Protective Effect Of Sphingosine-1-phosphate Research Articles

Role of sphingosine 1-phosphate (S1P) in sepsis-associated intestinal injury.

Sphingosine-1-phosphate (S1P) is a widespread lipid signaling molecule that binds to five sphingosine-1-phosphate receptors (S1PRs) to regulate downstream signaling pathways. Sepsis can cause intestinal injury and intestinal injury can aggravate sepsis. Thus, intestinal injury and sepsis are mutually interdependent. S1P is more abundant in intestinal tissues as compared to other tissues, exerts anti-inflammatory effects, promotes immune cell trafficking, and protects the intestinal barrier. Despite the clinical importance of S1P in inflammation, with a very well-defined mechanism in inflammatory bowel disease, their role in sepsis-induced intestinal injury has been relatively unexplored. In addition to regulating lymphocyte exit, the S1P-S1PR pathway has been implicated in the gut microbiota, intestinal epithelial cells (IECs), and immune cells in the lamina propria. This review mainly elaborates on the physiological role of S1P in sepsis, focusing on intestinal injury. We introduce the generation and metabolism of S1P, emphasize the maintenance of intestinal barrier homeostasis in sepsis, and the protective effect of S1P in the intestine. We also review the link between sepsis-induced intestinal injury and S1P-S1PRs signaling, as well as the underlying mechanisms of action. Finally, we discuss how S1PRs affect intestinal function and become targets for future drug development to improve the translational capacity of preclinical studies to the clinic.

Sphingosine 1-phosphate alleviates radiation-induced ferroptosis in ovarian granulosa cells by upregulating glutathione peroxidase 4

Ferroptosis is a form of cell death caused by the accumulation of lipid peroxidation products due to abnormal iron metabolism. However, it remains unknown whether ferroptosis participates in the process of radiation-induced ovarian injury. Sphingosine-1-phosphate (S1P) is an important bioactive sphingolipid that has a protective effect on ovarian injury. The present study aims to determine whether X-ray radiation induces ferroptosis in the ovarian granulosa KGN cell line, and explore the potential effect of S1P and its mechanism in radiation-induced ferroptosis. The results indicated that irradiation reduced the viability of KGN cells, altered the mitochondrial morphology, induced the intracellular accumulation of iron ions, increased oxidative stress, and induced lipid peroxidation. Furthermore, the radiation exposure triggered the ferroptosis in KGN cells. S1P can alleviate radiation-induced ferroptosis. Furthermore, the protective effect of S1P was reversed after the application of siRNA to interfere with the glutathione peroxidase 4 expression. Ferroptosis might be pervasive in radiation-induced ovarian injury, and S1P may serve as a potential therapeutic approach to protect against the toxic effect of radiation in female gonads by inhibiting ferroptosis.

Sphingosine 1-phosphate protects against radiation-induced ovarian injury in female rats\u2014impact on mitochondrial-related genes

The toxic effects of ionizing radiation on the gonads have been widely recognized. Sphingosine 1-phosphate (S1P) has a protective effect on ovarian injury, and although it is known that mitochondria are involved in this process, the specific mechanism is not fully understood. The present study analysed the changes in the serum AMH and ovarian histology in Sprague-Dawley female rats exposed to X-ray radiation only or co-administered with S1P. The mRNA expression profile of ovarian tissue was further analysed via next-generation sequencing and bioinformatics approaches to screen out candidate mitochondria-related genes. Finally, differentially expressed target genes were verified by real-time PCR. The results showed that ionizing radiation could reduce the serum AMH level, destroy ovarian structure and decrease the number of follicles in rats, while S1P administration significantly attenuated the impairment of ovarian function. Gene ontology (GO) and KEGG pathway analysis revealed that a variety of genes related to mitochondrial function were differentially expressed, and the protective effect of S1P on mitochondria was more obvious in the acute phase 24 h after radiation. The differentially expressed mitochondrial function-related genes associated with the protective effect of S1P were UQCRH, MICU2 and GPX4, which were subsequently verified by RT-PCR. Therefore, ionizing radiation has a significant effect on ovarian function, and S1P has a protective effect on radiation-induced ovarian injury, in which mitochondria may play an important role. This study sheds new light on the mechanism of radiation-induced ovarian injury and helps develop a novel potential strategy to control it.

Sphingosine-1-phosphate promotes the proliferation and attenuates apoptosis of Endothelial progenitor cells via S1PR1/S1PR3/PI3K/Akt pathway.

