Design, synthesis, and biological evaluation of phenylpropenamides compounds as anti-platelet aggregation / 药学学报

Twenty phenylpropenamide analogs with structural novelty were designed and synthesized upon pharmacophore-combination strategy. The structures of target compounds were elucidated by IR, 1H NMR, 13C NMR and MS, and all the target compounds were biologically evaluated for the inhibitory activities of platelet aggregation induced by adenosine diphoshate (ADP) and (AA) arachidonic acid via Bron method. As a result, compounds 6b, 9b, 9d and 9h demonstrated potent inhibitory activity against platelet aggregation induced by AA. Meanwhile, compounds 6b, 6d, 6j, 9b and 9g exhibited significant suppression of platelet aggregation induced by ADP.

Dl-PHPB inhibits platelet aggregation and affects the balance of PGI2/TXA2 and fibrinolytic system of rats / 中国药学杂志

OBJECTIVE: To investigate the effect of potassiam 2-(1-hydroxypentyl)-benzoae (dl/-PHPB) on platelet aggregation, the balance of PGI2/TXA, and fibrinolytic system of rats. METHODS: Rats were randomly divided into 5 groups; control group, low (1.3 mg·kg-1), middle (3.9 mg·kg-1) and high (12.9 mg·kg-1) dose of dl-PHPB groups and ticlopidine group. Blood was taken from the abdominal aorta 30 min after dl-PHPB administrated intravenously, and the rate of platelet aggregation was detected by platelet aggregometer. The expression of CD62p on the surface of platelet was determined by flow cytometry. The contents of 6-Keto-PGF1α, thromboxane B2 (TXB2), t-PA and PAT-1 in serum were measured by radio-immuno assay and FLISA kit, respectively. RESULTS: dl-PHPB inhibited rat platelet aggregation induced by A DP in dose-dependent manner more potently compared with AA, collagen and thrombin. dl-PHPB also decreased the expression of CD62p. It increased the level of 6-keto-PGF1α, the metabolite of prostaglandin I2 (PGL2) and reduced the content of PAI-1. But dl/-PHPB had no effect on the contents of TXB2 the metabolite of TXA2 and t-PA. CONCLUSION: dl-PHPB may significantly inhibit rat platelet aggregation induced by ADP, increase the ratio of PG12/TXA2 and enhance the activity of fibrinolytic system.

The change of TXA2 and PGI2 in Rabbit model of pulmonary hypertension after progenitor cell transplantation / 中国生化药物杂志

Objective To discuss the changes of plasma TXA2 and PGI2 levels in the rabbit model of pulmonary hypertension (PHA)induced by monocrotaline (MCT)when transplanted with endothelial progenitor cells (EPCs). Methods The rabbit pulmonary hypertension model was constructed by MCT induction. Rabbit endothelial progenitor cells were induced,separated and identified in vitro.50 New Zealand white rabbits were randomly divided into 3 groups,normal control group and model group were given M199 culture medium by tail vein injection,EPCs treatment group were given EPCs marked with fluorescent though tail vein injection. The levels of plasma TXB2 and 6-keto-PGF1αwere detected and their ratio were calculated after three weeks. Results Compared with model group,the content of 6-keto-PGFlαin plasma in EPCs group was (130.67 ±17.54)u mol/L,which was increased sinnificantly. The content of TXB2 was (402.89 ±27.98 )u mol/L,which was decreased significantly.The ratio of TXB2 to 6-keto-PGF1 alpha between two groups was statistically significant(P<0.01 ). Conclusion EPCs transplantation can reduce the content of TXA2 and increase the content of PGI2 in the pulmonary hypertension rabbits induced by monocrotaline,then reverse the damage of pulmonary hypertension.

