bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships among changes of serum leptin concentration, leptin mRNA expression in white adipose tissue (WAT), and WAT fat-cell size in female Japanese black bears (Ursus thibetanus japonicus)
Authors: Nakamura S. , Okano T. , Shibata H. , Saito M. , Komatsu T. , Asano M. , Sugiyama M. , Tsubota T. , Suzuki M.
Published: September 2008

As a first step to study the relationship between fat accumulation and reproductive success in Japanese black bears ( Ursus thibetanus japonicus Schlegel, 1857) with the focus on leptin, we determined leptin cDNA sequences in the bears. Next, we studied the possibility of white adipose tissue (WAT) as a leptin secretion source by observing the changes of leptin mRNA expression in WAT by semiquantitative real-time reverse transcript – polymerase chain reaction, the index of WAT fat-cell size, and serum leptin concentration in pregnant bears. Then, based on our results, we discussed roles of leptin in those bears. The amino acid sequences of leptin from the bears were highly identical to that of other carnivores. The expression of leptin mRNA in WAT was detected from September to January, with a tendency to increase in late November and January; the relationship between changes in the index of WAT fat-cell size and those in serum leptin concentration was high (r = 0.55, P < 0.01), with an increase in both in mid-November. These results suggested that leptin was mainly secreted from WAT in bears and that serum leptin concentrations might reflect their nutritional condition. Moreover, leptin might serve as an indicator of their fat mass, which would affect their survival during hibernation and their reproductive success.
Interactions between seabirds and endemic deer mouse populations on Santa Barbara Island, California
Authors: Millus Sarah A. , Stapp Paul
Published: September 2008

Nesting seabirds alter habitat and food availability for insular rodent populations; in turn, rodents can reduce seabird nest success by consuming eggs and chicks. Predation by deer mice ( Peromyscus maniculatus elusus Nelson and Goldman, 1931) is considered a significant threat to reproductive success of Xantus’ Murrelet ( Synthliboramphus hypoleucus (Xantus de Vesey, 1860)), a small, burrow-nesting seabird that breeds off the coast of southern California and Baja California. We live-trapped mice in and out of seabird colonies on Santa Barbara Island, California, USA, to determine the effects of seabirds on mouse populations. We used stable isotope analysis to determine if mice fed on murrelet eggs and chicks. Mouse densities increased significantly on all sites from winter to summer, but there were no significant differences in densities between areas with and without seabirds. Although mice were abundant in murrelet colonies, mouse populations appeared to be affected more by habitat factors than seabird populations: areas with greater rock cover supported higher densities, fewer juveniles, and larger adults in winter and spring, whereas grassland sites had high densities and more reproductive adults in summer. We found no evidence of consumption of murrelet chicks or eggs, suggesting that eggs are not a major component of the diet of most mice. However, mice can still have a significant impact on local murrelet productivity because few eggs are laid each season relative to the high numbers of mice present.
Adipose fin condition and flow regime in catfish
Authors: Temple N. F. , Reimchen T. E.
Published: September 2008

Based on recent evidence suggesting a hydrodynamic function of the small adipose fin in salmonids to turbulent flow conditions, we test for associations between presence and absence of the adipose fin and flow regime in Siluriformes, one of the largest freshwater groups of fish with variable expression of this fin. Among 1906 species from multiple families, those living in habitats with flow (streams or rivers) exhibited an adipose fin significantly more frequently than expected relative to no-flow habitats (lakes, marine, parasitic). These trends were robust and occurred on different continents and among multiple paired comparisons within sister groups. Exceptions to these trends generally had atypical body shape or occupied divergent habitat types. These results are concordant with the hydrodynamic function of this small fin.
ELECTROMAGNETIC FIELD QUANTIZATION IN AN ANISOTROPIC AND INHOMOGENEOUS MAGNETODIELECTRIC MEDIUM
Authors: AMOOSHAHI M. , KHEIRANDISH F.
Published: September 2008

The electromagnetic field in an anisotropic and inhomogeneous magnetodielectric medium is quantized by modelling the medium with two independent quantum fields. Maxwell and constitutive equations of the medium are obtained using a minimal coupling scheme. The electric and magnetic susceptibility tensors of the medium are calculated. Finally the efficiency of the approach is elucidated by some examples.
A COMMENTARY ON RUPPEINER METRICS FOR BLACK HOLES
Authors: MEDVED A. J. M.
Published: September 2008

There has been some recent controversy regarding the Ruppeiner metrics that are induced by Reissner–Nordström (and Reissner–Nordström-like) black holes. Most infamously, why does this family of metrics turn out to be flat, how is this outcome to be physically understood, and can/should the formalism be suitably modified to induce curvature? In this paper, we provide a novel interpretation of this debate. For the sake of maximal analytic clarity and tractability, some supporting calculations are carried out for the relatively simple model of a rotating BTZ black hole.
INVESTIGATION ON LIGHT DARK MATTER
Authors: BERNABEI R. , BELLI P. , CAPPELLA F. , CERULLI R. , DAI C. J. , HE H. L. , INCICCHITTI A. , KUANG H. H. , MA J. M. , MA X. H. , MONTECCHIA F. , NOZZOLI F. , PROSPERI D. , SHENG X. D. , YE Z. P. , WANG R. G. , ZHANG Y. J.
Published: September 2008

