bluuebunny/crossref_metadata_2025 huggingface dataset:
Rubus sanctusprotects against carbon tetrachloride-induced toxicity in rat isolated hepatocytes: isolation and characterization of its galloylated flavonoids
Authors: Badr Amira M , El-Demerdash Ebtehal , Khalifa Amani E , Ghoneim Asser I , Ayoub Nahla A , Abdel-Naim Ashraf B
Published: October 2010

Objectives

Rubus sanctus Schreb., known from the Bible as ‘holy thorn bush’, grows wild in Egypt. Rubus sanctus aqueous alcoholic extract (RE) contains a complicated phenolic mixture (ellagitanins, flavonoids and caffeic acid derivatives). In this study, the phytochemical investigation of the plant was re-evaluated. Herein, we report on the isolation and identification of three galloylated flavonoids, namely kaempferol-3-O-(6″-O-galloyl)-4C1-β-d-galactopyranoside, quercetin-3-O-(6″-O-galloyl)-4C1-β-d-galactopyranoside and myricetin-3-O-(6″-O-galloyl)- C1-β-d-galactopyranoside for the first time from the Rubus genus. We further aimed at evaluating the potential protective effects of RE against carbon tetrachloride (CCl4)-induced toxicity in isolated rat hepatocytes.

Methods

Based on an initial concentration-response experiment, a concentration of 100 μg/ml was selected to investigate the hepatoprotective activity of RE.

Key findings

Pretreatment with RE afforded protection as indicated by counteracting CCl4-induced cell death, and reduced glutathione depletion. In addition, RE ameliorated CCl4-induced enzyme leakage by 40% for lactate dehydrogenase, 30% for alanine aminotransferase and 20% for aspartate aminotransferase as compared with CCl4-treated cells. Moreover, RE counteracted CCl4-induced lipid peroxidation and inhibited spontaneous lipid peroxidation in the control group.

Conclusions

In conclusion, RE protects against CCl4-induced toxicity in isolated rat hepatocytes.
Central nervous system effects of the essential oil of the leaves of Alpinia zerumbet in mice
Authors: De Araújo Fernanda Yvelize Ramos , Silva Maria Izabel Gomès , Moura Brinell Arcanjo , De Oliveira Gersilene Valente , Leal Luzia Kalyne A Moreira , Vasconcelos Silvânia Maria Mendes , Viana Glauce Socorro Barros , De Moraes Manoel Odorico , De Sousa Francisca Cléa Florenço , Macêdo Danielle Silveira
Published: October 2010

Objectives

Alpinia zerumbet, known in Brazil as colônia, is popularly used as a diuretic, antihypertensive, anti-ulcerogenic and sedative. Based on this, we have investigated the central effects of the essential oil isolated from A. zerumbet leaves.

Methods

Mice were treated once with 50 or 100 mg/kg of the essential oil, intraperitoneally, 30 min before being submitted to behavioural models of: locomotor activity (open-field), catalepsy, anxiety (elevated plus maze), depression (forced swimming test and tail suspension tests) as well as apomorphine-induced stereotypy.

Key findings

Results showed a dose-related decrease on locomotor activity and apomorphine-induced stereotypy. There was a decrease to the order of 55% of the grooming behaviour with both doses studied. The essential oil 100 mg/kg increased cataleptic activity (167%) and the immobility time in the forced swimming and tail suspension tests. Pretreatment with haloperidol (0.2 mg/kg, i.p.) alone also decreased locomotion, increased cataleptic activity and immobility time in the tail suspension test. No alterations in the elevated plus maze test were registered.

Conclusions

The essential oil of A. zerumbet leaves had depressant and possible antipsychotic activity, since it could reverse the stereotypy induced by apomorphine, presenting effects comparable with those obtained with haloperidol treatment.
Raphanus sativusextract prevents and ameliorates zearalenone-induced peroxidative hepatic damage in Balb/c mice
Authors: Salah-Abbès Jalila Ben , Abbès Samir , Haous Zohra , Oueslati Ridha
Published: October 2010

Objectives

Raphanus sativus (radish) is a species of crucifer, which includes widely consumed vegetables, distributed in Asia, Africa and Europe. It is a rich source of bioactive molecules including anthocyanins, glucosinolates, isothiocyanates and other flavonoids, and miscellaneous phenolic substances. We have evaluated the hepatoprotection of R. sativus extract against zearalenone, an estrogenic mycotoxin initiating hepatotoxicity in male Balb/c mice.

Methods

Animals were divided into seven treatment groups and treated orally each day for twenty eight days as follows: a control, an olive oil group, group I, group II, and group III treated with radish extract alone (5, 10 and 15 mg/kg, respectively), group IV treated with zearalenone (40 mg/kg), and group V treated with zearalenone plus the lowest dose of radish extract.

Key findings

Administration of zearalenone alone resulted in significant decreases in the levels of alkaline phosphatase, lactate dehydrogenase, alanine and aspartate aminotransferases in the liver, suggesting hepatic damage. Moreover, a marked increase in the level of lipid peroxide and concomitant decrease of glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, glutathione-S-transferase, RNA and DNA concentrations were also observed in the liver tissue of zearalenone-treated mice. Co-treatment with R. sativus extract plus zearalenone succeeded in reversing the condition back to normal levels for all studied parameters.

