ABSTRACT
Resumen Los esfingolípidos (esfingomielina, glucolípidos y gangliósidos) se localizan en las membranas celulares, el plasma y las lipoproteínas. En pacientes con enfermedades cardiovasculares, renales y metabólicas, el perfil de los esfingolípidos y sus metabolitos (ceramida, esfingosina y esfingosina-1-fosfato) se modifica, y estos cambios pueden explicar las alteraciones en algunas respuestas celulares, como la apoptosis. Además, se ha sugerido que la esfingosina y la esfingosina-1-fosfato previenen la COVID-19. En esta revisión también se mencionan brevemente las técnicas que permiten el estudio de los esfingolípidos y sus metabolitos.
Abstract Sphingolipids (sphingomyelin, glycolipids, gangliosides) are located in cell membranes, plasma, and lipoproteins. In patients with cardiovascular, renal, and metabolic diseases, the profile of sphingolipids and their metabolites (ceramide, sphingosine, and sphingosine-1-phosphate) is modified, and these changes may explain the alterations in some cellular responses such as apoptosis. Furthermore, sphingosine and sphingosine-1-phosphate have been suggested to prevent COVID-19. This review also briefly mentions the techniques that allow us to study sphingolipids and their metabolites.
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.
ABSTRACT
Sphingolipid metabolism is widely involved in the functional regulation of different cells, and also plays an important role in ocular tissues.Sphingosine 1-phosphate (S1P) is the end product of sphingolipid metabolism and has been shown to play an important role in the onset and development of eye diseases.S1P signaling pathway is widely expressed in various ocular cells and is involved in the regulation of cell proliferation, differentiation, migration and apoptosis.S1P activates a variety of signaling pathways by binding to corresponding receptors and thus plays a wide range of physiological and pathological effects in the eye.Recent studies have found that the S1P signaling pathway can not only mediate the normal development of blood vessels and nerves in the eye, maintain the normal structure of the ocular tissues, and participate in the metabolism of lipids in the eye, but also has a close relationship with immune-related inflammatory response, pathological fibrosis, destruction of cell functional barrier and other related pathological changes.This paper mainly reviewed the basic overview of the S1P signaling pathway, its physiological role in the eye, and its role in the pathological changes of anterior and posterior segment diseases, so as to provide new directions and targets for the treatment of eye diseases.
ABSTRACT
ObjectiveTo investigate the effects of hydroxycamptothecin liposomes （LHCPT） on myocardial fibrosis in rats with heart failure by regulating the sphingosine kinase 1 （SphK1）/sphingosine-1-phosphate （S1P） signaling pathway. MethodsSD rats were divided into control group， model group， hydroxycamptothecin （HCPT） group， LHCPT group， captopril group， and LHCPT+K6PC-5 （SphK1 activator） group， with 12 rats in each group. The heart failure rat models in all groups except the control group were established by intraperitoneal injection of doxorubicin and then the corresponding drugs were given once a day. After four weeks， we applied color Doppler ultrasound to detect left ventricular end systolic diameter （LVESD）， left ventricular end diastolic diameter （LVEDD）， and left ventricular ejection fraction （LVEF） in rats； HE and Masson staining for myocardial pathological damage and myocardial fibrosis in rats， respectively； ELISA method for the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in rat myocardial tissues； qRT-PCR for the expression of transforming growth factor-β1 （TGF-β1）， type I collagen （Collagen I）， and type Ⅲ collagen （Collagen Ⅲ） in rat myocardial tissues； Western blot for the expression of SphK1 and S1P proteins in rat myocardial tissues. ResultsCompared with the control group， the model group showed severe myocardial pathological damage and myocardial fibrosis， increased LVESD， LVEDD， levels of TNF-α and IL-6， expression of TGF-β1， Collagen I， Collagen Ⅲ， SphK1， S1P and decreased LVEF （P<0.05）. Compared with the model group， the HCPT group， LHCPT group and captopril group showed alleviated myocardial pathological damage and myocardial fibrosis， decreased LVESD， LVEDD， levels of TNF-α and IL-6， expression of TGF-β1， Collagen I， Collagen Ⅲ， SphK1， S1P and increased LVEF （P<0.05）. Compared with the LHCPT group， the LHCPT+K6PC-5 group showed aggravated myocardial pathological damage and myocardial fibrosis， increased LVESD， LVEDD， levels of TNF-α and IL-6， expression of TGF-β1， Collagen I， Collagen Ⅲ， SphK1， S1P and decreased LVEF （P<0.05）. ConclusionLHCPT may inhibit myocardial fibrosis in heart failure rats by inhibiting the SphK1/S1P signaling pathway.
