bluuebunny/crossref_metadata_2025_split huggingface dataset:
IGF-I and IGFBP-3 and the risk of lung cancer: A meta-analysis based on nested case-control studies
Authors: Chen Bo , Liu Shan , Xu Wei , Wang Xueli , Zhao Weihong , Wu Jianqing 
Published: June 2009

Abstract

Background
Lung cancer is the leading cause of death from cancer worldwide. Conventional studies mainly think that insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may promote and inhibit tumor growth, respectively. However, there are many different results about their function in some recent epidemiological studies. To evaluate the relationship between circulating serum levels of IGF-I, IGFBP-3 and lung cancer, a systematic review and meta-analysis of the published data was performed.

Methods
Literatures searched on PubMed and Embase databases were enrolled in the Meta-analysis. The Meta-analysis of all eligible studies was applied with Stata 10.0 software, and the pooled odds ratio(OR) and weighted mean difference (WMD) value were obtained. The Q test, Egger's test and Begg's funnel plot were used to evaluate the heterogeneity and publication bias between the studies.

Results
There are no statistically significant heterogeneity and publication bias between the studies. For IGF- I, the pooled OR and WMD were 0.87(95%CI: 0.60~1.13,) and -3.04(95%CI: -7.10~1.02, P = 0.14), respectively. For IGFBP-3, the pooled OR and WMD were 0.68(95%CI: 0.48~0.88,) and -112.28(95%CI: -165.88~-58.68, P < 0.0001), respectively.

Conclusion
The association between circulating IGF- I levels and the risk of lung cancer were not statistically significant; IGFBP-3, acts as a tumor suppressor and has a inverse correlation with the risk of lung cancer.
Factors associated with septic shock and mortality in generalized peritonitis: comparison between community-acquired and postoperative peritonitis
Authors: Riché Florence C , Dray Xavier , Laisné Marie-Josèphe , Matéo Joaquim , Raskine Laurent , Sanson-Le Pors Marie-José , Payen Didier , Valleur Patrice , Cholley Bernard P 
Published: June 2009

Abstract
Introduction
The risk factors associated with poor outcome in generalized peritonitis are still debated. Our aim was to analyze clinical and bacteriological factors associated with the occurrence of shock and mortality in patients with secondary generalized peritonitis.

Methods
This was a prospective observational study involving 180 consecutive patients with secondary generalized peritonitis (community-acquired and postoperative) at a single center. We recorded peri-operative occurrence of septic shock and 30-day survival rate and analyzed their associations with patients characteristics (age, gender, SAPS II, liver cirrhosis, cancer, origin of peritonitis), and microbiological/mycological data (peritoneal fluid, blood cultures).

Results
Frequency of septic shock was 41% and overall mortality rate was 19% in our cohort. Patients with septic shock had a mortality rate of 35%, versus 8% for patients without shock. Septic shock occurrence and mortality rate were not different between community-acquired and postoperative peritonitis. Age over 65, two or more microorganisms, or anaerobes in peritoneal fluid culture were independent risk factors of shock. In the subgroup of peritonitis with septic shock, biliary origin was independently associated with increased mortality. In addition, intraperitoneal yeasts and Enterococci were associated with septic shock in community-acquired peritonitis. Yeasts in the peritoneal fluid of postoperative peritonitis were also an independent risk factor of death in patients with septic shock.

Conclusions
Unlike previous studies, we observed no difference in incidence of shock and prognosis between community-acquired and postoperative peritonitis. Our findings support the deleterious role of Enterococcus species and yeasts in peritoneal fluid, reinforcing the need for prospective trials evaluating systematic treatment against these microorganisms in patients with secondary peritonitis.
Insulin-Stimulated Translocation of Glucose Transporter (GLUT) 12 Parallels That of GLUT4 in Normal Muscle
Authors: Stuart Charles A. , Howell Mary E. A. , Zhang Yi , Yin Deling 
Published: June 2009

