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Proceedings of the National Academy of... Feb 2024Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV-infected animals indicate that the virus penetrates the brain. Pyroptosis...
Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV-infected animals indicate that the virus penetrates the brain. Pyroptosis is an inflammatory type of regulated cell death, resulting from plasma membrane rupture (PMR) due to oligomerization of cleaved gasdermins to cause membrane pore formation. Herein, we investigated the human neural cell tropism of MPXV compared to another orthopoxvirus, vaccinia virus (VACV), as well as its effects on immune responses and cell death. Astrocytes were most permissive to MPXV (and VACV) infections, followed by microglia and oligodendrocytes, with minimal infection of neurons based on plaque assays. Aberrant morphological changes were evident in MPXV-infected astrocytes that were accompanied with viral protein (I3) immunolabelling and detection of over 125 MPXV-encoded proteins in cell lysates by mass spectrometry. MPXV- and VACV-infected astrocytes showed increased expression of immune gene transcripts (, and ). However, MPXV infection of astrocytes specifically induced proteolytic cleavage of gasdermin B (GSDMB) (50 kDa), evident by the appearance of cleaved N-terminal-GSDMB (30 kDa) and C-terminal- GSDMB (18 kDa) fragments. GSDMB cleavage was associated with release of lactate dehydrogenase and increased cellular nucleic acid staining, indicative of PMR. Pre-treatment with dimethyl fumarate reduced cleavage of GSDMB and associated PMR in MPXV-infected astrocytes. Human astrocytes support productive MPXV infection, resulting in inflammatory gene induction with accompanying GSDMB-mediated pyroptosis. These findings clarify the recently recognized neuropathogenic effects of MPXV in humans while also offering potential therapeutic options.
Topics: Animals; Humans; Monkeypox virus; Mpox (monkeypox); Pyroptosis; Astrocytes; Gasdermins
PubMed: 38346199
DOI: 10.1073/pnas.2315653121 -
PeerJ 2024PM is a well-known harmful air pollutant that can lead to acute exacerbation and aggravation of respiratory diseases. Although ferroptosis is involves in the...
BACKGROUND
PM is a well-known harmful air pollutant that can lead to acute exacerbation and aggravation of respiratory diseases. Although ferroptosis is involves in the pathological process of pulmonary disease, the potential mechanism of ferroptosis in PM-caused lung inflammation and fibrosis need to be further clarified. Quercetin is a phenolic compound that can inhibit ferroptosis in various diseases. Hence, this study explores the role of ferroptosis in lung injury induced by PM in order to further elucidate the beneficial effect of quercetin and its underlying mechanism.
METHODS
C57BL/6J mice were treated with either saline or PM by intratracheal instillation 20 times (once every two days). Additionally, PM-treated mice were supplemented with two doses of quercetin. Lung injury, lipid peroxidation, iron content and ferroptosis marker protein expression and the Nrf2 signaling pathway were evaluated. , cell experiments were applied to verify the mechanisms underlying the links between Nrf2 signaling pathway activation and ferroptosis as well as between ferroptosis and inflammation.
RESULTS
, PM increased lung inflammation and caused lung fibrosis and increased lipid peroxidation contents, iron contents and ferroptosis markers in lung tissues; these effects were significantly reversed by quercetin. Additionally, quercetin upregulated the nuclear Nrf2 expression and downregulated Keap1 expression in lung tissues of PM-exposed mice. Quercetin decreased lipid peroxidation products, iron contents and ferroptosis levels and increased the nuclear translocation of Nrf2 and the degradation of Keap1 in PM-exposed BEAS-2B cells. Moreover, we found that quercetin and dimethyl fumarate markedly decreased lipid peroxidation production and ferroptosis by activating the Nrf2-Keap1 pathway in PM-exposed cells. Furthermore, quercetin reduced inflammatory cytokines and TGF-1 in PM-exposed cells.
