Inhalation of nitric oxide in the treatment of SARS in Beijing

BACKGROUND: Patients with severe acute respiratory syndrome (SARS) frequently suffer from hypoxemia despite supplemental oxygen and mechanical ventilator support. Inhalation of nitric oxide (INO) could improve oxygenation in intubated ARDS patients. However, whether INO has similar effect in the patients with severe acute respiratory syndrome (SARS), and whether INO could be administrated in adults with non-invasive ventilator support is not known yet. METHOD: Fourteen patients with severe SARS (in two ICU units) were studied. Six patients received INO (30 ppm, 3-7 d), and eight patients served as controls. Oxygen saturation, hemodynamic index, inspired oxygen fraction, and chest x-ray were studied. A 4-week follow up was made. RESULTS: In the INO group, oxygen index (.P_(aO_2)/F_(iO_2)) increased from 94 till 250 mmHg. CPAP/BiPAP could be discontinued in all four patients and PEEP lowered in the intubated patient with no decrease of arterial oxygenation. The effects were remained after INO was discontin     

Mediation of calcitonin gene-related peptide in protection of ischemic preconditioning in rat hindlimbs

目的：研究降钙素基因相关肽（ＣＧＲＰ）介导缺血预适应对血管内皮的保护．方法：大鼠后肢缺血２ｈ后，观察乙酰胆碱诱导血管内皮依赖性舒张反应．结果：缺血不影响去甲肾上腺素的缩血管效应，但能显著削弱乙酰胆碱的舒血管效应．缺血预适应能阻止长时间缺血对乙酰胆碱舒血管效应的抑制作用，这种保护作用可被反复应用辣椒素耗竭ＣＧＲＰ所取消．急性应用辣椒素促进ＣＧＲＰ释放或外源性应用ＣＧＲＰ均可产生预适应样的保护作用．结论：大鼠后肢缺血预适应对内皮细胞的保护与辣椒素敏感的感觉神经有关；ＣＧＲＰ能模拟缺血预适应保护血管．     

Involvement of diacylglycerol kinase γ in modulation of iNOS synthesis in Golgi apparatus of vascular endothelial cells

The aim of this study was to clarify the role of diacylglycerol kinase (DGK)γ in vascular endothelial cells. The mRNA and protein expression of DGKγ and inducible nitric oxide synthase (iNOS) in rat aortic endothelial cells (RAECs) were investigated using RT-PCR, immunocytochemical, and immunoblot analyses. In RAECs, immunoreactivity of DGKγ was detected in the cytoplasm as a tubular or reticular structure. DGKγ immunoreactivity colocalized with those for GM130 and Golgin 97 but not with that for protein disulfide isomerase (PDI). In the presence of brefeldin A, DGKγ immunoreactivity was markedly decreased and displayed an aggregation-like pattern. After treatment of RAECs with nocodazole, DGKγ immunoreactivity was detected in Golgi stacks, which were severely segmented and appeared in vesicular shape. Stimulation with IL-1β increased mRNA expression of DGKγ, which was strongly attenuated by SB203580, a p38 MAPK inhibitor. IL-1β also induced expression of iNOS, which was observed as a tubular structure, and this distribution coincided with DGKγ immunoreactivity. Brefeldin A reduced both iNOS immunoreactivity and DGKγ immunoreactivity. iNOS expression was impaired by DGK inhibitors, R59022 and R59949. These results suggest that DGKγ is upregulated by IL-1β through the p38 MAPK pathway and may be involved in protein trafficking of iNOS in vascular endothelial cells.     

