4-Octyl Itaconate
(Synonyms: 4-辛基衣康酸) 目录号 : GC31648
4-Octyl Itaconate 是一种可渗透细胞的衣康酸酯衍生物。
Cas No.:3133-16-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| 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 first 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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References: [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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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].
References:
[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]。
| Cas No. | 3133-16-2 | SDF | |
| 别名 | 4-辛基衣康酸 | ||
| Canonical SMILES | O=C(OCCCCCCCC)CC(C(O)=O)=C | ||
| 分子式 | C13H22O4 | 分子量 | 242.31 |
| 溶解度 | DMSO : ≥ 150 mg/mL (619.04 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.1269 mL | 20.6347 mL | 41.2694 mL |
| 5 mM | 0.8254 mL | 4.1269 mL | 8.2539 mL |
| 10 mM | 0.4127 mL | 2.0635 mL | 4.1269 mL |
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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects
Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U13C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.
4-Octyl Itaconate Alleviates Lipopolysaccharide-Induced Acute Lung Injury in Mice by Inhibiting Oxidative Stress and Inflammation
Background: Acute lung injury (ALI) is a fatal disease in the absence of pharmacological treatment. Oxidative stress and inflammation are closely related to ALI. Innate immune cells are the main source of reactive oxygen species (ROS). Macrophages play an extremely important role in ALI through the activation of inflammation and oxidative stress. Itaconate, a metabolite of tricarboxylic acid, has been reported to have strong antioxidant and anti-inflammatory effects. However, the role of itaconate in ALI is unclear. Herein, we use 4-octyl itaconate (OI), the cellular permeable derivate of itaconate, to study the effects of itaconate in vivo and in vitro.
Methods: We used OI to pretreat C57BL/6 mice and LPS-induced ALI models to illustrate the role of itaconate in acute lung injury. The mice were randomly divided into four groups: control group, OI (100 mg/kg) group, ALI Group, ALI + OI (50 mg/kg) group, and ALI + OI (100 mg/kg) group. RAW264.7 cells were used to further prove the role and mechanism of itaconate in vitro.
Results: According to the H&E staining of the lung, OI was observed to significantly reduce lung inflammation. The active oxygen content of tissues was also significantly reduced (P<0.05). OI reduced the accumulation of neutrophils and secretion of inflammatory factors in LPS-induced ALI (P<0.05). At the cellular level, OI also reduced oxidative stress and inflammation. Intervention with OI was also observed to upregulate the expression of nuclear factor erythroid 2-related factor-2 (Nrf-2) and Nrf-2 target genes in the lung tissue and RAW264.7 cells.
Conclusion: OI alleviates LPS-induced ALI. Moreover, the antioxidant and anti-inflammatory effects of OI might depend on the activation of Nrf-2. Therefore, OI might have therapeutic potential for the treatment of ALI.
4-octyl Itaconate inhibits lipopolysaccharide (LPS)-induced osteoarthritis via activating Nrf2 signalling pathway
Small molecule drug intervention for chondrocytes is a valuable method for the treatment of osteoarthritis (OA). The 4-octyl itaconate (OI) is a cellular derivative of itaconate with sound cell permeability and transformation rate. We attempted to confirm the protective role of OI in chondrocytes and its regulatory mechanism. We used lipopolysaccharide (LPS) to induce chondrocyte inflammation injury. After the OI treatment, the secretion and mRNA expression of Il-6, Il-10, Mcp-1 and Tnf-α were detected by ELISA and qPCR. The protective effect of OI on articular cartilage was further verified in surgical destabilization of the medial meniscus model of OA. Cell death and apoptosis were evaluated based on CCK8, LDH, Typan blue staining, Annexin V and TUNEL analyses. The small interfering RNAs were used to knockout the Nrf2 gene of chondrocytes to verify the OI-mediated Nrf2 signalling pathway. The results revealed that OI protects cells from LPS-induced inflammatory injury and attenuates cell death and apoptosis induced by LPS. Similar protective effects were also observed on articular cartilage in mice. The OI activated Nrf2 signalling pathway and promoted the stable expression and translocation of Nrf2 into the nucleus. When the Nrf2 signalling pathway was blocked, the protective effect of OI was significantly counteracted in chondrocytes and a mouse arthritis model. Both itaconate and its derivative (i.e., OI) showed important medical effects in the treatment of OA.
SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF 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-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.
4-Octyl itaconate suppresses the osteogenic response in aortic valvular interstitial cells via the Nrf2 pathway and alleviates aortic stenosis in mice with direct wire injury
Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in older individuals, but there is a lack of drug treatment. The cellular biological mechanisms of CAVD are still unclear. Oxidative stress and endoplasmic reticulum stress (ER stress) have been suggested to be involved in the progression of CAVD. Many studies have demonstrated that 4-octyl itaconate (OI) plays beneficial roles in limiting inflammation and oxidative injury. However, the potential role of OI in CAVD has not been thoroughly explored. Thus, we investigated OI-mediated modulation of ROS generation and endoplasmic reticulum stress to inhibit osteogenic differentiation in aortic valve interstitial cells (VICs). In our study, calcified aortic valves showed increased levels of ER stress and superoxide anion, as well as abnormal expression of Hmox1 and NQO1. In VICs, OI activated the Nrf2 signaling cascade and contributed to Nrf2 stabilization and nuclear translocation, thus augmenting the expression of genes downstream of Nrf2 (Hmox1 and NQO1). Moreover, OI ameliorated osteogenic medium (OM)-induced ROS production, mitochondrial ROS levels and the loss of mitochondrial membrane potential in VICs. Furthermore, OI attenuated the OM-induced upregulation of ER stress markers, osteogenic markers and calcium deposition, which were blocked by the Nrf2-specific inhibitor ML385. Interestingly, we found that OM-induced ER stress and osteogenic differentiation were ROS-dependent and that Hmox1 silencing triggered ROS production, ER stress and elevated osteogenic activity, which were inhibited by NAC. Overexpression of NQO1 mediated by adenovirus vectors significantly suppressed OM-induced ER stress and osteogenic markers. Collectively, these results showed the anti-osteogenic effects of OI on AVICs by regulating the generation of ROS and ER stress by activating the Nrf2 signaling pathway. Furthermore, OI alleviated aortic stenosis in a mouse model with direct wire injury. Due to its antioxidant properties, OI could be a potential drug for the prevention and/or treatment of CAVD.