Pyridazine-derived γ-secretase modulators

SAR of a novel series of pyridazine-derived γ-secretase modulators is described. Compound 25 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aβ42 and Aβ40, and maintain the levels of total Aβ. Furthermore, 25 demonstrated excellent pharmacokinetic parameters as well as good CNS penetration in the rat.     

n-3脂肪酸代谢产物抗炎作用的研究进展

炎症反应是机体正常组织对感染和损伤的应答,然而过度的炎症反应往往会引起急性和慢性疾病的发生.最近研究发现,由n-3多不饱和脂肪酸二十碳五烯酸和二十二碳六烯酸代谢产生的resolvins和protectins两类化合物,具有很强的抗炎和炎症修复活性.综述了resolvins和protectin D1的来源、抗炎作用和抗炎机制,为进一步开展n-3多不饱和脂肪酸及其代谢产物的抗炎作用研究、为炎症的防治提供新的思路.     

Protective effect of exogenously applied nitric oxide on aluminum-induced oxidative stress in soybean plants

Aluminum (Al) toxicity promotes oxidative damage in plants, while nitric oxide (NO) may exert a beneficial effect on Al toxicity condition in soybean. Pretreatment with NO donor sodium nitroprusside (SNP) before soybean exposure to Al significantly reduced Al accumulation and MDA induction in the root apex. Pretreatment with SNP also increased the relative root elongation, chlorophyll content, and activity of the protective enzyme peroxidase compared to Al treatment alone. These results show the effect of exogenously applied NO as a protector against oxidative stress induced by Al. Moreover, the ameliorating effect can be reversed by the addition of NO scavenger 2-(4-carboxy-2-phenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) in the presence of Al.     

Biological stability evaluation of the α2β1 receptor imaging agents: diamsar and DOTA conjugated DGEA peptide

Robust chelating stability under biological condi-tions is critical for the design of copper-based radiopharmaceuticals. In this study, the stabilities of (64)Cu-DOTA and diamsar (two bifunctional Cu-64 chelators (BFCs)) conjugated DGEA peptides were evaluated. The in vitro stabilities of (64)Cu-DOTA-DGEA, (64)Cu-DOTA-Ahx-DGEA, and (64)Cu-Z-E(diamsar)-Ahx-DGEA were evaluated in PBS. A carboxyl-protected DOTA-DGEA was also synthesized to study the potential inter- and intramolecular interactions between DOTA and the carboxylate groups of DGEA peptide. microPET imaging of (64)Cu-DOTA-DGEA and (64)Cu-Z-E(diamsar)-Ahx-DGEA were performed in PC-3 prostate tumor model to further investigate the in vivo behavior of the tracers. DOTA-DGEA, DOTA-Ahx-DGEA, Z-E(diamsar)-Ahx-DGEA, and protected DOTA-DGEA peptides were readily obtained, and their identities were confirmed by MS. (64)Cu(2+) labeling was performed with high radiochemical yields (>98%) for all tracers after 1 h incubation. Stability experiments revealed that (64)Cu-DOTA-DGEA had unexpectedly high (64)Cu(2+) dissociation when incubated in PBS (>55% free (64)Cu(2+) was observed at 48 h time point). The (64)Cu(2+) dissociation was significantly reduced in the carboxyl-protected (64)Cu-DOTA-DGEA complex but not in the (64)Cu-DOTA-Ahx-DGEA complex, which suggests the presence of competitive binding for (64)Cu(2+) between DOTA and the carboxyl groups of the DGEA peptide. In contrast, no significant (64)Cu(2+) dissociation was observed for (64)Cu-Z-E(diamsar)-Ahx-DGEA in PBS. For microPET imaging, the PC-3 tumors were clearly visualized with both (64)Cu-DOTA-DGEA and (64)Cu-Z-E(diamsar)-Ahx-DGEA tracers. However, (64)Cu-DOTA-DGEA demonstrated 5× higher liver uptake than (64)Cu-Z-E(diamsar)-Ahx-DGEA. This biodistribution variance could be attributed to the chelating stability difference between these two tracers, which correlated well with the PBS stability experiments. In summary, the in vitro and in vivo evaluations of (64)Cu-Z-E(diamsar)-Ahx-DGEA and (64)Cu-DOTA-DGEA have demonstrated the significantly superior Cu-chelation stability for the diamsar derivative compared with the established DOTA chelator. The results also suggest that diamsar may be preferred for Cu chelation especially when multiple carboxylic acid groups are present. Free carboxyl groups may naturally compete with DOTA for (64)Cu(2+) binding and therefore reduce the complex stability.     

Immunohistochemical localization of mu opioid receptor in the marginal division with comparison to patches in the neostriatum of the rat brain

Background  

Mu opioid receptor (MOR), which plays key roles in analgesia and also has effects on learning and memory, was reported to distribute abundantly in the patches of the neostriatum. The marginal division (MrD) of the neostriatum, which located at the caudomedial border of the neostriatum, was found to stain for enkephalin and substance P immunoreactivities and this region was found to be involved in learning and memory in our previous study. However, whether MOR also exists in the MrD has not yet been determined.     

