Background
Acetylcysteine is the N-acetyl derivative of CYSTEINE. NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS.Acetylcysteine (N-Acetylcysteine) is a mucolytic agent which reduces the thickness of the mucus[1]. It has also been shown to have antiviral effects in patients with HIV due to inhibition of viral stimulation by reactive oxygen intermediates. Acetylcysteine also has anti-influenza virus activities[5].
Millimolar concentrations of Acetylcysteine potentiated markedly the inhibitory effect of nitroglycerin on platelet aggregation induced by ADP, epinephrine, collagen, and arachidonate, decreasing the 50% inhibitory concentration (IC50) approximately 50-fold for each of these agents.In the absence of Acetylcysteine, nitroglycerin induced a marked decrease in platelet-reduced glutathione content as S-nitroso-thiol adducts were produced. The synthetic S-nitroso-thiol, S-nitroso-N-acetylcysteine, markedly inhibited platelet aggregation with an IC50 of 6 nM[7].Acetylcysteine increased ERK-1 activity in PC12 cells after 15 min of treatment and maximal stimulatory activity for 60 min. We also observed that Acetylcysteine caused tyrosine phosphorylation of ERK-1 in cells treated with this compound for 30 min[4].Acetylcysteine induces cell apoptosis. When used serum-deprived PC12 cells, neuronally differentiated PC12 cells deprived of serum and NGF, and NGF-deprived neonatal sympathetic neurons. In each case L-Acetylcysteine prevents apoptotic DNA fragmentation and maintains long-term survival in the absence of other trophic support[3].Acetylcysteine prevents hemin-induced ferroptosis by neutralizing toxic lipids generated by arachidonate-dependent activity of 5-lipoxygenases[2].
In mice, Acetylcysteine exerts a significant protective role in liver injury following IIR, which seems to be independent of an intestinal protective effect. Additional administration of Acetylcysteine before reperfusion was of no further benefit. The most effective regimen among the compared regimens was that of 300 mg/kg before ischemia[6].
参考文献:
[1]: Halasi M, Wang M, et,al. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors. Biochem J. 2013 Sep 1;454(2):201-8. doi: 10.1042/BJ20130282. PMID: 23772801; PMCID: PMC4322432.
[2]: Farr SA, Poon HF, et,al. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem. 2003 Mar;84(5):1173-83. doi: 10.1046/j.1471-4159.2003.01580.x. PMID: 12603840.
[3]: Ferrari G, Yan CY, et,al. N-acetylcysteine (D-and L-stereoisomers) prevents apoptotic death of neuronal cells. J Neurosci. 1995 Apr;15(4):2857-66. doi: 10.1523/JNEUROSCI.15-04-02857.1995. PMID: 7722634; PMCID: PMC6577755.
[4]: Yan CY, Greene LA. Prevention of PC12 cell death by N-acetylcysteine requires activation of the Ras pathway. J Neurosci. 1998 Jun 1;18(11):4042-9. doi: 10.1523/JNEUROSCI.18-11-04042.1998. PMID: 9592085; PMCID: PMC6792807.
[5]: Garigliany MM, Desmecht DJ. N-acetylcysteine lacks universal inhibitory activity against influenza A viruses. J Negat Results Biomed. 2011 May 9;10:5. doi: 10.1186/1477-5751-10-5. PMID: 21554703; PMCID: PMC3104374.
[6]: Kalimeris K, Briassoulis P, et,al. N-acetylcysteine ameliorates liver injury in a rat model of intestinal ischemia reperfusion. J Surg Res. 2016 Dec;206(2):263-272. doi: 10.1016/j.jss.2016.08.049. Epub 2016 Aug 19. PMID: 27884318.
[7]: Loscalzo J. N-Acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. J Clin Invest. 1985 Aug;76(2):703-8. doi: 10.1172/JCI112024. PMID: 2863286; PMCID: PMC423881.
