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
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
The reverse cholesterol transport mediated by highdensity lipoprotein(HDL)is an important mechanism for maintaining body cholesterol,and hence,the crucial anti-atherogenic action of the lipoprotein.Recent studies,howe...The reverse cholesterol transport mediated by highdensity lipoprotein(HDL)is an important mechanism for maintaining body cholesterol,and hence,the crucial anti-atherogenic action of the lipoprotein.Recent studies,however,have shown that HDL exerts a variety of anti-inflammatory and anti-atherogenic actions independently of cholesterol metabolism.The present review provides an overview of the roles of sphingosine 1-phosphate(S1P)/S1P receptor and apolipoprotein A-I/ scavenger receptor class B typeⅠsystems in the antiatherogenic HDL actions.In addition,the physiological significance of the existence of S1P in the HDL particles is discussed.展开更多
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
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
Background:Endothelial cells play a key role in the cytokine storm caused by influenza A virus. MicroRNA-155 (miR-155) is an important regulator in inflammation. Its role in the inflammatory response to influenza A in...Background:Endothelial cells play a key role in the cytokine storm caused by influenza A virus. MicroRNA-155 (miR-155) is an important regulator in inflammation. Its role in the inflammatory response to influenza A infection, however, has yet to be elucidated. In this study, we explored the role as well as the underlying mechanism of miR-155 in the cytokine production in influenza A-infected endothelial cells.Methods:Human pulmonary microvascular endothelial cells (HPMECs) were infected with the influenza A virus strain H1N1. The efficiency of H1N1 infection was confirmed by immunofluorescence. The expression levels of proinflammatory cytokines and miR-155 were determined using real-time polymerase chain reaction. A dual-luciferase reporter assay characterized the interaction between miR-155 and sphingosine-1-phosphate receptor 1 (S1PR1). Changes in the target protein levels were determined using Western blot analysis.Results:MiR-155 was elevated in response to the H1N1 infection in HPMECs (24 h post-infection vs. 0 h post-infection, 3.875 ± 0.062 vs. 1.043 ± 0.013, P = 0.001). Over-expression of miR-155 enhanced inflammatory cytokine production (miR-155 mimic vs. negative control, all P < 0.05 in regard of cytokine levels) and activation of nuclear factor kappa B in infected HPMECs (miR-155 mimic vs. negative control, P = 0.004), and down-regulation of miR-155 had the opposite effect. In addition, S1PR1 was a direct target of miR-155 in the HPMECs. Inhibition of miR-155 enhanced the expression of the S1PR1 protein. Down-regulation of S1PR1 decreased the inhibitory effect of the miR-155 blockade on H1N1-induced cytokine production and nuclear factor kappa B activation in HPMECs. Conclusion:MiR-155 maybe modulate influenza A-induced inflammatory response by targeting S1PR1.展开更多
异基因造血干细胞移植(allo-HSCT)后,供者来源的自然杀伤细胞(NK)可在保留移植物抗白血病(GVL)效应的同时发挥控制移植物抗宿主病(GVHD)作用。NK细胞表面的1磷酸鞘氨醇受体5(S1PR5)通过与胞外的第一信使1磷酸鞘氨醇(S1P)相互作用,调节N...异基因造血干细胞移植(allo-HSCT)后,供者来源的自然杀伤细胞(NK)可在保留移植物抗白血病(GVL)效应的同时发挥控制移植物抗宿主病(GVHD)作用。NK细胞表面的1磷酸鞘氨醇受体5(S1PR5)通过与胞外的第一信使1磷酸鞘氨醇(S1P)相互作用,调节NK细胞的迁移和在外周血、脾、淋巴结等器官中的分布。本研究旨在探讨allo-HSCT后外周血NK细胞S1PR5表达变化及对GVHD的影响。分离纯化17例供者及相应受者移植后1个月外周血NK细胞,通过荧光探针实时定量PCR技术检测S1PR5 mRNA的表达情况,并结合患者临床资料和随访结果进行分析。结果表明,供者与allo-HSCT后患者外周血中NK细胞S1PR5表达变化(0.235±0.191 vs0.330±0.261,P>0.05)不具有统计学意义;急性GVHD(aGVHD)患者组移植后外周血NK细胞S1PR5表达水平较无aGVHD的患者组明显下降(0.973±0.834 vs 6.166±5.32,P<0.05);移植后患者与相应供者相比,外周血NK细胞S1PR5表达水平下降超过10%时易发生aGVHD;NK细胞S1PR5表达变化与慢性GVHD发生率无明显相关性(3.401±2.324 vs 2.762±1.972,P>0.05)。结论:NK细胞S1PR5表达水平下调与aGVHD发生有关,可能机制是由于S1PR5的低表达影响了NK细胞在体内的分布,从而影响到调控aGVHD的作用。展开更多
