2,100 research outputs found
Yd-3, a Novel Inhibitor of Protease-Induced Platelet Activation
No full text1 In the present study, the antiplatelet effects and mechanisms of a new synthetic compound YD-3 [1-benzyl-3( ethoxycarbonylphenyl)-indazole] were examined.2 YD-3 inhibited the aggregation of washed rabbit platelets caused by thrombin (IC50 = 28.3 mu M), but had no or little inhibitory effect on that induced by arachidonic acid, collagen, platelet-activating factor (PAF) or U46619. YD-3 also suppressed generation of inositol phosphates caused by thrombin. On the other hand, thrombin-induced fibrin formation was not affected by YD-3, indicating YD-3 does not inhibit the proteolytic activity of thrombin.3 In washed human platelets, however, YD- 3 had only mild inhibitory effect on the low concentration (0.05 u ml(-1)) of thrombin- induced human platelet aggregation, and did not affect that induced by higher concentrations (greater than or equal to 0 .1 u ml(-1)) of thrombin or SFLLRN, the protease-activated receptor 1 (PAR1) agonist peptide. By contrast, YD-3 inhibited both human and rabbit platelet aggregation elicited by trypsin with IC50 values of 38.1 mu M and 5.7 mu M , respectively.4 YD-3, at 100 mu M, had no effect on ristocetin-induced glycoprotein Ib (GPIb)-dependent aggregation of human platelets. In addition, platelets treated with chymotrypsin, which cleaves GPIb, enhanced rather than attenuated the inhibition of YD-3 on thrombin- induced human platelet aggregation. These data indicate that GPIb plays no role in the antiplatelet effect of YD-3.5 In SFLLRN-desensitized human platelets, high concentration of thrombin (1 u ml (-1)) could still elicit intracellular Ca2+ mobilization, and the rise of [Ca2+], was prevented by either leupeptin or YD-3.6 Our results suggest that YD-3 inhibits a non- PAR1 thrombin receptor which mediates the major effect of thrombin in rabbit platelets, but in human platelets, this receptor function becomes significant only when the function of PAR1 has been blocked or attenuated
The Indazole Derivative Yd-3 Inhibits Thrombin-Induced Vascular Smooth Muscle Cell Proliferation and Attenuates Intimal Thickening after Balloon Injury
No full textProliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the key events in the pathogenesis of atherosclerosis and restenosis.We investigated whether YD -3, a lowmolecular weight, non- peptide compound, could modulate proliferation of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD -3 on thrombininduced VSMC proliferation by [3H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation in a concentration-dependent manner. To define the mechanisms of YD-3 action,we found that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities by using Western blotting analysis . Furthermore, oral adminis tration of YD-3 exhibited a marked reduction in neointimal thickness using the carotid injury model in rats. Using immunochemical detection, our experiments also revealed that YD-3 significantly suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1- activating peptide (SFLLRN)-induced VSMC proliferation in a concentration- dependent manner. These results suggest that YD-3 inhibits thrombin- induced VSMC growth via the Ras- and ERK1/2-mediated signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment of atherosclerosis and restenosis after vascular injury
Selective Inhibition of Protease-Activated Receptor 4-Dependent Platelet Activation by Yd-3
No full textIn the present study, the antiplatelet effect and its mechanism of a new synthetic compound YD-3 [1-benzyl-3-( ethoxycarbonylphenyl)indazole] were examined. YD-3 inhibited the aggregation of washed human platelets caused by protease-activated receptor (PAR) 4 agonist peptide GYPGKF ( IC50 = 0. 13 +/- 0.02 muM), but had no or little effect on that by thrombin, PAR1 agonist peptide SFLLRN, collagen or U 46619. YD-3 produced a parallel, rightward shift of the concentration-response curve for GYPGKF without decreasing of the maximum platelet aggregation, indicating a competitive antagonism. In contrast to human platelets, both thrombin- and GYPGKF- induced mouse platelet shape change and aggregation were completely inhibited by YD-3. YD-3 also selectively prevented GYPGKF-induced intracellular Ca2+ mobilization in human platelets. Furthermore, in the PAR1- desensitized human platelets. thrombin induced a relatively slow rise and decay of calcium mobilization that was significantly inhibited by YD-3. In addition, the synergistic effect of SFLLRN and GYPGKF on platelet activation was prevented by YD-3. YD-3 also inhibits both fMLP- stimulated neutrophil- and purified cathepsin G-induced platelet aggregation, which has been demonstrated to be PAR 4-dependent. Taken together, our results suggest that YD-3 selectively inhibits PAR4- dependent platelet activation through blockade of PAR4. To the best of our knowledge, it is the first non-peptide PAR4 antagonist
HIGH RESOLUTION FOURIER TRANSFORM EMISSION SPECTROSCOPY OF YH AND YD.
