Professors and Graduates from Peking University School of Pharmaceutical Sciences Attending the 67th FIP Congress and CPA Centennial Anniversary

During the first week of September, 2007, the 67th world congress of pharmacy and pharmaceutical sciences,jointly hosted by the International Pharmaceutical Federation (FIP) and the Chinese Pharmaceutical

Rapid Determination of Dopamine and Its Metabolites During in vivo Cerebral Microdialysis by Routine High Performance Liquid Chromatography With Electrochemical Detection

Objective To determine dopamine and its metabolites during in vivo cerebral microdialysis by routine high performance liquid chromatography with electrochemical detection.Methods Microdialysis probes were placed into the right striatum of Wistar rat brains and perfused with Ringer's solution at a rate of 1.5 μL/min.A reverse phase HPLC with electrochemistry was used to assay DA,DOPAC,and HVA after cerebral microdialysates were collected every 20 minutes from awake and freely moving rats.In order to identify the reliability of this method,its selectivity,linear range,precision and accuracy were tested and the contents of DA,DOPAC,and HVA in rat microdialysates were determined.Results The standard curve was in good linear at the concentration ranging from 74 nmol/L to 1.5 μmol/L for DOPAC(r2= 0.9996),from 66 nmol/L to 1.3 μmol/L for DA(r2=1.0000)and from 69 nmol/L to 1.4 μmol/L for HVA(r2=0.9992).The recovery of DOPAC(0.30,0.77,1.49 μmol/L),DA(0.26,0.69,1.32 μmol/L),and HVA(0.27,0.71,1.37 μmol/L)was 82.00±1.70%,104.00±4.00%,98.70±3.10%;92.30±1.50%,105.30±2.30%,108.00±2.00%;80.00±7.80%,107.69±8.00%,and 108.66±3.10%,respectively at each concentration.Their intra-day RSD was 3.3%,3.4%,and 2.5%,and inter-day RSD was 4.2%,2.3%,and 5.6%,respectively.The mean extracellular concentrations of DOPAC,DA,and HVA in rat brain microdialysates were 10.7,2.4,and 9.2 μmol/L(n=6),respectively.Conclusion The findings of our study suggested that the simple,accurate and stable method can be applied to basic researches of diseases related to monoamines neurotransmitters by cerebral microdialysis in rats.

Sulforaphane enhances Nrf2-mediated antioxidant responses of skeletal muscle induced by exhaustive exercise in HIIT mice

Nuclear factor erythroid-derived 2-like 2(Nrf2)is the master regulator of antioxidant defenses.High-intensity interval training(HIIT)has been proposed as a time-efficient training program and has become a substantial component of modern training program In the present study,we evaluated the effects of sulforaphane(SFN),a dietary isothiocyanate derived from cruciferous vegetables and a potent Nrf2 activator,on Nrf2-mediated antioxidant defense responses of skeletal muscle induced by exhaustive exercise in HIIT mice.Male C57 BL/6 J mice were randomly allocated into control group,HIIT group,and HIIT pretreated with SFN(HIIT+SFN)group.On the third day after completion of a 6-weeks HIIT protocol,an exhaustive treadmill test was conducted in all mice.Mice were intraperitoneally injected with SFN(HIIT+SFN group)or PBS(HIIT and control mice)4 times in 3 days prior to the exhaustive treadmill test.The results indicated that the 6-weeks HIIT protocol did not increase the antioxidative capacity of skeletal muscle during exhaustive exercise.Importantly,SFN treatment improved anti oxidative capacity of skeletal muscle in response to the acute exhaustive exercise by increasing mRNA and nucleoprotein expression of Nrf2 and these genes involved in antioxidant generation and decreasing blood creatine kinase(CK)and 4-hydroxy-2-nonenal(4-HNE)-modified protein levels in the HIIT mice.

Quality Control for Traditional Medicines–Chinese Crude Drugs

Distinguished guests,ladies and gentlemen,I am very happy to meet many of my old friends today.I would also like to thank Chinese Pharmaceutical Association for providing me with such a good opportunity to communicate with Chinese and European friends.The topic of my report today is the quality standard of Chinese crude drugs and the development ideas.Director Ma introduced the relevant situation of the quality standards of Chinese patent medicines.

