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Potential Roles of Escherichia coli in IgA Nephropathy: Evidence, Mechanistic Hypotheses and Microbiota-Targeted Strategies.

IgA nephropathy (IgAN), the most common primary glomerular disease, involves mucosa-kidney axis dysregulation, with gut dysbiosis increasing … ic and renal inflammation. Second, metabolic reprogramming is associated with increased circulating sphingosine-1-phosphate (S1P) and altered production of indole and trimethylamine (TMA); S1P may promote mesangial proliferation and fibrosis, whereas indole- and TMA-related pathways may contribute to tubulointerstitial injury and chronic kidney disease (CKD) …

Endothelial S1PR3 downregulation exacerbates pressure overload-induced cardiac remodeling by promoting fibrosis and inflammation.

Endothelial dysfunction and inflammation are pivotal contributors to pathological cardiac remodeling and its progression toward heart failure (HF). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor enriched in endothelial cells (ECs), is an important regulator of endothelial function, but its role in pressure overload-induced cardiac remodeling remains unclear. In this study, we observed a substantial reduction in S1PR3 levels in cardiac ECs following transverse aortic constriction (TAC). Endothelial-targeted S1PR3 knockdown aggravated TAC-induced cardiac remodeling, as …

An Update on Bile Acid-Regulated Signalling in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common metabolic disorder with rising global incidence without effecti … e membrane-bound G protein-coupled receptors such as Takeda G protein-coupled receptor 5 (TGR5) and sphingosine-1-phosphate receptor 2 (S1PR2). The distinct roles of these BA receptor-dependent signalling pathways in lipid homeostasis underscore their importance in MASLD development. Pharmacological strategies targeting BA-regulated pathways, particularly the …

Cheminformatics and Machine Learning-Driven QSAR Analysis of SPHK2 Inhibitors for Anticancer Drug Design.

INTRODUCTION: Sphingosine kinase 2 (SPHK2) plays a pivotal role in sphingolipid metabolism and has emerged as a therapeutic target in cancer due to its involvement in tumor proliferation and resistance mechanisms. METHODS: A dataset of 269 SPHK2-targeting compounds from ChEMBL was analyzed using five molecular descriptor sets: PubChem, MACCS, CDK, Substructure, and Klekota- Roth. Six machine learning algorithms were applied to develop QSAR models, and they were validated using ROC-AUC, PCA, R2, and Q2 metrics. Top-ranked compounds were subsequently evaluated using Glide docking and MMGBSA ene…

Shedding of endothelial glycocalyx and increased vascular permeability in patients with obstructive jaundice: A prospective observational study.

During the perioperative period, increased vascular permeability is associated with elevated morbidity and mortality. Obstructive jaundice ( … ular permeability-related mediators, including vascular endothelial growth factor (VEGF), thrombin, sphingosine-1-phosphate, atrial natriuretic peptide, cyclic adenosine monophosphate, and nitric oxide (NO) were quantified. Transendothelial electrical resistance was used to assess endothelial permeability. OJ patients showed significantly increased vascular p …

Efferocytosis enhances macrophage pro-angiogenic functions for bone marrow regeneration.

Myeloablative treatments before bone marrow (BM) transplantation severely disrupt the microvasculature of the BM, and its regeneration prece … roangiogenic state and enhance vascular regeneration in the BM. Mechanistically, dying cell-derived sphingosine-1-phosphate (S1P) primes hypoxia-inducible factor-1α (HIF-1α) gene expression in macrophages. Importantly, our results revealed that the degradation of apoptotic bodies (ApoBDs) elevates intracellular cholesterol levels and activates their sensor, l …

CTL lymph node entrapment drives lymphopenia in severe influenza infection.

Influenza virus infection can result in outcomes ranging from moderate, self-limiting illness to severe, life-threatening disease. Although … of effector CD8+ T cells to re-express the transcription factor KLF2 and its downstream target, the sphingosine-1-phosphate receptor S1PR1, a defect we show to be independent of both TGFβ and sustained TCR signalling. To evaluate the consequences of this impaired trafficking, we transferred effector CD8+ T cells directly into the bloodstream during severe inf …

Metabolic dysfunction-associated steatohepatitis (MASH): intersections with type 2 diabetes and insulin resistance.

