AA147 is an endoplasmic reticulum (ER) proteostasis regulator. It enhances protection against oxidative damage in neuronal cells and prevents endothelial barrier dysfunction by selectively activating the ATF6 arm of the unfolded protein response (UPR) and the NRF2 oxidative stress response. In vivo, AA147 rebalances XBP1s expression and induces survival motor neuron (SMN) expression, thereby protecting spinal motor neurons [1][2][3][4].
体内研究
AA147 (intrathecal injection; single for 3 days) rebalances XBP1s expression in severe SMA-like mice by activating ATF6. Additionally, it induces expression of survival motor neuron and protects spinal motor neurons [3].
体外研究
AA147 (20-0.078 μM (dilution in half); 6 or 16 h) shields against glutamate-induced oxidative toxicity in HT22 cells by reducing reactive oxygen species (ROS)-associated damage [1].
AA147 (10 μM; 16 h) triggers NRF2-dependent upregulation of oxidative stress response genes in HT22 cells [1].
AA147 (10 μM; 16 h) covalently alters KEAP1 to enhance NRF2 activation in HT22 cells [1].
AA147 (5, 10, 15 μM; 4, 8, 16, 24, 48 h) triggers ATF6 activation and increases phosphorylation of cofilin in BPAEC [2].
Increased total protein levels of γ2(R177G) subunits
Cell Biosci. 2022 Apr 27;12(1):48
HT22 cells
10 μM
6 h or 16 h
To evaluate the protective effect of AA147 against glutamate-induced oxidative toxicity. Results showed that AA147 pretreatment significantly improved the viability of HT22 cells after glutamate challenge and reduced cell death and ROS accumulation.
ACS Chem Biol. 2021 Dec 17;16(12):2852-2863
retinal organoids
10 µM
4 days
To investigate the protective effects of AA147 against 1-dSA-induced toxicity. AA147 increased the expression of ATF6 target genes and reduced cell death in ROs treated with 1-dSA. The protection was lost upon co-treatment with Ceapin-A7, confirming an ATF6-dependent mechanism
Nat Commun. 2023 Jul 11;14(1):4119
iPSC-derived hepatocytes
1, 5, 10 μM
24 h
Dose-dependently increased AAT-ZZ monomer secretion and NE inhibitory activity, reduced intracellular and secreted polymer
Cell Chem Biol. 2023 Jan 19;30(1):22-42. e5
IB3 cells
10 μM
24 h
Increased AAT-Z monomer secretion and NE inhibitory activity, while reducing intracellular and secreted polymer
Cell Chem Biol. 2023 Jan 19;30(1):22-42. e5
Huh7.5null cells
10 μM
24 h
Increased ER to Golgi trafficking and total secretion of AAT-Z
Cell Chem Biol. 2023 Jan 19;30(1):22-42. e5
HEK293T cells
5 μM
24 h
Increased total protein levels and surface expression of γ2(R177G) subunits
Cell Biosci. 2022 Apr 27;12(1):48
Bovine pulmonary artery endothelial cells (BPAEC)
5, 10, 15 μM
24 h
To evaluate the effect of AA147 on ATF6 activation and Cofilin phosphorylation. Results showed that AA147 increased ATF6 activation and Cofilin phosphorylation.
Cell Signal. 2022 Nov;99:110432.
Bovine pulmonary artery endothelial cells (BPAEC)
10 μM
4, 8, 16, 24, 48 h
To evaluate the effect of AA147 on ATF6 activation and Cofilin phosphorylation. Results showed that AA147 significantly induced ATF6 activation and upregulated Cofilin phosphorylation.
Cell Signal. 2022 Nov;99:110432.
Bovine pulmonary artery endothelial cells (BPAEC)
1-200 μM
24 h and 48 h
To evaluate the effect of AA147 on cell viability. Results showed that AA147 at 1-50 μM (24 hours) and 1-25 μM (48 hours) did not significantly affect BPAEC viability, but higher doses were toxic.
Cell Signal. 2022 Nov;99:110432.
AA147 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) model
Intraperitoneal and intravenous injection
2 mg/kg
Once 1 day before surgery and once 15 min after ROSC
AA147 restored neurological function and reduced dead neurons in mice suffering from CA. Moreover, AA147 inhibited CA/CPR-caused neuronal apoptosis and ER stress, indicated by reduced TUNEL-positive neurons, surged expression of Bcl-2/Bax, and down expression of cleaved caspase-3, caspase-12, C/EBP homologous protein (CHOP). The expression of ATF6 and its regulated gene glucose-regulated protein 78 (GRP78) increased significantly after the administration of AA147, suggesting the activation of the ATF6 pathway. In addition, AA147 also alleviated the upsurge of the ROS generation and MDA levels as well as increased SOD activity, accompanied by enhancement of the nuclear factor E2-related factor 2 (Nrf2) and its modulated heme-oxygenase-1 (HO-1) expressions.
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