bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycine modulates cytokine secretion, inhibits hepatic damage and improves survival in a model of endotoxemia in mice
Authors: Bruck Rafael , Wardi Joram , Aeed Hussein , Avni Yona , Shirin Haim , Avinoach Ilana , Shahmurov Mark , Hershkoviz Rami 
Published: July 2003

AbstractBackground and aim: There is substantial experimental evidence that the amino acid glycine may have a role in protecting tissues against insults such as ischemia, hypoxia and reperfusion. Our aim was to investigate the ability of the amino acid glycine to prevent hepatic damage induced by injection of lipopolysaccharide and d‐galactosamine (d‐Gal), to modulate pro‐ and anti‐inflammatory cytokine levels, and to improve survival.Methods: Mice were challenged with an intraperitoneal injection of d‐Gal (16 mg/mouse) and lipopolysaccharide (LPS, 1 μg/mouse). The intervention group also received an intraperitoneal injection of glycine (150 mg/kg) in two doses: 24 h before and just after LPS challenge. Serum cytokine levels were measured 2 h after challenge, and liver enzymes and histology were determined 16 h after LPS. Separate groups of mice received the same treatment and the survival rate was determined 24 h and ten days after endotoxin administration. In in vitro experiments, cultured mononuclear cells were stimulated by LPS, and TNF‐α and IL‐10 secretion were measured, in the presence or absence of glycine.Results: In the glycine‐treated mice, the serum levels of liver enzymes and TNF‐α, the histologic necroinflammation score and the mortality rate were significantly reduced compared to control mice (P<0.001). Serum IL‐10 levels in the glycine‐treated mice were increased (P<0.01). In vitro studies in cultured lymphocytes isolated from either normal or glycine pretreated mice, demonstrated a significant and dose‐dependent inhibition of LPS‐induced TNF‐α secretion and increase in IL‐10 response after treatment with glycine (P<0.01). In conclusion, glycine reduces hepatic damage and improves survival rate in this mouse model of endotoxemia. The protective effect of glycine is associated with modulation of TNF‐α and IL‐10 secretion.
CC531s colon carcinoma cells induce apoptosis in rat hepatic endothelial cells by the Fas/FasL‐mediated pathway
Authors: Vekemans Katrien , Timmers Maarten , Vermijlen David , De Zanger Ronald , Wisse Eddie , Braet Filip 
Published: July 2003

AbstractThe mechanisms involved in colorectal carcinoma with liver metastasis are not well known. Metastasizing colon carcinoma cells express more FasL than primary colon carcinoma cells and cancer cells induce apoptosis in hepatocytes by the Fas/FasL pathway. Therefore, this study focused on Fas/FasL expression and functionality in rat liver sinusoidal endothelial cells (LSECs) and CC531s colon carcinoma cellsin vitroandin vivo. RT‐PCR and immunochemistry revealed Fas and FasL in LSECs and CC531s, respectively. Functionality of Fas was assessedin vitroby incubation with human recombinant FasL (1–100 ng/ml) with or without enhancer. At concentrations of 10 and 100 ng/ml with enhancer, respectively 21% and 44% of endothelial cells showed signs of apoptosis using Hoechst 33342/propidium iodide staining and electron microscopy. In co‐cultures, apoptosis could be detected in endothelial cells neighboring the CC531s and could be inhibited by an antagonistic FasL antibody. Moreover, 18 h after mesenteric injection of CC531s, the sinusoidal endothelium revealed disruption. In conclusion, (i) CC531s cells induce apoptosis in LSECsin vitroby using Fas/FasL; (ii) CC531s cells damage the sinusoidal endothelial liningin vivo; and (iii) this might provide FasL‐positive tumor cells a gateway towards the hepatocytes.
Insulin resistance/β‐cell function and serum ferritin level in non‐diabetic patients with hepatitis C virus infection
Authors: Furutani Masanori , Nakashima Toshiaki , Sumida Yoshio , Hirohama Akihisa , Yoh Takaharu , Kakisaka Yuko , Mitsuyoshi Hironori , Senmaru Hiroshi , Okanoue Takeshi 
Published: July 2003

