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  • 1
    Online Resource
    Online Resource
    NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease
    American Physiological Society ; 2014
    In:  American Journal of Physiology-Renal Physiology Vol. 306, No. 12 ( 2014-06-15), p. F1499-F1506
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 306, No. 12 ( 2014-06-15), p. F1499-F1506
    Abstract: Oxidative stress promotes vascular dysfunction in chronic kidney disease (CKD). We utilized the cutaneous circulation to test the hypothesis that reactive oxygen species derived from NADPH oxidase and xanthine oxidase impair nitric oxide (NO)-dependent cutaneous vasodilation in CKD. Twenty subjects, 10 stage 3 and 4 patients with CKD (61 ± 4 yr; 5 men/5 women; eGFR: 39 ± 4 ml·min −1 ·1.73 m −2 ) and 10 healthy controls (55 ± 2 yr; 4 men/6 women; eGFR: 〉 60 ml·min −1 ·1.73 m −2 ) were instrumented with 4 intradermal microdialysis fibers for the delivery of 1) Ringer solution (Control), 2) 10 μM tempol (scavenge superoxide), 3) 100 μM apocynin (NAD(P)H oxidase inhibition), and 4) 10 μM allopurinol (xanthine oxidase inhibition). Skin blood flow was measured via laser-Doppler flowmetry during standardized local heating (42°C). N g -nitro-l-arginine methyl ester (l-NAME; 10 mM) was infused to quantify the NO-dependent portion of the response. Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum CVC achieved during sodium nitroprusside infusion at 43°C. Cutaneous vasodilation was attenuated in patients with CKD (77 ± 3 vs. 88 ± 3%, P = 0.01), but augmented with tempol and apocynin (tempol: 88 ± 2 ( P = 0.03), apocynin: 91 ± 2% ( P = 0.001). The NO-dependent portion of the response was reduced in patients with CKD (41 ± 4 vs. 58 ± 2%, P = 0.04), but improved with tempol and apocynin (tempol: 58 ± 3 ( P = 0.03), apocynin: 58 ± 4% ( P = 0.03). Inhibition of xanthine oxidase did not alter cutaneous vasodilation in either group ( P 〉 0.05). These data suggest that NAD(P)H oxidase is a source of reactive oxygen species and contributes to microvascular dysfunction in patients with CKD.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00058.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1477287-5
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  • 2
    Online Resource
    Online Resource
    Context-dependent effects of CCN2 on β-cell mass expansion and indicators of cell stress in the setting of acute and chronic stress
    American Physiological Society ; 2023
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 325, No. 3 ( 2023-09-01), p. E280-E290
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 325, No. 3 ( 2023-09-01), p. E280-E290
    Abstract: Stimulation of functional β-cell mass expansion can be beneficial for the treatment of type 2 diabetes. Our group has previously demonstrated that the matricellular protein CCN2 can induce β-cell mass expansion during embryogenesis, and postnatally during pregnancy and after 50% β-cell injury. The mechanism by which CCN2 stimulates β-cell mass expansion is unknown. However, CCN2 does not induce β-cell proliferation in the setting of euglycemic and optimal functional β-cell mass. We thus hypothesized that β-cell stress is required for responsiveness to CCN2 treatment. In this study, a doxycycline-inducible β-cell-specific CCN2 transgenic mouse model was utilized to evaluate the effects of CCN2 on β-cell stress in the setting of acute (thapsigargin treatment ex vivo) or chronic [high-fat diet or leptin receptor haploinsufficiency (db/+) in vivo] cellular stress. CCN2 induction during 1 wk or 10 wk of high-fat diet or in db/ + mice had no effect on markers of β-cell stress. However, CCN2 induction did result in a significant increase in β-cell mass over high-fat diet alone when animals were fed high-fat diet for 10 wk, a duration known to induce insulin resistance. CCN2 induction in isolated islets treated with thapsigargin ex vivo resulted in upregulation of the gene encoding the Nrf2 transcription factor, a master regulator of antioxidant genes, suggesting that CCN2 further activates this pathway in the presence of cell stress. These studies indicate that the potential of CCN2 to induce β-cell mass expansion is context-dependent and that the presence of β-cell stress does not ensure β-cell proliferation in response to CCN2. NEW & NOTEWORTHY CCN2 promotes β-cell mass expansion in settings of suboptimal β-cell mass. Here, we demonstrate that the ability of CCN2 to induce β-cell mass expansion in the setting of β-cell stress is context-dependent. Our results suggest that β-cell stress is necessary but insufficient for CCN2 to increase β-cell proliferation and mass. Furthermore, we found that CCN2 promotes upregulation of a key antioxidant transcription factor, suggesting that modulation of β-cell oxidative stress contributes to the actions of CCN2.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00051.2023