Context: GLUT4 is the predominant glucose transporter isoform expressed in fat and muscle. In GLUT4 null mice, insulin-stimulated glucose uptake into muscle was diminished but not eliminated, suggesting that another insulin-sensitive system was present.Objective: This study was intended to determine whether insulin caused GLUT12 translocation in muscle.Design: Six normal volunteers had muscle biopsies before and after euglycemic insulin infusions.Setting: Infusions and biopsies were performed in an outpatient clinic.Participants: Subjects were nonobese, young adults with no family history of diabetes.Main Outcome Measures: GLUT12, GLUT4, and GLUT1 proteins were quantified in muscle biopsy fractions. Cultured myoblasts were used to determine whether GLUT12 translocation was phosphatidyl inositol-3 kinase (PI3-K)-dependent.Intervention. Insulin was infused at 40 mU/m2 · min for 3 h.Results: In human muscle, insulin caused a shift of a portion of GLUT12 from intracellular low-density microsomes to the plasma membrane (PM) fraction (17% in PM at baseline, 38% in PM after insulin). Insulin increased GLUT4 in PM from 13 to 42%. GLUT1 was predominantly in the PM fractions at baseline and did not change significantly after insulin. L6 myoblasts in culture also expressed and translocated GLUT12 in response to insulin, but inhibiting PI3-K prevented the translocation of GLUT12 and GLUT4.Conclusions: Insulin causes GLUT12 to translocate from an intracellular location to the plasma membrane in normal human skeletal muscle. Translocation of GLUT12 in cultured myoblasts was dependent on activation of PI3-K. GLUT12 may have evolutionarily preceded GLUT4 and now provides redundancy to the dominant GLUT4 system in muscle.Insulin induces sequestered GLUT12 to move to the muscle cell surface.
Aging Attenuates the Pituitary Response to Gonadotropin-Releasing Hormone
Authors: Shaw Natalie D. , Srouji Serene S. , Histed Stephanie N. , McCurnin Kristin E. , Hall Janet E. 
Published: June 2009

Context: Complex changes in GnRH secretion occur with aging in women, but little is known about the effect of aging on the pituitary per se.Objective: The aim of the study was to determine whether pituitary responsiveness to GnRH is attenuated with aging.Design and Setting: A GnRH antagonist and graded doses of GnRH were used to isolate pituitary responsiveness in Clinical Research Center studies at an academic medical center.Subjects: Subjects were healthy postmenopausal women (PMW) aged 48–57 yr (n = 10) or 70–77 yr (n= 9).Interventions: A suppressive dose of the NAL-GLU GnRH antagonist (150 μg/kg sc) was administered and was followed by GnRH doses of 25, 75, 250, or 750 ng/kg iv every 4 h.Results: The LH response to GnRH was attenuated with aging (P = 0.05) with an interaction between age and dose (P = 0.01) such that the LH amplitude was less in older PMW at the higher doses (250 ng/kg, 50 ± 9 vs. 29 ± 4.9 IU/liter, for young and old PMW, respectively, P = 0.02; and 750 ng/kg, 97.7 ± 11 vs. 70.2 ± 9.3 IU/liter, P = 0.002), but not the lower doses of GnRH. The FSH response to GnRH was also attenuated with aging in PMW (P = 0.005).Conclusions: In studies that isolated the pituitary from endogenous GnRH stimulation, aging attenuated the LH and FSH responses to exogenous GnRH in PMW. These studies indicate that the pituitary plays a role in the decline in gonadotropin levels with aging, further supporting the potential contribution of age-associated changes in both hypothalamic and pituitary function to reproductive senescence.Studies using a hypothalamic clamp to isolate the pituitary from endogenous GnRH input in postmenopausal women demonstrate that the LH and FSH responses to GnRH are diminished with aging.
Improving glyburide solubility and dissolution by complexation with hydroxybutenyl-β-cyclodextrin
Authors: Klein Sandra , Wempe Michael F , Zoeller Thomas , Buchanan Norma L , Lambert Juanelle L , Ramsey Michael G , Edgar Kevin J , Buchanan Charles M 
Published: June 2009

Abstract

Objectives
Glyburide, an important drug for type 2 diabetes, has extremely poor aqueous solubility and resulting low bioavailability. This study describes the ability of hydroxybutenyl-β-cyclodextrin (HBenBCD) to form complexes with glyburide, with enhanced solubility and dissolution rate in vitro.

Method
Glyburide and glyburide-HBenBCD were evaluated in various test media known to simulate human gastrointestinal conditions in the fasted and fed states, respectively.

Key findings
At ∼14 wt% drug load, in the presence of HBenBCD, an almost 400-fold increase in glyburide aqueous solubility was observed. In the presence of HBenBCD, glyburide solubility was also significantly improved in all physiologically relevant test media. Subsequent dissolution experiments confirmed the solubility study results; the dissolution rate and total amount of drug released were significantly increased.

Conclusions
Complexation with HBenBCD may be an effective way to increase the bioavailability of glyburide.
The role of molecular physicochemical properties and apolipoproteins in association of drugs with triglyceride-rich lipoproteins: in-silico prediction of uptake by chylomicrons
Authors: Gershkovich Pavel , Fanous Joseph , Qadri Bashir , Yacovan Avihai , Amselem Shimon , Hoffman Amnon 
Published: June 2009

Abstract

Objectives
The uptake of drugs by chylomicrons is a key element in both intestinal lymphatic transport and postprandial alterations in the disposition profile of lipophilic drugs. The aim of this article was to elucidate the factors that affect this phenomenon.

