bluuebunny/crossref_metadata_2025_split huggingface dataset:
An AICD-based functional screen to identify APP metabolism regulators
Authors: Zhang Can , Khandelwal Preeti J , Chakraborty Ranjita , Cuellar Trinna L , Sarangi Srikant , Patel Shyam A , Cosentino Christopher P , O'Connor Michael , Lee Jeremy C , Tanzi Rudolph E , Saunders Aleister J 
Published: August 2007

Abstract

Background
A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the β-amyloid precursor protein (APP), to generate the β-amyloid (Aβ) peptide and the APP intracellular domain (AICD). Aβ is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered.

Results
To validate this experimental approach we modulated α-, β-, and γ-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis.

Conclusion
Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.
Solid lipid nanoparticles (SLN) as carriers for the topical delivery of econazole nitrate: in-vitro characterization, ex-vivo and in-vivo studies
Authors: Sanna Vanna , Gavini Elisabetta , Cossu Massimo , Rassu Giovanna , Giunchedi Paolo 
Published: August 2007

Abstract
Solid lipid nanoparticles (SLN) designed for topical administration of econazole nitrate (ECN), were prepared by o/w high-shear homogenization method using different ratios of lipid and drug (5:1 and 10:1). SLN were characterized in terms of particle size, morphology, encapsulation efficiency and crystalline structure. After incorporation of SLN into hydrogels, rheological measurements were performed, and ex-vivo drug permeation tests were carried out using porcine stratum corneum (SC). In-vivo study of percutaneous absorption of ECN as a function of application time and composition of gels was carried out by tape-stripping technique. Penetration tests of the drug from a conventional gel were performed as comparison. High-shear homogenization method resulted in a good technique for preparation of ECN-loaded SLN. Particles had a mean diameter of about 150 nm and a regular shape and smooth surface. The encapsulation efficiency values were about 100%. Ex-vivo tests showed that SLN were able to control the drug release through the SC; the release rate depended upon the lipid content on the nanoparticles. In-vivo studies demonstrated that SLN promoted a rapid penetration of ECN through the SC after 1 h and improved the diffusion of the drug in the deeper skin layers after 3 h of application compared with the reference gel.
Novel, cell-penetrating molecular transporters with flexible backbones and permanently charged side-chains
Authors: Bodor N , Tóth-Sarudy É , Holm T , Pallagi I , Vass E , Buchwald P , Langel Ü 
Published: August 2007

Abstract
Various cell-penetrating peptides have been discovered recently that can translocate across plasma membranes and can even carry large cargo molecules into the cells. Because under physiological conditions most of these peptides carry considerable positive charges due to the presence of basic amino acids such as arginine, we decided to investigate whether molecular transporters composed of permanently charged side-chains also possess such cell penetrating ability. Arginine-rich oligomers that have a backbone with increased flexibility due to incorporation of non-α-amino acids (ε-aminocaproic acid) have been found to be effective molecular transporters. Here, we report the preparation of analogue structures by replacing the arginine residues with the quaternary form of a novel redox amino acid (Nys+) that contain a trigonelline moiety; it has already been shown possible to replace the original basic amino acid side-chain of neuropeptides without significant activity-loss due to the sufficiently close steric and electronic analogy between the new Nys+ and the original side-chains (in their protonated form, e.g., Arg+, Lys+). A nonamer analogue showed transporter activity resulting in increased cellular uptake in human carcinoma (HeLa) cells.
Central nervous system distribution kinetics of indinavir in rats
Authors: Hamidi Mehrdad 
Published: August 2007

