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Reversal of angiotensin ll-induced ?-cell dedifferentiation via inhibition of NF-?b signaling.

ABSTRACT: BACKGROUND:Type 2 diabetes mellitus (T2DM) is characterized by pancreatic ?-cell failure, which arises from metabolic stress and results in ? cell dedifferentiation, leading to ?-cell death. Pathological activation of the renin-angiotensin system (RAS) contributes to increase cell stress, while RAS intervention reduces the onset of T2DM in high-risk populations and promotes insulin secretion in rodents. In this study, we investigated whether and how RAS induces ?-cell dedifferentiation and the mechanism underlying this process. METHODS:In vitro, with the methods of quantitative real-time reverse transcriptase-PCR (qRT-PCR) and western blotting, we examined the change of cell identity-related gene expression, progenitor like gene expression, cellular function, and nuclear factor kappa b (NF-?b) signaling activity in ? cell lines after exposure to angiotensin II (AngII) and disruption of RAS. In vivo, parallel studies were performed using db/db mice. Related protein expression was detected by Immunofluorescence analysis. RESULT:Activation of RAS induced dedifferentiation and impaired insulin secretion, eventually leading to ?-cell failure. Mechanistically, Angll induced ?-cell dedifferentiation via NF-?b signaling, while treatment with lrbesartan and sc-514 reversed the progenitor state of ? cells. CONCLUSION:The present study found that RAS might induce ?-cell dedifferentiation via angiotensin II receptor type 1 activation, which was promoted by NF-?b signaling. Therefore, blocking RAS or NF-kb signaling efficiently reversed the dedifferentiated status of ? cells, suggesting a potential therapy for patients with type 2 diabetes.

SUBMITTER: Chen H

PROVIDER: S-EPMC6092859 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Reversal of angiotensin ll-induced β-cell dedifferentiation via inhibition of NF-κb signaling.

Chen Hong H Zhou Wenjun W Ruan Yuting Y Yang Lei L Xu Ningning N Chen Rongping R Yang Rui R Sun Jia J Zhang Zhen Z

Molecular medicine (Cambridge, Mass.) 20180814 1

<h4>Background</h4>Type 2 diabetes mellitus (T2DM) is characterized by pancreatic β-cell failure, which arises from metabolic stress and results in β cell dedifferentiation, leading to β-cell death. Pathological activation of the renin-angiotensin system (RAS) contributes to increase cell stress, while RAS intervention reduces the onset of T2DM in high-risk populations and promotes insulin secretion in rodents. In this study, we investigated whether and how RAS induces β-cell dedifferentiation a ...[more]

PMID: 30134927

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Project description:BACKGROUND:Lymphotoxin β receptor (LTβR) plays important roles in the development of the immune system and immune response. At the cellular level, ligand-bound LTβR activates the pro-inflammatory NF-κB pathway but the detailed mechanisms regulating its signaling remain unknown. Understanding them is of high importance since LTβR and its ligands are promising therapeutic targets. Here, we studied the consequences of perturbed cellular cholesterol content on LTβR-induced NF-κB signaling. METHODS:To modulate cholesterol availability and/or level in lung carcinoma A549 and H2228, and endothelial HUVEC cells different treatment regimens with filipin, methyl-β-cyclodextrin and simvastatin were applied. LTβR localization was studied by confocal microscopy. The activity of LTβR-induced NF-κB pathway was assessed by measuring the levels of NF-κB pathway inhibitor IκBα and phosphorylation of RelA transcription factor by Western blotting. The NF-κB transcriptional response, production of chemokines and adhesion molecules were examined by qRT-PCR, ELISA, and Western blotting, respectively. Adherence of different types of primary immune cells to epithelial A549 cells and endothelial HUVECs was measured fluorometrically. Interactions of LTβR with its protein partners were investigated by immunoprecipitation. RESULTS:We showed that filipin-mediated sequestration of cholesterol or its depletion from the plasma membrane with methyl-β-cyclodextrin impaired LTβR internalization and potentiated LTβR-dependent activation of the canonical branch of the NF-κB pathway. The latter was manifested by enhanced degradation of IκBα inhibitor, elevated RelA phosphorylation, substantial increase in the expression of NF-κB target genes encoding, among others, cytokines and adhesion molecules known to play important roles in immune response. It was followed by robust secretion of CXCL8 and upregulation of ICAM1, that favored the adhesion of immune cells (NK and T cells, neutrophils) to A549 cells and HUVECs. Mechanistically, we showed that cholesterol depletion stabilized interactions of ligand-stimulated LTβR with modified forms of TRAF2 and NEMO proteins. CONCLUSIONS:Our results showed that the reduction of the plasma membrane content of cholesterol or its sequestration strongly potentiated signaling outcome initiated by LTβR. Thus, drugs modulating cholesterol levels could potentially improve efficacy of LTβR-based therapies. Video abstract.

Project description:BackgroundNeuroinflammation is a principal element in Alzheimer's disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells.MethodsAPP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aβ), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B.ResultsIn APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aβ and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity.ConclusionsFTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.

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Reversal of angiotensin ll-induced ?-cell dedifferentiation via inhibition of NF-?b signaling.

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Reversal of angiotensin ll-induced β-cell dedifferentiation via inhibition of NF-κb signaling.

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