bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular targets of [6]‐gingerol: Its potential roles in cancer chemoprevention
Authors: Oyagbemi Ademola A. , Saba Adebowale B. , Azeez Odunayo I.
Published: March 2010

A wide variety of phenolic compounds derived from spices possess potent antioxidant, anti‐inflammatory, antimutagenic, and anticarcinogenic activities. [6]‐gingerol (1‐[4′‐hydroxy‐3′‐methoxyphenyl]‐5‐hydroxy‐3‐decanone) is the major pungent principle of ginger, with numerous pharmacological properties including antioxidant, anti‐inflammation, and antitumor promoting properties. It could decrease inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF‐α) expression through suppression of I‐kappaB alpha (IκBα) phosphorylation, nuclear factor kappa B (NF‐κB) nuclear translocation. Other antiproliferative mechanisms of [6]‐gingerol include the release of Cytochrome c, Caspases activation, and increase in apoptotic protease‐activating factor‐1 (Apaf‐1) as mechanism of apoptosis induction. Taken together, the chemopreventive potentials of [6]‐gingerol present a promising future alternative to therapeutic agents that are expensive, toxic, and might even be carcinogenic.
Iron in neuronal function and dysfunction
Authors: Salvador Gabriela A.
Published: March 2010

Iron (Fe) is an essential element for many metabolic processes, serving as a cofactor for heme and nonheme proteins. Cellular iron deficiency arrests cell growth and leads to cell death; however, like most transition metals, an excess of intracellular iron is toxic. The ability of Fe to accept and donate electrons can lead to the formation of reactive nitrogen and oxygen species, and oxidative damage to tissue components; contributing to disease and, perhaps, aging itself. It has also been suggested that iron‐induced oxidative stress can play a key role in the pathogenesis of several neurodegenerative diseases. Iron progressively accumulates in the brain both during normal aging and neurodegenerative processes. However, iron accumulation occurs without the concomitant increase in tissue ferritin, which could increase the risk of oxidative stress. Moreover, high iron concentrations in the brain have been consistently observed in Alzheimer's disease (AD) and Parkinson's disease (PD). In this regard, metalloneurobiology has become extremely important in understanding the role of iron in the onset and progression of neurodegenerative diseases. Neurons have developed several protective mechanisms against oxidative stress, among them the activation of cellular signaling pathways. The final response will depend on the identity, intensity, and persistence of the oxidative insult. The characterization of the mechanisms involved in high iron induced in neuronal dysfunction and death is central to understanding the pathology of a number of neurodegenerative disorders.
Influence of copper on early development: Prenatal and postnatal considerations
Authors: Uriu‐Adams Janet Y. , Scherr Rachel E. , Lanoue Louise , Keen Carl L.
Published: March 2010

Copper (Cu) is an essential nutrient whose requirement is increased during pregnancy and lactation. These represent times of critical growth and development, and the fetus and neonate are particularly vulnerable to deficiencies of this nutrient. Genetic mutations that predispose the offspring to inadequate stores of Cu can be life threatening as is observed in children with Menkes disease. During the last decade, severe Cu deficiency, once thought to be a rare condition, has been reported in the literature at an increasing frequency. Secondary Cu deficiencies can be induced by a variety of ways such as excessive zinc or iron intake, certain drugs, and bariatric surgery. Premature and low birth weight infants can be born with low Cu stores. A number of mechanisms can contribute to the teratogenicity of Cu including decreased activity of select cuproenzymes, increased oxidative stress, decreased nitric oxide availability, altered iron metabolism, abnormal extracellular matrix protein crosslinking, decreased angiogenesis and altered cell signaling among others. The brain, heart, and vessels as well as tissues such as lung, skin and hair, and systems including the skeletal, immune, and blood systems, are negatively affected by suboptimal Cu during development. Additionally, persistent structural, biochemical, and functional adverse effects in the offspring are noted even when Cu supplementation is initiated after birth, supporting the concept that adequate Cu nutriture during pregnancy and lactation is critical for normal development. Although Cu‐containing IUDs are an effective method for increasing intrauterine Cu concentrations and for reducing the risk of pregnancy, high amounts of dietary Cu are not thought to represent a direct developmental risk.
Chemotaxonomic Investigations of Peel and Petitgrain Essential Oils from 17 Citron Cultivars
Authors: Venturini Nicolas , Curk Franck , Desjobert Jean‐Marie , Karp David , Costa Jean , Paolini Julien
Published: March 2010

Chemical compositions of essential oils from 17 citron cultivars were studied using GC and GC/MS. To the best of our knowledge, chemical compositions of peel and petitgrain oils from seven of them were reported for the first time. Combined analysis of peel and petitgrain essential oils led to the identification of 37 components (amounting to 98.2–99.9% of the total oil) and 42 components (97.0–99.9%), respectively. Statistical analysis was applied to identify possible relationships between citron cultivars. The levels of seven components, i.e., limonene, β‐pinene, γ‐terpinene, neral, geranial, nerol, and geraniol, indicated that the cultivars could be classified in four main chemotypes for peel and petitgrain oils. Chemotaxonomic investigations were carried out to establish relations between the morphological characteristics of citron cultivars and their corresponding oil compositions.
Synthesis of Oleanolic Acid Dimers as Inhibitors of Glycogen Phosphorylase
Authors: Cheng Keguang , Liu Jun , Sun Hongbin , Xie Juan
Published: March 2010