ABSTRACT
Sphingosine kinase (SphK), sphingosine-1-phosphate (S1P) and S1P receptor (S1PR) are involved in the tumor biological processes such as tumor cell proliferation and migration, and play an important role in the development of cancer. In recent years, researchers have increasingly focused on the interaction between cancer cells and the tumor microenvironment. The tumor microenvironment is genetically stable and can be induced to an antitumor phenotype, which has significant therapeutic advantages. Studies have shown that SphK/S1P/S1PR can regulate multiple aspects of the tumor microenvironment. This review summarizes the effects of SphK and S1P/S1PR signaling on the tumor microenvironment from four perspectives: tumor immune microenvironment, cancer associated fibroblasts, tumor angiogenesis and tumor hypoxic microenvironment, and also outlines potential drug research related to these signal molecules, aiming to elucidate the role of SphK/S1P/S1PR in tumor occurrence and development and provide new ideas for the research of anti-tumor drugs.
ABSTRACT
This study assessed and explored the pharmacological effects and mechanisms of action of IMMH002 {2-amino-2-(2-(4ʹ-(2-ethyloxazol-4-yl)-[1,1ʹ-biphenyl]-4-yl)ethyl)propane-1,3-dio}, a selective sphingosine-1-phosphate receptor subtype 1 (S1P1) modulator, in a concanavalin A (ConA)-induced autoimmune hepatitis (AIH) mouse model. The experimental protocol strictly adhered to the guidelines of the Ethics Committee for Animal Research of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (Approval No.: 00004046). Male ICR mice were pre-treated with the drug for four days, followed by induction of AIH through tail vein injection of ConA protein. Liver function, hepatic tissue pathology, peripheral blood parameters, as well as immunoglobulin G (IgG), inflammatory cytokines, T cell distribution, and inflammatory pathways were evaluated in mice. Results demonstrated that IMMH002 significantly reduced liver function indicators such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated hepatic tissue inflammation and necrotic damage, decreased serum IgG levels, and lowered the expression of inflammatory mediators including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). Additionally, it facilitated T lymphocyte homing, downregulated the phosphorylation of nuclear factor kappa-B (NF-κB), IκB kinase β (IKKβ) and nuclear factor inhibitor protein-α (IκBα) proteins in hepatic tissue and cellular inflammation models. Collectively, IMMH002 effectively ameliorated ConA-induced autoimmune hepatitis in mice, exhibiting extensive anti-inflammatory and anti-necrotic effects, thereby laying a theoretical foundation for AIH clinical treatment.
ABSTRACT
ObjectiveTo investigate the value of the serum levels of Clusterin and sphingosine 1-phosphate （S1P） in assessing the prognosis of sepsis patients with acute liver injury. MethodsA total of 127 sepsis patients with acute liver injury who were admitted to Lianyungang Hospital， Xuzhou Medical University， from March 2019 to May 2022 were enrolled， and according to their prognosis after 28 days of treatment， they were divided into death group with 35 patients and survival group with 92 patients. The independent-samples t test was used for comparison of continuous data between two groups， and the chi-square test was used for comparison of categorical data between groups. A pearson correlation analysis was used to investigate the correlation. The prognostic value of serum Clusterin and S1P was analyzed by receiver operating characteristic curve. ResultsThere were significant differences between the two groups in the degree of liver injury， Acute Physiology and Chronic Health Evaluation Ⅱ （APACHEⅡ） score， Sequential Organ Failure Assessment （SOFA） score， the presence or absence of acute kidney injury， prothrombin time （PT）， international normalized ratio （INR）， Child-Pugh class， and C-reactive protein （all P<0.05）. The death group had significantly lower serum levels of Clusterin and S1P than the survival group （t=11.094 and 10.390， both P<0.05）. The patients with severe liver injury had significantly lower serum levels of Clusterin and S1P than those with mild or moderate liver injury （t=9.825 and 11.418， both P<0.05）. The multivariate regression analysis showed that the degree of liver injury （odds ratio ［OR］=1.260， 95% confidence interval ［CI］： 1.081 — 1.468， P<0.05）， APACHEII score （OR=1.031， 95%CI： 1.019 — 1.044， P<0.05）， SOFA score （OR=1.066， 95%CI： 1.039 — 1.094， P<0.05）， Clusterin （OR=0.899， 95%CI： 0.859 — 0.940， P<0.05）， and S1P （OR=0.824， 95%CI： 0.749 — 0.908， P<0.05） were independent risk factors for the prognosis of patients with sepsis. The ROC curve analysis showed that serum Clusterin and S1P used alone or in combination had an area under the ROC curve of 0.864， 0.861， and 0.949， respectively. Serum Clusterin and S1P were significantly negatively correlated with alanine aminotransferase， total bilirubin， PT， and INR in sepsis patients with acute liver injury （all P<0.05）. ConclusionThe sepsis patients with acute liver injury who died had significant reductions in serum Clusterin and S1P compared with those who survived， and the levels of Clusterin and S1P are closely associated with the degree of liver injury. The combination of Clusterin and S1P has a good value in predicting the prognosis of sepsis patients with acute liver injury and is expected to become a potential marker for predicting the prognosis of sepsis patients with acute liver injury.