Methods
The degree of association of 22 model lipophilic molecules with rat chylomicrons was assessed and correlated in silico with calculated physicochemical properties. The in-silico model was then validated using an external set of molecules. The uptake by chylomicrons was also compared to the association with a marketed artificial emulsion.

Key findings
The most important physicochemical property that affects the affinity to chylomicrons was found to be LogD7.4; however, a multiparameter model was required to describe properly the uptake process. The in-silico model (R2Y = 0.91, R2X = 0.91 and Q2 = 0.82) that was created using a combination of eight molecular descriptors enabled successful prediction of the affinity of the external set of molecules to chylomicrons. The association with the artificial emulsion was statistically different from the uptake by chylomicrons for four (out of nine) molecules.

Conclusions
The association of drugs with chylomicrons is a complex process, which involves the lipophilic core as well as surface apoproteins. The in-silico model based on multiple physicochemical properties of the drugs is able to predict successfully the degree of association with chylomicrons.
Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans
Authors: Fuchs Holger , Tillement Jean-Paul , Urien Saik , Greischel Andreas , Roth Willy 
Published: June 2009

AbstractObjectivesThe purpose of this study was to characterise the plasma protein binding of BI 1356.MethodsBI 1356 (proposed trade name ONDERO) is a novel dipeptidyl peptidase 4 (DPP-4) inhibitor, which is under clinical development for the treatment of type 2 diabetes. DPP-4 is expressed in various tissues but soluble DPP-4 is also present in plasma. Therefore, binding to soluble DPP-4 may influence the pharmacokinetics of BI 1356. Plasma protein binding of BI 1356 was determined in vitro for wild type mice and rats and the results compared with those for DPP-4 knockout mice and DPP-4 deficient Fischer rats. In addition, protein binding of BI 1356 was examined in plasma from healthy human volunteers and renal excretion of the compound in the DPP-4 knockout mice was compared with that occurring in wild type mice.Key findingsThe results showed that BI 1356 exhibited a prominent concentration-dependent plasma protein binding due to a saturable high affinity binding to the DPP-4 target in plasma. Differences in renal excretion of BI 1356 between DPP-4 knockout mice and wild type mice suggested that saturable binding of BI 1356 to DPP-4 in the body also influenced elimination.ConclusionsHigh affinity, but readily saturable binding of BI 1356 to its target DPP-4 accounted primarily for the concentration-dependent plasma protein binding at therapeutic plasma concentrations of BI 1356.
Human phenylalanine monooxygenase and thioether metabolism
Authors: Boonyapiwat Boontarika , Panaretou Barry , Forbes Ben , Mitchell Stephen C , Steventon Glyn B 
Published: June 2009

AbstractObjectivesThe substrate specificity of wild-type human phenylalanine monooxygenase (wt-hPAH) has been investigated with respect to the mucoactive drug, S-carboxymethyl-L-cysteine and its thioether metabolites. The ability of wt-hPAH to metabolise other S-substituted cysteines was also examined.MethodsDirect assays of PAH activity were by HPLC with fluorescence detection; indirect assays involved following disappearance of the cofactor by UV spectroscopy.Key findingswt-hPAH catalysed the S-oxygenation of S-carboxymethyl-L-cysteine, its decarboxylated metabolite, S-methyl-L-cysteine, and both their corresponding N-acetylated forms. However, thiodiglycolic acid was not a substrate. The enzyme profiles for both phenylalanine and S-carboxymethyl-L-cysteine showed allosteric kinetics at low substrate concentrations, with Hill constants of 2.0 and 1.9, respectively, for the substrate-activated wt-hPAH. At higher concentrations, both compounds followed Michaelis–Menten kinetics, with non-competitive substrate inhibition profiles. The thioether compounds, S-ethyl-L-cysteine, S-propyl-L-cysteine and S-butyl-L-cysteine were all found to be substrates for phenylalanine monooxygenase.ConclusionsPhenylalanine monooxygenase may play a wider role outside intermediary metabolism in the biotransformation of dietary-derived substituted cysteines and other exogenous thioether compounds.
Andrographolide inhibits growth of acute promyelocytic leukaemia cells by inducing retinoic acid receptor-independent cell differentiation and apoptosis
Authors: Manikam Shiamala T , Stanslas Johnson 
Published: June 2009

Abstract

Objectives
The growth inhibiting potential of andrographolide was evaluated in three acute promyelocytic leukaemia cell line models (HL-60, NB4 and all-trans retinoic acid (ATRA)-resistant NB4-R2).

