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  • Nature Publishing Group (NPG)  (11)
  • The American Physiological Society (APS)  (10)
  • American Society of Hematology (ASH)  (3)
Publikationsart
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  • 1
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    Adenylyl cyclase type 5 in cardiac disease, metabolism, and aging (2013)
    The American Physiological Society (APS)
    Details
    Publikationsdatum: 2013-07-02
    Beschreibung: G protein-coupled receptor/adenylyl cyclase (AC)/cAMP signaling is crucial for all cellular responses to physiological and pathophysiological stimuli. There are nine isoforms of membrane-bound AC, with type 5 being one of the two major isoforms in the heart. Since the role of AC in the heart in regulating cAMP and acute changes in inotropic and chronotropic state are well known, this review will address our current understanding of the distinct regulatory role of the AC5 isoform in response to chronic stress. Transgenic overexpression of AC5 in cardiomyocytes of the heart (AC5-Tg) improves baseline cardiac function but impairs the ability of the heart to withstand stress. For example, chronic catecholamine stimulation induces cardiomyopathy, which is more severe in AC5-Tg mice, mediated through the AC5/sirtuin 1/forkhead box O3a pathway. Conversely, disrupting AC5, i.e., AC5 knockout, protects the heart from chronic catecholamine cardiomyopathy as well as the cardiomyopathies resulting from chronic pressure overload or aging. Moreover, AC5 knockout results in a 30% increase in a healthy life span, resembling the most widely studied model of longevity, i.e., calorie restriction. These two models of longevity share similar gene regulation in the heart, muscle, liver, and brain in that they are both protected against diabetes, obesity, and diabetic and aging cardiomyopathy. A pharmacological inhibitor of AC5 also provides protection against cardiac stress, diabetes, and obesity. Thus AC5 inhibition has novel, potential therapeutic applicability to several diseases not only in the heart but also in aging, diabetes, and obesity.
    Print ISSN: 0363-6135
    Digitale ISSN: 1522-1539
    Thema: Medizin
    Publiziert von The American Physiological Society (APS)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    Disruption of type 5 adenylyl cyclase prevents {beta}-adrenergic receptor cardiomyopathy: A novel approach to {beta}-adrenergic receptor blockade (2014)
    The American Physiological Society (APS)
    Details
    Publikationsdatum: 2014-11-16
    Beschreibung: β-Adrenergic receptor (β-AR) blockade is widely used to treat heart failure, since the adverse effects of chronic β-AR stimulation are central to the pathogenesis of this disease state. Transgenic (Tg) mice, where β-AR signaling is chronically enhanced by overexpression of cardiac β 2 -ARs, is a surrogate for this mechanism, since these mice develop cardiomyopathy as reflected by reduced left ventricular (LV) function, increased fibrosis, apoptosis, and myocyte hypertrophy. We hypothesized that disruption of type 5 adenylyl cyclase (AC5), which is in the β-AR signaling pathway in the heart, but exerts only a minor β-AR blocking effect, could prevent the cardiomyopathy in β 2 -AR Tg mice without the negative effects of full β-AR blockade. Accordingly, we mated β 2 -AR Tg mice with AC5 knockout (KO) mice. The β 2 -AR Tg x AC5 KO bigenic mice prevented the cardiomyopathy as reflected by improved LV ejection fraction, reduced apoptosis, fibrosis, and myocyte size and preserved exercise capacity. The rescue was not simply due to a β-blocking effect of AC5 KO, since neither baseline LV function nor the response to isoproterenol was diminished substantially compared with the negative inotropic effects of β-blockade. However, AC5 disruption in β 2 -AR Tg activates the antioxidant, manganese superoxide dismutase, an important mechanism protecting the heart from cardiomyopathy. These results indicate that disruption of AC5 prevents the cardiomyopathy induced by chronically enhanced β-AR signaling in mice with overexpressed β 2 -AR, potentially by enhancing resistance to oxidative stress and apoptosis, suggesting a novel, alternative approach to β-AR blockade.