Cordycepin-Enriched WIB801C from Cordyceps militaris Inhibits Collagen-Induced Ca2+i Mobilization via cAMP-Dependent Phosphorylation of Inositol 1, 4, 5-Trisphosphate Receptor in Human Platelets

In this study, we prepared cordycepin-enriched (CE)-WIB801C, a n-butanol extract of Cordyceps militaris-hypha, and investigated the effect of CE-WIB801C on collagen-induced human platelet aggregation. CE-WIB801C dose-dependently inhibited collagen-induced platelet aggregation, and its IC50 value was 175 microg/ml. CE-WIB801C increased cAMP level more than cGMP level, but inhibited collagen-elevated [Ca2+]i mobilization and thromboxane A2 (TXA2) production. cAMP-dependent protein kinase (A-kinase) inhibitor Rp-8-Br-cAMPS increased the CE-WIB801C-downregulated [Ca2+]i level in a dose dependent manner, and strongly inhibited CE-WIB801C-induced inositol 1, 4, 5-trisphosphate receptor (IP3R) phosphorylation. These results suggest that the inhibition of [Ca2+]i mobilization by CE-WIB801C is resulted from the cAMP/A-kinase-dependent phosphorylation of IP3R. CE-WIB801C suppressed TXA2 production, but did not inhibit the activities of cyclooxygenase-1 (COX-1) and TXA2 synthase (TXAS). These results suggest that the inhibition of TXA2 production by WIB801C is not resulted from the direct inhibition of COX-1 and TXAS. In this study, we demonstrate that CE-WIB801C with cAMP-dependent Ca2+-antagonistic antiplatelet effects may have preventive or therapeutic potential for platelet aggregation-mediated diseases, such as thrombosis, myocardial infarction, atherosclerosis, and ischemic cerebrovascular disease.

Comparison of the efects of compound s alvia miltiorrhiza pli l and salviami ltiorrhiza pill on platelet activation in hematoplasma in patients with coronary atherosclerosis / 中国医师杂志

Objective To compare the effects of compound salvia miltiorrhiza pill and salvia milti-orrhiza pill on platelet activation in hematoplasma in patients with coronary atherosclerosis , and guide clini-cal medication .Methods Ninety cases suffered coronary atherosclerosis who were treated with compound salvia miltiorrhiza, salvia miltiorrhiza and palcebo for two months course of treatment were divided into com-pound salvia miltiorrhiza , salvia miltiorrhiza and control groups , Normal group included 30 physical fitness were treated with placebo.Contents of PTGIS mRNA, cAMP, TXA2 and PGI2 in hematoplasma were treated with palcebo.Contents of PTGIS mRNA, cAMP, TXA2 and PGI2 in hematoplasma were detected by real-time RT-PCR and radioimmunoassay , respectively.Res ults In coronary atherosclerosis groups , cAMP, TXA2 ., PTGIS mRNA were decreased markedly , TXA2 were increased markedly. Compund salvia miltior-rhiza and salvia miltiorrhiza could increase the expression of cAMP , PGI2 and PTGIS mRNA but TXA2 , the content of TXA2 .in compund salvia miltiorrhza and salvia miltiorrhiza groups were decreased .Conclusion Compound salvia miltiorrhiza and salvia miltiorrhiza can inhibit plateled activation .The effect on inhibi-ting platelet activation of compound salvia miltiorrhiza is better than salvia miltiorrhiza .

Involvement of Thromboxane A2 in the Modulation of Pacemaker Activity of Interstitial Cells of Cajal of Mouse Intestine

Although many studies show that thromboxane A2 (TXA2) has the action of gastrointestinal (GI) motility using GI muscle cells and tissue, there are no reports on the effects of TXA2 on interstitial cells of Cajal (ICC) that function as pacemaker cells in GI tract. So, we studied the modulation of pacemaker activities by TXA2 in ICC with whole cell patch-clamp technique. Externally applied TXA2 (5 micrometer) produced membrane depolarization in current-clamp mode and increased tonic inward pacemaker currents in voltage-clamp mode. The tonic inward currents by TXA2 were inhibited by intracellular application of GDP-beta-S. The pretreatment of ICC with Ca2+ free solution and thapsigargin, a Ca2+-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker currents and suppressed the TXA2-induced tonic inward currents. However, chelerythrine or calphostin C, protein kinase C inhibitors, did not block the TXA2-induced effects on pacemaker currents. These results suggest that TXA2 can regulate intestinal motility through the modulation of ICC pacemaker activities. This modulation of pacemaker activities by TXA2 may occur by the activation of G protein and PKC independent pathway via extra and intracellular Ca2+ modulation.