Metabolic dysfunction-associated fibrotic/steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-assoc … iglycerides, and peroxisome proliferator-activated receptor biology. Furthermore, it introduces how sphingosine-1-phosphate signaling, mesenchymal stromal cell biology, and endogenous stromal repair failure could be a functional part of this overall integration of dyslipidemia/insulin resistance-driven/conditioned MASLD/MASH. For each axis, the review summari …

CD22 is upregulated and displays suppressive properties on CD4+ T cells upon a persistent virus infection.

Chronic viral infections evade or suppress host immunity, posing risks to global human health. However, the underlying mechanisms of viral immune suppression are incompletely defined. Previously, we have demonstrated that sphingosine kinase 2 (SphK2) represses CD4+ T-cell immunity during lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl 13) infection. Here, our study indicates that CD22 is significantly upregulated on virus-specific T cells, which is largely dependent on SphK2, upon LCMV infection. The upregulation of CD22 on virus-specific T cells is sustained during persistent LCMV Cl 1…

Discovery of an Adaptive Neuroimmune Response Driving Itch and Fast Tick Removal with Implications for Preventing Pathogen Transmission.

Acquired tick resistance (ATR) is well characterized in tick-exposed animals, compromising tick fitness through antibody-mediated activation … development of acquired T cell memory by averting naive lymphocyte egress from lymph nodes with the sphingosine-1-phosphate receptor modulator FTY720, before tick sensitization, prevents Iba-1+ macrophage and CD3+ T cell infiltration to the tick bite site and abrogates scratching and tick removal. This neuroimmune response is independent of Trpv1 as tick-sens …

Positioning siponimod and the post-treatment gap: the unmet needs of SPMS patients in Italian real-world practice.

BACKGROUND: Siponimod, a selective sphingosine-1-phosphate receptor modulator was approved for patients with Secondary progressive Multiple Sclerosis (SPMS) with ongoing disease activity. However, its real-world positioning and management after discontinuation remain challenging. OBJECTIVES: To evaluate the real-world use of siponimod in Italian real world setting, focusing on discontinuation rates, possible predictors, and post-treatment management. METHODS: A retrospective, multicenter study on patients treated with siponimod across six Italian MS centers. Demographics, prior disease modif…

Role of S1PR1 in Modulating Airway Epithelial Responses to Pseudomonas aeruginosa in Cystic Fibrosis.

Background:Pseudomonas aeruginosa infection is a major driver of morbidity and mortality in cystic fibrosis (CF), yet disease severity varies widely among people with CF (pwCF). This clinical heterogeneity suggests the involvement of host genetic modifiers beyond CFTR. We previously identified sphingosine 1-phosphate receptor 1 (S1PR1) as a candidate gene associated with susceptibility to P. aeruginosa. Here, we investigated its role in modulating airway epithelial responses to infection. Methods: Using CRISPR/Cas9, we generated S1PR1-knockout bronchial epithelial cells with (IB3-1) and withou…

Differential Effects of Sphingolipids on Cell Death and Antioxidant Defenses in Type 1 and Type 2 Endometrial Cancer Cells.

Endometrial cancer (EC) is classified into two main subtypes with distinct molecular profiles. Sphingolipids, particularly ceramide and sphingosine-1-phosphate (S1P), are crucial regulators of cell survival, apoptosis, and oxidative stress. This study examined the impact of sphingolipid metabolism in Ishikawa (type 1) and HEC-1A (type 2) EC cells following the silencing of Sptlc1 and Sptlc2, which encode subunits of serine palmitoyltransferase (SPT), a key enzyme in de novo sphingolipid synthesis. Gene silencing was confirmed by RT-PCR and Western blot, while sphingolipid levels were quantifie…

Resveratrol ameliorates streptozotocin induced renal inflammation and promotes autophagy by mediating the SphK1 pathway via Sirt1 in Wistar rats.

Streptozocin (STZ) has toxic effects on pancreatic β-cells and induces diabetic nephropathy (DN). Resveratrol (RSV), a natural agonist of Sirtuin-1 (Sirt1), has demonstrated its capacity to reduce mesangial cell inflammation via the sphingosine kinase 1 (SphK1) pathway in our in vitro study. However, the relationship between the SphK1 signaling pathway and Sirt1 in STZ-induced DN remains largely unexplored. Our silico study suggested that Sirt1 stably bound to SphK1. In our study rats were randomly divided into 3 groups: control group, STZ group, RSV group. Results showed that RSV pretreatment…

NXC736, a Functional Antagonist of S1P4, Attenuates Brain Injury in Mice with Permanent Ischemic Stroke.