Methods
In elucidating the mechanisms of growth inhibition, a special emphasis was placed on assessing the induction of differentiation and apoptosis by andrographolide in the primary acute promyelocytic leukaemia NB4 cells.

Key findings
The compound was 2- and 3-fold more active in inhibiting the growth of HL-60 and NB4-R2 cells compared with NB4 cells, respectively. At IC50 (concentration at which growth of 50% of the cells (compared with medium only treated control cells) is inhibited; 4.5 μM) the compound exhibited strong cell-differentiating activity in NB4 cells, similar to ATRA (IC50 1.5 μM). In the presence of a pure retinoic acid receptor antagonist AGN193109, the growth inhibition of NB4 cells by ATRA was reversed, whereas the activity of andrographolide was not affected. This clearly suggested that andrographolide's cell differentiating activity to induce growth inhibition of NB4 cells most likely occurred via a retinoic acid receptor-independent pathway. At higher concentration (2 × IC50), andrographolide was an efficient inducer of apoptosis in NB4 cells.

Conclusions
Taken together, these results suggest andrographolide and its derivatives, apparently with a novel cell differentiating mechanism and with ability to induce apoptosis, might be beneficial in the treatment of primary and ATRA-resistant acute promyelocytic leukaemia.
Increased sensitivity to diltiazem hypotensive effect in an experimental model of high-renin hypertension
Authors: Bertera Facundo M , Mayer Marcos A , Opezzo Javier A W , Taira Carlos A , Höcht Christian 
Published: June 2009

Abstract

Objectives
The aim of this work was to evaluate the pharmacokinetic–pharmacodynamic properties of diltiazem in an experimental model of high-renin hypertension, such as the aortic coarctated (ACo) rat, to further characterize the responsiveness of this model to calcium channel blockers.

Methods
A ‘shunt’ microdialysis probe was inserted in a carotid artery of anaesthetized ACo and control sham-operated (SO) rats for simultaneous determination of diltiazem plasma concentrations and their effects on mean arterial pressure and heart rate after the intravenous application of 3 and 6 mg/kg of the drug. Correlation between plasma levels and cardiovascular effects was established by fitting the data to a modified Emax model.

Key findings
Volume of distribution was greater in ACo than in SO rats. Diltiazem plasma clearance (Cl) was significantly greater in ACo rats than in normotensive SO rats after administration of diltiazem (6 mg/kg). Moreover, Cl increased with dose in ACo but not in SO rats. No differences were observed in the maximal bradycardic effect comparing both experimental groups, and sensitivity (S0) to diltiazem chronotropic effect was similar comparing SO and ACo rats. Differences were not found in the maximal response of the hypotensive effect comparing SO and ACo rats, but the S0 to diltiazem hypotensive effect was greater in ACo rats than in SO rats.

Conclusions
ACo induced profound changes in diltiazem pharmacokinetic behaviour. In addition, our results suggested an increased sensitivity to diltiazem blood pressure lowering effect in experimental renovascular hypertension with high-renin levels.
Triclisia sacleuxii(Pierre) Diels (Menispermaceae), a potential source of acetylcholinesterase inhibitors
Authors: Murebwayire Sengabo , Ingkaninan Kornkanok , Changwijit Kanokwan , Frédérich Michel , Duez Pierre 
Published: June 2009

AbstractObjectivesTo search for compounds possibly useful for the treatment of Alzheimer's disease.MethodsAlkaloid fractions from the roots, stems and leaves of Triclisia sacleuxii (Menispermaceae) and pure bisbenzylisoquinoline alkaloids isolated from the roots (phaeanthine, N-methylapateline, 1,2-dehydroapateline and gasabiimine) were assessed for acetylcholin-esterase inhibitory activity.Key findingsAll extracts and compounds tested inhibited acetylcholinesterase to varying degrees; the leaf tertiary alkaloid fractions and the root quaternary alkaloid fractions exhibited the strongest inhibitory potential (90% at 0.1 mg/ml). The leaf tertiary alkaloid fraction was selected for further analysis (the quaternary alkaloids, which are too polar for absorption and brain distribution, were presumed to be clinically uninteresting). TLC bioautography using Ellman's reagent allowed the detection of acetylcholinesterase inhibitors and the isolation of the major active constituent, which was identified as lindoldhamine, a one-bridged bisbenzylisoquinoline alkaloid. Lindoldhamine displayed high acetylcholinesterase inhibitory activity with a 50% inhibition concentration in the micromolar range.ConclusionsAll T. sacleuxii alkaloid fractions tested exhibited anti-acetylcholinesterase activity; isolated bisbenzylisoquinoline alkaloids showed weak-to-high inhibition depending on their structural features. Structure modification could provide interesting derivatives with enhanced anti-acetylcholinesterase activity.
Effect of natsudaidain isolated fromCitrusplants on TNF-α and cyclooxygenase-2 expression in RBL-2H3 cells
Authors: Matsui Takuya , Ito Chihiro , Itoigawa Masataka , Okada Tadashi , Furukawa Hiroshi 
Published: June 2009

