4-Octyl Itaconate (4-OI) is a cell-permeable itaconate derivative. Itaconate and 4-Octyl Itaconate had similar thiol reactivity, making 4-Octyl Itaconate a suitable itaconate surrogate to study its biological function. 4-Octyl Itaconate is reported to alkylate cysteine residues on kelchlike ECH-associated protein 1 (KEAP1) and then activate nuclear factor (erythroid derived 2)-related factor 2 (Nrf2) to exert antioxidant and anti-inflammatory effects. [1]. 4-Octyl Itaconate can halt the progress of various diseases, including ischemiareperfusion injury, osteoclast-related diseases, and renal fibrosis, by reducing oxidative stress and modifying the immune response of macrophages to lipopolysaccharide (LPS) [2].
The inhibitory effect of 4-octyl itaconate extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)- independent mechanism. In addition, 4-Octyl Itaconate limit host inflammatory responses to SARS-CoV2 infection [3].
Treat Vero cells with 4-octyl itaconate enerated before infection with SARS-CoV2 resulted in a 102–104 eduction in SARS-CoV2 RNA levels in a dose dependent manner, while not affecting cell viability, as determined by lactate dehydrogenase (LDH) release assay. The antiviral effect of 4-Octyl Itaconate was also demonstrated in the lung cancer cell line Calu-3, where SARS-CoV2 RNA levels were reduced by >2-logs, while release of progeny virus was reduced by >6-logs. 4-Octyl Itaconate effect SARSCoV2 in primary human airway epithelial (HAE) cultures, also, 4-Octyl Itaconate treatment significantly reduced viral RNA levels. The antiviral effect of 4-Octyl Itaconate was reproduced using a different SARS-CoV-2 isolate [3].
4-Octyl Itaconate (50 mg/ kg) were administered to 57BL/6J mice or vehicle 2 h before intraperitoneal injection of LPS (5 mg/kg). 4-Octyl Itaconate treatment significantly prolonged the survival rate and simultaneously decreased the serum levels of IL-1β, IL-6 and lactate in mice induced by LPS. 4-Octyl Itaconate protects mice against experimental lethal endotoxaemia partly by inhibiting cytokine release and lactate production [1].
参考文献:
[1] Liao, S. T. et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat. Commun. 10, 5091, 2019.
[2] Li, Y., Chen, X., Zhang, H., et al. 4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation. Dddt 14, 5547–5558. 2020. doi:10.2147/DDDT.S280922.
[3] Olagnier, D. et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat. Commun. 11, 4938, 2020.
4-Octyl Itaconate (4-OI) 是一种可渗透细胞的衣康酸酯衍生物。衣康酸酯和 4-Octyl Itaconate 具有相似的硫醇反应性，使 4-Octyl Itaconate 成为研究其生物学功能的合适的衣康酸酯替代物。据报道，4-Octyl Itaconate 可使 kelchlike ECH 相关蛋白 1 (KEAP1) 上的半胱氨酸残基烷基化，然后激活核因子（红细胞衍生 2）相关因子 2 (Nrf2) 以发挥抗氧化和抗炎作用。 [1]。衣康酸 4-辛酯可通过减少氧化应激和改变巨噬细胞对脂多糖 (LPS) 的免疫反应来阻止多种疾病的进展，包括缺血再灌注损伤、破骨细胞相关疾病和肾纤维化[2].
衣康酸 4-辛酯的抑制作用通过 I 型干扰素 (IFN) 独立机制扩展到其他几种致病病毒的复制，包括单纯疱疹病毒 1 和 2、痘苗病毒和寨卡病毒。此外，衣康酸 4-辛酯可限制宿主对 SARS-CoV2 感染的炎症反应[3]。
用在感染 SARS-CoV2 之前产生的衣康酸 4-辛酯处理 Vero 细胞，导致 SARS-CoV2 RNA 水平以剂量依赖性方式减少 102-104，同时不影响细胞活力，这由乳酸脱氢酶 (LDH) 确定) 释放测定。衣康酸 4-辛酯的抗病毒作用也在肺癌细胞系 Calu-3 中得到证实，其中 SARS-CoV2 RNA 水平降低了 >2-logs，而后代病毒的释放减少了 >6-logs。 4-Octyl Itaconate 在原代人气道上皮 (HAE) 培养物中影响 SARSCoV2，此外，4-Octyl Itaconate 处理显着降低了病毒 RNA 水平。使用不同的 SARS-CoV-2 分离株重现了衣康酸 4-辛酯的抗病毒作用 [3]。
在腹膜内注射 LPS (5 mg/kg) 前 2 小时，将 4-衣康酸辛酯 (50 mg/kg) 给予 57BL/6J 小鼠或载体。 4-Octyl Itaconate 处理显着延长了 LPS 诱导的小鼠的存活率，同时降低了 IL-1β、IL-6 和乳酸的血清水平。衣康酸 4-辛酯部分通过抑制细胞因子释放和乳酸生成来保护小鼠免受实验性致死性内毒素血症[1]。
| Cell experiment [1]: | |
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Cell lines |
C28/I2 chondrocytes |
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Preparation Method |
Cells were stimulated with 10 ng/mL interleukin 1β(IL-1β) for 24 h. CQ (50 μM) was incubated with chondrocytes for 48 h in the CQ group, chondrocytes were pretreated with 4-Octyl Itaconate (100 μM) for 48 h followed by treatment with IL-1β (1 ng/mL) for 24 h in the IL-1β + 4-Octyl Itaconate group, and chondrocytes were pretreated with 4-Octyl Itaconate (100 μM) for 48 h followed by treatment with CQ (50 μM) for 48 h in the CQ + 4-Octyl Itaconate group. The control group was untreated chondrocytes cultured in regular medium. |
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Reaction Conditions |
100μM for 48 hours |
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Applications |
IL-1β (interleukin 1β) treatment significantly inhibited the growth of chondrocytes, but the cell growth of chondrocytes was restored after the pretreatment of 4-Octyl Itaconate. The IL-1β induces chondrocyte apoptosis and participates in the pathogenesis of OA (Osteoarthritis), 4-Octyl Itaconate protected chondrocytes from IL-1β-induced apoptosis. |
| Animal experiment [2]: | |
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Animal models |
Male C57BL/6 mice aged 8–10-weeks-old |
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Preparation Method |
The control group (rats were shamoperated and given saline solution on the ?rst day of every week from the 4th to the12th week following surgery, n = 6), the OA group (subjected to DMM, 100 μLof normal saline treatment injected at the same as in the control group, n = 6), and the OA + OI group (subjected to DMM, 100 μL of OI (100 μM) injected at the same as in the control group, n = 6). |
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Dosage form |
Inject 50 mg/kg or 100 mg/kg |
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Applications |
The histopathology indicated that 4-Octyl Itaconate reduced the LPS-induced pulmonary edema, hemorrhage and inflammatory cell infiltration. The inflammation scores of 4-Octyl Itaconate intervention groups were lower than those of the ALI group. 4-Octyl Itaconate could alleviate acute lung tissue injury induced by lipopolysaccharide. |
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参考文献: [1]. X. Pan, H. Shan, J. Bai et al. Four-octyl itaconate improves osteoarthritis by enhancing autophagy in chondrocytes via PI3K/AKT/mTOR signalling pathway inhibition. Communications Biology, vol. 5, no. 1, p. 641, 2022. [2]. Li, Y., Chen, X., Zhang, H., et al. 4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation. Dddt 14, 5547–5558. 2020. doi:10.2147/DDDT.S280922 |
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