The liver is the central organ involved in lipid metabolism and the gastrointestinal(GI)tract is responsible for nutrient absorption and partitioning.Obesity,dyslipidemia and metabolic disorders are of increasing publ...The liver is the central organ involved in lipid metabolism and the gastrointestinal(GI)tract is responsible for nutrient absorption and partitioning.Obesity,dyslipidemia and metabolic disorders are of increasing public health concern worldwide,and novel therapeutics that target both the liver and the GI tract(gut-liver axis)are much needed.In addition to aiding fat digestion,bile acids act as important signaling molecules that regulate lipid,glucose and energy metabolism via activating nuclear receptor,G protein-coupled receptors(GPCRs),Takeda G protein receptor 5(TGR5)and sphingosine-1-phosphate receptor 2(S1PR2).Sphingosine-1-phosphate(S1P)is synthesized by two sphingosine kinase isoforms and is a potent signaling molecule that plays a critical role in various diseases such as fatty liver,in-flammatory bowel disease(IBD)and colorectal cancer.In this review,we will focus on recent findings related to the role of S1P-mediated signaling pathways in the gut-liver axis.展开更多
Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)i...Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities,and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases.In the current research,the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model.Our results revealed that FTY-720 markedly decreased infarct volume,promoted neurological function recovery,and weakened the blood-brain barrier permeability of ischemic rats.The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels.These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.展开更多
Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Take...Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.展开更多
Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities...Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.展开更多
Bile acids(BA)are synthesized from cholesterol in the liver.They are essential for promotion of the absorption of lipids,cholesterol,and lipid-soluble vitamins from the intestines.BAs are hormones that regulate nutrie...Bile acids(BA)are synthesized from cholesterol in the liver.They are essential for promotion of the absorption of lipids,cholesterol,and lipid-soluble vitamins from the intestines.BAs are hormones that regulate nutrient metabolism by activating nuclear receptors(farnesoid X receptor(FXR),pregnane X receptor,vitamin D)and G protein-coupled receptors(e.g.,TGR5,sphingosine-1-phosphate receptor 2(S1PR2))in the liver and intestines.In the liver,S1PR2 activation by conjugated BAs activates the extracellular signal-regulated kinase 1/2 and AKT signaling pathways,and nuclear sphingosine kinase 2.The latter produces sphingosine-1-phosphate(S1P),an inhibitor of histone deacetylases 1/2,which allows for the differential up-regulation of expression of genes involved in the metabolism of sterols and lipids.We discuss here the emerging concepts of the interactions of BAs,FXR,insulin,S1P signaling and nutrient metabolism.展开更多
基金National Natural Science Foundation of China(No.82260270)Hainan Clinical Medical Center(No.2021)Innovation Team for Epilepsy Research at Hainan Medical College(No.2022)。
文摘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.
文摘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.
基金Supported by Grants-in-Aid for scientific research from the Japan Society for the Promotion of Science,No.20015008,20054003,and 21390016
文摘The reverse cholesterol transport mediated by highdensity lipoprotein(HDL)is an important mechanism for maintaining body cholesterol,and hence,the crucial anti-atherogenic action of the lipoprotein.Recent studies,however,have shown that HDL exerts a variety of anti-inflammatory and anti-atherogenic actions independently of cholesterol metabolism.The present review provides an overview of the roles of sphingosine 1-phosphate(S1P)/S1P receptor and apolipoprotein A-I/ scavenger receptor class B typeⅠsystems in the antiatherogenic HDL actions.In addition,the physiological significance of the existence of S1P in the HDL particles is discussed.
基金supported by the National Natural Science Foundation of China(No.81873505).
文摘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.
文摘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.
基金a grant from the National Nature Science Foundation of China(No.81470206).