Cistanche Deserticola for Regulation of Bone Metabolism:Therapeutic Potential and Molecular Mechanisms on Postmenopausal Osteoporosis

Osteoporosis is a generalized disease of bone that leads to a loss of bone density and bone mass,destruction of bone microstructure,increased brittleness and therefore fracture.At present,the main treatment of Western medicine is drug therapy such as bisphosphonates,calcitriol,vitamin D,etc.However,long-term use of these drugs may bring some adverse reactions.Chinese herbal medicine Cistanche deserticola could regulate bone metabolism by promoting osteoblast activity and inhibiting osteoclast activity with low toxicity and adverse reactions.Therefore,Cistanche deserticola has attracted increasing attention for its efficacy in the prevention and treatment of osteoporosis in recent years.Here we present a literature review of the molecular pathways involved in osteoporosis and the effects of Cistanche deserticola on bone metabolism.Our objective is to clarify the mechanism of Cistanche deserticola in the treatment of osteoporosis.

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995–2015

Stroke is a brain damage caused by a loss of blood supply to a portion of the brain, which requires prompt and effective treatment. The current pharmacotherapy for ischemic stroke primarily relies on thrombolysis using recombinant tissue plasminogen activators(rt-PAs) to breakdown blood clots. Neuroprotective agents that inhibit excitatory neurotransmitters are also used to treat ischemic stroke but have failed to translate into clinical benefits. This poses a major challenge in biomedical research to understand what causes the progressive brain cell death after stroke and how to develop an effective pharmacotherapy for stroke. This brief review analyzes the fate of about 430 potentially useful stroke medications over the period 1995–2015and describes in detail those that successfully reached the market. Hopefully, the information from this analysis will shed light on how future stroke research can improve stroke drug discovery.

Icariin suppresses bone resorption activity of rabbit osteoclasts in vitro

The effect of icariin on the bone resorption activity of rabbit osteoclasts is assessed in vitro. Osteoclasts were isolated from Japanese white rabbits and cultured on plates with a sterilized bone slice in each well. After treatment with icariin at various concentrations, the bone resorption activity of osteoclasts was evaluated by examining pit areas, superoxide anion (·O2-) generation, size and number of actin rings and intracellular calcium concentration [Ca2+]i. As revealed by these data, icariin elicited continuous decline of [Ca2+]i, making actin ring constricted and ·O2- generation decreased. These events resulted in smaller and fewer pits which indicate suppressed bone resorption activity of rabbit osteoclasts by icariin.

Studies on Absorption and Tansport of Limoninoids from Fructus Evodiae in Caco-2 Cell Monolayer Model

Objective To study the intestinal absorption and transepithelial transport of three limoninoids: evodol (EVO), limonin (LIM), and shihulimonin A (SHIA), isolated from Fructus Evodiae [the unripe fruit of Evodia rutaecarpa and Evodia rutaecarpa var. bodinieri] in the human intestine. Methods The in vitro cultured human colon carcinoma cell line, Caco-2 cell monolayer model, was applied to studying the absorption and transepithelial transport of the three limoninoids from apical (AP) to basolateral (BL) side and from BL to AP side. The three limoninoids were measured by reversed-phase high performance liquid chromatography coupled with ultraviolet absorption detector. Transport parameters and apparent permeability coefficients (Papp) were then calculated and compared with those of Propranolol as a control substance of high permeability and Atenolol as a control substance of poor permeability. Results The Papp value of EVO and LIM from AP to BL side for absorption and transport were 1.78 × 10-5 cm/s and 1.16 × 10-5 cm/s, respectively, which was comparable to that of Propranolol with Papp 2.18 × 10-5 cm/s. Conclusion The absorption and transport of both EVO and LIM are main passive diffusion as the dominating process in Caco-2 cell monolayer model, and they were estimated to be high absorbed compounds. SHIA in Caco-2 cell monolayer model may be involved in metabolism in the transport processes.