Recently, oleanolic acid was found to be an inhibitor of glycogen phosphorylase. For further structural modification, we have synthesized several dimers of oleanolic acid by using amide, ester, or triazole linkage with click chemistry. The click chemistry was shown to be the most efficient method for the dimer synthesis. Nearly quantitative yield of triazole‐linked dimers was obtained. Biological evaluation of the synthesized dimers as inhibitors of glycogen phosphorylase has been described. Four of six dimers exhibited inhibitory activity against rabbit muscle glycogen phosphorylase a (RMGPa), with compounds 2 and 7 as the most potent inhibitors, which displayed an IC50 value (ca. 3 μM) lower than that of oleanolic acid (IC50=14 μM).
Variation in Volatile Leaf Oils of Twelve Eucalyptus Species Harvested from Hajeb Layoun Arboreta (Tunisia)
Authors: Elaissi Ameur , Medini Hanène , Marzouki Hanène , Larbi Khouja Mohamed , Lynene Fréderic , Chemli Rachid , Harzallah‐Skhiri Fethia
Published: March 2010

Hydrodistillation of the dried leaves of twelve species of the genus Eucalyptus L' Hér., i.e., E. brockwayi C. A. Gardn., E. gracilis F. Muell., E. gillii Maiden, E. largiflorens F. Muell., E. loxophleba Benth., E. occidentalis Endl., E. oldfieldii F. Muell., E. salmonophloia F. Muell., E. sargentii Maiden, E. stricklandii Maiden, E. torquata Luehm., and E. woodwardii Maiden, harvested from Hajeb Layoun arboreta (region of Kairouan, central Tunisia) in January 2005, afforded essential oils in yields varying from 0.5±0.1 to 5.7±0.5%, dependent on the species. E. sargentii and E. brockwayi provided the highest and the lowest percentage of essential oil amongst all the species examined, respectively. Analysis by GC (RI) and GC/MS allowed the identification of 133 components, representing 92.9–98.8% of the total oil. The contents of the different samples varied according to the species. The main components were 1,8‐cineole, terpinen‐4‐ol, α‐pinene (2), p‐cymene, aromadendrene (1), globulol (5), trans‐pinocarveol (6), spathulenol (7), β‐eudesmol, torquatone (3), and 4‐methylpentan‐2‐yl acetate (8). The principal component analysis and the hierarchical clustering indicated that the volatile leaf oil composition of the twelve Eucalyptus species could be clearly differentiated.
A New Long‐Chain Alkene and Antituberculosis Constituents from the Leaves of Pourthiaea lucida
Authors: Chen Jih‐Jung , Lin Wen‐Jiou , Shieh Po‐Chuen , Chen Ih‐Sheng , Peng Chien‐Fang , Sung Ping‐Jyun
Published: March 2010

A new long‐chain alkene, dotriacont‐1‐ene (1), was isolated from the leaves of Pourthiaea lucida, together with twelve known compounds. The structure of this new compound was determined by NMR and mass‐spectrometric analyses. Among the isolated compounds, α‐tocospiro A (2), α‐tocopheryl quinone (4), and (E)‐phytol (5) exhibited antituberculosis activities (MICs ≤30 μg/ml) against Mycobacterium tuberculosis H37Rv in vitro.
Putative One‐Pot Prebiotic Polypeptides with Ribonucleolytic Activity
Authors: López‐Alonso Jorge P. , Pardo‐Cea Miguel A. , Gómez‐Pinto Irene , Fernández Irene , Chakrabartty Avijit , Pedroso Enrique , González Carlos , Laurents Douglas V.
Published: March 2010

KIA7, a peptide with a highly restricted set of amino acids (Lys, Ile, Ala, Gly and Tyr), adopts a specifically folded structure. Some amino acids, including Lys, Ile, Ala, Gly and His, form under the same putative prebiotic conditions, whereas different conditions are needed for producing Tyr, Phe and Trp. Herein, we report the 3D structure and conformational stability of the peptide KIA7H, which is composed of only Lys, Ile, Ala, Gly and His. When the imidazole group is neutral, this 20‐mer peptide adopts a four‐helix bundle with a specifically packed hydrophobic core. Therefore, one‐pot prebiotic proteins with well‐defined structures might have arisen early in chemical evolution. The Trp variant, KIA7W, was also studied. It adopts a 3D structure similar to that of KIA7H and its previously studied Tyr and Phe variants, but is remarkably more stable. When tested for ribonucleolytic activity, KIA7H, KIA7W and even short, unstructured peptides rich in His and Lys, in combination with Mg++, Mn++ or Ni++ (but not Cu++, Zn++ or EDTA) specifically cleave the single‐stranded region in an RNA stem–loop. This suggests that prebiotic peptide–divalent cation complexes with ribonucleolytic activity might have co‐inhabited the RNA world.
Dynamic Vapochromic Behaviors of Organic Crystals Based on the Open–Close Motions of S‐Shaped Donor–Acceptor Folding Units
Authors: Takahashi Eiji , Takaya Hikaru , Naota Takeshi
Published: March 2010