文摘Background:Endothelial cells play a key role in the cytokine storm caused by influenza A virus. MicroRNA-155 (miR-155) is an important regulator in inflammation. Its role in the inflammatory response to influenza A infection, however, has yet to be elucidated. In this study, we explored the role as well as the underlying mechanism of miR-155 in the cytokine production in influenza A-infected endothelial cells.Methods:Human pulmonary microvascular endothelial cells (HPMECs) were infected with the influenza A virus strain H1N1. The efficiency of H1N1 infection was confirmed by immunofluorescence. The expression levels of proinflammatory cytokines and miR-155 were determined using real-time polymerase chain reaction. A dual-luciferase reporter assay characterized the interaction between miR-155 and sphingosine-1-phosphate receptor 1 (S1PR1). Changes in the target protein levels were determined using Western blot analysis.Results:MiR-155 was elevated in response to the H1N1 infection in HPMECs (24 h post-infection vs. 0 h post-infection, 3.875 ± 0.062 vs. 1.043 ± 0.013, P = 0.001). Over-expression of miR-155 enhanced inflammatory cytokine production (miR-155 mimic vs. negative control, all P < 0.05 in regard of cytokine levels) and activation of nuclear factor kappa B in infected HPMECs (miR-155 mimic vs. negative control, P = 0.004), and down-regulation of miR-155 had the opposite effect. In addition, S1PR1 was a direct target of miR-155 in the HPMECs. Inhibition of miR-155 enhanced the expression of the S1PR1 protein. Down-regulation of S1PR1 decreased the inhibitory effect of the miR-155 blockade on H1N1-induced cytokine production and nuclear factor kappa B activation in HPMECs. Conclusion:MiR-155 maybe modulate influenza A-induced inflammatory response by targeting S1PR1.
文摘异基因造血干细胞移植(allo-HSCT)后,供者来源的自然杀伤细胞(NK)可在保留移植物抗白血病(GVL)效应的同时发挥控制移植物抗宿主病(GVHD)作用。NK细胞表面的1磷酸鞘氨醇受体5(S1PR5)通过与胞外的第一信使1磷酸鞘氨醇(S1P)相互作用,调节NK细胞的迁移和在外周血、脾、淋巴结等器官中的分布。本研究旨在探讨allo-HSCT后外周血NK细胞S1PR5表达变化及对GVHD的影响。分离纯化17例供者及相应受者移植后1个月外周血NK细胞,通过荧光探针实时定量PCR技术检测S1PR5 mRNA的表达情况,并结合患者临床资料和随访结果进行分析。结果表明,供者与allo-HSCT后患者外周血中NK细胞S1PR5表达变化(0.235±0.191 vs0.330±0.261,P>0.05)不具有统计学意义;急性GVHD(aGVHD)患者组移植后外周血NK细胞S1PR5表达水平较无aGVHD的患者组明显下降(0.973±0.834 vs 6.166±5.32,P<0.05);移植后患者与相应供者相比,外周血NK细胞S1PR5表达水平下降超过10%时易发生aGVHD;NK细胞S1PR5表达变化与慢性GVHD发生率无明显相关性(3.401±2.324 vs 2.762±1.972,P>0.05)。结论:NK细胞S1PR5表达水平下调与aGVHD发生有关,可能机制是由于S1PR5的低表达影响了NK细胞在体内的分布,从而影响到调控aGVHD的作用。
基金This work was supported by the USA National Institutes of Health(NIH)grants R01 DK104893 and R01DK-057543VA Merit Award I01BX004033 and 1I01BX001390Research Career Scientist Award(IK6BX004477)from the Department of Veterans Affairs.
文摘The liver is the central organ involved in lipid metabolism and the gastrointestinal(GI)tract is responsible for nutrient absorption and partitioning.Obesity,dyslipidemia and metabolic disorders are of increasing public health concern worldwide,and novel therapeutics that target both the liver and the GI tract(gut-liver axis)are much needed.In addition to aiding fat digestion,bile acids act as important signaling molecules that regulate lipid,glucose and energy metabolism via activating nuclear receptor,G protein-coupled receptors(GPCRs),Takeda G protein receptor 5(TGR5)and sphingosine-1-phosphate receptor 2(S1PR2).Sphingosine-1-phosphate(S1P)is synthesized by two sphingosine kinase isoforms and is a potent signaling molecule that plays a critical role in various diseases such as fatty liver,in-flammatory bowel disease(IBD)and colorectal cancer.In this review,we will focus on recent findings related to the role of S1P-mediated signaling pathways in the gut-liver axis.
