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Platelet-derived growth factor B restores vascular barrier integrity and diminishes permeability in ovarian hyperstimulation syndrome.

Although advances in the prediction and management of ovarian hyperstimulation syndrome (OHSS) have been introduced, complete prevention is not yet possible. Previously, we and other authors have shown that vascular endothelial growth factor, angiopoietins (ANGPTs) and sphingosine-1-phosphate are involved in OHSS etiology. In addition, we have demonstrated that ovarian protein levels of platelet-derived growth factor (PDGF) ligands -B and -D decrease in an OHSS rat model, whilst PDGFR-β and ANGPT2 remain unchanged. In the present work, we investigated the role of PDGF-B in OHSS by evaluating l…

Evaluation of the splenic injury following exposure of mice to bisphenol S: A mass spectrometry-based lipidomics and imaging analysis.

BACKGROUND: The widespread use of bisphenol A (BPA) substitutes has aroused great attention towards their toxicological evaluation in vivo a … nic white pulp. Lipidome profiling of spleen after BPS treatment was also changed with up-regulated sphingosine [So], neutral glycosphingolipids [CerG], cholesteryl ester [ChE], diacylglycerols [DAG], lysophosphatidylcholine [LPC], lysophosphatidylethanolamine [LPE], phosphatidylglycerols [PG], phosphatidylinositols [PI] and phosphatidylserine [PS] as well as …

FTY720 controls disease severity and attenuates sciatic nerve damage in chronic experimental autoimmune neuritis.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune-mediated inflammatory disease of the peripheral nervous system characterized by a response directed against certain myelin proteins and for which therapies are limited. Previous studies have suggested a beneficial role of FTY720, a sphingosine 1-phosphate (S1P) receptor agonist, known to deplete lymphocytes from the peripheral blood by sequestering them into lymph nodes, in the treatment of experimental autoimmune neuritis (EAN). Therefore, we investigated whether FTY720 is also beneficial in chronic …

Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis.

BACKGROUND: In spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug … n patient's MM cells and MM cell lines and was further increased by co-culture with BMSC, IL-6, and sphingosine-1-phosphate. Modulation of Gfi1 in MM cells had major effects on their survival and growth. Knockdown of Gfi1 induced apoptosis in p53-wt, p53-mutant, and p53-deficient MM cells, while Gfi1 overexpression enhanced MM cell growth and protected MM cel …

Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma.

Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assa…

The role of ANK interactions with MYBBP1a and SPHK1 in catabolic events of articular chondrocytes.

OBJECTIVE: To determine the role of progressive ankylosis protein (ANK)/Myb-binding protein 1a (MYBBP1a) and sphingosine kinase 1 (SPHK1) interactions in catabolic events of articular chondrocytes. METHOD: ANK/MYBBP1a and SPHK1 interactions were identified using yeast two-hybrid screening and co-immunoprecipitation. To determine the role of these interactions in catabolic events of articular chondrocytes, ank/ank and wild type (WT) mouse chondrocytes transfected with full-length or mutant ank expression vectors (EVs) or femoral heads were treated with interleukin-1beta (IL-1β) in the absence …

Ectopic germinal centers are rare in Sjogren's syndrome salivary glands and do not exclude autoreactive B cells.

This study reports on the characterization of B cells of germinal center (GC)-like structures infiltrating the salivary glands (SGs) of pati … a in support of this dichotomy included the restriction of CXCR5 expression to real GC cells, while sphingosine 1-phosphate receptor 1 was expressed only in aggregates. In contrast, both types of B cell clusters expressed the idiotype recognized by the 9G4 mAb. Our data indicate that, in SGs, a minority of B cell clusters represent genuine GC cells, while the …

SiO2 dust induces the transformation of lung fibroblasts to myofibroblasts by activating the S1P-RhoA-YAP signaling pathway.

Silicosis, a prevalent and severe form of pneumoconiosis, is characterized by silicotic nodule formation and extensive pulmonary fibrosis. Caused by prolonged inhalation of free silica (SiO₂) dust, its pathogenesis involves complex regulatory mechanisms that remain unclear. Using a co-culture model of THP-1 macrophages and HFL-1 cells exposed to SiO₂, we investigated the role of the S1P-RhoA-YAP pathway in fibroblast-to-myofibroblast transformation. Intervention with fingolimod or si-RhoA was employed. Results showed that SiO₂ exposure significantly reduced HFL-1 cell viability, induced morpho

KLF2 expression in IgG plasma cells at their induction site regulates the migration program.

Newly generated plasma cells in secondary lymphoid organs migrate to niches in the bone marrow, wherein they survive as long-lived plasma cells (LLPCs). Although LLPCs have been extensively characterized, it is still unclear what the key determinant(s) are for plasma cell longevity. One model postulates that plasma cell heterogeneity is established at the induction site, thereby instructing their longevity. Here, we found that, among newly generated IgG plasma cells, integrin β7hi marks plasma cells predisposed to home to the bone marrow, whereas integrin β7lo cells remain in secondary lymphoi

EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress.

The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal.

Glial Fibrilar Acidic Protein как знак болезни в повторном многоразовом склерозе: постспециальный анализ испытаний этапа 3 Ozanimod.

