Sphingosine-1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions in both intracellular and extracellular compartments. It interacts with five G protein-coupled receptors subtypes (S1PR(1-5)) to generate multiple downstream signaling. Activation of S1PR1 has been validated to be involved in the process of immune modulation. Fingolimod (FTY720), the novel S1PR1 agonist, has been approved for the treatment of multiple sclerosis in clinical trials. The study towards discovery of selective S1PR1 agonists has become hot spot for immunological diseases. This article summarized the research progress of S1PR1 agonists, emphasizing their structure types, structure-activity relationship and direction of development.
Animals ; Fingolimod Hydrochloride ; Humans ; Immunosuppressive Agents ; pharmacology ; therapeutic use ; Lysophospholipids ; physiology ; Multiple Sclerosis ; drug therapy ; Propylene Glycols ; pharmacology ; therapeutic use ; Receptors, Lysosphingolipid ; agonists ; classification ; metabolism ; physiology ; Sphingosine ; analogs & derivatives ; pharmacology ; physiology ; therapeutic use ; Structure-Activity Relationship

FTY720 is a novel immunomodulator that has proven effective in animal models of transplantation and autoimmunity, has achieved promising results in Phase I and Phase II studies of renal transplantation in humans, and is currently undergoing phase III studies. FTY720 acts as a high-affinity agonist at the sphingosine 1-phosphate receptor-1 (S1P1), where it internalises the receptor and causes alterations to the normal circulation of lymphocytes between the blood and lymphoid tissue. Unlike conventional immunosuppressants, FTY720 does not impair the activation, proliferation or effector functions of T- and B-cells. Further development of FTY720 is in progress, including trials in autoimmune disorders as well as transplantation. This review summarises the mechanism of action of FTY720, its effects in models of transplantation and autoimmunity, and results from clinical trials in humans.
Animals ; Autoimmune Diseases/drug therapy ; Clinical Trials ; Endothelium, Vascular/drug effects ; Humans ; Immune System/drug effects ; Immunosuppressive Agents/*therapeutic use ; *Organ Transplantation ; Propylene Glycols/*therapeutic use ; Receptors, Lysosphingolipid/agonists ; Transplantation Immunology

Animals ; Apoptosis ; drug effects ; Capillaries ; pathology ; Fibrosis ; Fingolimod Hydrochloride ; Kidney Diseases ; metabolism ; pathology ; Kidney Tubules ; blood supply ; Male ; Propylene Glycols ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sphingosine ; analogs & derivatives ; pharmacology ; therapeutic use ; Vascular Diseases ; prevention & control

AIMTo study the effect of propylene glycol mannate sulfate (PGMS) on blood lipids and lipoprotein lipase in hyperlipidemic rat, and its anti-hyperlipidemic mechanism.

METHODSPGMS was administered ig at different doses (37.8 mg.kg-1.d-1 and 75.6 mg.kg-1.d-1) to hyperlipidemic rats for three weeks and blood serum was obtained after starved 12 h. Total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were examined. The mRNA expression of lipoprotein lipase (LPL) in liver, spleen and artery was detected by reverse transcription polymerase chain reaction (RT-PCR).

RESULTSPGMS significantly decreased the levels of TC, TG and LDL-C and increased that of HDL-C in hyperlipidemic serum dose-dependently. PGMS was shown to increase the level of LPL mRNA expression, which is related directly to the controlling effects of PGMS on blood lipids.

CONCLUSIONPGMS modulated blood lipids by promoting mRNA expression of LPL. This may be one important mechanism of PGMS to modulate blood lipids.

Animals ; Cholesterol, HDL ; blood ; Disease Models, Animal ; Hyperlipidemias ; blood ; drug therapy ; enzymology ; Lipoprotein Lipase ; biosynthesis ; genetics ; Male ; Propylene Glycols ; therapeutic use ; RNA, Messenger ; biosynthesis ; Random Allocation ; Rats ; Rats, Wistar ; Triglycerides ; blood

OBJECTIVETo study the effect of FTY720 on glomerulosclerosis and expression of cell cycle regulatory proteins in subtotal nephrectomized rats.

METHODSTwenty-four rats were divided into sham-operation group, glomerulosclerosis model group and FTY720 treated glomerulosclerosis group with 8 rats in each group. The rats in the latter two groups were subjected to subtotal nephrectomy. After operation, the FTY720 treated group was fed with FTY720 at a dose of 0.5 mg/(kg x d) for 12 weeks. Urine protein excretion was measured before operation and 2 w, 4 w, 8 w and 12 w after operation. Then the rats were sacrificed and the left kidney was subjected to pathological evaluation. The expression of collagen IV, fibronectin, and cyclin E, p21, p27 were determined by immunohistochemical methods.

RESULTSCompared with the control group, the model group showed higher daily urine protein (Up) excretion from 2 w, (8.07 +/- 1.61) mg/d and thereafter. At 12 w, Up increased to (28.60 +/- 12.21) mg/d in model group, significantly higher than that in control group (P < 0.05). After treatment with FTY720, Up began to decrease from 4 w after operation, (9.90 +/- 1.49) mg/d at that time and (11.35 +/- 2.09) mg/d at 12 w, both were significantly lower than those in model group (P < 0.01). The model group showed higher level of serum creatinine from 8 w, (61.08 +/- 4.28) micromol/L at that time, (130.20 +/- 23.90) micromol/L at 12 w, both were much higher than those in control group (P < 0.05). In FTY720 treated group, serum creatinine level was (80.19 +/- 7.11) micromol/L at 12 w, much lower than that in model group. The changes of BUN were similar to those of creatinine in each group. Renal pathology and immunohistological evaluation showed that FTY720 could significantly inhibit the expression of collagen-IV and fibronectin in glomeruli and attenuate the extent of glomerulosclerosis. Moreover, FTY720 could upregulate glomerular expression of p21 and downregulate glomerular expression of p27 and cyclin E. The expression levels of p21 and cyclin E were significantly lower in treatment group than in model group (P < 0.05), but still higher than those in control group (P < 0.05). p27 expression in glomeruli was stronger in treatment group than that in model group (P < 0.05), and lower than that in normal group but the difference was not significant.

CONCLUSIONFTY720 can diminish urine protein excretion and prevent glomerulosclerosis in subtotally nephrectomized rats. This protective effect is presumed to be associated with its effect on expression of cell cycle regulatory proteins, and inhibition of extracellular matrix accumulation in glomeruli.

Animals ; Cell Cycle Proteins ; biosynthesis ; Disease Models, Animal ; Fingolimod Hydrochloride ; Glomerulosclerosis, Focal Segmental ; metabolism ; pathology ; therapy ; Immunosuppressive Agents ; pharmacology ; therapeutic use ; Kidney ; pathology ; surgery ; Male ; Nephrectomy ; adverse effects ; Postoperative Period ; Propylene Glycols ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sphingosine ; analogs & derivatives ; pharmacology ; therapeutic use

