RESUMEN
Angiogenesis refers to the process of forming new blood vessels based on original blood vessels. Pathological angiogenesis is a sign of a series of diseases such as cancer, cardiovascular diseases, and retinopathy. Sphingosine 1-phosphate (S1P) is a signaling lipid synthesized by sphingosine kinase (SPHK) that exerts its diverse biological and pathophysiological roles through five G protein-coupled receptors (S1PR1-5) and initiates various signaling cascades by activating receptors that affect cell fate, vascular tension, endothelial function and integrity, and lymphocyte transport. The imbalance ofproduction and signal is closely related to pathological processes such as endothelial dysfunction and abnormal angiogenesis. Accumulating evidence suggests that the SPHK-S1P axis plays an important role in angiogenesis, especially in the development of tumors, diabetes retinopathy, atherosclerosis, myocardial infarction and other cardiovascular diseases. Studies on its roles and functions can provide new insights and drug therapeutic targets for the treatment of angiogenesis-related diseases. This review describes the molecular mechanisms by which the SPHK-S1P axis affects endothelial cell and smooth muscle cellproliferation, endothelial cell migration and the formation of lumen by endothelial cells, pericytes and smooth muscle cells through SPHK and S1PR1-5. The review also elaborates how the SPHK-S1P axis affects angiogenesis in tumors, cardiovascular diseases, diabetes and retinopathy through SPHK and S1PR1-5, and aims to provide new therapeutic strategy for related diseases by understanding the molecular mechanism of the SPHK-S1P axis in angiogenesis.
RESUMEN
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.
RESUMEN
Sphingosine 1-phosphate (S1P) is one of the crucial signal molecules, which can regulate many biological functions inside and outside cells. It plays an important role in regulating numerous physiological and pathological processes after being combined with S1P receptors (S1PRs). S1P/S1PRs signaling pathways have become a hot spot in the current research on endothelial inflammation and atherosclerosis. This review described the current development of the role of S 1P and its receptors in atherosclerosis.
RESUMEN
Sphingosine-1-phosphate(S1P) is an important bioactive lipid produced from cell membrane sphingomyelin metabolism process.S1P and cell membrane surface S1P receptors(S1PR1-5) are G protein coupled receptors(GPCRs), which influence the formation of new blood vessels in the immune system via combining the related inflammatory signaling pathway.This review describes briefly the effects of S1P and S1PRs on autoimmune disease angiogenesis through intracellular signal transduction, such as rheumatoid arthritis, multiple sclerosis, colitis, systemic lupus erythematosus.Further research will be a new therapeutic target on vascular inflammation of autoimmune diseases.
RESUMEN
Objective: To modify the structure of fingolimod which was derived from the extract of medicinal plant Cordyceps ISP-1 and evaluate the antitumor activity of the derivatives. Methods: According to the synthesis way developed before, target compounds were synthesized by using suitable substitued benzenes, through chemical reactions such as Friedel-Crafts reaction, Nitros-substitution reaction, Carbonyl reduction, Henry reaction, and Nitro-reduction. The cytotoxicities to three cell lines, Siha, PC-3, and MKN-45, were evaluated through MTT method. Results: Fingolinod and 18 fingolimod analogues were synthesized, and compounds 10-12 had the equal antitumor activities like fingolimod. Conclusion: The compounds 2-10, 12-19 are new compounds not reported before. This study provides the foundation for finding antitumor compounds with S1PRs inhibiting effect.