INT-777
(Synonyms: 6ALPHA-乙基-23(S)-甲基胆酸,S-EMCA) 目录号 : GC13681
INT-777 是一种新型特异性半合成 TGR5 激动剂，用于减轻 AD 小鼠模型的心肌细胞损伤，改善认知障碍和突触功能障碍。
Cas No.:1199796-29-6
Sample solution is provided at 25 µL, 10mM.
INT-777 is a novel specific semisynthetic TGR5 agonist used for alleviating cardiomyocyte injury and improving cognitive impairment and synaptic dysfunction in mice model of AD.[1][2]
In vitro, INT-777 induced a dose-dependent (10 μM to 60 μM) decrease in Isc, when INT-777 added on the serosal side of seromuscular stripped distal colon segments in Ussing chambers.[5] In vitro experiment it shown that treatment with 25 μm of INT-777 for 48 h in αTC1-6 cells as well as in mouse and human islets under high glucose conditions obviously increased PC1 mRNA. However, INT-777 (25 μm) had no effect on PC1 mRNA in cells exposed to low glucose conditions.[6] In vitro, combination 100 ng/ml LPS with treatment of 30 μM INT-777 dramatically decreased the transient increase in mRNA levels for Tnfα, monocyte chemoattractant protein-1 (Mcp-1), Il-6 and Il-1β in macrophages.[7]
In vivo efficacy test it indicated that treatment with 30μg/kg of INT-777 dramatically reduced NLRP3-ASC inflammasome activation in microglia, decreased brain edema and neuroinflammation, resulted in improved short-term neurobehavioral functions at 24 h after subarachnoid hemorrhage.[3] In vivo study it suggested that mice were treated with 1.5 or 3.0 μg/mouse INT-777, single intracerebroventricular (i.c.v.) injection of LPS obviously induced mouse behavioral impairments in Morris water maze, novel object recognition, and Y-maze avoidance tests were ameliorated.[7].
References:
[1]. Wu X, et al. Neuroprotective effects of INT-777 against Aβ1-42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice. Brain Behav Immun. 2018 Oct;73:533-545.
[2]. Deng L, et al. Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress. Oxid Med Cell Longev, 2019: 6372786.
[3]. Hu X, et al. INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats. Brain Behav Immun. 2021 Jan;91:587-600.
[4]. Wu X, et al. Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jan 10;88:360-374.
[5]. Sorrentino G, et al. Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration. Gastroenterology. 2020 Sep;159(3):956-968.e8.
[6]. Kumar DP, et al. Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis. J Biol Chem. 2016 Mar 25;291(13):6626-40.
[7]. Pols TW, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 2011 Dec 7;14(6):747-57.
INT-777 是一种新型特异性半合成 TGR5 激动剂，用于减轻 AD 小鼠模型的心肌细胞损伤，改善认知障碍和突触功能障碍。[1][2]
在体外，当 INT-777 添加到 Ussing 室的浆膜剥离的远端结肠段的浆膜侧时，INT-777 诱导 Isc 剂量依赖性（10 μM 至 60 μM）减少。[5] 体外实验表明，25 μm INT-777 处理 αTC1-6 细胞以及高糖条件下小鼠和人胰岛细胞 48 小时后，PC1 mRNA 明显增加。然而，INT-777 (25 μm) 对暴露于低葡萄糖条件的细胞中的 PC1 mRNA 没有影响。[6] 在体外，100 ng/ml LPS 与 30 μM INT-777 的组合显着降低巨噬细胞中 Tnfα、单核细胞趋化蛋白-1 (Mcp-1)、IL-6 和 Il-1β mRNA 水平的瞬时升高。[7]
体内药效试验表明，用 30μg/kg 的 INT-777 治疗可显着降低小胶质细胞中 NLRP3-ASC 炎性体的激活，减少脑水肿和神经炎症，从而改善蛛网膜下腔出血后 24 小时的短期神经行为功能。 [3] 体内研究表明，小鼠经 1.5 或 3.0 μg/小鼠 INT-777 处理后，单次侧脑室 (i.c.v.) 注射 LPS 可明显诱导小鼠在 Morris 水迷宫中的行为障碍，新颖的对象识别和 Y 迷宫回避测试得到改善。[7]。
| Cell experiment [1]: | |
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Cell lines |
podocytes |
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Preparation Method |
1.75 × 104 podocytes per well were seeded in 24-well microplates for 7 days. Baseline OCR was measured in control (vehicle) or INT-777 (10 μM) treated cells. To determine fatty acid β-oxidation cells were treated with BAS-complexed palmitate (0.5 mM) followed by treatment with control or INT-777 (10 μM). |
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Reaction Conditions |
10 μM; 7 days |
|
Applications |
INT-777 increased mitochondrial oxygen consumption rate and suppressed mitochondrial ROS production as determined by Mito Sox staining. INT-777 also induced increases in mitochondrial p-AMPK and PGC-1α protein. |
| Animal experiment [2]: | |
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Animal models |
Sprague-Dawley rats |
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Preparation Method |
A total volume of 30 μL vehicle (10% dimethyl sulfide) or INT-777 at three different doses (10 μg/kg, 30 μg/kg, and 90 μg/kg) were administered into the right and left nares, alternating 10 μL in one naris per 5 minutes. H89 was diluted in 10% dimethyl sulfide (DMSO) and was administrated by intraperitoneally (i.p.) at 1 h before SAH. |
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Dosage form |
10 μg/kg, 30 μg/kg, and 90 μg/kg; Intranasal |
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Applications |
The medium (30μg/kg) and high (90μg/kg) doses of INT-777 administration significantly improved the neurological deficits on modified Garcia test and beam balance test at 24 h after SAH compared with the vehicle group. |
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References: [1]. Wang XX, et al. G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes. J Am Soc Nephrol. 2016 May;27(5):1362-78. [2]. Hu X, et al. INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats. Brain Behav Immun. 2021 Jan;91:587-600. |
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| Cas No. | 1199796-29-6 | SDF | |
| 别名 | 6ALPHA-乙基-23(S)-甲基胆酸,S-EMCA | ||
| 分子式 | C27H46O5 | 分子量 | 450.65 |
| 溶解度 | 20mg/mL in DMSO,30mg/mL in DMF, 25mg/mL in Ethanol | 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 | 2.219 mL | 11.0951 mL | 22.1902 mL |
| 5 mM | 0.4438 mL | 2.219 mL | 4.438 mL |
| 10 mM | 0.2219 mL | 1.1095 mL | 2.219 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Quality Control & SDS
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- Purity: >98.00%
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