MG-132|133407-82-6|安捷凯

Background

MG-132 is a potent, reversible, and cell-permeable proteasome inhibitor. It belongs to the class of synthetic peptide aldehydes. It reduces the degradation of ubiquitin-conjugated proteins in mammalian cells and permeable strains of yeast by the 26S complex without affecting its ATPase or isopeptidase activities.MG-132 activates c-Jun N-terminal kinase (JNK1), which initiates apoptosis.MG-132 also inhibits NF-κB activation and prevents β-secretase cleavage.

MG-132 inhibits 20S proteasome with IC50 of 100 nM in vitro. Furthermore,MG-132 treatment induces apoptosis in a cell cycle dependent manner.^[1][2]

MG-132 can treat mdx Mice by rescuing the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins. For in vivo experiment,MG-132 was administrated into mdx mice by injection into the gastrocnemius muscles or subcutaneously implanted Alzet Minipumps. As a result,MG-132, as a proteasomal inhibitor, effectively rescues the expression levels and plasma membrane localization of dystrophin, β-dystroglycan, α-dystroglycan, and α-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore,MG-132 reduces muscle membrane damage, as revealed by vital staining of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice.^[3]

参考文献:
[1]. Tsubuki, S et al. Differential inhibition of calpain and proteasome activities by peptidyl aldehydes of di-leucine and tri-leucine. Journal of biochemistry vol. 119,3 (1996): 572-6.
[2]. MacLaren, A P et al. p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells. Cell death and differentiation vol. 8,3 (2001): 210-8.
[3]. Bonuccelli, Gloria et al. Proteasome inhibitor (MG-132) treatment of mdx mice rescues the expression and membrane localization of dystrophin and dystrophin-associated proteins. The American journal of pathology vol. 163,4 (2003): 1663-75.

MG-132是一种强效、可逆和细胞渗透的蛋白酶体抑制剂，属于合成肽醛类。它可以减少哺乳动物细胞和可渗透的酵母菌株中26S复合物对泛素结合蛋白的降解，而不影响其ATPase或异构肽酶活性。MG-132激活c-Jun N末端激酶（JNK1），从而引发细胞凋亡。此外，MG-132还能抑制NF-κB的激活并防止β秘密酶裂解作用。

MG-132在体外的IC50为100纳摩尔，可以抑制20S蛋白酶。此外，MG-132处理会以细胞周期依赖性方式诱导凋亡。

MG-132可以通过挽救Dystrophin和Dystrophin相关蛋白的表达和膜定位来治疗mdx小鼠。在体内实验中，MG-132被注射到腓肠肌或皮下植入Alzet微型泵中进行治疗。结果显示，作为一种蛋白酶体抑制剂，MG-132有效地挽救了mdx小鼠骨骼肌纤维中Dystrophin、β-dystroglycan、α-dystroglycan和α-sarcoglycan的表达水平和质膜定位。此外，MG-132减少了肌肉膜损伤，在经过处理的mdx小鼠隔膜和腓肠肌的活性染色中得以证实，并改善了肌萎缩的组织学病理学特征，在经过处理的mdx小鼠取样后用苏木精伊红染色判断出来。^[3]

Protocol

Cell experiment [1]:

Cell lines

KIM-2

Preparation Method

MG-132 were diluted in Me2SO. Cells were treated with protease inhibitors or dilutant alone. Supernatant and monolayer cells were harvested by centrifugation and fixed in 70% ethanol in PBS for staining with acridine orange. Equal volumes of cells and acridine orange (5?mg/ml in PBS) were mixed on a microscope slide and examined by fluorescence microscopy.

Reaction Conditions

0, 1.5, 5 μM, 24 h

Applications

MG-132 treatment induces apoptosis in a cell cycle dependent manner.

Animal experiment [2]:

Animal models

C57BL/10ScSn DMD mdx mice

Preparation Method

Localized administration was performed by injection of MG-132 into the gastrocnemius muscles of mdx mice. To visualize the injected muscle, MG-132 (final concentration of 20 μmol/L) was pre-mixed with 1% India ink in phosphate-buffered saline (PBS) for a total volume of 100 μl. Mice were sacrificed 24 hours after injection, and skeletal muscles were quickly isolated for further analysis. To systemically administer MG-132, Alzet Minipumps was subcutaneously implanted in the anterior back region of mdx mice. Experiments were conducted on 6-month-old mdx mice. For 8 days, administration of either different concentrations of MG-132 (delivered at rate of either 1 μg, or 5 μg or 10 μg/kg/24 hours) or the inhibitor-diluent (PBS only) was enforced, as a negative control. Skeletal muscle tissues were collected from untreated (PBS only) and MG-132-treated mdx mice for further analysis.

Dosage form

1 μg, 5 μg, 10 μg/kg, injection into the gastrocnemius muscles or subcutaneously implanted Alzet Minipumps

Applications

MG-132, as a proteasomal inhibitor, effectively rescues the expression levels and plasma membrane localization of dystrophin, β-dystroglycan, α-dystroglycan, and α-sarcoglycan in skeletal muscle fibers from mdx mice. Furthermore, MG-132 reduces muscle membrane damage, as revealed by vital staining of the diaphragm and gastrocnemius muscle isolated from treated mdx mice, and ameliorates the histopathological signs of muscular dystrophy, as judged by hematoxylin and eosin staining of muscle biopsies taken from treated mdx mice.

参考文献:

[1]. Tsubuki, S et al. Differential inhibition of calpain and proteasome activities by peptidyl aldehydes of di-leucine and tri-leucine. Journal of biochemistry vol. 119,3 (1996): 572-6.

[2]. MacLaren, A P et al. p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells. Cell death and differentiation vol. 8,3 (2001): 210-8.

[3]. Bonuccelli, Gloria et al. Proteasome inhibitor (MG-132) treatment of mdx mice rescues the expression and membrane localization of dystrophin and dystrophin-associated proteins. The American journal of pathology vol. 163,4 (2003): 1663-75.

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MG-132

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