Gastroprotective activity of α-terpineol in two experimental models of gastric ulcer in rats

BACKGROUND AND THE PURPOSE OF THE STUDY: Several plant essential oils, as well as terpenes present in essential oils, have shown gastroprotective activity. The aim of the present work was to evaluate the gastroprotective activity of α-terpineol, a monoterpene alcohol which is present in essential oils of various plants. METHODS: The gastroprotective activity of α-terpineol was evaluated in rats by assessing the changes in ethanol and indomethacin-induced gastric ulcer scores and on gastric secretory volume and total acidity in pylorus-ligated rats. Alpha-terpineol was administrated orally at the doses of 10, 30, and 50 mg/kg one hour before administration of the ulcer inducing agents by the pylorus ligation procedure. The involvement of endogenous prostaglandins in the protective effect of α-terpineol in ethanol-induced gastric lesions test was assessed by administration of indomethacin (10 mg/kg, s.c.) 30 min before oral administration of α-terpineol at the dose of 50 mg/kg. RESULTS: α-terpineol presented gastroprotective activity against ethanol-induced ulcers at the doses of 10, 30, and 50 mg/kg. Epoxy-carvone at the dose of 10 mg/kg did not present gastroprotective activity against ulcer induced by indomethacin, but at the doses of 30 and 50 mg/kg it attenuated the gastric damages induced by this agent significantly. Pretreatment with indomethacin did not prevent the gastroprotective effect of α-terpineol on ethanol-induced ulcers. Alpha-terpineol also did not affect the gastric secretion in pylorus-ligated rats. MAJOR CONCLUSION: The results suggest that α-terpineol presents gastroprotective action which does not involve either an increase in the synthesis of endogenous prostaglandin or a decrease in the gastric acid secretion.     

P10 Thinking of bilingual-teaching of Pharmacology in China

The Specialty of Clinical Pharmacy of 7-year program is an important and specific one of School of Pharmacy, Shandong University. The training aim is to achieve to master level of senior clinical pharmacist. Pharmacology is a subject that plays crucial role of two kinds of bridge between medicine and pharmacy, basic medicine and clinical medicine. It is the main basic professional course for clinical pharmacy students. Students learn basic content of pharmacology, at the same time they can use English as a language tool to study academic knowledge of pharmacology skillfully if we conduct pharmacology as bilingual-teaching lesson. By this event, students may improve their reading and comprehending talent of professional literature written in English. Teachers could lead students to the access to scientific researches.     

Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo

Ketamine is an NMDA antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in small-scale human clinical trials. Ketamine also binds to σ receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine the involvement of σ receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for σ(1) and σ(2) receptors. The antidepressant-like effects of ketamine were assessed in vitro using a neurite outgrowth model and PC12 cells, and in vivo using the forced swim test. The σ receptor antagonists, NE-100 and BD1047, were evaluated in conjunction with ketamine in these assays to determine the involvement of σ receptors in the antidepressant-like effects of ketamine. Ketamine bound to both σ(1) and σ(2) receptors with μM affinities. Additionally, ketamine potentiated NGF-induced neurite outgrowth in PC12 cells and this effect was attenuated in the presence of NE-100. Ketamine also displayed antidepressant-like effects in the forced swim test; however, these effects were not attenuated by pretreatment with NE-100 or BD1047. Taken together, these data suggest that σ receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine.     

Measurement of biological activity of somatotropin in hypophysectomized rats

目的：建立测定生长激素（ＧＨ）在体生物活性的方法．方法：以去垂体大鼠体重增长（ＢＷＧ）和胫骨骺软骨板宽度（ＴＥＷ）为指标，观察动物性别、给药途径、次数和周期不同对效应的影响；同时进行４ｄＢＷＧ，６ｄＢＷＧ和６ｄＴＥＷ法，测定ＧＨ的效价（平行线３×３设计）．结果：♀和♂ｓｃ和ｉｍ给药以及每日给药１次和２次的ＢＷＧ和ＴＥＷ差异无显著意义．给药６ｄ比给药４ｄ引起较大的ＢＷＧ和ＴＥＷ（Ｐ＜００５）．４ｄＢＷＧ法和６ｄＢＷＧ法在００２０－０５００ＩＵ·ｄ－１有较好的λ值（００６６０和０１７４７）和ｒ值（０９０００和０９２３７）；４ｄＢＷＧ，６ｄＢＷＧ和６ｄＴＥＷ法测得ｒｈＧＨ的效价为４６１３２，３９８２９和４８０２３ＩＵ／ａｍｐ．６ｄＢＷＧ法有较小的λ值和较低的ＡＲＦＬ值．结论：可在同一组去垂体大鼠体内同时用４ｄＢＷＧ，６ｄＢＷＧ和６ｄＴＥＷ法测ＧＨ活性，以６ｄＢＷＧ法较好．     