ABSTRACT
Objective:To evaluate the role of sphingosine-1-phospho-1 receptor(S1PR1)in the dorsal root ganglion in remifentanil-induced hyperalgesia in rats with incisional pain.Methods:Forty-eight male Sprague-Dawley rats with successful intrathecal and caudal vein catheterization, weighing 260-280 g, aged 2-3 months, were divided into 6 groups ( n= 8 each) using a random number table method: control group (group C), S1PR1 antagonist (FTY720) group (group F), remifentanil group (group R), remifentanil + S1PR1 antagonist (FTY720) group (group R+ F), remifentanil + incisional pain group (group R+ I), and remifentanil + incisional pain + S1PR1 antagonist (FTY720) group (group R+ I+ F). In C group, normal saline 0.1 μg·kg -1·min -1 was intravenously infused for 60 min. In R group, remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In F group, FTY720 3 nmol was intrathecally injected, and 10 min later normal saline 1.0 μg· kg -1·min -1 was infused for 60 min via the caudal vein. In R+ F group, FTY720 3 nmol was intrathecally injected, and 10 min later remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In R+ I group, remifentanil 1.0 μg·kg -1·min -1 was infused for 60 min through the caudal vein while the model of incisional pain was developed. In R+ I+ F group, FTY720 3 nmol was intrathecally injected, 10 min later the incisional pain model was prepared, and remifentanil 1.0 μg·kg -1·min -1 was injected for 60 min through the caudal vein at the same time. The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 24 h before remifentanil or normal saline infusion (T 0) and 2, 6, 24 and 48 h after stopping remifentanil or normal saline infusion (T 1-4). Rats were sacrificed after the last measurement of pain threshold, and the L 4-6 segments of dorsal root ganglion were taken for determination of the expression of S1PR1, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), interleukin-1β (IL-1β) and glutamate transporter-1 (GLT-1) protein and mRNA (by Western blot and quantitative polymerase chain reaction). Results:Compared with C group, the MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and the expression of GLT-1 protein and mRNA in dorsal root ganglion was down-regulated in R group ( P<0.05), and no significant change was found in the parameters mentioned above in group F ( P>0.05). Compared with R group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and GLT-1 protein and mRNA expression in dorsal root ganglion was down-regulated in R+ I group, and MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and GLT-1 protein and mRNA expression in the dorsal root ganglion was up-regulated in R+ F group ( P<0.05). Compared with R+ I group, MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and the expression of GLT-1 protein and mRNA in the dorsal root ganglion was up-regulated in R+ I+ F group( P<0.05). Conclusions:The mechanism by which remifentanil induces hyperalgesia is associated with up-regulation of S1PR1 expression, activation of inflammatory factors, and down-regulation of GLT-1 expression in the rats with incisional pain.