AbstractObjectivesFlavonoids inhibit the activity of chemical mediators released from mast cells. Our aim was to investigate the effects of natsudaidain, a polymethoxyflavone isolated from Citrus plants, on mast cells.MethodsWe investigated the inhibitory effects of natsudaidain, which is a polymethoxy-flavone isolated from Citrus plants, on histamine release, tumour necrosis factor-α production and cyclooxygenase-2 expression in Ca ionophore-stimulated rat basophilic leukemia cells (A23187-stimulated RBL-2H3 cells) by spectrofluorometric, ELISA and immunoblotting methods.Key findingsThe percent of histamine release from A23187-stimulated RBL-2H3 cells pretreated with natsudaidain at 5, 25 and 50 μM was not changed as compared with non-treated A23187-stimulated cells. At 100 and 200 μM, natsudaidain pretreatment resulted in slightly reduced histamine release (% histamine release, 89.8 ± 3.5% and 71.5 ± 5.6% at 100 and 200 μM). Thus, natsudaidain hardly affects histamine release from RBL-2H3 cells, except at high concentrations. On the other hand, natsudaidain dose-dependently inhibited tumour necrosis factor-α protein and mRNA levels in A23187-stimulated RBL-2H3 cells; a concentration of 6.8 μM was required for a 50% reduction. In addition, all concentrations of this compound that we tested also inhibited cyclooxygenase-2 protein expression. The mRNA levels of cyclooxygenase-2 in A23187-stimulated RBL-2H3 cells treated with natsudaidain were also markedly decreased. The phosphorylated-p38 MAPK protein levels in A23187-stimulated RBL-2H3 cells treated with natsudaidain were lower than in the non-treated cells.ConclusionsThese findings suggest that natsudaidain inhibits tumour necrosis factor-α and cyclooxygenase-2 production by suppressing p38 MAPK phosphorylation but not p65 NFKB phosphorylation, and that natsudaidain might alleviate inflammatory diseases.
Inhibitory effect of quercetin on rat trachea contractility in vitro
Authors: Capasso Raffaele , Aviello Gabriella , Romano Barbara , Atorino Giuseppina , Pagano Ester , Borrelli Francesca 
Published: June 2009

Abstract

Objectives
The effect of quercetin, a naturally occurring flavonoid traditionally used to treat airway diseases such as bronchial asthma, on the contractile response elicited by electrical field stimulation or carbachol in rat isolated trachea was investigated.

Methods
Isolated tracheal tissue was subjected to contractions by an electrical field stimulation of 5 Hz for 30 s, 400 mA, and the responses in the presence of cumulative concentrations of quercetin (10−6−3 × 10−4 M) were observed. The effect of quercetin was also evaluated after administration of phentolamine plus propranolol (to block α- and β-adrenergic receptors), NG-nitro-L-arginine methyl ester (to block nitric oxide synthesis), capsaicin (to desensitise sensory C fibres), α-chymotrypsin (a proteolytic enzyme that rapidly degrades vasoactive intestinal peptide), SR140333 and SR48968 (tackykinin NK1 and NK2 receptor antagonists, respectively).

Key findings
Quercetin produced a concentration-dependent inhibition of contractions induced by both carbachol and electrical field stimulation. However, quercetin was more active in inhibiting the contractions produced by electrical field stimulation than those induced by carbachol, suggesting a presynaptic site of action (in addition to a postsynaptic effect, as revealed by the inhibitory action of quercetin on carbachol-induced contractions). The inhibitory effect of quercetin on contractions induced by electrical field stimulation was unaffected by phentolamine plus propranolol, SR 140333 and SR 48968, capsaicin treatment or by the proteolytic enzyme α-chymotrypsin. In contrast, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester significantly reduced the inhibitory effect of quercetin on contractions induced by electrical field stimulation.

Conclusions
Quercetin inhibits rat tracheal contractility through a presynaptic (involving nitric oxide) and a postsynaptic site of action.