Enhancing Perpendicular Magnetic Anisotropy in Garnet Ferrimagnet by Interfacing with Few-Layer WTe2.

Engineering magnetic anisotropy in a ferro- or ferrimagnetic (FM) thin film is crucial in a spintronic device. One way to modify the magnetic anisotropy is through the surface of the FM thin film. Here, we report the emergence of a perpendicular magnetic anisotropy (PMA) induced by interfacial interactions in a heterostructure comprised of a garnet ferrimagnet, Y3Fe5O12 (YIG), and a low-symmetry, high spin-orbit coupling (SOC) transition metal dichalcogenide, WTe2. At the same time, we also observed an enhancement in Gilbert damping in the WTe2-covered YIG area. Both the magnitude of interface-induced PMA and the Gilbert damping enhancement have no observable WTe2 thickness dependence down to a single quadruple layer, indicating that the interfacial interaction plays a critical role. The ability of WTe2 to enhance the PMA in FM thin film, combined with its previously reported capability to generate out-of-plane damping like spin torque, makes it desirable for magnetic memory applications.

Nonlocal Uniform-Mode Ferromagnetic Resonance Spin Pumping.

Nonlocal spin transport using lateral structures is attractive for spintronic devices. Typically, a spin current is generated by a ferromagnetic (FM) or a heavy metal (HM) electrode in a nonlocal structure, which can be detected by another FM or HM electrode. Here, we report a new nonlocal spin injection scheme using uniform-mode ferromagnetic resonance (FMR) spin pumping in Pt/Y3Fe5O12 (YIG) lateral structures. This scheme is enabled by well-separated resonant fields of Pt/YIG and bare YIG due to substantial change of anisotropy in YIG films induced by a Pt overlayer, allowing for clearly distinguishable local and nonlocal spin pumping. Our results show that the spin decay length of nonlocal uniform-mode spin pumping in 20 nm YIG films is 2.1 µm at room temperature.

Opto-Valleytronic Spin Injection in Monolayer MoS2/Few-Layer Graphene Hybrid Spin Valves.

Two-dimensional (2D) materials provide a unique platform for spintronics and valleytronics due to the ability to combine vastly different functionalities into one vertically stacked heterostructure, where the strengths of each of the constituent materials can compensate for the weaknesses of the others. Graphene has been demonstrated to be an exceptional material for spin transport at room temperature; however, it lacks a coupling of the spin and optical degrees of freedom. In contrast, spin/valley polarization can be efficiently generated in monolayer transition metal dichalcogenides (TMD) such as MoS2 via absorption of circularly polarized photons, but lateral spin or valley transport has not been realized at room temperature. In this Letter, we fabricate monolayer MoS2/few-layer graphene hybrid spin valves and demonstrate, for the first time, the opto-valleytronic spin injection across a TMD/graphene interface. We observe that the magnitude and direction of spin polarization is controlled by both helicity and photon energy. In addition, Hanle spin precession measurements confirm optical spin injection, spin transport, and electrical detection up to room temperature. Finally, analysis by a one-dimensional drift-diffusion model quantifies the optically injected spin current and the spin transport parameters. Our results demonstrate a 2D spintronic/valleytronic system that achieves optical spin injection and lateral spin transport at room temperature in a single device, which paves the way for multifunctional 2D spintronic devices for memory and logic applications.

Molecular mechanisms involved in podocyte EMT and concomitant diabetic kidney diseases: an update.