The first vapochromic organic crystals are described with respect to their preparation, color change, adsorption/desorption properties, crystal structures, and color‐change mechanism. Non‐solvatochromic, 1,4,5,8‐naphthalene‐tetracarboxylic diimide (NDI) derivatives 1 a bearing two pyrrole imine (PI) tethers have been used as a motif for the crystal packing template. Red‐purple vapochromic solid 3 was prepared by evacuation of orange crystals 2 (equivalent to 1 a⋅2 MeOH), obtained by recrystallization of 1 a from MeOH. Solid 3 showed high‐adsorption ability and unprecedented vapor‐dependent color changes upon exposure to a variety of organic vapors, whereas light brown amorphous solid 1 a, did not show vapo‐ or solvatochromic behavior toward any organic solvent. The strong adsorption capability of 3 was confirmed by TGA experiments and adsorption/desorption isotherms. Analysis of the solid‐state UV/Vis analysis revealed that the vapor‐dependent color changes of 3 were owed to the specific interference of solvent vapors with its broad CT absorbance at λ=450–650 nm. Packing structures of 1 a in orange crystals 2, red‐purple solid 3, and regenerated orange solid 2 were unequivocally established by single crystal and synchrotron powder X‐ray diffraction, respectively. Molecular structures and arrays of 1 a in these materials indicated that 1) unit 1 a had an S‐shaped folded conformation in 2 and 3 by intramolecular donor–acceptor interactions between NDI and two PI units; 2) inclusion of the guest vapor into the S‐shaped template decreased the intramolecular PI‐NDI interactions, accompanied by increasing intermolecular NDI‐NDI and PI‐PI interactions; and 3) such flexible, open–close motions of the S‐shaped template could be repeated during reversible adsorption/desorption processes without degradation of crystal packing. The adsorption properties and mechanism of molecular shape‐dependent vapochromic behavior of 3 are discussed with reference to experimental results, crystallographic data, and theoretical calculations.
Biolubricants: Raw materials, chemical modifications and environmental benefits
Authors: Salimon Jumat , Salih Nadia , Yousif Emad
Published: March 2010

The depletion of the world's crude oil reserve, increasing crude oil prices, and issues related to conservation have brought about renewed interest in the use of bio‐based materials. Emphasis on the development of renewable, biodegradable, and environmentally friendly industrial fluids, such as lubricants, has resulted in the widespread use of natural oils and fats for non‐edible purposes. In this study, we have reviewed the available literature and recently published data related to bio‐based raw materials and the chemical modifications of raw materials. Additionally, we have analyzed the impacts and benefits of the use of bio‐based raw materials as functional fluids or biolubricants. The term biolubricants applies to all lubricants, which are both rapidly biodegradable and non‐toxic to humans and other living organisms, especially in aquatic environments. Biodegradability provides an indication of the persistence of the substance in the environment and is the yardstick for assessing the eco‐friendliness of substances. Scientists are discovering economical and safe ways to improve the properties of biolubricants, such as increasing their poor oxidative stability and decreasing high pour points. “Green” biolubricants must be used for all applications where there is an environmental risk.
Esterification of olive acid oil in supercritical methanol
Authors: Akgün Nalan , Yaprakçı Anıl , Candemir Cansu
Published: March 2010

The aim of this work was to produce biodiesel from olive acid oil with free fatty acid content of 91.67 wt% by using non‐catalytic esterification in supercritical methanol. Design of experiments was used to evaluate the effects of various values of pressure (200–280 bar), temperature (300–380°C), methanol to acid oil volumetric ratio (0.7–1.5), and flow rate (0.4–1.2 mL/min). The optimum process conditions such as temperature of 380°C, pressure of 240 bar, volumetric ratio of acid oil to methanol of 1.12, and flow rate of 0.4 mL/min were obtained using response surface methodology (RSM) coupled with Central Composite Design (CCD). Moreover, it was found that the most effective parameters were temperature and flow rate, which was in good agreement with the experimental value. Furthermore, the fuel properties of biodiesel were upgraded, and then tested following the European standard EN 14214.
Effect of phospholipidn‐3 polyunsaturated fatty acids on rat lipid metabolism
Authors: Hosomi Ryota , Fukunaga Kenji , Arai Hirofumi , Kanda Seiji , Nishiyama Toshimasa , Kanada Teruyuki , Yoshida Munehiro
Published: March 2010

It has been demonstrated that the amount and type of dietary fat are factors involved in the risk of arteriosclerosis and coronary or cerebral artery disease through lipid metabolism. In this study, we investigated the effects of phospholipids (PLs) containingn‐3PUFAs on lipid metabolism in rats. PLs containingn‐3PUFAs were prepared from squid (Todarodes pacificus) mantle muscle. Groups of male Wistar rats were fed AIN93G diet containing soybean oil (SO, 7%), fish oil (1.2%) + SO (5.8%), soybean PLs (1.8%) + SO (5.2%), or PLs containingn‐3PUFAs (1.8%) + SO (5.2%). The following indicators were assayed as indexes of lipid metabolism: TAG and cholesterol in serum and liver, fecal cholesterol, bile‐acid excretion, and liver mRNA expression levels of genes encoding proteins involved in cholesterol homeostasis. Serum and liver TAG contents decreased significantly in the group fed PLs containingn‐3PUFAs as compared to other groups, accompanied by a significant decline in the expression level of sterol regulatory element binding protein‐1c. The decrease in cholesterol content in the group fed PLs containingn‐3PUFAs was due to the increase in fecal cholesterol excretion and the increase of mRNA expression levels of ATP‐binding cassette (ABC) G5 and ABCG8 in liver.

