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白藜芦醇通过调控microRNA-506/sphingosine kinase 1抑制非小细胞肺癌细胞的增殖及促进其凋亡 被引量:3
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作者 黎展华 周继红(指导) +6 位作者 陈斯宁 潘玲 冯原 罗美群 李瑞祥 王浩舟 刘剑 《中国免疫学杂志》 CAS CSCD 北大核心 2021年第4期443-447,453,共6页
目的:探讨白藜芦醇对A549细胞增殖、细胞周期及凋亡的影响及机制。方法:实验分为空白对照组、白藜芦醇干预组,miR-506-inhibitor组及白藜芦醇干预miR-506-inhibitor组。CCK-8法检测A549细胞增殖;流式细胞术检测A549的细胞周期及凋亡;qRT... 目的:探讨白藜芦醇对A549细胞增殖、细胞周期及凋亡的影响及机制。方法:实验分为空白对照组、白藜芦醇干预组,miR-506-inhibitor组及白藜芦醇干预miR-506-inhibitor组。CCK-8法检测A549细胞增殖;流式细胞术检测A549的细胞周期及凋亡;qRT-PCR检测miR-506表达及SPHK1的mRNA表达;Western blot法检测SPHK1的蛋白表达。结果:白藜芦醇抑制A549细胞的增殖,使G0-G1期的细胞数量增加,S期的细胞数量减少并且诱导A549细胞的凋亡。白藜芦醇上调miR-506的表达及下调SPHK1的表达。结论:白藜芦醇通过调控miR-506/SPHK1轴从而抑制A549细胞的增殖并且诱导其凋亡。 展开更多
关键词 非小细胞肺癌 A549细胞 白藜芦醇 microRNA-506 鞘磷脂蛋白激酶1
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Inhibition of sphingosine kinase 1 ameliorates acute liver failure by reducing high-mobility group box 1 cytoplasmic translocation in liver cells 被引量:6
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作者 Yan-Chang Lei Ling-Ling Yang +2 位作者 Wen Li Pan Luo Pei-Fen Zheng 《World Journal of Gastroenterology》 SCIE CAS 2015年第46期13055-13063,共9页
AIM: To determine the therapeutic potential of sphingosine kinase 1(Sphk1) inhibition and its underlying mechanism in a well-characterized mouse model of D-galactosamine(D-Gal N)/lipopolysaccharide(LPS)-induced acute ... AIM: To determine the therapeutic potential of sphingosine kinase 1(Sphk1) inhibition and its underlying mechanism in a well-characterized mouse model of D-galactosamine(D-Gal N)/lipopolysaccharide(LPS)-induced acute liver failure(ALF).METHODS: Balb/c mice were randomly assigned to different groups,with ALF induced by intraperitoneal injection of D-Ga IN(600 mg/kg) and LPS(10 μg/kg). The Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels at different time points within one week were determined using a multi-parametric analyzer. Serum high-mobility group box 1(HMGB1),tumor necrosis factor-α(TNF-α),interleukin(IL)-1β,IL-6,IL-10,and sphingosine-1-phosphate were detected by enzyme-linked immunosorbent assay. Hepatic morphological changes at 36 h after acute liver injury induction were assessed by hematoxylin and eosin staining. HMGB1 expression in hepatocytes and cytoplasmic translocation were detected by immunohistochemistry. Expression of Sphk1 in liver tissue and peripheral blood mononuclear cells(PBMCs) was analyzed by Western blot.RESULTS: The expression of Sphk1 in liver tissue and PBMCs was upregulated in Gal N/LPS-induced ALF. Upregulated Sphk1 expression in liver tissue was mainly caused by Kupffer cells,the resident macrophages of the liver. The survival rates of mice in the N,Ndimethylsphingosine(DMS,a specific inhibitor of Sph K1) treatment group were significantly higher than that of the control group(P < 0.001). DMS treatment significantly decreased the levels of serum ALT and AST at 6,12,and 24 h compared with that of the control group(P < 0.01 for all). Serum HMGB1 levels at 6,12,and 24 h,as well as serum TNF-α,IL-6,and IL-1β levels at 12 h,were significantly lower in the DMS treatment group than in the control group(P < 0.01 for all). Furthermore,hepatic inflammation,necrosis,and HMGB1 cytoplasm translocation in liver cells were significantly decreased in the DMS treatment group compared to the control group(43.72% ± 5.51% vs 3.57% ± 0.83%,χ2 = 12.81,P < 0.01).CONCLUSION: Inhibition of Sph K1 ameliorates ALF by reducing HMGB1 cytoplasmic translocation in liver cells,and so might be a potential therapeutic strategy for this disease. 展开更多
关键词 Acute liver failure sphingosine kinase 1 High-mobi
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Sphingosine kinase 1 is upregulated with lysophosphatidic acid receptor 2 in human colorectal cancer 被引量:6
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作者 Dai Shida Satoru Inoue +3 位作者 Yuki Yoshida Atsushi Kodaka Tsutomu Tsuji Makoto Tsuiji 《World Journal of Gastroenterology》 SCIE CAS 2016年第8期2503-2511,共9页
AIM: To examine the expression of SphK1, an oncogenic kinase that produces sphingosine 1-phosphate (S1P), and its correlation with the expression of LPAR2, a major lysophosphatidic acid (LPA) receptor overexpressed in... AIM: To examine the expression of SphK1, an oncogenic kinase that produces sphingosine 1-phosphate (S1P), and its correlation with the expression of LPAR2, a major lysophosphatidic acid (LPA) receptor overexpressed in various cancers, in human colorectal cancer.METHODS: Real-time reverse-transcription polymerase chain reaction was used to measure the mRNA expression of SphK1, LPAR2, and the three major S1P receptors in 27 colorectal cancer samples and corresponding normal tissue samples. We also examined