    Print ISSN: 0363-6135
    Digitale ISSN: 1522-1539
    Thema: Medizin
    Publiziert von The American Physiological Society (APS)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    Adenanthin targets peroxiredoxin I/II to kill hepatocellular carcinoma cells (2014)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2014-09-05
    Beschreibung: Adenanthin targets peroxiredoxin I/II to kill hepatocellular carcinoma cells Cell Death and Disease 5, e1400 (September 2014). doi:10.1038/cddis.2014.345 Authors: J-K Hou, Y Huang, W He, Z-W Yan, L Fan, M-H Liu, W-L Xiao, H-D Sun & G-Q Chen
    Digitale ISSN: 2041-4889
    Thema: Biologie , Medizin
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
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    Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner (2012)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2012-10-09
    Beschreibung: Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner Nutrition and Diabetes 2, e49 (October 2012). doi:10.1038/nutd.2012.23 Authors: J Yan, L B Winter, B Burns-Whitmore, F Vermeylen & M A Caudill
    Schlagwort(e): cholinebetainebody mass indexmetabolic stressphosphatidylethanolamine N-methyltransferase 5465GA (rs7946)methylenetetrahydrofolate dehydrogenase 1 1958GA (rs2236225)
    Digitale ISSN: 2044-4052
    Thema: Medizin
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance (2018)
    Nature Publishing Group (NPG)
    In: Oncogene
    Details
    Publikationsdatum: 2018-11-03
    Beschreibung: Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance, Published online: 02 November 2018; doi:10.1038/s41388-018-0557-9 Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance
    Print ISSN: 0950-9232
    Thema: Medizin
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    Catalpol restores LPS-elicited rat microcirculation disorder by regulation of a network of signaling involving inhibition of TLR-4 and SRC (2016)
    The American Physiological Society (APS)
    Details
    Publikationsdatum: 2016-12-15
    Beschreibung: LPS-induced microvascular hyperpermeability and hemorrhage play a key role in the development of sepsis, the attenuation of which might be an important strategy to prevent sepsis. However, the current clinical therapies have proven to be inefficient in improving the prognosis for patients with sepsis. Catalpol, an iridoid glycoside extracted from the roots of Rehmannia , has been reported to protect against LPS-induced acute lung injury through a Toll-like receptor-4 (TLR-4)-mediated NF-B signaling pathway. However, it is still unknown whether catalpol can be an effective treatment to ameliorate the LPS-induced microvascular disorder. The present study aimed to investigate the impact of catalpol on LPS-induced mesenteric microvascular disorder and its underlying mechanism. Male Wistar rats were challenged by infusion of LPS (10 mg·kg –1 ·h –1 ) through the left femoral vein for 120 min. Post-treatment with catalpol (10 mg/kg) alleviated the LPS-induced microvascular hyperpermeability and hemorrhage; reduced mortality; ameliorated the alteration in the distribution of claudin-5 and the junctional adhesion molecule-1, as well as the degradation of collagen IV and laminin; and attenuated the increase of TLR-4 level, phosphorylations of Src tyrosine kinase, phosphatidyl inositol 3-kinase, focal adhesion kinase, and cathepsin B activation. In vitro study in human umbilical vein endothelial cells verified these results and further revealed that inhibition of TLR-4 and Src each simulated some, but not all, of the effects that catalpol exerted. Besides, surface plasmon resonance showed that catalpol could directly bind to TLR-4 and Src. These results demonstrated that catalpol was able to ameliorate the LPS-induced microvascular barrier damage and hemorrhage by targeting both TLR-4 and Src, thus attenuating the phosphorylation of Src kinase, phosphatidyl inositol 3-kinase, and focal adhesion kinase, as well as cathepsin B activation.
    Print ISSN: 0193-1857
    Digitale ISSN: 1522-1547
    Thema: Medizin
    Publiziert von The American Physiological Society (APS)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation (2018)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publikationsdatum: 2018-06-01
    Beschreibung: Although survival outcomes have significantly improved, up to 40% of patients die within 1 year of HLA-matched unrelated-donor blood and marrow transplantation (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2473 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome and 2221 10/10 HLA-matched donors treated from 2000 to 2011. Single-variant and gene-level analyses were performed on overall survival (OS), transplantation-related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of testis-expressed gene TEX38 significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using the SKAT-O test to evaluate gene-level effects, variant genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, 4 ( ALPP , EMID1 , SLC44A5 , LRP1 ), 1 ( HHAT ), and 2 genes ( LYZL4 , NT5E ) were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures showed 4 of the associated variants affected the enzyme structure and likely decreased the catalytic efficiency of the enzyme. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies.
