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排序方式: 共有104条查询结果,搜索用时 296 毫秒
11.
Mells JE Fu PP Sharma S Olson D Cheng L Handy JA Saxena NK Sorescu D Anania FA 《American journal of physiology. Gastrointestinal and liver physiology》2012,302(2):G225-G235
The aims of this study were designed to determine whether liraglutide, a long-acting glucagon-like peptide, could reverse the adverse effects of a diet high in fat that also contained trans-fat and high-fructose corn syrup (ALIOS diet). Specifically, we examined whether treatment with liraglutide could reduce hepatic insulin resistance and steatosis as well as improve cardiac function. Male C57BL/6J mice were pair fed or fed ad libitum either standard chow or the ALIOS diet. After 8 wk the mice were further subdivided and received daily injections of either liraglutide or saline for 4 wk. Hyperinsulinemic-euglycemic clamp studies were performed after 6 wk, revealing hepatic insulin resistance. Glucose tolerance and insulin resistance tests were performed at 8 and 12 wk prior to and following liraglutide treatment. Liver pathology, cardiac measurements, blood chemistry, and RNA and protein analyses were performed. Clamp studies revealed hepatic insulin resistance after 6 wk of ALIOS diet. Liraglutide reduced visceral adiposity and liver weight (P < 0.001). As expected, liraglutide improved glucose and insulin tolerance. Liraglutide improved hypertension (P < 0.05) and reduced cardiac hypertrophy. Surprisingly, liver from liraglutide-treated mice had significantly higher levels of fatty acid binding protein, acyl-CoA oxidase II, very long-chain acyl-CoA dehydrogenase, and microsomal triglyceride transfer protein. We conclude that liraglutide reduces the harmful effects of an ALIOS diet by improving insulin sensitivity and by reducing lipid accumulation in liver through multiple mechanisms including, transport, and increase β-oxidation. 相似文献
12.
From nutrient uptake to chemoreception to synaptic transmission, many systems in cell biology depend on molecules diffusing and binding to membrane receptors. Mathematical analysis of such systems often neglects the fact that receptors process molecules at finite kinetic rates. A key example is the celebrated formula of Berg and Purcell for the rate that cell surface receptors capture extracellular molecules. Indeed, this influential result is only valid if receptors transport molecules through the cell wall at a rate much faster than molecules arrive at receptors. From a mathematical perspective, ignoring receptor kinetics is convenient because it makes the diffusing molecules independent. In contrast, including receptor kinetics introduces correlations between the diffusing molecules because, for example, bound receptors may be temporarily blocked from binding additional molecules. In this work, we present a modeling framework for coupling bulk diffusion to surface receptors with finite kinetic rates. The framework uses boundary homogenization to couple the diffusion equation to nonlinear ordinary differential equations on the boundary. We use this framework to derive an explicit formula for the cellular uptake rate and show that the analysis of Berg and Purcell significantly overestimates uptake in some typical biophysical scenarios. We confirm our analysis by numerical simulations of a many-particle stochastic system. 相似文献
13.
Marla J. S. Mickleborough Christine M. Chapman Andreea Simina Toma Jeremy H. M. Chan Grace Truong Todd C. Handy 《PloS one》2013,8(11)
Research has established decreased sensory habituation as a defining feature in migraine, while decreased cognitive habituation has only been found with regard to cognitive assessment of the relative probability of the occurrence of a stimulus event. Our study extended the investigation of interictal habituation in migraine to include cognitive processing when viewing of a series of visually-complex images, similar to those we encounter on the internet everyday. We examined interictal neurocognitive function in migraine from a habituation perspective, using a novel paradigm designed to assess how the response to a series of images changes over time. Two groups of participants--migraineurs (N = 25) and non-migraine controls (N = 25)--were asked to view a set of 232 unfamiliar logos in the context of a target identification task as their brain electrical responses were recorded via event-related potentials (ERPs). The set of logos was viewed serially in each of 10 separate trial blocks, with data analysis focusing on how the ERP responses to the logos in frontal electrodes from 200-600 ms changed across time within each group. For the controls, we found that the amplitude of the late positive potential (LPP) ERP component elicited by the logos had no significant change across trial blocks. In contrast, in migraineurs we found that the LPP significantly increased in amplitude across trial blocks, an effect consistent with a lack of habituation to visual stimuli seen in previous research. Our findings provide empirical support abnormal cognitive processing of complex visual images across time in migraineurs that goes beyond the sensory-level habituation found in previous research. 相似文献
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16.