Conclusions

By itself R. sativus extract did not show any toxic effects and could be considered as a potent hepatoprotectant.
Effect of dimethylnitrosamine-induced liver dysfunction on the pharmacokinetics of 5-fluorouracil after administration of S-1, an antitumour drug, to rats
Authors: Yoshisue Kunihiro , Kanie Shohei , Nishimura Takako , Chikamoto Junko , Nagayama Sekio
Published: October 2010

Objectives

The anti-tumour agent S-1 comprises tegafur (a prodrug of 5-fluorouracil; 5-FU), gimeracil (2-chloro-2,4-dihydroxypyridine (CDHP); a competitive inhibitor of 5-FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5-FU after administration of S-1 to rats was investigated.

Methods

S-1 (5 mg/kg) was administered intravenously and orally to rats with DMN-induced liver dysfunction. Plasma concentrations of S-1 components and 5-FU were measured by HPLC and LC/MS-MS. Blood tests and in-vitro enzymatic investigations were also conducted.

Key findings

DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5-FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S-1, the blood concentration-time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half-life of tegafur was significantly prolonged. The maximum plasma concentration (Cmax) of 5-FU was significantly reduced and the area under the blood concentration-time curve (AUC) was reduced by 22%. Following oral administration, the Cmax of tegafur, 5-FU and CDHP were significantly decreased and half-lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5-FU (13.6% reduction).

Conclusions

The pharmacokinetic profiles of tegafur, 5-FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5-FU. However, hepatic dysfunction had less of an effect on the AUC of 5-FU, which correlates with anti-tumour effect, after the oral administration of S-1.
Inhibitory effects of 1,3-thiazine derivatives on melanogenesis
Authors: Ha Sang Keun , Koketsu Mamoru , Lee Minjae , Moon Eunjung , Kim Sung-Hoon , Yoon Tae-Jin , Kim Sun Yeou
Published: October 2010

Objectives

The aim of this study was to identify a novel skin-depigmenting agent from synthetic 1,3-thiazine derivatives.

Methods

We investigated the inhibitory effects of six kinds of 1,3-thiazine derivative on melanogenesis by examining their effects on tyrosinase activity and melanin biosynthesis in melan-a cells and the zebrafish model.

Key findings

Of the six compounds, 4-hydroxy-2,6-dimethyl-5,6-dihydro-4H-1,3-thiazine (TZ-6) had the strongest anti-melanogenic effects in cultured melan-a cells (30.4% inhibition at 100 μM). In addition, TZ-6 exhibited an inhibitory effect on mushroom and cellular tyrosinase. Based on the results of Western blotting, TZ-6 reduced the expression of tyrosinase at 100 mM. Additionally, TZ-6 reduced body pigmentation and inhibited tyrosinase activity in the zebrafish model.

Conclusions

The results have provided useful information for the development of a skin whitening agent.
Gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean LamiaceaeSphacele chamaedryoides(Balbis) Briq.
Authors: Areche Carlos , Schmeda-Hirschmann Guillermo , Theoduloz Cristina , Rodríguez Jaime A
Published: October 2010

Objectives

The aim of this report was to isolate, identify and assess the gastroprotective effect and cytotoxicity of abietane diterpenes from the Chilean medicinal plant Sphacele chamaedryoides (Balbis) Briq. (Lamiaceae).

Methods

The isolated compounds were identified by spectroscopic means. The gastroprotective effect of the compounds was studied on the HCl/EtOH-induced gastric lesions model in mice. The cytotoxicity of the compounds was assessed on human normal lung fibroblasts (MRC-5) and gastric adenocarcinoma cells (AGS).

Key findings

From the aerial parts of the plant, five phenolic and five p-quinone abietanes, the sesquiterpene spathulenol and two flavonoids were obtained. The main diterpene from the plant was carnosol (7). Lansoprazole at 20 mg/kg reduced gastric lesions by 64.7% (P < 0.01), being statistically similar to carnosol at doses of 10 and 20 mg/kg; the percent lesion reduction with 7 at 5 mg/kg was 49.3%. At a single oral dose of 5 mg/kg, the diterpenes bearing a p-quinone moiety −6,7-dehydroroyleanone (1), royleanone (2), 7,20-epoxyroyleanone (3), taxoquinone (5) and horminone (6) - presented a gastroprotective effect of 54.4, 70.8, 65.0, 35.8 and 52.7%, respectively. Of the C-7 hydroxy derivatives, the activity was much lower for the 7β-OH isomer. The phenolic diterpenes 7 and 7-oxo-11,12,14-trihydroxy-8,11,13-abietatrien-20-al (8) inhibited gastric lesions by 49.3 and 53.0%, respectively. Royleanone (2), 7,20-epoxyroyleanone (3), horminone (6), 8 and spathulenol proved to be cytotoxic with IC50 values in the range of 11–67 μM. The selective cytotoxicity of compounds 1 (IC50: 61 and 366 μM) and 5 (IC50: 310 and 27 μM) against AGS cells and fibroblasts, respectively, merit additional studies.