Some extensions of the Standard Model provide Dark Matter candidate particles with sub-GeV mass. These Light Dark Matter particles have been considered for example in Warm Dark Matter scenarios (e.g. the keV scale sterile neutrino, axino or gravitino). Moreover, MeV scale DM candidates have been proposed in supersymmetric models and as source of the 511 keV line from the Galactic center. In this paper the possibility of direct detection of a Light Dark Matter candidate is investigated considering the inelastic scattering processes on the electron or on the nucleus targets. Some theoretical arguments are developed and related phenomenological aspects are discussed. Allowed volumes and regions for the characteristic phenomenological parameters of the considered scenarios are derived from the DAMA/NaI annual modulation data.
DARK MATTER AND LHC: WHAT IS THE CONNECTION?
Authors: KANE GORDON , WATSON SCOTT
Published: September 2008

We review what can (and cannot) be learned if dark matter is detected in one or more experiments, emphasizing the importance of combining LHC data with direct, astrophysical and cosmological probes of dark matter. We briefly review the conventional picture of a thermally produced WIMP relic density and its connection with theories of electroweak symmetry breaking. We then discuss both experimental and theoretical reasons why one might generically expect this picture to fail. If this is the case, we argue that a combined effort bringing together all types of data — combined with explicitly constructed theoretical models — will be the only way to achieve a complete understanding of the dark matter in our universe and become confident that any candidate actually provides the relic density.
Altered response to metabolic challenges in mice with genetically targeted deletions of galanin-like peptide
Authors: Dungan Lemko Heather M. , Clifton Donald K. , Steiner Robert A. , Fraley Gregory S.
Published: September 2008

Galanin-like peptide (GALP) is expressed in the arcuate nucleus and is implicated in the neuroendocrine regulation of metabolism and reproduction. To investigate the physiological significance of GALP, we generated and characterized a strain of mice with a genetically targeted deletion in the GALP gene [GALP knockout (KO) mice]. We report that GALP KO mice have a subtle, but notable, metabolic phenotype that becomes apparent during adaptation to changes in nutrition. GALP KO mice are indistinguishable from wild-type (WT) controls in virtually all aspects of growth, sexual development, body weight, food and water consumption, and motor behaviors, when they are allowed unlimited access to standard rodent chow. However, GALP KO mice have an altered response to changes in diet. 1) Male GALP KO mice consumed less food during refeeding after a fast than WT controls ( P < 0.01). 2) GALP KO mice of both sexes gained less weight on a high-fat diet than WT controls ( P < 0.01), despite both genotypes having consumed equal amounts of food. We conclude that although GALP signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, GALP may play a role in readjusting energy balance under changing nutritional circumstances.
Role of cyclooxygenase isoforms in prostacyclin biosynthesis and murine prehepatic portal hypertension
Authors: Skill N. J. , Theodorakis N. G. , Wang Y. N. , Wu J. M. , Redmond E. M. , Sitzmann J. V.
Published: September 2008

Portal hypertension (PHT) is a common complication of liver cirrhosis and significantly increases morbidity and mortality. Abrogation of PHT using NSAIDs has demonstrated that prostacyclin (PGI2), a direct downstream metabolic product of cyclooxygenase (COX) activity, is an important mediator in the development of experimental and clinical PHT. However, the role of COX isoforms in PGI2biosynthesis and PHT is not fully understood. Prehepatic PHT was induced by portal vein ligation (PVL) in wild-type, COX-1−/−, and COX-2−/−mice treated with and without COX-2 (NS398) or COX-1 (SC560) inhibitors. Hemodynamic measurements and PGI2biosynthesis were determined 1–7 days after PVL or sham surgery. Gene deletion or pharmacological inhibition of COX-1 or COX-2 attenuated but did not ameliorate PGI2biosynthesis after PVL or prevent PHT. In contrast, treatment of COX-1−/−mice with NS398 or COX-2−/−mice with SC560 restricted PGI2biosynthesis and abrogated the development of PHT following PVL. In conclusion, either COX-1 or COX-2 can mediate elevated PGI2biosynthesis and the development of experimental prehepatic PHT. Consequently, PGI2rather then COX-selective drugs are indicated in the treatment of PHT. Identification of additional target sites downstream of COX may benefit the >27,000 patients whom die annually from cirrhosis in the United States alone.
Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent
Authors: Tetri Laura H. , Basaranoglu Metin , Brunt Elizabeth M. , Yerian Lisa M. , Neuschwander-Tetri Brent A.
Published: September 2008

The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1–16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-α and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.
Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors
Authors: Ravid Z. , Bendayan M. , Delvin E. , Sane A. T. , Elchebly M. , Lafond J. , Lambert M. , Mailhot G. , Levy E.
Published: September 2008