ABSTRACT
Abstract The aim of this study was the quantification of Sphingosine-1-phosphate (S1P) in periodontal pockets of patients with periodontitis. This is an observational, descriptive, case-control study. Thirty subjects were selected: 15 controls and 15 cases. A periodontal study was conducted following the parameters of AAP 2017 for the diagnosis of periodontal diseases. A sample of saliva and gingival crevicular fluid was obtained from each subject and then analyzed with the Human S1P Elisa kit (MyBioSource #MBS2516132) accordingly to the manufacturer's instructions, in order to verify the presence of S1P and quantify it´s concentration when founded. Results showed a significant difference (p=0.05) between cases and controls. In the case of saliva samples, the concentration of S1P was higher than the ones found in the control group (72.94 ng/mL and 45.12 ng/mL). For GCF, a higher amount of S1P was found in patients with POD (20.09 ng/mL and 15.20 ng/mL). This work raises a possible route of bone metabolism, inflammatory process, and identification of periodontitis through oral quantification of S1P, however, future studies are needed.
Resumen El propósito de este estudio fue la cuantificación de Esfingosina-1-Fosfato (S1P) en las bolsas periodontales de pacientes con periodontitis. Estudio observacional, descriptivo de casos y controles. 30 sujetos fueron seleccionados de los cuales 15 controles y 15 casos. Se realizó un estudio periodontal completo siguiendo los parámetros establecidos por la AAP en 2017 para el diagnóstico de las enfermedades periodontales. Se tomaron muestras de saliva y de líquido crevicular gingival de cada sujeto estudiado y se analizaron con el ELISA kit humano para S1P (MyBiosource #MBS2516132) y de acuerdo con las instrucciones del fabricante, se realizó para cuantificar la presencia d S1P en las muestras estudiadas. Los resultados mostraron diferencia significativa (p=0.05) entre casos y controles. En el caso de las muestras de saliva, la concentración de S1P en controles fue mayor (72.94 ng/mL y 45.12 ng/mL). Para Líquido crevicular gingival, se encontró mayor cantidad de S1P en los pacientes con periodontitis (20.09 ng/mL y 15.20 ng/mL). Este estudio plantea una posible ruta de metabolismo óseo, proceso inflamatorio e identificación de la Periodontitis a través de la cuantificación oral de S1P, sin embargo se necesitan estudios futuros.
Subject(s)
Humans , Periodontitis , Sphingosine-1-Phosphate Receptors/analysisABSTRACT
The data of a child with sphingosine phosphate lyase insufficiency syndrome (SPLIS) admitted to Children′s Hospital of Hebei Province on February 4, 2020 were retrospectively analyzed.The child had edema, complicated with ichthyosis, adrenal calcification, and hearing loss from the early infancy.Laboratory examination results suggested a low albumin level, hypercholesterolemia, a high proteinuria level, abnormal liver and renal functions, and hyponatremia.The child gave up treatment and died at home.Whole Exome Sequencing (WES) results showed two hete-rozygous mutations of SGPL1 gene (chr10: 72604336, c.134G>A, p.W45X; chr10: 72629563, c.719G>T, p.S240I). SPLIS is inherited in an autosomal recessive manner.It starts in infancy, and affects the kidney, skin, endocrine, nervous and immune systems.It is suggested that SPLIS patients should take genetic examination.Early diagnosis, appropriate intervention, and vitamin B 6 treatment may relieve some symptoms of SPLIS patients.Adeno-associated virus mediated SGPL1 gene replacement therapy can be a novel cure of SPLIS and is worthy of investigation.
ABSTRACT
Sphingosine 1-phosphate (S1P) is a lipid mediator with biological activity, which is widely expressed in various tissues. Via combining with G-protein-coupled receptors (S1PR1-5) in different tissues, S1P can regulate Ras /MEK/ERK, PI3K/AKT, PLC/IP3, Rho/NF-κB and other signaling pathways and mediate various physiological and pathological reactions. The interaction of S1P and its receptors can affect the proliferation, migration and apoptosis of cells in airway and lung tissue, and it also plays an important role in inflammation and immune regulation. S1P mediates the pathogenic process of diseases such as asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary fibrosis, pulmonary infection and acute lung injury, while antagonizing S1P could relieve symptoms and delay the development of these diseases. Further study of S1P may provide a new therapeutic target for respiratory diseases.