Consideration of dosimetry in evaluation of ToxCast™ data

The US Environmental Protection Agency (US EPA) Toxcast? program has the stated goal of predicting hazard, characterizing toxicity pathways and prioritizing the toxicity testing of environmental chemicals through the use of in vitro high‐throughput screening (HTS) assays. This analysis integrates data from biomonitoring and from in vivo toxicity and pharmacokinetic studies to examine the physiological relevance of the tested and responding in vitro concentrations for five case study chemicals: triclosan, 2,4‐dichlorophenoxyacetic acid, perfluorooctanoic acid, monobutyl phthalate and mono‐2(ethylhexyl)phthalate. This analysis also examines the ToxCast? phase 1 data set for approximately 50 chemicals belonging to four ‘common mechanism groups’ which have been the subject of cumulative risk assessments by the US EPA for both the pattern of key responses and the relative potencies of included chemicals compared with the in vivo relative potencies. Responding concentrations in vitro were generally in the range of serum or plasma concentrations associated with no‐observed to lowest‐observed effect levels for the case study chemicals, while available biomonitoring data demonstrating actual exposures were generally lower. ToxCast? assay endpoints related to acetylcholinesterase (AChE) inhibition had low sensitivity for detecting organophosphate pesticides but good sensitivity for detecting N‐methyl carbamates. However, in vitro relative potencies did not correlate with in vivo potency. Both qualitative and quantitative predictive power is probably affected by the lack of comprehensive metabolic activity in most current in vitro systems explored in the ToxCast? program, and this remains a fundamental challenge for high‐throughput toxicity screening efforts. Copyright © 2011 John Wiley & Sons, Ltd.     

Modulation of release of ATP in the major pelvic ganglion of rats

用荧光素－荧光素酶方法测定大鼠盆总神经节腺苷三磷酸（ＡＴＰ）释放．钠通道阻断剂河豚毒素（１μｍｏｌ·Ｌ－１）抑制电刺激诱发的盆总神经节ＡＴＰ的释放．灌流液中去除Ｃａ２＋并加入ＥＧＴＡ（１ｍｍｏｌ·Ｌ－１）后消除ＡＴＰ的释放．腺苷（１００μｍｏｌ·Ｌ－１），Ａ１腺苷受体激动剂环戊腺苷（０．１μｍｏｌ·Ｌ－１），毒蕈碱性受体激动剂氧化震颤素（１μｍｏｌ·Ｌ－１）和５－羟色胺（１００μｍｏｌ·Ｌ－１）减少ＡＴＰ的释放．Ａ１腺苷受体拮抗剂８－环戊基－１，３－二丙基黄嘌呤（１０ｎｍｏｌ·Ｌ－１），α２肾上腺素受体拮抗剂育亨宾（３μｍｏｌ·Ｌ－１），Ｄ２多巴胺受体拮抗剂舒必利（２０μｍｏｌ·Ｌ－１）和组胺（１００μｍｏｌ·Ｌ－１）增加ＡＴＰ的释放．结果提示，在大鼠盆总神经节存在着作为神经递质参与突触传递的ＡＴＰ释放．Ａ１腺苷受体，毒蕈碱性受体，α２肾上腺素受体，Ｄ２多巴胺受体，５－羟色胺受体及Ｈ１组胺受体激动剂或拮抗剂可以通过节前机制影响ＡＴＰ的释放     