Epithelial-mesenchymal transition (EMT) is a tightly regulated process by which epithelial cells lose their hallmark epithelial characteristics and gain the features of mesenchymal cells. For podocytes, expression of nephrin, podocin, P-cadherin, and ZO-1 is downregulated, the slit diaphragm (SD) will be altered, and the actin cytoskeleton will be rearranged. Diabetes, especially hyperglycemia, has been demonstrated to incite podocyte EMT through several molecular mechanisms such as TGF-ß/Smad classic pathway, Wnt/ß-catenin signaling pathway, Integrins/integrin-linked kinase (ILK) signaling pathway, MAPKs signaling pathway, Jagged/Notch signaling pathway, and NF-κB signaling pathway. As one of the most fundamental prerequisites to develop ground-breaking therapeutic options to prevent the development and progression of diabetic kidney disease (DKD), a comprehensive understanding of the molecular mechanisms involved in the pathogenesis of podocyte EMT is compulsory. Therefore, the purpose of this paper is to update the research progress of these underlying signaling pathways and expound the podocyte EMT-related DKDs.

Research progress in phytochemistry and biology of Aframomum species.

CONTEXT: The African genus Aframomum (Zingiberaceae) is a group of diverse tropical plants frequently collected yet largely neglected taxonomically. The current and unprecedented loss of species due to man-made habitat destruction and climate change adds a desperate urgency not only to understand the phylogenetics, chemotaxonomy and biology, but also to preserve the quickly disappearing species. OBJECTIVES: The present systematic review reports on the research progress in phytochemistry, pharmacology and toxicology of Aframomum species. METHODOLOGY: Scientific databases such as MedSci, PubMed, Scopus, Google Scholar and Web of Knowledge were used to retrieve publications (from the year 1990 to 2014) related to Aframomum plants, isolated compounds and their bioactivity, phytochemistry and toxicology. The keywords combinations for the search were: Aframomum; chemotaxonomy, phylogenetics, pharmacology and bioactive metabolites and toxicology. A total of 71 research articles that report on the biological activity of extracts and chemical constituents were recovered and presented in this review. RESULTS: Most published data related to the potential of Aframomum melegueta, a medicinal plant from West and Central Africa. The potential of phenols and terpenoids isolated from Aframomum plants were generally much better documented than that of arylalkanoids. CONCLUSION: Aframomum genus represents an enormous resource for novel compounds with a range of medicinal properties. However, these plants are under-researched and their conservation is poor. To unravel their full potential, efforts should be strengthened throughout the continent to establish the taxonomy, preserve the genus and explore novel medicinal properties.

De novo design of caseinolytic protein proteases inhibitors based on pharmacophore and 2D molecular fingerprints.

Caseinolytic protein proteases (ClpP) are large oligomeric protein complexes that contribute to cell homeostasis as well as virulence regulation in bacteria. Inhibitors of ClpP can significantly attenuate the capability to produce virulence factors of the bacteria. In this work, we developed a workflow to expand the chemical space of potential ClpP inhibitors based on a set of ß-lactones. In our workflow, an artificial pharmacophore model was generated based on HipHop and HYPOGEN method. A de novo compound library based on molecular fingerprints was constructed and virtually screened by the pharmacophore model. The results were further investigated by molecular docking study. The workflow successfully achieved potential ClpP inhibitors. It could be applied to design more novel potential ClpP inhibitors and provide theoretical basis for the further optimization of the hit compounds.

Antiplatelet aggregation and endothelial protection of I4, a new synthetic anti-diabetes sulfonylurea compound.