AbstractBackground/Aims: Since impaired glucose tolerance and iron overload are frequently demonstrated in hepatitis C virus (HCV)‐related liver diseases, in this study we investigated insulin resistance, pancreatic β‐cell function, i.e., insulin secretion, and serum ferritin levels in patients with HCV infection, especially non‐diabetic patients.Methods: Homeostasis model assessments for insulin resistance (HOMA‐IR) and β‐cell function (HOMA‐β) were performed in 92 HCV‐infected patients.Results: The levels of plasma immunoreactive insulin (IRI), HOMA‐IR, and HOMA‐β were significantly correlated with fasting plasma glucose (FPG) levels. Among the 86 non‐diabetics (with an FPG of <126 mg/dl), IRI, HOMA‐IR, and HOMA‐β were significantly higher in patients with liver cirrhosis than in patients with persistently normal alanine aminotransferase levels. The IRI and HOMA‐IR values, but not the HOMA‐β values, were correlated with both serum transaminase and ferritin levels in the 65 non‐diabetic chronic hepatitis patients.Conclusion: Insulin resistance was connected with impaired glucose tolerance and the severity of liver diseases in non‐diabetic patients with HCV infection. Iron overload may be responsible for insulin resistance, or vice versa. Pancreatic β‐cell function was unrelated to the patients' serum ferritin levels.
Antiapoptotic and protective effects of roscovitine on ischemia–reperfusion injury of the rat liver
Authors: Topaloglu Serdar , Abbasoglu Osman , Ayhan Ayse , Sokmensuer Cenk , Kılınc Kamer 
Published: July 2003

AbstractObjective: This study was designed to investigate the role of apoptosis on liver IR injury and to determine the effects of roscovitine on this process.Materials and methods: Rat livers pretreated with roscovitine received 60 min right lobe ischemia followed by 4 h (n=8) and 24 h (n=8) reperfusion. Tissue injury was evaluated by serum alanine aminotransferase, aspartate aminotransferase, tissue malondialdehyde, myeloperoxidase measurements and histological examination. Dead (apoptotic and necrotic) hepatocytes were determined by trypan blue dye and apoptosis was evaluated with M30 monoclonal antibody.Results: Administration of roscovitine significantly decreased both apoptotic and dead hepatocyte counts compared to controls (P<0.01). Liver transaminase levels were decreased significantly in the roscovitine‐pretreated groups (P<0.05). In the groups evaluated 24 h after reperfusion, MPO levels (P<0.02) and leukocyte infiltration on histologic sections were decreased significantly in the roscovitine‐administered group compared to its control.Conclusions: This study indicates that hepatocyte apoptosis may play a role in the development of IR injury of the liver. Administration of roscovitine may be beneficial in preventing this injury.
Alternative medicines and the liver
Authors: Fogden Edward , Neuberger James 
Published: July 2003

AbstractComplementary and Alternative Medicine (CAM) is a heterogeneous group of theories and practices that are becoming increasingly popular in the West – between 20% and 65% of patients use CAM on a regular basis. In the UK, CAM is provided by over a third of general practitioners as well as by hospitals. The subject of much debate in both the lay and medical press, CAM is subject to increasing scrutiny from clinical research. In this review, we discuss the available evidence for herbal medicines, including that for silymarin, glycyrrhizin, Chinese herbal medicines and other herbal mixtures. We also review evidence regarding the safety of herbal medicines, both in terms of hepatotoxicity and drug interactions. We conclude that although CAM may be of benefit in the treatment of liver disease, the available evidence is insufficient to recommend any of the available therapies. CAM has not yet been well studied in liver disease and rigorous evaluation with well‐designed double‐blind randomised controlled trails is required. Doctors need to be aware of the widespread use of CAM, ask their patients specifically regarding their use of CAM and be aware of the potential for hepatotoxicity and interactions.
Environmental noise and population dynamics of the ciliated protozoa Tetrahymena thermophila in aquatic microcosms
Authors: Laakso Jouni , Löytynoja Katja , Kaitala Veijo 
Published: August 2003

Population theory predicts that the reddened environmental noise, especially in combination with high population growth rate, reddens population dynamics, increases population variability and strengthens environment–population correlation. We tested these predictions with axenic populations of ciliated protozoa Tetrahymena thermophila. Populations with low and high growth rate were cultured in a stable environment, and in environments with sublethal temperature fluctuations that had blue, white and red spectra (i.e. negatively autocorrelated, uncorrelated, or positively autocorrelated, respectively). Population size and biomass of individuals were determined at 3‐h intervals for 18 days.Dynamics of all populations were reddened, suggesting that internal mechanisms can redden the population spectra. However, population dynamics were reddest, variability highest, and environment–population correlation strongest in the red environment as predicted. Contrary to theoretical predictions and previous empirical findings, population growth rate (rmax being equal to 0.05 and 0.3 h−1) had no effect on population dynamics.Mean cell size and variability of cell size were affected by the presence and type of environmental noise suggesting that the physiological consequences of variability depend on colour. Environmental variability decreased mean population size and biomass and the decrease was strongest in rapidly fluctuating blue and white environments. The latter finding implies that rapid fluctuations are physiologically stressful, an effect that is not accounted for in the basic population models.
Flibanserin, a potential antidepressant drug, lowers 5‐HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5‐HT1A receptors
Authors: Invernizzi Roberto William , Sacchetti Giuseppina , Parini Stefania , Acconcia Sabrina , Samanin Rosario 
Published: July 2003