ABSTRACT
@#Introduction: Prevention of osteoporotic fracture requires identification of individuals at high risk. Bone mineral density(BMD) is commonly used to estimate fracture probability despite inadequate predictive discrimination ability. Sphingosine-1-phosphate(S1P), a new marker of bone metabolism and bone turnover markers(BTM) such as procollagen-type-1 amino-terminal propeptide(P1NP) and C-terminal telopeptide of type I collagen(CTX) may complement current assessment. The study determined P1NP, CTX and S1P levels and their correlation with BMD, 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone(PTH) in selected subjects. Method: A cross-sectional study involving Malaysian Chinese men and women aged 50-90 years old from Puchong and Kajang, Selangor. Each subject had BMD determined by dual-energy x-ray absorptiometry and blood samples taken for 25(OH)D, PTH, P1NP, CTX and S1P. Results: A total of 131 subjects [45(34.4%) males and 86(65.6%) post-menopausal women] with median age of 65(IQR=17) were recruited. P1NP and CTX were significantly higher in post-menopausal women (P1NP=61.71 ng/ml, CTX=0.489 ng/ml) compared to men (P1NP=46.94 ng/ml, CTX=0.381 ng/ml). P1NP and CTX differed significantly according to BMD categories with values highest in osteoporosis. S1P between men (2.12±0.75 µmol/L) and post-menopausal women (1.96±0.68 µmol/L) did not differ significantly and did not differ according to BMD categories. S1P did not correlate with BMD, P1NP, CTX and 25(OH)D. P1NP and CTX negatively correlated with BMD at all measured sites but not 25(OH)D. Conclusion: CTX and P1NP, but not S1P negatively correlated with BMD. CTX and P1NP were highest in those with osteoporosis. In this group of Malaysian Chinese subjects, CTX and P1NP rather than S1P reflects bone health.
ABSTRACT
The alveolar capillary endothelial barrier is mainly composed of alveolar capillary endothelial cells and alveolar epithelial cells. The destruction of this barrier and the continuous infiltration of inflammatory cells have been considered to play an important role in the development of chronic obstructive pulmonary disease, acute lung injury, and idiopathic pulmonary fibrosis. Therefore, it is of great significance to understand the mechanism of alveolar capillary endothelial barrier regulation. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite produced by sphingosine kinase. A large number of studies have shown that S1P not only regulates immune cell transport, but also plays important roles in regulating cell apoptosis, vascular endothelial barrier, and alveolar epithelial barrier. S1P exerts different regulatory effects on alveolar capillary endothelial barrier by activating S1P1 and S1P3. Activation of S1P1 on the alveolar capillary endothelial cells by S1P mediates barrier protection, while the barrier can be broken when S1P3 is stimulated by S1P. S1P can also regulate alveolar epithelial barrier. By activating S1P3 on the alveolar epithelial cells, S1P leads to epithelial barrier damage, which makes interstitial proteins and body fluids infiltrate into alveolar space and causes pulmonary edema. Therefore, it may be a target for the treatment of lots of lung diseases by regulating the homeostasis of alveolar capillary endothelial barrier. This paper reviews the research advancement of S1P in alveolar capillary endothelial barrier regulation.
ABSTRACT
Cardiomyopathy is the leading cause of mortality worldwide. While the causes of cardiomyopathy continue to be elucidated, current evidence suggests that aberrant bioactive lipid signaling plays a crucial role as a component of cardiac pathophysiology. Sphingolipids have been implicated in the pathophysiology of cardiovascular disease, as they regulate numerous cellular processes that occur in primary and secondary cardiomyopathies. Experimental evidence gathered over the last few decades from both in vitro and in vivo model systems indicates that inhibitors of sphingolipid synthesis attenuate a variety of cardiomyopathic symptoms. In this review, we focus on various cardiomyopathies in which sphingolipids have been implicated and the potential therapeutic benefits that could be gained by targeting sphingolipid metabolism.
Subject(s)
Cardiomyopathies , Cardiovascular Diseases , Ceramides , In Vitro Techniques , Metabolism , Mortality , Myocytes, Cardiac , Pathology , Receptors, Lysosphingolipid , SphingolipidsABSTRACT
Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tuberculosis) infection remains a major public health problem of global concern, largely due to antibiotics resistance, persistence and immune evasion. Sphingolipid bioactive molecules are involved in several important pathophysiological processes. Sphingosine-1-phosphate is a key product of sphingolipid metabolism, and can play a role in two manners: autocrine and/or paracrine. Sphingosine-1-phosphate regulates T cells and a variety of antigen-presenting cells during M. tuberculosis infection, promotes antigen processing and expression in monocytes, is involved in the maturation of phagolysosome, regulates Ca2+ homeostasis, participates in the autophagy of macrophages, inhibits the survival and proliferation of M. tuberculosis within host cells, and effectively reduces the necrosis of the mouse lungs infected by M. tuberculosis. Injection of 20 nmol per mouse sphingosine-1-phosphate inhibited up to 47% of mycobacterial growth in the lung and spleen of mice infected by M. tuberculosis. In this paper, sphingosine-1-phosphate, its receptors and regulatory network were reviewed, and the specific mechanism of sphingosine-1-phosphate inhibiting the survival of M. tuberculosis-infected host cells was elaborated. This will provide novel insights into the new targets for tuberculosis prevention and treatment.
