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  • Ovid Technologies (Wolters Kluwer Health)  (18)
  • 1
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    Online Resource
    Abstract 12656: Phosphodiesterase 4 (PDE4) Inhibition Induces Weight Loss and Improves Insulin Resistance via cAMP-EPAC-AMPK Mediated Reprogramming of Macrophages
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Vol. 132, No. suppl_3 ( 2015-11-10)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)
    Abstract: Objective: Recent evidence suggests an important role for cAMP-dependent pathways in modulation of innate immune function. Phosphodiesterase 4 (PDE4) is widely expressed in innate immune cells such as macrophages/dendritic cells with potent anti-inflammatory effects on pharmacologic inhibition of the enzyme. We investigated the importance of PDE4 in diet-induced obesity (DIO) and hypothesized that PDE4 inhibition will improve insulin sensitivity and reduce inflammation. Methods and Results: PDE4 was upregulated in both visceral and subcutaneous (SubQ) white adipose tissue (WAT) in DIO mice (12 weeks of high-fat diet, HFD, 60% fat) compared to normal-chow diet (NCD) mice (↑4∼10-folds, p 〈 0.01). The degree of expression was correlated with macrophage infiltration in stromal vascular fraction from WAT (CD11b + F4/80 + cells, r=0.56, p 〈 0.05). Treatment with Roflumilast (3mg/kg/day), a high affinity inhibitor of PDE4 (IC 50 0.39 nM) versus vehicle control (n=6∼10 in each group) for 21 days concomitant with HFD, resulted in rapid and substantial weight loss (↓45.8% fat content), enhanced thermogenesis [(∼20% higher oxygen consumption and heat production, 0.7∼1.1°C higher core body temperature in a cold environment (4°C)], brown adipose reprogramming, improvement in insulin resistance (HOMA-IR ↓ from 0.69±0.04 to 0.44±0.01, p 〈 0.01) and hepatic steatosis. These changes were paralleled by increased alternative macrophage activation (Altf), reduced inflammation in WAT [↑CD206 and CD301 by flow cytometry with ↓ TNF/IL-6 gene expression] and activation of thermogenic genes in brown adipose tissue. In-vitro treatment of mouse bone marrow-derived macrophages (BMDM) promoted Altf and increased expression of tyrosine hydroxylase (↑2.5 folds) and catecholamines secretion. Additional experiments with agents that augment/reduce intracellular cAMP/EPAC/AMPK revealed an essential role for this cascade in Altf activation and catecholamine release. Conclusions: PDE4 antagonism improves obese diabetic symptoms through convergent pathways involving Altf activation and enhancing thermogenesis via cAMP dependent modulation of macrophage catecholamine release.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.132.suppl_3.12656
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1466401-X
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  • 2
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    Effect of Early Particulate Air Pollution Exposure on Obesity in Mice : Role of p47 phox
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 30, No. 12 ( 2010-12), p. 2518-2527
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 12 ( 2010-12), p. 2518-2527
    Abstract: Objective— To evaluate the role of early-life exposure to airborne fine particulate matter (diameter, 〈 2.5 μm [PM 2.5 ]) pollution on metabolic parameters, inflammation, and adiposity; and to investigate the involvement of oxidative stress pathways in the development of metabolic abnormalities. Methods and Results— PM 2.5 inhalation exposure (6 h/d, 5 d/wk) was performed in C57BL/6 mice (wild type) and mice deficient in the cytosolic subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47 phox (p47 phox−/− ) beginning at the age of 3 weeks for a duration of 10 weeks. Both groups were simultaneously fed a normal diet or a high-fat diet for 10 weeks. PM 2.5 -exposed C57BL/6 mice fed a normal diet exhibited metabolic abnormalities after exposure to PM 2.5 or FA for 10 weeks. Consistent with insulin resistance, these abnormalities included enlarged subcutaneous and visceral fat contents, increased macrophage infiltration in visceral adipose tissue, and vascular dysfunction. Ex vivo–labeled and infused monocytes demonstrated increased adherence in the microcirculation of normal diet– or high-fat diet–fed PM 2.5 -exposed mice. p47 phox−/− mice exhibited an improvement in parameters of insulin resistance, vascular function, and visceral inflammation in response to PM 2.5 . Conclusion— Early-life exposure to high levels of PM 2.5 is a risk factor for subsequent development of insulin resistance, adiposity, and inflammation. Reactive oxygen species generation by NADPH oxidase appears to mediate this risk.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.110.215350
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2010
    detail.hit.zdb_id: 1494427-3
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  • 3
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    Chronic Fine Particulate Matter Exposure Induces Systemic Vascular Dysfunction via NADPH Oxidase and TLR4 Pathways
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Research Vol. 108, No. 6 ( 2011-03-18), p. 716-726
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 108, No. 6 ( 2011-03-18), p. 716-726