Practical applications: PLs containingn‐3PUFAs decreased serum and liver TAG contents compared with that induced by soybean PLs. Further, PLs containingn‐3PUFAs can induce a reduction in serum and liver cholesterol concentrations as well as the triglyceride‐reducing effect of conventionaln‐3PUFAs containing TAG. In other words, dietaryn‐3PUFAs contained in PLs can prevent life‐style diseases such as hyperlipidemia, arteriosclerosis and coronary, or cerebral artery disease more effectively than TAG containingn‐3PUFAs. Therefore, it is expected that the risk of lifestyle diseases would be decreased if PL containingn‐3PUFAs can be supplied routinely. In this study, PLs containingn‐3PUFAs were prepared from squid mantle muscle. On an industrial scale, such PLs can be produced from various unused resources and waste materials of fisheries. We conclude that highly functional foods could be developed based on the findings of this study, and would be available for health promotion worldwide.
Planar‐Chiral Thioureas as Hydrogen‐Bond Catalysts
Authors: Schneider Jakob F. , Falk Florian C. , Fröhlich Roland , Paradies Jan
Published: March 2010

The synthesis of the first enantiopure planar‐chiral thiourea catalysts is herewith described. New catalysts 1–3 were applied in asymmetric transformations, such as the Friedel–Crafts alkylation of indole, as well as in the transfer hydrogenation of nitroolefins. Bifunctional catalysts 2 and 3 exhibit enhanced activity in the investigated reactions, demonstrating their potential for organic synthesis.
Nucleophilic Substitution Reactions of meso‐5,10,15‐Tris(pentafluorophenyl)corrole; Synthesis of ABC‐Type Corroles and Corrole‐Based Organogels
Authors: Hori Takaaki , Osuka Atsuhiro
Published: March 2010

Nucleophilic substitution reactions of 5,10,15‐tris(pentafluorophenyl)corrole (1) with amines were examined as a post‐modification route to functional corroles. Reaction of 1 with an excess of amine nucleophiles led to exclusive formation of 5,10,15‐tris(4‐amino‐2,3,5,6‐tetrafluorophenyl)‐substituted corroles. In this nucleophilic reaction, 5‐ and 15‐pentafluorophenyl substituents were found to be more reactive than the substituent at the 10‐position. This substitution reaction was applied for the preparation of ABC‐type corroles and corrole‐based organogels. The latter exhibited a blue‐shifted Soret band and small fluorescence quantum yields in nonpolar hydrocarbon solvents due to the formation of H‐type aggregates.
MHD flow and heat transfer over permeable stretching sheet with slip conditions
Authors: Hayat T. , Qasim M. , Mesloub S.
Published: March 2010

The magnetohydrodynamic (MHD) flow and heat transfer characteristics for the boundary layer flow over a permeable stretching sheet are considered. Velocity and thermal slip conditions are taken into account. Problem formulation is developed in the presence of thermal radiation. Governing non‐linear problem is solved by a homotopy analysis method. Convergence of the derived solutions is studied. Numerical values of skin‐friction coefficient and local Nusselt number are tabulated. Effects of pertinent parameters on the velocity and temperature profiles are discussed. Comparison between the present and previous limiting results is shown. Copyright © 2010 John Wiley & Sons, Ltd.
Reviewing Metallic PEMFC Bipolar Plates
Authors: Wang H. , Turner J. A.
Published: March 2010

A bipolar plate is one of the most important components in a polymer exchange membrane fuel cell (PEMFC) stack and has multiple functions. Metallic bipolar plate candidates have advantages over composite rivals in excellent electrical and thermal conductivity, good mechanical strength, high chemical stability, very wide alloy choices, low cost and, most importantly, existing pathways for high‐volume, high‐speed mass production. The challenges with metallic bipolar plates are the higher contact resistance and possible corrosion products, which may contaminate the membrane electrode assembly. This review evaluates the candidate metallic and coating materials for bipolar plates and gives the perspective of the research trends.
Overexpression of dicer as a result of reduced let‐7 MicroRNA levels contributes to increased cell proliferation of oral cancer cells
Authors: Jakymiw Andrew , Patel Rushi S. , Deming Natasha , Bhattacharyya Indraneel , Shah Priya , Lamont Richard J. , Stewart Carol M. , Cohen Donald M. , Chan Edward K. L.
Published: March 2010

Recent reports have demonstrated that Dicer, an RNase III endonuclease required for microRNA (miRNA) maturation, is aberrantly expressed in different types of cancer. Furthermore, Dicer has been reported to be regulated by the let‐7 family of miRNA genes. We hypothesize that Dicer is aberrantly expressed in oral cancer cells due to altered expressions of let‐7 and that Dicer contributes to the development and progression of the disease. Western blot examination of Dicer protein levels in four head and neck squamous cell carcinoma (HNSCC) cell lines, including two oral cancer cell lines, demonstrated that Dicer had between 4‐ and 24‐fold higher expression levels when compared to normal human primary gingival epithelial cells. Furthermore, five of six oral cancer tissues analyzed by indirect immunofluorescence had increased Dicer protein expression, compared to normal gingival epithelial tissue. The Dicer mRNA levels were not found to correlate well with protein expression in the HNSCC cell lines, suggesting that Dicer protein expression was post‐transcriptionally regulated. Analysis of let‐7a and let‐7b levels in HNSCC cell lines by real‐time PCR demonstrated that let‐7b, but not let‐7a, was significantly reduced in the HNSCC cell lines compared to control cells. Lastly, transfection of oral cancer cells with chemically synthesized let‐7b and small interfering RNAs targeting Dicer significantly inhibited cell proliferation up to 83% and >100%, respectively, as early as 3 days post‐transfection. Together, these data demonstrate that elevated expression levels of Dicer in oral cancer cells correlate with downregulation of let‐7b and increased cell proliferation. © 2010 Wiley‐Liss, Inc.
Molecular characterization by array comparative genomic hybridization and DNA sequencing of 194 desmoid tumors
Authors: Salas Sébastien , Chibon Frederic , Noguchi Tetsuro , Terrier Philippe , Ranchere‐Vince Dominique , Lagarde Pauline , Benard Jean , Forget Sébastien , Blanchard Camille , Dômont Julien , Bonvalot Sylvie , Guillou Louis , Leroux Agnès , Mechine‐Neuville Agnes , Schöffski Patrick , Laë Marik , Collin Françoise , Verola Olivier , Carbonnelle Amelie , Vescovo Laure , Bui Binh , Brouste Véronique , Sobol Hagay , Aurias Alain , Coindre Jean‐Michel
Published: March 2010