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that involves in numerous pathophysiological processes. Endothelial progenitor cells (EPCs) play a crucial role in endothelial repair and tumor angiogenesis. The aim of study was to determine the effects of S1P on proliferation and anti-apoptosis of EPCs and their signaling pathways. In this study, we showed that S1P, SEW2871 (a selective S1P receptor 1 (S1PR1) agonist), or CYM5541 (a selective S1P receptor 3 (S1PR3) allosteric agonist promotes the proliferation and attenuates apoptosis of bone marrow (BM)-derived EPCs. Futhermore, it was showed that S1P could promote EPCs proliferation, which could be significantly inhibited by pretreatment with CAY10444 (an S1PR3 antagonist), VPC23019 (a selective S1PR(1)/S1PR(3) antagonist), or LY294002 (a PI3K inhibitor). Moveover, we discovered that S1P could significantly attenuate H2 O2 -induced apoptosis and activation of caspase-3 in vitro, while W146 (an S1PR1 antagonist), VPC23019, or LY294002 could significantly increase the activation of caspase-3 and subsequent augmented apoptosis. Our results indicated that the protective effect of S1P is mediated by activating the PI3K/Akt pathway. In addition, S1P promotion of EPCs proliferation was observed to be mainly mediated through S1PR3 and attenuation of EPCs apoptosis induced by H2 O2 was mainly mediated through S1PR1; both of these effects are mediated by activating the PI3K/Akt pathway, which provides potentially useful therapeutic targets for coronary artery disease, diabetes mellitus, and cancer treatment.

Sphingosine-1-Phosphate may Decrease the Cytotoxic Effect of Doxorubicin on Human Granulosa Cells

Context: The increase in malignancy of young women in the recent decades, combined with a significant improvement in long term survival after gonadotoxic chemotherapy, have brought about a ubiquitous interest in preservation of fertility in these young patients. The present study examines the effects of Sphingosine-1-Phosphate (S1P) on primary human granulosa cell cultures in-vitro as a possible protecting factor against Doxorubicin (DOX) and Cyclophosphamide associated toxicity. Understanding cytotoxic effects and gonadotoxicity in human luteinized Granulosa Cells (GC) may contribute to our understanding and preventing follicle loss. Study objective: To examine the possible protective effect of S1P on chemotherapy induced gonadotoxicity, in human luteinized Granulosa Cells (GCs). Design: Human GC’s were donated by women undergoing follicular aspiration for in vitro fertilization (IVF), after informed consent and institutional approval by ethics committee (IRB, Helsinki). The GCs were separated from RBC’s by centrifugation on ficoll and plated on multiwell plates for Lactate Dehydrogenase (LDH) assay, and on 6 well plates for flow cytometry. Each experiment was conducted in triplicates and repeated at least three times. Results: S1P significantly protected GCs against Doxorubicin (DOX) toxicity, but inconsistently against Cyclophosphamide. Conclusion: S1P may minimize the gonadotoxic effect of chemotherapy on human luteinized granulosa cells.

Sphingosine-1-phosphate inhibits H2O2-induced granulosa cell apoptosis via the PI3K/Akt signaling pathway

To investigate the protective effect of sphingosine-1-phosphate (S1P) against H(2)O(2)-induced apoptosis in human granulosa cell cultures with freshly harvested granulosa cells. Experimental study. Academic medical center for reproductive medicine. Cultures of primary granulosa cells isolated from women undergoing in vitro fertilization (IVF). None. Cell apoptosis and Western blot analysis of signaling pathway proteins. We found that S1P (1 and 10 mM) statistically significantly decreased granulosa cell apoptosis after H(2)O(2) treatment. The decreased cell apoptosis induced by S1P was abolished after treatment with VPC23019, an inhibitor of S1P1 and S1P3 receptors, W146, an inhibitor of S1P1 receptors, and CAY10444, an inhibitor of S1P3 receptors. A Western blot analysis revealed that the level of phospho-Akt increased and peaked at 10 minutes after 10 mM S1P exposure. Treatment with S1P can inhibit the apoptosis of granulosa cells in response to oxidative stress induced by H(2)O(2). The protective effect of S1P is mediated by activating the PI3K/Akt pathway, and the antiapoptotic effect of S1P is mainly mediated through the S1P1 and S1P3 receptor.

Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression

The enforcement of sphingosine-1-phosphate (S1P) signaling network protects from radiation-induced pneumonitis. We now demonstrate that, in contrast to early postirradiation period, late postirradiation sphingosine kinase-1 (SphK1) and sphingoid base-1-phosphates are associated with radiation-induced pulmonary fibrosis (RIF). Using the mouse model, we demonstrate that RIF is characterized by a marked upregulation of S1P and dihydrosphingosine-1-phosphate (DHS1P) levels in the lung tissue and in circulation accompanied by increased lung SphK1 expression and activity. Inhibition of sphingolipid de novo biosynthesis by targeting serine palmitoyltransferase (SPT) with myriocin reduced radiation-induced pulmonary inflammation and delayed the onset of RIF as evidenced by increased animal lifespan and decreased expression of markers of fibrogenesis, such as collagen and α-smooth muscle actin (α-SMA), in the lung. Long-term inhibition of SPT also decreased radiation-induced SphK activity in the lung and the levels of S1P-DHS1P in the lung tissue and in circulation. In vitro, inhibition or silencing of serine palmitoyltransferase attenuated transforming growth factor-β1 (TGF-β)-induced upregulation of α-SMA through the negative regulation of SphK1 expression in normal human lung fibroblasts. These data demonstrate a novel role for SPT in regulating TGF-β signaling and fibrogenesis that is linked to the regulation of SphK1 expression and S1P-DHS1P formation.