Changes of TXA2 and PGI2 during Postoperative Hypertensive Crisis in Patients with Hypertensive Intracerebral Hemorrhage / 华中科技大学学报（医学）（英德文版）

In order to explore the changes and the roles of TXA2 and PGI2 during postoperative hypertensive crisis in patients with hypertensive intracerebral hemorrhage, 31 cases subject to crani- otomy were divided into three groups: group A, 9 patients with postoperative hypertensive crisis; group B, 13 patients without postoperative hypertensive crisis; and group C, 9 patients without his- tory of hypertension and hypertensive intracerebral hemorrhage. TXA2＞, TXB2＞, 6-keto-PGF1α and PGI2＞ were measured after operation in the three groups respectively. The postoperative blood pres- sure in group A, including SBP and DBP, was elevated more obviously than that in the other two groups. TXA2＞ and PGI2＞ in group A were significantly higher than those in other two groups (P＜0.01). Moreover, the ratio of TXB2＞ to 6-keto-PGF1α in group A was significantly higher than that in other two groups (P＜0.05). The increase of TXA2＞ and the relative inadequacy of prostacyclin, especially 6-keto-PGF1α, may play roles in the postoperative hypertensive crisis. And the increased value of TXB2＞ to 6-keto-PGF1α could provide the basis for diagnosis of postoperative hypertensive crisis.

Relationship between therapeutic effects of ~(89)SrCl_2 on osteodynia induced by multiple bone metastases and ET,CGRP,TXB_2 and 6-K-PGF_(1a) / 吉林大学学报(医学版)

Objective To explore the relationship between therapeutic effects of 89SrCl2 on osteodynia induced by multiple bone metastasis and ET,CGRP,TXB2 and 6-K-PGF1a.Methods 89SrCl2 treatment was used in 39 cases of multiple bone metastasis,the serum content of ET,CGRP,TXB2 and 6-K-PGF1a were detected with radioimmunological method pre-treatment and 1,3,6 months post-treatment,respectively;the ET/CGRP value was calculated.Results The content of ET showed no obvious changes 1 month post-treatment compared with pre-treatment.However,the ET contents increased significantly 3 and 6 months post-treatment compared with 1 month post-treatment and before treatment(P

Effect of CLA (Conjugated Linoleic Acid) on the Anti-Atherosclerotic Factors in Human Hepatoma HepG2 Cells

Conjugated linoleic acid (CLA) is the mixture of positional and geometric isomers of linoleic acid (LA), which is found abundantly in dairy products and meats. This study was performed to investigate the anticarcinogenic effect of CLA in HepG2 hepatoma cells. HepG2 cell were treated with LA and CLA at the various concentrations of 10, 20, 40, 80 uM each at different incubation times. After each incubation times, cell proliferation, fatty acids incorporation into cell, peroxidation and postaglandin E2 (PGE2) and thromboxane A2 (TXA2) for the eicosanoid metabolism were measured. LA treated HepG2 cells were increased cell growth 6 - 70% of control whereas CLA increased cell death the half of those in LA group (p < 0.001). LA and CLA were incorporated very well into the cellular membranes four times higher than in control according to concentration and longer incubation times. Moreover, LA synthesized significantly arachidonic acids corresponding with LA concentration compared to CLA supplementation. The supplementation with LA increased intracellular lipid peroxides concentration corresponding with LA concentration and five times higher than those in CLA significantly at any incubation times (p < 0.001). PGE2 and TXA2 levels were three to twenty times lower in condition of CLA treatments than LA, respectively. Overall, the dietary CLA might change the HepG2 cell growth by the changes of cell composition, production of lipid peroxide. Since CLA have not changed the levels of arachidonic acid of cell membrane, which was sources of eicosanoids, eicosanoid synthesis was not increased in CLA compared to LA. Our results was suggest CLA has a possibility to protect the progress of atherosclerosis because CLA does not produce lipid production and endothelial contraction factors in liver.

