bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiplatelet effects of piplartine, an alkamide isolated fromPiper tuberculatum: possible involvement of cyclooxygenase blockade and antioxidant activity
Authors: Fontenele Juvenia B , Leal L Kalyne A M , Silveira Edilberto R , Felix F Helder , Felipe Cícero F Bezerra , Viana Glauce S B 
Published: October 2010

AbstractObjectivesPiplartine (piperlongumine; 5,6-dihydro-1-[1-oxo-3-(3,4,5-trimethoxyphenyl]-2(1H) pyridinone) is an alkaloid amide isolated from Piper species (Piperaceae). It has been reported to show multiple pharmacological activities in vitro and in vivo.MethodsWe evaluated the in-vitro antiplatelet effect of piplartine isolated from the roots of P. tuberculatum, on human platelet aggregation induced in platelet-rich plasma by the agonists collagen, adenosine 5′-diphosphate (ADP), arachidonic acid (AA) and thrombin.Key findingsPiplartine (100μg/ml) caused a 30% inhibition in platelet aggregation when collagen was the agonist. At 200 μg/ml, piplartine significantly inhibited the aggregation induced by arachidonic acid (100%), collagen (59%) or ADP (52%) but not that induced by thrombin. The highest concentration of piplartine (300 μg/ml) inhibited thrombin- (37%), ADP- (71%) and collagen- (98%) induced aggregation. The inhibitory effect of piplartine on ADP-induced platelet aggregation was not modified by pretreatment with pentoxifylline (a phosphodiesterase inhibitor), l-arginine (a substrate for nitric oxide synthase) or ticlopidine (a P2Y12 purinoceptor antagonist). However, aspirin, a well-known inhibitor of cyclooxygenase, greatly increased the inhibitory effect of piplartine on arachidonic-acid-induced platelet aggregation.ConclusionsThe mechanism underlying the piplartine antiplatelet action is not totally clarified. It could be related to the inhibition of cyclooxgenase activity and a decrease in thromboxane A2 formation, similar to that occurring with aspirin. This and other possible mechanisms require further study.
RT-PCR analysis of ABC, SLC and SLCO drug transporters in human lung epithelial cell models
Authors: Endter Sibylle , Francombe Danielle , Ehrhardt Carsten , Gumbleton Mark 
Published: October 2010

Abstract

Objectives
Carrier-mediated transport mechanisms play crucial roles in drug absorption and elimination processes, as well as in the transport of endogenous molecules affecting cellular regulation and function. In this study we used RT-PCR analysis to characterise the mRNA transcript expression of a wide range of membrane carrier transporters in several in-vitro lung epithelial cell models. Transporters studied included: 11 ATP-binding cassette (ABC) transporters, 11 solute carrier (SLC) transporters and 9 solute carrier organic anion (SLCO) transporters.

Methods
The cell culture models included both established cell lines (A549, Calu-3, 16HBE14o-, BEAS-2B) and freshly isolated lung epithelial cells in primary culture (human bronchial and alveolar epithelial cells).

Key findings
The expression profiles of several clinically relevant drug transporters were characterised using RT-PCR analysis. Our results showed differential transporter expression in cell culture models from different regions of the lung and also highlighted disparities when comparing lung cell lines with primary cell culture models. Differences in transporter expression between cell models of pulmonary and gastrointestinal origin were also noted.

Conclusions
The information will guide and validate the use of in-vitro lung epithelial cell lines in the study of pulmonary administered drugs and candidate molecules.
Specific aminopeptidases of excised human nasal epithelium and primary culture: a comparison of functional characteristics and gene transcripts expression
Authors: Agu Remigius U , Obimah Dominic U , Lyzenga Wendy J , Jorissen Mark , Massoud Emad , Verbeke Norbert 
Published: October 2010

Abstract

Objectives
To investigate whether growing human nasal epithelium as primary cultures alters aminopeptidase B (APB), aminopeptidase N (APN) and dipeptidyldipeptidase (DPPIV) metabolic characteristics, and mRNA gene transcript expression.

Methods
The formation of 7-amino-methyl coumarin from specific substrates for APN (l-alanine-4-methyl-coumaryl-7-amide, APB (l-arginine-4-methyl-coumaryl-7-amide) and DPPIV (glycyl-l-proline-4-methyl-coumaryl-7-amide) was used to estimate the Km, Vmax and the effect of aminopeptidases inhibitors on the enzymes. Polymerase chain reaction was used to investigate gene expression.