No full textAuthor Institution: Department of Chemistry, University of Arizona; Department of Chemistry, University of WaterlooThe electronic emission spectrum of YH and YD has been investigated in the 690 nm to 3 spectral region using a Fourier transform spectrometer. The YH and YD bands were excited in an yttrium hollow cathode lamp operated with neon gas and a trace of of The observed bands have been classified into three different electronic transitions; and . The transition of YD could not be identified due to its very weak intensity. The rotational analysis of several bands of the transition (up to for YH and for YD) provides improved equilibrium vibrational and rotational constants for the ground state of YH and YD. The excited state is involved in several perturbations
Selective Inhibition of Protease-activated Receptor 4-dependent Platelet Activation by YD-3
No full textSummaryIn the present study, the antiplatelet effect and its mechanism of a new synthetic compound YD-3 [1-benzyl-3-(ethoxycarbonylphenyl)-indazole] were examined. YD-3 inhibited the aggregation of washed human platelets caused by protease-activated receptor (PAR) 4 agonist peptide GYPGKF (IC50 = 0.13 ± 0.02 µM), but had no or little effect on that by thrombin, PAR1 agonist peptide SFLLRN, collagen or U46619. YD-3 produced a parallel, rightward shift of the concentration-response curve for GYPGKF without decreasing of the maximum platelet aggregation, indicating a competitive antagonism. In contrast to human platelets, both thrombin- and GYPGKF-induced mouse platelet shape change and aggregation were completely inhibited by YD-3. YD-3 also selectively prevented GYPGKF-induced intracellular Ca2+ mobilization in human platelets. Furthermore, in the PAR1-desensitized human platelets, thrombin induced a relatively slow rise and decay of calcium mobilization that was significantly inhibited by YD-3. In addition, the synergistic effect of SFLLRN and GYPGKF on platelet activation was prevented by YD-3. YD-3 also inhibits both fMLP-stimulated neutrophil- and purified cathepsin G-induced platelet aggregation, which has been demonstrated to be PAR4-dependent. Taken together, our results suggest that YD-3 selectively inhibits PAR4-dependent platelet activation through blockade of PAR4. To the best of our knowledge, it is the first non-peptide PAR4 antagonist.</jats:p
A Highly Selective Rasorber With Ultraminiaturized Unit Based on Interdigitated 2.5-D Parallel Resonator
No full textA high selectivity frequency selective rasorber (FSR) with an ultraminiaturized unit based on 2.5 dimensional (2.5-D) parallel resonator (PR), exhibiting low insertion loss passband between two absorption bands, is investigated. The lossy unit is realized by inserting a 2.5-D strip-type PR structure into the center of each side of the metal square ring and loaded with resistors connected at the four corners. The novel 2.5-D PR consists of interdigitated capacitors and strip metal wire connecting the other side of the lossy layer obtained by using metallized vias. The 2.5-D PR can effectively alleviate the congestion of the single-sided structures and achieve a high degree of miniaturization by means of tortuous extension inductance structure; as an additional feature, the values of L and C can be independently adjusted to determine the passband frequency allowing to provide additional degree of freedom to the design. An equivalent circuit model is proposed to analyze its operating principle. The dimensions of the miniaturized unit are (being the free space wavelength at the passband). A transmission window with low insertion loss of 0.125 dB is obtained at 4.65 GHz under normal incidence. The fractional bandwidth for -10 dB reflection is about 96%. The miniaturized FSR satisfies the characteristic of polarization insensitivity (TE and TM) and angular insensitivity (up to 45 degrees). A prototype of miniaturized FSR has been manufactured and measured, showing a reasonable agreement with simulations
