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Visual issues in multiple sclerosis.

Multiple sclerosis has several ophthalmic manifestations, including optic neuritis, internuclear ophthalmoplegia, and nystagmus. The presentation, treatment, and prognosis of visual complaints secondary to multiple sclerosis are discussed. Additionally, the use of optical coherence tomography and complications related to the use of fingolimod are considered.

Fingolimod to treat severe multiple sclerosis after natalizumab-associated progressive multifocal leukoencephalopathy: a valid option?

We report two cases of multiple sclerosis (MS) patients with natalizumab-associated progressive multifocal leukoencephalopathy. Severe MS relapses occurred between four and five months after natalizumab discontinuation. After failure of immunomodulatory treatment, both patients were treated with fingolimod. The outcome was positive on clinical and MRI disease activity, without worsening of the progressive multifocal leukoencephalopathy. These observations suggest that using fingolimod for severe multiple sclerosis after natalizumab-associated progressive multifocal leukoencephalopathy may be a

United airways: circulating Th2 effector cells in an allergic rhinitis model are responsible for promoting lower airways inflammation.

BACKGROUND: Allergic rhinitis (AR) and asthma often coexist and are referred to as 'united airways' disease. However, the molecular and cellular pathways that are crucially involved in the interaction between upper and lower airways remain to be identified. OBJECTIVE: We sought to assess whether and how AR exacerbates lower airway inflammation upon allergen challenge in mice. METHODS: We previously developed an intranasal ovalbumin (OVA)-driven AR model, characterized by nasal eosinophilic inflammation, enhanced serum levels of OVA-specific IgE and Th2 cytokine production in cervical lymph n

Design of a phytosphingosine-containing, positively-charged nanoemulsion as a colloidal carrier system for dermal application of ceramides.

Positively charged oil/water (o/w) nanoemulsions (PN) are effective vehicles to change the permeability of the skin. This study focused on the preparation and characterisation of phytosphingosine (PS) containing PN (PPN) which serve as colloidal carriers for the dermal application of ceramide IIIB (CIIIB) and the stratum corneum (SC) lipids (PPNSC) such as ceramide III (CIII), cholesterol, and palmitic acid. The investigations were conducted using appropriate emulsification and homogenisation processing conditions to optimise PPNSC with regard to droplet size, physical stability, and solubilit…

Efficient homing of antibody-secreting cells to the bone marrow requires RNA-binding protein ZFP36L1.

Cell migration relies on coordinated activity of chemotactic and guidance receptors. Here, we report a specific role for the RNA-binding protein ZFP36L1 in limiting the abundance of molecules involved in the homing of antibody-secreting cells (ASCs) to the bone marrow (BM). In the absence of ZFP36L1, ASCs build up in the spleen and the liver and show diminished accumulation in the BM. ZFP36L1 facilitates migration by directly regulating G protein-coupled receptor kinase 2 (GRK2) and the integrin chains α4 and β1 in splenic ASCs. Expression of CXCR4 and of the integrins α4 and β1 is differentia

Itaconate as the endogenous brake of proinflammatory macrophage activation alleviates inflammation in liver fibrogenesis.

BACKGROUND: Liver inflammation and fibrosis are reparative responses to chronic liver injury. Bone marrow-derived monocyte/macrophages (BMDMs) are key participants. Our previous study demonstrated that BMDM can be activated as a proinflammatory phenotype by sphingosine-1-phosphate (S1P). Aconitate decarboxylase 1 (ACOD1)/itaconate is an anti-inflammatory molecule. However, it remains unclear whether ACOD1/itaconate is involved in S1P-induced BMDM activation. METHODS: A methionine-choline-deficient and high-fat diet was used to induce liver injury and fibrosis in mice. To clarify the role of e…

Efficacy and Safety of Ozanimod in Ulcerative Colitis: A Real-World Pan-Hellenic Study.

Background and Objectives: Ozanimod is approved for the treatment of ulcerative colitis (UC). The aim of the present study was to evaluate the clinical, biochemical, and endoscopic outcomes. Materials and Methods: This was a retrospective, multicenter, cohort study. Clinical, biochemical, endoscopic, and safety data were collected from medical records. Τhe primary outcome was clinical response at week 12. Secondary outcomes included clinical remission, endoscopic improvement and remission, biochemical outcomes, treatment persistence, and safety. Clinical outcomes were assessed at weeks 12 and

Progression to Wheelchair in Secondary Progressive Multiple Sclerosis and Impact of Siponimod: Post Hoc Analyses From the EXPAND Study.

