| 1. |
- Georgiadi, A, et al.
(författare)
-
Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue
- 2021
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 2999-
-
Tidskriftsartikel (refereegranskat)abstract
- The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.
|
|
| 2. |
- Herrmann, Uli S., et al.
(författare)
-
Structure-based drug design identifies polythiophenes as antiprion compounds
- 2015
-
Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 7:299, s. 299ra123-
-
Tidskriftsartikel (refereegranskat)abstract
- Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by greater than80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.
|
|
| 3. |
- Hornemann, S, et al.
(författare)
-
Mechanistic and structural aspects of the interaction of luminescent conjugated polymers with amyloid oligomers
- 2010
-
Ingår i: Amyloid. - : Informa Healthcare. - 1350-6129 .- 1744-2818. ; 17:S1, s. 98-99
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Protein misfolding and aggregation diseases, such as e.g. Alzheimer’s disease, are associated by the accumulation of a disease-related protein. The pathogenic mechanisms involved in these confor- mational diseases are only poorly understood. Luminescent-conjugated polymers (LCPs) have been shown as a sensitive tool for detection of amyloid deposits. In contrast to commonly used amyloidotropic dyes such as thioflavins or Congo Red, LCPs are composed of flexible polythiophene chains which allow rotation of the molecule. Upon binding to amyloids, the LCPs alter their spectral properties in a conformation dependent manner. However, there is still limited information available on the binding mechanism and binding properties of the LCPs to amyloid fibrils and oligomers.We have produced recombinant human Aβ1-42 (recAβ1-42) protein in Escherichia coli and purified it by conventional chromatographic techniques in large quantities. The recAβ-protein was incubated in the presence of SDS to induce formation of homogenous, globular Aβ-oligomers with a size of approximately 60 kDa, known as Aβ-globulomers. We present first biophysical and spectroscopic data used to study the binding and structural properties of the complex formed by the globulomers and LCPs with various charged side chains. These data will provide a more detailed knowledge of the binding mode of amyloidogenic probes which is essential for understanding the structural char- acteristics of amyloid fibrils detected by thesemolecules.
|
|
| 4. |
- Sigurdson, C.J., et al.
(författare)
-
Prion strain discrimination using luminescent conjugated polymers
- 2007
-
Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 4:12, s. 1023-1030
-
Tidskriftsartikel (refereegranskat)abstract
- The occurrence of multiple strains of prions may reflect conformational variability of PrPSc, a disease-associated, aggregated variant of the cellular prion protein, PrPC. Here we used luminescent conjugated polymers (LCPs), which emit conformation-dependent fluorescence spectra, for characterizing prion strains. LCP reactivity and emission spectra of brain sections discriminated among four immunohistochemically indistinguishable, serially mouse-passaged prion strains derived from sheep scrapie, chronic wasting disease (CWD), bovine spongiform encephalopathy (BSE), and mouse-adapted Rocky Mountain Laboratory scrapie prions. Furthermore, using LCPs we differentiated between field isolates of BSE and bovine amyloidotic spongiform encephalopathy, and identified noncongophilic deposits in prion-infected deer and sheep. We found that fibrils with distinct morphologies generated from chemically identical recombinant PrP yielded unique LCP spectra, suggesting that spectral characteristic differences resulted from distinct supramolecular PrP structures. LCPs may help to detect structural differences among discrete protein aggregates and to link protein conformational features with disease phenotypes.
|
|
