A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis.

The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using (), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E (PGE) as a major immune regulatory mechanism of heGDH.

Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis.

Background: Autoantibodies are found in up to 80 % of patients with idiopathic inflammatory myopathies (IIM) and are associated with distinct clinical phenotypes. Autoantibodies targeting cytosolic 5'-nucleotidase 1A (anti-NT5C1A) are currently the only known serum biomarker for the subgroup inclusion body myositis (IBM), although detected even in other autoimmune diseases. The aim of the study was to identify new autoimmune targets in IIM.

NG2 glia protect against prion neurotoxicity by inhibiting microglia-to-neuron prostaglandin E2 signaling.

Oligodendrocyte-lineage cells, including NG2 glia, undergo prominent changes in various neurodegenerative disorders. Here, we identify a neuroprotective role for NG2 glia against prion toxicity. NG2 glia were activated after prion infection in cerebellar organotypic cultured slices (COCS) and in brains of prion-inoculated mice.

Strong damped Lyman-α absorption in young star-forming galaxies at redshifts 9 to 11.

Primordial neutral atomic gas, mostly composed of hydrogen, is the raw material for star formation in galaxies. However, there are few direct constraints on the amount of neutral atomic hydrogen (H i) in galaxies at early cosmic times. We analyzed James Webb Space Telescope (JWST) near-infrared spectroscopy of distant galaxies, at redshifts ≳8.

Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis.

Background: Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression.

In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation.

Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis.

Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline.

The anti-inflammatory and vasoprotective properties of mPGES-1 inhibition offer promising therapeutic potential.

Introduction: Prostaglandin E (PGE) is produced by cyclooxygenases (COX-1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). PGE is pro-inflammatory in diseases such as rheumatoid arthritis, cardiovascular disorders, and cancer. While Nonsteroidal anti-inflammatory drugs (NSAIDs) targeting COX can effectively reduce inflammation, their use is limited by gastrointestinal and cardiovascular side effects resulting from the blockade of all prostanoids.

Heavy-element production in a compact object merger observed by JWST.

The mergers of binary compact objects such as neutron stars and black holes are of central interest to several areas of astrophysics, including as the progenitors of gamma-ray bursts (GRBs), sources of high-frequency gravitational waves (GWs) and likely production sites for heavy-element nucleosynthesis by means of rapid neutron capture (the r-process). Here we present observations of the exceptionally bright GRB 230307A. We show that GRB 230307A belongs to the class of long-duration GRBs associated with compact object mergers and contains a kilonova similar to AT2017gfo, associated with the GW merger GW170817 (refs.

High-content screening of drug combinations of an mPGES-1 inhibitor in multicellular tumor spheroids leads to mechanistic insights into neuroblastoma chemoresistance.

High-throughput drug screening enables the discovery of new anticancer drugs. Although monolayer cell cultures are commonly used for screening, their limited complexity and translational efficiency require alternative models. Three-dimensional cell cultures, such as multicellular tumor spheroids (MCTS), mimic tumor architecture and offer promising opportunities for drug discovery.

Microsomal prostaglandin E synthase-1 inhibition promotes shunting in arachidonic acid metabolism during inflammatory responses in vitro.

Microsomal Prostaglandin E Synthase 1 (mPGES-1) is the key enzyme for the generation of the pro-inflammatory lipid mediator prostaglandin E (PGE), which contributes to several pathological features of many diseases. Inhibition of mPGES-1 has been shown to be a safe and effective therapeutic strategy in various pre-clinical studies. In addition to reduced PGE formation, it is also suggested that the potential shunting into other protective and pro-resolving prostanoids may play an important role in resolution of inflammation.

Microsomal prostaglandin E synthase-1 inhibition prevents adverse cardiac remodelling after myocardial infarction in mice.

Background And Purpose: Heart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). The microsomal prostaglandin E synthase-1 (mPGES-1)/PGE pathway has been shown to constrain reperfusion injury after acute myocardial ischaemia. However, it is unknown whether pharmacological inhibition of mPGES-1, a target with lower risk of thrombosis compared with selective inhibition of cyclooxygenase-2, affects chronic cardiac remodelling after MI.

Cerebrospinal Fluid Biomarkers of Synaptic Dysfunction are Altered in Parkinson's Disease and Related Disorders.

Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects.

Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies.

Objectives: Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM.

Biosynthesis of prostaglandin 15dPGJ -glutathione and 15dPGJ-cysteine conjugates in macrophages and mast cells via MGST3.

Inhibition of microsomal prostaglandin E synthase-1 (mPGES-1) results in decreased production of proinflammatory PGE and can lead to shunting of PGH into the prostaglandin D (PGD)/15-deoxy-Δ-prostaglandin J (15dPGJ) pathway. 15dPGJ forms Michael adducts with thiol-containing biomolecules such as GSH or cysteine residues on target proteins and is thought to promote resolution of inflammation. We aimed to elucidate the biosynthesis and metabolism of 15dPGJ via conjugation with GSH, to form 15dPGJ-glutathione (15dPGJ-GS) and 15dPGJ-cysteine (15dPGJ-Cys) conjugates and to characterize the effects of mPGES-1 inhibition on the PGD/15dPGJ pathway in mouse and human immune cells.

Autoantibodies targeting malondialdehyde-modifications in rheumatoid arthritis regulate osteoclasts via inducing glycolysis and lipid biosynthesis.

Proteins subjected to post-translational modifications, such as citrullination, carbamylation, acetylation or malondialdehyde (MDA)-modification are targeted by autoantibodies in seropositive rheumatoid arthritis (RA). Epidemiological and experimental studies have both suggested the pathogenicity of such humoral autoimmunity, however, molecular mechanisms triggered by anti-modified protein antibodies have remained to be identified. Here we describe in detail the pathways induced by anti-MDA modified protein antibodies that were obtained from synovial B cells of RA patients and that possessed robust osteoclast stimulatory potential and induced bone erosion in vivo.

Where traditional Chinese medicine meets Western medicine in the prevention of rheumatoid arthritis.

Chinese medicine has a long tradition of use against rheumatoid arthritis (RA). The formulations are based on combinations of typically 5-10 plants, which are usually boiled and administered as a decoction or tea. There are few clinical trials performed so the clinical evidence is sparse.

Helminthic dehydrogenase drives PGE and IL-10 production in monocytes to potentiate Treg induction.

Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation.

Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome.

Background: To address the reactivity and affinity against histidyl-transfer RNA synthetase (HisRS) autoantigen of anti-Jo1 autoantibodies from serum and bronchoalveolar lavage fluid (BALF) in patients with idiopathic inflammatory myopathies/anti-synthetase syndrome (IIM/ASSD). To investigate the associations between the reactivity profile and clinical data over time.

Methods: Samples and clinical data were obtained from (i) 25 anti-Jo1 patients (19 sera with 16 longitudinal samples and 6 BALF/matching sera at diagnosis), (ii) 29 anti-Jo1 patients (25 sera and 4 BALF/matching sera at diagnosis), and (iii) 27 age/gender-matched healthy controls (24 sera and 3 BALF/matching sera).

Omega-3 fatty acids decrease CRYAB, production of oncogenic prostaglandin E and suppress tumor growth in medulloblastoma.

Aims: Medulloblastoma (MB) is one of the most common malignant central nervous system tumors of childhood. Despite intensive treatments that often leads to severe neurological sequelae, the risk for resistant relapses remains significant. In this study we have evaluated the effects of the ω3-long chain polyunsaturated fatty acids (ω3-LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on MB cell lines and in a MB xenograft model.