ABSTRACT
Objective To evaluate therapeutic effect of the sphingosine-1-phosphate receptor antagonist FTY720 on the imiquimod-induced psoriasis-like mouse model,and to explore its molecular mechanism.Methods A total of 8 specific pathogen-free (SPF) female C57BL/6 mice were used in this study,and divided into experimental group (n =3) and control group(n =5):each mouse ear was topically treated with 10 mg/d imiquimod for 7 consecutive days,and the experimental group and control group were intraperitoneally injected with FTY720 and phosphate buffer saline (PBS) respectively on days 2,4 and 6.Ear skin thickness was measured every day.These mice were sacrificed on day 8,and histopathological changes of the ear skin were observed.The ear tissues and draining cervical lymph node cells were obtained.Flow cytometry was performed to analyze changes in the proportion of interleukin (IL)-17+ γδT cells in the mouse skin and draining lymph node tissues between the two above groups,and to determine the expression of sphingosine-1-phosphate receptor 1 (S 1P 1) and cutaneous lymphocyte antigen (CLA) on the surface of the γδT cells.The means of two independent samples were compared by using t test.Results After the 2-day topical application of imiquimod,the mouse ear thickness was significantly lower in the experimental group (0.217 mm± 0.003 mm) than in the control group (0.232 mm ± 0.002 mm,t =4.23,P ＜ 0.01) on day 3,and the significant difference existed till day 8 (all P ＜ 0.01).Histopathological examination of the ear skin revealed that the epidermal thickness was significantly lower in the experimental group (18.62 μm ± 0.19 μm) than in the control group (27.79 μm ± 1.58 μm,t =4.35,P ＜ 0.01).Immunofluorescence staining showed that the degree of neutrophil infiltration in the mouse ear tissue was lower in the experimental group than in the control group.As flow cytometry showed,the proportion of neutrophils was significantly lower in the experimental group (1.57％ ± 0.12％) than in the control group (3.03％ ± 0.33％,t =3.31,P =0.016).In the ear tissues,the experimental group showed significantly decreased proportion of γδT cells or IL-17+ γδT cells (4.88％ ± 0.42％,40.53％ ± 1.76％ respectively) compared with the control group (9.45％ ± 1.22％,56.56％ ± 0.66％ respectively;t =2.75,10.27 respectively,both P ＜ 0.05).In the draining lymph nodes,the experimental group showed significantly increased proportion of γδT cells or IL-17+ γδT cells compared with the control group (t =5.781,4.140 respectively,both P ＜ 0.05),and the fluorescence intensity of S1P1 and CLA in the γδT cells was significantly lower in the experimental group than in the control group (P ＜ 0.05).Conclusion FTY720 can alleviate imiquimod-induced psoriasis-like manifestations in mouse models,likely by down-regulating the expression of S1P1 and CLA in γδT cells,increasing the proportion of γδT cells in the draining lymph nodes followed by the decrease of their proportion in the skin,and decreasing the production of IL-17 in skin tissues.
