X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Type of Medium
Publisher
Person/Organisation
Language
Years
FID
Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    Novel Mechanism of Foxo1 Phosphorylation in Glucagon Signaling in Control of Glucose Homeostasis
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 11 ( 2018-11-01), p. 2167-2182
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 11 ( 2018-11-01), p. 2167-2182
    Abstract: Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes. The pancreatic hormone glucagon increases and insulin suppresses HGP, controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser256 in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A–dependent phosphorylation of Foxo1 at Ser276. Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser276 phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser276 is a new target site identified in the control of Foxo1 bioactivity and associated metabolic diseases.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db18-0674
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 2
    Online Resource
    Online Resource
    Towards a generic prototyping approach for therapeutically-relevant peptides and proteins in a cell-free translation system
    Springer Science and Business Media LLC ; 2022
    In:  Nature Communications Vol. 13, No. 1 ( 2022-01-11)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-01-11)
    Abstract: Advances in peptide and protein therapeutics increased the need for rapid and cost-effective polypeptide prototyping. While in vitro translation systems are well suited for fast and multiplexed polypeptide prototyping, they suffer from misfolding, aggregation and disulfide-bond scrambling of the translated products. Here we propose that efficient folding of in vitro produced disulfide-rich peptides and proteins can be achieved if performed in an aggregation-free and thermodynamically controlled folding environment. To this end, we modify an E. coli -based in vitro translation system to allow co-translational capture of translated products by affinity matrix. This process reduces protein aggregation and enables productive oxidative folding and recycling of misfolded states under thermodynamic control. In this study we show that the developed approach is likely to be generally applicable for prototyping of a wide variety of disulfide-constrained peptides, macrocyclic peptides with non-native bonds and antibody fragments in amounts sufficient for interaction analysis and biological activity assessment.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-27854-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2553671-0
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 3
    Online Resource
    Online Resource
    Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure
    Bioscientifica ; 2017
    In:  Journal of Endocrinology Vol. 233, No. 3 ( 2017-06), p. R131-R143
    Details
    In: Journal of Endocrinology, Bioscientifica, Vol. 233, No. 3 ( 2017-06), p. R131-R143
    Abstract: The heart is an insulin-dependent and energy-consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth and survival. Heart failure is highly associated with insulin resistance, and heart failure patients suffer from the cardiac energy deficiency and structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrates 1 and 2 (IRS-1,-2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in the activation of the phosphatidylinositide-3-dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism and the renin–angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function.
    Type of Medium: Online Resource
    ISSN: 0022-0795 , 1479-6805
    URL: Article
    DOI: 10.1530/JOE-16-0679
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2017
    detail.hit.zdb_id: 1474892-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 4
    Online Resource
    Online Resource
    RTEF-1 Attenuates Blood Glucose Levels by Regulating Insulin-Like Growth Factor Binding Protein-1 in the Endothelium
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Circulation Research Vol. 111, No. 8 ( 2012-09-28), p. 991-1001
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 111, No. 8 ( 2012-09-28), p. 991-1001
    Abstract: Related transcriptional enhancer factor-1 (RTEF-1) plays an important role in endothelial cell function by regulating angiogenesis; however, the mechanism underlying the role of RTEF-1 in the endothelium in vivo is not well defined. Objective: We investigated the biological functions of RTEF-1 by disrupting the gene that encodes it in mice endothelium -specific RTEF-1–deficient transgenic mice (RTEF-1 –/– ). Methods and Results: RTEF-1 −/− mice showed significantly increased blood glucose levels and insulin resistance, accompanied by decreased levels of insulin-like growth factor binding protein-1 (IGFBP-1) mRNA in the endothelium and decreased serum IGFBP-1 levels. Additionally, the RTEF-1 −/− phenotype was exacerbated when the mice were fed a high-fat diet, which correlated with decreased IGFBP-1 levels. In contrast, vascular endothelial cadherin/RTEF-1–overexpressing 1 transgenic mice (VE-Cad/RTEF1) demonstrated improved glucose clearance and insulin sensitivity in response to a high-fat diet. Furthermore, we demonstrated that RTEF-1 upregulates IGFBP-1 through selective binding and promotion of transcription from the insulin response element site. Insulin prevented RTEF-1 expression and significantly inhibited IGFBP-1 transcription in endothelial cells in a dose-dependent fashion. Conclusions: To the best of our knowledge, this is the first report demonstrating that RTEF-1 stimulates promoter activity through an insulin response element and also mediates the effects of insulin on gene expression. These results show that RTEF-1–stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels. These findings provide the basis for novel insights into the transcriptional regulation of IGFBP-1 and contribute to our understanding of the role of vascular endothelial cells in metabolism.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.112.268110
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467838-X
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 5
    Online Resource
    Online Resource
    Metformin Targets Foxo1 to Control Glucose Homeostasis
    MDPI AG ; 2021
    In:  Biomolecules Vol. 11, No. 6 ( 2021-06-11), p. 873-
    Details
    In: Biomolecules, MDPI AG, Vol. 11, No. 6 ( 2021-06-11), p. 873-
    Abstract: Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.
