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@#Worldwide morbidity and mortality of acute myocardial infarction (AMI) and related heart failure are still high.While effective early reperfusion of the criminal coronary artery after a confirmed AMI is the typical and effective treatment at present, collateral myocardial ischemia reperfusion injury (MIRI) and pertinent cardio-protection are still challenging to address and have inadequately understood mechanisms.One important reason might be that AMI is multifactorial, causing cardiomyocyte death via multiple mechanisms, as well as affecting other cell types, including platelets, fibroblasts, endothelial and smooth muscle cells, and immune cells.Many cardioprotective strategies act through common end-effectors and may be suboptimal in patients with comorbidities.Therefore, unveiling the related multitarget strategies participating in triggering and resisting the pathobiology of MIRI is a promising and valuable frontier.The review specifically focuses on the recent MIRI advances that are supported by multitarget strategies and new targets under development in order to bring the rational combination of multitarget therapies up to date, as well as to identify findings that may facilitate the new drug of novel targets.
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This study was designed to investigate inhibitory effects and possible mechanisms of snake venom tripeptide (pENW) on platelet adhesion in order to promote the development of a novel anti-platelet therapy. To study the inhibitory effects of pENW on platelet adhesion, washed platelets pre-incubated with pENW (116.5-466.2 μmol x L(-1)) were used to test the ability of platelet adhesion to fibrinogen. Effect of pENW on fibrin clot retraction was also tested. Effect of pENW on platelets viability was tested by MTT assay. Effect of pENW on reactive-oxygen species (ROS) levels of platelet was studied by flow cytometry assay. Calcium mobilization in Fura-2/AM-loaded platelets was monitored with a spectrofluorimeter. Cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP), thromboxane A2 (determined as its metabolite thromboxane B2) were measured using enzyme immunoassay kits. Akt, ERK and p38 phosphorylation were tested by Western blot. The results showed that pENW inhibited platelet adhesion and fibrin clot retraction in a concentration-dependent manner without cytotoxicity. Intracellular cGMP and cAMP in both resting and thrombin-activated platelets were increased by pENW. In addition, pENW attenuated intracellular Ca2+ mobilization and TXA2 production in platelets stimulated by thrombin. As shown by Western blot assay, Akt, ERK and p38 phosphorylation in thrombin-induced platelet were attenuated by pENW. However, inhibitory effects of pENW had nothing to do with ROS. Thus, pENW exhibited a significant inhibition on platelet adhesion to fibrinogen, which means pENW could block the first step of thrombosis as while as retard the more stable clot formation. The mechanisms of pENW on inhibition platelet adhesion might be related to instant regulations, such as protein kinases.
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In order to study the therapeutic time window of dimethylaminoethyl ginkgolide B mesylate(XQ-1H) in the permanent focal ischemia of rat,we used the rat model of the permanent middle cerebral artery occlusion (pMCAO).Doses of 15.6,7.8 and 3.9 mg/kg of XQ-1 H were intravenously administered at 0.5,1,2,3 h after MCAO,respectively.Neurological scores,infarct sizes,water contents and pathological changes in each interval were determined at 72 h after MCAO.It was observed that XQ-1 H administered at 0.5 and 1 h after MCAO significantly reduced the cerebral infarct size and edema,and produced significant reductions in the neurological deficits.The protective effect of XQ-1H on the neuron cells was proved by pathological observations.In addition,the contents of MDA,lactate,and the activities of SOD were measured.Reduction in the contents of MDA and lactate and enhancement in the activities of SOD were attributed to the pretreatment of XQ-1H at 0.5 and 1 h.Our results showed that the therapeutic time window of XQ-1H extended for up to 1 h after MCAO.
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Aim: To evaluate the effects of HZ08, a novel P-glycoprotein inhibitor, on reversing tumor resistance of K562/ADM to adriamycin in nude mice and on the activities of cytochromes P-450 (GYP) isoforms. Methods: Nude mice bearing K562/ADM were injected at different doses of HZ08 with adriamycin for 4 weeks. The tumor weights of HZ08 treatment groups were determined and compared to those of the control and positive groups. In addition, the effects of HZ08 were examined on GYP isoforms-mediated metabolism of specific substrates by GYP isoforms in rat liver microsomes in the presence or absence of HZ08. Results: The tumor weights of HZ08 treatment groups were significantly decreased and HZ08 was a relatively potent inhibitor of CYP3A4, with no significant effects on other isoforms tested. Conclusion: HZ08 has potent effects on reversing P-glycoprotein mediated tumor multidrug resistance in rive with little influence on cytoehrome P-450 activities of rat liver.
