jte-013 and Disease-Models--Animal

Periodontitis is an inflammatory bone loss disease initiated by oral bacterial inflammation. Herein, we determined whether inhibition of sphingosine-1-phosphate receptor 2 (S1PR2, a G protein-coupled receptor) by its specific antagonist, JTE013, could alleviate ligature-induced periodontitis in mice.. C57BL/6 mice were placed with silk ligatures at the left maxillary second molar to induce experimental periodontitis. Mice were treated with JTE013 or control vehicle (dimethyl sulfoxide, DMSO) oral topically on the ligatures once daily. After 15 days of treatment, RNA was extracted from the lingual mucosal tissues to quantify IL-1β, IL-6, and TNF mRNA levels in the tissues. Alveolar bone loss was determined by micro-computed tomography. Sagittal periodontal tissue sections were cut and stained by hematoxylin and eosin (H&E) for general histology, or stained by tartrate-resistant acid phosphatase (TRAP) for osteoclasts.. Treatment with JTE013 attenuated ligature-induced alveolar bone loss compared with DMSO treatment. Treatment with JTE013 reduced IL-1β, IL-6, and TNF mRNA levels in murine gingival mucosal tissues, inhibited leukocyte infiltration in the periodontal tissues, and decreased the number of osteoclasts in the periodontal tissues compared with controls.. Oral topical administration of JTE013 alleviated periodontal inflammatory bone loss induced by ligature placement in mice.

Topics: Alveolar Bone Loss; Animals; Disease Models, Animal; Mice; Mice, Inbred C57BL; Osteoclasts; Periodontitis; Pyrazoles; Pyridines; Sphingosine-1-Phosphate Receptors; X-Ray Microtomography

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

To discover novel therapies that lower IOP by increasing aqueous humor outflow facility, ex vivo ocular perfusion systems provide a valuable tool. However, currently available designs are limited by their throughput. Here we report the development of a compact, scalable perfusion system with improved throughput and its validation using bovine and porcine eyes.. At a fixed IOP of 6 mm Hg, flow rate was measured by flow sensors. We validated the system by measuring the outflow responses to Y-39983 (a Rho kinase inhibitor), endothelin-1 (ET-1), ambrisentan (an antagonist for endothelin receptor A [ETA]), sphigosine-1-phosphate (S1P), JTE-013 (antagonist for S1P receptor 2 [S1P2]), S-nitroso-N-acetylpenicillamine (SNAP, a nitric oxide [NO] donor), and 3-Morpholino-sydnonimine (SIN-1, another NO donor).. The instrument design enabled simultaneous measurements of 20 eyes with a footprint of 1 m2. Relative to vehicle control, Y-39983 increased outflow by up to 31% in calf eyes. On the contrary, ET-1 decreased outflow by up to 79%, a response that could be blocked by pretreatment with ambrisentan, indicating a role for ETA receptors. Interestingly, the effect of ET-1 was also inhibited by up to 70% to 80% by pretreatment with NO donors, SNAP and SIN-1. In addition to testing in calf eyes, similar effects of ET-1 and ambrisentan were observed in adult bovine and porcine eyes.. The compact eye perfusion platform provides an opportunity to efficiently identify compounds that influence outflow facility and may lead to the discovery of new glaucoma therapies.

Topics: Animals; Aqueous Humor; Cattle; Computer-Aided Design; Disease Models, Animal; Endothelin-1; Equipment Design; Glaucoma; Intraocular Pressure; Perfusion; Pyrazoles; Pyridines; Swine; Trabecular Meshwork

This study aimed to quantify the effects of tumor necrosis factor (TNF) inhibitor Etanercept and sphingosine-1-phosphate receptor 2 antagonist JTE-013 on cochlear blood flow in guinea pigs after TNF-induced decrease.. Sudden sensorineural hearing loss is a common cause for disability and reduced quality of life. Good understanding of the pathophysiology and strong evidence-based therapy concepts are still missing. In various inner ear disorders, inflammation and impairment of cochlear blood flow (CBF) have been considered factors in the pathophysiology. A central mediator of inflammation and microcirculation in the cochlea is TNF. S1P acts downstream in one TNF pathway.. Cochlea lateral wall vessels were exposed surgically and assessed by intravital microscopy in guinea pigs in vivo. Twenty-eight animals were randomly distributed into four groups of seven each. Exposed vessels were superfused by TNF (5.0 ng/ml) and afterward repeatedly either by Etanercept (1.0 μg/ml), JTE-013 (10 μmol/L), or vehicle (0.9 % NaCl solution or ethanol: phosphate-buffered saline buffer, respectively).. After decreasing CBF with TNF (p <0.001, two-way RM ANOVA), both treatments reversed CBF, compared with vehicle (p <0.001, two-way RM ANOVA). The comparison of the vehicle groups showed no difference (p = 0.969, two-way RM ANOVA), while there was also no difference between the treatment groups (p = 0.850, two-way RM ANOVA).. Both Etanercept and JTE-013 reverse the decreasing effect of TNF on cochlear blood flow and, therefore, TNF and the S1P-signalling pathway might be targets for treatment of microcirculation-related hearing loss.

Topics: Animals; Cochlea; Disease Models, Animal; Etanercept; Guinea Pigs; Hearing Loss, Sensorineural; Immunosuppressive Agents; Microcirculation; Pyrazoles; Pyridines; Random Allocation; Tumor Necrosis Factor-alpha

Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that acts as a signal transducer by binding to S1P receptors (S1PR) 1 to 5. The S1P/S1PRs pathway has been associated with remodeling and allergic inflammation in asthma, but the expression pattern of S1PR and its effects on non-immune cells have not been completely clarified. The aim of this study was to examine the contribution of the signaling of S1P and S1PRs expressed in airway epithelial cells (ECs) to asthma responses in mice.. Bronchial asthma was experimentally induced in BALB/c mice by ovalbumin (OVA) sensitization followed by an OVA inhalation challenge. The effects of S1PR antagonists on the development of asthma were analyzed 24 h after the OVA challenge.. Immunohistological analysis revealed S1PR1-3 expression on mouse airway ECs. Quantitative real-time polymerase chain reaction demonstrated that S1P greatly stimulated the induction of CCL3 and TIMP2 mRNA in human airway ECs, i.e., BEAS-2B cells, in a dose-dependent manner. Pretreatment with the S1PR2 antagonist JTE013 inhibited the CCL3 gene expression in BEAS-2B cells. Immunohistological analysis also showed that the expression level of CCL3 was attenuated by JTE013 in asthmatic mice. Furthermore, JTE013 as well as anti-CCL3 antibody attenuated allergic responses. Intratracheal administration of JTE013 also attenuated eosinophilic reactions in bronchoalveolar lavage fluids. S1P induced transcription factor NFκB activation, while JTE013 greatly reduced the NFκB activation.. JTE013 attenuated allergic airway reactions by regulating CCL3 production from bronchial ECs. The intratracheal administration of JTE013 may be a promising therapeutic strategy for bronchial asthma.

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchi; Chemokine CCL3; Cytokines; Disease Models, Animal; Epithelial Cells; Female; Inflammation Mediators; Lysophospholipids; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; Pyrazoles; Pyridines; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; STAT3 Transcription Factor; Tissue Inhibitor of Metalloproteinase-2

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid produced by mast cells (MCs) on cross-linking of their high-affinity receptors for IgE by antigen that can amplify MC responses by binding to its S1P receptors. An acute MC-dependent allergic reaction can lead to systemic shock, but the early events of its development in lung tissues have not been investigated, and S1P functions in the onset of allergic processes remain to be examined.. We used a highly specific neutralizing anti-S1P antibody (mAb) and the sphingosine-1-phosphate receptor 2 (S1PR2) antagonist JTE-013 to study the signaling contributions of S1P and S1PR2 to MC- and IgE-dependent airway allergic responses in mice within minutes after antigen challenge.. Allergic reaction was triggered by a single intraperitoneal dose of antigen in sensitized mice pretreated intraperitoneally with anti-S1P, isotype control mAb, JTE-013, or vehicle before antigen challenge.. Kinetics experiments revealed early pulmonary infiltration of mostly T cells around blood vessels of sensitized mice 20 minutes after antigen exposure. Pretreatment with anti-S1P mAb inhibited in vitro MC activation, as well as in vivo development of airway infiltration and MC activation, reducing serum levels of histamine, cytokines, and the chemokines monocyte chemoattractant protein 1/CCL2, macrophage inflammatory protein 1α/CCL3, and RANTES/CCL5. S1PR2 antagonism or deficiency or MC deficiency recapitulated these results. Both in vitro and in vivo experiments demonstrated MC S1PR2 dependency for chemokine release and the necessity for signal transducer and activator of transcription 3 activation.. Activation of S1PR2 by S1P and downstream signal transducer and activator of transcription 3 signaling in MCs regulate early T-cell recruitment to antigen-challenged lungs through chemokine production.

Topics: Adoptive Transfer; Animals; Antigens; Cell Degranulation; Chemokines; Cytokines; Disease Models, Animal; Female; Humans; Hypersensitivity; Lung; Lysophospholipids; Macrophage Activation; Macrophages; Mast Cells; Mice; Mice, Transgenic; Pyrazoles; Pyridines; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors; STAT3 Transcription Factor; T-Lymphocytes

Glucolipotoxic stress has been identified as a key player in the progression of pancreatic β-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic β-cells but also regulate β-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in β-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P2) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P2 axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by β-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P2, the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued β-cell damage clearly indicating an important role of the S1P2 in β-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish β-cell dysfunction and the development of T2D.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lysophospholipids; Male; Mice; Mice, Obese; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridines; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine

The use and effectiveness of current stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in experimental stroke. In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels. S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples. In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury. Therapeutic targeting of this novel pathway could have important translational relevance to stroke patients.

Topics: Adult; Aged; Animals; Brain; Capillary Permeability; Cells, Cultured; Cerebrovascular Circulation; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Female; Humans; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Mice, Knockout; Microvessels; Middle Aged; Neuroglia; Neurons; Pyrazoles; Pyridines; Random Allocation; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Young Adult

Bile acids have been shown to be important regulatory molecules for cells in the liver and gastrointestinal tract. They can activate various cell signaling pathways including extracellular regulated kinase (ERK)1/2 and protein kinase B (AKT) as well as the G-protein-coupled receptor (GPCR) membrane-type bile acid receptor (TGR5/M-BAR). Activation of the ERK1/2 and AKT signaling pathways by conjugated bile acids has been reported to be sensitive to pertussis toxin (PTX) and dominant-negative Gα(i) in primary rodent hepatocytes. However, the GPCRs responsible for activation of these pathways have not been identified. Screening GPCRs in the lipid-activated phylogenetic family (expressed in HEK293 cells) identified sphingosine-1-phosphate receptor 2 (S1P(2) ) as being activated by taurocholate (TCA). TCA, taurodeoxycholic acid (TDCA), tauroursodeoxycholic acid (TUDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and S1P-induced activation of ERK1/2 and AKT were significantly inhibited by JTE-013, a S1P(2) antagonist, in primary rat hepatocytes. JTE-013 significantly inhibited hepatic ERK1/2 and AKT activation as well as short heterodimeric partner (SHP) mRNA induction by TCA in the chronic bile fistula rat. Knockdown of the expression of S1P(2) by a recombinant lentivirus encoding S1P(2) shRNA markedly inhibited the activation of ERK1/2 and AKT by TCA and S1P in rat primary hepatocytes. Primary hepatocytes prepared from S1P(2) knock out (S1P(2) (-/-) ) mice were significantly blunted in the activation of the ERK1/2 and AKT pathways by TCA. Structural modeling of the S1P receptors indicated that only S1P(2) can accommodate TCA binding. In summary, all these data support the hypothesis that conjugated bile acids activate the ERK1/2 and AKT signaling pathways primarily through S1P(2) in primary rodent hepatocytes.

