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Enhancing Autophagy Protects Against Sepsis-Induced Neuromuscular Dysfunction Associated with Qualitative Changes to Acetylcholine Receptors.

Sepsis-induced myopathy is a heavy burden for patients during respiratory failure as well as after discharge, which could be characterized with qualitative changes to nAChR in a rat model of sepsis, regulated by NRG-1. Autophagy is an innate immune defense mechanism against microbial challenges. We found neuromuscular dysfunction in anterior tibial muscle of male Sprague-Dawley rats 24 h after cecal ligation and puncture (CLP). CLP resulted in increased systemic and local inflammation in anterior tibial muscle tissue. The start-up phase of autophagy, as measured by LC3II, was activated immedia

[Analyses of Ca-related ion channel currents and their involvement in Ca mobilization in smooth muscle and endothelial cells].

Changes in intracellular Ca concentration ([Ca2+]i) play dominant roles in the regulation of ion channel activity. Thus, analyses of Ca-rela … ns, mobilizes Ca in ECs via stimulation of endothelial differential gene (Edg) receptors. Moreover, sphingosine-1-phosphate, which is a lipid mediator and has a similar structure to PC, elevated [Ca2+]i in ECs via the activation of cation channels through Edg1 receptors. A myo-endothelial interaction is another regulatory factor of Ca mobilization in ECs as w …

Designing anticancer drugs via the achilles heel: ceramide, allylic ketones, and mitochondria.

Published reports are reviewed as the basis of a proposal that an effective antineoplastic drug should contain several features: (a) resemblance to the natural lipid, ceramide; (b) an allylic alcohol and/or allylic ketone moiety; (c) a hydroxyl and/or a nitrogen atom near the allylic group; (d) conjugated double bonds as part of the allylic region. The drug should produce reactive oxygen species in tumor mitochondria, stimulate the generation of ceramide in the tumor, and condense with mitochondrial glutathione. It is pointed out that some antibiotics with these features are also active agains

Accumulation of lysosphingolipids in tissues from patients with GM1 and GM2 gangliosidoses.

By using a sensitive method, we assayed lysocompounds of gangliosides and asialogangliosides in tissues from four patients with GM2 gangliosidosis (one with Sandhoff disease and three with Tay-Sachs disease) and from three patients with GM1 gangliosidosis [one with infantile type (fetus), one with late-infantile, and one with adult type]. In the brain and spinal cord of all the patients except for an adult GM1 gangliosidosis patient, abnormal accumulation of the lipids was observed, though the concentration in the fetal tissue was low. In GM2 gangliosidosis, the amounts of lyso GM2 ganglioside

Sphingolipid composition of human platelets.

Total lipid extracts from washed trypsinized human platelets were fractionated into neutral lipids, glycosphingolipids, and phospholipids by silicic acid chromatography. The concentrations and chemical structures of the neutral and acidic glycosphingolipids were then studied in detail. On the basis of sugar molar ratios, studies of permethylation products, and the action of stereospecific glycosidases on the lipids, identifications were made of four neutral glycosphingolipids. Lactosylceramide was the most abundant type and accounted for 64% of the total neutral glycolipid mixture. The major f

Exogenous S1P via S1P receptor 2 induces CTGF expression through Src-RhoA-ROCK-YAP pathway in hepatic stellate cells.

BACKGROUND: Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial. METHODS: In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmac…

Endothelial S1P1 Signaling Counteracts Infarct Expansion in Ischemic Stroke.

RATIONALE: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P1 modulation in stroke. OBJECTIVE: To address roles and mechanisms of engagement …

Administration of JTE013 abrogates experimental asthma by regulating proinflammatory cytokine production from bronchial epithelial cells.

BACKGROUND: Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that acts as a signal transducer by binding to S1P receptors (S1PR) 1 to 5. The S1P/S1PRs pathway has been associated with remodeling and allergic inflammation in asthma, but the expression pattern of S1PR and its effects on non-immune cells have not been completely clarified. The aim of this study was to examine the contribution of the signaling of S1P and S1PRs expressed in airway epithelial cells (ECs) to asthma responses in mice. METHODS: Bronchial asthma was experimentally induced in BALB/c mice by ovalbumin (OVA) sens…

Chronic exposure to polyethylene terephthalate microplastics induces gut microbiota dysbiosis and disordered hepatic lipid metabolism in mice.