Conclusions

All the abietanes obtained from S. chamaedryoides present either one or two phenolic OH groups, a quinone system, or both. Several compounds present in the plant showed higher gastroprotective effect than lansoprazole. The cytotoxic effect of most compounds was found at fairly high concentrations and lacked cell specificity. Further studies are required using different tumour cell lines and viability/proliferation assays to assess the specificity of the isolated compounds. The selective cytotoxicity of compounds 1 and 5 against AGS cells and fibroblasts, respectively, merit additional studies.
Huang-Lian-Jie-Du-Tang exerts anti-inflammatory effects in rats through inhibition of nitric oxide production and eicosanoid biosynthesis via the lipoxygenase pathway
Authors: Zeng Huawu , Liu Xiaohua , Dou Shengshan , Xu Wen , Li Na , Liu Xiaojun , Zhang Weidong , Hu Zhenlin , Liu Runhui
Published: October 2010

Objectives

Huang-Lian-Jie-Du-Tang (HLJDT) is a traditional Chinese medicine with a long history of anti-inflammatory use, but its pharmacological effects have not been thoroughly investigated. This study aimed to evaluate the anti-inflammatory activity of HLJDT in vivo and in vitro.

Methods

The carrageenan rat air pouch model was used to investigate the anti-inflammatory action of HLJDT after oral administration. Moreover, we exploited a modified method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique to assay the effects of HLJDT on arachidonic acid metabolites.

Key findings

Our data demonstrate that oral administration of HLJDT significantly inhibited the inflammatory responses in carrageenan-injected rat air pouches, and also significantly reduced the production of nitric oxide (NO) and leukotriene B4 (LTB4) in vivo, without any influence on biosynthesis of cyclooxygenase (COX)-derived eicosanoids. Similar behaviour of HLJDT was also observed by using calcium ionophore A23187-stimulated peritoneal macrophages, where HLJDT markedly inhibited eicosanoids derived from different lipoxygenases. The NO production and the mRNA expression of inducible nitric oxide synthase (iNOS) and chemotactic factors (CCL3, CCL4, CCL5 and CXCL2) were also inhibited by HLJDT in RAW 264.7 macrophages stimulated by lipopolysaccharide.

Conclusions

Our data revealed, for the first time, that HLJDT could inhibit biosynthesis of eicosanoids derived from different lipoxygenases. Also, HLJDT may exert its anti-inflammatory effects by its suppression on eicosanoid generation, NO production and gene transcription of chemotactic factors, which supports its effectiveness in the treatment of inflammatory diseases.
Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus
Authors: Lee Joo H , Yang Si H , Oh Jung M , Lee Myung G
Published: October 2010

Objectives

In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration–time curve from time zero to time infinity (AUC) of metabolites, AUCmetabolite/AUCparent drug ratios, or the time-averaged nonrenal and total body clearances (CLNR and CL, respectively) of parent drugs as reported in the literature have been compared.

Key findings

After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CLint) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster.

Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans.
Development of an original method to study drug release from polymeric nanocapsules in the skin
Authors: Weiss-Angeli Valeria , Bourgeois Sandrine , Pelletier Jocelyne , Guterres Silvia Stanisçuaski , Fessi Hatem , Bolzinger Marie-Alexandrine
Published: October 2010

Objectives

This study aimed to investigate the distribution and release profile in the skin of a lipophilic model molecule, octylmethoxycinnamate (OMC), loaded in poly(ε-caprolactone) nanocapsules (NC) by the Franz cell method.

Methods

Nanocapsules were formulated in a hydroxyethylcellulose gel and compared to the same gel containing 5% of free OMC as control. A new extraction method was used to discriminate the OMC still entrapped in the NC from free OMC released in the skin strata. The OMC extraction from the skin was performed using acetonitrile, which broke the NC, or isopropyl myristate, which kept the NC intact.

Key findings

When isopropylmyristate was used to determine the OMC released from NC, the results showed that more than 80% of the OMC was released from the NC at the skin surface after 6 h, whereas only 30% was released in the stratum corneum and epidermis.

Conclusions

It is suggested that the mechanism of release is different at the surface and in viable skin, probably due to the different local environments surrounding the NC. The small amount of OMC that reached the dermis was no longer encapsulated, suggesting that the NC did not reach the dermis. The viable epidermis seemed to be the limiting barrier against NC diffusion into the skin.
Geranylgeranylacetone preconditioning may attenuate heat-induced inflammation and multiorgan dysfunction in rats
Authors: Zhao Yong-Qi , Gao Jun-Tao , Liu Shou-Hong , Wu Yan , Lin Mao-Tsun , Fan Ming
Published: October 2010

Objectives

Geranylgeranylacetone, an acyclic isoprenoid, is a non-toxic inducer of heat shock protein (HSP)70. HSP70 overproduction is associated with heat tolerance in rats. This study aimed to investigate whether geranylgeranylacetone preconditioning of rats reduced heat-induced inflammation and multiple organ dysfunction.

Methods

Anaesthetised rats were given vehicle or geranylgeranylacetone (800 mg/kg) orally. After 48 h they were exposed to ambient temperature of 43°C for 70 min to induce heatstroke. Another group of rats kept at room temperature were used as normothermic controls.

Key findings

Vehicle-treated rats all succumbed to heat stress; their survival time was 25 ± 4 min. Pretreatment with geranylgeranylacetone significantly increased survival time to 92 ± 15 min. Compared with normothermic controls, all vehicle-treated heatstroke rats displayed hepatic and renal dysfunction (e.g. increased plasma levels of serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and active inflammation (e.g. increased plasma and brain levels of interleukin-1β, tumour necrosis factor-α and interleukin-6). These heat-stress response indicators were all significantly suppressed by geranylgeranylacetone pretreatment. In addition, the plasma and brain levels of interleukin-10 (an anti-inflammatory cytokine) and brain levels of HSP70 were significantly increased after geranylgeranylacetone preconditioning during heatstroke.