Desmoid tumors are fibroblastic/myofibroblastic proliferations. Previous studies reported that CTNNB1 mutations were detected in 84% and that mutations of the APC gene were found in several cases of sporadic desmoid tumors lacking CTNNB1 mutations. Forty tumors were analyzed by comparative genomic hybridization (CGH). Karyotype and fluorescence in situ hybridization revealed a nonrandom occurrence of trisomy 8 associated with an increased risk of recurrence. We report the first molecular characterization including a large series of patients. We performed array CGH on frozen samples of 194 tumors, and we screened for APC mutations in patients without CNNTB1 mutation. A high frequency of genomically normal tumors was observed. Four relevant and recurrent alterations (loss of 6q, loss of 5q, gain of 20q, and gain of Chromosome 8) were found in 40 out of 46 tumors with chromosomal changes. Gain of Chromosomes 8 and 20 was not associated with an increased risk of recurrence. Cases with loss of 5q had a minimal common region in 5q22.5 including the APC locus. Alterations of APC, including loss of the entire locus, and CTNNB1 mutation could explain the tumorigenesis in 89% of sporadic desmoids tumors and desmoids tumors occurring in the context of Gardner's syndrome. A better understanding of the pathogenetic pathways in the initiation and progression of desmoid tumors requires studies of 8q and 20q gains, as well as of 6q and 5q losses, and study of the Wnt/β‐catenin pathway. © 2010 Wiley‐Liss, Inc.
19q13 amplification is associated with high grade and stage in pancreatic cancer
Authors: Kuuselo Riina , Simon Ronald , Karhu Ritva , Tennstedt Pierre , Marx Andreas H. , Izbicki Jakob R. , Yekebas Emre , Sauter Guido , Kallioniemi Anne
Published: March 2010

Pancreatic cancer is a devastating disease with an extremely poor prognosis, and thus, there is a great need for better diagnostic and therapeutic tools. The 19q13 chromosomal locus is amplified in several cancer types, including pancreatic cancer, but the possible clinical significance of this aberration remains unclear. We used fluorescence in situ hybridization on tissue microarrays containing 357 primary pancreatic tumors, 151 metastases, and 24 local recurrences as well as 120 cancer cell lines from various tissues to establish the frequency of the 19q13 amplification and to find potential correlations to clinical parameters including patient survival. Copy number increases were found in 12.2% of the primary pancreatic tumors and 9.3% of the cell lines, including those derived from bladder, colorectal, ovarian, and thyroid carcinomas. Copy number changes were linked to high grade (P = 0.044) and stage (P = 0.025) tumors, and the average survival time of patients with 19q13 amplification was shorter than that of those without this aberration. Our findings revealed recurrent 19q13 amplification in pancreatic cancer and involvement of the same locus as in bladder, colorectal, ovarian, and thyroid carcinomas. More importantly, the 19q13 amplifications were associated with poor tumor phenotype and showed a trend toward shorter survival. © 2010 Wiley‐Liss, Inc.
Down-Regulated MicroRNA-152 Induces Aberrant DNA Methylation in Hepatitis B Virus–Related Hepatocellular Carcinoma by Targeting DNA Methyltransferase 1
Authors: Huang Jinfeng , Wang Yue , Guo Yingjun , Sun Shuhan
Published: March 2010

The hepatitis B virus (HBV) X protein has been implicated as a potential trigger of the epigenetic modifications of some genes during hepatocarcinogenesis, but the underlying mechanisms remain unknown. MicroRNAs (miRNAs), which are noncoding RNAs that regulate gene expression, are involved in diverse biological functions and in carcinogenesis. In this study, we investigated whether some miRNAs are aberrantly expressed and involved in the regulation of the abnormal DNA methylation status in HBV-related hepatocellular carcinoma (HCC). Our results showed that the expression of microRNA-152 (miR-152) was frequently down-regulated in HBV-related HCC tissues in comparison with adjacent noncancerous hepatic tissues and was inversely correlated to DNA methyltransferase 1 (DNMT1) messenger RNA (mRNA) expression in HBV-related HCCs. The forced expression of miR-152 in liver cell lines resulted in a marked reduction of the expression of DNMT1 at both the mRNA and protein levels by directly targeting the 3′ untranslated regions of DNMT1. This in turn led to a decrease in global DNA methylation, whereas inhibition of miR-152 caused global DNA hypermethylation and increased the methylation levels of two tumor suppressor genes, glutathione

S

-transferase pi 1 (GSTP1) and E-cadherin 1 (CDH1).

