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Evaluation of ATP12A and NFKBIZ as potential markers of inflammatory status in cystic fibrosis airway epithelial cells.

BACKGROUND: People with Cystic Fibrosis (pwCF) are prone to bacterial lung infections with P. aeruginosa, which have been linked to chronic inflammation in the lung. Although the highly effective CFTR modulator therapy (Elexacaftor-Tezacaftor-Ivacaftor, ETI) has dramatically improved respiratory outcomes in pwCF, airway inflammation and bacterial colonization persist in the upper and lower respiratory tracts. METHODS: We investigated the effect of ETI in both plasma and fresh primary nasal epithelial (HNE) cells obtained from pwCF pre- and post-three months of ETI treatment. Given that inflam

Macrophage-Targeted Nanocarriers Based on Tetrahedral DNA Nanostructure Alleviate Sepsis-Induced Acute Lung Injury by Triple-Pathway Suppression of Pyroptosis.

Sepsis-induced acute lung injury (SI-ALI) is a critical complication of sepsis characterized by severe pulmonary edema, hyper-inflammatory responses, and high mortality rates, for which precise therapeutic strategies remain limited. In this study, we developed a macrophage-targeting, dimethyl fumarate (DMF)-loaded tetrahedral DNA nanoplatform (T-D@TDN) and evaluated its physicochemical properties, antipyroptotic mechanisms, and therapeutic efficacy in SI-ALI. The nanostructure exhibits excellent biocompatibility, efficient alveolar macrophage (AM) targeting, and prolonged pulmonary retention f…

PRMT5 inhibition sensitizes B-cell lymphoma cells to ferroptosis.

Protein arginine methyltransferase 5 (PRMT5) is overexpressed in B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and mantl … this regulatory network. PRMT5 inhibition sensitizes lymphoma cells to ferroptosis inducers such as dimethyl fumarate (DMF), an electrophile that irreversibly depletes GSH via succination. Notably, combined treatment with the PRMT5 inhibitor GSK3326595 and DMF synergistically enhances anti-tumor activity in a patient-derived xenograft (PDX) model. These findings re …

Transsulfuration pathway activation attenuates oxidative stress and ferroptosis in sickle primary erythroblasts and transgenic mice.

The transsulfuration (TSS) pathway is an alternative source of cysteine for glutathione synthesis. Little of the TSS pathway in antioxidant … e TSS pathway and de novo cysteine biosynthesis. By contrast, the expression of CBS is inducible by dimethyl fumarate (DMF) through nuclear factor erythroid 2-related factor 2 (NRF2) activation and CpG islands DNA hydroxymethylation. DMF induces the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) to downregulate L-2-hydroxyglutarate (L2HG) and increase gl …

Prediction of disease activity and treatment failure in relapsing-remitting MS patients initiating daily oral DMTs.

BACKGROUND: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS) … failure by logistic regression analysis. RESULTS: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [ …

GAPDH-Silence Microsphere via Reprogramming Macrophage Metabolism and eradicating Bacteria for Diabetic infection bone regeneration.

Macrophage metabolism dysregulation, which is exacerbated by persistent stimulation in infectious and inflammatory diseases, such as diabetic infectious bone defects (DIBD), eventually leads to the failure of bone repair. Here, we have developed an injectable, macrophage-modulated GAPDH-Silence drug delivery system. This microsphere comprises chondroitin sulfate methacrylate (CM) and methacrylated gelatin (GM), while the dimethyl fumarate (DMF)-loaded liposome (D-lip) is encapsulated within the microsphere (CM@GM), named D-lip/CM@GM. Triggered by the over-expressed collagenase in DIBD, the mic…

Remodeling of the Intra-Conduit Inflammatory Microenvironment to Improve Peripheral Nerve Regeneration with a Neuromechanical Matching Protein-Based Conduit.

Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra-conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory-polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matc…

Рекомендации в отношении основных лекарственных средств для многоразового склероза в условиях низкой обеспеченности ресурсами.