Key findings
Results of this study showed that: (1) both the excised tissues and primary cultures of human nasal epithelium expressed APN, APB and DPPIV activity; (2) the Km of APB, APN and DPPIV was not significantly different in cell and tissue homogenates; (3) except for APN, the Vmax was not significantly different in the two metabolism models; (4) there was no statistically significant difference in the behaviours of APB, APN and DPPIV in response to inhibition by puromycin and bestatin in the two models; (5) the mRNA transcripts that encode APB, APN and DPPIV were expressed in both cell culture and tissue homogenate.

Conclusions
Based on the results of this study, it may be concluded that nasal primary culture system is suitable for investigating peptide and protein metabolism and enzymatic stability in human nasal epithelium. Except for APN, the tissue culture conditions did not significantly alter the functional and molecular expression of the aminopeptidases.
The importance of brain PGE2 inhibition versus paw PGE2 inhibition as a mechanism for the separation of analgesic and antipyretic effects of lornoxicam in rats with paw inflammation
Authors: Futaki Nobuko , Harada Masahiro , Sugimoto Masanori , Hashimoto Yuki , Honma Yusuke , Arai Iwao , Nakaike Shiro , Hoshi Keiko 
Published: October 2010

AbstractObjectivesLornoxicam is a non-selective cyclooxygenase inhibitor that exhibits strong analgesic and anti-inflammatory effects but a weak antipyretic effect in rat models. Our aim was to investigate the mechanism of separation of potencies or analgesic and antipyretic effecls of lornoxicam in relatioin to its effect on prostaglandin E2 (PGE2) production in the inflammatory paw and the brain.MethodsA model of acute or chronic paw inflammation was induced by Freund's complete adjuvant injection into the rat paw. Lornoxicam (0.01–1 mg/kg), celecoxib (0.3–30 mg/kg) or loxoprofen (0.3–30 mg/kg) was administered orally to the rats and the analgesic and antipyretic effects were compared. The paw hyperalgesia was assessed using the Randall–Selitto test or the flexion test. Dorsal subcutaneous body temperature was measured as indicator of pyresis. After the measurement of activities, the rats were sacrificed and the PGE2 content in the paw exudate, cerebrospinal fluid or brain hypothalamus was measured by enzme-immunoassay.Key findingsIn a chronic model of arthritis, lornoxicam, celecoxib and loxoprofen reduced hyperalgesia with an effective dose that provides 50% inhibition (ED50) of 0.083, 3.9 and 4.3 mg/kg respectively, whereas the effective dose of these drugs in pyresis was 0.58, 0.31 and 0.71 mg/kg respectively. These drugs significantly reduced the PGE2 level in paw exudate and the cerebrospinal fluid. In acute oedematous rats, lornoxicam 0.16 mg/kg, celecoxib 4 mg/kg and loxoprofen 2.4 mg/kg significantly reduced hyperalgesia to a similar extent. On the other hand, lornnoxicam did not affect the elevated body temperature, whereas celecoxib and loxoprofen siginificantly reduced the pyrexia to almost the normal level. These drugs significantly reduced the PGE2 level in inflamed paw exudate lo almost the normal level. On the other hand, lornoxicam did not change PGE2 level in the brain hypothalamus, whereas celecoxib and loxoprofen strongly decreased it.ConclusionsLornoxicam exhibits strong analgesic but weak antipyretic effects in rats with paw inflammation. Such a separation of effects is related to its efficacy in the reduction of PGE2 levels in the paw and brain hypothalamus.
Influence of dosing schedules on toxicity and antitumour effects of combined cisplatin and docetaxel treatment in mice
Authors: Kodama Ayumi , To Hideto , Kinoshita Tomohiro , Ieiri Ichiro , Higuchi Shun 
Published: October 2010

AbstractObjectivesThe combination of cisplatin and docetaxel shows a better cure rate against non-small-cell lung cancer than other drug combinations in clinical studies; however, severe myelosuppression and nephrotoxicity are dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule to reduce adverse effects and improve the antitumour effects.MethodsCisplatin and docetaxel were administered i.p. to male ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel–cisplatin and cisplatin–docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas.Key findingsThe simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the greatest in the docetaxel–cisplatin group.ConclusionsThe docetaxel–cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity.
Mechanisms involved in the antinociceptive and anti-inflammatory effects of bis selenide in mice
Authors: Jesse Cristiano R , Savegnago Lucielli , Nogueira Cristina W 
Published: October 2010

Abstract

Objectives
The present study examined the mechanisms involved in the antinociceptive effects of bis selenide [(Z)-2,3-bis(4-chlorophenylselanyl)prop-2-en-1-ol].