Conclusion:

Our findings suggest that miR-152 is frequently down-regulated and regulates DNMT1 in HBV-related HCC. These findings support a tumor-suppressive role of miR-152 in the epigenetic aberration of HBV-related HCC and the potential development of miRNA-based targeted approaches for the treatment of HBV-related HCC. Hepatology 2010
CD151 Modulates Expression of Matrix Metalloproteinase 9 and Promotes Neoangiogenesis and Progression of Hepatocellular Carcinoma
Authors: Shi Guo-Ming , Ke Ai-Wu , Zhou Jian , Wang Xiao-Ying , Xu Yang , Ding Zhen-Bin , Devbhandari Ranjan Prasad , Huang Xiao-Yong , Qiu Shuang-Jian , Shi Ying-Hong , Dai Zhi , Yang Xin-Rong , Yang Guo-Huan , Fan Jia
Published: March 2010

Tetraspanin CD151 is involved in several pathological activities associated with tumor progression, including neoangiogenesis. However, the role and molecular mechanism of CD151 in the neoangiogenesis of hepatocellular carcinoma (HCC) remain enigmatic. We found that the level of expression of matrix metalloproteinase 9 (MMP9) was positively associated with CD151 expression in HCC cells. We developed a zone-by-zone blockade and demonstrated that overexpression of CD151 in HCC cells facilitated MMP9 expression through a phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3β (GSK-3β)/Snail signaling pathway. In contrast, down-regulation of CD151 expression impaired the ability of HCC cells to form microvessels

in vitro

and reduced their

in vivo

metastatic potential. In a clinical setting, a significant correlation of the expression of CD151 with MMP9 expression and with microvessel density (MVD) was revealed by Pearson correlation analysis of HCC patients. The postoperative 3-, 5-, and 7-year overall survival rates of HCC patients with CD151high/MMP9high/MVDhigh were significantly lower than those of the CD151low/MMP9low/MVDlow group or groups in which only one or two of CD151, MMP9, and MVD were highly expressed. Cumulative recurrence rates were also highest in HCC patients with CD151high/MMP9high/MVDhigh in comparison with the other groups. Multivariate Cox proportional hazards analysis showed that the concomitant overexpression of CD151, MMP9, and MVD was an independent marker for predicting poor prognosis of HCC.

Conclusion:

Overexpression of CD151 up-regulated the expression of MMP9 through the PI3K/Akt/GSK-3β/Snail pathway. CD151-dependent neoangiogenesis appeared to promote the progression of HCC, and this suggests that CD151 may be useful as a high-priority therapeutic target for antiangiogenesis in HCC. Hepatology 2010
Carriage of a Tumor Necrosis Factor Polymorphism Amplifies the Cytotoxic T-Lymphocyte Antigen 4 Attributed Risk of Primary Biliary Cirrhosis: Evidence for a Gene–Gene Interaction
Authors: Juran Brian D. , Atkinson Elizabeth J. , Larson Joseph J. , Schlicht Erik M. , Liu Xiangdong , Heathcote E. Jenny , Hirschfield Gideon M. , Siminovitch Katherine A. , Lazaridis Konstantinos N.
Published: March 2010

Common genetic variants significantly influence complex diseases such as primary biliary cirrhosis (PBC). We recently reported an association between PBC and a single nucleotide polymorphism (rs231725) of the immunoreceptor gene cytotoxic T-lymphocyte antigen 4 (CTLA4). We hypothesized that PBC risk attributed to this polymorphism might be increased by propensity to an overly robust inflammatory response. Thus, we examined its potential interaction with the commonly studied −308AG promoter polymorphism (rs1800629) of the tumor necrosis factor (TNF) gene for which the variant TNF2A allele causes increased TNF production. The polymorphisms were genotyped in 866 PBC patients and 761 controls from independent US and Canadian registries; the effects of individual single nucleotide polymorphisms (SNPs) and their interaction on PBC risk was assessed by logistic regression. The reported association of PBC with the CTLA4 “A/A” genotype was replicated in the Canadian cohort and significant for PBC risk in the combined data (odds ratio [OR], 1.68;

P

= 0.0005). TNF2A allele frequency was elevated in PBC patients, but only reached borderline significance using the combined data (OR, 1.21;

P

= 0.042). Analysis showed that TNF2A carriage was significantly increased in CTLA4 “A/A” PBC patients compared with CTLA4 “A/A” controls (39.7% versus 16.5%,

P

= 0.0004); no apparent increase of TNF2A carriage was noted in CTLA4 “A/G” or “G/G” individuals. Finally, interaction under a logistic model was highly significant, as TNF2A carriage in combination with the CTLA4 “A/A” genotype was present in 6.5% of PBC patients, compared with 1.7% of controls (OR, 3.98;

P

< 0.0001).

Conclusion:

TNF2A amplifies the CTLA4 rs231725 “A/A” genotype risk for PBC. Although the mechanisms remain unclear, the premise that deficiency in T-cell regulation resulting in an increased risk of PBC is amplified by overexpression of an important proinflammatory cytokine provides a basis for future functional studies. Hepatology 2010
Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury
Authors: Lucena Isabel M. , García-Martín Elena , Andrade Raúl J. , Martínez Carmen , Stephens Camilla , Ruiz Jhon D. , Ulzurrun Eugenia , Fernandez Carmen M. , Romero-Gomez Manuel , Castiella Augustin , Planas Ramon , Durán José Antonio , De Dios Ana Melcón , Guarner Carlos , Soriano German , Borraz Yolanda , Agundez José A. G.
Published: March 2010

Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (

SOD2

Val16Ala) and glutathione peroxidase (

GPX1

Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex- and age-matched controls were analyzed. The

SOD2

and

GPX1

genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association of

SOD2

and

GPX1

, respectively. The

SOD2

Ala/Ala genotype was associated with cholestatic/mixed damage (OR = 2.3; 95% confidence interval [CI] = 1.4-3.8; corrected

P

[

Pc

] = 0.0058), whereas the

GPX1

Leu/Leu genotype was associated with cholestatic injury (OR = 5.1; 95%CI = 1.6-16.0;

Pc

= 0.0112). The presence of two or more combined risk alleles (

SOD2

Ala and

GPX1

Leu) was more frequent in DILI patients (OR = 2.1; 95%CI = 1.4-3.0;

Pc

= 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the

SOD2

Ala/Ala genotype (OR = 3.6; 95%CI = 1.4-9.3;

Pc

= 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR = 3.0; 95%CI = 1.7-5.5;

Pc

= 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR = 16.0; 95%CI = 1.8-146.1;

Pc

= 0.009).