Множественный склероз (MS) является демиелинизирующим заболеванием центральной нервной системы, которое, если его не лечить, может привести к значительной инвалидности у молодых людей. Несмотря на увеличение числа корректирующих болезни методов лечения (ДМТ), многие люди, живущие с МЗ в условиях низкой обеспеченности ресурсами, не имеют доступа к лечению. ЦЕЛЬ: Основная цель заключалась в разработке рекомендаций в отношении минимальных основных ДРТ для НР, которые должны быть доступны в условиях с низким уровнем ресурсов. МЕТОДЫ: Международная федерация по множественному склерозу создала незав

Совпадение в аннотации оригинала
BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that, when untreated, can lead to significant d … r worsening forms of relapsing MS, the panel recommends use of ocrelizumab, cladribine, fingolimod, dimethyl fumarate, interferon beta and glatiramer acetate. For active and/or worsening forms of progressive MS, the panel recommends use of rituximab, ocrelizumab, glatiramer acetate, fingolimod and interferon beta. CONCLUSIONS: Recommendations for the minimum essen …

GATA6 coordinates cross-talk between BMP10 and oxidative stress axis in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a progressive increase in pulmonary vascular resistan … PASMC, supporting the importance of GATA6 in pulmonary vascular cell communication. Treatment with dimethyl fumarate resolved oxidative stress and BMPR deficiency, reversed hemodynamic changes caused by endothelial Gata6 loss in mice, and inhibited proliferation and induced apoptosis in human PAH PASMC, strongly suggesting that targeting GATA6 deficiency may provi …

Switching to natalizumab or fingolimod in multiple sclerosis: Comparative effectiveness and effect of pre-switch disease activity.

BACKGROUND: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, "BRACETD") often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse. METHODS: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 …

In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3.

Unlike other nuclear factor erythroid-2-related factor 2 (Nrf2) activators, the mechanism of action of curcumin analog, ASC-JM17 (JM17), in regulating oxidative homeostasis remains unknown. Spinocerebellar ataxia type 3 (SCA3) is an inherited polyglutamine neurodegenerative disease caused mainly by polyglutamine neurotoxicity and oxidative stress. Presently, we compared actions of JM17 with those of known Nrf2 activators, omaveloxolone (RTA-408) and dimethyl fumarate (DMF), using human neuroblastoma SK-N-SH cells with stable transfection of full-length ataxin-3 protein with 78 CAG repeats (MJD…

The histone deacetylase inhibitor belinostat ameliorates experimental autoimmune encephalomyelitis in mice by inhibiting TLR2/MyD88 and HDAC3/ NF-κB p65-mediated neuroinflammation.

Multiple sclerosis (MS) is a Th cell-mediated inflammatory demyelinating autoimmune disease. MS cannot be cured, and long-term drug treatment is still needed for MS patients. In this study, we examined the effect of belinostat, a pan-histone deacetylase inhibitor (HDACi), on experimental autoimmune encephalomyelitis (EAE) and elucidated its mechanism of action. We found that belinostat alleviates the clinical symptoms, histopathological central nervous system (CNS) inflammation and demyelination outcomes in EAE mice. Compared to the MS oral drug dimethyl fumarate (DMF) (100 mg/kg), belinostat …

A retrospective analysis of changes in lymphocyte levels in patients with multiple sclerosis during and after Tecfidera® treatment.

BACKGROUND: There are currently no best practice recommendations for lymphocyte subset monitoring for patients with multiple sclerosis (pwMS) on disease-modifying therapies including Tecfidera® (dimethyl fumarate, DMF). However, there have been several cases of pwMS on DMF without severe lymphopenia who had high CD4:CD8 T cell ratios and went on to develop progressive multifocal leukoencephalopathy. OBJECTIVE: Our objective was to characterize the changes in immune profile during and after DMF treatment in pwMS. METHODS: A retrospective analysis of longitudinal data from 299 pwMS who have be…

Регулирование сосудистых каналов крупногабаритного кальция с помощью сигнализации Nrf2.