Conclusions

Geranylgeranylacetone preconditioning attenuates heat-induced inflammation and multiorgan dysfunction in rats.
Anti-ischaemic activity of an antioxidant aldose reductase inhibitor on diabetic and non-diabetic rat hearts
Authors: Calderone Vincenzo , Testai Lara , Martelli Alma , Motta Concettina La , Sartini Stefania , Da Settimo Federico , Breschi Maria C
Published: October 2010

Objectives

Many observations report the cardioprotective effects of inhibitors of aldose reductase in different models of ischaemia–reperfusion injury in diabetic myocardium. In this paper, the inhibitory effects of the new pyrido[1,2-a]-pyrimidin-4-one derivative PPO, whose aldose reductase-inhibitory and antioxidant effects were shown in a previous study, were evaluated.

Methods

The effect of PPO was evaluated on aldose reductase from hearts of diabetic and non-diabetic rats, and compared with that of the reference drug epalrestat. Moreover, the two drugs were tested on isolated and Langendorff-perfused diabetic and non-diabetic hearts submitted to ischaemia–reperfusion cycle.

Key findings

Epalrestat showed equivalent levels of potency in inhibiting the activity of the enzyme in the diabetic and in the non-diabetic hearts. On the contrary, the inhibitory potency of PPO was decreased in the diabetic organs. In the diabetic hearts submitted to ischaemia–reperfusion, an increased level of heart aldose reductase activity was recorded, and both PPO and epalrestat produced cardioprotective effects, suggesting that aldose reductase is deeply involved in the process of ischaemia–reperfusion injury in diabetic myocardium. In non-diabetic hearts, where aldose reductase has a lower activity, epalrestat failed to produce significant protection, while PPO still maintained cardioprotective effects, which may be reasonably attributed to useful ‘ancillary’ effects – such as antioxidant activity – independent from the aldose reductase inhibition.

Conclusions

Therefore PPO, a new molecule endowed with both aldose reductase-inhibitory effects and antioxidant activity, may represent the prototype of a new class of multitarget drugs, focused on two different steps deeply involved in the pathogenesis of ischaemic injury of diabetic hearts.
JS-K has potent anti-angiogenic activityin vitroand inhibits tumour angiogenesis in a multiple myeloma modelin vivo
Authors: Kiziltepe Tanyel , Anderson Kenneth C , Kutok Jeffery L , Jia Lee , Boucher Kenneth M , Saavedra Joseph E , Keefer Larry K , Shami Paul J
Published: October 2010

Objectives

Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases nitric oxide on metabolism by GST. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antineoplastic activity.

Methods

We studied the effect of JS-K on angiogenesis in human umbilical vein endothelial cells (HUVECs), OPM1 multiple myeloma cells, chick aortic rings and in mice.

Key findings

JS-K inhibited the proliferation of HUVECs with a 50% inhibitory concentration (IC50) of 0.432, 0.466 and 0.505 μm at 24, 48 and 72 h, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 μm, respectively. JS-K inhibited cell migration at 5 h using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 μm. In the chick aortic ring assay using VEGF or FGF-2 for vessel growth stimulation, 0.5 μm JS-K completely inhibited vessel growth. JS-K inhibited tumour angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells.

Conclusions

JS-K is a potent inhibitor of angiogenesis in vitro and tumour vessel growth in vivo. As such, it establishes a new class of antineoplastic agent that targets the malignant cells directly as well as their microenvironment.
Methodological and statistical issues in pharmacogenomics
Authors: Peters Bas J M , Rodin Andrei S , De Boer Anthonius , Maitland-van der Zee Anke-Hilse
Published: October 2010

Pharmacogenomics strives to explain the interindividual variability in response to drugs due to genetic variation. Although technological advances have provided us with relatively easy and cheap methods for genotyping, promises about personalised medicine have not yet met our high expectations. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA-B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir, thiopurine S-methyltransferase (TPMT) genotyping to avoid thiopurine toxicity, and CYP2C9 and VKORC1 genotyping for better dosing of the anticoagulant warfarin. However, few pharmacogenetic examples have made it into clinical practice in the treatment of complex diseases. Unfortunately, lack of reproducibility of results from observational studies involving many genes and diseases seems to be a common pattern in pharmacogenomic studies.

In this article we address some of the methodological and statistical issues within study design, gene and single nucleotide polymorphism (SNP) selection and data analysis that should be considered in future pharmacogenomic research. First, we discuss some of the issues related to the design of epidemiological studies, specific to pharmacogenomic research. Second, we describe some of the pros and cons of a candidate gene approach (including gene and SNP selection) and a genome-wide scan approach. Finally, conventional as well as several innovative approaches to the analysis of large pharmacogenomic datasets are proposed that deal with the issues of multiple testing and systems biology in different ways.
Anti-inflammatory effects of synthetic compound KT-14480 in lipopolysaccharide-stimulated microglia cells
Authors: Ock Jiyeon , Suk Kyoungho
Published: October 2010

Objectives

Neurodegenerative diseases have a prominent inflammatory component. Several synthetic fluorovinyloxyacetamide derivatives were screened by microglia cell-based assay in order to identify novel compounds that inhibit the inflammatory activation of microglia.