I4 is a new synthetic anti-diabetes sulfonylurea compound. The aim of present study was to investigate the preventive effects and primary action mechanisms of I4 on platelet-mediated arterial thrombosis. Platelet aggregation and 5-hydroxytryptamine (5-HT) secretion ex vivo was detected. The time-to-occlusion (TTO), thrombus weight and content of von Willebrand factor (vWF) in rat model of electrical- and ferric chloride-induced vessel occlusion were determined. Meanwhile, a rat model of type 2 diabetes mellitus (T2DM) was established to evaluate the effect of I4 on levels of plasma p-selectin, 6-keto-prostaglandin F1a (6-keto-PGF1a), thromboxane B2 (TXB2), tissue-type plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1). NO synthesis, NOS activity, adhesion of platelet toward endothelial cell and intercellular adhesion molecule-1 (ICAM-1) expression were examined. Results showed that I4 exhibited a higher inhibitory potency than Glimepiride on ADP-induced platelet aggregation and 5-HT release ex vivo. In addition, I4 reduced the thrombus weight and content of vWF and markedly prolonged TTO. Oral administration of I4 (1 ∼ 10 mg/kg) inhibited p-selectin production, elevated the ratio of plasma 6-keto-PGF1a/TXB2 and t-PA/PAI-1 in T2DM rats. Furthermore, I4 significantly improved NO synthesis and NOS activity, lowered adhesion ratio of platelet toward endothelial cells and ICAM-1 expression on HUVECs. These observations suggest that I4 markedly improves platelet-mediated arterial thrombosis by inhibiting platelet activation and release reaction, ameliorating the endothelial dysfunction such as the suppression of vWF production and the reduction of the overexpression of ICAM-1, displayed its potential in alleviating diabetes-associated vascular complications.

Hybrid spin Hall nano-oscillators based on ferromagnetic metal/ferrimagnetic insulator heterostructures.

Spin-Hall nano-oscillators (SHNOs) are promising spintronic devices to realize current controlled GHz frequency signals in nanoscale devices for neuromorphic computing and creating Ising systems. However, traditional SHNOs devices based on transition metals have high auto-oscillation threshold currents as well as low quality factors and output powers. Here we demonstrate a new type of hybrid SHNO based on a permalloy (Py) ferromagnetic-metal nanowire and low-damping ferrimagnetic insulator, in the form of epitaxial lithium aluminum ferrite (LAFO) thin films. The superior characteristics of such SHNOs are associated with the excitation of larger spin-precession angles and volumes. We further find that the presence of the ferrimagnetic insulator enhances the auto-oscillation amplitude of spin-wave edge modes, consistent with our micromagnetic modeling. This hybrid SHNO expands spintronic applications, including providing new means of coupling multiple SHNOs for neuromorphic computing and advancing magnonics.

Synthesis and biological evaluation of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups as potential hypoglycemic agents.

A novel class of sulfonylurea and thiourea derivatives substituted with benzenesulfonamide groups were designed and synthesized. The target compounds were assayed for the effects on the insulin release of isolated rat pancreatic islets and the glucose transport in adipocytes of rats. Some of them exhibited high potency. Compound 10 also had potent antiplatelet activity and showed an excellent property to protect collagen-epinephrine-induced mice mortality as well as plasma glucose-lowering activity in vivo. The preliminary pharmacological profile of compound 10 showed that it might be useful in the treatment of diabetics with cardiovascular and nephropathy complications.

[Design, synthesis and hypoglycemic activity of alpha-benzylsuccinic acid derivatives].

Based on the SAR of glinide agents, mitiglinide has been modified to study the SAR of glinides. a-Benzylsuccinic acid derivatives which were designed and synthesized in order to find some more hypoglycemic active agents and further investigate the SAR of this class of compounds. From ethyl succinate and substituded benzaldehydes, twelve new target compounds were synthesized by codensation, hydrolysis, anhydridization, amidation and hydrogenization reactions, and their hypoglycemic activity were evaluated with glucose oxidase kit. All the compounds were characterized by elemental analysis, IR, 1H NMR and ESI-MS. The preliminary pharmacological test showed that the compounds have good hypoglycemic activity, especially 6c, 6e and 6g, 6e showed the same hypoglycemic potency as nateglinide.

Luteolin attenuates high glucose-induced podocyte injury via suppressing NLRP3 inflammasome pathway.

