L-JNKI-1
目录号 : GC34275
L-JNKI-1是一种针对JNK的细胞渗透性多肽抑制剂。
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
Animal experiment: | Rats[1]Six-week-old male SD rats are used. The rats are injected with a bolus of JNK peptide inhibitor L-JNKI-1 (5 mg/kg) followed by infusion of JNKI 1 (5 mg/kg per hour) until the completion of the experiment. After a 30-minute infusion of JNK inhibitor, the pressor response to Ang II at the 3 doses described above is determined at 30-minute intervals[1]. |
References: [1]. Zhou MS, et al. Role of c-Jun N-terminal kinase in the regulation of vascular tone. J Cardiovasc Pharmacol Ther. 2010 Mar;15(1):78-83. | |
L-JNKI-1 is a cell-permeable peptide inhibitor specific for JNK.
L-JNKI-1 has been shown to effectively inhibit JNK activity in in vivo studies. It is shown that Ang II induces a dose-dependent pressor response, which was significantly attenuated by JNK inhibition[1]. It is also found that 10 μM L-JNKI-1 decreases phosphorylated c-Jun by 98% and phosphorylated Elk-1 by 100%. L-JNKI-1 is able to across the blood-brain barrier and penetrate neurons of adult mice and P5 rats within 1 h after an intraperitoneal injection[2].
[1]. Zhou MS, et al. Role of c-Jun N-terminal kinase in the regulation of vascular tone. J Cardiovasc Pharmacol Ther. 2010 Mar;15(1):78-83. [2]. Borsello T, et al. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med. 2003 Sep;9(9):1180-6.
| Cas No. | SDF | ||
| Canonical SMILES | Asp-Gln-Ser-Arg-Pro-Val-Gln-Pro-Phe-Leu-Asn-Leu-Thr-Thr-Pro-Arg-Lys-Pro-Arg-Pro-Pro-Arg-Arg-Arg-Gln-Arg-Arg-Lys-Lys-Arg-Gly-NH2 | ||
| 分子式 | C164H286N66O40 | 分子量 | 3822.44 |
| 溶解度 | Water: ≥ 100 mg/mL (26.16 mM) | 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 | 0.2616 mL | 1.3081 mL | 2.6161 mL |
| 5 mM | 0.0523 mL | 0.2616 mL | 0.5232 mL |
| 10 mM | 0.0262 mL | 0.1308 mL | 0.2616 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Stroke injury induced by distal middle cerebral artery occlusion is resistant to N-methyl-d-aspartate receptor antagonism in FVB/NJ mice
Neuroreport 2021 Sep 8;32(13):1122-1127.PMID:34284452DOI:10.1097/WNR.0000000000001697.
Although N-methyl-d-aspartate receptor (NMDAR) antagonism has been shown to have a neuroprotective effect in many preclinical stroke models, the efficacy of this antiexcitotoxicity strategy in clinical trials in stroke patients has been disappointing. Interestingly, it has been reported that NMDAR antagonism is not neuroprotective in C57BL/6 mice subjected to distal middle cerebral artery occlusion (dMCAO), supporting the notion that whether these treatments are neuroprotective depends on the type of cerebral ischemia. However, because C57BL/6 mice are inherently resistant to excitotoxicity, the reported lack of neuroprotection could also be explained by the difference in the mouse strain studied rather than the stroke model used. Here we examined the neuroprotective efficacy of NMDAR antagonism in FVB/NJ mice, an excitotoxicity-prone mouse strain, subjected to dMCAO. Although C57BL/6 mice are known to have an excitotoxicity-resistant genetic background and FVB/NJ mice are known to have an excitotoxicity-prone genetic background, the infarct volume and density of neurodegenerating neurons were similar in the two mouse strains following dMCAO. In addition, none of the antiexcitotoxicity agents studied, including the canonical NMDAR antagonist MK801 and the therapeutic peptides Tat-NR2B9c and L-JNKI-1, protected the FVB/NJ mouse brain against ischemic damage induced by dMCAO. In conclusion, our data demonstrated that FVB/NJ mice are no more susceptible to cerebral ischemia than C57BL/6 mice and that NMDAR antagonism is ineffective in mice, even in an excitotoxicity-prone strain, subjected to dMCAO.
The Src family kinase Fyn mediates hyperosmolarity-induced Mrp2 and Bsep retrieval from canalicular membrane
J Biol Chem 2011 Dec 30;286(52):45014-29.PMID:22057277DOI:10.1074/jbc.M111.292896.