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cβ
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 310, No. 8 ( 2016-04-15), p. L747-L758
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 310, No. 8 ( 2016-04-15), p. L747-L758
    Abstract: Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond β-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo ( n = 4 and n = 5, respectively, P 〈 0.001). Galangin and fisetin also relaxed acetylcholine-precontracted hASM strips ex vivo ( n = 6–8, P 〈 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine ( n = 6, P 〈 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) ( n = 7, P 〈 0.05; n = 7, P 〈 0.05, respectively), and PLCβ enzymes ( n = 6, P 〈 0.001 and n = 6, P 〈 0.001, respectively) attenuated procontractile G q agonists' increase in intracellular calcium ( n = 11, P 〈 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation ( n = 9, P 〈 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCβ and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00215.2015
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Designing Heart Performance by Gene Transfer
    American Physiological Society ; 2008
    In:  Physiological Reviews Vol. 88, No. 4 ( 2008-10), p. 1567-1651
    Details
    In: Physiological Reviews, American Physiological Society, Vol. 88, No. 4 ( 2008-10), p. 1567-1651
    Abstract: The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca 2+ handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.
    Type of Medium: Online Resource
    ISSN: 0031-9333 , 1522-1210
    URL: Article
    DOI: 10.1152/physrev.00039.2007
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1471693-8
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Ascorbic acid or l -arginine improves cutaneous microvascular function in chronic kidney disease
    American Physiological Society ; 2011
    In:  Journal of Applied Physiology Vol. 111, No. 6 ( 2011-12), p. 1561-1567
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 111, No. 6 ( 2011-12), p. 1561-1567
    Abstract: We sought to determine whether oxidative stress or a relative deficit of l-arginine plays a role in reducing cutaneous vasodilation in response to local heating in chronic kidney disease (CKD). Eight patients with stage 3–4 CKD and eight age- and sex-matched healthy control (HC) subjects were instrumented with four microdialysis (MD) fibers for the local delivery of 1) Ringers solution (R), 2) 20 mM ascorbic acid (AA), 3) 10 mM l-arginine (l-Arg), and 4) 10 mM N G -nitro-l-arginine methyl ester (l-NAME). Red blood cell (RBC) flux was measured via laser Doppler flowmetry. A standardized nonpainful local heating protocol (42°C) was used. Cutaneous vascular conductance (CVC) was calculated as RBC flux/MAP and all data were expressed as a percentage of the maximum CVC at each site (28 mM sodium nitroprusside, T loc = 43°C). The plateau %CVC max was attenuated in CKD (CKD: 76 ± 4 vs. HC: 91 ± 2%CVC max ; P 〈 0.05) and the NO contribution to the plateau was lower in CKD (CKD: 39 ± 7, HC: 54 ± 5; P 〈 0.05). The plateau %CVC max in the CKD group was significantly greater at the AA and l-Arg sites compared with R (AA: 89 ± 2; l-Arg: 90 ± 1; R: 76 ± 4; P 〈 0.05) and did not differ from HC. Initial peak %CVC max was also significantly attenuated at the R and l-Arg sites in CKD ( P 〈 0.05) but did not differ at the AA site. These results suggest that cutaneous microvascular function is impaired in stage 3–4 CKD and that oxidative stress and a deficit of l-arginine play a role in this impairment.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.00419.2011
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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