Background
nor-NOHA (acetate) (alpha-amino acid N(omega) -Hydroxy-Nor-L-arginine) is a potent and reversible selective arginase inhibitor, nor-NOHA (acetate) is about 40-fold more potent than NOHA to inhibit the hydrolysis of l-arginine to l-ornithine catalyzed by unstimulated murine macrophages (nor-NOHA IC(50) values 12 ±5μM[4].
nor-NOHA (acetate) effectively induced apoptosis in ARG2-expressing cells under hypoxia but not normoxia. Co-treatment with nor-NOHA (acetate) overcame hypoxia-mediated resistance towards BCR-ABL1 kinase inhibitors. its anti-leukemic activity was independent of ARG2 inhibition. nor-NOHA (acetate) has significant but off-target anti-leukemic activity among ARG2-expressing hypoxic cells[3]. nor-NOHA (acetate) could inhibit the proliferation and induce the apoptosis of HepG2 cells. nor-NOHA (acetate) inhibited the invasion and migration of HepG2 cells. These data indicated that nor-NOHA (acetate) could induce cell apoptosis and inhibit the ability of invasion and migration of HepG2 cells by inhibiting Arg1[1].Supplementation of nor-NOHA (acetate) in BMEC(bovine mammary epithelial cells) reduced cellular proliferation and casein synthesis. Addition of Arg to nor-NOHA (acetate) resulted in cellular proliferation and casein synthesis similar to that of nor-NOHA (acetate) alone. In contrast, addition of Orn to the medium with nor-NOHA (acetate) increased the synthesis of casein and cellular proliferation compared with nor-NOHA (acetate) [6].
nor-NOHA (acetate) treatment could fully restore the aortic response to Ach to that of healthy rats.Such beneficial effect was mediated by an increase in NOS activity and EDHF and reduced superoxide anion production, nor-NOHA (acetate) inhibited arginase activity in aorta with IC50 less than 1 μm [2].In Chinese Holstein cows .The activity of enzymes related to Arg metabolism, milk protein synthesis, and expression of AA transporters was determined. The infusion of nor-NOHA (acetate) decreased the activity of arginase. In addition, the infusion of nor-NOHA (acetate) also reduced protein and fat synthesis in milk but had no effect on milk yield[5].Hyperthyroidism in rats is associated with the increased expression and activity of arginase in aorta, heart, and kidney. Chronic arginase inhibition with nor-NOHA (acetate) suppresses the characteristic hemodynamic manifestations of hyperthyroidism in association with a reduced oxidative stress[7].
参考文献:
[1]: Li X, Zhu F, et,al. [Arginase inhibitor nor-NOHA induces apoptosis and inhibits invasion and migration of HepG2 cells]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017 Apr;33(4):477-482. Chinese. PMID: 28395717.
[2]: Prati C, Berthelot A, et,al. Treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine restores endothelial function in rat adjuvant-induced arthritis. Arthritis Res Ther. 2012 May 30;14(3):R130. doi: 10.1186/ar3860. PMID: 22647483; PMCID: PMC3446511.
[3]: Ng KP, Manjeri A, et,al. The arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target. PLoS One. 2018 Oct 11;13(10):e0205254. doi: 10.1371/journal.pone.0205254. PMID: 30307989; PMCID: PMC6181325.
[4]: Tenu JP, Lepoivre M, et,al. Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO synthase activity in murine macrophages. Nitric Oxide. 1999 Dec;3(6):427-38. doi: 10.1006/niox.1999.0255. PMID: 10637120.
[5]: Ding LY, Chen LM, et,al.Inhibition of arginase via jugular infusion of Nω-hydroxy-nor-l-arginine inhibits casein synthesis in lactating dairy cows. J Dairy Sci. 2018 Apr;101(4):3514-3523. doi: 10.3168/jds.2017-13178. Epub 2018 Feb 4. PMID: 29397169.
[6]: Wang MZ, Ding LY, et,al. Short communication: Arginase inhibition reduces the synthesis of casein in bovine mammary epithelial cells. J Dairy Sci. 2017 May;100(5):4128-4133. doi: 10.3168/jds.2016-11823. Epub 2017 Feb 23. PMID: 28237582.
[7]: Rodríguez-Gómez I, Manuel Moreno J, et,al. Effects of Arginase Inhibition in Hypertensive Hyperthyroid Rats. Am J Hypertens. 2015 Dec;28(12):1464-72. doi: 10.1093/ajh/hpv049. Epub 2015 Apr 23. PMID: 25907224.