Conclusion:

Patients homozygous for the

SOD2

Ala allele and the

GPX1

Leu allele are at higher risk of developing cholestatic DILI.

SOD2

Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates. (Hepatology 2010)
Comparison of Surrogate and Direct Measurement of Insulin Resistance in Chronic Hepatitis C Virus Infection: Impact of Obesity and Ethnicity
Authors: Lam Khoa D. , Bacchetti Peter , Abbasi Fahim , Ayala Claudia E. , Loeb Samuel M. , Shah Vidhi , Wen Michael J. , Reaven Gerald M. , Maher Jacquelyn J. , Khalili Mandana
Published: March 2010

Studies using surrogate estimates show high prevalence of insulin resistance in hepatitis C infection. This study prospectively evaluated the correlation between surrogate and directly measured estimates of insulin resistance and the impact of obesity and ethnicity on this relationship. Eighty-six nondiabetic, noncirrhotic patients with hepatitis C virus (age = 48 ± 7 years, 74% male, 44% white, 22% African American, 26% Latino, 70% genotype 1) were categorized into normal-weight (body mass index [BMI] < 25, n = 30), overweight (BMI = 25-29.9, n = 38), and obese (BMI ≥ 30, n = 18). Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during a 240-minute insulin suppression test. Surrogate estimates included: fasting glucose and insulin, glucose/insulin, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), insulin (I-AUC) and glucose (G-AUC) area under the curve during oral glucose tolerance test, and the Belfiore and Stumvoll indexes. All surrogate estimates correlated with SSPG, but the magnitude of correlation varied (r = 0.30-0.64). The correlation coefficients were highest in the obese. I-AUC had the highest correlation among all ethnic and weight groups (r = 0.57-0.77). HOMA-IR accounted for only 15% of variability in SSPG in the normal weight group. The common HOMA-IR cutoff of ≤3 to define insulin resistance had high misclassification rates especially in the overweight group independent of ethnicity. HOMA-IR > 4 had the lowest misclassification rate (75% sensitivity, 88% specificity). Repeat HOMA-IR measurements had higher within-person variation in the obese (standard deviation = 0.77 higher than normal-weight, 95% confidence interval = 0.25-1.30,

P

= 0.005).

Conclusion:

Because of limitations of surrogate estimates, caution should be used in interpreting data evaluating insulin resistance especially in nonobese, nondiabetic patients with HCV. Hepatology 2010
Hepatocyte NAD(P)H Oxidases as an Endogenous Source of Reactive Oxygen Species During Hepatitis C Virus Infection
Authors: de Mochel Nabora Soledad Reyes , Seronello Scott , Wang Shelley Hsiuying , Ito Chieri , Zheng Jasper Xi , Liang Jake T. , Lambeth David J. , Choi Jinah
Published: March 2010

Oxidative stress has been identified as a key mechanism of hepatitis C virus (HCV)–induced pathogenesis. Studies have suggested that HCV increases the generation of hydroxyl radical and peroxynitrite close to the cell nucleus, inflicting DNA damage, but the source of reactive oxygen species (ROS) remains incompletely characterized. We hypothesized that HCV increases the generation of superoxide and hydrogen peroxide close to the hepatocyte nucleus and that this source of ROS is reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase 4 (Nox4). Huh7 human hepatoma cells and telomerase-reconstituted primary human hepatocytes, transfected or infected with virus-producing HCV strains of genotypes 2a and 1b, were examined for messenger RNA (mRNA), protein, and subcellular localization of Nox proteins along with the human liver. We found that genotype 2a HCV induced persistent elevations of Nox1 and Nox4 mRNA and proteins in Huh7 cells. HCV genotype 1b likewise elevated the levels of Nox1 and Nox4 in telomerase-reconstituted primary human hepatocytes. Furthermore, Nox1 and Nox4 proteins were increased in HCV-infected human liver versus uninfected liver samples. Unlike Nox1, Nox4 was prominent in the nuclear compartment of these cells as well as the human liver, particularly in the presence of HCV. HCV-induced ROS and nuclear nitrotyrosine could be decreased with small interfering RNAs to Nox1 and Nox4. Finally, HCV increased the level of transforming growth factor beta 1 (TGFβ1). TGFβ1 could elevate Nox4 expression in the presence of infectious HCV, and HCV increased Nox4 at least in part through TGFβ1.

Conclusion:

HCV induced a persistent elevation of Nox1 and Nox4 and increased nuclear localization of Nox4 in hepatocytes

in vitro

and in the human liver. Hepatocyte Nox proteins are likely to act as a persistent, endogenous source of ROS during HCV-induced pathogenesis. Hepatology 2010
A medial temporal lobe division of labor: Insights from memory in aging and early Alzheimer disease
Authors: Wolk David A. , Dunfee Kathryn L. , Dickerson Bradford C. , Aizenstein Howard J. , DeKosky Steven T.
Published: March 2010