Methods

Microglia cell-based nitric oxide assay was employed to screen the compounds. RT-PCR and ELISA were conducted to evaluate the expression of inflammatory gene expression. Molecular mechanisms were determined by western blot analysis, immunocytochemistry, EMSA, and microglia/neuroblastoma cocultures.

Key findings

A fluorovinyloxyacetamide compound KT-14480 significantly suppressed nitric oxide production in lipopolysaccharide-stimulated microglia cells. KT-14480 also suppressed the secretion and expression of several inflammatory mediators such as tumour necrosis factor-α, interleukin-1β and inducible nitric oxide synthase. Additional studies showed that these inhibitory effects were accompanied by the suppression of nuclear factor-κB and neuroprotection in the microglia/neuroblastoma coculture.

Conclusions

Our results indicate that the anti-inflammatory compound KT-14480 may be a novel therapeutic drug candidate against neuroinflammatory diseases.
Intratumoural chemotherapy of lung cancer for diagnosis and treatment of draining lymph node metastasis
Authors: Celikoglu Firuz , Celikoglu Seyhan I , Goldberg Eugene P
Published: October 2010

Objectives

Reviewed here is the potential effectiveness of cytotoxic drugs delivered by intratumoural injection into endobronchial tumours through a bronchoscope for the treatment of non-small cell lung cancer and the diagnosis of occult or obvious cancer cell metastasis to mediastinal lymph nodes.

Key findings

Intratumoural lymphatic treatment may be achieved by injection of cisplatin or other cytotoxic drugs into the malignant tissue located in the lumen of the airways or in the peribronchial structures using a needle catheter through a flexible bronchoscope. This procedure is termed endobronchial intratumoural chemotherapy and its use before systemic chemotherapy and/or radiotherapy or surgery may provide a prophylactic or therapeutic treatment for eradication of micrometastases or occult metastases that migrate to the regional lymph nodes draining the tumour area.

Conclusions

To better elucidate the mode of action of direct injection of cytotoxic drugs into tumours, we review the physiology of lymphatic drainage and sentinel lymph node function. In this light, the potential efficacy of intratumoural chemotherapy for prophylaxis and locoregional therapy of cancer metastasis via the sentinel and regional lymph nodes is indicated. Randomized multicenter clinical studies are needed to evaluate this new and safe procedure designed to improve the condition of non-small cell lung cancer patients and prolong their survival.
Hydroxypropylmethylcellulose films for prolonged delivery of the antipsychotic drug chlorpromazine
Authors: Luppi Barbara , Bigucci Federica , Baldini Mattia , Abruzzo Angela , Cerchiara Teresa , Corace Giuseppe , Zecchi Vittorio
Published: October 2010

Objectives

The aim of this study was to develop transdermal films based on hydroxypropylmethylcellulose with the purpose of improving transdermal permeation of chlorpromazine hydrochloride, an antipsychotic drug used to alleviate the symptoms and signs of psychosis.

Methods

Hydroxypropylmethylcellulose films were prepared and evaluated for their drug content, film thickness, residual water content and bioadhesive properties. In-vitro permeation experiments were performed in the absence and in the presence of permeation enhancers (oleic acid, polysorbate 80, or both) with the purpose of improving drug availability. Other formulative parameters, such as drug and plasticizer concentration and hydroxypropylmethylcellulose type, were investigated.

Key findings

Both oleic acid and polysorbate 80 had significant effect on drug permeation with respect to the control formulation. In particular films containing a mixture of oleic acid and polysorbate 80 provided the best enhancement activity for chlorpromazine. Moreover, a decrease in propylene glycol or chlorpromazine content or an increase of hydroxypropylmethylcellulose viscosity provided lower cumulative amounts of drug permeated.

Conclusions

The results obtained confirm that chlorpromazine permeation can be easily modulated by varying the composition of hydroxypropylmethylcellulose-based films. These formulations could serve as candidates for transdermal delivery of antipsychotic drugs.
The pharmacokinetics of morphine and its glucuronide conjugate in a rat model of streptozotocin-induced diabetes and the expression of MRP2, MRP3 and UGT2B1 in the liver
Authors: Hasegawa Yoshitaka , Kishimoto Shuichi , Shibatani Naoki , Nomura Hiromichi , Ishii Yuko , Onishi Mika , Inotsume Nobuo , Takeuchi Yoshikazu , Fukushima Shoji
Published: October 2010

Objectives

The aim was to investigate the pharmacokinetics of morphine and its metabolite, morphine-3-glucuronide (M3G), in a rat model of streptozotocin (STZ)-induced diabetes.

Methods

Morphine (15 mg/kg) was administered intravenously, and the concentrations of morphine and M3G in the plasma, urine and bile were measured by HPLC. Changes in the expression of multidrug resistance-associated proteins (MRP2 and MRP3) and UDP-glucuronosyltransferase 2B1 (UGT2B1) mRNA in the liver were also estimated by reverse-transcriptase PCR.