    Type of Medium: Online Resource
    ISSN: 2218-273X
    URL: Article
    DOI: 10.3390/biom11060873
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2701262-1
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 6
    Online Resource
    Online Resource
    Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice
    The Endocrine Society ; 2019
    In:  Endocrinology Vol. 160, No. 5 ( 2019-05-01), p. 1333-1347
    Details
    In: Endocrinology, The Endocrine Society, Vol. 160, No. 5 ( 2019-05-01), p. 1333-1347
    Abstract: The transcription factor forkhead box O1 (FoxO1) is a key mediator in the insulin signaling pathway and controls multiple physiological functions, including hepatic glucose production (HGP) and pancreatic β-cell function. We previously demonstrated that S256 in human FOXO1 (FOXO1-S256), equivalent to S253 in mouse FoxO1 (FoxO1-S253), is a key phosphorylation site mediating the effect of insulin as a target of protein kinase B on suppression of FOXO1 activity and expression of target genes responsible for gluconeogenesis. Here, we investigated the role of FoxO1-S253 phosphorylation in control of glucose homeostasis in vivo by generating global FoxO1-S253A/A knockin mice, in which FoxO1-S253 alleles were replaced with alanine (A substitution) blocking FoxO1-S253 phosphorylation. FoxO1-S253A/A mice displayed mild increases in feeding blood glucose and insulin levels but decreases in fasting blood glucose and glucagon concentrations, as well as a reduction in the ratio of pancreatic α-cells/β-cells per islet. FoxO1-S253A/A mice exhibited a slight increase in energy expenditure but barely altered food intake and glucose uptake among tissues. Further analyses revealed that FoxO1-S253A/A enhances FoxO1 nuclear localization and promotes the effect of glucagon on HGP. We conclude that dephosphorylation of S253 in FoxO1 may reflect a molecular basis of pancreatic plasticity during the development of insulin resistance.
    Type of Medium: Online Resource
    ISSN: 1945-7170
    URL: Article
    DOI: 10.1210/en.2018-00853
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2019
    detail.hit.zdb_id: 2011695-0
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 7
    Online Resource
    Online Resource
    Effects of poly aluminum chloride dosing positions on the performance of a pilot scale anoxic/oxic-membrane bioreactor (A/O-MBR)
    IWA Publishing ; 2015
    In:  Water Science and Technology Vol. 72, No. 5 ( 2015-09-01), p. 689-695
    Details
    In: Water Science and Technology, IWA Publishing, Vol. 72, No. 5 ( 2015-09-01), p. 689-695
    Abstract: The effects of poly aluminum chloride (PACl) dosing positions on the performance of a pilot scale anoxic/oxic membrane bioreactor were investigated. PACl dosage was optimized at 19.5 mg Al2O3/L by jar test. Nutrients removal efficiencies and sludge properties were systematically investigated during periods with no PACl dosing (phase I), with PACl dosing in oxic tank (phase II) and then in anoxic tank (phase III). The results showed that total phosphorus removal efficiency increased from 18 to 88% in phase II and 85% in phase III with less than 0.5 mg P/L in effluent. Ammonia nitrogen removal efficiencies reached 99% in all phases and chemical oxygen demand removal efficiencies reached 92%, 91% and 90% in the three phases, respectively. Total nitrogen removal efficiency decreased from 59% in phase I to 49% in phases II and III. Dosing PACl in the oxic tank resulted in smaller sludge particle size, higher zeta potential, better sludge settleability and lower membrane fouling rate in comparison with dosing PACl in the anoxic tank.