Population pharmacokinetics of rocuronium delivered by target-controlled infusion in adult patients

背景控制目标的注入(TCI ) 最近在临床的实践被开发了并且成功地实现了。当前的学习是用非线性的混合效果模型( NONMEM )在成年病人估计 rocuronium TCI 的人口 pharmacokinetics ，并且在成年 patients.Methods 调查相关因素的影响十四 ASA -与一般麻醉经历选任的 laparoscopy 操作的病人是 included.After 感应，所有病人由 TCI 系统收到了 rocuronium 。开始的目标血浆集中(Cpt ) 是 2.0 g/ml，然后根据监视的神经与肌的传播增加了 Cpt。Cpt 的端点被决定 T1 规模是否被 90%-95% 堵住。 TCI rocuronium 被停止在 operation.Arterial 血的结束前的 30 分钟在 0 点在麻醉前被拉， 2 ， 4 ， 6 ， 8 ， 10 ， 15 ， 20 ， 30 ， 45 ， 60 ， 120 ， 180 ，在 rocuronium 的注入以后的 240 和 360 分钟被液体层析团 spectrometry/mass spectrometry ( LC-MS/MS )为 rocuronium 的血浆集中的分析停止。人口 pharmacokinetics 分析用 NONMEM program.Results 被执行在成年病人的 TCI rocuronium 的 pharmacokinetics 被参数是的 three-comparment model.Pharmacokintic 最好描述清理(CL ) 1=0.205 L/min， CL2=0.324 L/min， CL3=0.0292 L/min，分发(V) 1=4.00 L 的卷， V2=2.28 L， V3=4.26 L， Vdss=10.54 L。covariates 影响了 pharmacokinetic 参数的年龄和重量。V1 和 CL1 否定地与耐心的年龄被相关。CL1 断然与 weight.Conclusions 被相关当 rocuronium 经由 TCI 被管理时，没有 pharmacokinetic 变化被注意。covariates 影响了 pharmacokinetic 参数的年龄和重量。

Deficiency of anti-inflammatory cytokine IL-4 leads to neural hyperexcitability and aggravates cerebral ischemia-reperfusion injury

Systematic administration of anti-inflammatory cytokine interleukin 4(IL-4)has been shown to improve recovery after cerebral ischemic stroke.However,whether IL-4 affects neuronal excitability and how IL-4 improves ischemic injury remain largely unknown.Here we report the neuroprotective role of endogenous IL-4 in focal cerebral ischemia-repertusion(I/R)injury.In multi-electrode array(MEA)recordings,IL-4 reduces spontaneous firings and network activities of mouse primary cortical neurons.IL-4 mRNA and protein expressions are upregulated after I/R injury.Genetic deletion of 11-4 gene aggravates I/R injury in vivo and exacerbates oxygen-glucose deprivation(OGD)injury in cortical neurons.Conversely,supplemental IL-4 protects 11-4-/-cortical neurons against OGD injury.Mechanistically,cortical pyramidal and stellate neurons common for ischemic penumbra after I/R injury exhibit intrinsic hyperexcitability and enhanced excitatory synaptic transmissions in Il-4-/-mice.Furthermore,upregulation of Nav1.1 channel,and downregulations of KCa3.1 channel and a6 subunit of GABAA receptors are detected in the cortical tissues and primary cortical neurons from Il-4-/-mice.Taken together,our findings demonstrate that IL-4 deficiency results in neural hyperexcitability and aggravates I/R injury,thus activation of IL-4 signaling may protect the brain against the development of permanent damage and help recover from ischemic injury after stroke.

Crystal structure of the N-terminal ankyrin repeat domain of TRPV3 reveals unique conformation of fi nger 3 loop critical for channel function

In all six members of TRPV channel subfamily,there is an ankyrin repeat domain(ARD)in their intracellular N-termini.Ankyrin(ANK)repeat,a common motif with typi-cally 33 residues in each repeat,is primarily involved in protein-protein interactions.Despite the sequence similarity among the ARDs of TRPV channels,the struc-ture of TRPV3-ARD,however,remains unknown.Here,we report the crystal structure of TRPV3-ARD solved at 1.95Åresolution,which reveals six-ankyrin repeats.While overall structure of TRPV3-ARD is similar to ARDs from other members of TRPV subfamily;it,however,features a noticeable fi nger 3 loop that bends over and is stabilized by a network of hydrogen bonds and hydrophobic pack-ing,instead of being fl exible as seen in known TRPV-ARD structures.Electrophysiological recordings demonstrated that mutating key residues R225,R226,Q255,and F249 of fi nger 3 loop altered the channel activities and pharmacol-ogy.Taken all together,our findings show that TRPV3-ARD with characteristic fi nger 3 loop likely plays an im-portant role in channel function and pharmacology.