Key findings

Plasma morphine concentrations were lower in the STZ-diabetic rats than controls although the elimination half-life of morphine was similar in the two groups (47.9 ± 10.7 min and 47.2 ± 8.6 min, respectively). The concentration of M3G in plasma was higher in STZ-diabetic than control rats, and the biliary excretion of M3G was lower in the STZ-diabetic rats (7.4 ± 2.3% vs 13.3 ± 2.0%). The urinary excretion of M3G was similar in the two groups (10.1 ± 6.8% vs 10.9 ± 4.9%). The expression of MRP3 and UGT2B1 mRNA was increased in STZ-diabetic rats, whereas expression of MRP2 mRNA was decreased.

Conclusions

In STZ-diabetic rats, the distribution volume of morphine increased, the glucuronidation rate and M3G transportation into the blood were enhanced, and the excretion of M3G was decreased, leading to an increase in the plasma M3G concentration.
Evaluation of the effects ofOlea europaeaL. subsp. africana (Mill.) P.S. Green (Oleaceae) leaf methanol extract against castor oil-induced diarrhoea in mice
Authors: Amabeoku George J , Bamuamba Kapinga
Published: October 2010

Objectives

Olea europaea L. subsp. africana (Mill.) P.S. Green is widely used in South Africa by traditional medicine practitioners to treat diarrhoea. However, little is known scientifically about this South African species in the treatment of diarrhoea. The main aim of the study therefore was to investigate the antidiarrhoeal effect of the leaf methanol extract of the plant species in mice.

Methods

The antidiarrhoeal activity of the leaf methanol extract of O. europaea subsp. africana was studied using a castor oil-induced diarrhoeal test. The antipropulsive activity of the plant extract was also investigated using the charcoal meal transit test. Standard methods were used to investigate the acute toxicity and effect of O. europaea subsp. africana on castor oil-induced intraluminal fluid accumulation.

Results

Leaf methanol extract of O. europaea subsp. africana and loperamide, a standard antidiarrhoeal drug, significantly reduced the number of diarrhoeal episodes induced by castor oil, significantly decreased the stool mass, significantly delayed the onset of the diarrhoea and protected the animals against castor oil-induced diarrhoea. Both O. europaea subsp. africana and loperamide significantly decreased the gastrointestinal transit of charcoal meal and castor oil-induced intraluminal fluid accumulation in mice. The LD50 value was found to be 3475 mg/kg (p.o.).

Conclusions

The results obtained suggest that the leaf methanol extract of O. europaea subsp. africana has an antidiarrhoeal property and that, given orally, it may be non-toxic and/or safe in mice.
OSBP- and FAN-mediated sterol requirement for spermatogenesis inDrosophila
Authors: Ma Zhiguo , Liu Zhonghua , Huang Xun
Published: October 2010

Members of the oxysterol binding protein (OSBP) family are involved in diverse biological processes, including non-vesicular sterol transport and vesicle trafficking. The mechanisms by which OSBPs integrate functionally with developmental and physiological processes remain elusive. Here, we report the in vivo analysis of OSBP function in the model organism Drosophila. Osbp mutants are male-sterile and exhibit defects in individualization, the process by which each spermatid is packaged into its own membrane. Overexpression of OSBP leads to post-eclosion behaviour defects that can be suppressed by co-expression of endoplasmic reticulum-specific VAP family proteins. Most notably, FAN, a testis-specific VAP protein, acts together with OSBP genetically and physically to regulate the individualization process. OSBP-positive and sterol-enriched speckles are found at the leading edge of the individualization complex in wild type but not in Osbp or fan mutants, suggesting that sterol trafficking might play key roles during the membrane-remodelling phase of individualization. In addition, Osbp mutants that are fed additional sterols partially recover fertility, implying that male sterility is attributable to sterol shortage. Thus, we have identified an OSBP- and FAN-mediated sterol requirement in Drosophila spermatogenesis.
Id2a influences neuron and glia formation in the zebrafish retina by modulating retinoblast cell cycle kinetics
Authors: Uribe Rosa A. , Gross Jeffrey M.
Published: October 2010

Inhibitor of differentiation (Id) family helix-loop-helix proteins regulate the proliferation, survival and differentiation of numerous cell types during development; however, their functions during retinal development have not been analyzed. Using loss-of-function and overexpression assays in zebrafish, we demonstrate that Id2a levels modulate retinoblast cell cycle kinetics and thereby influence neuron and glia formation in the retina. Id2a-deficient retinas possess increased numbers of cells occupying S phase, at the expense of mitotic cells, and kinetic analyses demonstrate that Id2a is required for S-phase progression and/or the transition from S to M phase. Id2a-dependent defects in retinoblast proliferation lead to microphthalmia and to an absence of nearly all differentiated inner and outer nuclear layer cell types. Overexpression of id2a has the opposite effect on retinoblast cell cycle kinetics: id2a-overexpressing retinoblasts progress from S to M phase more rapidly and they undergo mitosis more frequently, which results in macrophthalmia. Mosaic analyses reveal that Id2a function in facilitating both cell cycle progression and neuronal differentiation in the retina is non-cell-autonomous, suggesting that Id2a functions upstream of the extrinsic pathways that regulate retinogenesis.
Inhibition of translation by cytotrienin A—a member of the ansamycin family
Authors: Lindqvist Lisa , Robert Francis , Merrick William , Kakeya Hideaki , Fraser Christopher , Osada Hiroyuki , Pelletier Jerry
Published: October 2010