Using in vivo intracerebral microdialysis in conscious, freely moving rats, we examined the effect of flibanserin, a potential antidepressant drug with high affinity for human 5‐HT1A receptors and four–50‐fold lower affinity for 5‐HT2A and D4 receptors, on basal extracellular concentrations of serotonin (5‐hydroxytryptamine, 5‐HT), dopamine (DA) and noradrenaline (NA) in selected regions of the rat brain.
Flibanserin at 3 and 10 mg kg−1 significantly reduced extracellular 5‐HT in the prefrontal cortex (by 30 and 45%) and dorsal raphe (35 and 44%), but had no effect on extracellular 5‐HT in the ventral hippocampus. The 3 and 10 mg kg−1 doses raised extracellular NA to a similar extent in the prefrontal cortex (47 and 50%). In all, 10 mg kg−1 raised extracellular DA in the prefrontal cortex (63%) whereas 3 mg kg−1 had no significant effect.
Pretreatment with the selective 5‐HT1A receptor antagonist WAY100,635 (0.3 mg kg−1) 30 min before 10 mg kg−1 flibanserin completely antagonized the latter's effects on extracellular 5‐HT, DA and NA in the prefrontal cortex. WAY100,635 by itself had no effect on cortical extracellular monoamines.
The results show that the stimulation of 5‐HT1A receptors plays a major role in the effect of flibanserin on brain extracellular 5‐HT, DA and NA.

British Journal of Pharmacology (2003) 139, 1281–1288. doi:10.1038/sj.bjp.0705341
Purification of a neuroprotective component of Parawixia bistriata spider venom that enhances glutamate uptake
Authors: Fontana Andréia Cristina Karklin , Guizzo Renato , Beleboni Renê de Oliveira , Meirelles e Silva Antonio Renato , Coimbra Norberto Cysne , Amara Susan G , Santos Wagner Ferreira dos , Coutinho‐Netto Joaquim 
Published: July 2003

In this study, we examined the effects of crude venom from the spider Parawixia bistriata on glutamate and GABA uptake into synaptosomes prepared from rat cerebral cortex. Addition of venom to cortical synaptosomes stimulated glutamate uptake and inhibited GABA uptake in a concentration‐dependent manner.
The venom was fractionated using reverse‐phase high‐performance liquid chromatography on a preparative column. The fraction that retained glutamate uptake‐stimulating activity was further purified on a reverse‐phase analytical column followed by ion‐exchange chromatography.
The active fraction, referred to as PbTx1.2.3, stimulated glutamate uptake in synaptosomes without changing the KM value, and did not affect GABA uptake. Additional experiments showed that the enhancement of glutamate uptake by PbTx1.2.3 occurs when ionotropic glutamate receptors or voltage‐gated sodium and calcium channels are completely inhibited or when GABA receptors and potassium channels are activated, indicating that the compound may have a direct action on the transporters.
In an experimental model for glaucoma in which rat retinas are subjected to ischemia followed by reperfusion, PbTx1.2.3 protected neurons from excitotoxic death in both outer and inner nuclear layers, and ganglion cell layers.
This active spider venom component may serve as a basis for designing therapeutic drugs that increase glutamate clearance and limit neurodegeneration.

British Journal of Pharmacology (2003) 139, 1297–1309. doi:10.1038/sj.bjp.0705352
Evidence that 5‐lipoxygenase and acetylated cyclooxygenase 2‐derived eicosanoids regulate leukocyte–endothelial adherence in response to aspirin
Authors: Fiorucci Stefano , Distrutti Eleonora , Mencarelli Andrea , Morelli Antonio , Laufor Stefan A , Cirino Giuseppe , Wallace John L 
Published: July 2003