Effect of La^(3+) on osteoblastic differentiation of rat bone marrow stromal cells

In the present work, the effect of La3+ on osteoblastic differentiation of primary rat bone mar- row stromal cells (MSCs) as well as the related mechanisms are studied. Differentiation is monitored by detection of alkaline phosphatase (ALP) activity, osteocalcin secretion, the mRNA levels of Type I collagen and osteocalcin, and matrix mineralization. The results show that La3+ inhibits osteoblastic differentiation of MSCs in the early and middle stages of culture, as demonstrated by the decrease of ALP activity, osteocalcin secretion, and down-regulation of the mRNA level of osteocalcin. However, La3+ does not affect the matrix mineralization in advanced MSCs, because it up-regulates the mRNA levels of Type I collagen, and promotes ALP activity and os- teocalcin secretion in MSCs in the late stage of cul- ture. In addition, Western blot analysis exhibits that La3+ induces the phosphorylation and activation of mitogen-activated protein kinase (MAPK). Further- more, MAPK kinase inhibitor PD98059 completely blocks the inhibitory effect of La3+ on ALP activity of MSCs in the middle stage of culture. These results suggest that La3+ affects MSCs osteoblastic differen- tiation depending on differentiation stages. La3+ in- hibits osteoblastic differentiation of MSCs in the early and middle stages by a MAPK-dependent mecha- nism, but does not affect the matrix mineralization in advanced MSCs.

Lanthanides-Induced Cellular Signal Transduction: Implications in Pathogenesis of Fibrosis

With the extensive mining and application of lanthanides in China and worldwide, the potential impact of lanthanides on human health is gaining increasing attentions. The recent etiological association of gadolinium-based contrast agents with nephrogenic systemic fibrosis (NSF) evoked widespread concerns regarding the safety issue of lanthanides. The elucidation of the cellular biological effects of and the signalling cascade induced lanthanides is essential for proper evaluation of their health impacts.

Dose-response relationship between physical activity and nonalcoholic fatty liver disease:A prospective cohort study

To the Editor:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally,and this systemic disease carries a substantial economic burden and will result in a greater disease burden in the future.[1]Mass screening of asymptomatic individuals using ultrasonography is not cost-effective.Therefore,simple,noninvasive tests are required to identify patients with NAFLD.The fatty liver index(FLI)and hepatic steatosis index(HSI)are accurate and easy to obtain.

How to make insulin-producing pancreatic β cells for diabetes treatment

Around 400 million people worldwide suffer from diabetes mellitus.The major pathological event for Type 1 diabetes and advanced Type 2 diabetes is loss or impairment of insulin-secreting β cells of the pancreas.For the past 100 years,daily insulin injection has served as a life-saving treatment for these patients.However,insulin injection often cannot achieve full glucose control,and over time poor glucose control leads to severe complications and mortality.As an alternative treatment,islet transplantation has been demonstrated to effectively maintain glucose homeostasis in diabetic patients,but its wide application is limited by the scarcity of donated islets.Therefore,it is important to define new strategies to obtain functional human β cells for transplantation therapies.Here,we summarize recent progress towards the production of β cells in vitro from pluripotent stem cells or somatic cell types including a cells,pancreatic exocrine cells,gastrointestinal stem cells,fibroblasts and hepatocytes.We also discuss novel methods for optimizing β cell transplantation and maintenance in vivo.From our perspective,the future of βcell replacement therapy is very promising although it is still challenging to control differentiation of β cells in vitro and to protect these cells from autoimmune attack in Type 1 diabetic patients.Overall,tremendous progress has been made in understanding βcell differentiation and producing functional β cells with different methods.In the coming years,we believe more clinical trials will be launched to move these technologies towards treatments to benefit diabetic patients.