The ansamycins are a diverse and often physiologically active group of compounds that include geldanamycin and rifamycin, inhibitors of heat shock protein 90 and prokaryotic DNA-dependent RNA synthesis, respectively. Cytotrienin A is an ansamycin-type small molecule with potent antiproliferative and proapoptotic properties. Here, we report that this compound inhibits eukaryotic protein synthesis by targeting translation elongation and interfering with eukaryotic elongation factor 1A function. We also find that cytotrienin A prevents HUVEC tube formation and diminishes microvessel formation in the chorioallantoic membrane assay. These results provide a molecular understanding into cytotrienin A's previously reported properties as an anticancer apoptosis-inducing drug.
An Improved Dynamic Programming Decomposition Approach for Network Revenue Management
Authors: Zhang Dan
Published: October 2010

We consider a nonlinear nonseparable functional approximation to the value function of a dynamic programming formulation for the network revenue management (RM) problem with customer choice. We propose a simultaneous dynamic programming approach to solve the resulting problem, which is a nonlinear optimization problem with nonlinear constraints. We show that our approximation leads to a tighter upper bound on optimal expected revenue than some known bounds in the literature. Our approach can be viewed as a variant of the classical dynamic programming decomposition widely used in the research and practice of network RM. The computational cost of this new decomposition approach is only slightly higher than the classical version. A numerical study shows that heuristic control policies from the decomposition consistently outperform policies from the classical decomposition.
Strategic Capacity Rationing when Customers Learn
Authors: Liu Qian , van Ryzin Garrett
Published: October 2010

Consider a firm that sells products over repeated seasons, each of which includes a full-price period and a markdown period. The firm may deliberately understock products in the markdown period to induce high-value customers to purchase early at full price. Customers cannot perfectly anticipate availability. Instead, they use observed past capacities to form capacity expectations according to a heuristic smoothing rule. Based on their expectations of capacity, customers decide to buy either in the full-price period or in the markdown period. We embed this customer learning process in a dynamic program of the firm's capacity choices over time. One main result demonstrates the existence of a monotone optimal path of customers' expectations, which converges to either a rationing equilibrium or a low-price-only equilibrium. Further, there exists a critical value of capacity expectation such that the market converges to a rationing equilibrium if customers' initial expectations are less than that critical value; otherwise, a low-price-only equilibrium is the limiting outcome. These results show how firms can be stuck with unprofitable selling strategies from incumbent customer expectations. We also examine numerically how this critical value is affected by the firm's discount factor and customers' learning speed and risk aversion. Last, we show that the equilibrium under adaptive learning converges to that under rational expectations as the firm's discount factor approaches one.
Managing Trade-in Programs Based on Product Characteristics and Customer Heterogeneity in Business-to-Business Markets
Authors: Li Kate J. , Fong Duncan K. H. , Xu Susan H.
Published: October 2010

Trade-in programs are offered extensively in business-to-business (B2B) markets. The success of such programs depends on well-designed and executed trade-in policies as well as accurate prediction of return flow to support operational decisions. Motivated by a real problem facing a high-tech company, this paper develops methods to segment customers and forecast product returns based on return merchandise authorization information. Noisy, yet proven to be valuable, returned quantity signals are adjusted by taking product characteristics and customer heterogeneity into account, and the resulting forecast outperforms two benchmark strategies that represent the high-tech company's current practice and a widely adopted method in the literature, respectively. In addition, our methods can serve as tools for companies to uncover the root causes of return merchandise authorization discrepancy, monitor and analyze customer behavior, design segment-specific trade-in policies, and evaluate the effectiveness and efficiency of trade-in programs on a continuous basis.
Centralizing Inventory in Supply Chains by Using Shapley Value to Allocate the Profits
Authors: Kemahlıoğlu-Ziya Eda , Bartholdi John J.
Published: October 2010

How should the excess profit because of inventory pooling be shared amongst firms at different levels along the supply chain? Suppose each of several retailers observes local demand for a common item and places an order at the supplier, which is immediately filled if the supplier has the item in stock. The supplier can fill retailer orders either from their reserved inventories or from a shareable pool of inventory. Using terminology from cooperative game theory, we say that the supplier and the retailers whose orders are filled from the common pool have formed an inventory-pooling coalition and study the use of Shapley value to allocate the expected excess profit because of pooling.

We find that under Shapley value allocations the retailers have incentive to join the inventory-pooling coalition, and the supplier carries the level of inventory that is optimal for the coalition. Shapley value allocations might not lie within the core of the game, but the grand coalition of all players is stable in the farsighted sense. And, although the supplier's share of the expected excess profit is largest when all the retailers participate in the inventory-pooling coalition, the allocations to the retailers may diminish as the coalition grows. Colluding against the supplier (by merging and forming larger retailers) may seem like an appealing strategy for the retailers to increase their share of the total supply chain profit, but we find that the total expected after-pooling profits of retailers may instead go down because of collusion.
Obesity, Food Selectivity, and Physical Activity in Individuals With Fragile X Syndrome
Authors: Raspa Melissa , Bailey Donald B. , Bishop Ellen , Holiday David , Olmsted Murrey
Published: October 2010