Effects of Baicalein, KS-5 and YD-3 on Growth Regulation in Vascular Smooth Muscle Cells and Endothelial Cells, and Therapeutic Evaluation in Models of Restenosis and Angiogenesis
No full text根據行政院衛生署公佈台灣地區九十五年度的十大死因中，惡性腫瘤排名第一，腦、心血管疾病分別佔第二及第三位，而這些疾病都與血管病變有關。血管主要由內層的內皮細胞和外側的平滑肌細胞所構成，平滑肌細胞的增生是血管再阻塞主因，也造成動脈粥狀硬化治療的瓶頸；而內皮細胞的增生，則是血管新生的必要步驟，控制血管新生對於治療發炎、風濕性關節炎甚至腫瘤的生長和轉移都有莫大的助益。因此，本論文分別探討對於血管平滑肌及血管內皮細胞增生具有抑制作用的藥物及研究其機轉。一部分討論中藥黃芩的主成分baicalein在體內及體外實驗中抑制血管平滑肌細胞的增生。實驗結果發現，baicalein對血清刺激造成的平滑肌細胞增生具有抑制作用，其機轉是經由抑制ERK1/2和Akt蛋白的磷酸化，影響Ras/Raf/MEK/ERK和PI-3K/Akt訊息傳遞路徑，同時也抑制IκB和DNA結合的能力。另外也減少cyclin D1的表現，使細胞週期無法進入S/G2/M期。在體內動物實驗中，口服baicalein可以有效抑制大鼠頸動脈氣球擴張損傷後的血管再阻塞。二部份探討acridone衍生物KS-5對血管新生促進因子bFGF引起血管內皮細胞增生的抑制作用及機轉。細胞增生 (cell proliferation) 要經過細胞生長 (cell growth) 使體積增加，和細胞分裂 (cell division) 使數目增多，過程中需要蛋白質和DNA合成。KS-5呈濃度相關性的抑制bFGF活化的ERK1/2和Akt訊息傳遞路徑並抑制細胞的DNA合成；同時KS-5也會抑制bFGF活化的mammalian target of rapamycin (mTOR)，以及mTOR下游主要的因子eIF4E和p70S6K進而抑制細胞的蛋白質合成，因此有效的抑制了bFGF造成的內皮細胞增生。利用Matrigel的實驗也證明KS-5在動物體內確實具有活性，可以明顯抑制bFGF造成的血管新生。三部份探討indazole衍生物YD-3抑制thrombin造成血管新生的作用和機轉。YD-3在細胞實驗中可以專一性的抑制thrombin造成的內皮細胞增生，對於PAR-1和PAR-4之activating peptides (APs) 也同樣具有作用，但對PAR-2 AP造成的細胞增生則沒有明顯的抑制作用。在體內動物實驗中也發現，不論是thrombin、PAR-1或PAR-4 AP造成的血管新生，YD-3都能有效抑制，卻不影響VEGF引起的血管新生作用。YD-3的抑制作用並不是透過抑制ERK1/2的磷酸化，而是和抑制thrombin造成的細胞Flk-1表現增加有關。由以上實驗結果認為baicalein、KS-5和YD-3可以抑制血管平滑肌細胞或是血管內皮細胞的增生，並且也在動物體內實驗中證明具有活性，因此很有潛力繼續研究發展成為預防血管再阻塞或是血管新生相關疾病的治療藥物。Arterial reconstruction procedures, including balloon angioplasty, stenting and coronary artery bypass, are used to restore blood flow in atherosclerotic arteries. Restenosis of these arteries is a major limitation of the application of these procedures. Post-angioplasty restenosis results from two major processes: neointimal formation and constrictive remodelling. Neointimal formation is initiated by arterial injury with a resultant loss of contractile phenotype in tunica media, leading to VSMC migration and proliferation. In this dissertation, we study the effects of some biologically active chemical compounds on the proliferation of VSMC and endothelail cells and trying to elucidate their action mechanisms.n the first chapter, we investigate baicalein-mediated inhibitory effects on VSMCs proliferation and intimal hyperplasia after balloon angioplasty in the rat. Baicalein significantly inhibits serum-induced cell proliferation via decreasing the phosphorylation of ERK1/2 and Akt proteins. Baicalein inhibits cyclin D1 expression resulting in the blockade of cell cycle progression. Furthermore, bacalein attenuates serum-induced DNA binding activity of NF-κB. It also inhibits intimal hyperplasia after balloon vascular injury in rat, implying its therapeutic potential for treating restenosis after angioplasty.ngiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions, including embryonic development, wound repair, inflammation, and tumor growth. Moreover, proliferating endothelial cells undergoing DNA synthesis are a common hallmark of angiogenic microvascular spouts. In the next two chapters, we investigate the effects of KS-5 and YD-3 on bFGF- and thrombin-induced angiogenesis in cultured human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. S-5, an acridone-derivative compound, inhibits bFGF-induced cell proliferation in a concentration-dependent manner without exhibiting any significant cytotoxicity. The inhibitory effect is associated with decreasing DNA synthesis and abrogating ERK1/2 and Akt protein phosphorylation in endothelial cells. In addition, KS-5 also inhibits bFGF-induced phosphorylation of mTOR and the major downstream effectors, eIF4E and p70S6K, and leading to decreasing protein synthesis. Most importantly, KS-5 treatment in nude mice inhibited in vivo angiogenesis as revealed by matrigel implant assay.D-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole], a selective thrombin