    Abstract: Chronic exposure to ambient air-borne particulate matter of 〈 2.5 μm (PM 2.5 ) increases cardiovascular risk. The mechanisms by which inhaled ambient particles are sensed and how these effects are systemically transduced remain elusive. Objective: To investigate the molecular mechanisms by which PM 2.5 mediates inflammatory responses in a mouse model of chronic exposure. Methods and Results: Here, we show that chronic exposure to ambient PM 2.5 promotes Ly6C high inflammatory monocyte egress from bone-marrow and mediates their entry into tissue niches where they generate reactive oxygen species via NADPH oxidase. Toll-like receptor (TLR)4 and Nox2 (gp91 phox ) deficiency prevented monocyte NADPH oxidase activation in response to PM 2.5 and was associated with restoration of systemic vascular dysfunction. TLR4 activation appeared to be a prerequisite for NAPDH oxidase activation as evidenced by reduced p47 phox phosphorylation in TLR4 deficient animals. PM 2.5 exposure markedly increased oxidized phospholipid derivatives of 1-palmitoyl-2-arachidonyl- sn -glycero-3-phosphorylcholine (oxPAPC) in bronchioalveolar lavage fluid. Correspondingly, exposure of bone marrow–derived macrophages to oxPAPC but not PAPC recapitulated effects of chronic PM 2.5 exposure, whereas TLR4 deficiency attenuated this response. Conclusions: Taken together, our findings suggest that PM 2.5 triggers an increase in oxidized phospholipids in lungs that then mediates a systemic cellular inflammatory response through TLR4/NADPH oxidase–dependent mechanisms.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.110.237560
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1467838-X
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  • 4
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    Long-Term Dipeptidyl-Peptidase 4 Inhibition Reduces Atherosclerosis and Inflammation via Effects on Monocyte Recruitment and Chemotaxis
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Vol. 124, No. 21 ( 2011-11-22), p. 2338-2349
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 124, No. 21 ( 2011-11-22), p. 2338-2349
    Abstract: Dipeptidyl-peptidase 4 (DPP-4) inhibitors are increasingly used to accomplish glycemic targets in patients with type II diabetes mellitus. Because DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. Methods and Results— Male LDLR −/− mice (6 weeks) were fed a high-fat diet or normal chow diet for 4 weeks and then randomized to vehicle or alogliptin, a high-affinity DPP-4 inhibitor (40 mg · kg −1 · d −1 ), for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden, and indexes of inflammation were obtained in target tissues, including the vasculature, adipose, and bone marrow, with assessment of global and cell-specific inflammatory pathways. In vitro and in vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE −/− mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (adipose tissue macrophages; CD11b + , CD11c + , Ly6C hi ) concomitant with upregulation of CD163. DPP-4 was highly expressed in bone marrow–derived CD11b + cells, with DPP-4i downregulating proinflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in vitro assays via Rac-dependent mechanisms and prevented in vivo migration of labeled monocytes to the aorta in response to exogenous tumor necrosis factor-α and DPP-4. Conclusion— DPP-4i exerts antiatherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.111.041418
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1466401-X
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  • 5
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    A Modified Sesamol Derivative Inhibits Progression of Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 31, No. 3 ( 2011-03), p. 536-542
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 3 ( 2011-03), p. 536-542
    Abstract: Sesamol, a phenolic component of lignans, has been previously shown to reduce lipopolysaccharide-induced oxidative stress and upregulate phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase pathways. In the present study, we synthesized a modified form of sesamol (INV-403) to enhance its properties and assessed its effects on atherosclerosis. Methods and Results— Watanabe heritable hyperlipidemic rabbits were fed with high-cholesterol chow for 6 weeks and then randomized to receive high-cholesterol diet either alone or combined with INV-403 (20 mg/kg per day) for 12 weeks. Serial MRI analysis demonstrated that INV-403 rapidly reduced atherosclerotic plaques (within 6 weeks), with confirmatory morphological analysis at 12 weeks posttreatment revealing reduced atherosclerosis paralleled by reduction in lipid and inflammatory cell content. Consistent with its effect on atherosclerosis, INV-403 improved vascular function (decreased constriction to angiotensin II and increased relaxation to acetylcholine), reduced systemic and plaque oxidative stress, and inhibited nuclear factor–κB activation via effects on nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation with coordinate reduction in key endothelial adhesion molecules. In vitro experiments in cultured endothelial cells revealed effects of INV-403 in reducing IκBα phosphorylation via inhibition of IκB kinase 2 (IKK2). Conclusion— INV-403 is a novel modified lignan derivative that potently inhibits atherosclerosis progression via its effects on IKK2 and nuclear factor–κB signaling.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.110.219287
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1494427-3
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  • 6