nor-NOHA（醋酸盐）（α-氨基酸 N(omega) -Hydroxy-Nor-L-arginine）是一种有效且可逆的选择性精氨酸酶抑制剂，nor-NOHA（醋酸盐）的效力大约是 40 倍NOHA 抑制未受刺激的小鼠巨噬细胞催化 l-精氨酸水解为 l-鸟氨酸（nor-NOHA IC(50) 值 12 77777#177;5μM[4]。
nor-NOHA（醋酸盐）在缺氧条件下有效诱导表达 ARG2 的细胞凋亡，但在常氧条件下无效。与 nor-NOHA（醋酸盐）共同治疗克服了缺氧介导的对 BCR-ABL1 激酶抑制剂的耐药性。其抗白血病活性是独立的nor-NOHA (acetate) 在表达 ARG2 的缺氧细胞中具有显着但脱靶的抗白血病活性[3]. nor-NOHA (acetate) 可抑制增殖并诱导nor-NOHA（醋酸盐）抑制HepG2细胞的侵袭和迁移。这些数据表明nor-NOHA（醋酸盐）可以诱导细胞凋亡。 l 通过抑制Arg1[1]使HepG2细胞凋亡并抑制其侵袭和迁移能力。在BMEC（牛乳腺上皮细胞）中添加nor-NOHA（醋酸盐）可减少细胞增殖和酪蛋白合成。向 nor-NOHA（醋酸盐）中添加 Arg 会导致细胞增殖和酪蛋白合成，类似于单独使用 nor-NOHA（醋酸盐）。相比之下，与 nor-NOHA（乙酸盐）相比，在含有 nor-NOHA（乙酸盐）的培养基中添加 Orn 可增加酪蛋白的合成和细胞增殖[6]。
nor-NOHA（醋酸盐）治疗可以完全恢复健康大鼠对 Ach 的主动脉反应。这种有益作用是通过增加 NOS 活性和 EDHF 以及减少超氧阴离子产生来介导的，nor-NOHA（醋酸盐）抑制精氨酸酶活性IC50 小于 1 的主动脉 μm [2]。在中国荷斯坦奶牛中。测定了与精氨酸代谢、乳蛋白合成和 AA 转运蛋白表达相关的酶的活性。 nor-NOHA（醋酸盐）的输注降低了精氨酸酶的活性。此外，nor-NOHA（醋酸盐）的注入也减少了牛奶中蛋白质和脂肪的合成，但对牛奶产量没有影响[5]。大鼠甲状腺功能亢进症与表达和活性增加有关主动脉、心脏和肾脏中的精氨酸酶。用 nor-NOHA（乙酸盐）慢性精氨酸酶抑制可抑制甲状腺机能亢进症的特征性血液动力学表现，同时减少氧化应激[7]。
Protocol
| Kinase experiment [1]: |
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Preparation Method
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Macrophages (enzymes) were incubated with different stimuli, alone or in the presence of the studied compounds( nor-NOHA (acetate) ) for different times. Aliquots were removed from the medium at selected times and subjected to HPLC analysis and nitrite determination.
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Reaction Conditions
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0.01-1000uM nor-NOHA (acetate) for 29.0min
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Applications
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Mouse macrophages with arginase activity Macrophages were cultured in medium containing -arginine, which was broken down and the addition of nor-NOHA (acetate) to these cells resulted in a concentration dependent decrease in L-ornithine formation.
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| Cell experiment [2]: |
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Cell lines
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K562 cells
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Preparation Method
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K562 cells were treated with vehicle (DMSO) or increasing concentrations of nor-NOHA (acetate) (0.1 0.5 or 1mM) for 72 h, and cell viability was determined by annexin V/ 7-aad staining.
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Reaction Conditions
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0.1-1mM nor-NOHA (acetate) for 72h
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Applications
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nor-NOHA (acetate) had little effect on cell viability under normoxia, it significantly induced apoptosis in a dose-dependent manner under hypoxia, the level of intracellular arginine was reduced upon induction of ARG2 under hypoxia but was restored by nor-NOHA (acetate), confirming the inhibition of arginase activity.
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| Animal experiment [3]: |
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Animal models
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AIA rats
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Preparation Method
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AIA rats were treated with nor-NOHA (acetate) (40 mg/kg/ day, IP) for 21 days after the onset of arthritis. A group of untreated AIA rats and a group of healthy rats served as controls.
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Dosage form
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nor-NOHA (acetate) (40 mg/kg/d, i.p) for 21 days
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Applications
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nor-NOHA (acetate) treatment could fully restore the aortic response to Ach to that of healthy rats. The results also showed that such beneficial effect was mediated by an increase in NOS activity and EDHF and reduced superoxide anion production. In addition, nor-NOHA (acetate) could decrease IL-6 and VEGF plasma levels in AIA rats. Whereas, the treatment did not modify arthritis severity in AIA rats.
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参考文献:
[1]. Tenu JP, Lepoivre M, et,al. Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO synthase activity in murine macrophages. Nitric Oxide. 1999 Dec;3(6):427-38. doi: 10.1006/niox.1999.0255. PMID: 10637120.
[2]. Ng KP, Manjeri A, et,al. The arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA) induces apoptosis in leukemic cells specifically under hypoxic conditions but CRISPR/Cas9 excludes arginase 2 (ARG2) as the functional target. PLoS One. 2018 Oct 11;13(10):e0205254. doi: 10.1371/journal.pone.0205254. PMID: 30307989; PMCID: PMC6181325.
[3]. Prati C, Berthelot A, et,al. Treatment with the arginase inhibitor Nw-hydroxy-nor-L-arginine restores endothelial function in rat adjuvant-induced arthritis. Arthritis Res Ther. 2012 May 30;14(3):R130. doi: 10.1186/ar3860. PMID: 22647483; PMCID: PMC3446511.
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