CONCLUSION
Our data suggested that Nrf2 is involved in ferroptosis in PM-induced lung injury, and quercetin can alleviate these adverse effects via activating Nrf2-Keap1 signaling pathway.
Topics: Animals; Mice; Mice, Inbred C57BL; Lung Injury; Quercetin; Kelch-Like ECH-Associated Protein 1; Ferroptosis; NF-E2-Related Factor 2; Iron; Pneumonia; Particulate Matter
PubMed: 38188138
DOI: 10.7717/peerj.16703 -
ACS Omega Jul 2023Crystallization has revolutionized the field of solid-state formulations by modulating the physiochemical and release profile of active pharmaceutical ingredients...
Crystallization has revolutionized the field of solid-state formulations by modulating the physiochemical and release profile of active pharmaceutical ingredients (APIs). Dimethyl fumarate (DF), an FDA-approved first-line drug for relapsing-remitting multiple sclerosis, has a sublimation problem, leading to loss of the drug during its processing. To tackle this problem, DF cocrystal has been prepared by using solvent evaporation technique using nicotinamide as a coformer, which has been chosen based on predictions and their ability to participate in hydrogen bonding. Fourier transform infrared (FT-IR), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and sublimation analysis have characterized the cocrystal and its thermostability. Comparative analysis of the release profile has been done by the dissolution and pharmacokinetic study of DF and its cocrystal. Formulated cocrystal is noncytotoxic, antioxidant and inhibits interleukin-6 and tissue necrosis factor-α in peripheral blood mononuclear cells induced by lipopolysaccharide. We have obtained a thermostable cocrystal of DF with a similar physicochemical and release profile to that of DF. The formulated cocrystal also provides a gastroprotective effect which helps counterbalance the adverse effects of DF by reducing lipid peroxidation and total nitrite levels.
PubMed: 37521634
DOI: 10.1021/acsomega.3c02463 -
Multiple Sclerosis and Related Disorders Oct 2023disease-modifying treatments (DMT) for Multiple Sclerosis (MS) have expanded in recent years making the shared-decision process challenging. Moreover, no head-to-head...
BACKGROUND AND PURPOSE
disease-modifying treatments (DMT) for Multiple Sclerosis (MS) have expanded in recent years making the shared-decision process challenging. Moreover, no head-to-head studies are available within the first-line options. Our aim is to compare therapeutic persistence within first-line DMT: teriflunomide (TER), dimethyl fumarate (DMF), and injectable drugs (INJ) in a real-world setting.
METHODS
Retrospective observational study analyzing diagnosed with Relapsing-Remitting Multiple Sclerosis (RRMS) who started DMT between January 2015 and April 2022 (TER=117, DMF=117, INJ=123). Clinical, radiological, and demographic variables were collected. The primary outcome was the median time to discontinuation of any DMT. Dropout was defined as discontinuation for 6 months for any reason.
RESULTS
Of the total of 357 patients, 155 withdraw with a median time-to-discontinuation of 1.427 years (IQR 2.410). The discontinuation rate was higher in the injectable group, 49.6%; compared to teriflunomide 40.2%, and dimethyl fumarate 39.8% (p = 0.201). The most frequent reason of discontinuation differs within groups (lack of efficacy in TER, 63.8%, and adverse effects in DMF and INJ (40.4% and 40.9% respectively). No difference in persistence was observed between DMT (p = 0.30). After 2018 there has been a tendency to treat in a quick and early manner (lower EDSS; relapse rate and number of naïve patients), statistically significant for TER (p = 0.005, p = 0.010, and p = 0.045).
CONCLUSIONS
Our study demonstrated no differences in persistence between the actual first-line DMT in a real-world setting, although a trend to favor oral-DMT was seen. Reasons for discontinuation differs within groups.
PubMed: 37603928
DOI: 10.1016/j.msard.2023.104909 -
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 -
Experimental Neurology Jan 2024Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of...
Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in the thalamocortical (TC) system. Substances used for the treatment of multiple sclerosis (MS) have been shown to normalize neuronal excitability in CPZ-treated mice. Therefore, we aimed to examine the effects of diroximel fumarate (DRF) and the sphingosine 1-phospate receptor (S1PR) modulator siponimod on action potential firing and the inward current (I) carried by HCN ion channels in naive conditions and during different stages of de- and remyelination. Here, DRF application reduced I current density in ex vivo patch clamp recordings from TC neurons of the ventrobasal thalamic complex (VB), thereby counteracting the increase of I during early remyelination. Siponimod reduced I in VB neurons under control conditions but had no effect in neurons of the auditory cortex (AU). Furthermore, siponimod increased and decreased AP firing properties of neurons in VB and AU, respectively. Computational modeling revealed that both DRF and siponimod influenced thalamic bursting during early remyelination by delaying the onset and decreasing the interburst frequency. Thus, substances used in MS treatment normalize excitability in the TC system by influencing AP firing and I.
Topics: Mice; Animals; Neuroprotective Agents; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Remyelination; Models, Theoretical
PubMed: 37852467
DOI: 10.1016/j.expneurol.2023.114572 -
Frontiers in Immunology 2024Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of...
Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.
Topics: Animals; Female; Mice; Asthma; Cytokines; Dimethyl Fumarate; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Ovalbumin; Signal Transduction; T-Lymphocytes, Regulatory
PubMed: 38711519
DOI: 10.3389/fimmu.2024.1375340 -
Micromachines Oct 2023Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as...
Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a brain-computer interface (BCI) system aimed at restoring function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5-11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (<12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals and assess its usefulness for specific applications.
PubMed: 37893339
DOI: 10.3390/mi14101902 -
Journal of Neurology, Neurosurgery, and... Jan 2024The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored...
BACKGROUND
The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs.
METHODS
A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored.
RESULTS
At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions).
CONCLUSIONS
Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.
Topics: Humans; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Fingolimod Hydrochloride; Recurrence
PubMed: 37775266
DOI: 10.1136/jnnp-2023-331920 -
International Immunopharmacology Jun 2024Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate...
BACKGROUND
Chronic stress-induced neuroinflammation plays a pivotal role in the development and exacerbation of mental disorders, such as anxiety and depression. Dimethyl Fumarate (DMF), an effective therapeutic agent approved for the treatment of multiple sclerosis, has been widely reported to display anti-inflammatory and anti-oxidative effects. However, the impact of DMF on chronic stress-induced anxiety disorders and the exact underlying mechanisms remain largely unknown.
METHODS
We established a mouse model of chronic social defeat stress (CSDS). DMF was administered orally 1 h before daily stress session for 10 days in CSDS + DMF group. qRT-PCR and western blotting were used to analyze mRNA and protein expression of NLRP3, Caspase-1 and IL-1β. Immunofluorescence staining was carried out to detect the expression of Iba 1 and c-fos positive cells as well as morphological change of Iba 1 microglia. Whole-cell patch-clamp recording was applied to evaluate synaptic transmission and intrinsic excitability of neurons.
RESULTS
DMF treatment significantly alleviated CSDS-induced anxiety-like behaviors in mice. Mechanistically, DMF treatment prevented CSDS-induced neuroinflammation by inhibiting the activation of microglia and NLRP3/Caspase-1/IL-1β signaling pathway in basolateral amygdala (BLA), a brain region important for emotional processing. Furthermore, DMF treatment effectively reversed the CSDS-caused disruption of excitatory and inhibitory synaptic transmission balance, as well as the increased intrinsic excitability of BLA neurons.
CONCLUSIONS
Our findings provide new evidence that DMF may exert anxiolytic effect by preventing CSDS-induced activation of NLRP3/Caspase-1/IL-1β signaling pathway and alleviating hyperactivity of BLA neurons.
PubMed: 38897132
DOI: 10.1016/j.intimp.2024.112414