Sphingosine‐1‐phosphate reduces hepatic ischaemia/reperfusion‐induced acute kidney injury through attenuation of endothelial injury in mice

Hepatic ischaemia/reperfusion injury (IRI) frequently complicates acute kidney injury (AKI) during the perioperative period. This study was to determine whether hepatic IRI causes AKI and the effect of the sphingosine-1-phosphate (S1P) on AKI. S1P and vehicle were given to mice before ischaemia and mice were subjected to hepatic IRI. Plasma creatinine (PCr), alanine transaminase (ALT), urinary neutrophil gelatinase-associated lipocalin (NGAL) and renal histological changes were determined. As a marker of endothelial injury, vascular permeability was measured. The effect of VPC 23019, a S1P(1) receptor antagonist, was also assessed. Hepatic IRI resulted in liver injury (increased ALT) and systemic inflammation. Kidneys showed elevated inflammatory cytokines, leucocyte infiltration, increased vascular permeability, tubular cell apoptosis and increased urinary NGAL, although PCr did not increase. Pretreatment with S1P resulted in an attenuation of systemic inflammation and kidney injury without any effect on plasma ALT or peripheral lymphocytes. The protective effect of S1P was partially reversed by VPC 23019, suggesting the important contribution of the S1P/S1P(1) pathway to protect against hepatic IRI-induced AKI. The study data demonstrate the important contribution of systemic inflammation and endothelial injury to AKI following hepatic IRI. Modulation of the S1P/S1P(1) receptor pathway might have some therapeutic potential in hepatic IRI-induced kidney injury.

Protective effect of sphingosine 1‐phosphate (S1P) in the cerebral microvasculature

Introduction: Sphingosine 1‐phosphate (S1P), an endogenous phospholipid, is involved in pre‐conditioning responses in the heart. The present study evaluated whether exogenous S1P could have a similar protective role in the cerebral microvasculature following hypoxic insult.Methods: Human brain microvessel endothelial cells (HBMECs) were exposed to oxygen‐glucose deprivation (OGD) for 0–6 hours. Cell viability was assessed using MTT assay immediately after OGD or following a 24‐hr re‐oxygenation period. The effects of S1P on OGD‐mediated cell toxicity was determined by pre‐treating the cells with various concentrations of S1P (0–10 μM) for 0, 1, or 24 hours.Results: Exposure of HBMECs to OGD resulted in a significant decrease (approximately 20%) in cell viability when assessed immediately after OGD. Pre‐treating HBMEC cells with S1P for 1 hr prior to OGD provided a dose dependent protection, with 1.0 and 10 μM S1P completely reversing the loss in cell viability associated with OGD at all time points examined. However, the protective effects of S1P were not apparent in the 24‐hour pre‐treatment protocol.Conclusion: Activation of S1P receptors within the brain microvasculature prior to hypoxic events may help prevent toxicity to the cerebral microvasculature.Funding support provided by Canadian Institutes of Health Research and Manitoba Health Research Council.

Sphingosine 1-Phosphate Protects Human Umbilical Vein Endothelial Cells from Serum-deprived Apoptosis by Nitric Oxide Production

Sphingosine 1-phosphate (S1P) can prevent endothelial cell apoptosis. We investigated the molecular mechanisms and signaling pathways by which S1P protects endothelial cells from serum deprivation-induced apoptosis. We show here that human umbilical vein endothelial cells (HUVECs) undergo apoptosis associated with increased DEVDase activity, caspase-3 activation, cytochrome c release, and DNA fragmentation after 24 h of serum deprivation. These apoptotic markers were suppressed by the addition of S1P, the NO donor S-nitroso-N-acetylpenicillamine (100 micrometer), or caspase-3 inhibitor z-VAD-fmk. The protective effects of S1P were reversed by the nitric-oxide synthase (NOS) inhibitor N-monomethyl-l-arginine, but not by the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo[4,3-a]-quanoxaline-1-one, suggesting that NO, but not cGMP, is responsible for S1P protection from apoptosis. Furthermore, S1P increased NO production by enhancing Ca(2+)-sensitive NOS activity without changes in the eNOS protein level. S1P-mediated cell survival and NO production were suppressed significantly by pretreatment with antisense oligonucleotide of EDG-1 and partially by EDG-3 antisense. S1P-mediated NO production was suppressed by the addition of pertussis toxin, an inhibitor of G(i) proteins, the specific inhibitor of phospholipase C (PLC), and the Ca(2+) chelator BAPTA-AM. These findings indicate that S1P protects HUVECs from apoptosis through the activation of eNOS activity mainly through an EDG-1 and -3/G(i)/PLC/Ca(2+) signaling pathway.