AbstractThe central nervous system (CNS) distribution kinetics of indinavir were extensively evaluated using a combinational in-vivo model comprising the integration plot method (a single-passage approach) and neuropharmacokinetic method (a multiple-passage approach). A 5 mg kg−1 dose of indinavir was administered intravenously to rats. Blood and cerebrospinal fluid (CSF) samples and whole brain were collected from the animals at specified time points and the drug concentration in each sample was determined using a high-performance liquid chromatography method. For the neuropharmacokinetic study, the simultaneous plasma, CSF and brain concentrations were fitted to an integrated model, which resulted in the estimation of the influx (Kin) and efflux (Kout) rate constants of the drug to/from CSF and brain parenchyma. The integration plot method involved plotting the brainplasma or CSF-plasma concentration ratios (Kp,app) against AUC0r&#x030a;t/Cp(t), and estimating the uptake clearance of the drug by brain/CSF from the slope of the initial linear portion of the plot. The Kin and Kout values of the drug to/from CSF were estimated to be 2.42 times 10−2 and 13.26 times 10−2min−1, respectively, and the corresponding values for brain parenchyma were 1.02 times 10−2 and 1.32 times 10−2 min−1, respectively. The uptake clearances of indinavir by CSF and brain parenchyma were 8.89 and 8.38 μLmin−1 g−1, respectively. The permeability surface area products of the drug for the blood-brain barrier and blood-CSF barrier were estimated as 1.05 times 10−2 and 2.45 times 10−2 mL min−1 g−1, respectively. The estimated kinetic parameters indicated limited CNS entry of the drug because of the limited blood-brain barrier permeability and the efficient drug efflux from CNS, particularly from CSF.
The influence of improved glycaemic control with chlorpropamide on microvascular reactivity and nitric oxide synthase activity in diabetic rats
Authors: Sartoretto J L , Santos R A , Scavone C , Tostes R C , Nigro D , Carvalho M H C , Cuman R K N , Fortes Z B 
Published: August 2007

AbstractHyperglycaemia is a primary cause of vascular complications in diabetes. A hallmark of these vascular complications is endothelial cell dysfunction, which is partly due to reduced production of nitric oxide. The aim of this study was to verify the influence of improved glycaemic control with chlorpropamide on microvascular reactivity, endothelial nitric oxide synthase (e-NOS) expression, and NOS activity in neonatal streptozotocin-induced diabetic rats (n-STZ). Diabetes was induced by STZ injection into neonates Wistar rats. n-STZ diabetic rats were treated with chlorpropamide (200 mg kg−1, 15 days, by gavage). The changes in mesenteric arteriolar and venular diameters were determined in anaesthetized control and n-STZ diabetic rats, before and after topical application of acetylcholine, bradykinin and sodium nitroprusside (SNP). We also assessed e-NOS expression (using polymerase chain reaction after reverse transcription of mRNAs into cDNAs) and NOS activity (conversion of L-arginine to citrulline) in the mesenteric vascular bed of chlorpropamide-treated n-STZ, vehicle-treated n-STZ, and control rats. In n-STZ, chlorpropamide treatment reduced high glycaemic levels, improved glucose tolerance and homoeostatic model assessment (HOMA-beta), and restored NOS activity. Impaired vasodilator responses of arterioles and venules to acetylcholine, bradykinin and SNP were partially corrected by chlorpropamide treatment in n-STZ. We concluded that improved metabolic control and restored NOS activity might be collaborating with improved microvascular reactivity found in chlorpropamide-treated n-STZ.
Scavenging properties of metronidazole on free oxygen radicals in a skin lipid model system
Authors: Narayanan Sabrina , Hùnerbein Andreas , Getie Melkamu , Jäckel Andreas , Neubert Reinhard H H 
Published: August 2007