OBJECTIVE: To observe the effect of FTY720 and ICAM-1 mAb mono and combination therapy in mouse-to-rat cardiac xenotransplantation. METHODS: Cardiac xenotransplantation was performed in abdominal site with micro-surgical technique. Recipients with xenografts were treated with different doses of FTY720 and/or ICAM-1 mAb. Graft survival, histopathology, infiltration of CD4+, and CD8+ T cells and levels of serum IL-2, IFN-gamma, IL-4, and IgM were investigated. RESULTS: Survival time of xenografts was (2.75+/- 0.43)d in the controls, survival of grafts treated with ICAM-1 mAb did not significantly improve. Treatment with large dose FTY720 led to a survival of (4.25+/- 0.71)d (P<0.01). Combination therapy with large dose FTY720 and ICAM-1 mAb achieved a significant prolongation of graft survival with (10.25+/- 2.12)d (P<0.01). Levels of serum IL-2, IFN-gamma and rat-anti-mouse IgM decreased in the combined therapy group. Pathologic lesion and infiltration of T cells in xenografts showed mitigated in the large dose combined therapy group. There was a significant negative correlation between the antibody level and the graft survival time (R=-0.754, P<0.01). CONCLUSION The combined therapy of FTY720 and ICAM-1 mAb can achieve a significant effect in the prolongation of heart xenograft survival and inhibition of xenoantibodies.
Animals ; Antibodies, Monoclonal ; therapeutic use ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Fingolimod Hydrochloride ; Graft Rejection ; blood ; etiology ; prevention & control ; Graft Survival ; drug effects ; Heart Transplantation ; adverse effects ; methods ; Immunoglobulin M ; blood ; Immunosuppressive Agents ; therapeutic use ; Intercellular Adhesion Molecule-1 ; immunology ; Interferon-gamma ; blood ; Interleukin-2 ; blood ; Interleukin-4 ; blood ; Mice ; Mice, Inbred BALB C ; Propylene Glycols ; therapeutic use ; Rats ; Rats, Wistar ; Sphingosine ; analogs & derivatives ; therapeutic use ; Time Factors ; Transplantation, Heterologous

Higher levels of body fat are associated with an increased risk for development numerous adverse health conditions. FTY720 is an immune modulator and a synthetic analogue of sphingosine 1-phosphate (S1P), activated S1P receptors and is effective in experimental models of transplantation and autoimmunity. Whereas immune modulation by FTY720 has been extensively studied, other actions of FTY720 are not well understood. Here we describe a novel role of FTY720 in the prevention of obesity, involving the regulation of adipogenesis and lipolysis in vivo and in vitro. Male C57B/6J mice were fed a standard diet or a high fat diet (HFD) without or with FTY720 (0.04 mg/kg, twice a week) for 6 weeks. The HFD induced an accumulation of large adipocytes, down-regulation of phosphorylated AMP-activated protein kinase alpha (p-AMPKalpha) and Akt (p-Akt); down-regulation of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and perilipin mRNA as well as up-regulation of phosphorylated HSL (p-HSL, Ser563) and glycogen synthase kinase 3 alpha/beta (p-GSK3alpha/beta). All these effects were blunted by FTY720 treatment, which inhibited adipogenesis and promoted lipolysis. Also, FTY720 significantly decreased lipid accumulation in maturing preadipocytes. FTY720 down-regulated the transcriptional levels of the PPARgamma, C/EBPalpha and adiponectin, which are markers of adipogenic differentiation. FTY720 significantly increased the release of glycerol and the expression of the HSL, ATGL and perilipin, which are regulators of lipolysis. These results show that FTY720 prevented obesity by modulating adipogenesis and lipolysis, and suggest that FTY720 is used for the treatment of obesity.
3T3-L1 Cells ; AMP-Activated Protein Kinases/metabolism ; Adipocytes/*drug effects/physiology ; Adipogenesis/drug effects ; Animals ; Anti-Obesity Agents/*pharmacology/therapeutic use ; Antigens, Differentiation/genetics/metabolism ; Carrier Proteins/genetics/metabolism ; Cell Size ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Enzyme Activation ; Gene Expression Regulation, Enzymologic/drug effects ; Glycogen Synthase Kinase 3/genetics/metabolism ; Lipase/genetics/metabolism ; Lipolysis/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/etiology/metabolism/*prevention & control ; Phosphoproteins/genetics/metabolism ; Phosphorylation ; Propylene Glycols/*pharmacology/therapeutic use ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-akt/metabolism ; Sphingosine/*analogs & derivatives/pharmacology/therapeutic use ; Sterol Esterase/metabolism