/evobrutinib 25 mg QD was noted. SEL volume significantly decreased with evobrutinib 75 mg BID vs placebo/evobrutinib 25 mg QD (-474.5 mm [-1,098.0 to -3.0], = 0.047) and vs DMF (-711.6 [-1,290.0 to -149.0], = 0.011). SEL volume was significantly reduced for evobrutinib high vs low dose within baseline Expanded Disability Status Scale ≥3.5 and longer disease duration (≥8.5 years) subgroups.
DISCUSSION
Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss.
TRIAL REGISTRATION INFORMATION
ClinicalTrials.gov number: NCT02975349. Submitted to ClinicalTrials.gov on November 29, 2016. First patient enrolled: March 7, 2017.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that evobrutinib reduces the volume of SELs assessed on MRI comparing baseline with week 48, in patients with RMS.
Topics: Adult; Humans; Female; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Dimethyl Fumarate; Piperidines; Double-Blind Method; Recurrence; Pyrimidines
PubMed: 38335474
DOI: 10.1212/WNL.0000000000208058 -
Annals of Medicine and Surgery (2012) Feb 2024To analyze the symptoms and severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (pwMS) on disease-modifying therapies using data from the...
Prognostic indicators for hospitalization and ICU admission in people with multiple sclerosis and COVID-19: an analysis of the COVID-19 in MS global data sharing initiative dataset.
OBJECTIVES
To analyze the symptoms and severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (pwMS) on disease-modifying therapies using data from the COVID-19 in multiple sclerosis (MS) Global Data Sharing Initiative dataset.
METHODS
The open-access COVID-19 in MS Global Data Sharing Initiative dataset was obtained through credentialed access using PhysioNet. The variables analyzed included BMI, symptoms of COVID-19, age, current use of disease-modifying therapy (DMT), efficacy of DMT, comorbidities, hospitalization status, and type of MS. A linear regression analysis was completed. Data analysis and visualization were completed using STATA , R-Studio , Python and its associated libraries, including NumPy, Pandas, and Matplotlib.
RESULTS
A total of 1141 participants were included in the analysis. 904 women and 237 men were diagnosed with MS. Among the pwMS included in the study; 208 (19.54%) had a suspected infection with COVID-19 and only 49 (5.25%) were confirmed. Any COVID-19 symptom was present in 360 individuals. The commonly reported DMT agents included dimethyl fumarate (12.71%) and fingolimod (10.17%). 101 in total (8.85%) reported not using any DMT. Factors associated with hospitalization and/or admission to the ICU included having any comorbidity (0.01), neuromuscular disorder (0.046), hypertension (0.005), chronic kidney disease (0.001), and immunodeficiency (0.003). The type of MS, the duration of the disease, and high-efficacy DMT therapy did not have a statistically significant influence on hospitalization.
CONCLUSION
This study underscores the importance of comorbidities, especially neuromuscular disorders, hypertension, chronic kidney disease, and immunodeficiencies, as possible prognostic indicators for worse outcomes of COVID-19 in pwMS. On the contrary, the type of MS, the duration of the disease, and the efficacy of disease-modifying therapy did not significantly affect the severity of the symptoms of COVID-19 in this cohort.
PubMed: 38333271
DOI: 10.1097/MS9.0000000000001676 -
Journal of Cardiothoracic Surgery Feb 2024This study examined the effect of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway on chronic obstructive pulmonary disease (COPD)...
BACKGROUND
This study examined the effect of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway on chronic obstructive pulmonary disease (COPD) and the potential molecular mechanism.
METHODS
A COPD mouse model was established by cigarette smoke exposure and administered with either ML385 or dimethyl fumarate (DMF). Airway resistance of mice was detected. IL-1β and IL-6 levels in mice alveolar lavage fluid were examined by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining and immunohistochemical of lung tissues were utilized to detect lung injury and NLRP3 expression. DMF was used to treat COPD cell model constructed by exposing normal human bronchial epithelial (NHBE) cells to cigarette smoke extract. NHBE cells were transfected by NLRP3-expression vectors. Expression of proteins was detected by Western blot.
RESULTS
COPD mice showed the enhanced airway resistance, the inactivated Nrf2/HO-1 pathway and the overexpressed NLRP3, Caspase-1 and GSDMD-N proteins in lung tissues, and the increased IL-1β and IL-6 levels in alveolar lavage fluid. ML385 treatment augmented these indicators and lung injury in COPD mice. However, DMF intervention attenuated these indicators and lung injury in COPD mice. Nrf2/HO-1 pathway inactivation and overexpression of NLRP3, Caspase-1 and GSDMD-N proteins were observed in COPD cells. DMF intervention activated Nrf2/HO-1 pathway and down-regulated NLRP3, Caspase-1 and GSDMD-N proteins in COPD cells. However, NLRP3 overexpression abolished the effect of DMF on COPD cells.
CONCLUSION
Nrf2/HO-1 pathway activation may alleviate inflammation in COPD by suppressing the NLRP3-related pyroptosis. Activating the Nrf2/HO-1 pathway may be an effective method to treat COPD.
Topics: Humans; Mice; Animals; NF-E2-Related Factor 2; Lung Injury; Pyroptosis; Interleukin-6; Heme Oxygenase-1; Cigarette Smoking; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Disease, Chronic Obstructive; Inflammation; Caspases
PubMed: 38317168
DOI: 10.1186/s13019-024-02530-3