Каналы BK являются основными ионными детерминантами водительности. Функционирование канала ВК ухудшается в состоянии диабетических сосудов из-за ускоренного протеолиза его бета-1 (ВК-β1) в ответ на повышенный окислительный стресс. Фактор, связанный с ядерным фактором E2-2 (Nrf2), появился в качестве главного регулятора состояния клеточного редукции, и мы предполагаем, что он играет центральную роль в регулировании функции канала ВК на судах, страдающих диабетом. Мы обнаружили, что выражение Nrf2 было заметно уменьшено в дБ/дБ диабетических аортах мыши, и это было связано со значительным снижен

Совпадение в аннотации оригинала
BK channels are major ionic determinants of vasodilation. BK channel function is impaired in diabetic vessels due to accelerated proteolysis … rf2 gene in these cells downregulated MuRF1 and upregulated BK-β1 expression. Activation of Nrf2 by dimethyl fumarate preserved BK-β1 expression and protected BK channel and vascular function in db/db coronary arteries. These results indicate that expression of BK-β1 is closely regulated by Nrf2 and vascular BK channel function can be restored by Nrf2 activation. N …

Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy.

Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspe … gliosis, as determined by an increase in GFAP, IBA1 and CD11b levels. The immunomodulatory molecule dimethyl fumarate (DMF), a drug already used for the treatment of multiple sclerosis whose main target is accepted to be NRF2, was tested in this preclinical model. Daily oral gavage of DMF during six weeks reduced glial and inflammatory markers and improved cognitio …

A target trial emulation of the CONFIRM study with an extension to subgroups: an example for relapsing-remitting multiple sclerosis.

Conclusions of target trial emulations (TTEs) are often limited to trial-like populations, leaving knowledge gaps for neglected subpopulations. We propose a two-step TTE approach to create methodologically-justified evidence for these subpopulations. Using the CONFIRM trial as an illustrative example, we first emulated the trial using strict eligibility criteria, and extended the analysis to a pragmatic scenario including trial-ineligible subgroups, allowing comparison of treatment effectiveness between these two study populations. CONFIRM studied efficacy of dimethyl fumarate (DMF) and glatir…

Treatment approaches to patients with multiple sclerosis and coexisting psoriasis - A longitudinal multicenter observational cohort study.

Neurologists frequently encounter multiple sclerosis (MS) patients with coexisting autoimmune disorders such as psoriasis (PsO). The evolvin … nuation, and adverse events were analyzed. Logistic regression assessed PsO and MS worsening, using dimethyl fumarate (DMF) as reference. MS/PsO patients were older at diagnosis (37.6 vs. 33.0 years). EDSS and disease course showed no statistically significant differences. DMF was most frequently used (68%), with low rates of PsO (8%) and MS worsening (15%). PsO wo …

Secondary Immunodeficiency and Risk of Infection Following Immune Therapies in Neurology.

Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of diseas … stematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk facto …

Current management of relapsing-remitting multiple sclerosis.

Multiple sclerosis was without effective disease-modifying therapy for many years. The introduction of the injectable therapies (interferon and glatiramer acetate) some 20 years ago was considered a major advance. Recent years have heralded a revolution in treatment options with the introduction of intravenous natalizumab and, even more recently, three oral agents. We are currently in a period of determining the best use of these therapies to ensure prevention of disease progression while maintaining patient safety. Despite these new treatments, there are still many patients living with disabi

The Patient and Clinician Assessment of Gastrointestinal (GI) Related Adverse Events Associated with Oral Disease-Modifying Therapies in Multiple Sclerosis: A Qualitative Study.

INTRODUCTION: Current guidelines for relapsing-remitting multiple sclerosis (RRMS) call for treatment with disease-modifying therapies (DMTs) early in the disease to prevent relapses and accumulation of neurologic impairment and disability. However, patients taking certain oral DMTs may experience gastrointestinal (GI)-related adverse events (AEs), particularly at dose titration. We conducted qualitative research with healthcare professionals (HCPs) and patients in Canada to contextualize their experiences with three oral DMTs: dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), and teriflu…