Stroke is the leading cause of death and long-term disability worldwide, with ischemic stroke accounting for nearly 87% of all cases. Vascular occlusion, a key pathological event in ischemic stroke, has been reliably reproduced in preclinical studies using permanent ischemic stroke models. This study demonstrated the neuroprotective effect of NXC736, a functional antagonist of sphingosine-1-phosphate receptor 4 (S1P4, currently in phase II clinical trials for alopecia areata), against acute injury in mice with permanent middle cerebral artery occlusion (pMCAO). pMCAO-challenged mice received o…

A novel peptide antagonist for SATB1 in the immune response to Leishmania infection.

Peptide-based therapies are emerging as powerful tools in the treatment of inflammatory and infectious diseases, offering high specificity, … stimulating factor (GM-CSF) production and inflammatory responses involving IL-6, IL-17, IL-23, and Sphingosine-1-phosphate (S1P). To restore immune balance, we strategically disrupt conserved residues Lysine (Lys) 29, Arginine (Arg) 32, Glutamic acid (Gln) 34, and Asparagine (Asn) 36 within SATB1's nuclear localization signal (NLS) using machine learning (ML …

Сипонимо ингибирует связанные с болезнью микроглиа-Т взаимодействие клеток в хронической экспериментальной аутоиммунной энцефаломиэлите.

Хронически воспламененный, реактивный микроглиа представляет собой одну из характерных черт вторичного прогрессивного множественного склероза (СПМС). Особенно их взаимодействие с энцефалитогенными Т клетками приводит к нейроаксональному повреждению, связанному с развитием болезни. В нашем исследовании мы стремились изучить потенциал сипонимода, фосфатного модулятора фингозина-1, который был утвержден для лечения активных СМПС, для подавления связанных с болезнями связей между клетками и микроглией с использованием хронической экспериментальной аутоиммунной энцефаломиелита (EAE) модели MS. Мы о

Совпадение в аннотации оригинала
Chronically inflamed, reactive microglia represent a prominent feature of secondary progressive multiple sclerosis (SPMS). Especially their interplay with encephalitogenic T cells promotes neuroaxonal damage associated with disease progression. In our study, we aimed to explore the potential of siponimod, a sphingosine-1-phosphate modulator approved for the …

Transposon-sequencing (Tn-seq) of the Candida glabrata reference strain CBS138 reveals epigenetic plasticity, structural variation, and intrinsic mechanisms of resistance to micafungin.

Candida glabrata (also called Nakaseomyces glabratus) is an opportunistic pathogen that can resist common antifungals and rapidly acquire mu … s were also revealed including mannosyltransferase activity and biosynthesis of the lipid precursor sphingosine, the inhibition of which by SDZ 90-215 and myriocin enhanced the potency of micafungin in vitro. These findings provide insights into the complexity of the C. glabrata species as well as strategies for improving antifungal efficacy.

Combined diet and exercise training decreases serum lipids associated with insulin resistance.

OBJECTIVE: Circulating lipids are linked with insulin resistance and increased cardiovascular disease risk. We previously reported that dihy … 12% and 57%, respectively; and total serum triacylglycerol (TAG), diacylglycerol, dihydroceramides, sphingosine-1-phosphate, and sphinganine-1-phosphate were significantly reduced, as were specific species of dihydroceramides (C18:0 and C24:1). Individuals with higher preintervention TAG concentrations had significant decreases in serum lipids, which were not …

New insight into primary hyperparathyroidism using untargeted metabolomics.

Primary Hyperparathyroidism (PHPT) is characterized by excessive parathormone (PTH) secretion and disrupted calcium homeostasis. Untargeted … lar complications. Several metabolites, such as gamma-glutamyls, caffeine, sex hormones, carnitine, sphingosine-1-phosphate (S-1-P), and steroids, were connected with reduced bone mineral density (BMD). Metabolic profiling identified distinct metabolic patterns between patients with PHPT and healthy controls. These findings provided valuable insights into the …