Growing evidence suggests that the small intestine may contribute to excessive postprandial lipemia, which is highly prevalent in insulin-resistant/Type 2 diabetic individuals and substantially increases the risk of cardiovascular disease. The aim of the present study was to determine the role of high glucose levels on intestinal cholesterol absorption, cholesterol transporter expression, enzymes controlling cholesterol homeostasis, and the status of transcription factors. To this end, we employed highly differentiated and polarized cells (20 days of culture), plated on permeable polycarbonate filters. In the presence of [14C]cholesterol, glucose at 25 mM stimulated cholesterol uptake compared with Caco-2/15 cells supplemented with 5 mM glucose ( P < 0.04). Because combination of 5 mM glucose with 20 mM of the structurally related mannitol or sorbitol did not change cholesterol uptake, we conclude that extracellular glucose concentration is uniquely involved in the regulation of intestinal cholesterol transport. The high concentration of glucose enhanced the protein expression of the critical cholesterol transporter NPC1L1 and that of CD36 ( P < 0.02) and concomitantly decreased SR-BI protein mass ( P < 0.02). No significant changes were observed in the protein expression of ABCA1 and ABCG8, which act as efflux pumps favoring cholesterol export out of absorptive cells. At the same time, 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity was decreased ( P < 0.007), whereas ACAT activity remained unchanged. Finally, increases were noted in the transcription factors LXR-α, LXR-β, PPAR-β, and PPAR-γ along with a drop in the protein expression of SREBP-2. Collectively, our data indicate that glucose at high concentrations may regulate intestinal cholesterol transport and metabolism in Caco-2/15 cells, thus suggesting a potential influence on the cholesterol absorption process in Type 2 diabetes.
The proteome of rodent mesenteric lymph
Authors: Mittal Anubhav , Middleditch Martin , Ruggiero Katya , Buchanan Christina M. , Jullig Mia , Loveday Benjamin , Cooper Garth J. S. , Windsor John. A. , Phillips Anthony R. J.
Published: September 2008

Mesenteric lymph contributes to normal homeostasis and has an emerging role in the pathogenesis of multiple organ dysfunction syndrome. The aim of this study was to define the proteome of normal rodent mesenteric lymph in the fasted and fed states. Eight male Wistar rats fed a standard rodent diet were randomized to two groups. Group 1 (fasted, n = 4) were fasted for 24 h before anesthetized collection of mesenteric lymph. Group 2 (fed, n = 4) were allowed ad libitum access to food before lymph collection. Mesenteric lymph was subjected to proteomic analysis using iTRAQ and liquid chromatography-tandem mass spectrometry (LC-MS/MS). One hundred fifty proteins, including 26 hypothetical proteins, were identified in this study. All proteins were identified in lymph from both the fasted and fed states. The relative distribution profiles of protein functional classes in the mesenteric lymph differed significantly from that reported for plasma. The most abundant classes identified in lymph were protease inhibitors (16%) and proteins related to innate immunity (12%). In conclusion, this study provides the first detailed description of the normal mesenteric lymph proteome in the fed and fasted states using iTRAQ and LC-MS/MS.
Characteristics of intracellular Ca2+ cycling in intact rat heart: a comparison of sex differences
Authors: Wasserstrom J. Andrew , Kapur Sunil , Jones Sabrina , Faruque Tania , Sharma Rohan , Kelly James E. , Pappas Amanda , Ho Wilson , Kadish Alan H. , Aistrup Gary L.
Published: September 2008

Males and females show distinct differences in action potential waveform, ion channel expression patterns, and ECG characteristics. However, it is not known how sex-based differences in Ca2+ cycling might contribute to these differences in electrophysiological activity. The goal of this study was to investigate the differences in cellular Ca2+ transients in males and females and to examine how these might contribute to electrophysiological function. Ca2+ transients were measured in individual myocytes within microscopic regions of the fluo-4 AM-loaded left ventricular epicardium of intact rat heart of both sexes (3 to 5 mo old). Pacing protocols were used to measure transient characteristics at a basic cycle length of 500 ms and during 10-s trains of rapid pacing delivered to the left ventricular apex. Ca2+ transients were smaller in magnitude and longer in duration in females than in males. More importantly, the variability in Ca2+ transient characteristics between myocytes in a microscopic recording site (heterogeneity index) was greater for females than males for characteristics related to transient duration. The rate sensitivity of Ca2+ alternans development in individual myocytes was greater in females than in males, but there was also a greater heterogeneity in cellular responses to the rate dependence of alternans development in females. The longer Ca2+ transients in females were also associated with slower restitution, which was likely to be responsible for the development of Ca2+ and repolarization alternans at slower heart rates. These results demonstrate that there are distinct differences in cellular Ca2+ cycling in male and female rat hearts. Not only is there slower reuptake of Ca2+ in female rats, but there is greater local variability in Ca2+ cycling at the microscopic level. These sex-based differences in Ca2+ cycling could contribute to differences in ECG morphology and in arrhythmia sensitivity in males and females.
Low-dose estrogen therapy does not change postexercise hypotension, sympathetic nerve activity reduction, and vasodilation in healthy postmenopausal women
Authors: Oneda Bruna , Forjaz Claudia L. M. , Bernardo Fernanda R. , Araújo Tatiana G. , Gusmão Josiane L. , Labes Eliana , Abrahão Sandra B. , Mion Decio , Fonseca Angela M. , Tinucci Tais
Published: September 2008

