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71.
Komal Sodhi Nitin Puri Gaia Favero Sarah Stevens Charles Meadows Nader G. Abraham Rita Rezzani Hayden Ansinelli Edward Lebovics Joseph I. Shapiro 《PloS one》2015,10(6)
Background
Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.Hypothesis
We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.Methods and Results
We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP.Conclusion
Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression. 相似文献72.
73.
Giselle?L?Ferrari Jefferson?LB?Marques Rajiv?A?Gandhi Simon?R?Heller Fábio?K?Schneider Solomon?Tesfaye Humberto?R?GambaEmail author 《Biomedical engineering online》2010,9(1):26
Background
Autonomic neuropathy is a common and serious complication of diabetes. Early detection is essential to enable appropriate interventional therapy and management. Dynamic pupillometry has been proposed as a simpler and more sensitive tool to detect subclinical autonomic dysfunction. The aim of this study was to investigate pupil responsiveness in diabetic subjects with and without cardiovascular autonomic neuropathy (CAN) using dynamic pupillometry in two sets of experiments. 相似文献74.
The aim of the present research was to evaluate the potential of galactosylated low molecular weight chitosan (Gal-LMWC) nanoparticles
bearing positively charged anticancer, doxorubicin (DOX) for hepatocyte targeting. The chitosan from crab shell was depolymerized,
and the lactobionic acid was coupled with LMWC using carbodiimide chemistry. The depolymerized and galactosylated polymers
were characterized. Two types of Gal-LMWC(s) with variable degree of substitution were employed to prepare the nanoparticles
using ionotropic gelation with pentasodium tripolyphosphate anions. Factors affecting nanoparticles formation were discussed.
The nanoparticles were characterized by transmission electron microscopy and photon correlation spectroscopy and found to
be spherical in the size range 106–320 nm. Relatively higher percent DOX entrapment was obtained for Gal-LMWC(s) nanoparticles
than for LMWC nanoparticles. A further increase in drug entrapment was found with nanoparticles prepared by Gal-LMWC with
higher degree of substitution. A hypothesis which correlates the ionic concentration of DOX in nanoparticles preparation medium
and percent DOX entrapment in cationic polymer has been proposed to explain the enhanced DOX entrapment. In-vitro drug release study demonstrated an initial burst release followed by a sustained release. The targeting potential of the
prepared nanoparticles was assessed by in vitro cytotoxicity study using the human hepatocellular carcinoma cell line (HepG2) expressing the ASGP receptors on their surfaces. The enthusiastic results showed the feasibility of Gal-LMWC(s) to entrap
the cationic DOX and targeting potential of developed Gal-LMWC(s) nanoparticles to HepG2 cell line. 相似文献
75.
Kirkpong Kiatpanichagij Nitin Afzulpurkar 《Biomedical signal processing and control》2009,4(2):127-138
This paper describes a preprocessing stage for nonlinear classifier used in wavelet packet transformation (WPT)-based multichannel surface electromyogram (EMG) classification. The preprocessing stage named sdPCA, which consists of supervised discretization coupled with principal component analysis (PCA), was developed for improving surface EMG classifier generalization ability and training speed on overlap segmented signals. The sdPCA outperforms the fast correlation-based filter (FCBF), PCA, supervised discretization, and their combinations in terms of the highest generalization ability, fast training speed, the small feature size, and an ability to reduce the risks of developing oscillation and being trapped in nonlinear classifier training. The experiments were conducted on a data set consisting of 4-channel surface EMG signals measured from 6 hand and wrist gestures of 12 subjects. The experimental results indicate that the classification system using sdPCA has the highest generalization ability along with the second fastest training speed. The classification accuracy in 12 subjects of the system using sdPCA is 93.30 ± 2.42% taking 400 epochs for training by overlap segmented signals within 100 s. This result is very attractive for further development because we can achieve high-classification accuracy for large data sets by means of the proposed sdPCA without the application of additional algorithms such as local discriminant bases (LDB), majority voting (MV), or WPT sub-bands clustering. 相似文献
76.
Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors
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Blankson JN Bailey JR Thayil S Yang HC Lassen K Lai J Gandhi SK Siliciano JD Williams TM Siliciano RF 《Journal of virology》2007,81(5):2508-2518
Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who control viremia to levels below the limit of detection of current assays. The mechanisms involved in this control have not been fully elucidated. Several studies have demonstrated that some ES are infected with defective viruses, but it remains unclear whether others are infected with replication-competent HIV-1. To answer this question, we used a sensitive coculture assay in an attempt to isolate replication-competent virus from a cohort of 10 ES. We successfully cultured six replication-competent isolates from 4 of the 10 ES. The frequency of latently infected cells in these patients was more than a log lower than that seen in patients on highly active antiretroviral therapy with undetectable viral loads. Full-length sequencing of all six isolates revealed no large deletions in any of the genes. A few mutations and small insertions and deletions were found in some isolates, but phenotypic analysis of the affected genes suggested that their function remained intact. Furthermore, all six isolates replicated as well as standard laboratory strains in vitro. The results suggest that some ES are infected with HIV-1 isolates that are fully replication competent and that long-term immunologic control of replication-competent HIV-1 is possible. 相似文献
77.