    Schlagwort(e): Transplantation
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology (ASH)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    FATS is an E2-independent ubiquitin ligase that stabilizes p53 and promotes its activation in response to DNA damage (2014)
    Nature Publishing Group (NPG)
    In: Oncogene
    Details
    Publikationsdatum: 2014-11-21
    Beschreibung: FATS is an E2-independent ubiquitin ligase that stabilizes p53 and promotes its activation in response to DNA damage Oncogene 33, 5424 (20 November 2014). doi:10.1038/onc.2013.494 Authors: S Yan, L Qiu, K Ma, X Zhang, Y Zhao, J Zhang, X Li, X Hao & Z Li
    Schlagwort(e): FATSubiquitin linkagep53DNA damageMdm2
    Print ISSN: 0950-9232
    Thema: Medizin
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    Short-chain fatty acids and acidic pH upregulate UT-B, GPR41, and GPR4 in rumen epithelial cells of goats (2015)
    The American Physiological Society (APS)
    Details
    Publikationsdatum: 2015-02-16
    Beschreibung: Currently, the mechanism(s) responsible for the regulation of urea transporter B (UT-B) expression levels in the epithelium of the rumen remain unclear. We hypothesized that rumen fermentation products affect ruminal UT-B expression. Therefore, the effects of short-chain fatty acids (SCFA), pH, ammonia, and urea on mRNA and protein levels of UT-B were assayed in primary rumen epithelial cell cultures and in rumen epithelium obtained from intact goats. In vitro, SCFA and acidic pH were found to synergetically stimulate both mRNA and protein expression of UT-B, whereas NH 4 Cl decreased mRNA and protein levels of UT-B at pH 6.8. Treatment with urea increased both levels at pH 7.4. When goats received a diet rich in nitrogen (N) and nonfiber carbohydrates (NFC), their rumen epithelium had higher levels of UT-B, and the rumen contained higher concentrations of SCFA and NH 3 -N with a lower pH. An increase in plasma urea-N concentration was also observed compared with the plasma of the goats that received a diet low in N and NFC. In a second feeding trial, goats that received a NFC-rich, but isonitrogenous, diet had higher mRNA and protein levels of UT-B, and higher levels of G protein-coupled receptor (GPR) 41 and GPR4, in their rumen epithelium. The ruminal concentrations of SCFA and NH 3 -N also increased, while a lower pH was detected. In contrast, the serum urea-N concentrations remained unchanged. These data indicate that ruminal SCFA and pH are key factors, via GPR4 and GPR41, in the dietary regulation of UT-B expression, and they have priority over changes in plasma urea.
    Print ISSN: 0363-6119
    Digitale ISSN: 1522-1490
    Thema: Medizin
    Publiziert von The American Physiological Society (APS)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate to the heart (2015)
    The American Physiological Society (APS)
    Details
    Publikationsdatum: 2015-02-02
    Beschreibung: Inhibition of β-adrenergic receptor (β-AR) signaling is one of the most common therapeutic approaches for patients with arrhythmias. Adenylyl cyclase (AC) is the key enzyme responsible for transducing β-AR stimulation to increases in cAMP. The two major AC isoforms in the heart are types 5 and 6. Therefore, it is surprising that prior studies on overexpression of AC5 and AC6 in transgenic (Tg) mice have not examined mediation of arrhythmogenesis. Our goal was to examine the proarrhythmic substrate in AC5Tg hearts. Intracellular calcium ion (Ca 2+ i ) was imaged in fluo-4 AM-loaded ventricular myocytes. The sarcoplasmic reticulum (SR) Ca 2+ content, fractional Ca 2+ release, and twitch Ca 2+ transient were significantly higher in the AC5Tg vs. wild-type (WT) myocytes, indicating Ca 2+ overload in AC5Tg myocytes. Action potential (AP) duration was significantly longer in AC5Tg than in WT myocytes. Additionally, AC5Tg myocytes developed spontaneous Ca 2+ waves in a larger fraction compared with WT myocytes, particularly when cells were exposed to isoproterenol. The Ca 2+ waves further induced afterdepolarizations and triggered APs. AC5Tg hearts had increased level of SERCA2a, oxidized Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), and phosphorylation of ryanodine receptors (RyR) at the CaMKII site, especially after isoproterenol treatment. This was consistent with higher reactive oxygen species production in AC5Tg myocytes after isoproterenol treatment. Isoproterenol induced more severe arrhythmias in AC5Tg than in WT mice. We conclude that AC5 overexpression promotes arrhythmogenesis, by inducing SR Ca 2+ overload and hyperactivation of RyR (phosphorylation by CaMKII), which in turn induces spontaneous Ca 2+ waves and afterdepolarizations.
    Print ISSN: 0363-6135
    Digitale ISSN: 1522-1539
    Thema: Medizin
    Publiziert von The American Physiological Society (APS)
    Standort Signatur Einschränkungen Verfügbarkeit
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