Topics: Animals; Bile Acids and Salts; Biliary Fistula; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; HEK293 Cells; Hepatocytes; Humans; Male; Mice; Mice, Knockout; Primary Cell Culture; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Lysosphingolipid; RNA, Small Interfering; Rodentia; Sphingosine-1-Phosphate Receptors; Taurocholic Acid

Sinusoidal vasoconstriction, in which hepatic stellate cells operate as contractile machinery, has been suggested to play a pivotal role in the pathophysiology of portal hypertension. We investigated whether sphingosine 1-phosphate (S1P) stimulates contractility of those cells and enhances portal vein pressure in isolated perfused rat livers with Rho activation by way of S1P receptor 2 (S1P(2) ). Rho and its effector, Rho kinase, reportedly contribute to the pathophysiology of portal hypertension. Thus, a potential effect of S1P(2) antagonism on portal hypertension was examined. Intravenous infusion of the S1P(2) antagonist, JTE-013, at 1 mg/kg body weight reduced portal vein pressure by 24% without affecting mean arterial pressure in cirrhotic rats induced by bile duct ligation at 4 weeks after the operation, whereas the same amount of S1P(2) antagonist did not alter portal vein pressure and mean arterial pressure in control sham-operated rats. Rho kinase activity in the livers was enhanced in bile duct-ligated rats compared to sham-operated rats, and this enhanced Rho kinase activity in bile duct-ligated livers was reduced after infusion of the S1P(2) antagonist. S1P(2) messenger RNA (mRNA) expression, but not S1P(1) or S1P(3) , was increased in bile duct-ligated livers of rats and mice and also in culture-activated rat hepatic stellate cells. S1P(2) expression, determined in S1P 2LacZ/+ mice, was highly increased in hepatic stellate cells of bile duct-ligated livers. Furthermore, the increase of Rho kinase activity in bile duct-ligated livers was observed as early as 7 days after the operation in wildtype mice, but was less in S1P 2-/- mice.. S1P may play an important role in the pathophysiology of portal hypertension with Rho kinase activation by way of S1P(2) . The S1P(2) antagonist merits consideration as a novel therapeutic agent for portal hypertension.

Topics: Animals; Bile Ducts; Cells, Cultured; Disease Models, Animal; Enzyme Activation; Gene Expression Regulation; Hemodynamics; Hepatic Stellate Cells; Hypertension, Portal; Immunoblotting; Immunohistochemistry; Infusions, Intravenous; Ligation; Male; Mice; Mice, Transgenic; Pyrazoles; Pyridines; Random Allocation; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Lysosphingolipid; Reference Values; rho-Associated Kinases; Sensitivity and Specificity

Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P), which activates G protein-coupled receptors to regulate vascular and immune cells. The role of S1P receptors in atherosclerosis has not been examined.. We tested the hypothesis that S1P receptor-2 (S1PR2) regulates atherosclerosis. Apoe(-/-) S1pr2(-/-) mice showed greatly attenuated atherosclerosis compared with the Apoe(-/-) mice. Bone marrow transplant experiments indicate that S1PR2 function in the hematopoietic compartment is critical. S1PR2 is expressed in bone marrow-derived macrophages and in macrophage-like foam cells in atherosclerotic plaques. Reduced macrophage-like foam cells were found in the atherosclerotic plaques of Apoe(-/-)S1pr2(-/-) mice, suggesting that S1PR2 retains macrophages in atherosclerotic plaques. Lipoprotein profiles, plasma lipids, and oxidized low-density lipoprotein uptake by bone marrow-derived macrophages were not altered by the S1pr2 genotype. In contrast, endotoxin-induced inflammatory cytokine (interleukin [IL]-1β, IL-18) levels in the serum of S1PR2 knockout mice were significantly reduced. Furthermore, treatment of wild-type mice with S1PR2 antagonist JTE-013 suppressed IL-1β and IL-18 levels in plasma.. These data suggest that S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis.