Study of the in vitro–in vivo correlation of Danshensu and protocatechuic aldehyde in a two-step release system

A two-step release system (TSRS) for the compound Danshen, which has drug-release behavior that is in accordance with the circadian rhythms of cardiovascular disease, was developed by combining an effervescent osmotic pump tablet and a pulsed-released tablet into one hard capsule by our lab. An in vivo study indicated that after oral administration of TSRS, two peaks of the plasma concentration of both Danshensu (DS) and protocatechuic aldehyde (PA) were observed, which suggested that the drug plasma concentration–time curve could meet the requirements for chronotherapy of cardiovascular disease after the bed-time administration of such a device. High performance liquid chromatography using an ultraviolet (UV) detector was used to simultaneously determine the concentrations of DS and PA in plasma. This method was simple, convenient, and appropriate for the quality control of DS and PA. A linear correlation model was established based on the percent absorbant data and percent in vitro dissolution data. Because the drugs were released from the device in an osmotic pressure-dependent manner and absorbed rapidly, a reasonable linear regression relationship was observed between the in vitro and in vivo performances. The current study highlights the potential use of such a device for chronopharmaceutical drug delivery.     

Disposition of β-methyldigoxin in man

Summary The time course of radioactivity in plasma and the excretion in urine and faeces over 7 days were determined in 12 healthy subjects after single oral and intravenous doses of a solution of³H--methyldigoxin. 62.2±2.1 and 29.0±5.2 per cent of the dose were excreted in urine and faeces, respectively, within 7 days of intravenous administration, compared with 55.2±2.8 and 28.6±5.7 per cent after oral administration. This indicates almost complete absorption of the glycoside when given in solution. 12 hours after its administration a pseudo-distribution equilibrium was reached and the average half life of tritiated compounds was 1.3 days. By 48 – 96 hours after treatment the average half life was 2.8 days. O-demethylation was revealed as the main metabolic degradation step in man. The rate of Demethylation was higher after oral than i.v. administration. Thus, only 31% of the radioactivity excreted in the urine consisted of unchanged -methyldigoxin after oral administration compared to 51% after i.v. dosing. Only traces of bis- and monoglycosides were excreted in urine, but there were considerable amounts in faeces, where they accounted for more than 35% of the total excretion. Up to 40% of the radioactivity in plasma and urine consisted of polar conjugates during the first 12 hours after administration of -methyldigoxin. The mono- and bisglycosides were identified as the main products of conjugation. During the 7 days approximately 15% of the administered dose was metabolized by splitting off glycosidic bonds and conjugation to polar compounds.Supported by the Deutsche Forschungsgemeinschaft and by Boehringer Mannheim, Germany     

Anticonvulsive effect of agmatine in mice

AIM: The present study was designed to examine the effect of agmatine, the decarboxylated product of L-arginine by L- arginine decarboxylase, on convulsion in the mouse maximal electroshock (MES) test and mouse glutamate-induced convulsion test. METHODS: MES convulsion and glutamate convulsion were respectively induced by an electrical stimulation     

Prediction of the disposition ofβ-lactam antibiotics in humans from pharmacokinetic parameters in animals

Various pharmacokinetic parameters (disposition half-life, total body clearance, renal clearance, hepatic clearance, volume of distribution, intrinsic clearance and volume of distribution of unbound drug) of six-lactam antibiotics were compared in mouse, rat, rabbit, dog, monkey, and human. Two methods for prediction of the disposition of the-lactam antibiotics in humans by extrapolation of the animal data were evaluated. One was the Adolph-Dedrick approach, which can be used to predict clearances in humans from the relationship between intrinsic clearances and body weight in the other five species. The volume of distribution in humans was predicted from the relationship between the volume of distribution and serum unbound fraction in the five species. The other was the Boxenbaum approach, which can be used to predict the pharmacokinetic parameters of the six-lactam antibiotics in humans by using the regression lines of log-log plots of intrinsic clearance and volume of distribution of unbound drug in a single species, in this case the monkey. The half-life calculated according to the latter method had a smaller absolute error than that calculated according to the former method, but the better method for extrapolation of animal data to humans seems to be the former method, which does not require a prioriinformation regarding structure-pharmacokinetic relationships among the antibiotics.     

