Celastrol prevents cadmium‐induced neuronal cell death via targeting JNK and PTEN‐Akt/mTOR network

Cadmium (Cd), a toxic environmental contaminant, induces neurodegenerative diseases. Celastrol, a plant‐derived triterpene, has shown neuroprotective effects in various disease models. However, little is known regarding the effect of celastrol on Cd‐induced neurotoxicity. Here, we show that celastrol protected against Cd‐induced apoptotic cell death in neuronal cells. This is supported by the findings that celastrol strikingly attenuated Cd‐induced viability reduction, morphological change, nuclear fragmentation, and condensation, as well as activation of caspase‐3 in neuronal cells. Concurrently, celastrol remarkably blocked Cd‐induced phosphorylation of c‐Jun N‐terminal kinase (JNK), but not extracellular signal‐regulated kinases 1/2 and p38, in neuronal cells. Inhibition of JNK by SP600125 or over‐expression of dominant negative c‐Jun potentiated celastrol protection against Cd‐induced cell death. Furthermore, pre‐treatment with celastrol prevented Cd down‐regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activation of phosphoinositide 3′‐kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in neuronal cells. Over‐expression of wild‐type PTEN enhanced celastrol inhibition of Cd‐activated Akt/mTOR signaling and cell death in neuronal cells. The findings indicate that celastrol prevents Cd‐induced neuronal cell death via targeting JNK and PTEN‐Akt/mTOR network. Our results strongly suggest that celastrol may be exploited for the prevention of Cd‐induced neurodegenerative disorders.

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Lipid‐Embedded Molecular Dynamics Simulation Model for Exploring the Reverse Prostaglandin D2 Agonism of CT‐133 towards CRTH2 in the Treatment of Type‐2 Inflammation Dependent Diseases

Chemoattractant receptor‐homologous molecule expressed on Th2 cells (CRTH2) has been involved in several inflammation dependent diseases by mediating the chemotaxis of pro‐inflammatory cells in response to allergy and other responses through PGD2 ligation. This CRTH2‐PGD2 signaling pathway has become a target for treating allergic and type 2 inflammation dependent diseases, with many inhibitors developed to target the PGD2 binding pocket. One of such inhibitors is the ramatroban analog, CT‐133, which exhibited therapeutic potency cigarette smoke‐induced acute lung injury in patients. Nonetheless, the molecular mechanism and structural dynamics that accounts for its therapeutic prowess remain unclear. Employing computational tools, this study revealed that although the carboxylate moiety in CT‐133 and the native agonist PGD2 aided in their stability within the CRTH2 binding pocket, the tetrahydrocarbazole group of CT‐133 engaged in strong interactions with binding pocket residues which could have formed as the basis of the antagonistic advantage of CT‐133. Tetrahydrocarbazole group interactions also enhanced the relative stability CT‐133 within the binding pocket which consequently favored CT‐133 binding affinity. CT‐133 binding also induced an inactive or ‘desensitized’ state in the helix 8 of CRTH2 which could conversely favor the recruitment of arrestin. These revelations would aid in the speedy development of small molecule inhibitors of CRTH2 in the treatment of type 2 inflammation dependent diseases.     

注册分类改革视角下药品数据保护制度效应分析

在国际趋势的压力下,兼受跨太平洋伙伴关系协定（TPP）影响,我国实施药品数据保护制度已成大势所趋。鉴于药品数据保护与药品注册审批体系紧密相关,我国化学药注册分类改革后,药品数据保护对医药产业发展必然会带来不同影响。结合我国分类注册改革新标准,在理论上对数据保护制度实施效果进行研究,进而探讨新注册分类下数据保护的实施对1至4类药品及医药产业的影响。     

NITRATE UPTAKE BY LAMINARIA LONGICRURIS (PHAEOPHYCEAE)1,2

Laminaria longicrucis De la Pylaie took up exogenous nitrate under both summer and winter conditions. During July and August no NO₃^- was detected in the ambient water or in algal tissues although it was present in both in February. Discs (2.3 cm diam.) of thin blade tissue were incubated with NO₃^- at four temperatures, with and without illumination. Similar values Jor NO₃^- uptake were found for both summer and winter collected plants when measured in light at 0 C. An apparent K of 4–6 μM was recorded for both types of plants; the V_max ranged from 7 to 10 μmol h^-1 g^-1 dry wt measured in ca. 1800 μW cm^-2 of cool-white fluorescent light. Uptake rates at 5 C were 66%, and at 0 C 30% of those for controls run at 15 C. The alga scavenged NO₃- from solutions <0.5 μM. Ammonia did not inhibit NO₃- uptake. Antibiotic pretreatment reduced NO₃- uptake by a maximum of 12%. Nitrite uptake was inhibited in proportion to the concentration of NO₃- in the medium.     

