IXA4
目录号 : GC63785
IXA4是一种高选择性、无毒的IRE1/XBP1s激活剂，可诱导内质网（ER）蛋白质稳态重塑。
Cas No.:1185329-96-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
Cell lines | T cells |
Preparation Method | Whole splenocytes from OT-1 mice were activated with 1μg/mL OVA peptide and expanded for 3 days with 200U/mL rhIL-2 (NCI) then split and expanded for 4 more days. IXA4 (30μM) was added at T cell activation and again at the cell split for 4 more days. Cell mitochondria were labeled with MitoTracker and then analyzed by confocal imaging and flow cytometry. |
Reaction Conditions | 30μM; 4 days |
Applications | IXA4 treatment increased mitochondrial mass and mitochondrial ATP reserves in T cells. |
| Animal experiment [2]: | |
Animal models | Diet-induced obese (DIO) mice |
Preparation Method | Diet-induced obese (DIO) mice were maintained on a high-fat diet for 3 weeks. IXA4 was formulated in 10% DMSO, 30% Kolliphor EL:ethanol (2:1 ratio), 60% saline. Mice were given vehicle, IXA4 (50mg/kg) once daily by intraperitoneal injection for up to 8 weeks. Body weight and food intake were measured weekly. At sacrifice, tissues were harvested and snap frozen for processing. |
Dosage form | 50mg/kg/day, for 8 weeks; i.p. |
Applications | IXA4 selectively activated IRE1/XBP1s signaling in the liver of DIO mice, improved glucose homeostasis, inhibited hepatic gluconeogenesis, and reduced the expression of key lipogenic genes in the liver, including Dgat2, Scd1, and Srebf1c. |
References: | |
IXA4 is a highly selective, non-toxic IRE1/XBP1s activator that induces endoplasmic reticulum (ER) proteostasis remodeling[1]. IXA4 activates IRE1/XBP1 signaling but does not fully activate the unfolded protein response (UPR) or other stress response signaling pathways[2]. IXA4 reduces the secretion of amyloid precursor protein (APP) through IRE1 activation and prevents APP-related mitochondrial dysfunction[3].
In vitro, IXA4 (30μM) treatment of mouse splenic T cells for 4 days significantly increased mitochondrial mass and mitochondrial ATP reserves in cells[4]. IXA4 (10μM) treatment of CHO7PA2 cells expressing the V717F APP (APPV717F) mutant for 18h reduced the level of β-amyloid protein (Aβ) by 50%[5].
In vivo, IXA4 (50mg/kg) was treated with diet-induced obese (DIO) mice by intraperitoneal injection for 8 weeks, which selectively activated IRE1/XBP1s signaling in the liver of mice, improved glucose homeostasis, inhibited hepatic gluconeogenesis, and reduced the expression of key lipogenic genes in the liver (including Dgat2, Scd1, and Srebf1c)[6].
References:
[1] Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, et al. The structure, activation and signaling of IRE1 and its role in determining cell fate[J]. Biomedicines, 2021, 9(2): 156.
[2] Wang H, Karnati S, Madhusudhan T. Regulation of the homeostatic unfolded protein response in diabetic nephropathy[J]. Pharmaceuticals, 2022, 15(4): 401.
[3] Cummins N, Taylor R C. A stress-free stress response[J]. Nature Chemical Biology, 2020, 16(10): 1038-1039.
[4] Riesenberg B P, Gandy E J, Kennedy A S, et al. Adaptive IRE1 Signaling Elicits T Cell Metabolic Remodeling and Tumor Control[J]. bioRxiv, 2023: 2023.11. 16.567431.
[5] Grandjean J M D, Madhavan A, Cech L, et al. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming[J]. Nature chemical biology, 2020, 16(10): 1052-1061.
[6] Madhavan A, Kok B P, Rius B, et al. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity[J]. Nature communications, 2022, 13(1): 608.
IXA4是一种高选择性、无毒的IRE1/XBP1s激活剂，可诱导内质网（ER）蛋白质稳态重塑[1]。IXA4激活IRE1/XBP1信号传导，但不全面激活未折叠蛋白反应（UPR）或其他应激反应信号传导途径[2]。IXA4通过IRE1的激活减少淀粉样前体蛋白（APP）的分泌，预防APP相关的线粒体功能障碍发生[3]。
在体外，IXA4（30μM）处理小鼠脾脏T细胞4天，显著增加了细胞中的线粒体质量和线粒体ATP储备[4]。IXA4（10μM）处理表达V717F APP（APPV717F）突变体的CHO7PA2细胞18h，使β-淀粉样蛋白（Aβ）水平降低了50%[5]。
在体内，IXA4（50mg/kg）通过腹腔注射治疗饮食诱导肥胖（DIO）小鼠8周，选择性激活了小鼠肝脏中的IRE1/XBP1s信号传导，改善了小鼠的葡萄糖稳态，抑制了肝脏糖异生，降低了肝脏中关键脂肪生成基因（包括Dgat2、Scd1和Srebf1c）的表达[6]。
| Cas No. | 1185329-96-7 | SDF | Download SDF |
| 分子式 | C24H28N4O4 | 分子量 | 436.5 |
| 溶解度 | DMSO : 100 mg/mL (229.10 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.291 mL | 11.4548 mL | 22.9095 mL |
| 5 mM | 0.4582 mL | 2.291 mL | 4.5819 mL |
| 10 mM | 0.2291 mL | 1.1455 mL | 2.291 mL |
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动物数量 | 只 |
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Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity
Nat Commun 2022 Feb 1;13(1):608.PMID:35105890DOI:10.1038/s41467-022-28271-2.
In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.