the correlation between the expression of SphK1 and LPAR2.RESULTS: Colorectal cancer tissue in 22 of 27 patients had higher levels of SphK1 mRNA than in normal tissue. In two-thirds of the samples, SphK1 mRNA expression was more than two-fold higher than in normal tissue. Consistent with previous reports, LPAR2 mRNA expression in 20 of 27 colorectal cancer tissue samples was higher compared to normal tissue samples. Expression profiles of all three major S1P receptors, S1PR1, S1PR2, and S1PR3, varied without any trend, with no significant difference in expression between cancer and normal tissues. A highly significant positive correlation was found between SphK1 and LPAR2 expression [Pearson&#x02019;s correlation coefficient (r) = 0.784 and P &#x0003c; 0.01]. The mRNA levels of SphK1 and LPAR2 did not correlate with TNM stage.CONCLUSION: Our findings suggest that S1P and LPA may play important roles in the development of colorectal cancer via the upregulation of SphK1 and LPAR2, both of which could serve as new therapeutic targets in the treatment of colorectal cancer. 展开更多
关键词 sphingosine kinase 1 Lysophosphatidic acid receptor 2 CARCINOGENESIS Colorectal cancer sphingosine 1-phosphate
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Sphingosine kinase 1 knockout alleviates hepatic ischemia/reperfusion injury by attenuating inflammation and oxidative stress in mice 被引量:4
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作者 Guang-Hui Qiang Zhong-Xia Wang +5 位作者 An-Lai Ji Jun-Yi Wu Yin Cao Guang Zhang Yi-Yang Zhang Chun-Ping Jiang 《Hepatobiliary & Pancreatic Diseases International》 SCIE CAS CSCD 2019年第3期255-265,共11页
Background: Hepatic ischemia/reperfusion(I/R) injury remains a significant problem in clinical practice. Sphingosine kinase 1(Sph K1) phosphorylates sphingosine to sphingosine-1-phosphate(S1 P) which participates in m... Background: Hepatic ischemia/reperfusion(I/R) injury remains a significant problem in clinical practice. Sphingosine kinase 1(Sph K1) phosphorylates sphingosine to sphingosine-1-phosphate(S1 P) which participates in multiple bioactive processes. However, little is known about the role of Sph K1 in hepatic I/R injury. This study aimed to investigate the effect of Sph K1 knockout on liver I/R injury and to explore underlying mechanisms. Methods: Sph K1 knockout and wild type mice were subjected to 70% partial hepatic I/R. Serum alanine aminotransferase was determined to indicate the degree of liver damage. Hematoxylin-eosin staining and TUNEL assay were used to assess histological changes and hepatocellular apoptosis, respectively. Immunohistochemistry was performed to detect the expression and translocation of phosphorylated p65 and signal transducer and activator of transcription 3(STAT3). Western blotting was used to determine the expression of S1 P receptor 1(S1 PR1), phosphorylated p65 and STAT3. Real-time PCR was used to demonstrate the changes of proinflammatory cytokines. Oxidative stress markers were also determined through biochemical assays. Results: Sph K1 knockout significantly ameliorated I/R-induced liver damage, mitigated liver tissue necrosis and apoptosis compared with wild type control. I/R associated inflammation was alleviated in Sph K1 knockout mice as demonstrated by attenuated expression of S1 PR1 and reduced phosphorylation of nuclear factor kappa B p65 and STAT3. The proinflammatory cytokines interleukin-1 β, interleukin-6 and tumor necrosis factor-α were also inhibited by Sph K1 genetic deletion. The oxidative stress markers were lower in Sph K1 knockout mice after I/R injury than wild type mice. Conclusions: Knockout of Sph K1 significantly alleviated damage after hepatic I/R injury, possibly through inhibiting inflammation and oxidative stress. Sph K1 may be a novel and potent target in clinical practice in I/R-related liver injury. 展开更多
关键词 ISCHEMIA/REPERFUSION injury sphingosine kinase 1 INFLAMMATION Oxidative stress
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KAI1 inhibits HGF-induced invasion of pancreatic cancer by sphingosine kinase activity 被引量:10
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作者 Xu Liu,Xiao-Zhong Guo,Wei-Wei Zhang,Zhuo-Zhuang Lu,Qun-Wei Zhang, Hai-Feng Duan and Li-Sheng Wang State Key Laboratory of Cancer Biology and Institute of Digestive Diseases,Xijing Hospital of Digestive Disease,Fourth Military Medical University,Xi’an 710032,China Department of Gastroenterology,Shenyang General Hospital of PLA,Shenyang 110016, China Department of Experimental Hematology,Beijing Institute of Radiation Medicine,Beijing 100850,China 《Hepatobiliary & Pancreatic Diseases International》 SCIE CAS 2011年第2期201-208,共8页