BACKGROUND: Delaying time to requiring a wheelchair in people living with MS is an important treatment goal to maintain quality of life and guard against increased healthcare costs. In this post hoc analysis, the effects of siponimod versus placebo on time to sustained Expanded Disability Status Scale (EDSS) ≥ 7.0 over the core part of the Phase 3 EXPAND study were assessed. METHODS: The time to sustained EDSS ≥ 7.0 (time to requiring a wheelchair) was analysed for participants with secondary progressive multiple sclerosis (SPMS). Analyses were based on a While on Treatment (WOT) set that cen

Phytosphingosine, a sphingolipid isolated from fungal endophyte Penicillium oxalicum, exerts cytotoxic effects against breast cancer cells and shows blood compatibility.

Plant-associated fungal endophytes hold great potential to synthesize metabolites similar to their host, with potential anticancer effects. … that validates the mass, structure, and functional groups of the lead compound, identified as Phytosphingosine. Further, DAPI assay revealed Phytosphingosine induced alteration of nuclear morphology in breast cancer cells, indicating apoptotic events. The blood compatibility of Phytosphingosine was evidenced through hemolysis assay, thus suggesting its safet …

The S1PR1-CCN1 axis drives endothelial-to-mesenchymal transition and vascular instability in brain arteriovenous malformations.

BACKGROUND: Endothelial-to-mesenchymal transition (EndoMT) contributes to the pathogenesis and rupture of brain arteriovenous malformations (bAVMs), yet its upstream regulatory mechanisms remain largely unclear. METHODS: S1PR1 expression was first examined across multiple public databases, including the Human Protein Atlas, and subsequently validated in human bAVM tissues via immunohistochemistry and immunofluorescence. Human umbilical vein endothelial cells (HUVECs) with S1PR1 knockdown or overexpression were used to perform transcriptomic (RNA-seq) and proteomic analyses. Enrichment analyse

Фолликулярная регуляционная Т-клетки стимулирует экспериментальный аутоиммунный энцефаломиэлит, поддерживая эгрессию клеток B из микробных центров.

Фолликулярные регуляционные Т клетки (Тфр-клетки) представляют собой поднабор регуляторных Т клеток, имеющих ключевое значение для иммунной реакции в микробных центрах (ГЦ), которые сдерживают производство автоантиорганизмов. Однако их роль в аутоиммунных болезнях, таких, как множественный склероз (MS) и его мусриновая модель, экспериментальный аутоиммунный энцефаломиелит (EAE), который представляет собой нейро-воспалительные заболевания, вызываемые Т и В клетками. Здесь мы оценили периферийные иммунные субпопуляции в двух группах пациентов с MS и обнаружили более высокую частоту циркулировани

Совпадение в аннотации оригинала
Follicular regulatory T cells (Tfr cells) constitute a subset of regulatory T cells pivotal to the immune response in germinal centers (GCs) … kine production by myelin oligodendrocyte glycoprotein-specific T cells. We furthermore showed that sphingosine-1-phosphate receptor 2 (S1PR2) expression in GC B cells was up-regulated in Tfr cell-deficient mice. Treatment with an S1PR2 receptor antagonist abrogated the improved EAE clinical scores in Tfr cell-deficient mice, and this loss of protection was a …

Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis.

OBJECTIVE: To report outcomes of pregnancies that occurred during the fingolimod clinical development program. METHODS: Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception. RESULTS: As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, the

Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients.

Fabry disease (FD) results from mutations in the gene (GLA) that encodes the lysosomal enzyme α-galactosidase A (α-Gal A), and involves pathological accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Migalastat hydrochloride (GR181413A) is a pharmacological chaperone that selectively binds, stabilizes, and increases cellular levels of α-Gal A. Oral administration of migalastat HCl reduces tissue GL-3 in Fabry transgenic mice, and in urine and kidneys of some FD patients. A liquid chromatography-tandem mass spectrometry method was developed to measure lyso-Gb3…

Blood sphingolipids in homeostasis and pathobiology.