Electrogenic behavior of the human red cell Ca2+ pump revealed by disulfonic stilbenes

Summary A systematic study was made of the action of 4-acetamido-4ontent/x6v650v571324253/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-isothiocyanostilbene-2,2ontent/x6v650v571324253/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-disulfonic acid (SITS) and 4,4ontent/x6v650v571324253/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-diisothiocyanostilbene-2,2ontent/x6v650v571324253/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-disulfonic acid (DIDS) on active Ca²⁺ transport of human erythrocytes. Pumping activity was estimated in inside-out vesicles (IOV's) by means of Ca²⁺-selective electrodes or use of tracer⁴⁵Ca²⁺. The stilbenes exhibited an approximately equal inhibitory potency and their action could be overcome by carbonyl cyanidep-trifluoromethoxyphenylhydrazone (FCCP) at low but not at high stilbene concentrations. In the absence of DIDS. Ca²⁺ transport was not affected upon addition of valinomycin, but it was appreciably reduced when vesicles were preincubated with low DIDS concentrations. Such an effect was strictly dependent on the external K⁺ concentration and it was abolished when valinomycin was added together with FCCP. Similar results were obtained using IOV's prepared from intact cells which had been previously exposed to the stilbene. The findings clearly demonstrate the presence in human red cells of a partially electrogenic Ca²⁺ pump, exchanging one Ca²⁺ ion for one proton.     

染色质调节元件与不同启动子的相互作用对基因表达调控的影响

为探究DNA序列元件对不同启动子调节转基因稳定表达的影响,利用遍在染色质开放元件 (Ubiquitous chromatin opening elements,UCOE) 和基质黏附序列 (Scaffold/matrix-attachment regions,MAR) 分别与含增强子的oct4基因启动子、含CpG岛的sox2基因启动子和不含调控元件的nanog基因启动子以及同时包含增强子和CpG岛的CMV启动子组合构建pOCT4-MAR、pOCT4-UCOE、pSOX2-MAR、pSOX2-UCOE、pNANOG-MAR、pNANOG-UCOE、pCMV-UCOE、pCMV-MAR等质粒,分析这些质粒稳定转染后的表达量和嵌合表达差异。结果发现,UCOE与含增强子元件的oct4启动子组合能较稳定高效表达,而MAR与含CpG岛的sox2启动子组合能较稳定高效表达。利用排除位置效应原因的嵌合表达对染色质高级结构调控基因表达的稳定性分析表明：(1) 通常情况下UCOE比MAR调节的表达载体的表达更高效和更稳定;UCOE连接含CpG岛的启动子形成开放染色质调节的高表达更稳定;(2) MAR与启动子上TATA盒或增强子可能通过染色质环产生高表达,但相对不稳定。结论：染色质调节元件UCOE和MAR与启动子调控元件之间能通过染色质开放状态或染色质环调控基因稳定表达。     

Preliminary Investigation of a 64-element Capacitive Micromachined Ultrasound Transducer (CMUT) Annular Array Designed for High Intensity Focused Ultrasound (HIFU)

Background

Treatment of prostate cancer using endocavitary High Intensity Focused Ultrasound (HIFU) has become more commonplace since the first treatments in the 1990s. The gold standard HIFU strategy to treat prostate cancer is the complete thermal ablation of the entire prostate gland under real-time ultrasound (US) image guidance. A more desirable treatment and the current trend, however, is towards a focal treatment but more accurate and finely tunable thermal lesions are needed along with improved US imaging guidance. In this study, Capacitive Micromachined Ultrasound Transducer (CMUT) technology is being investigated, as they have shown recent promise for US imaging and potential to be used for HIFU therapy. They offer potential advantages over current piezoelectric designs in the context of ultrasound-guided HIFU (USgHIFU) focal therapies.