PKSI-527 is an inhibitor of plasma kallikrein (Ki = 0.81 μM). It is selective for plasma kallikrein over glandular kallikrein, plasmin, thrombin, urokinase, and Factor Xa (Kis = >500, 390, >500, 200, and >500 μM, respectively). PKSI-527 reduces bradykinin generation induced by kaolin and λ-carrageenan ex vivo in human plasma. It also prolongs partial thromboplastin and euglobulin clot lysis times. In vivo, PKSI-527 (300 mg/kg per day) reduces hyperplasia, pannus formation, and infiltration of inflammatory cells in the tarsal joint of mice with collagen-induced arthritis.
Ajoene is a disulfide that has been found inA. sativumand has diverse biological activities, including antibacterial, anticancer, antiplatelet, and antioxidant properties.1,2,3,4It is active against Gram-positive (MICs = 5-160 µg/ml) and Gram-negative bacteria (MICs = 136-200 µg/ml), as well as yeasts (MICs = 10-20 µg/ml).1Ajoene is cytotoxic to mouse melanoma cells (IC50= 18 µM), as well as human colon, lung, mammary, and pancreatic cancer cells (IC50s = 7-41 µM).2It reduces tumor growth in a B16/BL6 mouse model of melanoma when administered at a dose of 25 mg/kg every other day and decreases the number of lung metastases when administered prior to tumor cell inoculation at doses ranging from 1-25 mg/kg. It inhibits ADP- or collagen-induced platelet aggregation in isolated baboon platelets when used at concentrations ranging from 75 to 150 µg/ml and in platelet-rich plasma isolated from baboons when administered at a dose of 25 mg/kg.3Ajoene (25 mg/kg) prevents thrombus formation on damaged arterial walls in heparinized pigs in anin situmodel of thrombogenesis.5It also reduces high-fat diet-induced hepatic steatosis, histopathological markers of liver damage, thiobarbituric acid reactive substances (TBARS) formation, and protein oxidation in a mouse model of non-alcoholic fatty liver disease (NAFLD).4
1.Naganawa, R., Iwata, N., Ishikawa, K., et al.Inhibition of microbial growth by ajoene, a sulfur-containing compound derived from garlicAppl. Environ. Microbiol.62(11)4238-4242(1996) 2.Taylor, P., Noriega, R., Farah, C., et al.Ajoene inhibits both primary tumor growth and metastasis of B16/BL6 melanoma cells in C57BL/6 miceCancer Lett.239(2)298-304(2006) 3.Teranishi, K., Apitz-Castro, R., Robson, S.C., et al.Inhibition of baboon platelet aggregation in vitro and in vivo by the garlic derivative, ajoeneXenotransplantation10(4)374-379(2003) 4.Han, C.Y., Ki, S.H., Kim, Y.W., et al.Ajoene, a stable garlic by-product, inhibits high fat diet-induced hepatic steatosis and oxidative injury through LKB1-dependent AMPK activationAntioxid. Redox Signal.14(2)187-202(2011) 5.Apitz-Castro, R., Badimon, J.J., and Badimon, L.A garlic derivative, ajoene, inhibits platelet deposition on severely damaged vessel wall in an in vivo porcine experimental modelThromb. Res.75(3)243-249(1994)
RWJ-56110 dihydrochloride is a potent, selective, peptide-mimetic inhibitor of PAR-1 activation and internalization (binding IC50=0.44 uM) and shows no effect on PAR-2, PAR-3, or PAR-4. RWJ-56110 dihydrochloride inhibits the aggregation of human platelets induced by both SFLLRN-NH2 (IC50=0.16 μM) and thrombin (IC50=0.34 μM), quite selective relative to U46619 . RWJ-56110 dihydrochloride blocks angiogenesis and blocks the formation of new vessels in vivo. RWJ-56110 dihydrochloride induces cell apoptosis[1][2].
Proteinase-activated receptors (PARs) are a family of G protein-coupled receptors activated by the proteolytic cleavage of their N-terminal extracellular domain, exposing a new amino terminal sequence that functions as a tethered ligand to activate the receptors.RWJ56110 inhibits the aggregation of human platelets induced by both SFLLRN-NH2 (IC50=0.16 μM) and thrombin (IC50=0.34 μM) while being quite selective relative to collagen and the thromboxane mimetic U46619 [1].RWJ-56110 dihydrochloride is fully inhibits thrombin-induced RASMC proliferation with an IC50 value of 3.5 μM. RWJ-56110 dihydrochloride shows blockade of thrombin's action with RASMC calcium mobilization (IC50=0.12 μM), as well as with HMVEC (IC50=0.13 μM) and HASMC calcium mobilization (IC50=0.17 μM)[1].RWJ56110 (0.1-10 μM; 24-96 hours) inhibits endothelial cell growth dose-dependently, with half-maximal inhibitory concentration of RWJ56110 is approximately 10 μM[2].RWJ56110 (0.1-10 μM; 6 hours) inhibits DNA synthesis of endothelial cells in a thymidine incorporation assays. Endothelial cells are in fast-growing state (50-60% confluence), RWJ56110 inhibits cell DNA synthesis in a dose-dependent manner, but when cells that are in the quiescent state (100% confluent), the inhibitory effect of PAR-1 antagonists is much less pronounced[2].RWJ56110 (0.1-10 μM; pretreatment for 15 min) inhibits thrombin-induced Erk1/2 activation in a concentration-dependent manner. However, when endothelial cells are stimulated by FBS (final concentration 4%), it reduces partially the activated levels of Erk1/2[2].RWJ56110 (30 μM; 24 hours) has an inhibitory effect on endothelial cell cycle progression. It reduces the percentage of cells in the S phase, while alterations in the percentages of G1 and G2/M cells are less pronounced[2]. Western Blot Analysis[2] Cell Line: Endothelial cells
[1]. Andrade-Gordon, et al.Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. oc Natl Acad Sci U S A. 1999 Oct 26;96(22):12257-62. [2]. Panagiota Zania, et al. Blockade of angiogenesis by small molecule antagonists to protease-activated receptor-1: association with endothelial cell growth suppression and induction of apoptosis. J Pharmacol Exp Ther. 2006 Jul;318(1):246-54.
Angiotensin II 是一种主要的生物活性血管收缩肽,通过与AT1R和AT2R受体结合,调节血压,刺激交感神经,促进醛固酮合成和肾脏功能。它还能诱导血管平滑肌细胞增生、胶原合成增加,导致血管和心肌增厚及纤维化,同时促进细胞凋亡和内皮细胞毛细血管形成。Angiotensin II常用于诱导高血压和心脏肥大动物模型。
Angiotensin II human TFA 是肾素-血管紧张素系统中的强效血管收缩剂,通过与 AT1R 和 AT2R 受体作用调节血压,可激活交感神经、促进醛固酮合成和肾功能,诱导血管平滑肌细胞增殖及成纤维细胞中 I 型和 III 型胶原合成,导致血管和心肌增厚、纤维化,并诱导凋亡及促进毛细血管生成,可用于构建心脏肥大、高血压和腹主动脉瘤模型。
Angiotensin II human acetate 是肾素-血管紧张素系统中的主要血管收缩肽,通过与AT1R和AT2R受体结合调节血压,刺激交感神经,促进醛固酮合成和肾脏功能,诱导血管平滑肌细胞增生和胶原合成,导致血管及心肌增厚和纤维化,同时促进细胞凋亡和内皮毛细血管形成。常用于诱导高血压和心脏肥大模型。