Sphingolipids have emerged as key signaling molecules involved in the regulation of a variety of cellular functions including cell growth and differentiation, proliferation and apoptotic cell death. Sphingolipids in blood constitute part of the circulating lipoprotein particles (HDL, LDL and VLDL), carried by serum albumin and also present in blood cells and platelets. Recent lipidomic and proteomic studies of plasma lipoproteins have provided intriguing data concerning the protein and lipid composition of lipoproteins in the context of disease. Sphingolipids have been implicated in several di

Role of proliferation in the toxicity of fumonisin B1: enhanced hepatotoxic response in the partially hepatectomized rat.

Fumonisin mycotoxins are common contaminants of maize and cause several fatal animal diseases. Liver is a target organ of fumonisins in intact animals, but liver slices and primary hepatocytes, which do not proliferate in culture, are resistant to fumonisin exposure. Hepatoma cell lines, on the other hand, undergo cell division in culture and are sensitive to the toxic effects of fumonisins. It was therefore hypothesized that fumonisin cytotoxicity is dependent on cell proliferation. To test this hypothesis, the partially hepatectomized rat was used as a model to determine whether fumonisin pr

Long-term safety and efficacy of ponesimod in participants with relapsing multiple sclerosis: results from the phase 3 OPTIMUM 5-year long term extension study.

INTRODUCTION: In phase 3 OPTIMUM study, ponesimod demonstrated superior efficacy and acceptable safety vs teriflunomide in participants with relapsing multiple sclerosis (RMS). This long-term extension (LTE) study was designed to assess the safety and efficacy of ponesimod 20 mg (P20 mg) during extended treatment. METHODS: Participants who completed core OPTIMUM study entered OPTIMUM-LTE; Participants receiving P20 mg once daily (OD) in core continued with the same dose (P20 mg/P20 mg) and those receiving teriflunomide 14 mg OD switched to P20 mg (T14 mg/P20 mg) in the LTE study. Safety asses

Etrasimod Corticosteroid-Free Efficacy, Impact of Concomitant Corticosteroids on Efficacy and Safety, and Corticosteroid-Sparing Effect in Ulcerative Colitis: Analyses of the ELEVATE UC Clinical Program.

BACKGROUND: Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). This post hoc analysis reports the efficacy and safety of etrasimod based on baseline corticosteroid (CS) use in the ELEVATE UC clinical program. METHODS: Patients with UC received etrasimod 2 mg or placebo for up to 52 weeks. CS use was permitted; tapering was recommended from Week 12. Efficacy was assessed at Weeks 12 and 52 in ELEVATE UC 52, and Week 12 in ELEVATE UC 12, for patients in the CS and no-CS sub…

IQGAP1 participates in bone marrow-derived macrophage recruitment and involves in liver inflammation/fibrosis.

IQ motif containing GTPase activating protein 1 (IQGAP1), a scaffold protein, is implicated in cell migration. Our previous studies demonstrate that sphingosine 1-phosphate (S1P) induces bone marrow-derived macrophages (BMDMs) recruitment and promotes chronic liver inflammation/fibrosis. However, the role of IQGAP1 in S1P-induced BMDM migration and liver inflammation/fibrosis remains unclear. Mouse liver fibrosis was induced by carbon tetrachloride (CCl4), bile duct ligation (BDL) or methionine-choline-deficient and high-fat (MCDHF) diet. Immunofluorescence and single-cell RNA sequencing were …

A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite-CerS6-ceramide axis.

The gut microbiota is known to be associated with a variety of human metabolic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). Fungi are increasingly recognized as important members of this community; however, the role of fungal symbionts in metabolic diseases is unknown. We have systematically isolated and characterized gut fungi, identifying Fusarium foetens as an intestinal symbiotic filamentous fungus in mice. F. foetens reverses MASH progression in mouse models through an intestinal ceramide synthetase 6 (CerS6)-ceramide axis. Moreover, we identified FF-C1, a

Loss of ceramide synthase 5 inhibits the development of experimentally induced aortic valve stenosis.

AIM: Inflammation and calcification are hallmarks in the development of aortic valve stenosis (AVS). Ceramides mediate inflammation and calcification in the vascular tissue. The highly abundant d18:1,16:0 ceramide (C16) has been linked to increased cardiovascular mortality and obesity. In this study, we investigate the role of ceramide synthase 5 (CerS5), a critical enzyme for C16 ceramide synthesis, in the development of AVS, particularly in conjunction with a high-fat/high-cholesterol diet (Western diet, WD). METHODS: We used wild-type (WT) and CerS5-/- mice on WD or normal chow in a wire i