    Type of Medium: Online Resource
    ISSN: 0273-1223 , 1996-9732
    URL: Article
    DOI: 10.2166/wst.2015.256
    Language: English
    Publisher: IWA Publishing
    Publication Date: 2015
    detail.hit.zdb_id: 764273-8
    detail.hit.zdb_id: 2024780-1
    SSG: 14
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 8
    Online Resource
    Online Resource
    Dipteran toxicity assays for determining the oral insecticidal activity of venoms and toxins
    Elsevier BV ; 2018
    In:  Toxicon Vol. 150 ( 2018-08), p. 297-303
    Details
    In: Toxicon, Elsevier BV, Vol. 150 ( 2018-08), p. 297-303
    Type of Medium: Online Resource
    ISSN: 0041-0101
    URL: Article
    DOI: 10.1016/j.toxicon.2018.06.077
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 1498784-3
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 9
    Online Resource
    Online Resource
    Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting
    Portland Press Ltd. ; 2001
    In:  Biochemical Journal Vol. 354, No. 3 ( 2001-03-15), p. 605-612
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 354, No. 3 ( 2001-03-15), p. 605-612
    Abstract: The transcription factor, forkhead in rhabdomyosarcoma (FKHR), is phosphorylated at three amino acid residues (Thr-24, Ser-256 and Ser-319) by protein kinase B (PKB)α. In the present study, mutagenesis has been used to study the roles of these phosphorylation events in regulating FKHR function in transfected HEK-293 cells. We find that the overexpression of FKHR[S256A] (where Ser-256 → Ala) blocks PKB activity in cells, preventing phosphorylation of the endogenous substrates FKHRL1 and glycogen synthase kinase-3. Thus some reported effects of overexpression of this and other mutants may be indirect, and result from suppression of the phosphorylation of other sites on FKHR and/or other PKB substrates. For example, we have shown that Thr-24 phosphorylation alone is critical for interaction with 14-3-3 proteins, and that the substitution of Ser-256 with an alanine residue indirectly blocks 14-3-3 protein binding by preventing the phosphorylation of Thr-24. We also found that insulin-like growth factor (IGF)-1 and serum-induced nuclear exclusion of FKHR[S256A] depends on the degree of overexpression of this mutant. Our results indicated that the interaction of FKHR with 14-3-3 proteins was not required for IGF-1-stimulated exclusion of FKHR from the nucleus. We present evidence in support of another mechanism, which depends on the phosphorylation of Ser-256 and may involve the masking of a nuclear localization signal. Finally, we have demonstrated that the failure of IGF-1 to suppress transactivation by FKHR[S256A] is not explained entirely by its failure to bind 14-3-3 proteins or to undergo nuclear exclusion. This result suggests that Ser-256 phosphorylation may also suppress transactivation by FKHR by yet another mechanism, perhaps by disrupting the interaction of FKHR with target DNA binding sites and/or the function of the transactivation domain.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/bj3540605
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2001
    detail.hit.zdb_id: 1473095-9
    SSG: 12
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 10
    Online Resource
    Online Resource
    A Reversible Chemogenetic Switch for Chimeric Antigen Receptor T Cells**
    Wiley ; 2022
    In:  Angewandte Chemie Vol. 134, No. 10 ( 2022-03)
    Details
    In: Angewandte Chemie, Wiley, Vol. 134, No. 10 ( 2022-03)
    Abstract: As a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR‐T cells that is achievable through regulatory display of CARs. By embedding the hepatitis C virus NS3 protease (HCV‐NS3) between the single‐chain variable fragment (scFv) and the hinge domain, we showed that the display of anti‐CD19 scFv on CAR‐T cells was positively correlated to the presence of a clinical HCV‐NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti‐CD19 scFv in the presence of ASV and its removal in the absence of ASV creates a practically reversible chemical switch. We demonstrated that the intact CAR on T cells can be repeatedly turned on and off by controlling the presence of ASV in a dose dependent manner both in vitro and in vivo, which enables delicate modulation of CAR‐T activation during cancer treatment.
    Type of Medium: Online Resource
    ISSN: 0044-8249 , 1521-3757
    URL: Issue
    URL: Article
    DOI: 10.1002/ange.v134.10
    DOI: 10.1002/ange.202109550
    RVK:
    VA 2100
    RVK:
    VN 5020
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 505868-5
    detail.hit.zdb_id: 506609-8
    detail.hit.zdb_id: 514305-6
    detail.hit.zdb_id: 505872-7
    detail.hit.zdb_id: 1479266-7
    detail.hit.zdb_id: 505867-3
    detail.hit.zdb_id: 506259-7
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
Nothing or not found what you are looking for? Please check your search query or use the Interlibrary Loan Search.
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages