bluuebunny/crossref_metadata_2025 huggingface dataset:
Poloxamer 407 increases soluble adhesion molecules, ICAM-1, VCAM-1 and E-selectin, in C57BL/6 mice
Authors: Johnston Thomas P
Published: October 2010

Objectives

Soluble shedded forms of cell adhesion molecules (sCAMs) found in plasma are regarded as surrogate markers for the cellular expression of CAMs. The presence of oxidised low-density lipoprotein (ox-LDL) cholesterol and fatty acids in the plasma, hypertriglyceridaemia and reduced plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are all thought to stimulate an increase in the cellular expression of CAMs such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Our objectives were to determine how plasma levels of the soluble CAMs were modulated in a mouse model of dyslipidaemia induced chemically with poloxamer 407, and how these changes might be related to changes in the plasma concentrations of total cholesterol, HDL-C, non-HDL-C and triglycerides.

Methods

C57BL/6 mice were given a single intraperitoneal dose of poloxamer 407 (0.5 g/kg) and plasma concentrations of lipid fractions and sCAMs were measured at predetermined time points thereafter.

Key findings

The plasma concentrations of each sCAM were significantly increased in our mouse model of atherogenic dyslipidaemia compared with control mice administered saline, although the temporal relationship between the plasma sCAM concentration-time profiles and the plasma lipid concentration-time profiles were not coincident.

Conclusions

The atherogenic profile in our mouse model was associated with increases in the plasma concentrations of sICAM-1, sVCAM-1 and sE-selectin. These changes precede the formation of atherosclerotic lesions shown in previous work. This suggests the use of these sCAMs as biomarkers of future atheroma formation in this particular animal model.
Cytotoxicity and antiangiogenic activity of grandisin
Authors: Valadares Marize C , De Carvalho Isabel Crhistyna Teles , Junior Luiz de Oliveira , De Sousa Vieira Marcelo , Benfica Polyana Lopes , De Carvalho Flávio Silva , Andrade Lorenna Vieira Silva , Lima Eliana Martins , Kato Massuo Jorge
Published: October 2010

Objectives

The antitumoural properties of grandisin, a tetrahydrofuran neolignan from Piper solmsianum, were investigated by in-vitro and in-vivo assays using the Ehrlich ascites tumoural (EAT) model.

Methods

Viability of the tumour cells was evaluated by Trypan blue exclusion and MTT methods, after incubation with grandisin (0.017-2.3 μM). The effects of grandisin on the activity of caspase-3, −6, −8, and −9 were also investigated using colorimetric protease kits. In-vivo studies were performed in EAT-bearing mice treated intraperitoneally with 2.5, 5 or 10 mg/kg grandisin for 10 days.

Key findings

Grandisin inhibited the growth of EAT cells, by both methods, with IC50 values less than 0.25 μM. The results showed that the activity of all the caspases studied increased in grandisin-treated cells, when compared with control, non-treated cells. Administering grandisin to EAT-bearing mice increased survival of the animals, in a dose-dependent manner. Simultaneously, we detected a 66.35% reduction of intraperitoneal tumour cell burden in the animals treated with 10 mg/kg grandisin. Additionally, in these animals, the marked increase of vascular endothelial growth factor (VEGF) levels, induced by EAT development, was decreased with treatment with grandisin, resulting in a reduction of 32.1% of VEGF levels in the peritoneal washing supernatant, when compared with the control.

Conclusions

The results demonstrated that grandisin induced in-vitro cytotoxicity and antiangiogenic effects in mice while it acted against tumour evolution, prolonging host survival.
Glucuronidation of piceatannol by human liver microsomes: major role of UGT1A1, UGT1A8 and UGT1A10
Authors: Miksits Michaela , Maier-Salamon Alexandra , Nha Vo Thanh Phuong , Sulyok Michael , Schuhmacher Rainer , Szekeres Thomas , Jäger Walter
Published: October 2010

Objectives

Piceatannol, a dietary polyphenol present in grapes and wine, is known for its promising anticancer and anti-inflammatory activity. The aim of this study was to analyse the concentration-dependent glucuronidation of piceatannol in vitro.

Methods

To determine the glucuronidation of piceatannol, experiments were conducted with human liver microsomes as well as using a panel of 12 recombinant UDP-glucuronosyltransferase isoforms. Furthermore, the chemical structures of novel glucuronides were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Key findings

Along with piceatannol it was possible to identify three metabolites whose structures were identified by LC-MS/MS as piceatannol monoglucuronides (M1–M3). Formation of M1 and M3 exhibited a pattern of substrate inhibition, with apparent Ki and Vmax/Km values of 103 ± 26.6 µm and 3.8 ± 1.3 µl/mg protein per min, respectively, for M1 and 233 ± 61.4 µm and 19.8 ± 9.5 µl/mg protein per min, respectively, for M3. In contrast, formation of metabolite M2 followed classical Michaelis–Menten kinetics, with a Km of 18.9 ± 8.1 µm and a Vmax of 0.21 ± 0.02 nmol/mg protein per min. Incubation in the presence of human recombinant UDP-glucuronosyltransferases (UGTs) demonstrated that M1 was formed nearly equally by UGT1A1 and UGT1A8. M2 was preferentially catalysed by UGT1A10 and to a lesser extent by UGT1A1 and UGT1A8. The formation of M3, however, was mainly catalysed by UGT1A1 and UGT1A8.

Conclusions

Our results elucidate the importance of piceatannol glucuronidation in the human liver, which must be taken into account in humans after dietary intake of piceatannol.
Assessment of the in-vivo drug release from pellets film-coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery
Authors: Freire Cristina , Podczeck Fridrun , Ferreira Dinora , Veiga Francisco , Sousa João , Pena Angelina
Published: October 2010

Objectives

The aim of this study was to test the ability of a colon targeting system comprising pellets film-coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5-aminosalicylic acid; 5-ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control.

Methods

Six New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5-ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre-determined times and the plasma analysed by a validated HPLC method with fluorescence detection.

Results

Analysis of the 5-ASA plasma levels following administration of the uncoated pellets showed a Cmax of 2.38 ± 0.49 μg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (Cmax 0.22 ± 0.19 μg/ml and tmax of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24-h study. They had a drug content of < 40%, suggesting that the film-coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits.

Conclusions

Results from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon.
Effects of polysorbate 80 on the in-vitro precipitation and oral bioavailability of halofantrine from polyethylene glycol 400 formulations in rats
Authors: Tønsberg Henrik , Holm René , Bisgaard Jette , Jacobsen Jette , Müllertz Anette
Published: October 2010

Objectives

The aim of this study was to examine the effects of formulations of polysorbate 80 (PS 80) and polyethylene glycol 400 (PEG 400) on the precipitation and oral bioavailability of the hydrophobic drug halofantrine.

Methods

The in-vitro dilution profile of the formulations was evaluated in phosphate buffer and in simulated intestinal fluids using a standard dissolution apparatus. The pharmacokinetic profile of the formulations was investigated in fasted rats at two dose levels, 5 and 17.5 mg/kg, with blood sampling by vein puncture in the tail.

Key findings

The solubility of halofantrine was found to be highest in PS 80, and in co-mixtures there was a correlation with the content of PS 80. The in-vitro dilution profile revealed precipitation of halofantrine when dissolved in pure PEG 400, although the precipitation was smaller in the simulated intestinal fluid. Addition of 25% PS 80 to the PEG 400 significantly decreased precipitation. The animals dosed with the PEG 400 formulation had significant lower bioavailability than the PS 80–PEG 400 co-mixtures, possibly due to halofantrine precipitation in the gastrointestinal tract.

Conclusions

Addition of PS80 to the formulation increased the bioavailability of halofantrine and the more compound, the more PS80 was needed to prevent precipitation.
Intracellular pharmacokinetics of telithromycin, a ketolide antibiotic, in alveolar macrophages
Authors: Togami Kohei , Chono Sumio , Seki Toshinobu , Morimoto Kazuhiro
Published: October 2010

Objectives

Telithromycin, a ketolide antibiotic, has an antibacterial range that covers intracellular parasitic pathogens that survive or multiply intracellularly in alveolar macrophages. The intracellular pharmacokinetics of TEL in alveolar macrophages was evaluated in vitro.

Methods

Telithromycin (50 µm) was applied to NR8383 as cultured alveolar macrophages, followed by incubation at 37°C or 4°C. After incubation, the amount of telithromycin in cells was determined.

Key findings

Telithromycin exhibited high accumulation in NR8383 and its intracellular accumulation was temperature dependent. Also, telithromycin distributed to the organelles and cytosol in NR8383 and, in particular, it accumulated in the acidic organelle compartments.

Conclusions

This study suggests that the high accumulation of telithromycin in NR8383 is due to its high influx via active transport systems and trapping in acidic organelles, such as lysosomes. Moreover, this study provides important information for optimizing the treatment of respiratory intracellular parasitic infections based on the intracellular pharmacokinetics of antibiotics and parasitic sites.
CPU228, a derivative of dofetilide, relieves cardiac dysfunction by normalizing FKBP12.6, NADPH oxidase and protein kinase C ε in the myocardium
Authors: Hamed Khan Hussien , Hu Chen , Dai De-Zai , Yu Feng , Dai Yin
Published: October 2010

Objectives

The aim of this study was to determine if CPU228, a derivative of dofetilide, is more effective than dofetilide in attenuating isoproterenol-induced heart failure by recovering downregulated FK506 binding protein (FKBP12.6), and suppressing oxidative stress, upregulated NADPH oxidase and protein kinase C ε (PKCε) hyperphosphorylation in the myocardium.

Methods

Heart failure was induced by isoproterenol (1 mg/kg s.c. for 5 days) in male Sprague-Dawley rats. Intervention with either CPU228 or dofetilide (2 mg/kg on Days 3–5) was then conducted in vivo and in vitro.

Key findings

Isoproterenol produced compromised left ventricular systolic pressure, left ventricular pressure rise (dp/dtmax) and fall (dp/dtmin), and left ventricular end-diastolic pressure, associated with oxidative stress, abnormal FKBP12.6, NADPH oxidase p67phox and PKCε in the myocardium. CPU228 was more effective in attenuating these changes than dofetilide in vivo. Dofetilide produced a prolonged QTc to replace a shortened one. In primary neonatal cardiomyocytes, cultured with isoproterenol and treated with either CPU228 or dofetilide at 10−8, 10−7 and 10−6 mol/l, isoproterenol produced a hyperadrenergic state characterized by downregulated FKBP12.6, upregulated NADPH oxidase p67phox and PKCε in vitro. CPU228 was more effective than dofetilide in recovering these changes in a dose-dependent manner without a prolonged QTc.

Conclusions

CPU228 was more effective than dofetilide in attenuating heart failure by normalizing isoproterenol-induced changes, including downregulation of FKBP12.6, upregulation of NADPH oxidase and PKCε hyperphosphorylation in vivo and in vitro.
The role of erythropoietin in the protection of gastric mucosa from indometacin-induced gastric injury and its relationship with oxidant and antioxidant parameters in rats
Authors: Albayrak Fatih , Odabasoglu Fehmi , Halici Zekai , Polat Beyzagul , Dursun Hakan , Uyanik Abdullah , Bayir Yasin , Koc Feride , Suleyman Halis , Albayrak Yavuz
Published: October 2010

Objectives

Erythropoietin has anti-oxidative and anti-inflammatory activity. We wanted to evaluate its activity in preventing damage to the gastric mucosa.

Methods

We examined the protective effect of erythropoietin on indometacin-induced gastric mucosa damage in the rat stomach and compared its potency with that of famotidine. We also measured effects on oxidant and antioxidant parameters in the rat stomach.

Key findings

Famotidine and erythropoietin 2500 and 5000 IU/kg reduced the ulcer area by 98%, 31% and 58%, respectively, compared with the indometacin group. Superoxide dismutase activity and glutathione level were decreased and myeloperoxidase activity increased in the indometacin group compared with healthy rats. Famotidine and erythropoietin at all doses increased superoxide dismutase and glutathione levels significantly compared with the indometacin group. Myeloperoxidase activity was decreased by erythropoietin and famotidine.

Conclusions

These results support the view that erythropoietin counteracts the effects of indometacin in inducing gastric ulcer and could be used as a an antiulcer compound. Its antiulcer effect is less potent than that of famotidine. The antiulcerogenic effects of erythropoietin may be related to its intrinsic ability to sustain the activities of free-radical scavenging enzymes and the bioavailability of glutathione.
Aloe veragel alleviates cardiotoxicity in streptozocin-induced diabetes in rats
Authors: Jain Neeti , Vijayaraghavan Rajagopalan , Pant Satish Chandra , Lomash Vinay , Ali Mohammed
Published: October 2010

Objectives

Persistent hyperglycaemia results in oxidative stress along with the generation of oxygen free radicals and appears to be an important factor in the production of secondary complications in diabetes. The aim of this work was to evaluate markers of oxidative stress in heart tissue along with the protective, antioxidant and antidiabetic activity of 30% Aloe vera gel in diabetic rats.

Methods

Streptozocin was given as a single intravenous injection and 30% Aloe vera gel was given in two doses for 20 days, orally. Blood glucose, glycosylated haemoglobin, blood reduced glutathione, serum lactate dehydrogenase and serum creatine kinase levels were measured on day 21 after drug treatment. Heart rate and mean blood pressure were recorded at the end of the study. Different biochemical variables were evaluated in the heart tissue, including thiobarbituric acid reactive substance (TBARS), reduced glutathione, superoxide dismutase and catalase in diabetic and in Aloe vera-treated diabetic rats.

Key findings

In streptozocin diabetic rats, the TBARS level was increased significantly, superoxide dismutase and reduced glutathione significantly decreased, and the catalase level was significantly increased. Aloe vera 30% gel (200 mg/kg) treatment in diabetic rats reduced the increased TBARS and maintained the superoxide dismutase and catalase activity up to the normal level. Aloe vera gel increased reduced glutathione by four times in diabetic rats.

Conclusions

Aloe vera gel at 200 mg/kg had significant antidiabetic and cardioprotective activity.
Application of hanging drop technique to optimize human IgG formulations
Authors: Li Guohua , Kasha Purna C , Late Sameer , Banga Ajay K
Published: October 2010

Objectives

The purpose of this work is to assess the hanging drop technique in screening excipients to develop optimal formulations for human immunoglobulin G (IgG).

Methods

A microdrop of human IgG and test solution hanging from a cover slide and undergoing vapour diffusion was monitored by a stereomicroscope. Aqueous solutions of IgG in the presence of different pH, salt concentrations and excipients were prepared and characterized.

Key findings

Low concentration of either sodium/potassium phosphate or McIlvaine buffer favoured the solubility of IgG. Addition of sucrose favoured the stability of this antibody while addition of NaCl caused more aggregation. Antimicrobial preservatives were also screened and a complex effect at different buffer conditions was observed. Dynamic light scattering, differential scanning calorimetry and size exclusion chromatography studies were performed to further validate the results.

Conclusions

In conclusion, hanging drop is a very easy and effective approach to screen protein formulations in the early stage of formulation development.
Inhibitory effects of uraemic toxins 3-indoxyl sulfate andp-cresol on losartan metabolismin vitro
Authors: Tsujimoto Masayuki , Higuchi Keishi , Shima Daisuke , Yokota Hitoshi , Furukubo Taku , Izumi Satoshi , Yamakawa Tomoyuki , Otagiri Masaki , Hirata Sumio , Takara Kohji , Nishiguchi Kohshi
Published: October 2010

Objectives

The purpose of this study was to clarify the cause of decreased metabolic clearance of losartan in patients with end-stage renal failure. The influence of serum from haemodialysis patients (uraemic serum) and uraemic toxins on the metabolism of losartan to EXP-3174 was investigated in vitro.

Methods

The formation of EXP-3174 was estimated using pooled human liver microsomes. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid, hippuric acid, indole-3-acetic acid, 3-indoxyl sulfate and p-cresol were used as uraemic toxins.

Key findings

Uraemic serum potently decreased the formation of EXP-3174 in pooled human liver microsomes. In addition, 3-indoxyl sulfate and p-cresol significantly decreased the formation of EXP-3174 in a concentration-dependent manner. Furthermore, normal serum (10% v/v) with both 3-indoxyl sulfate and p-cresol (both 20 μmol/l) significantly decreased the formation of EXP-3174 by 46%, which was similar to the level of inhibition with uraemic serum (10% v/v).

Conclusions

These results suggest that decreased the metabolic clearance of losartan in patients with end-stage renal failure is partly due to high concentrations of 3-indoxyl sulfate and p-cresol.
Preparation, characterisation and anti-tumour activity of Ganoderma lucidum polysaccharide nanoparticles
Authors: Li Ni , Hu Yu-Lan , He Cai-Xia , Hu Cheng-Jie , Zhou Jun , Tang Gu-Ping , Gao Jian-Qing
Published: October 2010

Objectives

The aim was to prepare novel Ganoderma lucidum polysaccharide nanoparticles and to evaluate the physicochemical properties and anti-tumour activity in in-vitro cytotoxicity studies using HepG2, HeLa and A549 cancer cell lines, and growth promotion effects on mouse spleen cells.

Methods

Chitosan nanoparticles loaded with G. lucidum polysaccharide were prepared using the ion-revulsion method. The diameter distribution of the particles and the surface charge were measured using a zetasizer analyser. The entrapment efficiency and drug loading capacity were examined by the diethylaminoethanol weak anion exchange method. The cytotoxic effects of nanoparticles on tumour cells and the growth promotion effects on mouse spleen cells were tested using the MTT assay.

Key findings

Nanoparticles loaded with G. lucidum polysaccharide at 6 μg/ml and chitosan/sodium tripolyphosphate (mass) ratio of 5.5 had significantly greater cytotoxic effects on tumour cells and growth promotion effects on mouse spleen cells than empty nanoparticles.

Conclusions

G. lucidum polysaccharide nanoparticles showed significant anti-tumour efficacy, having both cytotoxic effects on tumour cells and growth promotion effects on spleen cells, making it a promising candidate in the clinical setting.
Polymer film formulations for the preparation of enteric pharmaceutical capsules
Authors: Smith Alan M , Ingham Andrew , Grover Liam M , Perrie Yvonne
Published: October 2010

Objectives

Standard pharmaceutical capsules are designed to dissolve in the acidic environment of the stomach releasing the encapsulated contents for absorption. When release is required further along the gastrointestinal tract capsules can be coated with acid insoluble polymers to enable passage through the stomach and dissolution in the intestine. This paper describes formulations that have the potential to be used to produce two-piece hard capsules for post-gastric delivery without the requirement of an exterior coat.

Methods

The formulation uses three polysaccharides: sodium alginate, hypromellose and gellan gum to provide acid insolubility and the ability to form capsules using standard industrial equipment.

Key findings

The rheological profile, on cooling, of the base material, water content and thickness of the films were shown to be comparable with those of commercial capsules. The capsules remained intact for 2 h in 100 mm HCl at pH 1.2, and within 5 min of being removed from the acid and submerged in phosphate-buffered saline at pH 6.8 were ruptured.

Conclusions

Selected formulations from this study have potential for use as delayed release capsules.
Repeated administration of oxycodone modifies the gene expression of several drug metabolising enzymes in the hepatic tissue of male Sprague-Dawley rats, including glutathione S-transferase A-5 (rGSTA5) and CYP3A2
Authors: Myers Alan L , Hassan Hazem E , Lee Insong J , Eddington Natalie D
Published: October 2010

Objectives

Clinical use and illicit abuse of the potent opioid agonist oxycodone has dramatically increased over the past decade. Yet oxycodone remains one of the least studied opioids, particularly its interactions on the genomic level. The aim of this study was to examine potential alterations in gene expression of drug metabolising enzymes in the liver tissue of male Sprague-Dawley rats chronically treated with oxycodone.

Methods

Rats were administered saline or oxycodone 15 mg/kg i.p. twice a day for 8 days. Changes in RNA levels were detected using microarray analysis validated by quantitative real-time PCR; consequent changes in protein expression and functionality were further assessed by Western blotting and activity assays.

Key findings

The expression of several drug metabolising enzymes was modulated by oxycodone treatment: cytochrome P450 (CYP) 2B2, CYP2C13, CYP17A1, epoxide hydrolase 2, carboxylesterase 2, flavin-containing monooxygenase 1, glutathione S-transferase alpha 5 (rGSTA5) and CYP3A2. In particular, the mRNA level of rGSTA5 (formerly GSTYc2) was up-regulated by approximately 6.5 fold and CYP3A2 was down-regulated by approximately 7.0 fold. Immunoblotting assays demonstrated a corresponding significant elevation of rGSTA5 protein and repression of CYP3A2 protein. The apparent cytosolic GST activity towards 1-chloro-2,4-dinitrobenzene conjugation and reduction of cumene hydroperoxide were significantly higher in liver from oxycodone-treated rats than that of saline-treated rats. In addition, the microsomal activity of CYP3A2, measured via 6β-hydroxylation of testosterone, was significantly decreased in oxycodone-treated rats.

Conclusions

Repeated oxycodone administration is associated with a significant up-regulation of rGSTA5 and concomitant down-regulation of CYP3A2 mRNA, protein expression and functionality. These results support further in-vivo studies into the clinical impact of our findings.
Antinociceptive and anti-inflammatory properties of 7-hydroxycoumarin in experimental animal models: potential therapeutic for the control of inflammatory chronic pain
Authors: De Almeida Barros Taís A , De Freitas Luis A R , Filho José M B , Nunes Xirley P , Giulietti Ana M , De Souza Glória E , Dos Santos Ricardo R , Soares Milena B P , Villarreal Cristiane F
Published: October 2010

Objectives

In the present study we investigated the antinociceptive, anti-inflammatory and antipyretic effects of 7-hydroxycoumarin (7-HC) in animal models.

Methods

The effects of oral 7-HC were tested against acetic acid-induced writhing, formalin test, tail flick test, complete Freund's adjuvant (CFA)-induced hypernociception, carrageenan-induced paw oedema, lipopolysaccharide-induced fever and the rota rod test.

Key findings

7-HC (3–60 mg/kg) produced a dose-related antinociception against acetic acid-induced writhing in mice and in the formalin test. In contrast, treatment with 7-HC did not prevent thermal nociception in the tail flick test. A single treatment with 7-HC, 60 mg/kg, produced a long-lasting antinociceptive effect against CFA-induced hypernociception, a chronic inflammatory pain stimulus. Notably, at 60 mg/kg per day over 4 days the administration of 7-HC produced a continuous antinociceptive effect against CFA-induced hypernociception. 7-HC (30–120 mg/kg) produced anti-inflammatory and antipyretic effects against carrageenan-induced inflammation and lipopolysaccharide-induced fever, respectively. Moreover, 7-HC was found to be safe with respect to ulcer induction. In the rota rod test, 7-HC-treated mice did not show any motor performance alterations.

Conclusions

The prolonged antinociceptive and anti-inflammatory effects of 7-HC, in association with its low ulcerogenic activity, indicate that this molecule might be a good candidate for development of new drugs for the control of chronic inflammatory pain and fever.
Effects of Eriobotrya japonica seed extract on oxidative stress in rats with non-alcoholic steatohepatitis
Authors: Yoshioka Saburo , Hamada Atsuhide , Jobu Kohei , Yokota Junko , Onogawa Masahide , Kyotani Shojiro , Miyamura Mitsuhiko , Saibara Toshiji , Onishi Saburo , Nishioka Yutaka
Published: October 2010

Objectives

Non-alcoholic steatohepatitis is associated with the deposition of lipid droplets in the liver, and is characterised histologically by the infiltration of inflammatory cells, hepatocellular degeneration and liver fibrosis. Oxidative stress may play an important role in the onset and deterioration of non-alcoholic steatohepatitis. We previously reported that an Eriobotrya japonica seed extract, extracted in 70% ethanol, exhibited antioxidant actions in vitro and in vivo. In this study, we examined the effect of this extract in a rat model of non-alcoholic steatohepatitis.

Methods

The seed extract was given in the drinking water to fats being fed a methionine-choline-deficient diet for 15 weeks.

Key findings

Increases in alanine aminotransferase and aspartate aminotransferase levels were significantly inhibited in rats fed the seed extract compared with the group on the diet alone. Formation of fatty droplets in the liver was also inhibited. Antioxidant enzyme activity in liver tissue was higher than in the diet-only group and lipid peroxidation was reduced compared with rats that also received the extract. Expression of 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal was lower in the rats given the seed extract than in the diet-only group. In the former, liver tissue levels of transforming growth factor-β and collagen were also decreased.

Conclusions

Thus, the E. japonica seed extract inhibited fatty liver, inflammation and fibrosis, suggesting its usefulness in the treatment of non-alcoholic steatohepatitis.
In-vitro and in-vivo antivenin activity of 2-[2-(5,5,8a-trimethyl-2-methylene-decahydro-naphthalen-1-yl)-ethylidene]-succinaldehyde against Ophiophagus hannah venom
Authors: Lattmann Eric , Sattayasai Jintana , Sattayasai Nison , Staaf Alexander , Phimmasone Sysaaht , Schwalbe Carl H , Chaveerach Arunrat
Published: October 2010

Objectives

Curcuma zedoaroides A. Chaveerach & T. Tanee, locally known as Wan-Paya-Ngoo-Tua-Mia, is commonly used in the North-Eastern part of Thailand as a ‘snakebite antidote’. The aim of this study was to isolate the active compound from the rhizome of C. zedoaroides, to determine its structure and to assess its antagonistic activity in vitro and in vivo against King cobra venom.

Methods

The active compound was obtained from C. zedoaroides by extraction with acetone followed by purification using column chromatography; its X-ray structure was determined. Its inhibition of venom lethality was studied in vitro in rat phrenic nerve-hemidiaphragms and in vivo in mice.

Key findings

The acetone extract of the Curcuma rhizomes contained a C20 dialdehyde, [2-(5,5,8a-trimethyl-2-methylene-decahydro-naphthalen-1-yl)-ethylidene]-succinaldehyde, as the major component. The isolated curcuma dialdehyde was found active in vitro and in vivo for antivenin activity against the King cobra venom.

Using isolated rat phrenic nerve-hemidiaphragm preparations, a significant antagonistic effect on the inhibition of neuromuscular transmission was observed in vitro. Inhibition on muscle contraction, produced by the 4 μg/ml venom, was reversed by 2–16 μg/ml of Curcuma dialdehyde in organ bath preparations over a period of 2 h. Mice intraperitoneally injected with 0.75 mg/kg venom and dialdehyde at 100 mg/kg had a significantly increased survival time. Injection of Curcuma dialdehyde (100 mg/kg) 30 min before the subcutaneous injection of the venom resulted in a 100% survival time after 2 h compared with 0% for the control group.

Conclusions

The in vitro and in vivo evaluation confirmed the medicinal use of traditional snake plants against snakebites. The bioactivity is linked to an isolated molecule and not a result of synergistic effects of a mixture. The active compound was isolated and the structure fully elucidated, including its stereochemistry. This dialdehyde is a versatile chemical building block and can be easily obtained from this plant source.
Effect of wild ginseng on scopolamine-induced acetylcholine depletion in the rat hippocampus
Authors: Lee Bombi , Park Jongbong , Kwon Sunoh , Park Moo-Won , Oh Sang-Muk , Yeom Mi-Jung , Shim Insop , Lee Hye-Jung , Hahm Dae-Hyun
Published: October 2010

Objectives

The ameliorating effects of wild ginseng on learning and memory deficits were investigated in rats.

Methods

Rats were treated daily with wild ginseng or cultivated ginseng for 7 days at 30 min before scopolamine injection (2 mg/kg, i.p.). After inducing cognitive impairment by the administration of scopolamine, behavioural assessment using the Morris water maze was performed. Changes in cholinergic system reactivity were also examined by measuring the immunoreactive neurons of choline acetyltransferase and the reactivity of acetylcholinesterase in the hippocampus.

Key findings

Scopolamine injection induced impaired performance in the water maze test and severe cell losses in hippocampal cholinergic neurons, as indicated by decreased choline acetyltransferase immunoreactivity and increased acetylcholinesterase reactivity. Daily administration of wild ginseng produced a significant improvement in the escape latency for finding the platform in the Morris water maze and reduced the loss of cholinergic immunoreactivity in the hippocampus. The reduced expression of brain-derived neurotrophic factor mRNA due to the scopolamine injection was recovered to normal levels by the administration of wild ginseng.

Conclusions

Wild ginseng demonstrates a significant neuroprotective effect against scopolamine-induced neuronal and cognitive impairment.
3-Acetyl-11-keto-β-boswellic acid loaded-polymeric nanomicelles for topical anti-inflammatory and anti-arthritic activity
Authors: Goel Amit , Ahmad Farhan Jalees , Singh Raman Mohan , Singh Gyanendra Nath
Published: October 2010

Objectives

The aim of this study was to develop 3-acetyl-11-keto-β-boswellic acid (AKBA)-loaded polymeric nanomicelles for topical anti-inflammatory and anti-arthritic activity.

Methods

Polymeric nanomicelles of AKBA were developed by a radical polymerization method using N-isopropylacrylamide, vinylpyrrolidone and acrylic acid. The polymeric nanomicelles obtained were characterized by Fourier transform infrared (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). In-vitro and in-vivo evaluations of AKBA polymeric nanomicelles gel were carried out for enhanced skin permeability and anti-inflammatory and anti-arthritic activity.

Key findings

TEM and DLS results demonstrated that polymeric nanomicelles were spherical with a mean diameter approximately 45 nm. FTIR data indicated a weak interaction between polymer and AKBA in the encapsulated system. The release of drug in aqueous buffer (pH 7.4) from the polymeric nanomicelles was 23 and 55% after 2 and 8 h, respectively, indicating sustained release. In-vitro skin permeation studies through excised abdominal skin indicated a threefold increase in skin permeability compared with AKBA gel containing the same amount of AKBA as the AKBA polymeric nanomicelles gel. The AKBA polymeric nanomicelle gel showed significantly enhanced anti-inflammatory and anti-arthritic activity compared with the AKBA gel.

Conclusions

This study suggested that AKBA polymeric nanomicelle gel significantly enhanced skin permeability, and anti-inflammatory and anti-arthritic activity.
Design, synthesis, characterization and in-vivo activity of a novel salmon calcitonin conjugate containing a novel PEG-lipid moiety
Authors: Cheng Weiqiang , Lim Lee-Yong
Published: October 2010

Objectives

The aim of the study was to explore (1) the synthesis of a novel poly(ethylene glycol) modified lipid (PEG-lipid, PL) containing a chemically active tri-block linker, ε-maleimido lysine (Mal), and its conjugation with salmon calcitonin (sCT), and (2) the biophysical properties and activity of the resulting conjugate, Mal-PL-sCT, relative to the control, 2PEG-Mal-sCT, which comprises sCT conjugated with α-palmitoyl-N-ε-maleimido-l-lysine at cysteine 1 and cysteine 7, and PEG moieties at lysine 11 and lysine 18 via a conventional stepwise method.

Methods

The PEG-lipid was obtained by condensing palmitic acid derivative of ε-maleimido lysine with methoxy poly(ethylene glycol) amine. Under reductive conditions, the PEG-lipid readily reacted with sCT to yield the resultant compound, Mal-PL-sCT.

Key findings

Dynamic light scattering analyses suggested that Mal-PL-sCT and 2PEG-Mal-sCT exhibited robust helical structures with a high tendency to aggregate in water. Both compounds were more stable against intestinal degradation than sCT, although Mal-PL-sCT was less stable than 2PEG-Mal-sCT. However, 2PEG-Mal-sCT did not possess hypocalcaemic activity while Mal-PL-sCT retained the hypocalcaemic activity of sCT when it was subcutaneously injected in the rat model. Multiple functional groups may be conjugated to a peptide via a tri-block linker without the risk of obliterating the intrinsic bioactivity of the peptide.

Conclusions

The resultant novel PEG-lipid has a potential role to optimize protein and peptide delivery.
Regional variations of vasomotion to G-protein coupled receptor agonists following heat stress in rats
Authors: Li Jie , Cao Yong-Xiao , Chen Kun-Lun , Cao Lei , Ma Zhao , Xu Cang-Bao
Published: October 2010

Objectives

This study was designed to compare vascular contractile and relaxing responses to G-protein coupled receptor agonists among the different regions of arteries following heat stress in rats.

Methods

Heat exposure was performed by increasing the internal temperature of the rats to 42°C for 15 min. After heat stress for 48 h, a myograph system was used to monitor the contractile responses in rat renal, femoral and mesenteric arteries to agonists of endothelin type B (ETB) receptor, endothelin type A (ETA) receptor, serotonin receptor and α-adrenoceptor, respectively. In addition, calcitonin gene-related peptide (CGRP)-induced vasodilation was studied.

Key findings

The results showed that heat stress induced decreased contractions mediated by α-adrenoceptors and serotonin receptors (at lower concentration), while it increased contraction mediated by endothelin ETB receptors and enhanced relaxation mediated by CGRP receptors in the renal artery. Heat stress increased contractions mediated by endothelin ETB receptors, endothelin ETA receptors and α-adrenoceptors in the femoral artery. In the mesenteric artery, heat stress increased contractions mediated by endothelin ETB and serotonin receptors and relaxation mediated by CGRP receptors.

Conclusions

The vasomotor responses to the G-protein coupled receptor agonists with altered vascular contractions and relaxations were different in rat renal, femoral and mesenteric arteries after heat stress. This might have contributed to the redistribution of blood flow and aids understanding of the preconditioning phenomenon.
Bioavailability of lycopene in the rat: the role of intestinal lymphatic transport
Authors: Faisal Waleed , O'Driscoll Caitriona M , Griffin Brendan T
Published: October 2010

Objectives

As a natural antioxidant derived from dietary sources, lycopene has attracted considerable attention as a potent chemopreventative agent. Lycopene is an extremely lipophilic compound and absorption from dietary sources is estimated to be low and highly variable. As a result, plasma lycopene concentrations are poorly correlated with dietary intake of lycopene rich food stuffs. The development of an oral formulation remains a challenge that requires a better understanding of the mechanisms involved in the intestinal absorption of this compound.

Methods

The solubility of lycopene in simulated physiological fluids and bile salt mixed micelle formulations was determined. The extent of intestinal lymphatic transport and the absolute bioavailability of lycopene from a range of biorelevant media was evaluated in a mesenteric lymph duct cannulated anaesthetised rat model.

Results

The absolute bioavailability of lycopene after 8 h was 1.85 ± 0.39%. The overall extent of the intestinal lymphatic transport was in the range of 0.6–3.4% of the administered dose. A strong positive correlation (r2 > 0.9) between intestinal lycopene levels and intestinal triglyceride levels was demonstrated.

Conclusions

The intestinal lymphatic route is the major uptake mechanism of lycopene from the gastrointestinal tract. Lycopene transport in intestinal lymph was closely associated with triglyceride transport in the lymph. Formulation strategies designed to promote intestinal lymphatic uptake, such as lipid-based formulations containing long-chain fatty acids (LCFA) or lecithin, may serve to enhance oral bioavailability of lycopene.
Recombinant bovine pancreatic trypsin inhibitor protects the liver from carbon tetrachloride-induced acute injury in mice
Authors: Yang Lili , Dong Wen , Yan Fang , Ren Xiubao , Hao Xishan
Published: October 2010

Objectives

Toxicity caused by pharmacological and chemical substances, including carbon tetrachloride (CCl4), is a major pathological factor for liver injury. Therefore, strategies to prevent toxicity are needed for maintaining a healthy liver. This study was designed to determine whether recombinant bovine pancreatic trypsin inhibitor (rBPTI), a non-specific serine protease inhibitor, prevents CCl4-induced liver injury in mice.

Methods

Mice were treated with CCl4 in the presence or absence of co-treatment with rBPTI. Liver sections were prepared for histopathological assessment. Liver function was evaluated by detecting serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and liver index. Liver oxidative stress and inflammation were examined by detecting the liver malondialdehyde level and glutathione and superoxide dismutase activity, and serum tumour necrosis factor-α level, respectively.

Key findings

CCl4 induced hepatocyte necrosis, inflammatory cell infiltration and fatty degeneration, which were ameliorated by co-treatment with rBPTI in a concentration-dependent manner. Furthermore, rBPTI prevented CCl4-induced disruption of liver function. Importantly, rBPTI reduced CCl4-induced liver oxidative stress response and pro-inflammatory cytokine production.

Conclusions

These results indicated that rBPTI exerted a protective effect on CCl4-induced liver injury in mice. Thus, rBPTI may have potential application for prevention of liver injury induced by metabolism of drugs and toxic substances.
Inhibitory effects of 5-chloroacetyl-2-piperidino-1,3-selenazole, a novel selenium-containing compound, on skin melanin biosynthesis
Authors: Lee Eunjoo H , Lim Yu-Ji , Ha Sang Keun , Kang Tong Ho , Koketsu Mamoru , Kang Chulhun , Kim Sun Yeou , Park Ji-Ho
Published: October 2010

Objectives

Increased production and accumulation of melanin leads to many hyperpigmentation disorders such as melasma, freckles and geriatric pigment spots. Thus, there is a need for the development of depigmenting agents. Based on our previous reports, selenium derivatives as anti-melanogenic lead compounds could be very important. The aim of this study was to investigate the depigmenting effect of novel selenium-containing compounds.

Methods

The inhibitory effects of 5-chloroacetyl-2-piperidino-1,3-selenazole (CS1), a novel selenium-containing compound, on melanogenesis were investigated in B16F10 melanoma cells and cultured brownish guinea pig skin tissue with α-melanocyte-stimulating hormone stimulation.