Abstract
Reactive oxygen species (ROS) play a vital role in the pathophysiology of the skin disease rosacea, a chronic, genetically-determined and UV-triggered disease, leading to facial redness and blemishes and exhibiting a deep impact on a patient's self-esteem and quality of life. ROS can cause oxidative damage to nucleic acids, sugars, proteins and lipids, thereby contributing to adverse effects on the skin. Metronidazole has been the first-line topical agent therapy for many years; nevertheless the mechanism of action is still not well understood. The therapeutic efficacy of metronidazole has been attributed to its antioxidant effects, which can involve two pathways: decreased generation of ROS within tissues or scavenging and inactivation of existing ROS. Previous investigations have shown that metronidazole reduces ROS by decreasing ROS production in cellular in-vitro systems. The aim of the following study was to demonstrate that metronidazole additionally exhibits anti-oxidative properties in a cell-free system, by acting as an antioxidant scavenger. A simple skin lipid model (oxidative) system and a complex skin adapted lipid system in conjunction with thiobarbituric acid (TBA) test, a quantitative assay for the detection of malondialdehyde (MDA) and therefore lipid peroxidation, were used to determine the antioxidative properties of metronidazole after UV irradiation. Results clearly show that metronidazole has antioxidative properties in a cell-free environment, acting as a free radical scavenger. Simple skin lipid model: in the presence of 10, 100 and 500 μg mL−1 metronidazole the MDA concentration was reduced by 25, 36 and 49%, respectively. Complex skin lipid system: in the presence of 100 and 500 μg mL−1 metronidazole the MDA concentration was reduced by 19 and 34%, respectively. The results obtained in this study and from previous publications strongly suggest that metronidazole exhibits antioxidative effects via two mechanisms: decrease in ROS production through modulation of neutrophil activity and decrease in ROS concentration by exhibiting ROS scavenging properties. The remarkable clinical efficacy of metronidazole in the treatment of rosacea is probably due to its ability to decrease ROS via different mechanisms, thereby protecting skin components from induced damage.
Theogallin and L-theanine as active ingredients in decaffeinated green tea extract: I. electrophysiological characterization in the rat hippocampus in-vitro
Authors: Dimpfel Wilfried , Kler Adolf , Kriesl Erwin , Lehnfeld Romanus 
Published: August 2007

Abstract
The in-vitro hippocampus slice preparation was used to mimic a physiological situation where nervous tissue is exposed directly to the water soluble extract of green tea and some of its constituents. This investigation provides evidence that L-theanine- and theogallin-enriched decaffeinated green tea extract is able to change the physiological pattern of electrical hippocampus activity in a concentration dependent manner (EC50 3 mg L−1). Of the seven fractions or single components tested (fraction containing all amino acids without L-theanine, fractions containing all amino acids plus L-theanine, glutamic acid, theogallin, its metabolites quinic acid and gallic acid, and L-theanine alone), glutamic acid produced the strongest changes in terms of increased population spike amplitude after single stimuli and increased long-term potentiation, commonly taken as representative for enhancement of spatial and time dependent memory. The presence of theogallin alone shifted the activity in the same direction. Similar results as with theogallin were obtained in the presence of quinic acid. No effect was seen with gallic acid. Opposite changes (decrease of population spike amplitude and attenuated long-term potentiation) were observed in the presence of L-theanine alone. No effects were detected during the addition of the amino acid mixture unless L-theanine was added, leading to a decrease of the responses as observed for the action of L-theanine alone. The results provide evidence for the involvement of several active principles in the action of enriched green tea extract on electrical brain activity. The overall enhancement of hippocampal pyramidal cell responses as observed for the crude extract seems to be due to the combined action of glutamic acid and theogallin (or its presumable metabolite quinic acid), whereas L-theanine seems to have an opposite effect. However, this action was not strong enough to antagonize the effects of glutamic acid and theogallin. The results are in line with the observation that the tested green tea extract improves cognition at concomitant mental relaxation in man.
Combined effect of total alkaloids from Feculae Bombycis and natural flavonoids on diabetes
Authors: Geng Peng , Yang Yang , Gao Zhihui , Yu Yangsheng , Shi Qian , Bai Gang 
Published: August 2007

Abstract
Both total alkaloids from Feculae Bombycis (TAFB) and natural flavonoids can inhibit α-glucosidase activity to depress the glucose level in blood. To investigate the cooperative effect of TAFB and flavonoids on blood glucose, we have studied their combined function compared with individual ingredients on enzymology, in-vitro and in-vivo. In the enzymological assay, the combination of TAFB and flavonoids showed more effective inhibition, compared with either TAFB or flavonoids alone, to α-glucosidase activity. In the everted intestine model in-vitro, the combined inhibition of starch hydrolysation and glucose transference to blood was much stronger than with separate components. In short-term studies with normal and experimentally-induced diabetic mice in-vivo, the combination of TAFB and flavonoids also had a stronger suppressive effect on the postprandial elevation in blood glucose after oral administration. In long-term treatment to diabetic mice in-vivo, the compound prescription could depress not only the fasting blood glucose, but also the fasting blood total cholesterol. These results demonstrated that TAFB and flavonoids could inhibit α-glucosidase activity cooperatively, which would successfully depress blood glucose level in the therapy of diabetes.
Anti-inflammatory and analgesic activities of the ethanolic extracts fromZanthoxylum riedelianum(Rutaceae) leaves and stem bark
Authors: Lima Leonardo Mandalho , Perazzo Fábio Ferreira , Carvalho José Carlos Tavares , Bastos Jairo Kenupp 
Published: August 2007