In perfused rat liver, hyperosmolarity induces Mrp2- (Kubitz, R., D'urso, D., Keppler, D., and Häussinger, D. (1997) Gastroenterology 113, 1438-1442) and Bsep retrieval (Schmitt, M., Kubitz, R., Lizun, S., Wettstein, M., and Häussinger, D. (2001) Hepatology 33, 509-518) from the canalicular membrane leading to cholestasis. The aim of this study was to elucidate the underlying signaling events. Hyperosmolarity-induced retrieval of Mrp2 and Bsep from the canalicular membrane in perfused rat liver was accompanied by an activating phosphorylation of the Src kinases Fyn and Yes but not of c-Src. Both hyperosmotic transporter retrieval and Src kinase activation were sensitive to apocynin (300 μmol/liter), N-acetylcysteine (NAC; 10 mmol/liter), and SU6656 (1 μmol/liter). Also PP-2 (250 nmol/liter), which inhibited hyperosmotic Fyn but not Yes activation, prevented hyperosmotic transporter retrieval from the canalicular membrane, suggesting that Fyn but not Yes mediates hyperosmotic Bsep and Mrp2 retrieval. Neither hyperosmotic Fyn activation nor Bsep/Mrp2 retrieval was observed in livers from p47(phox) knock-out mice. Hyperosmotic activation of JNKs was sensitive to apocynin and NAC but insensitive to SU6656 and PP-2, indicating that JNKs are not involved in transporter retrieval, as also evidenced by experiments using the JNK inhibitors L-JNKI-1 and SP6001255, respectively. Hyperosmotic transporter retrieval was accompanied by a NAC and Fyn knockdown-sensitive inhibition of biliary excretion of the glutathione conjugate of 1-chloro-2,4-dinitrobenzene in perfused rat liver and of cholyl-L-lysyl-fluorescein secretion into the pseudocanaliculi formed by hepatocyte couplets. Hyperosmolarity triggered an association between Fyn and cortactin and increased the amount of phosphorylated cortactin underneath the canalicular membrane. It is concluded that the hyperosmotic cholestasis is triggered by a NADPH oxidase-driven reactive oxygen species formation that mediates Fyn-dependent retrieval of the Mrp2 and Bsep from the canalicular membrane, which may involve an increased cortactin phosphorylation.
Role of JNK in network formation of human lung microvascular endothelial cells
Am J Physiol Lung Cell Mol Physiol 2008 Apr;294(4):L676-85.PMID:18263671DOI:10.1152/ajplung.00496.2007.
The signaling mechanisms in vasculogenesis and/or angiogenesis remain poorly understood, limiting the ability to regulate growth of new blood vessels in vitro and in vivo. Cultured human lung microvascular endothelial cells align into tubular networks in the three-dimensional matrix, Matrigel. Overexpression of MAPK phosphatase-1 (MKP-1), an enzyme that inactivates the ERK, JNK, and p38 pathways, inhibited network formation of these cells. Adenoviral-mediated overexpression of recombinant MKP-3 (a dual specificity phosphatase that specifically inactivates the ERK pathway) and dominant negative or constitutively active MEK did not attenuate network formation in Matrigel compared with negative controls. This result suggested that the ERK pathway may not be essential for tube assembly, a conclusion which was supported by the action of specific MEK inhibitor PD 184352, which also did not alter network formation. Inhibition of the JNK pathway using SP-600125 or l-stereoisomer (L-JNKI-1) blocked network formation, whereas the p38 MAPK blocker SB-203580 slightly enhanced it. Inhibition of JNK also attenuated the number of small vessel branches in the developing chick chorioallantoic membrane. Our results demonstrate a specific role for the JNK pathway in network formation of human lung endothelial cells in vitro while confirming that it is essential for the formation of new vessels in vivo.
Hypothermia but not NMDA receptor antagonism protects against stroke induced by distal middle cerebral arterial occlusion in mice
PLoS One 2020 Mar 3;15(3):e0229499.PMID:32126102DOI:10.1371/journal.pone.0229499.
Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3-72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24-48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials.
c-Jun N-terminal kinase mediates constitutive human eosinophil apoptosis
Pulm Pharmacol Ther 2007;20(5):580-7.PMID:16934508DOI:10.1016/j.pupt.2006.06.004.
Eosinophils are considered to play an important role in the pathogenesis of asthma. Glucocorticoids are potent anti-inflammatory agents for the treatment of chronic inflammatory diseases and they have been shown to increase the rate of eosinophil apoptosis. c-Jun N-terminal kinase (JNK) has been suggested to participate in the signaling pathways of apoptosis. The aims of the present study were to examine whether JNK is involved in the regulation of constitutive eosinophil apoptosis and whether it mediates dexamethasone-induced apoptosis of human eosinophils. Isolated human eosinophils were cultured with and without dexamethasone and the JNK inhibitor L-JNKI-1. Apoptosis was assessed by measuring the relative DNA content of propidium iodide-stained cells and confirmed by Annexin V-binding and morphological analysis with bright field microscopy. The phosphorylation of both JNK and c-Jun were measured by Western blotting. During a 40h culture, dexamethasone (1muM) enhanced human eosinophil apoptosis by 10-30%. Culture with L-JNKI1 (10muM) inhibited apoptosis in dexamethasone-treated cells by 53%. Furthermore, L-JNKI1 decreased the rate of constitutive eosinophil apoptosis by 64%. However, the enhancement of eosinophil apoptosis by dexamethasone was not reversed by L-JNKI1. Slow activation of JNK in constitutive apoptosis as well as a similar tendency in dexamethasone-induced eosinophil apoptosis could be observed by Western blot analyses. c-Jun was found to be active both in the presence and absence of dexamethasone. However, no further phosphorylation of the serine residue 63 of c-Jun could be seen. Taken together, our present results suggest that JNK is active during apoptosis of human eosinophils both in the presence and absence of glucocorticoids. JNK seems to mediate constitutive human eosinophil apoptosis. However, the activity of JNK is not enhanced by glucocorticoids and the effects of glucocorticoids cannot be reversed by JNK inhibition. JNK therefore seems not to mediate glucocorticoid-induced human eosinophil apoptosis.