BACKGROUND:KAI1/CD82 has been reported to attenuate the process of metastases in a variety of tumors;however,its mechanism of action in invasion has not been fully elucidated. The present study aimed to investigate th... BACKGROUND:KAI1/CD82 has been reported to attenuate the process of metastases in a variety of tumors;however,its mechanism of action in invasion has not been fully elucidated. The present study aimed to investigate the importance of KAI1 in invasion and its correlation with activation of sphingosine kinase(SPK)in human pancreatic cancer PANC1 and Miapaca-2 cell lines. METHODS:The expression of KAI1 in PANC1 and Miapaca-2 cells,which was mediated by recombinant adenovirus(Ad-KAI1), was assessed by a flow cytometer and Western blotting.After successful infection was established,in vitro growth curve and invasive ability in Boyden Chamber assay were studied.The presence of KAI1 correlating with c-Met and SPK was detected by co-immunoprecipitation and[γ-32P]ATP incorporation. RESULTS:KAI1 genes had no significant effects on the curve representing cell growth.After infection with the KAI1 gene,decreased invasive ability in the Boyden Chamber assay was observed in PANC1 and Miapaca-2 cells that were induced by hepatocyte growth factor.Over-expression of KAI1 in the cells led to the deactivation of SPK and a decreased level of intracellular sphingosine-1-phosphate.No correlation was observed between c-Met and KAI1 during co-immunoprecipitation. CONCLUSION:The results of this study for the first time demonstrated a regulatory role for KAI1 in SPK activation, which leads to decreased invasive ability in disease progression of human pancreatic cancer. 展开更多
关键词 adenovirus vector KAI1 gene sphingosine kinase pancreatic cancer cell lines
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Role of sphingosine kinase and sphingosine-1-phosphate in inflammatory arthritis 被引量:3
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作者 Alirio J Melendez Bernard P Leung 《World Journal of Biological Chemistry》 CAS 2010年第11期321-326,共6页
The importance of sphingosine kinase(SphK)and sphingosine-1-phosphate(S1P)in inflammation has been extensively demonstrated.As an intracellular second messenger,S1P plays an important role in calcium signaling and mob... The importance of sphingosine kinase(SphK)and sphingosine-1-phosphate(S1P)in inflammation has been extensively demonstrated.As an intracellular second messenger,S1P plays an important role in calcium signaling and mobilization,and cell proliferation and survival.Activation of various plasma membrane receptors,such as the formyl methionyl leucyl phenylalanine receptor,C5a receptor,and tumor necrosis factor α receptor,leads to a rapid increase in intracellular S1P level via SphK stimulation.SphK and S1P are implicated in various chronic autoimmune conditions such as rheumatoid arthritis, primary Sjgren's syndrome,and inflammatory bowel disease.Recent studies have demonstrated the important role of SphK and S1P in the development of arthritis by regulating the pro-inflammatory responses.These novel pathways represent exciting potential therapeutic targets. 展开更多
关键词 CYTOKINES Inflammation RHEUMATOID ARTHRITIS sphingosine kinase sphingosine-1-phosphate
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Regulatory role of sphingosine kinase and sphingosine-1-phosphate receptor signaling in progenitor/stem cells 被引量:2
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作者 Mei Li Ng Nagendra S Yarla +1 位作者 Mario Menschikowski Olga A Sukocheva 《World Journal of Stem Cells》 SCIE CAS 2018年第9期119-133,共15页
Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in n... Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in normal and disease-affected tissues. Particularly, sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) operate as mediators and facilitators of proliferation-linked signaling. Unlimited proliferation (selfrenewal) within the regulated environment is a hallmark of progenitor/stem cells that was recently associated with the S1P signaling network in vasculature, nervous,muscular, and immune systems. S1P was shown to regulate progenitor-related characteristics in normal and cancerstemcells(CSCs) viaG-protein coupled receptorsS1Pn(n=1 to 5). The SphK/S1P axis is crucially involved in the regulation of embryonic development of vasculature and the nervous system, hematopoietic stem cell migration, regeneration of skeletal muscle, and development of multiple sclerosis. The ratio of the S1P receptor expression, localization, and specific S1P receptoractivated downstream effectors influenced the rate of selfrenewal and should be further explored as regeneration related targets. Considering malignant transformation,it is essential to control the level of self-renewal capacity.Proliferation of the progenitor cell should be synchronized with differentiation to provide healthy lifelong function of blood, immune systems, and replacement of damaged ordead cells. The differentiation-related role of SphK/S1P remains poorly assessed. A few pioneering investigations exploredpharmacologicaltoolsthattargetsphingolipid signaling and can potentially confine and direct self-renewal towards normal differentiation. Further investigation is required to test the role of the SphK/S1P axis in regulation of self-renewal and differentiation. 展开更多