Filomena G. Ottaviano Shiow-Shih Tang Diane E. Handy Joseph Loscalzo 《Molecular and cellular biochemistry》2009,327(1-2):111-126
Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing extracellular antioxidant protein that catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides. Selenoprotein expression involves the alternate recognition of a UGA codon as a selenocysteine codon and requires signals in the 3′-untranslated region (UTR), including a selenocysteine insertion sequence (SECIS), as well as specific translational cofactors. To ascertain regulatory determinants of GPx-3 expression and function, we generated recombinant GPx-3 (rGPX-3) constructs with various 3′-UTR, as well as a Sec73Cys mutant. In transfected Cos7 cells, the Sec73Cys mutant was expressed at higher levels than the wild type rGPx-3, although the wild type rGPx-3 had higher specific activity, similar to plasma purified GPx-3. A 3′-UTR with only the SECIS was insufficient for wild type rGPx-3 protein expression. Selenocompound supplementation and co-transfection with SECIS binding protein 2 increased wild type rGPx-3 expression. These results demonstrate the importance of translational mechanisms in GPx-3 expression. 相似文献
17.
Sara M. Handy Tsvetan R. Bachvaroff Ruth E. Timme D. Wayne Coats Sunju Kim Charles F. Delwiche 《Journal of phycology》2009,45(5):1163-1174
Dinoflagellates are a highly diverse and environmentally important group of protists with relatively poor resolution of phylogenetic relationships, particularly among heterotrophic species. We examined the phylogeny of several dinophysiacean dinoflagellates using samples collected from four Atlantic sites. As a rule, 3.5 kb of sequence including the nuclear ribosomal genes SSU, 5.8S, LSU, plus their internal transcribed spacer (ITS) 1 and 2 regions were determined for 26 individuals, including representatives of two genera for which molecular data were previously unavailable, Ornithocercus F. Stein and Histioneis F. Stein. In addition, a clone library targeting the dinophysiacean ITS2 and LSU sequences was constructed from bulk environmental DNA from three sites. Three phylogenetic trees were inferred from the data, one using data from this study for cells identified to genus or species (3.5 kb, 28 taxa); another containing dinoflagellate SSU submissions from GenBank and the 12 new dinophysiacean sequences (1.9 kb, 56 taxa) from this study; and the third tree combing data from identified taxa, dinophysiacean GenBank submissions, and the clone libraries from this study (2.1 kb, 136 taxa). All trees were congruent and indicated a distinct division between the genera Phalacroma F. Stein and Dinophysis Ehrenb. The cyanobionts containing genera Histioneis and Ornithocercus were also monophyletic. This was the largest molecular phylogeny of dinophysoid taxa performed to date and was consistent with the view that the genus Phalacroma may not be synonymous with Dinophysis. 相似文献
18.
Choudhary S Doherty KM Handy CJ Sayer JM Yagi H Jerina DM Brosh RM 《The Journal of biological chemistry》2006,281(9):6000-6009
RecQ helicases are believed to function in repairing replication forks stalled by DNA damage and may also play a role in the intra-S-phase checkpoint, which delays the replication of damaged DNA, thus permitting repair to occur. Since little is known regarding the effects of DNA damage on RecQ helicases, and because the replication and recombination defects in Werner syndrome cells may reflect abnormal processing of damaged DNA associated with the replication fork, we examined the effects of specific bulky, covalent adducts at N(6) of deoxyadenosine (dA) or N(2) of deoxyguanosine (dG) on Werner (WRN) syndrome helicase activity. The adducts are derived from the optically active 7,8-diol 9,10-epoxide (DE) metabolites of the carcinogen benzo[a]pyrene (BaP). The results demonstrate that WRN helicase activity is inhibited in a strand-specific manner by BaP DE-dG adducts only when on the translocating strand. These adducts either occupy the minor groove without significant perturbation of DNA structure (trans adducts) or cause base displacement at the adduct site (cis adducts). In contrast, helicase activity is only mildly affected by intercalating BaP DE-dA adducts that locally perturb DNA double helical structure. This differs from our previous observation that intercalating dA adducts derived from benzo[c]phenanthrene (BcPh) DEs inhibit WRN activity in a strand- and stereospecific manner. Partial unwinding of the DNA helix at BaP DE-dA adduct sites may make such adducted DNAs more susceptible to the action of helicase than DNA containing the corresponding BcPh DE-dA adducts, which cause little or no destabilization of duplex DNA. The single-stranded DNA binding protein RPA, an auxiliary factor for WRN helicase, enabled the DNA unwinding enzyme to overcome inhibition by either the trans-R or cis-R BaP DE-dG adduct, suggesting that WRN and RPA may function together to unwind duplex DNA harboring specific covalent adducts that otherwise block WRN helicase acting alone. 相似文献
19.