乙酰半胱氨酸是半胱氨酸的 N-乙酰基衍生物。 NAC（N-乙酰基-L-半胱氨酸）通常用于识别和测试 ROS（活性氧）诱导剂，并抑制 ROS。乙酰半胱氨酸（N-乙酰半胱氨酸）是一种粘液溶解剂，可降低粘液的厚度 [1]。由于活性氧中间体抑制病毒刺激，它还被证明对 HIV 患者具有抗病毒作用。乙酰半胱氨酸还具有抗流感病毒活性[5]。
毫摩尔浓度的乙酰半胱氨酸显着增强硝酸甘油对 ADP、肾上腺素、胶原蛋白和花生四烯酸诱导的血小板聚集的抑制作用, 将这些药物中的每一种的 50% 抑制浓度 (IC50) 降低约 50 倍。在没有乙酰半胱氨酸的情况下，硝酸甘油会导致血小板还原谷胱甘肽含量显着降低，因为会产生 S-亚硝基-硫醇加合物。合成的 S-亚硝基硫醇，S-亚硝基-N-乙酰半胱氨酸显着抑制血小板聚集，IC50 为 6 nM[7]。乙酰半胱氨酸在 15 分钟后增加 PC12 细胞中的 ERK-1 活性治疗和最大刺激活动 60 分钟。我们还观察到乙酰半胱氨酸在用该化合物处理 30 分钟的细胞中引起 ERK-1 的酪氨酸磷酸化[4]。乙酰半胱氨酸诱导细胞凋亡。当使用剥夺血清的 PC12 细胞、剥夺血清和 NGF 的神经元分化 PC12 细胞以及剥夺 NGF 的新生儿交感神经元时。在每种情况下，L-乙酰半胱氨酸都可以防止凋亡的 DNA 片段化，并在没有其他营养支持的情况下维持长期存活[3]。乙酰半胱氨酸通过中和花生四烯酸依赖性活动产生的有毒脂质来防止血红素诱导的铁死亡5-脂氧合酶[2]。
在小鼠中，乙酰半胱氨酸在 IIR 后的肝损伤中发挥重要的保护作用，这似乎与肠道保护作用无关。再灌注前额外给予乙酰半胱氨酸没有进一步的益处。比较方案中最有效的方案是缺血前300 mg/kg[6]。
Protocol
| Kinase experiment [1]: |
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Preparation Method
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PRP was preincubated at 37°C for 4 min with Acetylcysteine or with nitroglycerin, or first with Acetylcysteine and then nitroglycerin, and sodium nitroprusside, sodium azide, sodium nitrite, or S-nitroso-N-acetylcysteine for 1 min before addition of agonist.
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Reaction Conditions
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5.5 mM Acetylcysteine for 4 min
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Applications
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Millimolar concentrations of Acetylcysteine potentiated markedly the inhibitory effect of nitroglycerin on platelet aggregation induced by ADP, epinephrine, collagen, and arachidonate, decreasing the 50% inhibitory concentration (IC50) approximately 50-fold for each of these agents.
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| Cell experiment [2]: |
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Cell lines
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PC12 cell line
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Preparation Method
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Cells were treated with 100 ng/ml NGF or 60 mm Acetylcysteine in serum-containing medium for the indicated times.
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Reaction Conditions
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60 mm Acetylcysteine for 15min-4h
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Applications
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Acetylcysteine activates the Ras-ERK pathway
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| Animal experiment [3]: |
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Animal models
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Thirty-five male Wistar rats
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Preparation Method
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Group control underwent IIR without Acetylcysteine. In the other groups, Acetylcysteine was administered intraperitoneally with different regimens: 150 mg/kg before ischemia, 300 mg/kg before ischemia, and 150 mg/kg before ischemia plus 150 mg/kg 5 min before reperfusion.
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Dosage form
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150-300 mg/kg Acetylcysteine(Intraperitoneal administration)
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Applications
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Acetylcysteine exerts a significant protective role in liver injury following IIR, which seems to be independent of an intestinal protective effect. Additional administration of Acetylcysteine before reperfusion was of no further benefit. The most effective regimen among the compared regimens was that of 300 mg/kg before ischemia.
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参考文献:
[1]. Loscalzo J. N-Acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. J Clin Invest. 1985 Aug;76(2):703-8. doi: 10.1172/JCI112024. PMID: 2863286; PMCID: PMC423881.
[2]. Yan CY, Greene LA. Prevention of PC12 cell death by N-acetylcysteine requires activation of the Ras pathway. J Neurosci. 1998 Jun 1;18(11):4042-9. doi: 10.1523/JNEUROSCI.18-11-04042.1998. PMID: 9592085; PMCID: PMC6792807.
[3]. Kalimeris K, Briassoulis P, et,al. N-acetylcysteine ameliorates liver injury in a rat model of intestinal ischemia reperfusion. J Surg Res. 2016 Dec;206(2):263-272. doi: 10.1016/j.jss.2016.08.049. Epub 2016 Aug 19. PMID: 27884318.
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