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AIM: To study the effect of Lomerizine on the activity of P-glycoprotein (P-gp) in the bloodbrain barrier(BBB) and search for novel effective P-gp inhibiting agent against multidrug resistance. METH-ODS: Rhodamine123 (Rh123) was used to examine the activity of P-gp and RT-PCR to study the mdr mRNA expression in cultured rat brain microvessel endothelial cells (RBMECs). RESULTS: Lomerizine could increase the cellular Rh123 in RBMECs in a concentration-dependent manner. RT-PCR indicated that lomerizine could not down-regulate the expression of mdr mRNA. CONCLU-SION: Lomerizine can reverse multidrug resistance in the blood-brain barrier by inhibiting the activity of P-gp.KEY WORDS lomerizine; P-glycoprotein; bloodbrain barrier; RT-PCR
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It is meaningful to prompt the research-aimed experiments in the laboratory edu-cation of undergraduate students majoring in pharmacy,which means under the guidance of tutors, students collect information,design the experiment procedure and conduct the whole experiment independently. Under this novel mode of laboratory education, students’ abilities of indepen-dent-thinking and comprehensive-experimental conduction are largely improved. Meanwhile,the sense of team-work is enhanced. To sum up,the research-aimed experiments is significantly ben-eficial to training undergraduate students for future scientific researches.
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Multidrug resistance to chemotherapeutic drugs is an important reason for clinical chemotherapy failure. The mechanisms of the classical drug resistance such as P-gp, MRP have been clarified. Hence, it is very important to further study the non-classical mechanism of multidrug resistance. We introduced the effects on MDR, the possible mechanisms of glutathione and related enzymes, as well as the relationship between structure of GSH analogues and the transport activity in this paper.
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AIM: To observe protective effects of sanguis draxonis flavones on myocardial ischemia in rats and dogs. METHODS: Acute myocardial ischemia in rats was produced by iv pituitrin and ECG indexes were observed. Myocardial ischemia was induced by ligating coronary artery in anaesthetized dogs, and then EEC, CK,LDH, and LD in serum were determined respectively. RESULTS: J point and T wave in rats changed evidently after iv pituitrin, which was reversed by sanguis draxonis flavones (360, 180 mg?kg~ -1). In coronary artery ligation model, infraction range, △N-ST, △?-ST and some serum indexes (such as CK, LDH and LD) was decreased after ig sanguis draxonis flavones (120, 60, 30 mg?kg~ -1). CONCLUSION: Acute myocardial ischemia is protected effectively by sanguis draxonis flavones.
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As the effects of the nitric oxide and nitric oxide synthase have been investigated a lot,the nitric oxide synthase inhibitors were widely explored and become one of the highlights in the cerebral ischemia research.This paper reviewed the effects of nitric oxide synthase inhibitors especially the nNOS inhibitors and iNOS inhibitors on the cerebral ischemia damage.
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Objective To observe the effect of Naomaitai Capsule on the learning and memory abilities and cerebral lipid-peroxidation in rat with vascular dementia(VD).Methods Two VD models were(established).The first one was produced by occlusion of bilateral common carotid arteries in rats with the(following) steps: ischemia 20 min—reperfusion 10 min—ischemia 20 min.The learning and memory abilities were tested by Y type maze.Meanwhile,malondiadehyde(MDA) content and superoxide dismutase(SOD) activity in brain tissue of ischemia-reperfusion rats were measured.The second model was formed by injecting thrombin NS solution into internal carotid artery.The learning and memory abilities were studied by Y type Maze.The content of Evans blue in brain tissue was measured.Results In the model caused by cerebral ischemia-reperfusion,Naomaitai Capsule significantly improved the learning and memory abilities((P