Unlike other nonsteroidal anti‐inflammatory drugs that inhibit formation of cyclooxygenase (COX)‐dependent eicosanoids, acetylation of COX‐2 by aspirin switches eicosanoid biosynthesis from prostaglandin E2 (PGE2) to 15‐epi‐lipoxin A4 (15‐epi‐LXA4 or aspirin‐triggered lipoxin, ATL). ATL formation by activated leukocytes (PMN) requires the intervention of 5‐lipoxygenase (5‐LOX), an enzyme that is involved in leukotriene B4 (LTB4) formation.
In the present study, we have examined the role of acetylated COX‐2 and 5‐LOX in modulating antiadhesive effects of aspirin on adhesion of PMN to endotoxin (LPS)‐primed human umbilical endothelial cells (HUVEC).
Treating PMN/HUVEC cocultures with aspirin resulted in a concentration‐dependent inhibition of cell‐to‐cell adhesion induced by LPS. Treating HUVEC with selective COX‐2 inhibitors, celecoxib and rofecoxib, caused an ∼70% reversion of antiadhesive effect of aspirin. In contrast, inhibition of neutrophil's 5‐LOX pathway with 1 μM ZD2138, a selective 5‐LOX inhibitor, 1 μM BAY‐X‐1005, a FLAP inhibitor, or 100 μM licofelone, a dual COX/5‐LOX inhibitor, did not affect antiadhesive properties of aspirin.
Exposure to celecoxib (100 μM) or rofecoxib (10 μM) completely suppressed ATL formation caused by aspirin without affecting LTB4 levels. ZD2138, licofelone and BAY‐X‐1005 inhibited ATL formation as well as LTB4 generation.
Treatment with LXA4 reduced PMN adhesion to HUVEC and counteracted the proadhesive effect of celecoxib. In contrast, exposure to Boc‐1, an LXA4 antagonist, counteracts the antiadhesive activities of aspirin. Exposure to U75302, an LTB4 receptor antagonist, enhances the antiadesive effect of aspirin.
Reversal of antiadhesive activities of aspirin by celecoxib was associated with increased expression of LFA‐1 on PMN and E‐selectin on HUVEC. Addition of LXA4, ZD2138 and U75302 inhibited these changes.
The present results support the notion that inhibition of ATL formation is mechanistically linked to the reversal of the antiadhesive activity of aspirin caused by selective COX‐1 inhibitors and suggests that the LTB4/ATL balance modulates pro‐ and antiadhesive activity of nonsteroidal anti‐inflammatory drugs at the leukocyte–endothelial cell interface.

British Journal of Pharmacology (2003) 139, 1351–1359. doi:10.1038/sj.bjp.0705356
Diadenosine‐5‐phosphate exerts A1‐Receptor‐mediated proarrhythmic effects in rabbit atrial myocardium
Authors: Brandts B , Borchard R , Dirkmann D , Wickenbrock I , Sievers B , van Bracht M , Prull M W , Trappe H ‐J 
Published: July 2003

Diadenosine polyphosphates have been described to be present in the myocardium and exert purinergic‐ and nonreceptor‐mediated effects. Since the electrophysiological properties of atrial myocardium are effectively regulated by A1 receptors, we investigated the effect of diadenosine pentaphosphate (Ap5A) in rabbit myocardium.
Parameters of supraventricular electrophysiology and atrial vulnerability were measured in Langendorff‐perfused rabbit hearts. Muscarinic potassium current (IK(ACh/Ado)) and ATP‐sensitive potassium current (IK(ATP)) were measured by using the whole‐cell voltage clamp method.
Ap5A prolonged the cycle length of spontaneously beating Langendorff perfused hearts from 225±14 (control) to 1823±400 ms (Ap5A 50 μM; n=6; P<0.05). This effect was paralleled by higher degree of atrio‐ventricular block. Atrial effective refractory period (AERP) in control hearts was 84±14 ms (n=6). Ap5A1 μM reduced AERP (100 μM, 58±11 ms; n=6).
Extrastimuli delivered to hearts perfused with Ap5A‐ or adenosine ( μM)‐induced atrial fibrillation, the incidence of which correlated to the concentration added to the perfusate. The selective A1‐receptor antagonist CPX (20 μM) inhibited the Ap5A‐ and adenosine‐induced decrease of AERP. Atrial fibrillation was no longer observed in the presence of CPX.
The described Ap5A‐induced effects in the multicellular preparation were enhanced by dipyridamole (10 μM), which is a cellular adenosine uptake inhibitor. Dipyridamole‐induced enhancement was inhibited by CPX.
Ap5A (1 mM) did neither induce IK(Ado) nor IK(ATP). No effect on activated IK(Ado/ATP) was observed in myocytes superfused with Ap5A. However, effluents from Langendorff hearts perfused with Ap5A 100 μM activated IK(Ado) by using A1 receptors.
Ap5A did not activate A1 receptors in rabbit atrial myocytes. The Ap5A induced A1‐receptor‐mediated effects on supraventricular electrophysiology and vulnerability suggest that in the multicellular preparation Ap5A is hydrolyzed to yield adenosine, which acts via A1 receptors. An influence on atrial electrophysiology or a facilitation of atrial fibrillation under conditions resulting in increased interstitial Ap5A concentrations might be of physiological/pathophysiological relevance.

