Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents

Agonists of the 5-HT_2C receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT_2B receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT_2C agonists with no detectable agonism of the 5-HT_2B receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.     

A new strategy for photoelectrochemical DNA biosensor using chemiluminescence reaction as light source

Physical light source is absolutely necessary for usual photoelectrochemical measurement. In this work, chemiluminescence reaction rather than physical light source was used for the development of a novel photoelectrochemical DNA biosensor. CIPO (bis(2,4,5-trichlro-6-n-pentoxycarbonylphenyl)oxalate)-H(2)O(2)-9,10-diphenylanthrancene was selected as a CL system, which can produce appropriate exciting light and excite photoelectro active materials Ru(bpy)(2)dppz(2+) intercalated into the double-stranded DNA. Using such simple intercalation method, a detection limit of 4.5×10(-9) M target DNA was achieved without any amplification process. In addition, the selected CL system could be used to excite AuNPs-Ru(bpy)(2)dppz(2+) complex as well as CdSe QD multilayer, which indicated a good applicability for the established method.     

Chronic Sleep Restriction Induces Aβ Accumulation by Disrupting the Balance of Aβ Production and Clearance in Rats

Amyloid-β (Aβ) plays an important role in Alzheimer’s disease (AD) pathogenesis, and growing evidence has shown that poor sleep quality is one of the risk factors for AD, but the mechanisms of sleep deprivation leading to AD have still not been fully demonstrated. In the present study, we used wild-type (WT) rats to determine the effects of chronic sleep restriction (CSR) on Aβ accumulation. We found that CSR-21d rats had learning and memory functional decline in the Morris water maze (MWM) test. Meanwhile, Aβ₄₂ deposition in the hippocampus and the prefrontal cortex was high after a 21-day sleep restriction. Moreover, compared with the control rats, CSR rats had increased expression of β-site APP-cleaving enzyme 1 (BACE1) and sAPPβ and decreased sAPPα levels in both the hippocampus and the prefrontal cortex, and the BACE1 level was positively correlated with the Aβ₄₂ level. Additionally, in CSR-21d rats, low-density lipoprotein receptor-related protein 1 (LRP-1) levels were low, while receptor of advanced glycation end products (RAGE) levels were high in the hippocampus and the prefrontal cortex, and these transporters were significantly correlated with Aβ₄₂ levels. In addition, CSR-21d rats had decreased plasma Aβ₄₂ levels and soluble LRP1 (sLRP1) levels compared with the control rats. Altogether, this study demonstrated that 21 days of CSR could lead to brain Aβ accumulation in WT rats. The underlying mechanisms may be related to increased Aβ production via upregulation of the BACE1 pathway and disrupted Aβ clearance affecting brain and peripheral Aβ transport.

     

Inhibition of fibroblast growth factor 2-induced apoptosis involves survivin expression, protein kinase C alpha activation and subcellular translocation of Smac in human small cell lung cancer cells

To investigate the mechanism by which fibroblast growth factor 2 (FGF-2) inhibits apoptosis in the human small cell lung cancer cell line H446 subjected to serum starvation, apoptosis was evaluated by flow cytometry, Hoechst 33258 staining, caspase-3 activity, and DNA fragmentation. Survivin expression induced by FGF-2 and protein kinase Cα (PKCα) translocation was detected by subcellular frac-tionation and Western blot analysis. In addition, FGF-2-in-duced release of Smac from mitochondria to the cytoplasm was analyzed by Western blotting and immunofluorescence. FGF-2 reduced apoptosis induced by serum starvation and up-regulated survivin expression in H446 cells in a dose-dependent andtime-dependentmanner, andinhibitedcaspase-3 activity. FGF-2 also inhibited the release of Smac from mitochondria to the cytoplasm induced by serum starvation and increased PKCα translocation from the cytoplasm to the cell membrane. In addition, PKC inhibitor inhibited the expression of survivin. FGF-2 up-regulates the expression of survivin protein in H446 cells and blocks the release of Smac from mitochondria to the cytoplasm. PKCα regulated FGF-2-induced survivin expression. Thus, survivin, Smac, and PKCα might play important roles in the inhibition of apoptosis by FGF-2 in human small cell lung cancer cells.     

干旱胁迫下硫营养对小麦光合色素及MDA含量的影响

选用郑引1号（高水肥型）和陕合6号（抗旱型）2个小麦品种,通过室内盆栽试验比较了干旱及硫胁迫情况下小麦苗期功能叶片中叶绿素（Chla和Chlb）及丙二醛（MDA）含量的变化。采用自然渐进干旱法控制水分,每天称重。结果表明：无论在正常供水还是干旱胁迫时,供硫处理的叶绿素含量始终高于无硫处理,郑引1号的这种优势明显优于陕合6号,硫营养显示出对叶绿素含量的调节能力。干旱胁迫下,供硫处理的小麦叶片MDA含量始终低于无硫处理。两个试验结果均证实了硫营养能通过调节光合色素及MDA的含量增强作物的抗旱能力。     

细胞色素c在氨基酸及二肽修饰金电极上的电化学反应

系统地研究了细胞色素ｃ在多种氨基酸和多肽修饰电极上的电化学反应。并对影响加速细胞色素ｃ电化学反应的因素进行了讨论。     

The Role of Nucleus Accumbens Core/Shell in Sleep-Wake Regulation and their Involvement in Modafinil-Induced Arousal

Background

We have previously shown that modafinil promotes wakefulness via dopamine receptor D₁ and D₂ receptors; however, the locus where dopamine acts has not been identified. We proposed that the nucleus accumbens (NAc) that receives the ventral tegmental area dopamine inputs play an important role not only in reward and addiction but also in sleep-wake cycle and in mediating modafinil-induced arousal.

Methodology/Principal Findings

In the present study, we further explored the role of NAc in sleep-wake cycle and sleep homeostasis by ablating the NAc core and shell, respectively, and examined arousal response following modafinil administration. We found that discrete NAc core and shell lesions produced 26.5% and 17.4% increase in total wakefulness per day, respectively, with sleep fragmentation and a reduced sleep rebound after a 6-hr sleep deprivation compared to control. Finally, NAc core but not shell lesions eliminated arousal effects of modafinil.

Conclusions/Significance

These results indicate that the NAc regulates sleep-wake behavior and mediates arousal effects of the midbrain dopamine system and stimulant modafinil.