Methods
The effects of oral bis selenide were tested against licking behaviour and oedema in mice induced by formalin, serotonin, histamine, glutamate, phorbol 12-myristate 13-acetate (PMA), 8-bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP) and pros-taglandin E2. The effects of a variety of receptor antagonists on the antinociceptive activity were tested to determine the likely mechanism of action of bis selenide.

Key findings
Bis selenide caused antinociception on the first and second phases of the formalin test, with mean ID50 values of 34.21 (29.66–39.45) and 15.86 (12.17–20.67) mg/kg and maximal inhibition of 65 ± 3% and 90 ± 1%, respectively. At 50 mg/kg bis selenide significantly inhibited (31 ± 2%) paw oedema induced by intraplantar injection of formalin. At 25 mg/kg given 5 min after the formalin injection, bis selenide caused a significant inhibition (42 ± 5%) in the second phase of the formalin test, whereas the prophylactic treatment caused more intense inhibition (64 ± 3%). Oral administration of bis selenide reduced licking and paw oedema induced by serotonin, histamine, glutamate, PGE2, PMA and 8-BrcAMP. The antinociceptive effect of bis selenide (25 mg/kg, p.o.) on the formalin test was reversed by i.p. administration of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis), ketanserin (a selective 5-HT2a receptor antagonist), ondansetron (a 5-HT3 receptor antagonist) and ranitidine (a histamine H2-receptor antagonist).

Conclusions
Glutamatergic, prostaglandin E2, serotonergic (5-HT2a and 5-HT3) and histamine H2 receptors are involved in the antinociceptive effects of bis selenide in mice. The interaction of bis selenide with protein kinase C and A signalling pathways was also demonstrated.
Recent cancer drug development with xanthone structures
Authors: Na Younghwa 
Published: October 2010

Abstract

Objectives
Xanthones are simple three-membered ring compounds that are mainly found as secondary metabolites in higher plants and microorganisms. Xanthones have very diverse biological profiles, including antihypertensive, antioxidative, antithrombotic and anticancer activity, depending on their diverse structures, which are modified by substituents on the ring system. Although several reviews have already been published on xanthone compounds, few of them have focused on the anticancer activity of xanthone derivatives. In this review we briefly summarize natural and synthetic xanthone compounds which have potential as anticancer drugs.

Key findings
The interesting structural scaffold and pharmacological importance of xanthone derivatives have led many scientists to isolate or synthesize these compounds as novel drug candidates. In the past, extensive research has been conducted to obtain xanthone derivatives from natural resources as well as through synthetic chemistry. Xanthones interact with various pharmacological targets based on the different substituents on the core ring. The anticancer activities of xanthones are also dramatically altered by the ring substituents and their positions.

Summary
The biological activities of synthetic xanthone derivatives depend on the various substituents and their position. Study of the biological mechanism of action of xanthone analogues, however, has not been conducted extensively compared to the diversity of xanthone compounds. Elucidation of the exact biological target of xanthone compounds will provide better opportunities for these compounds to be developed as potent anticancer drugs. At the same time, modification of natural xanthone derivatives aimed at specific targets is capable of expanding the biological spectrum of xanthone compounds.
l-Carnosine: multifunctional dipeptide buffer for sustained-duration topical ophthalmic formulations
Authors: Singh Swita R , Carreiro Samantha T , Chu Jessie , Prasanna Ganesh , Niesman Michael R , Collette Walter W , Younis Husam S , Sartnurak Soisurin , Gukasyan Hovhannes J 
Published: October 2010

Abstract

Objectives
The use of L-carnosine as an excipient in topical ophthalmic formulations containing gellan gum, a carbohydrate polymer with in-situ gelling properties upon mixing with mammalian tear fluid, was developed as a novel platform to extend precorneal duration. Specific utilisation of L-carnosine as a buffer in gellan gum carrying vehicles was characterised.