基金supported by grants from the National Natural Science Foundation of China,No.81971231(to JL)Liaoning Revitalization Talents Program,No.XLYC1907178(to JL)。
文摘Recent research on the underlying mechanisms of cerebral ischemia indicates that the neurovascular unit can be used as a novel subject for general surveys of neuronal damage and protein mechanisms.Fingolimod(FTY-720)is a newly developed immunosuppressant isolated from Cordyceps sinensis that exhibits a wide range of biological activities,and has recently attracted much attention for the treatment of ischemic cerebrovascular diseases.In the current research,the role of FTY-720 and its possible mechanisms were assessed from an neurovascular unit perspective using a rat cerebral ischemia model.Our results revealed that FTY-720 markedly decreased infarct volume,promoted neurological function recovery,and weakened the blood-brain barrier permeability of ischemic rats.The protective roles of FTY-720 in ischemic stroke are ascribed to a combination of sphingosin-1-phosphate receptor-1 and reduced expression of sphingosin-1-phosphate receptor-1 in microvessels and reduction of interleukin-17A protein levels.These findings indicate that FTY-720 has promise as a new therapy for neurovascular protection and functional recovery after ischemic stroke.
基金This study was supported by grants funded by the USA National Institutes of Health(NIH)U01CA179582 and R01 CA222490.
文摘Many receptors can be activated by bile acids(BAs)and their derivatives.These include nuclear receptors farnesoid X receptor(FXR),pregnane X receptor(PXR),and vitamin D receptor(VDR),as well as membrane receptors Takeda G protein receptor 5(TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cholinergic receptor muscarinic 2(CHRM2).All of them are implicated in the development of metabolic and immunological diseases in response to endobiotic and xenobiotic exposure.Because epigenetic regulation is critical for organisms to adapt to constant environmental changes,this review article summarizes epigenetic regulation as well as post-transcriptional modification of bile acid re-ceptors.In addition,the focus of this review is on the liver and digestive tract although these receptors may have effects on other organs.Those regulatory mechanisms are implicated in the disease process and critically important in uncovering innovative strategy for prevention and treatment of metabolic and immunological diseases.
基金the USA National Institutes of Health(NIH)R01CA222490.
文摘Over 20%of mortality during acute liver failure is associated with the development of hepatic encephalopathy(HE).Thus,HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma.HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels.Thus,the brain is exposed to intestinal-derived toxic substances.Moreover,the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation.This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE.Together,the significance of the gut-liver-brain axis in human health warrants attention.This review paper focuses on the roles of bacteria metabolites,mainly ammonia and bile acids(BAs)as well as BA receptors in HE.The literature search conducted for this review included searches for phrases such as BA receptors,BAs,ammonia,farnesoid X receptor(FXR),G protein-coupled bile acid receptor 1(GPBAR1 or TGR5),sphingosine-1-phosphate receptor 2(S1PR2),and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy.PubMed,as well as Google Scholar,was the search engines used to find relevant publications.
基金This work was supported by the US National Institutes of Health(grants R01DK57543 and R01DK104893).
文摘Bile acids(BA)are synthesized from cholesterol in the liver.They are essential for promotion of the absorption of lipids,cholesterol,and lipid-soluble vitamins from the intestines.BAs are hormones that regulate nutrient metabolism by activating nuclear receptors(farnesoid X receptor(FXR),pregnane X receptor,vitamin D)and G protein-coupled receptors(e.g.,TGR5,sphingosine-1-phosphate receptor 2(S1PR2))in the liver and intestines.In the liver,S1PR2 activation by conjugated BAs activates the extracellular signal-regulated kinase 1/2 and AKT signaling pathways,and nuclear sphingosine kinase 2.The latter produces sphingosine-1-phosphate(S1P),an inhibitor of histone deacetylases 1/2,which allows for the differential up-regulation of expression of genes involved in the metabolism of sterols and lipids.We discuss here the emerging concepts of the interactions of BAs,FXR,insulin,S1P signaling and nutrient metabolism.