The aim of this study was to determine whether estrogen therapy enhances postexercise muscle sympathetic nerve activity (MSNA) decrease and vasodilation, resulting in a greater postexercise hypotension. Eighteen postmenopausal women received oral estrogen therapy (ET; n = 9, 1 mg/day) or placebo ( n = 9) for 6 mo. They then participated in one 45-min exercise session (cycle ergometer at 50% of oxygen uptake peak) and one 45-min control session (seated rest) in random order. Blood pressure (BP, oscillometry), heart rate (HR), MSNA (microneurography), forearm blood flow (FBF, plethysmography), and forearm vascular resistance (FVR) were measured 60 min later. FVR was calculated. Data were analyzed using a two-way ANOVA. Although postexercise physiological responses were unaltered, HR was significantly lower in the ET group than in the placebo group (59 ± 2 vs. 71 ± 2 beats/min, P < 0.01). In both groups, exercise produced significant decreases in systolic BP (145 ± 3 vs. 154 ± 3 mmHg, P = 0.01), diastolic BP (71 ± 3 vs. 75 ± 2 mmHg, P = 0.04), mean BP (89 ± 2 vs. 93 ± 2 mmHg, P = 0.02), MSNA (29 ± 2 vs. 35 ± 1 bursts/min, P < 0.01), and FVR (33 ± 4 vs. 55 ± 10 units, P = 0.01), whereas it increased FBF (2.7 ± 0.4 vs. 1.6 ± 0.2 ml·min−1·100 ml−1, P = 0.02) and did not change HR (64 ± 2 vs. 65 ± 2 beats/min, P = 0.3). Although ET did not change postexercise BP, HR, MSNA, FBF, or FVR responses, it reduced absolute HR values at baseline and after exercise.
Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage
Authors: Mitchell Gary F.
Published: September 2008

Over the past decade, numerous studies have shown that increased aortic stiffness is associated with major cardiovascular disease end points, including heart disease, stroke, and kidney disease. Cardiac abnormalities and enhanced atherogenesis in the setting of increased pulsatile load on heart and arteries have been well described. However, recent studies have shown a further association between excessive pressure pulsatility and a number of afflictions of aging that share a predominant microvascular etiology, including many forms of kidney disease and cognitive impairment. In these disorders, microvascular remodeling and impaired regulation of local blood flow, which are related to large artery stiffness and pressure pulsatility, are associated with evidence of diffuse microscopic tissue damage. This brief review will summarize age-related changes in aortic and peripheral vascular function and will discuss potential mechanisms leading from changes in properties of large arteries to excessive pressure pulsatility, abnormal microvascular structure and function, and end-organ dysfunction and damage.
Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure
Authors: Shifren Adrian , Durmowicz Anthony G. , Knutsen Russell H. , Faury Gilles , Mecham Robert P.
Published: September 2008

Elastin is a major structural component of large elastic arteries and a principal determinant of arterial biomechanical properties. Elastin loss-of-function mutations in humans have been linked to the autosomal-dominant disease supravalvular aortic stenosis, which is characterized by stenotic lesions in both the systemic and pulmonary circulations. To better understand how elastin insufficiency influences the pulmonary circulation, we evaluated pulmonary cardiovascular physiology in a unique set of transgenic and knockout mice with graded vascular elastin dosage (range 45–120% of wild type). The central pulmonary arteries of elastin-insufficient mice had smaller internal diameters ( P < 0.0001), thinner walls ( P = 0.002), and increased opening angles ( P = 0.002) compared with wild-type controls. Pulmonary circulatory pressures, measured by right ventricular catheterization, were significantly elevated in elastin-insufficient mice ( P < 0.0001) and showed an inverse correlation with elastin level. Although elastin-insufficient animals exhibited mild to moderate right ventricular hypertrophy ( P = 0.0001) and intrapulmonary vascular remodeling, the changes were less than expected, given the high right ventricular pressures, and were attenuated compared with those seen in hypoxia-induced models of pulmonary arterial hypertension. The absence of extensive pathological cardiac remodeling at the high pressures in these animals suggests a developmental adaptation designed to maintain right-sided cardiac output in a vascular system with altered elastin content.
The role of p66Shcdeletion in age-associated arterial dysfunction and disease states
Authors: Camici Giovanni G. , Cosentino Francesco , Tanner Felix C. , Lüscher Thomas F.
Published: September 2008

Accumulation of oxidative stress with age is hypothesized to be the primary causative mediator of age-associated diseases. Among different tissues, aging vessels are known to accumulate oxidative damage and undergo functional impairment. Oxidative stress affects the availability and/or balance of key regulators of vascular homeostasis and favors the development of cardiovascular disease. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial enzyme p66Shcis an adaptor protein and plays an important role as a redox enzyme implicated in mitochondrial eactive oxygen species generation and translation of oxidative signals into apoptosis. Mice lacking p66Shc−/−gene display reduced production of intracellular oxidants and a 30% prolonged life span. For this reasons, a series of studies conceived to elucidate the function of p66Shcand its possible implication in age-associated cardiovascular diseases have been carried out. Indeed, p66Shc−/−mice have been shown to be protected from age-dependent endothelial dysfunction as well as age-related risk factors such as diabetes and hypercholesterolemia. This review focuses on delineating the role of the p66Shcadaptor protein and its potential implication in the pathophysiology of aging and age-related cardiovascular disease.
Hypoglossal premotor neurons of the intermediate medullary reticular region express cholinergic markers
Authors: Volgin Denys V. , Rukhadze Irma , Kubin Leszek
Published: September 2008