Despite the widespread presence of polyethylene terephthalate microplastics (PET MPs) in the environment, their biotoxicity, target organs, … d, accompanied by elevated levels of lipid metabolites such as linoleic acid, taurocholic acid, and sphingosine. These changes disrupted metabolic processes and accelerated lipid deposition in the mouse liver, thereby inducing hepatotoxicity. Moreover, a validation experiment confirmed that depletion of the gut microbiota in mice alleviated PET MPs-induced he …

Сфинголидное сигналирование и метаболизм в нейрональных и глиальных клетках: последствия для цереброваскулярных и нейродегенеративных расстройств.

Сфинголипиды являются важнейшими биоактивными липидами, играющими ключевую роль в поддержании структурной целостности клеточных мембран и регулировании ключевых каналов подачи сигналов в центральной нервной системе (КНС). Как в нейронных, так и в глиальных клетках финголипидный метаболизм регулирует различные процессы, включая выживаемость клеток, апоптоз, нейроинфламмацию и миелинирование. Растущие данные свидетельствуют о дисрегуляции шинголипидных путей в патогенезе различных нарушений CNS, в частности цереброваскулярных заболеваний, таких, как болезнь маленьких сосудов и инсульт, а также о

Совпадение в аннотации оригинала
Sphingolipids are essential bioactive lipids that play pivotal roles in maintaining the structural integrity of cellular membranes and regul … tributes to CNS pathology. Key sphingolipid metabolites such as ceramide, ceramide-1-phosphate, and sphingosine-1-phosphate emerge as critical mediators of neuroinflammation, blood-brain barrier disruption, and cognitive impairment. Furthermore, we explore emerging therapeutic strategies targeting sphingolipid pathways and their potential to slow disease prog …

Response to Fingolimod in Multiple Sclerosis Patients Is Associated with a Differential Transcriptomic Regulation.

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (five responder…

Endo-lysosomal dysfunction and neuronal-glial crosstalk in Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a rare progressive lysosomal lipid storage disorder that manifests with a heterogeneous spectrum of cli … accumulation of diverse lipid species, including cholesterol, glycosphingolipids, sphingomyelin and sphingosine. The NPC1-mediated dysfunction of lipid transport has severe consequences for all brain cells, leading to neurodegeneration. Besides the cell-autonomous contribution of neuronal NPC1, aberrant NPC1 signalling in other brain cells is critical for the …

The repertoire of protein-sulfatide interactions reveal distinct modes of sulfatide recognition.

Sulfatide is an abundant glycosphingolipid in the mammalian nervous system, kidney, trachea, gastrointestinal tract, spleen, and pancreas and is found in low levels in other tissues. Sulfatide is characterized by the presence of a sulfate group in the hydrophilic galactose moiety, with isoforms differing in their sphingosine base and the length, unsaturation, and hydroxylation of their acyl chain. Sulfatide has been associated with a variety of cellular processes including immune responses, cell survival, myelin organization, platelet aggregation, and host-pathogen interactions. Structural stu…

Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease.

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular … ses intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabol …

Protective Effects of Complement Component 8 Gamma Against Blood-Brain Barrier Breakdown.

The blood-brain barrier (BBB) regulates the traffic of micromolecules and macromolecules between the peripheral blood and the central nervous system, to maintain brain homeostasis. BBB disruption and dysfunction accompany a variety of neurological disorders and are closely related with the neuroinflammatory cascades that are triggered by leukocyte infiltration and glial activation. Here, we explored the role of complement component 8 gamma (C8G) in the maintenance of BBB integrity. Previously, C8G was shown to inhibit neuroinflammation by interfering with the sphingosine-1-phosphate (S1P)-S1PR…

Control of Skeletal Muscle Atrophy Associated to Cancer or Corticosteroids by Ceramide Kinase.

Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and degradation. Although the signaling pathways involved in SkM mass wasting are multiple, the regulatory role of simple sphingolipids is limited. Here, we report the impairment of ceramide kinase (CerK), the enzyme responsible for the phosphorylation of ce…

The Glucosylceramide Synthase Inhibitor PDMP Causes Lysosomal Lipid Accumulation and mTOR Inactivation.

For many years, the biology of glycosphingolipids was elucidated with the help of glucosylceramide synthase (GCS) inhibitors such as 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). Additionally, PDMP gained interest because of its chemosensitizing effects. Several studies have successfully combined PDMP and anti-cancer drugs in the context of cancer therapy. However, the mechanism of action of PDMP is not fully understood and seems to go beyond glycolipid inhibition. Here, we used a functionalized sphingosine analogue (pacSph) to investigate the acute effects of PDMP on cellular sphin…