AA147 是一种内质网 (ER) 蛋白稳态调节剂。AA147 可通过选择性激活未折叠蛋白反应的ATF6臂以及激活NRF2氧化应激反应来促进对神经元细胞氧化损伤的保护，并防止内皮屏障功能失调。AA147 还可重新平衡XBP1s在体内的表达，并诱导运动神经元存活基因的表达并保护脊柱运动神经元。
| 生物活性 | AA147 is aendoplasmic reticulum (ER)proteostasis regulator. AA147 promotes protection against oxidative damage in neuronal cells and prevents endothelial barrier dysfunction by activatingATF6arm (selectively) of the unfolded protein response (UPR) and theNRF2oxidative stress response. AA147 can rebalancesXBP1sexpression in vivo, and also induces survival motor neuron (SMN) expression and spinal motorneuron (MN) protection[1][2][3][4]. |
体外研究
(In Vitro) | AA147 (20-0.078 μM (dilution in half); 6 or 16 h) protects against glutamate-induced oxidative toxicity in HT22 cells by decreasing the reactive oxygen species (ROS)-associated damage[1].
AA147 (10 μM; 16 h) induces NRF2-dependent upregulation of oxidative stress response genes in HT22 cells[1].
AA147 (10 μM; 16 h) covalently modifies KEAP1 to promote NRF2 activation in HT22 cells[1].
AA147 (5, 10, 15 μM; 4, 8, 16, 24, 48 h) induces ATF6 activation and upregulates phosphorylation of cofilin in BPAEC[2].
AA147 (10 μM; 24 h) reduces LPS-induced endothelial barrier disruption in BPAEC[2].
AA147 (5, 10 μM; 135 h) enhances lung endothelial barrier integrity[2].
Cell Viability Assay[1] | Cell Line: | HT22 cells | | Concentration: | 0.078, 0.156, 0.312, 0.625, 1.25, 2.5, 5, 10, 20 μM | | Incubation Time: | 6 or 16 h (pre-incubation) | | Result: | Showed dose-dependent increases in the viability of glutamate-treated HT22 cells when pretreated with AA147 for 6 or 16 h prior to the glutamate challenge (addition concurrently with the glutamate challenge did not improve the viability of glutamate-treated cells).
Reduced ROS accumulation in cells when pre-incubation of 16 h. |
Cell Viability Assay[1] | Cell Line: | HT22 cells | | Concentration: | 10 μM | | Incubation Time: | 16 h | | Result: | Significant increased the expression of genes associated with antioxidant activity in neuronal models, including prolactins and glutathione transferases.
Activated NRF2 through a mechanism involving metabolic activation and covalent KEAP1 protein modification. |
Cell Viability Assay[2] | Cell Line: | BPAEC | | Concentration: | 5, 10 μM | | Incubation Time: | 135 h | | Result: | Decreased permeability of cells by activation of ATF6. |
Western Blot Analysis[2] | Cell Line: | BPAEC | | Concentration: | 5, 10, 15 μM | | Incubation Time: | 4, 8, 16, 24, 48 h | | Result: | Significantly induced ATF6 activation and upregulated cofilin phosphorylation (in a concentration-dependent manner). |
Western Blot Analysis[2] | Cell Line: | BPAEC | | Concentration: | 10 μM | | Incubation Time: | 24 h | | Result: | Reduced LPS-induced cATF6 suppression (Fig.5A) and VE-cadherin phosphorylation.
Inhibited cofilin and MLC2 activation in the inflamed cells.
Inhibited LPS-induced hyperpermeability in BPAEC. |
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体内研究
(In Vivo) | AA147 (intrathecal injection; single for 3 days) can rebalance XBP1s expression in severe SMA-like mice by activating ATF6, and also induce survival motor neuron expression and spinal motorneuron protection[3].
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 50 mg/mL(195.84 mM;Need ultrasonic) 配制储备液 | 1 mM | 3.9168 mL | 19.5840 mL | 39.1681 mL | | 5 mM | 0.7834 mL | 3.9168 mL | 7.8336 mL | | 10 mM | 0.3917 mL | 1.9584 mL | 3.9168 mL |
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储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂： ——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶 1. 请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 5 mg/mL (19.58 mM); Clear solution
此方案可获得 ≥ 5 mg/mL (19.58 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 50.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂： 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: 5 mg/mL (19.58 mM); Suspended solution; Need ultrasonic
此方案可获得 5 mg/mL (19.58 mM) 的均匀悬浊液，悬浊液可用于口服和腹腔注射。 以 1 mL 工作液为例，取 100 μL 50.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。 *以上所有助溶剂都可在本网站选购。
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