The inspiratory drive to hypoglossal (XII) motoneurons originates in the caudal medullary intermediate reticular (IRt) region. This drive is mainly glutamatergic, but little is known about the neurochemical features of IRt XII premotor neurons. Prompted by the evidence that XII motoneuronal activity is controlled by both muscarinic (M) and nicotinic cholinergic inputs and that the IRt region contains cells that express choline acetyltransferase (ChAT), a marker of cholinergic neurons, we investigated whether some IRt XII premotor neurons are cholinergic. In seven rats, we applied single-cell reverse transcription-polymerase chain reaction to acutely dissociated IRt neurons retrogradely labeled from the XII nucleus. We found that over half (21/37) of such neurons expressed mRNA for ChAT and one-third (13/37) also had M2 receptor mRNA. In contrast, among the IRt neurons not retrogradely labeled, only 4 of 29 expressed ChAT mRNA ( P < 0.0008) and only 3 of 29 expressed M2 receptor mRNA ( P < 0.04). The distributions of other cholinergic receptor mRNAs (M1, M3, M4, M5, and nicotinic α4-subunit) did not differ between IRt XII premotor neurons and unlabeled IRt neurons. In an additional three rats with retrograde tracers injected into the XII nucleus and ChAT immunohistochemistry, 5–11% of IRt XII premotor neurons located at, and caudal to, the area postrema were ChAT positive, and 27–48% of ChAT-positive caudal IRt neurons were retrogradely labeled from the XII nucleus. Thus the pre- and postsynaptic cholinergic effects previously described in XII motoneurons may originate, at least in part, in medullary IRt neurons.
Differential Modulation of Leukotriene B4 Synthesis and Degradation in Human Bronchoalveolar Lavage Cells by Lipopolysaccharide and Tobacco Smoke
Authors: Mao Jenny T. , Tashkin Donald P. , Tsu I-Hsien , Serio Kenneth J.
Published: September 2008

Leukotrienes have been implicated to play a prominent inductive role in carcinogenesis. We previously reported that bronchoalveolar lavage (BAL) cells from smokers manifested higher levels of leukotriene B4 (LTB4) production than ex-smokers. This study aims to elucidate the underlying mechanism(s). BAL cells from current and former smokers were exposed to lipopolysaccharide (LPS) for up to 7 days. LPS induced the release of LTB4 from BAL cells and down-regulated 5-lipoxygenase (5-LOX) mRNA expression in a dose-dependent manner, followed by a decrease in 5-LOX protein production and normalization of LTB4 levels. Exogenous LTB4 inhibited LPS-induced 5-LOX activity and accentuated the down-regulation of 5-LOX mRNA, whereas suppression of 5-LOX abrogated the LPS-induced changes, suggesting a negative feedback mechanism. LPS concomitantly induced expression and activity of the LTB4 metabolizing enzyme LTB4 ω-hydroxylase (LTB4OH) in ex-smokers' BAL cells, but not in smokers' BAL cells. In vitro smoke exposure of ex-smokers' BAL cells also abrogated the LPS-induced up-regulation of LTB4OH mRNA expression. Furthermore, ex-smokers' BAL cells expressed significantly higher LTB4OH mRNA levels than smokers' BAL cells. Such differential modulation of LTB4 synthesis and degradation by LPS in the setting of tobacco smoke exposure suggests that mechanisms responsible for sustained elevation of LTB4 levels in the lung microenvironment may contribute to the pathogenesis of tobacco-related respiratory diseases such as lung cancer. By regulating the balance of LTB4 in the lung, LTB4OH may function as a suppressor of lung carcinogenesis.
(−)-Epigallocatechin Gallate Suppresses Azoxymethane-Induced Colonic Premalignant Lesions in Male C57BL/KsJ-db/db Mice
Authors: Shimizu Masahito , Shirakami Yohei , Sakai Hiroyasu , Adachi Seiji , Hata Kazuya , Hirose Yoshinobu , Tsurumi Hisashi , Tanaka Takuji , Moriwaki Hisataka
Published: September 2008