AIMS: Diabetic nephropathy is a growing health concern, which is reported to be associated with inflammation. Luteolin has been explored for the treatment of some diabetic complications. Although several studies have verified the effect of luteolin on diabetic nephropathy, the mechanism by which the therapeutic effects of luteolin on diabetic nephropathy has not been established. Therefore, we aimed to investigate the effect of luteolin on diabetic nephropathy and its underlying mechanism. MAIN METHODS: We used western blot, Real-time PCR, immunofluorescence and flow cytometry to analyze the effects of luteolin on podocyte injury and NOD-like receptor family and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in high glucose (HG) condition. Reactive oxygen species (ROS) generation was measured by flow cytometry and malondialdehyde (MDA) level. To investigate the potential mechanism, we examined cell apoptosis upon transfection of siNLRP3. KEY FINDINGS: We showed that luteolin treatment could protect podocyte against HG-induced cell apoptotic and mitochondrial membrane potential collapse. In addition, luteolin significantly reduced NLRP3 inflammasome formation and subsequent interleukin-1ß (IL-1ß) secretion in HG-induced MPC-5 cells. Interestingly, siNLRP3 abolished the effect of luteolin on cell apoptosis, suggesting that the anti-apoptotic effect was found to be mostly related to NLRP3 inflammasome. SIGNIFICANCE: In summary, our data demonstrated the abilities of luteolin to inhibit podocyte injury and NLRP3 inflammasome activation, which could be used in the treatment of diabetic nephropathy.

Spin inversion in graphene spin valves by gate-tunable magnetic proximity effect at one-dimensional contacts.

Graphene has remarkable opportunities for spintronics due to its high mobility and long spin diffusion length, especially when encapsulated in hexagonal boron nitride (h-BN). Here, we demonstrate gate-tunable spin transport in such encapsulated graphene-based spin valves with one-dimensional (1D) ferromagnetic edge contacts. An electrostatic backgate tunes the Fermi level of graphene to probe different energy levels of the spin-polarized density of states (DOS) of the 1D ferromagnetic contact, which interact through a magnetic proximity effect (MPE) that induces ferromagnetism in graphene. In contrast to conventional spin valves, where switching between high- and low-resistance configuration requires magnetization reversal by an applied magnetic field or a high-density spin-polarized current, we provide an alternative path with the gate-controlled spin inversion in graphene.

Bio-preparation of (R)-DMPM using whole cells of Pseudochrobactrum asaccharolyticum WZZ003 and its application on kilogram-scale synthesis of fungicide (R)-metalaxyl.

Methyl (R)-N-(2,6-dimethylphenyl)alaninate ((R)-DMPM) is a key chiral intermediate for the production of (R)-metalaxyl, which is one of the best-selling fungicides. A new strain, Pseudochrobactrum asaccharolyticum WZZ003, was identified as a biocatalyst for the enantioselective hydrolysis of (R,S)-DMPM. The key parameters including pH, temperature, rotation speed and substrate concentrations were optimized in the enantioselective hydrolysis of (R,S)-DMPM. After the 48 h hydrolysis of 256 mM (R,S)-DMPM under the optimized reaction conditions, the enantiomeric excess of product (e.e.p ) was up to 99% and the conversion was nearly 50%. Subsequently, the unhydrolyzed (S)-DMPM was converted to (R,S)-DMPM through the n-butanal-catalyzed racemization. Furthermore, stereoselective hydrolysis of (R,S)-DMPM catalyzed by whole cells of P. asaccharolyticum WZZ003 was scaled up to kilogram-scale, offering (R)-MAP-acid with 98.6% e.e.p and 48.0% yield. Moreover, (R)-metalaxyl was prepared at kilogram scale after subsequent esterification and coupling reactions. Therefore, a practical production process of (R)-DMPM and (R)-metalaxyl with the prospect of industrialization was developed in this study. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:921-928, 2018.

I4, a synthetic anti-diabetes agent, attenuates atherosclerosis through its lipid-lowering, anti-inflammatory and anti-apoptosis properties.

