4μ8C
(Synonyms: 4u8C) 目录号 : GC14493
4μ8C（7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran8-carboxaldehyde）是肌醇需求酶1α（IRE1α）RNAse的小分子抑制剂。
Cas No.:14003-96-4
Sample solution is provided at 25 µL, 10mM.
4μ8C (7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran8-carboxaldehyde) is a small molecule inhibitor of inositol-requiring enzyme 1α (IRE1α) RNAse[1]. 4μ8C can form a Schiff base with a specific lysine located in the active site of the IRE1 RNAse domain, blocking its function[2]. 4μ8C can be used to study endoplasmic reticulum stress-related diseases (such as diabetes, neurodegenerative diseases, cancer) and inflammation regulation[3]. 4μ8C can inhibit insulin secretion independently of IRE1α RNase activity[4].
In vitro, 4μ8C (60μM) treatment of H4IIE hepatoma cells for 2-6h significantly reduced the expression of X-box binding protein 1 (XBP1s) in both control cells and cells treated with the endoplasmic reticulum stress inducer thapsigargin (Thap)[5].
In vivo, 4μ8C (10mg/kg) was intraperitoneally injected into atherosclerotic mice for 4 weeks, which significantly reduced the area of atherosclerotic lesions, significantly reduced the expression of spliced Xbp1 mRNA, and reduced the area of foam cells in mice[6]. Oral administration of 4μ8C (10, 50, 100mg/kg) to treat passive cutaneous anaphylaxis (PCA) mice inhibited the allergic response of PCA mice in a dose-dependent manner[7].
References:
[1] Chan S M H, Lowe M P, Bernard A, et al. The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant[J]. Biochemical Journal, 2018, 475(5): 923-929.
[2] Cross B C S, Bond P J, Sadowski P G, et al. The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule[J]. Proceedings of the National Academy of Sciences, 2012, 109(15): E869-E878.
[3] Zhang Y, Zhang Y, Lu M, et al. IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress[J]. International Immunopharmacology, 2024, 133: 112056.
[4] Sato H, Shiba Y, Tsuchiya Y, et al. 4μ8C inhibits insulin secretion independent of IRE1α RNase activity[J]. Cell Structure and Function, 2017, 42(1): 61-70.
[5] Stewart C, Estrada A, Kim P, et al. Regulation of IRE1α by the small molecule inhibitor 4μ8c in hepatoma cells[J]. Cell Pathology, 2017, 4(1): 1-10.
[6] Tufanli O, Telkoparan Akillilar P, Acosta-Alvear D, et al. Targeting IRE1 with small molecules counteracts progression of atherosclerosis[J]. Proceedings of the National Academy of Sciences, 2017, 114(8): E1395-E1404.
[7] Nam S T, Park Y H, Kim H W, et al. Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4μ8C[J]. Toxicology and Applied Pharmacology, 2017, 332: 25-31.
4μ8C（7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran8-carboxaldehyde）是肌醇需求酶1α（IRE1α）RNAse的小分子抑制剂[1]。4μ8C能够与位于IRE1 RNA酶结构域活性位点的特异性赖氨酸形成席夫碱，阻断其功能[2]。4μ8C能够用于研究内质网应激相关疾病（如糖尿病、神经退行性疾病、癌症）及炎症调控[3]。4μ8C能够抑制胰岛素分泌，且不依赖于IRE1α RNase活性[4]。
在体外，4μ8C（60μM）处理H4IIE肝癌细胞细胞2-6h，在对照细胞和用内质网应激诱导剂毒胡萝卜素（Thap）处理的细胞中，均显著降低了细胞中X盒结合蛋白1（XBP1s）的表达[5]。
在体内，4μ8C（10mg/kg）通过腹腔注射治疗动脉粥样硬化小鼠4周，显著减少了小鼠动脉粥样硬化病变面积，显著减少了剪接的Xbp1 mRNA表达，减少了泡沫细胞面积[6]。4μ8C（10, 50, 100mg/kg）通过口服治疗被动皮肤过敏反应（PCA）小鼠，以剂量依赖性方式抑制了PCA小鼠的过敏反应[7]。
| Cell experiment [1]: | |
Cell lines | H4IIE cells |
Preparation Method | H4IIE cells were incubated for 2, 4, or 6h in low glucose (LG) control media or LG supplemented with thapsigargin (Thap; 780nM), in the absence(-) or presence (+; 60μM) of 4μ8c. XBP1s expression was measured using qRT-PCR. |
Reaction Conditions | 60μM; 2, 4, 6h |
Applications | Incubation with 4μ8c significantly decreased XBP1s at 2, 4, and 6h in control cells (LG) and in cells treated with the ER stress inducer, thapsigargin (Thap). |
| Animal experiment [2]: | |
Animal models | ApoE−/− mice |
Preparation Method | ApoE−/− mice that were used in atherosclerosis experiments were fed a Western diet for 8 weeks. Then, they were injected with 4µ8c (10mg/kg) or DMSO, both given in 16% (vol/vol) Cremophor EL saline solution via i.p. injections, for 4 more weeks while mice were continued on Western diet. Weights were measured every other day, whereas blood glucose concentrations were measured before and after treatments. At the end of the experiment, mice were anesthetized, and blood was collected by cardiac puncture. Bone marrow, spleen, and liver tissues were collected, frozen immediately into liquid nitrogen, and stored at −80 °C. Perfusion was performed with ice-cold PBS and heparin (1000U/mL) followed by 10% formalin solution. After fixation, the aorta was dissected intact, immersed immediately in 10% formalin, and stored at 4°C until analysis. The heart was removed at the proximal aorta, placed into a tissue mold, covered with OCT, frozen in cold isobutene solution, and stored at −80°C. |
Dosage form | 10mg/kg; 4 weeks; i.p. |
Applications | 4μ8c treatment led to a significant reduction in atherosclerotic lesion area in en face aorta preparations and a significant reduction in the spliced Xbp1 mRNA but no change in IRE1 phosphorylation in the spleens. Furthermore, 4μ8c treatment led to a reduced foam cell area without overt differences in body weight, blood glucose levels, liver morphology, and plasma ALT activity between the inhibitor-treated and control mice. |
References: | |
| Cas No. | 14003-96-4 | SDF | |
| 别名 | 4u8C | ||
| 化学名 | 7-hydroxy-4-methyl-2-oxochromene-8-carbaldehyde | ||
| Canonical SMILES | CC1=CC(=O)OC2=C1C=CC(=C2C=O)O | ||
| 分子式 | C11H8O4 | 分子量 | 204.18 |
| 溶解度 | ≥ 8.65mg/mL in DMSO | 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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1 mg | 5 mg | 10 mg |
| 1 mM | 4.8976 mL | 24.4882 mL | 48.9764 mL |
| 5 mM | 0.9795 mL | 4.8976 mL | 9.7953 mL |
| 10 mM | 0.4898 mL | 2.4488 mL | 4.8976 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
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2.
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- Purity: >98.50%
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