Effect of Jiuqiang Naoliqing on the TXA_2 and PGI_2 level in spontaneous hypertension rat plasma / 中国康复理论与实践

@#ObjectiveTo investigate the effect of Jiuqiang Naoliqing(JNQ) on the TXA2 and PGI2 level in spontaneous hypertension rat (SHR) plasma.MethodsThe plasma was separated after the SHR and Wistar rats were treated with JNQ at the dose of 0.133g/kg,0.265g/kg,0.530g/kg and 1% carboxymethyl cellulose respectively for 5 weeks. The level of TXB2 and 6 keto PGF1α ,stable metabolin of TXA2 and PGI 2,in SHR plasma was tested by radioimmunoassay.ResultsThe level of TXB2 and the ratio of TXB2/6 keto PGF1α (T/P) in SHR plasma increased significantly(P<0.01),and there was no significant difference in the concentration of 6 keto PGF1α between Wistar rats and SHR plasma(P>0.05). JNQ could increase the generation of 6 keto PGF1α and decrease the level of TXB2 and T/P in SHR plasma after treated with different dosages for 5 weeks.ConclusionJNQ may improve the balance between TXA2 and PGI2 in SHR plasma.

Experimental study of the effects of ultrashortwave diathermy or Chinese medicine in early stage of hormon-induced ischemic femoral head necrosis / 中华物理医学与康复杂志

Objective To investigate the pathogenesis of avascular necrosis of femoral head (ANFH) and to compare the effectiveness of ultrashort wave diathermy and Chinese medicine in the treatment of avascular necrosis of femoral head (ANFH) through animal experiment. Methods A total of 40 New Zealand white rabbits were divided into four groups: a control group, a model group, an ultrashort wave group, a Chinese me-dicine group. All the groups were injected with horse blood serum and methyl-prednisolone, which can induce ANFH. The TXB_2, 6-keto-PGF_ 1? , TG, TCh and hemorheology index were observed in the study. Results When compared with control group, the difference of model group was significant (P0.05) between ultrashort wave group and Chinese group. Conclusion Both ultrashort wave diathermy and Chinese medicine were effective for the treatment of ANTH in the early stage.

Study on the antiplatelet effect of phospholipase C: release function and metabolism / 中国药理学通报

AIM To investigate the antiplatelet effect of PLC by de termining the concentration of TXB 2, 6-keto-PGF 1? and bleeding time( BT). METHODS TXB 2 and 6-keto-PGF 1? were detected by ra dioimmunity kit. Bleeding time were measured by routine methods. RESULTS Six doses of PLC can prolong BT significantly(P0 05). The inhibition on TXB 2 generation, of PLC 60 0～ 1 000 U?kg -1 with ADP revulsant, PLC 800～1000 U?kg -1 with AA revulsant and PLC 1 000 U?kg -1 with Collagen revulsant, is more significant than ASA (P

Effects of puerarin on the levels of PGI_2 and TXA_2 in plasma of rats with hyperlipidemia / 第三军医大学学报

Objective To investigate the effects of puerarin on levels of thromboxane A 2 (TXA 2) and prostaglandin I 2 (PGI 2) in plasma of rats with hyperlipidemia. Methods A total of 48 Wistar juvenile rats were randomly divided into four groups: normal diet, high fat and high cholesterol diet (HFD), HFD supplemented respectively with 1 g/kg puerarin (puerarin group Ⅰ) or 2 g/kg puerarin (puerarin group Ⅱ). After eight weeks of feeding, the rats were sacrificed for detection of the levels of lipid, TXA 2, and PGI 2. Results The blood triglycerol, total cholesterol, LDL C, TXA 2, and TXA 2/PGI 2 were significantly lower in puetarin Ⅰ and puerarin Ⅱ groups than those in HFD group, but the concentration of HDL C was significantly increased in the supplemented group( F =109 163, P =0 000; P

