4-Hydroxy Nonenal (4-HNE) is a product of lipid peroxidation (LPO), an α,β-unsaturated hydroxyalkenal formed from the oxidation of ω-6 polyunsaturated fatty acids, it is a colorless oil[1]. 4-Hydroxynonenal is considered a biomarker of oxidative stress and acts as a secondary signaling molecule to regulate many cell signaling pathways[2]. 4-Hydroxynonenal is electrophilic and highly reactive and can form 4-HNE-protein adducts with proteins, either through Michael addition reactions or by forming Schiff bases[3]. 4-Hydroxynonenal has biological activities such as cytotoxicity and genotoxicity and is widely used to study diseases related to oxidative stress, including cardiovascular diseases and neurodegenerative diseases [4].
In vitro, 4-hydroxy Nonenal (0-40μM) treatment of human hepatocellular carcinoma HepG2 cells for 2 h induced ASK1-SEK1-JNK caspase-3 activation and apoptosis, induced death domain-associated protein (Daxx) translocation, activated heat shock factor 1 (HSF1) and increased nuclear accumulation, and upregulated heat shock protein 70 (Hsp70) levels[5]. 4-hydroxy Nonenal (1-100μM) treatment of human osteosarcoma HOS cells for 48 h induced apoptosis in a concentration-dependent manner and inhibited cell proliferation and differentiation [6].
In vivo, 4-hydroxy Nonenal (4 mg/kg) was intravenously injected into mice with cardiac ischemia/reperfusion injury, activated the Nrf2 transcription factor in the heart and increased the content of glutathione (GSH) in the myocardium, promoted the functional recovery of the left ventricle, but had no cardioprotective effect on Nrf2 knockout mice[7]. Oral administration of 4-hydroxy Nonenal (12.5 mg/kg) to SD rats for 28 days caused hepatotoxicity and nephrotoxicity, leading to the accumulation of hyaline masses in the renal tubules and degeneration of tubular epithelial cells[8].
References:
[1] Poli G, Schaur R J, Siems W G, et al. 4‐Hydroxynonenal: A membrane lipid oxidation product of medicinal interest[J]. Medicinal research reviews, 2008, 28(4): 569-631.
[2]Sonowal H, Ramana K V. 4-Hydroxy-trans-2-nonenal in the regulation of anti-oxidative and pro-inflammatory signaling pathways[J]. Oxidative medicine and cellular longevity, 2019, 2019.
[3]Milkovic L, Zarkovic N, Marusic Z, et al. The 4-Hydroxynonenal–Protein Adducts and Their Biological Relevance: Are Some Proteins Preferred Targets?[J]. Antioxidants, 2023, 12(4): 856.
[4]Shoeb M, H Ansari N, K Srivastava S, et al. 4-Hydroxynonenal in the pathogenesis and progression of human diseases[J]. Current medicinal chemistry, 2014, 21(2): 230-237.
[5]Chaudhary P, Sharma R, Sharma A, et al. Mechanisms of 4-hydroxy-2-nonenal induced pro-and anti-apoptotic signaling[J]. Biochemistry, 2010, 49(29): 6263-6275.
[6]Sunjic S B, Cipak A, Rabuzin F, et al. The influence of 4-hydroxy-2-nonenal on proliferation, differentiation and apoptosis of human osteosarcoma cells[J]. Biofactors, 2005, 24(1‐4): 141-148.
[7]Zhang Y, Sano M, Shinmura K, et al. 4-Hydroxy-2-nonenal protects against cardiac ischemia–reperfusion injury via the Nrf2-dependent pathway[J]. Journal of molecular and cellular cardiology, 2010, 49(4): 576-586.
[8]Kang S C, Kim H W, Kim K B, et al. Hepatotoxicity and nephrotoxicity produced by 4-hydroxy-2-nonenal (4-HNE) following 4-week oral administration to Sprague-Dawley rats[J]. Journal of Toxicology and Environmental Health, Part A, 2011, 74(12): 779-789.
4-羟基壬烯醛（4-hydroxy Nonenal，4-HNE）是一种脂质过氧化（LPO）产物，是一种α，β不饱和羟基烯醛，由ω-6多不饱和脂肪酸氧化形成，它是一种无色油[1]。 4-hydroxy Nonenal被认为是氧化应激的生物标志物，作为次级信号分子来调节许多细胞信号传导途径[2]。4-hydroxy Nonenal具有亲电性和高反应性，可以与蛋白质形成 4-HNE-蛋白质加合物，通过迈克尔加成反应或通过形成席夫碱连接到蛋白质上[3]。4-hydroxy Nonenal具有细胞毒性和遗传毒性等生物活性，广泛用于研究氧化应激相关的疾病，包括心血管疾病和神经退行性疾病等[4]。
在体外，4-hydroxy Nonenal（0-40 μM）处理人肝癌HepG2细胞2 h，诱导了 ASK1-SEK1-JNK caspase-3的激活和细胞凋亡，还诱导了死亡结构域相关蛋白（Daxx）易位，激活了热休克因子1（HSF1）并增加核积累，上调了热休克蛋白70（Hsp70）水平[5]。4-hydroxy Nonenal（1-100 μM）处理人骨肉瘤HOS细胞48 h，以浓度依赖性方式引起细胞凋亡，抑制细胞的增殖和分化[6]。
在体内，4-hydroxy Nonenal（4 mg/kg）通过静脉注射治疗心脏缺血/再灌注损伤小鼠，激活了心脏中的Nrf2转录因子并增加心肌内谷胱甘肽（GSH）含量，促进了左心室的功能恢复，但是对Nrf2敲除小鼠没有心脏保护作用[7]。4-hydroxy Nonenal（12.5 mg/kg）通过口服饲喂SD大鼠28天，会产生肝毒性和肾毒性，导致肾小管内有透明小体积聚和肾小管上皮细胞变性[8]。