В ходе этого постспециального анализа были изучены взаимосвязи между исходным плазменным фиброзным кислотным белоком (GFAP), потенциальным биомаркером множественного склероза (MS) и базовыми характеристиками и результатами обработки у участников с повторной пощечиной MS (RMS) в ходе двух испытаний этапа 3, в ходе которых случайным образом был присвоен озанимод 0,46 мг или 0,92 мг или интерферон β-1a 30 мкг. МЕТОДЫ: На этапе 3 судебных процессов (SUNBEAM [Clinical Processures.gov: NCT02294058; EudraCT: 2014-002320-27] продолжительность: ≥ 12 месяцев; и RADIANS [Clinical Processors.gov: NCT02047

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… Here, the potential for baseline plasma GFAP as a biomarker for relapsing MS (RMS) was assessed using pooled data from two Phase 3, randomized, active‐comparator trials of ozanimod [ 19 , 20 ], an oral sphingosine 1‐phosphate receptor modulator that reduces the migration of lymphocytes into the CNS …

Stress-Induced Changes in the Lipid Microenvironment of β-(1,3)-d-Glucan Synthase Cause Clinically Important Echinocandin Resistance in Aspergillus fumigatus.

Aspergillus fumigatus is a leading cause of invasive fungal infections. Resistance to first-line triazole antifungals has led to therapy wit … the enzyme with resistance induced by CAS revealed a prominent increase in the abundances of dihydrosphingosine (DhSph) and phytosphingosine (PhSph). Exogenous addition of DhSph and PhSph to the sensitive enzyme recapitulated the drug insensitivity of the CAS-derived enzyme. Further analysis demonstrated that CAS induces mitochondrion-derived reactive oxygen …

Systemic influence of immunosuppressive drugs on small and large bowel transport and barrier function.

Immunosuppressive drug (ISD)-associated gastrointestinal disorders are a relevant risk factor for graft loss or patient death. The pathomechanisms and the incidence of post-transplantation diarrhea remain to be fully understood. The aim of this study was to characterize the impact of cyclosporine A, tacrolimus (TAC), mycophenolate mofetil (MMF), enteric coated mycophenolic acid (EC-MPA), sirolimus, everolimus (EVE) and fingolimod (FTY 720) on small and large bowel transport and barrier function. Functions of the small bowel and distal colon of Wistar rats treated for 14 days with one of the dr

Functional modulation of mitochondria by eicosapentaenoic acid provides protection against ceramide toxicity to C6 glioma cells.

Mitochondrial dysfunction and associated apoptosis have been reported in the pathogenesis of neuron degeneration. The effects of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on the mitochondrial membrane potential, mitochondrial biogenesis, and mitochondrial function of rat C6 glioma cells were determined in this study. Increased cytochrome c release and activated caspase-3 expression were determined in cells treated with >20 microM C(2) ceramide. There were significant repressive effects on ceramide-induced cell death with 25-100 microM EPA and 25 microM AA pretreatment. However, sig

Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3.

Patients with Gaucher disease have been classified as type 1 nonneuronopathic, type 2 acute neuronopathic, and type 3 chronic neuronopathic phenotypes. Increased quantities of glucocerebroside and glucosylsphingosine (glucopsychosine) are present in the brain of type 2 and type 3 Gaucher patients. Galactosylsphingosine has previously been shown to be neurotoxic in globoid cell leukodystrophy (Krabbe disease). To determine whether glucosylsphingosine is also neurotoxic, we examined its effect on cultured cholinergic neuron-like LA-N-2 cells. When these cells were exposed to 1, 5, or 10 microM g…

Differential activation of phosphoinositide 3-kinase by endothelin and ceramide in colonic smooth muscle cells.

We have investigated the hypothesis that different contractile agonists activate distinct catalytic subunits of phosphoinositide (PI) 3-kinase in smooth muscle cells. Endothelin (10(-7) M) induced a sustained increase in PI 3-kinase activity at both 30 s and 4 min of stimulation (151.5 +/- 8.5% at 30 s and 175.8 +/- 8.7% at 4 min, P < 0.005). Preincubation of smooth muscle cells with the tyrosine kinase inhibitor genistein (3 microM) resulted in a significant inhibition of both C2 ceramide-induced and endothelin-induced PI 3-kinase activation and contraction. Preincubation with herbimycin A, a

Differential effects of long-chain (sphingoid) bases on the monocytic differentiation of human leukemia (HL-60) cells induced by phorbol esters, 1 alpha, 25-dihydroxyvitamin D3, or ganglioside GM3.

Conditions were developed to prolong the ability of sphinganine, a potent inhibitor of protein kinase C, to block the phorbol ester-induced adherence of HL-60 cells beyond 24 h. The loss of inhibition after this time seen previously (A.H. Merrill, Jr., A.M. Sereni, V.L. Stevens, Y.A. Hannun, R.M. Bell, and J.M. Kinkade, Jr., J. Biol. Chem., 261: 12610-12615, 1986), which appeared to be due to metabolism of this long-chain base, was overcome by supplying sphinganine daily. After 4 days, phorbol myristate acetate-induced adherence was inhibited approximately 50% by sphinganine. Sphinganine signi

Increase in BACE1 Phosphorylation in the Rat Hippocampus and Phytosphingosine in Plasma After Chronic Administration of Scopolamine.

Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with the accumulation of amyloid-β (Aβ) peptides and d … d be present in the scopolamine model were carried out by UHPLC-MS/MS, finding elevated plasma phytosphingosine and decreased acetylcarnitine, suggesting disrupted lipid metabolism associated with scopolamine-induced cognitive impairment.

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD)

LncRNA CERS6 - AS1 mediates the IGF2BP1/LIN28B axis to promote proliferation, migration and invasion in ovarian cancer.

Ovarian cancer remains a significant clinical challenge for women's health, making it imperative to elucidate its underlying molecular mechanisms. LncRNA CERS6-AS1 and LIN28B-binding proteins play a vital role in the development of ovarian cancer. The expression levels of CERS6-AS1 and LIN28B in ovarian cancer tissues and cell lines were evaluated using qPCR. Protein levels were analyzed through IHC. The survival rate was assessed using the Kaplan-Meier curve. LIN28B or CERS6-AS1 was silenced via RNA interference (shRNA), and the effects on proliferation, migration, and invasion were examined