Effects and mechanisms of compound G004 on experimental thrombosis / 中国临床药理学与治疗学

AIM:To study the effects and mechanisms of a novel sulfonylureous compound 1 ｛4 [2 (4 bromobenzenesulfonaminoethyl)phenylsufonyl｝ 3 (trans 4 methylcyclohexyl) urea, G004, on antithrombosis. METHODS: The influence of compound G004 on the vasoconstrictor action, platelet aggregation and thrombosis formation was studied. The effects of compound G004 on the tail vein bleeding time in mice was examined. The influence of compound G004 on the release of prostanglandin I 2 and thromboxan A 2 from ECV304 cells was investigated. The measurement of cytosolic free Ca 2+ in attached ECV304 cells loaded with Fluo3/AM was carried out. RESULTS: Compound G004 did not inhibit the contraction of rat aorta rings induced by norepinephrine or potassium chloride, but potently inhibit human platelet aggregation challenged by arachidonic acid and adenosine diphosphate. Compound G004 significantly prolonged the tail vein bleeding time in mice and occlusion time of carotid artery in experimentally thrombotic rats. Compound G004 reduced mice mortality induced by the collagen plus epinephrine in a dose dependent manner. Compound G004 enhanced PGI 2 release and reduced TXA 2 secretion from ECV304 cells. G004 had no effect on the increase of cytosolic free Ca 2+ induced by patassium chloride. CONCLUSION: The compound G004 has a remarkable antithrombotic effect in vivo. Its active mechanism may be attributed to inhibition of platelet aggregation, enhancing PGI 2 generation and decreasing TXA 2 secretion from human umbilical vein endothelium.

A research on PGI_2 and TXA_2 for lung cancer patients and ones with lung cancer metastasis / 临床外科杂志

Objective To explore the PGI 2 and TXA 2 for lung cancer patients and ones with lung cancer metastasis,in onder to provide nomal index for diagnosis and differential diagnosis in lung cancer metastasis.Methods To test plasma PGI 2 and TXA 2 by means of RIA in all cases.One group of patients who received non operative treatment:Six cases of patients with distant metastasis;Eight cases with hilus of long metastasis;Seven cases without metastasis.The other group of patients who received radical operation;Six cases of patients with distant metastasis;Seven cases with hilus of lung metastasis;Six cases without metastasis.Result The PGI 2/TXA 2 ratio of the patient whether distant metastasis or hilus of lung metastasis was obviously lower than that of the patients without metastasis( P

Effect of 20S-protopanaxadiol saponins on blood lipid metabolism and antioxidative activity in hyperlipidemia rats / 中草药

Object To observe the effect of 20S-protopanaxadiol saponins from Panax quinquefolium (PPDS) on total cholesterol, lipoprotein cholesterol metabolism and antioxidative activity in experimental hyperlipidemia rats. Methods The total cholesterol (TC), lipoprotein cholesterol, and lipid peroxidation (LPO) contents, prostaglandin I 2 (PGI 2), thromboxane A 2 (TXA 2) levels, superoxide dismutase (SOD) activity and blood viscosity were measured in hyperlipidemia rats which have been given PPDS 25, 50, 100 mg/(kg?d) by ip, continuously for 12 days. In addition, fat accumulation in liver was observed. Results Triglyceride (TG), TC, low density lipoprotein cholesterol (LDL-c) in serum, TXA 2 in plasma, LPO in serum and liver, and blood viscosity were decreased significantly; and high density lipoprotein cholesterol (HDL-c) in serum, PGI 2 in plasma, and SOD in serum and liver were significantly increased by given PPDS [50, 100 mg/(kg?d)] in experimental hyperlipidemia rats. Moreover, PPDS can decrease TC/HDL-c and LDL-c/HDL-c ratio, increase PGI 2/TXA 2 ratio, and inhibit fat accumulation in liver. Conclusion PPDS could inhibit arteriosclerosis by improving cholesterol and lipoprotein-cholesterol metabolism, suppressing LPO, and increasing the activity of SOD.