Methods
Buffer capacity was evaluated using 7.5, 13.3, and 44.2 mM L-carnosine in a pH range of 5.5–7.5. Accelerated chemical stability was determined by HPLC at L-carnosine concentrations of 5–100 mM. Combinations of 7.5 mM L-carnosine with 0.06–0.6% (w/v) gellan gum were characterised rheologically. L-Carnosine-buffered solutions of gellan gum were tested for acute topical ocular tolerance in vivo in pigmented rabbits. A unique formulation combining timolol (which lowers intraocular pressure) in L-carnosine-buffered gellan gum was compared with Timoptic-XE in normotensive dogs.

Key findings
L-Carnosine exhibited optimal pharmaceutical characteristics for use as a buffer in chronically administered topical ocular formulations. Enhancement trends were observed in solution-to-gel transition of L-carnosine-buffered vehicles containing gellan gum vs comparators. Topical tolerability of L-carnosine-buffered gellan gum formulations and lowering of intraocular pressure were equivalent with timolol and Timoptic-XE.

Conclusions
Functional synergy between excipients in gellan gum formulations buffered with L-carnosine has potential for topical ocular dosage forms with sustained precorneal residence.
Evaluation of population pharmacokinetic models for amikacin dosage individualization in critically ill patients
Authors: de Gatta María del Mar Fernández , Moreno Silvia Romano , Calvo María Victoria , Ardanuy Ramón , Domínguez-Gil Alfonso , Lanao José M 
Published: October 2010

Abstract

Objectives
The aim of this study was to evaluate the reliability for dosage individualization and Bayesian adaptive control of several literature-retrieved amikacin population pharmacokinetic models in patients who were critically ill.

Methods
Four population pharmacokinetic models, three of them customized for critically-ill patients, were applied using pharmacokinetic software to fifty-one adult patients on conventional amikacin therapy admitted to the intensive care unit. An estimation of patient-specific pharmacokinetic parameters for each model was obtained by retrospective analysis of the amikacin serum concentrations measured (n = 162) and different clinical covariates. The model performance for a priori estimation of the area under the serum concentration-time curve (AUC) and maximum serum drug concentration (Cmax) targets was obtained.

Key findings
Our results provided valuable confirmation of the clinical importance of the choice of population pharmacokinetic models when selecting amikacin dosages for patients who are critically ill. Significant differences in model performance were especially evident when only information concerning clinical covariates was used for dosage individualization and over the two most critical determinants of clinical efficacy of amikacin i.e. the AUC and Cmax values.

Conclusions
Only a single amikacin serum level seemed necessary to diminish the influence of population model on dosage individualization.
Hypercholesterolaemia induces early renal lesions characterized by upregulation of MMP-9 and iNOS and ETAR: alleviated by a dual endothelin receptor antagonist CPU0213 and simvastatin
Authors: Luo Lu , Dai De-Zai , Zheng Yu-Fen , Dai Yin 
Published: October 2010

Abstract

Objectives
We aimed to investigate hypercholesterolaemia-induced early renal lesions which result in abnormal expression of endothelin A receptor (ETAR), induced nitric oxide synthase (iNOS) and matrix metalloproteinase 9 (MMP-9). We hypothesized that this is due to an upregulated endothelin (ET) pathway consequent to hypercholesterolaemia and that CPU0213, a dual ET antagonist, could mitigate these changes.

Methods
Rats were randomly divided into four groups: (1), control; (2), high-fat diet for 60 days (HFD); HFD rats medicated in the last 15 days with either (3) CPU0213 (30 mg/kg daily, s.c.) or (4) simvastatin (4 mg/kg daily, p.o.).

Key findings
Body weight, serum triglycerides, total cholesterol and low-density-lipoprotein cholesterol were significantly increased, whereas high-density lipoprotein cholesterol decreased in the HFD group, relative to normal. Meanwhile, these changes were associated with upregulation of mRNA and protein of ETAR, iNOS and MMP-9 in the kidney. The lipid-lowering effect of simvastatin was predominant, lessening abnormal expression of these molecules in the kidney dramatically. Interestingly, CPU0213 significantly normalized expression of mRNA and protein of ETAR, iNOS and MMP-9, comparable with simvastatin, leaving no changes in hyperlipidaemia.

Conclusions
CPU0213 relieves renal lesions by blunting hypercholesterolaemia caused by the upregulated ET system, iNOS and MMP-9 in the kidney. This indicates that CPU0213 is promising in treating patients with end stage renal disease.
Study on the antidiabetic mechanism of a shark liver peptide, S-8300, in alloxan-induced diabetes
Authors: Huang Fengjie , Wu Wutong 
Published: October 2010

Abstract

Objectives
The aim was to evaluate the antidiabetic mechanism of S-8300 in alloxandiabetic mice.