Obesity and diabetes mellitus are risk factors for colon cancer. The activation of the insulin-like growth factor (IGF)/IGF-IR axis plays a critical role in this carcinogenesis. (−)-Epigallocatechin gallate (EGCG), the major constituent of green tea, seems to have both antiobesity and antidiabetic effects. This study examined the effects of EGCG on the development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes mellitus. Male db/db mice were given four weekly s.c. injections of azoxymethane (15 mg/kg body weight) and then they received drinking water containing 0.01% or 0.1% EGCG for 7 weeks. At sacrifice, drinking water with EGCG caused a significant decrease in the number of total aberrant crypt foci, large aberrant crypt foci, and β-catenin accumulated crypts in these mice, all of which are premalignant lesions of the colon. The colonic mucosa of db/db mice expressed high levels of the IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3β, β-catenin, cyclooxygenase-2, and cyclin D1 proteins, and EGCG in drinking water caused a marked decrease in the expression of these proteins. Treating these mice with EGCG also caused an increase in the serum level of IGFBP-3 while conversely decreasing the serum levels of IGF-I, insulin, triglyceride, cholesterol, and leptin. EGCG overcomes the activation of the IGF/IGF-IR axis, thereby inhibiting the development of colonic premalignant lesions in an obesity-related colon cancer model, which was also associated with hyperlipidemia, hyperinsulinemia, and hyperleptinemia. EGCG may be, therefore, useful in the chemoprevention or treatment of obesity-related colorectal cancer.
NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase Regulates Levels of Bioactive Lipids in Non–Small Cell Lung Cancer
Authors: Hughes Duncan , Otani Taisuke , Yang Peiying , Newman Robert A. , Yantiss Rhonda K. , Altorki Nasser K. , Port Jeff L. , Yan Min , Markowitz Sanford D. , Mazumdar Madhu , Tai Hsin-Hsiung , Subbaramaiah Kotha , Dannenberg Andrew J.
Published: September 2008

Elevated levels of procarcinogenic prostaglandins (PG) are found in a variety of human malignancies including non–small cell lung cancer (NSCLC). Overexpression of cyclooxygenase-2 and microsomal prostaglandin synthase 1 occurs in tumors and contributes to increased PG synthesis. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for metabolic inactivation of PGs, is down-regulated in various malignancies. The main objective of this study was to elucidate the effect of loss of 15-PGDH on levels of bioactive lipids in NSCLC. We found that levels of cyclooxygenase-2 and microsomal prostaglandin synthase 1 were commonly increased whereas the amount of 15-PGDH was frequently decreased in NSCLC compared with adjacent normal lung. Reduced expression of 15-PGDH occurred in tumor cells and was paralleled by decreased 15-PGDH activity in tumors. Amounts of PGE1, PGE2, and PGF2α, known substrates of 15-PGDH, were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE2, a catabolic product of PGE2, were markedly reduced in NSCLC compared with normal lung. Complementary in vitro and in vivo experiments were done to determine whether these changes in PG levels were a consequence of down-regulation of 15-PGDH in NSCLC. Similar to NSCLC, amounts of PGE1, PGE2, and PGF2α were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE2 were decreased in the lungs of 15-PGDH knockout mice compared with wild-type mice or when 15-PGDH was silenced in A549 lung cancer cells. Collectively, these data indicate that 15-PGDH is commonly down-regulated in NSCLC, an effect that contributes to the accumulation of multiple bioactive lipids in NSCLC.
An Expanded Risk Prediction Model for Lung Cancer
Authors: Spitz Margaret R. , Etzel Carol J. , Dong Qiong , Amos Christopher I. , Wei Qingyi , Wu Xifeng , Hong Waun Ki
Published: September 2008

Risk prediction models are useful in clinical decision making. We have published an internally validated prediction tool for lung cancer based on easily obtainable epidemiologic and clinical data. Because the precision of the model was modest, we now estimate the improvement obtained by adding two markers of DNA repair capacity.

Assay data (host-cell reactivation and mutagen sensitivity) were available for 725 White lung cancer cases and 615 controls, all former or current smokers, a subset of cases and controls from the previous analysis. Multivariable models were constructed from the original variables with addition of the biomarkers separately and together. Pairwise comparisons of the area under the receiver operating characteristic curves (AUC) and 3-fold cross-validations were done.

For former smokers, the AUC and 95% confidence intervals were 0.67 (0.63–0.71) for the baseline model and 0.70 (0.66–0.74) for the expanded model. For current smokers, the comparable AUC values were 0.68 (0.64–0.72) and 0.73 (0.69–0.77). For both groups, the expanded models were statistically significantly better than the baseline models (P = 0.006 and P = 0.0048, respectively), although the increases in the concordance statistics were modest. We also recomputed 1-year absolute risks of lung cancer as described previously for two different risk profiles and showed that individuals who exhibited poor repair capacity or heightened mutagen sensitivity had increased absolute risks of lung cancer.

Addition of biomarker assays improved the sensitivity of the expanded models.
Development and Validation of a Lung Cancer Risk Prediction Model for African-Americans
Authors: Etzel Carol J. , Kachroo Sumesh , Liu Mei , D'Amelio Anthony , Dong Qiong , Cote Michele L. , Wenzlaff Angela S. , Hong Waun Ki , Greisinger Anthony J. , Schwartz Ann G. , Spitz Margaret R.
Published: September 2008