National survey data from 884 families were used to examine the overall health of children and adults with fragile X syndrome. Results indicate the rate of obesity in adults with fragile X syndrome is similar to the general population (∼30%). Male children with fragile X syndrome, however, had higher rates of obesity (31%) when compared with typically developing same-aged peers (18%). Both males and females displayed food selectivity, especially with regard to texture. Physical activity levels for children were higher than for adults, but neither group met recommended levels. Several cognitive and behavioral characteristics, food selectivity, and physical activity were related to overall health and body mass index. Continued monitoring of the health status of individuals with fragile X syndrome is recommended.
Effectiveness of a Novel Community-Based Early Intervention Model for Children With Autistic Spectrum Disorder
Authors: Smith Isabel M. , Koegel Robert L. , Koegel Lynn K. , Openden Daniel A. , Fossum Kristin L. , Bryson Susan E.
Published: October 2010

The Nova Scotia early intensive behavior intervention model—NS EIBI (Bryson et al., 2007) for children with autistic spectrum disorders was designed to be feasible and sustainable in community settings. It combines parent training and naturalistic one-to-one behavior intervention employing Pivotal Response Treatment—PRT (R. Koegel & Koegel, 2006). We followed 45 children (33 males, mean baseline age  =  50 months) for 12 months. Mean gains of 14.9 and 19.5 months were observed on expressive and receptive language measures, respectively, for children with an IQ of 50 or more at baseline versus 6.1 and 8.4 months for children with IQs less than 50. Behavior problems decreased significantly over the 1-year treatment for both groups, but autism symptoms decreased only for those with an IQ of 50 or more.
Expression Profile of MicroRNAs in Serum: A Fingerprint for Esophageal Squamous Cell Carcinoma
Authors: Zhang Chunni , Wang Cheng , Chen Xi , Yang Cuihua , Li Ke , Wang Junjun , Dai Juncheng , Hu Zhibin , Zhou Xiaojun , Chen Longbang , Zhang Yanni , Li Yanfang , Qiu Hong , Xing Jicheng , Liang Zhichao , Ren Binhui , Yang Chen , Zen Ke , Zhang Chen-Yu
Published: October 2010

BACKGROUND

Sensitive and specific biomarkers for the early detection of esophageal squamous cell carcinoma (ESCC) are urgently needed to reduce the high morbidity and mortality of the disease. The discovery of serum microRNAs (miRNAs) and their unique concentration profiles in patients with various diseases makes them attractive, novel noninvasive biomarkers for tumor diagnosis. In this study, we investigated the serum miRNA profile in ESCC patients to develop a novel diagnostic ESCC biomarker.

METHODS

Serum samples were taken from 290 ESCC patients and 140 age- and sex-matched controls. Solexa sequencing technology was used for an initial screen of miRNAs in serum samples from 141 patients and 40 controls. A hydrolysis probe–based stem–loop quantitative reverse-transcription PCR (RT-qPCR) assay was conducted in the training and verification phases to confirm the concentrations of selected miRNAs in serum samples from 149 patients and 100 controls.

RESULTS

The Solexa sequencing results demonstrated marked upregulation of 25 serum miRNAs in ESCC patients compared with controls. RT-qPCR analysis identified a profile of 7 serum miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) as ESCC biomarkers. The area under the ROC curve for the selected miRNAs ranged from 0.817 to 0.949, significantly higher than for carcinoembryonic antigen (0.549; P < 0.0005). More importantly, this panel of 7 miRNAs clearly distinguished stage I/II ESCC patients from controls.

CONCLUSIONS

This panel of 7 serum miRNAs holds promise as a novel blood-based biomarker for the diagnosis of ESCC.
CA125 Immune Complexes in Ovarian Cancer Patients with Low CA125 Concentrations
Authors: Cramer Daniel W , O'Rourke Dennis J , Vitonis Allison F , Matulonis Ursula A , DiJohnson Daniel A , Sluss Patrick M , Crum Christopher P , Liu Brian C-S
Published: October 2010

BACKGROUND

About 20% of women with ovarian cancer have low concentrations of serum cancer antigen 125 (CA125), and this important tumor marker cannot be used to monitor their disease. The measured concentration for mucin 1 (MUC1), or CA15-3, another tumor marker, can be lowered in breast and ovarian cancer patients when circulating immune complexes (CICs) containing antibodies bound to the free antigen are present. Because CA125 and MUC1 are related members of the mucin family, we sought to determine whether CICs might also exist for CA125 and interfere with its clinical assay.

METHODS

We developed an antigen capture–based assay to determine the presence of CICs for CA125. We spotted mouse antibodies to CA125 onto nanoparticle slides, incubated them with patient serum, and added Cy5-tagged goat antihuman IgG antibodies. Fluorescence intensities were read and normalized to the intensities for glutathione S-transferase A1 as a control.

RESULTS

Assay results for 23 ovarian cancer cases with high CA125 concentrations, 43 cases with low CA125 concentrations, and 19 controls (mean CA125 concentrations, 2706, 23, and 11 kilounits/L, respectively) revealed mean fluorescence intensities for CA125 CIC of 2.30, 2.72, and 1.99 intensity units (iu), respectively. A generalized linear model adjusted for batch and age showed higher CA125 CIC fluorescence intensities in low-CA125 cases than in high-CA125 cases (P = 0.03) and controls (P = 0.0005). Four ovarian cancer patients who had recurrent disease and always had low CA125 values had a mean CA125 CIC value of 3.06 iu (95% CI, 2.34–4.01 iu).

CONCLUSIONS

These preliminary results suggest the existence of CICs involving CA125, which may help explain some ovarian cancer cases with low CA125 concentrations.