British Journal of Pharmacology (2003) 139, 1265–1272. doi:10.1038/sj.bjp.0705361
Protective effects of curcumin against amiodarone‐induced pulmonary fibrosis in rats
Authors: Punithavathi Durairaj , Venkatesan Narayanan , Babu Mary 
Published: July 2003

We have studied whether curcumin prevents amiodarone‐induced lung fibrosis in rats. Intratracheal instillation of amiodarone (6.25 mg kg−1 on days 0 and 2, and then killed on day 3, day 5, week 1, week 3 and week 5 after amiodarone administration) induced increases in total protein and lactate dehydrogenase (LDH) activity on days 3 and 5 in bronchoalveolar lavage fluid (BALF). Total cell counts, alveolar macrophages, neutrophils and eosinophils recovered by BAL, and lung myeloperoxidase (MPO) activity were significantly higher in amiodarone rats.
Tumor necrosis factor‐α (TNF‐α) release after lipopolysaccharide (LPS) stimulation and superoxide anion generation after phorbol myristate acetate (PMA) stimulation were higher in the alveolar macrophages of amiodarone rats at 3 and 5 weeks postamiodarone instillation than in controls. Amiodarone also induced increases in transforming growth factor‐β1 (TGF‐β1) expression, collagen deposition, type I collagen expression and c‐Jun protein in lungs.
Curcumin (200 mg kg−1 body weight after first amiodarone instillation and daily thereafter for 5 weeks)‐treated amiodarone rats had reduced levels of protein, LDH activity, total cell numbers and differential cell counts in BALF. LPS‐stimulated TNF‐α release and PMA‐stimulated superoxide generation were significantly suppressed by curcumin. Furthermore, curcumin inhibited the increases in lung MPO activity, TGF‐β1 expression, lung hydroxyproline content, expression of type I collagen and c‐Jun protein in amiodarone rats. Our results have important implications for the treatment of amiodarone‐induced lung fibrosis.

British Journal of Pharmacology (2003) 139, 1342–1350. doi:10.1038/sj.bjp.0705362
Local anaesthetics block hyperpolarization‐activated inward current in rat small dorsal root ganglion neurones
Authors: Bischoff Ulrike , Bräu Michael E , Vogel Werner , Hempelmann Gunter , Olschewski Andrea 
Published: July 2003

Hyperpolarizing voltage steps evoke slowly activating inward currents in a variety of neurones and in cardiac cells. This hyperpolarization‐activated inward current (Ih) is thought to play a significant role in cell excitability, firing frequency, or in setting of the resting membrane potential in these cells. We studied the effects of lidocaine, mepivacaine, QX‐314 and bupivacaine as well as its enantiomers on Ih in the membrane of dorsal root ganglion neurones (DRG).
The patch‐clamp technique was applied to small dorsal root ganglion neurones identified in 200 μM thin slices of young rat DRGs. Under voltage‐clamp conditions, the whole‐cell Ih current was recorded in the presence of different concentrations of the local anaesthetics. In current‐clamp mode the resting membrane potential and the voltage response of DRG neurones to injected current pulses were investigated.
Ih was reversibly blocked by bupivacaine, lidocaine and mepivacaine applied externally in clinically relevant concentrations. Concentration–response curves gave half‐maximum inhibiting concentrations of 55, 99 and 190 μM, respectively. Bupivacaine block of the Ih current was not stereoselective. No significant effect was observed when QX‐314 was applied to the external surface of the membrane.
In current‐clamp experiments 60 μM bupivacaine slightly hyperpolarized the membrane. The membrane stimulation by low‐amplitude current pulses in the presence of bupivacaine showed an increase of the hyperpolarizing responses.
Our findings suggest an important role of the Ih‐block by local anaesthetics in the complex mechanism of drug action during epidural and spinal anaesthesia.

British Journal of Pharmacology (2003) 139, 1273–1280. doi:10.1038/sj.bjp.0705363