| 1. |
- He, Shijun, et al.
(författare)
-
GLP-1 Receptor Activation Abrogates β-Cell Dysfunction by PKA Cα-Mediated Degradation of Thioredoxin Interacting Protein
- 2019
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 receptor (GLP-1R) agonist (Exendin-4) is a well-known agent used to improve β-cell dysfunctions via protein kinase A (PKA), but the detailed downstream molecular mechanisms are still elusive. We have now found that PKA Cα mediated- TXNIP phosphorylation and degradation played a vital role in the β-cell protective role of exendin-4. After PKA activator (Exendin-4 or FSK) treatment, PKA Cα could directly interact with TXNIP by bimolecular fluorescence complementation and Co-IP assays in INS-1 cells. And PKA Cα overexpression decreased TXNIP level, whereas TXNIP level was largely increased in PKA Cα-KO β-cells by CRISPR-Cas9. Interestingly, TXNIP overexpression or PKA Cα-KO has impaired β-cell functions, including loss of insulin secretion and activation of inflammation. PKA Cα directly phosphorylated TXNIP at Ser307 and Ser308 positions, leading to its degradation via activation of cellular proteasome pathway. Consistent with this observation, TXNIP (S307/308A) mutant resisted the degradation effects of PKA Cα. However, exendin-4 neither affected TXNIP level in TXNIP (S307/308A) mutant overexpressed β-cells nor in PKA Cα-KO β-cells. Moreover, exendin-4 treatment reduced the inflammation gene expression in TXNIP overexpressed β-cells, but exendin-4 treatment has no effect on the inflammation gene expression in TXNIP (S307/308A) overexpressed β-cells. In conclusion, our study reveals the integral role of PKA Cα/TXNIP signaling in pancreatic β-cells and suggests that PKA Cα-mediated TXNIP degradation is vital in β-cell protective effects of exendin-4.
|
|
| 2. |
- Yao, Xingang, et al.
(författare)
-
Q63, a novel DENV2 RdRp non-nucleoside inhibitor, inhibited DENV2 replication and infection
- 2018
-
Ingår i: Journal of Pharmacological Sciences. - Amsterdam : Elsevier. - 1347-8613 .- 1347-8648. ; 138:4, s. 247-256
-
Tidskriftsartikel (refereegranskat)abstract
- Dengue virus (DENV) annually infects 400 million people worldwide. Unfortunately, there is lack ofwidely protective vaccine or drugs against DENV. The viral RNA-dependent RNA polymerase (RdRp) ofNS5 protein is highly conserved among different DENV subtypes, thus presenting itself as an attractivetarget for drug design. In the current research, SPRi was performed to screen compounds against DENV2RdRp and 5(1H)-Quinazolinone,2-(4-bromophenyl)-2,3,4,6,7,8-hexahydro-7,7-dimethyl-1,3-diphenyl(Q63) was successfully screened out with a KD of 0.9 mM. Then, ITC and molecular docking assay wasperformed to access the binding mechanism between Q63 and DENV2 RdRp. Meanwhile, Q63 alsodecreased the intermediate dsRNA production, which was the product of RdRp. Further the antiviraleffects of Q63 were evaluated on mosquito C6/36 cells and mammalian BHK-21 cells. Q63 reduced CPEand cell toxicity effect after DENV2 infection on C6/36 and BHK-21 cells, with an EC50 of 2.08 mM. Time ofaddition assay revealed that Q63 affected the early genome RNA replication stage, including genome RNAreplication. In addition, Q63 down-regulated STAT1 phosphorylation, ISG15 and ISG54 after DENV2infection. In summary, Q63 was found to be a novel RdRp non-nucleoside inhibitor and a potential leadcompound for coping with DENV infectious disease in the future. © 2018 The Authors.
|
|