Here, we investigated whether I4, which was initially developed as a hypoglycemic agent, possesses anti-atherosclerotic activity and attempted to elucidate the probable mechanism of action underlying this activity. ApoE-/- mice were fed a Western diet and simultaneously administered I4, glimepiride, or pioglitazone once daily for 12 weeks, and the atherosclerotic vascular lesions, lipid content, and expression levels of LOX-1, ICAM-1, VCAM-1 and Bax/Bcl-2 in mouse aortas were assessed. RAW264.7 macrophage-derived foam cells were obtained via ox-LDL stimulation to investigate the lipid-lowering, anti-atherosclerotic inflammation and anti-apoptotic effect of I4. The data indicated that I4 significantly decreased the lipid accumulation in the circulation and tissue, especially for TG and FFA levels (p < 0.05 vs model group), alleviating the arterial and liver lesions induced by lipotoxicity. Its lipid-reducing effects may due to LOX-1and CD36 expression suppression. I4, at doses of 20 mg/kg and 10 mg/kg, significantly decreased serum IL-6, IL-1ß, and TNF-α production and suppressed the expression of p-ERK, p-p38, VCAM-1 and ICAM-1 protein. I4 attenuated atherosclerotic inflammation by blocking NF-κB nuclear translocation, suppressing MAPK/NF-κB signaling pathway and diminishing NF-κB-VCAM-1 promoter region binding. Additionally, I4 suppressed p-p53 and cleaved-caspase-3 expression to inhibit foam cell apoptosis induced by ox-LDL uptake. Overall, I4 exerts potent inhibitory effects on atherosclerosis onset and development.

G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in ApoE-/- mice.

Atherosclerosis attracts increasing global attention because of its morbidity and mortality. G004, as a synthetic sulfonylurea compound, has been confirmed to have anti-hyperglycaemia, anti-platelet and anti-thrombus effects. The aim of the present study was to investigate whether G004 suppress the onset and development of atherosclerosis and illuminate its probable mechanism of action. ApoE-/- mice that were fed a high-fat diet were randomly divided into five groups by weight; subsequently, they were treated with vehicle, G004, at different doses or atorvastatin once daily for 12weeks. Meanwhile, C57BL/6 mice with the same diet served as the normal controls. Then, the serum lipid profiles and histopathological damage to the liver, kidney, aortic arch and aortic root were analysed. The activation of endothelial nitric oxide synthase (eNOS) and levels of inflammatory markers were detected. Reverse cholesterol transport (RCT) was assessed in vivo by intraperitoneal injection of RAW264.7 cells that were radiolabelled with 3H-cholesterol. The results indicated that G004 ameliorated the serum lipid accumulation, atherosclerotic lesions and liver steatosis. Additionally, this compound increased the expression of SIRT1 and eNOS as well as the phosphorylation and deacetylation of eNOS in the aorta, alleviating the inflammatory state. RCT was promoted in ApoE-/- mice, which was accompanied by increased expression of SIRT1/LXRα/ABCA1/G1 in the liver, and similar results appeared in the cholesterol efflux assay in RAW264.7 cells. The results provide a strong rationale for G004 to be an efficient anti-atherosclerosis agent that improved vascular endothelial dysfunction by stimulating SIRT1/eNOS and promoted RCT by stimulating SIRT1/LXRα/ABCA1/G1.

Hepatoprotective effects of AdipoRon against d-galactosamine-induced liver injury in mice.