Effects of Fufang Xiaojingtong Capsule on dysmenorrhea induced by oxytocin in rats / 中成药

AIM: To investigate the analgesic effect and possible mechanism of Fufang Xiaojingtong Capsule(Radix astragali;Radix paeoniae alba,Radix et Rhizoma ginseng,Radix rehmanniae praeparata;Rhizoma chuanxiong)(FFXJTC) on oxytocin-induced dysmenorrhea in rats. METHODS: Sixty rats were randomly divided into normal control group(control),dysmenorrhea model group(model),high dose(2.0 g/kg),middle dose(1.0 g/kg) and low dose(0.5 g/kg)groups of treatment by FFXJTC,and Tianqi Tongjing Capsule(TQTJC) group(2.0 g/kg).Diethylstilbestrol was continuously subcutaneous injection for 10 d once a day in rats of all groups except rats of control group.FFXJTC was administrated ig for 7 d in rats of all groups except for model group given distillated water.After administration of oxytocin(0.2U) in every rat,the frequency of stretching writhing was recorded within 30 min.The blood was drawn 1 h after administration of oxytocin.The contents of nitric oxide(NO)and malondiadehyde(MDA) and activities of SOD and GSH-PX were respectively determined in serum. The contents of 6-Keto PGF_(1?) and TXB_2 were respectively determined in plasma.Uterus was dissected and homogenated for endothelin(ET-1) measurement. RESULTS: Compared with that of model group,frequency of stretching writhing decreased significantly,the activities of SOD and GSH-PX were markedly enhanced,NO content increased and MDA content decreased in serum,and 6-Keto PGF_(1?) content increased and TXB_2 content decreased in plasma in FFXJTC group. CONCLUSION: FFXJTC has an analgesic effect on dysmenorrhea induced by oxytocin in rats,its mechanism may be related to anti-oxidization,decreasing the contents of TXA_2 and ET-1,increasing the contents of NO and PGI_2.

The role of dimethylaminoethyl ginkgolide B mesylate on inhibiting platelet ag- gregation and release function / 中成药

AIM: To investigate the inhibiting effect and mechanism of dimethylaminoethyl ginkgolide B mesylate on platelet aggregation and release function.METHODS: The effect of dimethylaminoethyl ginkgolide B mesylate on inhibiting PAF-induced platelet aggregation was measured by turbidimetry method through giving rabbits dimethylaminoethyl ginkgolide B mesylate at different final concentration via i.v.for 5 days.The release of Ca2 + from PAF-induced platelet in rabbits was assayed with fluorospectrophotometry and the contents of TXA2 and PGI2 were measured by radio-immunity method.RESULTS: Three groups of dimethylaminoethyl ginkgolide B mesylate (1.95,3.90,7.80 mg/kg) had significant effect on inhibiting PAF-induced platelet aggregation in rabbits (compared to normal,P

Research on antithrombotic effect of total saponins of Astragalus / 中成药

Objective: To research antithrombotic effect and mechanism of total saponins of Astragalus (TSA).Methods: Effects of TSA on artery thrombosis anud platelet aggregation were studied, at dosage of 50,100,200mg/kg. And level of TXA 2,PGI 2 in plasma, content of NO in serum of rats were determined.Results: TSA could restrain artery thrombosis and platelet aggregation of rats, and increase PGI 2 and NO.Conclusion: There was apparently antithrombotic effect of TSA.

THE MECHANISM OF DEXAMETHASONE EFFECT ON RABBIT PLATELET AGGREGATION AND RELEASE / 中国药理学通报

The effect of dexamethason ( Dex ) on the rabbit platelet aggregation and release was studided. The results were showed that the platelet aggregation and release induced by collagen were inhibited markedly by Dex, TXA2 production of platelets also reduced, but the platelet activation induced by AA was not affected by Dex. The results were further showed that the PLA2 activity was depressed by Dex, and the action of Dex can be antagonized partly by increase of extracellular Ca2+, it suggests that Dex inhibited the activity of PLA2 with the reduction of Ca2+ inflow into cell. The activity of CaM and AC, the production of cAMP and cGMP were not affected by Dex.