关键词 sphingosine-1-phosphate SPHINGOLIPIDS Embryonic STEM CELLS Mesenchymal STEM CELLS Bone marrow hematopoietic STEM CELLS sphingosine kinase PROGENITOR
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Sphingosine kinase 1 dependent protein kinase C-δ activation plays an important role in acute liver failure in mice 被引量:1
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作者 Yan-Chang Lei Ling-Ling Yang +1 位作者 Wen Li Pan Luo 《World Journal of Gastroenterology》 SCIE CAS 2015年第48期13438-13446,共9页
AIM: To investigate the role of protein kinase C(PKC)-δ activation in the pathogenesis of acute liver failure(ALF) in a well-characterized mouse model of D-galactosamine(D-Gal N)/lipopolysaccharide(LPS)-induced ALF.M... AIM: To investigate the role of protein kinase C(PKC)-δ activation in the pathogenesis of acute liver failure(ALF) in a well-characterized mouse model of D-galactosamine(D-Gal N)/lipopolysaccharide(LPS)-induced ALF.METHODS: BALB/c mice were randomly assigned to five groups, and ALF was induced in mice by intraperitoneal injection of D-Ga IN(600 mg/kg) and LPS(10 μg/kg). Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels at different time points within one week were determined using a multiparameteric analyzer. Serum levels of high-mobility group box 1(HMGB1), tumor necrosis factor(TNF)-α, interleukin(IL)-1β, IL-6, and IL-10 as well as nuclear factor(NF)-κB activity were determined by enzyme-linked immunosorbent assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of PKC-δ in liver tissue and peripheral blood mononuclear cells(PBMCs) was analyzed by Western blot.RESULTS: The expression and activation of PKC-δ were up-regulated in liver tissue and PBMCs of mice with D-Gal N/LPS-induced ALF. Inhibition of PKC-δ activation with rottlerin significantly increased the survival rates and decreased serum ALT/AST levels at 6, 12 and 24 h compared with the control group(P < 0.001). Rottlerin treatment also significantly decreased serum levels of HMGB1 at 6, 12, and 24 h, TNF-α, IL-6 and IL-1 β at 12 h compared with the control group(P < 0.01). The inflammatory cell infiltration and necrosis in liver tissue were also decreased in the rottlerin treatment group. Furthermore, sphingosine kinase 1(Sph K1) dependent PKC-δ activation played an important role in promoting NF-κB activation and inflammatory cytokine production in ALF.CONCLUSION: Sph K1 dependent PKC-δ activation plays an important role in promoting NF-κB activation and inflammatory response in ALF, and inhibition of PKC-δ activation might be a potential therapeutic strategy for this disease. 展开更多
关键词 ACUTE liver failure Protein kinase C-δ sphingosine kinase 1 NUCLEAR factor-κB
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Sphingosine-1-Phosphate Protects Against the Development of Cardiac Remodeling via Sphingosine Kinase 2 and the S1PR2/ERK Pathway
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作者 Hui YAN Hu ZHAO +4 位作者 Shao-wei YI Hang ZHUANG Dao-wen WANG Jian-gang JIANG Gui-fen SHEN 《Current Medical Science》 SCIE CAS 2022年第4期702-710,共9页
Objective:Cardiac remodeling is a common pathological change in various cardiovascular diseases and can ultimately result in heart failure.Thus,there is an urgent need for more effective strategies to aid in cardiac p... Objective:Cardiac remodeling is a common pathological change in various cardiovascular diseases and can ultimately result in heart failure.Thus,there is an urgent need for more effective strategies to aid in cardiac protection.Our previous work found that sphingosine-1-phosphate(S1P)could ameliorate cardiac hypertrophy.In this study,we aimed to investigate whether S1P could prevent cardiac fibrosis and the associated mechanisms in cardiac remodeling.Methods:Eight-week-old male C57BL/6 mice were randomly divided into a sham,transverse aortic constriction(TAC)or a TAC+S1P treatment group.Results:We found that S1P treatment improved cardiac function in TAC mice and that the cardiac fibrosis ratio in the TAC+S1P group was significantly lower and was accompanied by a decrease inα-smooth muscle actin(α-SMA)and collagen type I(COL I)expression compared with the TAC group.We also found that one of the key S1P enzymes,sphingosine kinase 2(SphK2),which was mainly distributed in cytoblasts,was downregulated in the cardiac remodeling case and recovered after S1P treatment in vivo and in vitro.In addition,our in vitro results showed that S1P treatment activated extracellular regulated protein kinases(ERK)phosphorylation mainly through the S1P receptor 2(S1PR2)and spurred p-ERK transposition from the cytoplasm to cytoblast in H9c2 cells exposed to phenylephrine.Conclusion:These findings suggest that SphK2 and the S1PR2/ERK pathway may participate in the anti-remodeling effect of S1P on the heart.This work therefore uncovers a novel potential therapy for the prevention of cardiac remodeling. 展开更多