Methods
Diabetes was induced by a single intravenous injection of alloxan (60 mg/kg). The effects of S-8300 on diabetic mice were investigated by observing the change in fasting plasma glucose, detecting Fas mRNA by reverse transcriptase-polymerase chain reaction, Fas protein expression in the pancreas by immunohistochemistry and Western blot, and the DNA fragmentation pattern forming a ladder by electrophoresis.

Key findings
A significant decrease in fasting plasma glucose was observed, and Fas mRNA and Fas protein expression in the pancreas were attenuated in diabetic mice treated with S-8300. Treatment with S-8300 also attenuated DNA ladder formation.

Conclusions
The results suggest that S-8300 inhibits Fas protein-mediated apoptosis of pancreas cells.
Hepatoprotective effect of chrysin on prooxidant-antioxidant status during ethanol-induced toxicity in female albino rats
Authors: Sathiavelu Jayanthi , Senapathy Giftson Jebakkan , Devaraj Rajkumar , Namasivayam Nalini 
Published: October 2010

Abstract

Objectives
To evaluate the effect of chrysin, a natural, biologically active compound extracted from many plants, honey and propolis, on the tissue and circulatory antioxidant status, and lipid peroxidation in ethanol-induced hepatotoxicity in rats.

Methods
Rats were divided into four groups. Groups 1 and 2 received isocaloric glucose. Groups 3 and 4 received 20% ethanol, equivalent to 5 g/kg bodyweight every day. Groups 2 and 4 received chrysin (20 mg/kg bodyweight) dissolved in 0.5% dimethylsulfoxide.

Key findings
The results showed significantly elevated levels of tissue and circulatory thiobarbituric acid reactive substances, conjugated dienes and lipid hydroperoxides, and significantly lowered enzymic and non-enzymic antioxidant activity of superoxide dismutase, catalase and glutathione-related enzymes such as glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione, vitamin C and vitamin E in ethanol-treated rats compared with the control. Chrysin administration to rats with ethanol-induced liver injury significantly decreased the levels of thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes, and significantly elevated the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and the levels of reduced glutathione, vitamin C and vitamin E in the tissues and circulation compared with those of the unsupplemented ethanol-treated rats. The histological changes observed in the liver and kidney correlated with the biochemical findings.

Conclusions
Chrysin offers protection against free radical-mediated oxidative stress in rats with ethanol-induced liver injury.
Glutathione depletion upregulates P-glycoprotein expression at the blood-brain barrier in rats
Authors: Wu Jing , Hong Hao , Ji Hui , Wang Ying Yu , Wang Ying , Li Yong Qi , Li Wei Guang , Long Yan , Xia Yuan Zheng 
Published: October 2010

AbstractObjectivesGlutathione (GSH) depletion has been implicated in the pathogenesis of neurological diseases. During GSH depletion, cells of the blood-brain barrier are subjected to chronic oxidative stress. Using an in-vivo system, we have investigated whether glutathione depletion changed expression of P-glycoprotein at the blood-brain barrier in rats.MethodsDiethyl maleate was intraperitoneally injected to induce GSH depletion in rats. P-glycoprotein expression at the blood-brain barrier was examined by Western blotting and RT-PCR, and its function was assessed by measuring the brain-to-plasma concentration ratios (Kp values) of rhodamine 123 (Rh123). Evans Blue dye was used as a blood-brain barrier indicator for examining the extravasation from the blood to the brain.Key findingsFour hours after treatment of rats with diethyl maleate, the brain GSH content significantly reduced. The mdr1a mRNA expression at the blood-brain barrier was upregulated, whereas no significant change in mdr1b mRNA expression was found. The P-glycoprotein level was significantly increased compared with control rats. At the same time, the Kp values of Rh123 suggested that function of P-glycoprotein was significantly enhanced at the blood-brain barrier in rats with GSH depletion induced by diethyl maleate. No significant difference of the Evans Blue dye concentration in the brain cortex was found between GSH depletion rats and control rats. Treatment of rats with N-acetylcysteine decreased P-glycoprotein upregulation induced by diethyl maleate.ConclusionsThe oxidative stress induced by GSH depletion played a positive role in the regulation of function and expression of P-glycoprotein at the blood-brain barrier in rats.