The effects of 7-dehydrocholesterol on the structural properties of membranes

Smith-Lemli-Opitz syndrome, a congenital and developmental malformation disease, is typified by abnormal accumulation of 7-dehydrocholesterol (7DHC), the immediate precursor of cholesterol (CHOL), and depletion thereof. Knowledge of the effect of 7DHC on the biological membrane is, however, still fragmentary. In this study, large-scale atomistic molecular dynamics simulations, employing two distinct force fields, have been conducted to elucidate differences in the structural properties of a hydrated dimyristoylphosphatidylcholine bilayer due to CHOL and 7DHC. The present series of results indicate that CHOL and 7DHC possess virtually the same ability to condense and order membranes. Furthermore, the condensing and ordering effects are shown to be strengthened at increasing sterol concentrations.     

MicroSyn: A user friendly tool for detection of microsynteny in a gene family

Background  

The traditional phylogeny analysis within gene family is mainly based on DNA or amino acid sequence homologies. However, these phylogenetic tree analyses are not suitable for those "non-traditional" gene families like microRNA with very short sequences. For the normal protein-coding gene families, low bootstrap values are frequently encountered in some nodes, suggesting low confidence or likely inappropriateness of placement of those members in those nodes.     

Surface functionalization of TiO2 nanotubes with bone morphogenetic protein 2 and its synergistic effect on the differentiation of mesenchymal stem cells

To investigate the influence of surface-functionalized substrates with nanostructures on the behaviors of mesenchymal stem cells, we conjugated bone morphogenetic protein 2 (BMP2) onto TiO(2) nanotubes with different diameter sizes of 30, 60, and 100 nm for in vitro study. Polydopamine was employed as the intermediate layer for the conjugation of BMP2. The successful conjugation of BMP2 onto TiO(2) nanotubes was revealed by field-emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), and contact angle measurements. Immunofluorescence staining of vinculin, osteocalcin (OCN), and osteopontin (OPN) revealed that BMP2-functionalized TiO(2) nanotubes was favorable for cell growth. More importantly, MSCs cultured onto BMP2-functionalized TiO(2) nanotubes displayed significantly higher (p < 0.05 or p < 0.01) differentiation levels of ALP and mineralization after 7 and 14 day cultures, respectively. The results suggested that surface functionalization of TiO(2) nanotubes with BMP2 was beneficial for cell proliferation and differentiation. The approach presented here has potential application for the development of titanium-based implants for enhanced bone osseointegration.     

Development of casparian strip in rice cultivars

The development of Casparian strips (CSs) on the endo- and exodermis and their chemical components in roots of three cultivars of rice (Oryza sativa) with different salt tolerance were compared using histochemistry and Fourier transform infrared (FTIR) spectroscopy. The development and deposition of suberin lamellae of CSs on the endo- and exodermis in the salt-tolerant cultivar Liaohan 109 was earlier than in the moderately tolerant cultivar Tianfeng 202 and the sensitive cultivar Nipponbare. The detection of chemical components indicated major contributions to the structure of the outer part from aliphatic suberin, lignin and cell wall proteins and carbohydrates to the rhizodermis, exodermis, sclerenchyma and one layer of cortical cells in series (OPR) and the endodermal Casparian strip. Moreover, the amounts of these major chemical components in the outer part of the Liaohan 109 root were higher than in Tianfeng 202 and Nipponbare, but there was no distinct difference in endodermal CSs among the three rice cultivars. The results suggest that the exodermis of the salt-tolerant cultivar Liaohan 109 functions as a barrier for resisting salt stress.Key words: casparian strip, chemical components, development, rice, rootPlant roots are in direct contact with the soil environment and thus particularly affected by unfavorable conditions. To withstand the surrounding environment, roots have developed anatomical and physiological adaptations. The development of Casparian strips (CSs) in the root endo- and exodermis is one such strategy.^1–3 In roots of most species, the sequence of development of the endo- and exodermis is roughly the same and involves two consecutive developmental stages: (1) formation of CSs in radial and transverse walls impregnating the primary cell wall pores with lipophilic and aromatic substances and (2) deposition of suberin lamellae to the inner surface of anticlinal and tangential cell walls.^4–6A major function of the CS is to block the non-selective apoplastic bypass flow of water and ions into the stele.³ Therefore, the structure,^7–9 chemical nature,^10–12 and physiological function^13,14 of endo- and exdodermal CSs in roots have been the focus of many investigations. Although oxygen loss, drought and salinity can influence the development and chemical nature of CSs in different rice cultivars,^15–19 few investigations have considered the development and formation of endo- and exdodermal CSs in the roots of rice cultivars with different salt tolerance under normal growing conditions.In the present paper, light microscopy and Fourier transform infrared (FTIR) spectroscopy were used to examine the cytochemistry and root anatomy of isolated CSs. The aim was to compare anatomical development and chemical characteristics of the endoand exdodermal CSs of three rice (Oryza sativa L.) cultivars having different salt tolerance in north China: the salt-tolerant Liaohan 109 and two widely grown cultivars, Tianfeng 202 and Nipponbare.