Handy DE Hang G Scolaro J Metes N Razaq N Yang Y Loscalzo J 《The Journal of biological chemistry》2006,281(6):3382-3388
Cellular glutathione peroxidase is a key intracellular antioxidant enzyme that contains a selenocysteine residue at its active site. Selenium, a selenocysteine incorporation sequence in the 3'-untranslated region of the glutathione peroxidase mRNA, and other translational cofactors are necessary for "read-through" of a UGA stop codon that specifies selenocysteine incorporation. Aminoglycoside antibiotics facilitate read-through of premature stop codons in prokayotes and eukaryotes. We studied the effects of G418, an aminoglycoside, on cellular glutathione peroxidase expression and function in mammalian cells. Insertion of a selenocysteine incorporation element along with a UGA codon into a reporter construct allows for read-through only in the presence of selenium. G418 increased read-through in selenium-replete cells as well as in the absence of selenium. G418 treatment increased immunodetectable endogenous or recombinant glutathione peroxidase but reduced the specific activity of the enzyme. Tandem mass spectrometry experiments indicated that G418 caused a substitution of l-arginine for selenocysteine. These data show that G418 can affect the biosynthesis of this key antioxidant enzyme by promoting substitution at the UGA codon. 相似文献
20.
Diane E. Handy Edith Lubos Yi Yang John D. Galbraith Neil Kelly Ying-Yi Zhang Jane A. Leopold Joseph Loscalzo 《The Journal of biological chemistry》2009,284(18):11913-11921
Glutathione peroxidase-1 (GPx-1) is a selenocysteine-containing enzyme that
plays a major role in the reductive detoxification of peroxides in cells. In
permanently transfected cells with approximate 2-fold overexpression of GPx-1,
we found that intracellular accumulation of oxidants in response to exogenous
hydrogen peroxide was diminished, as was epidermal growth factor receptor
(EGFR)-mediated Akt activation in response to hydrogen peroxide or EGF
stimulation. Knockdown of GPx-1 augmented EGFR-mediated Akt activation,
whereas overexpression of catalase decreased Akt activation, suggesting that
EGFR signaling is regulated by redox mechanisms. To determine whether
mitochondrial oxidants played a role in these processes, cells were pretreated
with a mitochondrial uncoupler prior to EGF stimulation. Inhibition of
mitochondrial function attenuated EGF-mediated activation of Akt in control
cells but had no additional effect in GPx-1-overexpressing cells, suggesting
that GPx-1 overexpression decreased EGFR signaling by decreasing mitochondrial
oxidants. Consistent with this finding, GPx-1 overexpression decreased global
protein disulfide bond formation, which is dependent on mitochondrially
produced oxidants. GPx-1 overexpression, in permanently transfected or
adenovirus-treated cells, also caused overall mitochondrial dysfunction with a
decrease in mitochondrial potential and a decrease in ATP production. GPx-1
overexpression also decreased EGF- and serum-mediated [3H]thymidine
incorporation, indicating that alterations in GPx-1 can attenuate cell
proliferation. Taken together, these data suggest that GPx-1 can modulate
redox-dependent cellular responses by regulating mitochondrial function.Accumulation of reactive oxygen species
(ROS),2 such as
superoxide anion and hydrogen peroxide, is thought to contribute to cellular
damage, apoptosis, and cell death
(1–3);
however, ROS production is part of normal cellular metabolism, and evidence is
accumulating that hydrogen peroxide, in particular, may function as a
signaling molecule necessary for cell growth and survival
(4–8).
Superoxide is generated as a byproduct of mitochondrial respiration and by
cellular redox enzymes, such as NADPH oxidase, that are stimulated through
receptor-mediated mechanisms
(9). Hydrogen peroxide is
formed from the dismutation of superoxide, which occurs spontaneously or can
be catalyzed by superoxide dismutase
(10) or, alternatively, is
produced by the two-electron enzymatic reduction of molecular oxygen by
various oxidases, such as xanthine oxidase
(11). Recent studies also
suggest that hydrogen peroxide may be directly generated by receptor-ligand
interactions (12). One
mechanism by which hydrogen peroxide may modulate signal transduction is
through the reversible oxidation of proteins at redox-active cysteines,
including, for example, thiols in tyrosine kinase phosphatases. Oxidation and
inactivation of phosphatases, such as PTEN, have been shown to promote the
activity of the pro-growth and -survival kinase, Akt
(13).Antioxidant enzymes, such as glutathione peroxidase, catalase, and
peroxiredoxins, serve to eliminate hydrogen peroxide, thereby regulating
cellular responses to this endogenous oxidant. GPx-1 is a selenoprotein and
one of a family of peroxidases that reductively inactivate peroxides using
glutathione as a source of reducing equivalents
(14,
15). GPx-1, in particular, is
a major intracellular antioxidant enzyme that is found in the cytoplasm and
mitochondria of all cell types. In cell culture models as well as in genetic
mouse models, GPx-1 overexpression is associated with enhanced protection
against oxidative stress
(16–19);
however, GPx-1-overexpressing mice can become obese and insulin-resistant, and
have attenuated insulin-mediated activation of Akt
(20). Thus, to study how GPx-1
modulates the effects of cellular oxidants on cell signaling and cell growth,
we analyzed cellular responses to hydrogen peroxide and EGF in permanently
transfected cells overexpressing GPx-1. 相似文献