关键词 sphingosine-l-phosphate cardiac remodeling sphingosine kinase 2 sphingosine-1-phosphate receptor extracellular regulated protein kinase
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Role of sphingosine kinases and sphingosine 1-phosphate in mediating adipogenesis
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作者 Lucy D. Mastrandrea 《Journal of Diabetes Mellitus》 2013年第2期52-61,共10页
Recent Background: Development of obesity involves promotion of preadipocyte differrentiation. This study investigated the role that sphingosine kinases (SPHK) and ceramide-derived sphingosine 1-phosphate (S1P) play i... Recent Background: Development of obesity involves promotion of preadipocyte differrentiation. This study investigated the role that sphingosine kinases (SPHK) and ceramide-derived sphingosine 1-phosphate (S1P) play in adipocyte terminal differentiation. Materials and Methods: The mouse 3T3-L1 cell line was used as a model for adipogenesis. Cells were harvested at specific time points after initation of differentiation, and SPHK activity was measured. 3T3-L1 cells were treated with S1P and expression of early adipogenesis transcription markers was measured by real time PCR. The expression of S1P-receptors (S1PRs) during differentiation was measured. Results: SPHK activity is induced when 3T3-L1 cells are treated with insulin, dexamethasone, and isobutylmethylxanthine to induce differentiation. SPHK1 is active in preadipocytes and early in the differentiation process. Both SPHK1 and SPHK2 isozymes contribute to activity in differentiated adipocytes. Inhibition of SPHK1 attenuates adipocyte differentiation;however, extracellular S1P does not rescue the effect of SPHK1 inhibition on adipogenesis. Although treatment of preadipocytes with S1P induced message expression of the early adipogenesis transcription factor CC AAT/ binding proteinalpha, continued treatment did not fully support the development of differentiated adipocytes. Sphingosine 1-phosphate receptors (S1PRs) are expressed in preadipocytes and message expression declines markedly during adipocyte differentiation. Conclusion: These results demonstrate that the contribution of SPHK and S1P to adipogenesis is mediated primarily through biphasic activation of SPHK1 and 2 with extracellular S1P and S1PRs playing little role during preadipocyte differentiation. 展开更多
关键词 ADIPOCYTE ADIPOGENESIS Obesity sphingosine kinase 3T3-L1 Cells sphingosine 1-Phosphate sphingosine 1-Phosphate Receptor
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Expressions of Sphingosine-1-phosphate (S1P) Receptors, Sphingosine Kinases in Malignant Bone and Soft Tissue Tumors, and The role of Sphingosine Kinase-1 in Growth of MFH Cell Lines
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作者 Shin-ichiro Kishimoto Toshihiro Akisue +8 位作者 Kenta Kishimoto Hitomi Hara Masaya Imabori Yoshiyuki Okada Naomasa Fukase Teruya Kawamoto Ikuo Fujita Takuya Fujimoto Masahiro Kurosaka 《Journal of Cancer Therapy》 2011年第2期288-294,共7页
Sphingolipids are ubiquitous components of cell membranes. Their metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have important physiological functions, including regulation of cell growth and sur... Sphingolipids are ubiquitous components of cell membranes. Their metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have important physiological functions, including regulation of cell growth and survival. S1P is generated by phosphorylation of sphingosine catalyzed by sphingosine kinase-1 (SPHK1). The purpose of this study is to explore the roles of S1P, S1P receptors, and sphingosine kinases in malignant musculoskeletal tumors. Twenty-one tumor samples (7 liposarcomas, 3 chondrosarcomas, 6 osteosarcomas, 5 MFH) obtained at open biopsy, and four human MFH cell lines (Nara H, Nara F, TNMY1, GBS-1) were used. We examined the mRNA expression of S1P receptors by RT-PCR, and the expression levels of SPHK by Real-time PCR. We used 4 MFH cell lines to analyze SPHK1 proteins by Western blotting. SPHK1 siRNA was transfected into MFH cell lines by lipofection method. Cell proliferation (control and transfected with siRNA) was assayed using WST-8 (Cell Counting Kit-8) assay. All high grade malignant tumors expressed S1P1, S1P2, S1P3 receptors, whereas the expression of S1P1 receptor was detected in 50% of low-grade malignant tumors, S1P2 receptor in 30%, and S1P3 in 50%. No statistically significant difference was found in the expression level of SPHK1 between high-grade and low-grade malignant tumors by Real-time PCR. By results of Western blotting, proteins of SPHK1 were expressed in all MFH cell lines. In MFH cell lines, transfection with SPHK1 siRNA oligonucleotides resulted in approximately 50 to 80% suppression of SPHK1 mRNA expression as determined by real-time PCR. Down-regulation of SPHK1 with small interfering RNA significantly reduced SPHK1 protein levels by Western blotting. Knock down of SPHK1 expression significantly decreased cell proliferation of all MFH cells. These results suggest that the expression of S1P receptors may play an important role for cell proliferation and may correlate with histologic grade in malignant bone and soft tissue tumors, and that SPHK1 may be one of essential molecules for cell proliferation in MFH cell lines. 展开更多
关键词 SARCOMA sphingosine-1-Phosphate S1p Receptor sphingosine kinase MIB-1 MFH
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贝母素乙调节SphK1/S1P信号通路对心房颤动大鼠心肌纤维化的影响
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作者 崔冬玲 王璐 +1 位作者 曾理 王虹 《中药新药与临床药理》 北大核心 2025年第1期66-71,共6页
目的探讨贝母素乙(PMI)调节鞘氨醇激酶1(SphK1)/鞘氨醇-1-磷酸(S1P)信号通路对心房颤动(简称房颤)大鼠心肌纤维化的影响。方法构建房颤大鼠模型,将建模成功的大鼠分为房颤模型组,低剂量贝母素乙及高剂量贝母素乙组(分别腹腔注射2、5 mg&... 目的探讨贝母素乙(PMI)调节鞘氨醇激酶1(SphK1)/鞘氨醇-1-磷酸(S1P)信号通路对心房颤动(简称房颤)大鼠心肌纤维化的影响。方法构建房颤大鼠模型,将建模成功的大鼠分为房颤模型组,低剂量贝母素乙及高剂量贝母素乙组(分别腹腔注射2、5 mg·kg^(-1)贝母素乙),贝母素乙+PMA组(腹腔注射5 mg·kg^(-1)贝母素乙+100mg·kg^(-1) SphK1激活剂PMA),每组各10只,另选择10只正常大鼠作为对照组,房颤模型组和对照组注射等量生理盐水。电子心电图记录房颤持续时间;超声心动图检测房颤大鼠心功能;Masson染色检测房颤大鼠心肌组织纤维化;ELISA法检测房颤大鼠血清中TGFβ1、activin A、collagen Ⅰ、collagen Ⅲ表达;Western Blot法检测大鼠心脏组织中SphK1、S1P蛋白的表达。结果对照组心肌细胞排列整齐;房颤模型组心肌细胞排列紊乱、胶原纤维较多,房颤持续时间、LAD、TGFβ1、activin A、collagen Ⅰ、collagen Ⅲ、SphK1、S1P蛋白表达高于对照组,LVEF、LVFS低于对照组(P<0.05);低、高剂量贝母素乙组心肌细胞排列稍有紊乱,可见少量纤维,房颤持续时间、LAD、TGFβ1、activin A、collagen Ⅰ、collagen Ⅲ、SphK1、S1P蛋白表达低于房颤模型组,LVEF、LVFS高于房颤模型组(P<0.05);贝母素乙+PMA组心肌细胞排列进一步紊乱,纤维增多,房颤持续时间、LAD、TGFβ1、activin A、collagen Ⅰ、collagen Ⅲ、SphK1、S1P蛋白表达高于高剂量贝母素乙组,LVEF、LVFS低于高剂量贝母素乙组(P<0.05)。结论贝母素乙可以抑制房颤大鼠心肌纤维化,其机制可能是通过抑制SphK1/S1P信号通路实现的。 展开更多
关键词 贝母素乙 鞘氨醇激酶1 鞘氨醇-1-磷酸 房颤 心肌纤维化 大鼠
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Roles of sphingosine 1-phosphate on tumorigenesis 被引量:5
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作者 Hsinyu Lee 《World Journal of Biological Chemistry》 CAS 2011年第2期25-34,共10页
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with a variety of biological activities.It is generated from the conversion of ceramide to sphingosine by ceramidase and the subsequent conversion of sphingosi... Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with a variety of biological activities.It is generated from the conversion of ceramide to sphingosine by ceramidase and the subsequent conversion of sphingosine to S1P,which is catalyzed by sphingosine kinases.Through increasing its intracellular levels by sphingolipid metabolism and binding to its cell surface receptors,S1P regulates several physiological and pathological processes,including cell proliferation,migration,angiogenesis and autophagy.These processes are responsible for tumor growth,metastasis and invasion and promote tumor survival.Since ceramide and S1P have distinct functions in regulating in cell fate decision,the balance between the ceramide/sphingosine/S1P rheostat becomes a potent therapeutic target for cancer cells.Herein,we summarize our current understanding of S1P signaling on tumorigenesis and its potential as a target for cancer therapy. 展开更多
关键词 sphingosine 1-phosphate sphingosine kinase CERAMIDE ANGIOGENESIS Autophagy TUMORIGENESIS
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Research progress of sphingosine 1-phosphate and its signal transduction in central nervous system diseases
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作者 BEN Xin-yu YI Xi-nan LI Qi-fu 《Journal of Hainan Medical University》 CAS 2023年第23期64-69,共6页
Sphingosine 1-phosphate(S1P),as a sphingolipid metabolite,has become a key substance in regulating various physiological processes,involved in differentiation,proliferation,migration,morphogenesis,cytoskeleton formati... Sphingosine 1-phosphate(S1P),as a sphingolipid metabolite,has become a key substance in regulating various physiological processes,involved in differentiation,proliferation,migration,morphogenesis,cytoskeleton formation,adhesion,apoptosis,etc.process.Sphingosine 1-phosphate can not only activate the S1P-S1PR signaling pathway by binding to the corresponding receptors on the cell membrane,but also play a role in the cell.In recent years,studies have found that there is a certain relationship between its level changes and the occurrence and development of central nervous system diseases.This article reviews the latest knowledge of sphingosine-1-phosphate in the occurrence and treatment of nervous system diseases,and further clarifies its molecular mechanism in the treatment and development of central nervous system diseases. 展开更多
关键词 sphingosine 1-phosphate Sphingolipid metabolism Central nervous system diseases sphingosine kinase S1P receptor
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山姜素调节VEGF/SphK1/S1P信号通路对膝骨关节炎大鼠血管生成的影响 被引量:3
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作者 罗锟 王智 王柯 《天津医药》 CAS 2024年第5期480-485,共6页
目的探讨山姜素(APT)调节血管内皮生长因子/鞘氨醇激酶1/1磷酸鞘氨醇(VEGF/SphK1/S1P)信号通路对膝骨关节炎(KOA)大鼠血管生成的影响。方法采用改良的Videman法构建KOA大鼠模型,将90只大鼠分为对照组(Control组)、模型组(Model组)、山... 目的探讨山姜素(APT)调节血管内皮生长因子/鞘氨醇激酶1/1磷酸鞘氨醇(VEGF/SphK1/S1P)信号通路对膝骨关节炎(KOA)大鼠血管生成的影响。方法采用改良的Videman法构建KOA大鼠模型,将90只大鼠分为对照组(Control组)、模型组(Model组)、山姜素低剂量组(L-APT组)、山姜素高剂量组(H-APT组)、山姜素高剂量组+慢病毒阴性对照组(APT+NC组)、山姜素高剂量组+过表达SphK1慢病毒组(APT+SphK1组),每组15只。HE染色观察大鼠软骨组织病理变化;酶联免疫吸附试验测定软骨组织白细胞介素(IL)-1β、肿瘤坏死因子α(TNF-α)、IL-6、基质金属蛋白酶-13(MMP-13)水平;TUNEL检测软骨组织细胞凋亡情况;免疫组化检测血管内皮生长因子(VEGF)、CD31蛋白表达情况;Western blot检测血管内皮生长因子受体2(VEGFR2)、磷酸化VEGFR2(p-VEGFR2)、SphK1、S1P蛋白水平。结果与Control组比较,Model组大鼠出现病理损伤,细胞凋亡率、IL-1β、TNF-α、IL-6、MMP-13、VEGF阳性表达、CD31阳性表达和p-VEGFR2、SphK1、S1P蛋白表达水平增加(P<0.05);与Model组比较,L-APT组、H-APT组病理损伤明显减轻,细胞凋亡率、IL-1β、TNF-α、IL-6、MMP-13、VEGF阳性表达、CD31阳性表达和pVEGFR2、SphK1、S1P蛋白表达水平降低(P<0.05);与APT+NC组比较,APT+SphK1组软骨组织病理损伤加重,细胞凋亡率、IL-1β、TNF-α、IL-6、MMP-13、VEGF阳性表达、CD31阳性表达和p-VEGFR2、SphK1、S1P蛋白表达水平增加(P<0.05)。结论APT通过抑制VEGF/SphK1/S1P信号通路抑制KOA大鼠血管生成。 展开更多
关键词 骨关节炎 新生血管化 病理性 血管内皮生长因子类 山姜素 鞘氨醇激酶1 1磷酸鞘氨醇
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阿芬太尼调节SphK1/S1P信号通路保护心肌缺血再灌注损伤大鼠 被引量:2
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作者 王盛华 黄庆先 李庆丰 《中国动脉硬化杂志》 CAS 2024年第5期402-409,共8页
[目的]探究阿芬太尼对心肌缺血再灌注损伤(MIRI)大鼠的作用及在该过程中对鞘氨醇激酶1(SphK1)/鞘氨醇-1-磷酸(S1P)信号通路的调节机制。[方法]将SPF级SD雄性大鼠随机分为假手术组、模型组、阳性药物组(复方丹参组)和阿芬太尼低剂量组、... [目的]探究阿芬太尼对心肌缺血再灌注损伤(MIRI)大鼠的作用及在该过程中对鞘氨醇激酶1(SphK1)/鞘氨醇-1-磷酸(S1P)信号通路的调节机制。[方法]将SPF级SD雄性大鼠随机分为假手术组、模型组、阳性药物组(复方丹参组)和阿芬太尼低剂量组、阿芬太尼高剂量组、阿芬太尼高剂量+SphK1激动剂组(阿芬太尼+PMA组),每组20只。除假手术组,其余组均利用结扎左前降支冠状动脉后再灌注复制MIRI模型。全自动生物化学分析仪检测血清乳酸脱氢酶(LDH)、肌酸激酶(CK)和谷草转氨酶(AST)的活性;TTC检测大鼠心肌梗死面积;HE染色观察大鼠心肌组织形态学特征;TUNEL染色检测大鼠心肌细胞凋亡;ELISA检测血清肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)、白细胞介素1β(IL-1β)及S1P的水平;试剂盒检测心肌组织中丙二醛(MDA)含量和超氧化物歧化酶(SOD)的活性;Western blot检测心肌组织SphK1蛋白表达。[结果]相较于假手术组,模型组大鼠心肌组织病理损伤严重,血清中心肌损伤标志物LDH、CK和AST的活性,心肌梗死面积和心肌细胞凋亡率,TNF-α、IL-6、IL-1β、MDA、S1P水平及SphK1蛋白表达均升高,SOD活性降低(P<0.05);相较于模型组,阳性药物组和阿芬太尼低、高剂量组大鼠心肌组织损伤减轻,血清中心肌损伤标志物LDH、CK和AST的活性,心肌梗死面积和心肌细胞凋亡率,TNF-α、IL-6、IL-1β、MDA、S1P水平及SphK1蛋白表达均降低,SOD活性升高(P<0.05)。SphK1激动剂可逆转高剂量阿芬太尼对上述指标的影响(P<0.05)。[结论]阿芬太尼对MIRI大鼠发挥保护作用,其机制可能与抑制SphK1/S1P信号通路有关。 展开更多
关键词 阿芬太尼 鞘氨醇激酶1/鞘氨醇-1-磷酸信号通路 心肌缺血再灌注损伤 保护作用
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和血柔肝方含药血清通过鞘氨醇激酶-1对肝星状细胞增殖与凋亡的作用
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作者 王燕 肖雄 +1 位作者 马丽 蒲诗云 《中西医结合肝病杂志》 CAS 2024年第10期903-908,共6页
目的:和血柔肝方(HXRGF)含药血清调节鞘氨醇激酶-1(SphK1)对肝星状细胞(HSC)增殖与凋亡的作用。方法:采用Resistin处理HSC-T6细胞,建立纤维化HSC模型,采用LV-rSphK1-OE、LV-rSphk1-shRNA慢病毒方法构建SphK1过表达、低表达稳转细胞株,... 目的:和血柔肝方(HXRGF)含药血清调节鞘氨醇激酶-1(SphK1)对肝星状细胞(HSC)增殖与凋亡的作用。方法:采用Resistin处理HSC-T6细胞,建立纤维化HSC模型,采用LV-rSphK1-OE、LV-rSphk1-shRNA慢病毒方法构建SphK1过表达、低表达稳转细胞株,运用实时定量PCR、WB检测TGF-β、α-SMA、Col I、FN、Smad、SphK1mRNA及蛋白的表达、CCK8实验检测细胞活力、AnnexinV-APC/7-AAD流式细胞学检测细胞凋亡情况。结果:与对照组比较,MF-HSC-T6细胞中可见TGF-β、α-SMA、Col I、FN、SphK1mRNA及蛋白表达水平升高,Smad mRNA水平降低(P<0.01);HSC-T6 SphK1过表达细胞株中SphK1及相关纤维化标志物的表达水平升高(P<0.01);HSC-T6 SphK1低表达细胞株中TGF-β、α-SMA、Col I、FN mRNA等纤维化相关标志物降低,Smad mRNA水平升高(P<0.01)。与模型组比较,中药复方HXRGF含药血清干预后,可见MF-HSC T6 SphK1mRNA及蛋白表达水平降低,并同时伴有α-SMA、Col I、FN表达水平的下降(P<0.01),HSC细胞增殖率下降(110.85%);shRNA-SphK1转染组细胞增殖率下降,凋亡率(12.14%)升高(P<0.01);HSC-T6 SphK1低表达组细胞凋亡率(16.48%)升高(P<0.01)。结论:SphK1可作为肝纤维化潜在治疗靶点。HXRGF干预通过抑制SphK1表达,下调TGF-β、α-SMA等促纤维化因子的表达水平,抑制活化的HSC增殖,诱导HSC凋亡,缓解肝纤维化。 展开更多
关键词 肝星状细胞 鞘氨醇激酶-1 和血柔肝方
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p38 mitogen-activated protein kinase regulates type-Ⅰ vs type-Ⅱ phenotyping of human vascular endothelial cells 被引量:1
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作者 Masako Nakahara Miwako Nishio +2 位作者 Koichi Saeki Akira Yuo Kumiko Saeki 《World Journal of Translational Medicine》 2015年第3期101-112,共12页
AIM: To identify kinases involved in phenotype regulation of vascular endothelial cells(VECs): Proproliferative G-protein signaling 5(RGS5)^(high)(typeⅠ) vs anti-proliferative RGS5^(low)(typeⅡ) VECs.METHODS: Proteom... AIM: To identify kinases involved in phenotype regulation of vascular endothelial cells(VECs): Proproliferative G-protein signaling 5(RGS5)^(high)(typeⅠ) vs anti-proliferative RGS5^(low)(typeⅡ) VECs.METHODS: Proteomic kinase assays were performed to identify the crucial kinase involved in the phenotype regulation of human VECs using typeⅠ VECs, which promotes the proliferation of human vascular smooth muscle cells(VSMCs), and typeⅡ VECs, which suppress the proliferation of human VSMCs. The assays were performed using multiple pairs of typeⅠ and typeⅡ VECs to obtain the least number of candidates. The involvement of the candidate kinases was verified by evaluating the effects of their specific inhibitors on the phenotype regulation of human VECs as well as the expression levels of regulator of RGS5, which is the causative gene for the "typeⅡ to typeⅠ" phenotype conversion of human VECs. RESULTS: p38α mitogen-activated protein kinase(p38α MAPK) was the only kinase that showed distinctive activities between typeⅠ and typeⅡ VECs: p38α MAPK activities were low and high in type-Ⅰand typeⅡ VECs, respectively. We found that an enforced expression of RGS5 indeed lowered p38α MAPK activitiesin typeⅡ VECs. Furthermore, treatments with a p38α MAPK inhibitor nullified the anti-proliferative potential in typeⅡ VECs. Interestingly, MAPK inhibitor treatments enhanced the induction of RGS5 gene. Thus, there is a vicious cycle between "RGS5 induction" and "p38α MAPK inhibition", which can explain the unidirectional process in the stress-induced "typeⅡ to typeⅠ" conversions of human VECs. To understand the upstream signaling of RGS5, which is known as an inhibitory molecule against the G protein-coupled receptor(GPCR)-mediated signaling, we examined the effects of RGS5 overexpression on the signaling events from sphingosine-1-phosphate(S1P) to N-cadherin, because S1 P receptors belong to the GPCR family gene and N-cadherin, one of their downstream effectors, is reportedly involved in the regulation of VEC-VSMC interactions. We found that RGS5 specifically bound with S1P1. Moreover, N-cadherin localization at intercellular junctions in typeⅡ VECs was abolished by "RGS5 overexpression" and "p38α MAPK inhibition".CONCLUSION: p38α MAPK plays crucial roles in "type-Ⅰ vs type-Ⅱ" phenotype regulations of human VECs at the downstream of RGS5. 展开更多
关键词 VASCULAR endothelial CELLS VASCULAR smooth muscle CELLS proteomic kinase assay p38αmitogenactivated protein kinase regulator of G-PROTEIN signaling 5 sphingosine-1-phosphate N-cadherin
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SphK/S1P在心血管疾病中的作用
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作者 唐丽鸿 陈春玲 《基础医学与临床》 CAS 2024年第8期1175-1179,共5页
磷酸鞘氨醇(S1P)是一种活性高的膜磷脂类代谢物,对心血管系统具有重要的生理作用。鞘氨醇激酶(SphK)是一种脂肪酶,对维持体内S1P水平的稳定非常重要。S1P通过催化调节与细胞表面的G蛋白偶联受体(S1PR1-5)的结合,从而在心血管疾病中发挥... 磷酸鞘氨醇(S1P)是一种活性高的膜磷脂类代谢物,对心血管系统具有重要的生理作用。鞘氨醇激酶(SphK)是一种脂肪酶,对维持体内S1P水平的稳定非常重要。S1P通过催化调节与细胞表面的G蛋白偶联受体(S1PR1-5)的结合,从而在心血管疾病中发挥不同的生理学效应,如参与调控动脉粥样硬化、心肌缺血再灌注损伤、心肌梗死、心力衰竭等疾病的发生发展,维持血管内皮细胞屏障功能,保护内皮糖萼层,白细胞黏附以及炎性反应等生理病理过程。 展开更多
关键词 1-磷酸鞘氨醇 鞘胺醇激酶 心血管疾病 内皮糖萼层
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不同分型急性缺血性脑卒中患者血清OPN、IRAK4和S1P水平及其预后分析 被引量:1
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作者 朱静 连宗德 +3 位作者 陈明 周新艳 李华敏 黄灿 《疑难病杂志》 CAS 2024年第9期1043-1048,共6页
目的探究不同分型急性缺血性脑卒中患者血清骨桥蛋白(OPN)、白介素1受体关联激酶4(IRAK4)和1-磷酸鞘氨醇(S1P)水平及与改良Rankin量表(mRS)评分的关系。方法选取2022年1月—2023年12月东莞松山湖东华医院神经内科收治的急性缺血性脑卒... 目的探究不同分型急性缺血性脑卒中患者血清骨桥蛋白(OPN)、白介素1受体关联激酶4(IRAK4)和1-磷酸鞘氨醇(S1P)水平及与改良Rankin量表(mRS)评分的关系。方法选取2022年1月—2023年12月东莞松山湖东华医院神经内科收治的急性缺血性脑卒中患者150例为病例组,根据分型分为大动脉粥样硬化型(n=23)、小动脉闭塞型(n=52)、心源性栓塞型(n=60)、其他病因型(n=11)及不明原因型(n=4)。根据mRS评分分为预后良好亚组(n=117)与预后不良亚组(n=33)。另选取健康志愿者120例纳入健康对照组。采用酶联免疫吸附法检测OPN、IRAK4、S1P水平,记录患者神经功能缺损(NIHSS)评分、mRS评分;Pearson相关性分析NIHSS评分、mRS评分与血清OPN、IRAK4和S1P的相关性;受试者工作特征曲线(ROC)分析血清OPN、IRAK4和S1P对急性缺血性脑卒中患者预后的预测价值。结果与健康对照组比较,病例组血清OPN、IRAK4和S1P水平升高(t/P=25.882/<0.001、14.910/<0.001、50.674/<0.001);不同类型急性缺血性脑卒中患者血清OPN、IRAK4和S1P比较,小动脉闭塞型>心源性栓塞型>其他病因型>大动脉粥样硬化型>不明原因型(F/P=60.344/<0.001、17.798/<0.001、67.339/<0.001、124.678/<0.001);与预后良好亚组比较,预后不良亚组血清OPN、IRAK4和S1P水平、NIHSS评分显著更高(t/P=5.377/<0.001、3.829/<0.001、3.285/<0.001、4.805/<0.001);血清OPN、IRAK4和S1P水平与NIHSS评分、mRS评分均呈正相关(NIHSS评分:r/P=0.459/0.009、0.423/0.017、0.525/<0.001;mRS评分:r=0.493、0.479、0.487,P均<0.001);血清OPN、IRAK4、S1P及三者联合预测急性缺血性脑卒中患者预后价值AUC分别为0.656、0.740、0.804、0.872,三者联合预测急性缺血性脑卒中预后的AUC大于OPN、IRAK4、S1P单独预测(Z/P=3.237/0.001,5.181/0.001,2.018/0.035)。结论急性缺血性脑卒中患者血清OPN、IRAK4和S1P水平升高,且小动脉闭塞型和心源性栓塞型分型OPN、IRAK4、S1P水平和NIHSS评分显著高于其他分型,血清OPN、IRAK4及S1P联合检测对急性缺血性脑卒中患者预后具有较高的预测价值。 展开更多
关键词 急性缺血性脑卒中 骨桥蛋白 白介素1受体关联激酶4 1-磷酸鞘氨醇 改良Rankin量表评分 神经功能缺损评分 预后
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