Because existing risk prediction models for lung cancer were developed in white populations, they may not be appropriate for predicting risk among African-Americans. Therefore, a need exists to construct and validate a risk prediction model for lung cancer that is specific to African-Americans. We analyzed data from 491 African-Americans with lung cancer and 497 matched African-American controls to identify specific risks and incorporate them into a multivariable risk model for lung cancer and estimate the 5-year absolute risk of lung cancer. We performed internal and external validations of the risk model using data on additional cases and controls from the same ongoing multiracial/ethnic lung cancer case-control study from which the model-building data were obtained as well as data from two different lung cancer studies in metropolitan Detroit, respectively. We also compared our African-American model with our previously developed risk prediction model for whites. The final risk model included smoking-related variables [smoking status, pack-years smoked, age at smoking cessation (former smokers), and number of years since smoking cessation (former smokers)], self-reported physician diagnoses of chronic obstructive pulmonary disease or hay fever, and exposures to asbestos or wood dusts. Our risk prediction model for African-Americans exhibited good discrimination [75% (95% confidence interval, 0.67–0.82)] for our internal data and moderate discrimination [63% (95% confidence interval, 0.57–0.69)] for the external data group, which is an improvement over the Spitz model for white subjects. Existing lung cancer prediction models may not be appropriate for predicting risk for African-Americans because (a) they were developed using white populations, (b) level of risk is different for risk factors that African-American share with whites, and (c) unique group-specific risk factors exist for African-Americans. This study developed and validated a risk prediction model for lung cancer that is specific to African-Americans and thus more precise in predicting their risks. These findings highlight the importance of conducting further ethnic-specific analyses of disease risk.
Transcriptional Analysis of Estrogen Effects in Human Embryonic Neurons and Glial Cells
Authors: Csöregh Linda , Andersson Eva , Fried Gabriel
Published: September 2008

Estrogen exerts many effects in the central nervous system which extend beyond regulating sexual behavior and gonadal function in reproduction. It has been shown that estrogen has a range of both neuroprotective and neuromodulatory effects, but little is known about the molecular mechanisms underlying estrogen actions in the human brain. We therefore analyzed the transcriptional response to estrogen by microarray technology in primary cell cultures of neurons and glial cells derived from 8- to 12-week human fetal brain tissue. Estrogen treatment of the cell cultures during a 7-day culture period revealed a number of genes with significantly altered expression. Fourteen genes were selected for further analysis by quantitative real-time PCR in order to confirm the gene expression changes observed by the microarray analysis. Six genes were identified with important roles in the nervous system that have not been described before to be estrogen-regulated. Three genes, IGFBP7, Transgelin and Cyr61, were further analyzed by immunostaining, and were found to be expressed in both primary neurons and glial cells. Our results indicate that estrogen may influence developing human neurons and glia through regulating expression of genes that are important for the development of the nervous system.
Estrogen-Stimulated Endothelial Repair Requires Osteopontin
Authors: Lam Shang Leen Laetitia , Filipe Cédric , Billon Audrey , Garmy-Susini Barbara , Jalvy Sandra , Robbesyn Fanny , Daret Danièle , Allières Cécile , Rittling Susan R. , Werner Nikos , Nickenig Georg , Deutsch Urban , Duplàa Cécile , Dufourcq Pascale , Lenfant Françoise , Desgranges Claude , Arnal Jean-François , Gadeau Alain-Pierre
Published: September 2008

Objective—

Estradiol (E
2
) is known to accelerate reendothelialization and thus prevent intimal thickening and in-stent restenosis after angioplasty. Transplantation experiments with ERα
−/−
mice have previously shown that E
2
acts through local and bone marrow cell compartments to enhance endothelial healing. However, the downstream mechanisms induced by E
2
to mediate endothelial repair are still poorly understood.

Methods and Results—

We show here that after endovascular carotid artery injury, E
2
-enhanced endothelial repair is lost in osteopontin-deficient mice (OPN
−/−
). Transplantation of OPN
−/−
bone marrow into wild-type lethally irradiated mice, and vice versa, suggested that osteopontin plays a crucial role in both the local and the bone marrow actions of E
2
. In the vascular compartment, using transgenic mice expressing doxycyclin regulatable-osteopontin, we show that endothelial cell specific osteopontin overexpression mimics E
2
-enhanced endothelial cell migration and proliferation in the regenerating endothelium. In the bone marrow cell compartment, we demonstrate that E
2
enhances bone marrow–derived mononuclear cell adhesion to regenerating endothelium in vivo, and that this effect is dependent on osteopontin.

Conclusions—

We demonstrate here that E
2
acceleration of the endothelial repair requires osteopontin, both for bone marrow–derived cell recruitment and for endothelial cell migration and proliferation.
Metalloproteinase Expression in Monocytes and Macrophages and its Relationship to Atherosclerotic Plaque Instability
Authors: Newby Andrew C.
Published: September 2008

Matrix metalloproteinases (MMPs) can degrade strength-giving collagens and other structural proteins of the arterial extracellular matrix. Overproduction of MMPs by monocyte/macrophages could therefore promote atherosclerotic plaque rupture and myocardial infarction. Freshly-recruited monocyte macrophages appear to use a prostaglandin (PG)-dependent pathway to coordinately upregulate a broad and potentially highly-destructive spectrum of MMPs. Differentiated macrophages rely on a series of distinct pathways to selectively upregulate groups of MMPs. Moreover, recent evidence suggests that different macrophage phenotypes express characteristically different spectra of MMPs and their inhibitors. New therapies may result from targeting matrix MMP overproduction.
Contribution of Host-Derived Tissue Factor to Tumor Neovascularization
Authors: Yu Joanne , May Linda , Milsom Chloe , Anderson G. Mark , Weitz Jeffrey I. , Luyendyk James P. , Broze George , Mackman Nigel , Rak Janusz
Published: September 2008

Objective—

The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study.