Adiponectin is an antidiabetic and antiatherogenic adipokine, which plays distinct roles in the balance of energy homoeostasis. As an insulin sensitizing hormone, adiponectin exerts multiple biological effects by the specific receptors (AdipoR1 and AdipoR2), through activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)α pathways. AdipoRon, an orally active synthetic small-molecule AdipoR agonist, shows very similar effects to adiponectin in vitro and in vivo, which could be a promising therapeutic approach for obesity-related disorders. In view of the regulatory effects of adiponectin or AdipoRon on inflammatory response and energy metabolism, they might be endowed a curative potential for tissue damage. Hence, its effects and possible mechanism were investigated. In vitro studies on hepatocytes (L02) and macrophages (RAW264.7) suggested a protective and anti-inflammatory potential of AdipoRon. The effects were verified in acute hepatic injury mice induced by d-galactosamine (D-GalN): hepatic lesions were restored by AdipoRon or bicyclol (positive reference drug) pretreatment, which were characterized by a significant increase in serological and hepatic biomarkers (AST, ALT, MDA and NOSs). Besides, AdipoRon attenuated the inflammation in the liver, characterized by the dwindling proinflammatory macrophage infiltration, as well as the shrinkage of tumor necrosis factor-α (TNF-α), transforming growth factor beta 1 (TGF-ß1), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6); meanwhile conversely promoted AMPK activation by phosphorylation. Combined with liver histopathology, these results demonstrated the hepatoprotective effects of AdipoRon against D-GalN-induced damage, which might be ascribed to the attenuation of inflammation, inhibition of free radical reactions, as well as enhancement of liver energy metabolism.

Reno-protection of G004, a novel anti-diabetic sulfonylurea in db/db mice.

1-[4-[2-(4-Bromobenzene-sulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcyclohexyl) urea (G004, CAS865483-06-3) is a synthetic sulfonylurea, incorporating the hypoglycemic active structure of glimepiride (CAS 93479-97-1) and anti-TXA2 receptor (TP) active structure of BM-531(CAS 284464-46-6). In this study, we evaluated the effect of G004 on hyperglycemia and dyslipidemia as well as diabetic nephropathy (DN) in db/db mice by gavage over 90 consecutive days of treatment. The fasting blood glucose (FBG), glucose, and insulin tolerance as well as dyslipidemia were effectively ameliorated in db/db mice treated with G004. Interestingly, renal histological results of db/db mice revealed that G004 markedly reversed the expansion of mesangial extracellular matrix (ECM), the early hallmark of DN. Indeed, G004 treatment downregulated the renal expressions of type 4 collagen (Col IV) and transforming growth factor-ß1 (TGF-ß1) in db/db mice. In addition, imbalance in expressions of matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor-1 (TIMP-1) in db/db mice kidneys was observed. However, G004 increased and decreased the expressions of MMP-9 and TIMP-1, respectively. It is well known that TGF-ß pathway signaling plays an essential role in hyperglycemia-induced cell protein synthesis. On the other hand, MMP/TIMP system is responsible for the breakdown and turnover of ECM. Thus, we speculate that G004 possibly attenuated ECM accumulation via remodeling the synthesis and degradation of ECM component Col IV through modulation in TGF-ß1 and MMP-9/TIMP-1 expressions in kidneys of db/db mice. Results from this study provide a strong rationale for G004 to be an efficient glucose-controlling agent with significant reno-protective properties.

Genistein: a promising therapeutic agent for obesity and diabetes treatment.

Obesity and type 2 diabetes are serious public health problems worldwide. Considerable efforts have highlighted the link between these two diseases. The high levels of pro-inflammatory cytokines and leptin, secreted by the adipose tissue, contribute actively to the insulin resistance induction; and the high levels of free fatty acids leads to an overproduction of reactive oxygen species that participate in pancreatic ß cells failure and apoptosis. These two induced dysfunctions are the fundamental defects that precede type 2 diabetes. Genistein, an isoflavone present in a number of edible plants, has been reported as a potential therapeutic agent with anti-cancer, anti-oxidant, anti-inflammatory and anti-osteoporosis effects and proposed as a promising compound for the treatment of metabolic disorders. The pleiotropic effects of genistein are due to its multiple mechanisms of action and the multitude of cell signaling pathways involved. Here, we review the effects of genistein on obesity and type 2 diabetes and emphasize on its action on adipocyte life-cycle, obesity-related low-grade inflammation, oxidative stress and the protective effects on pancreatic ß cells.