AbstractWe have evaluated the anti-inflammatory and analgesic properties of the leaves (LCE) and stem bark (BCE) crude extracts of Zanthoxylum riedelianum (Rutaceae). Different fractions of the stem bark extract (hexane, BCEH; dichloromethane, BCED; ethyl acetate, BCEE; and lyophilized aqueous residual, BCEW) were also investigated. We studied the effects of the extracts and fractions using the rat paw oedema test induced by carrageenan, dextran, histamine or nystatin; the mouse abdominal constriction test; the mouse hot-plate test (only for LCE and BCE); and the mouse formalin test. Both extracts and all BCE fractions displayed anti-inflammatory activity in the carrageenan-induced oedema model, but not for dextran, histamine or nystatin. Considering the analgesic models, both extracts showed antinociceptive activity, but BCE was more active than LCE in models of central pain. All BCE fractions showed significant inhibition in the abdominal constriction test and in both phases of the formalin test. When BCED was submitted to phytochemical procedures it led to the isolation of six lignans (sesamin, methylpluviatolide, dimethylmatairesinol, piperitol-4′-O-γ,γ-dimethylallyl ether, kaerophyllin and hinokinin), and a triterpene (lupeol). Inhibition of cyclooxygenase and its metabolites may have been involved in the mechanism of action of this plant, considering previous studies reporting the anti-inflammatory and analgesic activity for the identified lignans, as well as anti-inflammatory activity for lupeol.
Salutary effects of Corydalis yanhusuo extract on cardiac hypertrophy due to pressure overload in rats
Authors: Wen Chengping , Wu Limao , Ling Haiyun , Li Lianda 
Published: August 2007

Abstract
We have evaluated the effects of an alcohol extract from the rhizome of Corydalis yanhusuo W.T. (CY), a well-known traditional Chinese medicinal herb, on pressure-overloaded cardiac hypertrophy induced by transverse abdominal aorta constriction (TAAC) in rats. Rats were given vehicle or CY extract (200 or 50 mg kg−1 per day) from the second week after induction of pressure overload, for a period of 7 weeks. Haemodynamic parameters, relative heart weight and myocyte cross-sectional area were measured in each group. We also estimated left ventricular (LV) collagen volume fraction (CVF) using Masson trichrome staining, and type I collagen expression by Western blot assay. Chronic TAAC caused notable cardiac hypertrophy and heart dysfunction. Significant collagen deposition and greater type I collagen expression were found in model control rats. These changes were not significantly reversed after treatment with 50 mgkg−1 CY, whereas 200 mgkg−1 significantly improved heart function and prevented cardiac hypertrophy, with parallel reductions in myocardial fibrosis, as evidenced by reduced LV CVF and reduced levels of type I collagen. In conclusion, chronic treatment of rats with CY extract attenuated development of cardiac hypertrophy.
Gu Ling Pian, a traditional Chinese medicine, regulates function and OPG/RANKL synthesis of osteoblasts via the p38 MAPK pathway
Authors: Zhao Yi , Li Juan , Liu Yi , Yu Ke-qiang , Zhang Juan , Chen Xiao-guang 
Published: August 2007