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    Abstract 155: Antiatherosclerotic Effects of a Novel Pharmacologic Inhibitor of Myeloperoxidase in Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32, No. suppl_1 ( 2012-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. suppl_1 ( 2012-05)
    Abstract: Objective: Inflammation and oxidative stress play fundamental roles in the pathogenesis of atherosclerosis. Myeloperoxidase (MPO) has been extensively implicated as a key mediator of inflammatory and redox-dependent processes in atherosclerosis including reverse cholesterol transport. In this study, we investigated safety and efficacy of a novel small molecule inhibitor of MPO (INV-315) in atherosclerosis. Methods and results: ApoE -/- mice were randomized to low- and high-dose INV-315 groups for 16 weeks on high-fat diet. INV-315 resulted in reduced plaque burden and improved endothelial function in response to acetylcholine (26±4, 25±3 and 36±2% for atherosclerosis burden respectively and 42±7, 49±11 and 60.3±6% for maximal relaxation to acetylcholine in low, high dose and control groups respectively, p 〈 0.05 for high-dose vs. placebo for both). These effects occurred without adverse events or changes in body weight or blood pressure. INV-315 treatment resulted in a 2-3.5 fold decrease in iNOS gene expression, 1.9 fold decrease in superoxide production and 2-3.5 fold decrease in nitrotyrosine content in the aorta. Circulating IL-6 and inflammatory CD11b + /Ly6G low /7/4 hi monocytes were significantly decreased in response to INV-315 treatment. Acute pretreatment with INV-315 blocked TNFα-mediated leukocyte adhesion in cremasteric venules and inhibited MPO activity. Cholesterol efflux was significantly increased by high-dose INV-315 via ex-vivo reverse cholesterol transport assays. Conclusions: MPO inhibition may exert anti-atherosclerotic effects via inhibition of MPO-mediated oxidative stress and enhancement of cholesterol efflux. These findings demonstrate a role for pharmacologic modulation of MPO in atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.32.suppl_1.A155
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
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  • 7
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    Abstract 405: Central IKKß Inhibition Prevents Air Pollution--Mediated Peripheral Inflammation and Exaggeration of Type 2 Diabetes
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Abstract: Objective: Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter ( 〈 2.5 μm in aerodynamic diameter, PM 2.5 ) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM 2.5 -mediated diabetes development and the underlying mechanism. Approach and results: KKay mice, which are susceptible to Type II DM, were assigned to either concentrated PM 2.5 or filtered air (FA) for 4-8 weeks via a versatile aerosol concentrator and exposure system (n=7-8 for each group). PM 2.5 exposure led to hyperglycemia and insulin resistance, which were accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and increased microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor (IMD-0354, n=8 for each group), but not TNFα blockade with infliximab (n=6) for each group), improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O 2 consumption, CO 2 production, respiratory exchanging ratio and heat generation) and reduced peripheral inflammation in response to PM 2.5 . Conclusions: Central inhibition of IKKβ prevents PM 2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.405
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
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  • 8
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    Single ethanol binge causes severe liver injury in mice fed Western diet
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Hepatology Communications Vol. 7, No. 7 ( 2023-06-14)
    Details
    In: Hepatology Communications, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. 7 ( 2023-06-14)
    Type of Medium: Online Resource
    ISSN: 2471-254X
    URL: Article
    DOI: 10.1097/HC9.0000000000000174
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2881134-3
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  • 9
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    Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Hepatology Vol. 77, No. 5 ( 2023-05), p. 1688-1701
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 77, No. 5 ( 2023-05), p. 1688-1701
    Type of Medium: Online Resource
    ISSN: 0270-9139
    URL: Article
    DOI: 10.1002/hep.32675
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1472120-X
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  • 10
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    PYK2/PDZ-RhoGEF Links Ca 2+ Signaling to RhoA
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 29, No. 10 ( 2009-10), p. 1657-1663
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 10 ( 2009-10), p. 1657-1663
    Abstract: The mechanism by which vasoconstrictors activate RhoA remains elusive. In the present study, we show that in response to angiotensin II, PYK2 is activated and subsequently phosphorylates PDZ-RhoGEF. The PYK2/PDZ-RhoGEF pathway is sufficient to couple Ca 2+ signaling to RhoA, thus offering a mechanism involved in constrictor responses.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.109.190892
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
    detail.hit.zdb_id: 1494427-3
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