Role of TGF-β in melanoma

Human malignant melanoma is highly resistant to chemotherapy and current immunotherapeutic approaches induce long term remission only in the minority of patients. The transforming growth factor-β (TGF-β) has attracted much attention as a therapeutic target because it plays an important and pleiotropic role in melanoma progression. TGF-β is a multifunctional cytokine involved in the regulation of many cellular processes including cell proliferation, differentiation and survival. Resistance to the growth inhibitory effects of TGF-β without alterations of TGF-β signaling molecules is characteristic of cutaneous melanoma. Melanoma produces increasing amounts of TGF-β with disease progression, inhibiting immune responses and providing an optimal microenvironment for undisturbed tumor growth. In addition, TGF-β exerts its tumor promoting functions via direct effects on tumor cell motility and invasiveness and indirectly by modulating tumor stroma and extracellular matrix, supporting angiogenesis and inhibiting immune surveillance. TGF-β acts through multiple intracellular signaling pathways and the outcome of TGF-β signaling is context-dependent. Defining the impact of the different TGF-β signaling pathways on melanoma progression will help to identify suitable therapeutic targets. Here we review the current knowledge of TGF-β in melanoma and discuss recent therapeutic approaches targeting the TGF-β pathway.     

Targeting distribution of monomethylhydrazine in mice

<正> Mice which had been administered monomethylhydrazine (MMH) 20 mg/kg iv were killed at 5, 15, 30, 60,120 and 180 min and blood, heart, liver, spleen, lung, kidney, brain, muscle and intestine samples were collected.These tissues were weighted and homogenized in 4 volumes of 0.1 mol/L HCl. The concentration of MMH in blood and the homogenate of tissues were quantitated by a p-dimethylaminobenzaldehyde colorimetric method. The targeting distribution characteristics of MMH in mice were quantitatively discribed by the parameters of tar-     

Tissue distribution of hydrazine in mice

ＴｉｓｕｅｄｉｓｔｒｉｂｕｔｉｏｎｏｆｈｙｄｒａｚｉｎｅｉｎｍｉｃｅＧＵＡＮＹｏｎｇ－Ｂｉａｏ，ＺＨＡＮＧＢａｏ－Ｚｈｅｎ（ＩｎｓｔｉｔｕｔｅｏｆＰｈａｒｍａｃｏｌｏｇｙａｎｄＴｏｘｉｃｏｌｏｇｙ，ＡｃａｄｅｍｙｏｆＭｉｌｉｔａｒｙＭｅｄｉｃａｌＳｃ...     

Identification of critical molecular pathways involved in exosome-mediated improvement of cardiac function in a mouse model of muscular dystrophy