Topics: Animals; Aortic Diseases; Apolipoproteins E; Atherosclerosis; Bone Marrow Transplantation; Disease Models, Animal; Endotoxins; Inflammation; Inflammation Mediators; Interleukin-18; Interleukin-1beta; Lipids; Lipoproteins; Lipoproteins, LDL; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyrazoles; Pyridines; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors

S1P acts via the S1PR family of G protein-coupled receptors to regulate a variety of physiological responses. Whereas S1P1R activates G(i)- and PI-3-kinase-dependent signals to inhibit vascular permeability, the related S1P2R inhibits the PI-3-kinase pathway by coupling to the Rho-dependent activation of the PTEN phosphatase. However, cellular consequences of S1P2R signaling in the vascular cells are not well understood.. Selective signaling of the S1P2R was achieved by adenoviral-mediated expression in endothelial cells. Secondly, endogenously expressed S1P2R was blocked by the specific pharmacological antagonist JTE013. Activation of S1P2R in endothelial cells resulted in Rho-ROCK- and PTEN-dependent disruption of adherens junctions, stimulation of stress fibers, and increased paracellular permeability. JTE013 treatment of naive endothelial cells potentiated the S1P1R-dependent effects such as formation of cortical actin, blockade of stress fibers, stimulation of adherens junction assembly, and improved barrier integrity. This observation was extended to the in vivo model of vascular permeability in the rat lung: the S1P2R antagonist JTE013 significantly inhibited H2O2-induced permeability in the rat lung perfused model.. S1P2R activation in endothelial cells increases vascular permeability. The balance of S1P1 and S1P2 receptors in the endothelium may determine the regulation of vascular permeability by S1P.

Topics: Adherens Junctions; Animals; Antigens, CD; Cadherins; Capillary Permeability; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Humans; Hydrogen Peroxide; Intracellular Signaling Peptides and Proteins; Lysophospholipids; Phosphorylation; Protein Serine-Threonine Kinases; PTEN Phosphohydrolase; Pulmonary Edema; Pyrazoles; Pyridines; rac GTP-Binding Proteins; Rats; Receptors, G-Protein-Coupled; Receptors, Lysosphingolipid; rho GTP-Binding Proteins; rho-Associated Kinases; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Stress Fibers; Time Factors; Transfection

Blood platelets store sphingosine 1-phosphate (S1P) abundantly and release this bioactive lipid extracellularly. S1P acts as an intercellular mediator through interaction with the endothelial differentiation gene (EDG)/S1P family of G protein-coupled receptors. Of the EDG family S1P receptors, EDG-5 (S1P2) is inhibited in migration induced by S1P. Diabetes impairs numerous aspects of tissue repair. Failure of wound angiogenesis is known to delay diabetic wound healing.. We examined whether S1P subcutaneous injection could improve the healing of full-thickness skin wounds in healthy and diabetic mice. We further determine if the combined S1P and EDG-5 (S1P2) antagonist injection in diabetic mice could affect wound healing. Finally, we examined the histopathological findings of the wound following S1P injection in diabetic mice.. Eight- to 10-week-old BALA/c mice, diabetic db/db mice and Wister rats were used for the studies. A full-thickness wound was made on the dorsal skin of the healthy and diabetic mice. Either 10 microM or 100 microM of S1P or vehicle control (BSA/PBS) was injected into the wound bed every day. We calculated the wound area after each injection. EDG-5 (S1P2) antagonist (JTE-013) or vehicle (DMSO) was then injected in addition to the S1P around the dorsal wound of diabetic mice and the wound diameter was measured. Wound tissue samples were excised following injection for histopathological examination.. Wound area in normal BALA/c mice did not significantly decrease upon S1P injection compared to S1P-untreated controls. S1P injection alone showed significant promotion of wound healing in diabetic mice compared to no S1P treatment. The combination of S1P and EDG-5 (S1P2) receptor antagonist administration induced maximal wound healing in diabetic mice. Histopathological examination revealed that S1P induces neo-vascularization potential in rats and diabetic mice wound.. S1P injection in diabetic mice significantly accelerated cutaneous wound healing in the neo-vascularization process. The results demonstrate that S1P affects and sustains all key cellular processes responsible for wound repair and point to a unique potential for this molecule in the therapy of diabetic wounds, particularly as an angiogenic agent in treatment of diabetic wounds.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Drug Therapy, Combination; Injections, Subcutaneous; Lysophospholipids; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Neovascularization, Physiologic; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptors, Lysosphingolipid; Skin; Sphingosine; Wound Healing