Aggarwal NT Holmes BB Cui L Viita H Yla-Herttuala S Campbell WB 《American journal of physiology. Heart and circulatory physiology》2007,292(2):H1033-H1041
Endothelium-dependent vasorelaxation of the rabbit aorta is mediated by either nitric oxide (NO) or arachidonic acid (AA) metabolites from cyclooxygenase (COX) and 15-lipoxygenase (15-LO) pathways. 15-LO-1 metabolites of AA, 11,12,15-trihydroxyeicosatrienoic acid (THETA), and 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA) cause concentration-dependent relaxation. We tested the hypothesis that in the 15-LO pathway of AA metabolism, 15-LO-1 is sufficient and is the rate-limiting step in inducing relaxations in rabbit aorta. Aorta and rabbit aortic endothelial cells were treated with adenoviruses containing human 15-LO-1 cDNA (Ad-15-LO-1) or beta-galactosidase (Ad-beta-Gal). Ad-15-LO-1-transduction increased the expression of a 75-kDa protein corresponding to 15-LO-1, detected by immunoblotting with an anti-human15-LO-1 antibody, and increased the production of HEETA and THETA from [(14)C]AA. Immunohistochemical studies on Ad-15-LO-1-transduced rabbit aorta showed the presence of 15-LO-1 in endothelial cells. Ad-15-LO-1-treated aortic rings showed enhanced relaxation to AA (max 31.7 +/- 3.2%) compared with Ad-beta-Gal-treated (max 12.7 +/- 3.2%) or control nontreated rings (max 13.1 +/- 1.6%) (P < 0.01). The relaxations in Ad-15-LO-1-treated aorta were blocked by the 15-LO inhibitor cinnamyl-3,4-dihydroxy-a-cyanocinnamate. Overexpression of 15-LO-1 in the rabbit aortic endothelium is sufficient to increase the production of the vasodilatory HEETA and THETA and enhance the relaxations to AA. This confirms the role of HEETA and THETA as endothelium-derived relaxing factors. 相似文献
78.
Musayev FN di Salvo ML Ko TP Gandhi AK Goswami A Schirch V Safo MK 《Protein science : a publication of the Protein Society》2007,16(10):2184-2194
Pyridoxal kinase catalyzes the transfer of a phosphate group from ATP to the 5' alcohol of pyridoxine, pyridoxamine, and pyridoxal. In this work, kinetic studies were conducted to examine monovalent cation dependence of human pyridoxal kinase kinetic parameters. The results show that hPLK affinity for ATP and PL is increased manyfold in the presence of K(+) when compared to Na(+); however, the maximal activity of the Na(+) form of the enzyme is more than double the activity in the presence of K(+). Other monovalent cations, Li(+), Cs(+), and Rb(+) do not show significant activity. We have determined the crystal structure of hPLK in the unliganded form, and in complex with MgATP to 2.0 and 2.2 A resolution, respectively. Overall, the two structures show similar open conformation, and likely represent the catalytically idle state. The crystal structure of the MgATP complex also reveals Mg(2+) and Na(+) acting in tandem to anchor the ATP at the active site. Interestingly, the active site of hPLK acts as a sink to bind several molecules of MPD. The features of monovalent and divalent metal cation binding, active site structure, and vitamin B6 specificity are discussed in terms of the kinetic and structural studies, and are compared with those of the sheep and Escherichia coli enzymes. 相似文献
79.
Gandhi SG Rafii B Harris MS Garces A Mahuran D Chen XJ Bao HF Jain L Eaton DC Otulakowski G O'Brodovich H 《American journal of physiology. Lung cellular and molecular physiology》2007,293(3):L651-L659
We have previously shown that cardiogenic pulmonary edema fluid (EF) increases Na(+) and fluid transport by fetal distal lung epithelia (FDLE) (Rafii B, Gillie DJ, Sulowski C, Hannam V, Cheung T, Otulakowski G, Barker PM and O'Brodovich H. J Physiol 544: 537-548, 2002). We now report the effect of EF on Na(+) and fluid transport by the adult lung. We first studied primary cultures of adult type II (ATII) epithelium and found that overnight exposure to EF increased Na(+) transport, and this effect was mainly due to factors other than catecholamines. Plasma did not stimulate Na(+) transport in ATII. Purification of EF demonstrated that at least some agent(s) responsible for the amiloride-insensitive component resided within the globulin fraction. ATII exposed to globulins demonstrated a conversion of amiloride-sensitive short-circuit current (I(sc)) to amiloride-insensitive I(sc) with no increase in total I(sc). Patch-clamp studies showed that ATII exposed to EF for 18 h had increased the number of highly selective Na(+) channels in their apical membrane. In situ acute exposure to EF increased the open probability of Na(+)-permeant ion channels in ATII within rat lung slices. EF did increase, by amiloride-sensitive pathways, the alveolar fluid clearance from the lungs of adult rats. We conclude that cardiogenic EF increases Na(+) transport by adult lung epithelia in primary cell culture, in situ and in vivo. 相似文献
80.
MeTaDoR: a comprehensive resource for membrane targeting domains and their host proteins 总被引:1,自引:0,他引:1
MOTIVATION: Protein-lipid interactions play a central role in cellular signaling and membrane trafficking and at the core of these interactions are domains specialized in lipid binding and membrane targeting. Considering the importance of these domains, we have created MeTaDoR, a comprehensive resource dedicated to membrane targeting domains (MTDs). RESULT: MeTaDoR begins with a brief introduction about all the important MTDs including their subcellular localization and structural features. Sequences of all known MTDs are then provided in two formats: standard Prosite format and a parsed tab-delimited format that provides a manually curated classification into binding or non-binding. Structures of all MTDs and host proteins known so far are provided with links to PDB and Pfam databases. Membrane-binding orientation of these proteins, whether experimentally determined or proposed, is also provided with links to the appropriate literature. To facilitate molecular dynamics studies of these proteins, the force-field parameters for many non-standard lipids that commonly interact with these proteins are also provided. Finally, an online server for predicting membrane-binding proteins and a search function with various search fields are included. The resource is publicly available and will be updated on a regular basis. 相似文献