Oroxylin A reverses P-glycoprotein-mediated multidrug resistance of MCF7/ADR cells by G2/M arrest.

Oroxylin A is a naturally occurring monoflavonoid isolated from the root of Scutellaria baicalensis Georgi, which has been used in traditional Chinese medicine for its anti-tumor, anti-inflammatory and anti-bacterial properties. The purpose of this study is to investigate the reversal effect and the fundamental mechanisms of oroxylin A in MCF7/ADR cells. Data indicated that oroxylin A showed strong reversal potency in MCF7/ADR cells and the reversal fold (RF) reached 4.68. After treatment with oroxylin A, MCF7/ADR cells displayed reduced functional activity and expression of MDR1 at both the protein and mRNA levels. Meanwhile, oroxylin A induced cells G2/M arrest in a concentration-dependent manner by increasing the expression of p-Chk2 (Thr68). Moreover, western blot and EMSA assays were used to reveal the inhibition of NF-κB in nucleus and the suppression of NF-κB binding activity by oroxylin A. NSC 109555 ditosylate-Chk2 inhibitor partly dismissed G2/M arrest induced by oroxylin A, reversed the increased trend of p-Chk2 and p-P53 (Ser20), inhibited the decreasing effect of oroxylin A on the expression of P-gp and decreased the reversal fold of 90 µM oroxylin A from 4.68 fold to 1.73 fold. In conclusion, we suggested that oroxylin A reversed MDR by G2/M arrest and the underlying mechanism attributed to the suppression of P-gp expression via Chk2/P53/NF-κB signaling pathway.

I4, a new synthetic sulfonylurea compound, inhibits the action of TXA2 in vivo and in vitro on platelets and aorta vascular smooth muscle.

INTRODUCTION: 1-[4-[2-(4-Bromobenzene-sulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcy-clohexyl)urea(I(4), CAS865483-06-3); a totally synthetic new sulfonylurea compound, combining the hypoglycemic active structure of Glimepiride (CAS 93479-97-1) and anti-TXA(2) receptor (TP) active structure of BM-531(CAS 284464-46-6), was designed and synthesized. Its effects on TXA(2) synthesis and TP have not been reported yet. AIM: To study the inhibitory effects of I(4) and its mechanisms of action on TXA(2) and TP. METHODS: Platelet aggregation studies were performed on human platelet, rat whole blood platelet and rabbit platelet, platelets aggregation was induced by TP agonist U-46619(stable analog of TXA(2), CAS 56985-40-1). Plasma TXB(2) and 6-keto-prostaglandin F(1α) (6-keto-PGF(1α)) were used as markers to determine the effect of I(4) on thromboxane synthesis. Fluo-3-AM was used to measure the cytosolic Ca(2+) concentrations ([Ca(2+)](i)) in rabbit platelet. Aorta rings with and without endothelium were prepared and aorta contraction was induced by U-46619. A model of type 2 diabetes mellitus was established by intraperitoneal injection of low dose of streptozocin to rats fed a high-calorie diet. Both normal rats and type 2 diabetic rats were used to assay the inhibitory effect of I(4) on platelet aggregation induced by U-46619. RESULTS: I(4) exhibited a higher inhibitory potency than Glimepiride on U-46619 induced platelet aggregation in vitro and in vivo. I(4) increased the ratio of plasma PGI(2)/TXA(2) and decreased [Ca(2+)](i) release from platelet internal stores. In addition, I(4) presented a vasorelaxant activity on isolated rat aorta contraction induced by U-46619.Oral administration of I(4) (1~10mg/kg) markedly and dose-dependently inhibited platelet aggregation in both normal rats and type 2 diabetic rats. CONCLUSION: I(4) significantly inhibited platelet aggregation induced by U-46619 in vitro and in vivo, and rat aorta contraction. It probably acts by partly blocking TXA(2) action, decreasing the platelet intracellular Ca(2+), and increasing the PGI(2)/TXA(2) ratio.