Abstract
Osteoporosis is a common disease that makes bones prone to fracture and can affect both men and women. Many traditional Chinese medicine formulations have the potential effect of preventing osteoporosis. Gu Ling Pian (GLP), a traditional Chinese medicine formulation, comprised of tonifying kidney herbal medicines, has been demonstrated to prevent osteoporosis by increasing bone mineral density, however the exact mechanism has not yet been elucidated. Osteoprotegerin (OPG), a receptor activator of NF-κB (RANK), and RANK ligand (RANKL) play critical roles in bone remodelling by regulating the function of osteoclasts. In this study, we investigated the effect of GLP on osteoblasts, namely MG-63 cells. The cell proliferation and differentiation, synthesis of OPG/RANKL and p38 expression were tested on MG-63 cells exposed to serum from rats fed with GLP or not. The results showed that GLP significantly promoted MG-63 cell proliferation and differentiation. Upregulation of OPG and down-regulation of RANKL at the protein and mRNA level were observed in GLP serum treated MG-63 cells using an enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Further, treatment with GLP serum increased the level of p38 phosphorylation but did not affect the total p38 expression. These effects can be blocked by the p38 specific inhibitor SB203580. The results indicate that GLP can effectively promote the proliferation and differentiation of osteoblasts and regulate their OPG/RANKL expression, while the effects may be mediated via the p38 MAPK pathway. The findings suggest that GLP induces bone formation and may be beneficial for patients with osteoporosis.
Separation and purification of saponins from Semen Ziziphus jujuba and their sedative and hypnotic effects
Authors: Jiang Jian-Guo , Huang Xiao-Juan , Chen Jian 
Published: August 2007

Abstract
Semen Ziziphus jujuba (SZJ) has long been used in Chinese traditional medicine for the treatment of anxiety and insomnia because of its effect of decreasing monoaminergic system activity; saponins are thought to be the main bioactive factors. To investigate the sedative and hypnotic effects of saponins from SZJ, silica gel column chromatography and thin-layer chromatography were used to purify the crude extract of total saponins from SZJ. High-performance liquid chromatography showed that saponins from SZJ comprised two components, compounds I and II. Animal tests were conducted using these two compounds to compare their sedative and hypnotic effects. Results showed that both compounds had a significant effect (P &lt; 0.05, P &lt; 0.01) on walking time compared with that of the control group. Compound I had a significant effect on coordinated movement (P &lt; 0.05). Both compounds prolonged the suprathreshold barbiturate induced sleeping time (P &lt; 0.05). The number of sleeping animals increased by 30% and 20% for compounds I and II, respectively, under the sub-threshold dose of sodium barbital.
Fallowfield's Sexual Activity Questionnaire in women with without and at risk of cancer
Authors: Atkins Louise , Fallowfield Lesley J 
Published: August 2007

Objectives. To determine the effect of cancer, cancer risk, menopausal status and psychological factors on sexual activity as measured by Fallowfield's Sexual Activity Questionnaire (FSAQ). Study design and main outcome measures. Five groups of women completed the FSAQ: 1451 healthy women who were participating in an ovarian cancer screening trial; 488 healthy women at increased risk of breast cancer who were participating in a chemoprevention trial; 154 healthy women at increased risk of breast cancer who had been offered risk-reducing surgery; 117 women with advanced ovarian cancer; and a healthy non-study sample of 162 women. Results. There were significant between-group differences regarding age ( F=1373.79, P<0.01) and the proportion of women who were sexually active (χ2(4)=212.62, P<0.01) (more younger women reported being sexually active). The most commonly cited reason for sexual inactivity was the absence of a partner. In relation to their sexual activity, women with ovarian cancer reported less pleasure ( F=18.27, P<0.01), more discomfort ( F=21.33, P<0.01) and less frequency ( F=200.01, P<0.01) than the other groups. Premenopausal women reported more pleasure ( t=4.41, P<0.01), less discomfort ( t=11.79, P<0.01) and greater frequency of sexual activity ( t=8.58, P<0.01) than postmenopausal women. Psychological morbidity was associated with decreased pleasure in sexual activity among the women with an elevated risk of cancer – that is, those participating in the chemoprevention trial ( t=4.20, P<0.01) and those offered risk-reducing surgery ( t=3.32, P<0.01). Conclusions: The FSAQ is a useful tool for measuring sexual activity in women with cancer and women at a normal or increased risk of developing cancer. Age, cancer, psychological distress and menopausal status affect sexual activity in these groups of women and should be considered in future investigations.