ABSTRACT
Objective@#To investigate the expression of LIM domain binding 2 (LDB2) in lung cancer tissues and its correlation with sphingosine-1 phosphate receptor 1 (S1PR1). @*Methods@#Lung cancer tissues and the corresponding adjacent tissues from 52 patients in Nantong Tumor Hospital during April 2010 and May 2011 were collected as the experimental group and the control group, respectively. The expression levels of LDB2 and S1PR1 were detected by the real-time PCR (qRT-PCR). The expression results of LDB2 gene were further verified by the Oncomine database, and its correlations with clinicopathological parameters were analyzed. The ROC curve was drawn to evaluate the diagnosis value of LDB2 expression in lung cancer. The correlation of LDB2 expression with the prognosis of lung cancer was analyzed by the “Kaplan-Meier Plotter” database. In addition, the relationship between LDB2 and S1PR1 was also analyzed. @*Results@#The expression levels of LDB2 in lung cancer tissues (0.158 [0.062,0.383]) were significantly lower than that in the adjacent tissues (0.403 [0.261,0.711], U=700.0, P＜ 0.01). A total of 9 eligible studies were retrieved from the Oncomine database, and their expressions of LDB2 were also low (P＜0.01). The expressions of LDB2 in lung cancer tissues were not related to gender, age, smoking history, pathological type, tumor size, TNM staging and lymphatic metastasis (P＞0.05). The results of ROC curve showed that when the area under the ROC curve (AUC ROC ) was 0.741 (95% CI:0.643-0.839) and the cut-off value was 0.247, the sensitivity and specificity of LDB2 in the diagnosis of lung cancer were 80.8% and 61.5%, respectively. The Kaplan-Meier survival analysis showed that the 5-year overall survival time of the patients with low expression of LDB2 was shorter than that of the patients with high expression of LDB2(P＜0.01). In addition, the expression levels of S1PR1 in lung cancer tissues (0.710[0.337,1.523]) were significantly lower than that in the adjacent tissues (1.582[0.913,3.533],U=780.0, P＜0.01), and the expression levels of S1PR1 in lung cancer tissues were positively correlated with that of LDB2(r=0.827,P＜0.01). @*Conclusion@#The expressions of LDB2 and S1PR1 in lung cancer tissues are down-regulated, and have a positive correlation, and they may play an important role in the occurrence and development of lung cancer.
ABSTRACT
Sphingosine 1-phosphate(SIP) is an important signal molecule produced by the metabolism of cell membrane sphingomyelin. SIP can be transported to the extracellular domain, and plays a role in activating a series of downstream signals, such as Ras/RafyERK, PI3K/AKT, by acting on SIP receptors. It can also act as a second messenger directly on intracellular targets such as HDAC, TRAF2. Its mediated signaling pathway plays a role in many physiological and pathological processes such as cell proliferation and migration, inflammatory cytokine infiltra tion, angiogenesis and autoimmunity. This article explores the role of SIP and its signaling pathways in inflammation-related diseases from the extracellular and intracellular roles of SIP, and reviews the research progress of SI P signaling pathway related drugs.
ABSTRACT
Ischemic stroke is one of the most important causes of death and disability in humans,but the effective methods for treating brain injury after stroke are quite limited.Sphingosine 1-phosphate (S1P) is a pleiotropic lipid.There is certain interdependence between its metabolism and regulation and the molecular mechanisms involved in important biological events following cerebral ischemia.Membrane lipid therapy with S1P as the core may be an effective neuroprotective strategy of ischemic stroke.
ABSTRACT
Sphingosine 1-phosphate (S1P) levels are often found to be elevated in serum, bronchoalveolar lavage, and lung tissue of idiopathic pulmonary fibrosis patients and experimental mouse models. Although the roles of sphingosine kinase 1 and S1P receptors have been implicated in fibrosis, the underlying mechanism of fibrosis via Sphingosine 1-phosphate receptor 2 (S1P₂) has not been fully investigated. Therefore, in this study, the roles of S1P₂ in lung inflammation and fibrosis was investigated by means of a bleomycin-induced lung fibrosis model and lung epithelial cells. Bleomycin was found to induce lung inflammation on day 7 and fibrosis on day 28 of treatment. On the 7(th) day after bleomycin administration, S1P₂ deficient mice exhibited significantly less pulmonary inflammation, including cell infiltration and pro-inflammatory cytokine induction, than the wild type mice. On the 28(th) day after bleomycin treatment, severe inflammation and fibrosis were observed in lung tissues from wild type mice, while lung tissues from S1P₂ deficient mice showed less inflammation and fibrosis. Increase in TGF-β1-induced extracellular matrix accumulation and epithelial-mesenchymal transition were inhibited by JTE-013, a S1P₂ antagonist, in A549 lung epithelial cells. Taken together, pro-inflammatory and pro-fibrotic functions of S1P₂ were elucidated using a bleomycin-induced fibrosis model. Notably, S1P₂ was found to mediate epithelial-mesenchymal transition in fibrotic responses. Therefore, the results of this study indicate that S1P₂ could be a promising therapeutic target for the treatment of pulmonary fibrosis.