Methods and Results—

We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 different types of transplantable tumors (LLC, B16F1, and ES teratoma) or metastasis were unchanged in low-TF mice. However, several unexpected tumor/context-specific alterations were observed in these mice, including: (1) reduced tumor blood vessel size in B16F1 tumors; (2) larger spleen size and greater tolerance to CTX toxicity in the LLC model; (3) aborted tumor growth after inoculation of TF-deficient tumor cells (ES TF
−/−
) in low-TF mice. TF-deficient tumor cells grew readily in mice with normal TF levels and attracted exclusively host-related blood vessels (without vasculogenic mimicry). We postulate that this complementarity may result from tumor-vascular transfer of TF-containing microvesicles, as we observed such transfer using human cancer cells (A431) and mouse endothelial cells, both in vitro and in vivo.

Conclusions—

Our study points to an important but context-dependent role of host TF in tumor formation, angiogenesis and therapy.
Angiopoietin-2 Stimulates Blood Flow Recovery After Femoral Artery Occlusion by Inducing Inflammation and Arteriogenesis
Authors: Tressel Sarah L. , Kim Hyongbum , Ni Chih-Wen , Chang Kyunghwa , Velasquez-Castano Juan C. , Taylor W. Robert , Yoon Young-sup , Jo Hanjoong
Published: September 2008

Objective—

Recently, we have shown that shear stress regulates the angiogenic potential of endothelial cells in vitro by an Angiopoietin-2 (Ang2)–dependent mechanism; however its pathophysiological significance in vivo was not clear. We hypothesized that Ang2 plays an important role in blood flow recovery after arterial occlusion in vivo by regulating angiogenesis and arteriogenesis.

Methods and Results—

C57Bl/6J mice underwent femoral artery ligation and were injected with a specific Ang2 inhibitor, L1-10, or vehicle for 10 days. Ang2 mRNA was upregulated at day 2, and Ang2 protein was upregulated at day 2, 5, and 7 in the ligated hindlimb. L1-10 treatment significantly blunted blood flow recovery. L1-10 decreased smooth muscle cell coverage of neovessels without affecting capillary density, suggesting a specific role for Ang2 in arteriogenesis. Mechanistically, L1-10 decreased expression of intercellular and vascular cell adhesion molecules as well as infiltrating monocytes/macrophages in the ischemic tissue. Although L1-10 had no effect on the number of CD11b+ cells (monocytes/macrophages) mobilized in the bone marrow, it maintained elevated numbers of circulating CD11b+ cells in the peripheral blood.

Conclusions—

These results suggest that Ang2 induced in ischemic tissue plays a critical role in blood flow recovery by stimulating inflammation and arteriogenesis.
Experimental Model of Warfarin-Associated Intracerebral Hemorrhage
Authors: Foerch Christian , Arai Ken , Jin Guang , Park Kyung-Pil , Pallast Stefanie , van Leyen Klaus , Lo Eng H.
Published: September 2008

Background and Purpose—

Future demographic changes predict an increase in the number of patients with atrial fibrillation. As long-term anticoagulation for the prevention of ischemic strokes becomes more prevalent, the burden of warfarin-associated intracerebral hemorrhage (W-ICH) is likely to grow. However, little is known about the clinical aspects and pathophysiologic mechanisms of W-ICH. This study describes the development of a mouse model of W-ICH in which hematoma growth and outcomes can be correlated with anticoagulation parameters.

Methods—

CD-1 mice were treated with warfarin (2 mg/kg per 24 hours) added to drinking water. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum. Hemorrhagic blood volume was quantified by means of a photometric hemoglobin assay 2 and 24 hours after hemorrhage induction. Neurologic outcomes were assessed on a 5-point scale.

Results—

The international normalized ratio in nonanticoagulated mice was 0.8±0.1. After 24 (W-24) and 30 (W-30) hours of warfarin pretreatment, international normalized ratio values increased to 3.5±0.9 and 7.2±3.4, respectively. Compared with nonanticoagulated mice, mean hemorrhagic blood volume determined 24 hours after hemorrhage induction was found to be 2.5-fold larger in W-24 mice (
P
=0.019) and 3.1-fold larger in W-30 mice (
P
<0.001, n=10 per group). Mortality at 24 hours after hemorrhage induction was 0% in nonanticoagulated mice, 10% in W-24 mice, and 30% in W-30 mice. Hematoma enlargement between 2 and 24 hours after hemorrhage induction was −1.4% for nonanticoagulated mice, 22.9% for W-24 mice, and 62.2% for W-30 mice.

Conclusions—

This study characterizes the first experimental model of W-ICH. It may be helpful in gaining further insights into the pathophysiology of W-ICH and may be used for testing the efficacy of treatment strategies, such as hemostatic therapy, in this severe subtype of stroke.