Duchenne muscular dystrophy(DMD)is a progressive disease characterized by skeletal muscle atrophy,respiratory failure,and cardiomyopathy.Our previous studies have shown that transplantation with allogeneic myogenic progenitor-derived exosomes(MPC-Exo)can improve cardiac function in X-linked muscular dystrophy(Mdx)mice.In the present study we explored the molecular mechanisms underlying this beneficial effect.We quantified gene expression in the hearts of two strains of Mdx mice(D2.B10-Dmd^Mdx/J and Utrn^tm1Ked-Dmd^Mdx/J).Two days after MPC-Exo or control treatment,we performed unbiased next-generation RNA-sequencing to identify differentially expressed genes(DEGs)in treated Mdx hearts.Venn diagrams show a set of 780 genes that were≥2-fold upregulated,and a set of 878 genes that were≥2-fold downregulated,in both Mdx strains following MPC-Exo treatment as compared with control.Gene ontology(GO)and protein-protein interaction(PPI)network analysis showed that these DEGs were involved in a variety of physiological processes and pathways with a complex connection.qRT-PCR was performed to verify the upregulated ATP2B4 and Bcl-2 expression,and downregulated IL-6,MAPK8 and Wnt5a expression in MPC-Exo-treated Mdx hearts.Western blot analysis verified the increased level of Bcl-2 and decreased level of IL-6 protein in MPC-Exo-treated Mdx hearts compared with control treatment,suggesting that anti-apoptotic and anti-inflammatory effects might be responsible for heart function improvement by MPC-Exo.Based on these findings,we believed that these DEGs might be therapeutic targets that can be explored to develop new strategies for treating DMD.     

Evaluation of chlorinated pesticides residues in foodstuff of animal origin from middle districts of Jordan in 2013–2014

This study was carried out to find chlorinated pesticides residues in foodstuff of animal origin in Jordan through 2013 and 2014. Ministry of Environment of Jordan asked the Royal Scientific Society to monitor the pesticides residues of these persistent organic pollutants (POPs) in foodstuff of animal origin under the supervision of official scientific committee. Results of milk products showed that there were two samples from 30 were contaminated, but less than the maximum residue limit (MRL). Results of table eggs showed that 11 samples from 35 were contaminated, but less than MRL. Results of meat and poultry analysis showed that 21 samples from 55 were contaminated, but less than MRL. However, the contaminated samples were contained β-HCH, γ-HCH, p,p′-DDT, p,p′-DDE, p,p′-DDD, heptachlor and aldrin. Conclusions and recommendations were reported to minimize pesticides residues in foodstuff of animal origin in Jordan.     

Metabolism of α-thujone in human hepatic preparations in vitro

1. This study aims to characterize the metabolism of α-thujone in human liver preparations in vitro and to identify the role of cytochrome P450 (CYP) and possibly other enzymes catalyzing α-thujone biotransformations.

2. With a liquid chromatography–mass spectrometry (LC-MS) method developed for measuring α-thujone and four potential metabolites, it was demonstrated that human liver microsomes produced two major (7- and 4-hydroxy-thujone) and two minor (2-hydroxy-thujone and carvacrol) metabolites. Glutathione and cysteine conjugates were detected in human liver homogenates, but not quantified. No glucuronide or sulphate conjugates were detected. Major hydroxylations accounted for more than 90% of the primary microsomal metabolism of α-thujone.

3. Screening of α-thujone metabolism with CYP recombinant enzymes indicated that CYP2A6 was principally responsible for the major 7- and 4-hydroxylation reactions, although CYP3A4 and CYP2B6 participated to a lesser extent and CYP3A4 and CYP2B6 catalyzed minor 2-hydroxylation. Based on the intrinsic efficiencies of different recombinant CYP enzymes and average abundances of these enzymes in human liver microsomes, CYP2A6 was calculated to be the most active enzyme in human liver microsomes, responsible for 70–80% of the metabolism on average.

4. Inhibition screening indicated that α-thujone inhibited both CYP2A6 and CYP2B6, with 50% inhibitory concentration values of 15.4 and 17.5 µM, respectively.

     

Noradrenergic mechanism in the regulation of seizures in GEPR.

Genetically epilepsy prone rat (GEPR) is a model of generalized tonic/clonic epilepsy and a useful tool in the understanding of basic mechanisms of human epilepsy. GEPR is susceptible to audiogenic seizure, hyperthermia induced seizure,and has lower threshold for electrical and chemical stimuli. Several strains of GEPR, from GEPR-3 to GEPR-9, are available depending on the degree of the intensity of audiogenic seizure.