inhibitor, inhibits neovascularization in vivo induced by thrombin, protease-activated receptor (PAR) -1, and PAR-4, but not by vascular endothelial growth factor (VEGF). YD-3 also inhibits thrombin-, PAR-1- and PAR-4-, but not PAR-2-induced cell proliferation. YD-3 predominantly inhibits thrombin-induced VEGF receptor 2 (Flk-1) up-regulation, but not phosphorylation of ERK1/2 protein. Moreover, in a murine xenograft tumor model, YD-3 administered orally reveals significant antitumor activity without cytotoxicity. n conclusion, the present study suggests that baicalein, KS-5 and YD-3 have antiproliferative effects both in vitro and in vivo and worthy of further development into drug candidates for treating restenosis and angiogenesis-dependent diseases.縮寫表……………………………………………………………… 1文摘要………………………………………………………… 3文摘要…………………………………………………………. 5一章 緒論獻回顧………………………………………………………… 9究動機與目的………………………………………………… 32二章 Baicalein抑制大鼠頸動脈氣球擴張損傷後之內膜增生是經由停滯血管平滑肌的細胞週期和抑制ERK、Akt及NFκB蛋白活化文摘要………………………………………………………… 34文摘要………………………………………………………… 35言……………………………………………………………… 36料與方法……………………………………………………… 38果……………………………………………………………… 43論……………………………………………………………… 46三章 KS-5在體內及體外實驗抑制 bFGF 造成的血管新生之機轉探討文摘要………………………………………………………… 57文摘要………………………………………………………… 58言……………………………………………………………… 59料與方法……………………………………………………… 61果………………………………………………………………. 64論………………………………………………………………. 67四章 Indazole衍生物YD-3專一性地抑制thrombin所造成的血管新生文摘要…………………………………………………………. 76文摘要…………………………………………………………. 77言………………………………………………………………. 78料與方法………………………………………………………. 80果………………………………………………………………. 82論………………………………………………………………. 85五章 結論與展望…………………………………………………… 97考文獻………………………………………………………………… 104作……………………………………………………………………… 11
Effect of Porous Microstructures on the Biomechanical Characteristics of a Root Analogue Implant: An Animal Study and a Finite Element Analysis
No full textBackground: Full ceramic or metal custom-made root analogue implants (RAIs) are made by replicating the natural tooth geometry. However, it may lead to the stress shielding of the surrounding bone, and an RAI is unable to easily achieve primary stability. Therefore, to improve primary stability and reduce stress shielding, RAI porous structures are proposed. The purpose of this study was to evaluate the effect of porous microstructures on the biomechanical characteristics of the custom-made RAT. Methods: Porous and bulk titanium cylinders and porous RAI and conventional implants for in vivo tests were fabricated using a selective laser melting (SLM) technology. The elastic modulus and the compressive strength of porous titanium cylinders were evaluated. These samples were then implanted into rabbit femurs (cylinders) and beagle dog mandibles (RAI and conventional implants). A simplified three-dimensional geometry of the anterior maxilla of a patient was constructed. Then, based on the extracted standard template library (STL) data, five different RAI models were constructed: (A) smooth surface, (B) pit surface, (C) bulb surface, (D) threaded surface, and (E) porous surface. A conventional implant model was also constructed. A static load of 100 N was applied to the crown in the multivectoral direction. Results: The results of the in vivo experiment confirmed that the porous structure decreased the elastic modulus of Ti6AI4V. Additionally, the implantation of the porous custom-made RAIs resulted in increased new bone ingrowth and decreased bone resorption compared to conventional implants. Moreover, the 3D finite element analysis suggested that the bone surrounding porous custom-made RAIs was subjected to a more uniform stress distribution, and the strain values of the surrounding bone were more conducive to bone formation. Conclusion: Based on these findings, a custom-made RAI with a porous surface accelerates bone formation and might reduce the stress-shielding effect
A novel picoliter droplet array for parallel real-time polymerase chain reaction based on double-inkjet printing
No full text
- …