Key findings

We found that CS1 inhibited melanin production in B16F10 cells by suppressing tyrosinase activity and its protein expression. In addition, Western blotting analysis revealed that CS1 suppressed the expression of tyrosinase-related protein (TRP)-1 and TRP-2. Therefore, the depigmenting effect of CS1 might have been due to inhibition of tyrosinase activity and expression of melanogenic enzymes. Furthermore, CS1 had inhibitory effects on melanin biosynthesis of primary cultured skin of brownish guinea pig.

Conclusions

The results suggested that CS1 could be a useful candidate for the treatment of skin hyperpigmentation.
Pharmacokinetic interaction between puerarin and edaravone, and effect of borneol on the brain distribution kinetics of puerarin in rats
Authors: Gao Chunyan , Li Xiaorong , Li Yuhang , Wang Lijuan , Xue Ming
Published: October 2010

Objectives

The aim was to investigate the pharmacokinetic interaction between puerarin and edaravone, and the effect of borneol on the brain distribution kinetics of puerarin in rats.

Methods

A reversed-phase high performance liquid chromatography method was developed and validated for the simultaneous determination of puerarin and edaravone in rat plasma. The detection method was successfully applied to compare the pharmacokinetic interaction and brain distribution kinetics of puerarin and edaravone using in-situ microdialysis sampling in rats after intravenous administration and co-administration with a single dose.

Key findings

The method gave good linearity and no endogenous material interfered with the two target compounds and internal standard peaks. The limit of detection of puerarin and edaravone was 0.03 and 0.05 μg/ml, respectively. The average recovery of the two compounds from rat plasma was >94%. The precision of the test was determined to be within 10%. The combination of puerarin and edaravone reduced drug elimination rates, gave a wider distribution, and the disposition of both drugs in rats was optimized. The distribution of puerarin in brain tissues was significantly increased and its elimination was noticeably slower with borneol pretreatment.

Conclusions

The results provide important information for the improved combined use of puerarin and edaravone with borneol pretreatment in clinical practice.
Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin
Authors: Gao Aili , Wang Xiangjing , Xiang Wensheng , Liang Hongsheng , Gao Jiguo , Yan Yijun
Published: October 2010

Objectives

Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment. This study was performed to explore the reversal of MDR by doramectin from the avermectin family and nemadectin belonging to the milbemycin family.

Methods

The MTT assay was used to evaluate the abilities of the two compounds to reverse drug resistance in adriamycin-resistant human breast carcinoma cells (MCF-7/adr). Intracellular accumulation of adriamycin was determined by HPLC. The effects of the two compounds on inhibiting P-glycoprotein (P-gp) efflux was demonstrated by accumulation of rhodamine 123 in MCF-7/adr cells. To investigate the mechanism of reversal by the two compounds, the expressions of P-gp and the MDR1 gene encoding P-gp were tested by flow cytometry and reverse-transcriptase PCR.

Key findings

Doramectin and nemadectin at the high dose of 8 μmol/l significantly increased the sensitivity of MCF-7/adr cells to adriamycin by 49.35- and 23.97-fold, respectively. They also increased the intracellular accumulation of adriamycin and rhodamine 123 in MCF-7/adr cells in a dose-dependent manner. Expression of both P-gp and MDR1 were down-regulated.

Conclusions

Doramectin and nemadectin are promising agents for overcoming MDR in cancer therapy. Doramectin was more potent in reversing MDR.
Achieving a Long-Term Service Target with Periodic Demand Signals: A Newsvendor Framework
Authors: Bensoussan Alain , Feng Qi , Sethi Suresh P.
Published: October 2010

We deal with the problem of a profit-maximizing vendor selling a perishable product. At the beginning of a planning cycle, the vendor determines a minimum committed order per period. During the cycle, he may also place a supplemental order in each period based on the observed demand signal in that period. Moreover, the vendor is committed to a specific service target evaluated over the planning cycle. This is a complex problem, and we, as an approximation, offer a single-period, two-stage modeling approach. Under this approach, the vendor determines a first-stage order as the minimum committed order with the possibility of supplementing it based on a demand signal observed at the second stage. The problem is to maximize his expected profit subject to a constraint on his overall service performance across all possible values of the demand signal. We characterize the optimal policy for in-stock rate and fill-rate targets, and make comparisons. Whereas in the classical newsvendor model a service target can be replaced by a single unit shortage cost, it is not so in our model. Instead, a set of unit shortage costs are imputed—one for each demand signal. The imputed shortage costs reflect trade-offs among the profits under different demand signals in meeting the service targets. We also show that under a given ordering policy, the in-stock rate is lower (higher) than the fill rate when the demand has an increasing (decreasing) hazard rate. This result suggests that the vendor can infer a fill-rate measure from the corresponding in-stock rate without the difficult task of tracking lost sales. Furthermore, we analyze how the order quantity varies according to the observed signal, which allows us to formalize the notion of a valuable demand signal.
Retail Assortment Planning Under Category Captainship
Authors: Kurtuluş Mümin , Nakkas Alper
Published: October 2010

Retail assortment planning can have a tremendous impact on a retailer's bottom-line performance. Over the past years, retailers have increasingly relied on their leading manufacturers for recommendations regarding the assortment to be offered to the consumers in a particular category, a practice often referred to as category captainship. Our research investigates the consequences of using category captains for assortment selection decisions. We develop a game-theoretic model where multiple manufacturers sell their products to consumers through a single retailer. We compare a model where the retailer selects the assortment in the category with a model where the retailer relies on a category captain for assortment decisions in return for a target category profit. We show that category captainship can, in some circumstances, benefit not only the retailer and the category captain, but also the noncaptain manufacturers. Our results have implications regarding the implementation of category captainship practices.