Dual process theories of recognition memory posit that recollection and familiarity represent dissociable processes. Animal studies and human functional imaging experiments support an anatomic dissociation of these processes in the medial temporal lobes (MTL). By this hypothesis, recollection may be dependent on the hippocampus, while familiarity appears to rely on extrahippocampal MTL (ehMTL) structures, particularly perirhinal and lateral entorhinal cortices. Despite these findings, the dual process model and these anatomic mappings remain controversial, in part because the study of patients with lesions to the MTL has been limited and has revealed predominantly single dissociations. We examined measures of recollection and familiarity in three groups (normal older adults, amnesic‐mild cognitive impairment, Alzheimer's disease) in which these memory measures and the relative integrity of MTL structures are variable, thus enhancing our power to detect MTL‐memory relationships. Recollection and familiarity and volumes of hippocampus and ehMTL, defined as a region including entorhinal/perirhinal cortices and parahippocampus, were measured. Regression analyses revealed a stronger relationship of recollection with the hippocampus compared to ehMTL, while familiarity was more highly related to ehMTL compared to hippocampus. These results are consistent with a division of labor in the MTL and the dual process model. © 2010 Wiley‐Liss, Inc.
Water maze experience and prenatal choline supplementation differentially promote long‐term hippocampal recovery from seizures in adulthood
Authors: Wong‐Goodrich Sarah J.E. , Glenn Melissa J. , Mellott Tiffany J. , Liu Yi B. , Blusztajn Jan K. , Williams Christina L.
Published: March 2010

Status epilepticus (SE) in adulthood dramatically alters the hippocampus and produces spatial learning and memory deficits. Some factors, like environmental enrichment and exercise, may promote functional recovery from SE. Prenatal choline supplementation (SUP) also protects against spatial memory deficits observed shortly after SE in adulthood, and we have previously reported that SUP attenuates the neuropathological response to SE in the adult hippocampus just 16 days after SE. It is unknown whether SUP can ameliorate longer‐term cognitive and neuropathological consequences of SE, whether repeatedly engaging the injured hippocampus in a cognitive task might facilitate recovery from SE, and whether our prophylactic prenatal dietary treatment would enable the injured hippocampus to more effectively benefit from cognitive rehabilitation. To address these issues, adult offspring from rat dams that received either a control (CON) or SUP diet on embryonic days 12–17 first received training on a place learning water maze task (WM) and were then administered saline or kainic acid (KA) to induce SE. Rats then either remained in their home cage, or received three additional WM sessions at 3, 6.5, and 10 weeks after SE to test spatial learning and memory retention. Eleven weeks after SE, the brains were analyzed for several hippocampal markers known to be altered by SE. SUP attenuated SE‐induced spatial learning deficits and completely rescued spatial memory retention by 10 weeks post‐SE. Repeated WM experience prevented SE‐induced declines in glutamic acid decarboxylase (GAD) and dentate gyrus neurogenesis, and attenuated increased glial fibrilary acidic protein (GFAP) levels. Remarkably, SUP alone was similarly protective to an even greater extent, and SUP rats that were water maze trained after SE showed reduced hilar migration of newborn neurons. These findings suggest that prophylactic SUP is protective against the long‐term cognitive and neuropathological effects of KA‐induced SE, and that rehabilitative cognitive enrichment may be partially beneficial. © 2010 Wiley‐Liss, Inc.
Estimations of copper roof runoff rates in the United States
Authors: Arnold Ray
Published: March 2010

Copper (Cu) concentrations in waterways of the United States are of widespread concern. Presently, 692 waterway segments around the United States are listed by the U.S. Environmental Protection Agency (USEPA) as having unacceptably high copper concentrations. As part of their water quality management strategy, the USEPA is mandated to understand and manage sources and impacts of nonpoint releases of chemicals of concern. One potential nonpoint source of Cu is the runoff of precipitation falling onto Cu used in external architecture (e.g., roofing). However, few studies of Cu roof runoff have been published. This article is intended to provide estimations of Cu runoff rates and concentrations across the United States. Copper runoff rates and concentrations are predicted at 179 locations with a recently developed model. The average and range (in parentheses) of annual Cu loading rates, based on roof area; Cu export rates, based on amount of precipitation; and Cu concentrations for the United States are 2.12 (1.05–4.85) g Cu/m2/y; 2.72 (0.69–16.48) mg Cu/m2/mm; and 2.72 (0.69–16.48) mg Cu/L as total Cu, respectively. Statistics are presented that describe site-specific data distributions for use in probabilistic exposure and risk assessments. The effects of air quality as well as the potential fate and risks of Cu from roof runoff are discussed.
Polybrominated diphenylether levels among united states residents: Daily intake and risk of harm to the developing brain and reproductive organs
Authors: McDonald Thomas A.
Published: March 2010

Data on Polybrominated diphenylether (PBDE) concentrations in individual U.S. women were compiled. PBDE levels in adipose tissue, serum, and breast milk from individual U.S. women were found to follow similar lognormal distributions, which exhibited a high degree of variability. The distribution of lipid-normalized PBDE concentrations for all media combined had a median of 47.9 ng/g and a 95th percentile estimate of 302 ng/g. Estimates of congener-specific kinetic parameters were used to calculate the total daily intake of the PBDEs (sum of 5 PBDE prominent congeners, PBDE-47, -99, -100, -153, and -154) that would be required to achieve the measured body burdens. PBDE intake estimates from all routes of exposure were 8.5 ng/kg/d (median) and 54 ng/kg/d (95th percentile). The potential health risks posed by the PBDEs were examined by comparing 95th percentile tissue concentrations in humans (Chuman) to modeled and measured tissue concentrations in rodents that caused no developmental neurotoxicity and reproductive effects (Crodent). The ratio of rodent-to-human PBDE concentrations (Crodent:Chuman) was <1 for alterations of male and female reproductive organs in rats, <10 for neurodevelopmental effects in mice, and <100 for neurodevelopmental effects in rats. If humans are as sensitive as animals to PBDE-induced developmental toxicity, the current margin of safety appears low for a fraction of the population.