Limonin
(Synonyms: 柠檬苦素; Limonoic acid 3,19) 目录号 : GC16589
柠檬苦素是一种天然的四环三萜类化合物，广泛存在于桉树、黄柏和黄连中。
Cas No.:1180-71-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Colon cancer (SW480) and fibroblast (112CoN) cells |
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Preparation Method |
Cells were treated with different concentrations (6.25, 12.5,25,50 and 100 µM) of limonin, LG, and camptothecin after incubation for 24, 48, and 72 h; 50 µL of supernatant medium was removed without disturbing the cells, mixed with an equal volume of LDH reagent, and incubated for 30 min in the dark at ambient temperature. |
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Reaction Conditions |
6.25, 12.5,25,50 and 100 µM for 24, 48, and 72 h |
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Applications |
Maximum release of LDH into the medium was observed after 48 h of incubation with limonoids. |
| Animal experiment [2]: | |
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Animal models |
Male Wistar rats |
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Preparation Method |
Animals were randomly divided into three experimental groups (each containing eight animals): sham, ischemia/reperfusion (I/R) injury, limonin (100 mg/kg). Sham group received vehicle then anesthetized, the portal vein and bile duct exposed but not occluded. Rats of I/R group were anesthetized by i.p injection of ketamine (75 mg/kg) and subjected to partial liver ischemia (70%) followed by reperfusion. Ischemia was induced by occluding hepatic portal vein and bile duct with a traumatic vascular clamp. After 45 min of ischemia, the clamp was removed to start reperfusion for 1 h. Limonin dissolved in dimethyl sulfoxide (DMSO) then given i.p as single dose 30 min before ischemia. Blood was collected from the retro-orbital plexus and centrifuged (3000×g, 4 °C, 20 min) for separation of serum. |
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Dosage form |
15 or 30 mg/kg, Miniature osmotic infusion pump |
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Applications |
Rats subjected to I/R showed a marked increase in inflammatory cytokines (TNF-α) by 347.4%, and marked decrease in anti-inflammatory mediators (IL-10) in liver tissue by 54.5% as compared to sham group. Limonin treatment significantly reduced liver TNF-α by 43.8%, and increased liver IL-10 by 154.9% as compared to I/R group. |
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References: [1]: Chidambara Murthy K N, Jayaprakasha G K, Kumar V, et al. Citrus limonin and its glucoside inhibit colon adenocarcinoma cell proliferation through apoptosis[J]. Journal of agricultural and food chemistry, 2011, 59(6): 2314-2323. |
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Limonin is a natural tetracyclic triterpenoid compound, which widely exists in Euodia rutaecarpa (Juss.) Benth., Phellodendron chinense Schneid., and Coptis chinensis Franch [1]. Limonin has pharmacological effects in anti-tumor, anti-inflammatory and analgesic, anti-bacterial and anti-virus, anti-oxidation, nerve protection, liver protection, and blood lipid regulation. Modern pharmacological effects indicate that limonin has value in the prevention and treatment of certain diseases, including cancer, enteritis, hepatitis, hemorrhoids, osteoporosis, obesity, anaphylactic reaction, and brain aging [2].
Limonin has an anti-hepatocarcinoma effect. In vitro, limonin inhibited the growth of hepatocellular carcinoma cell line (SMMC-7721) cells (IC50 = 24.42 μg/mL) in a concentration and time-dependent manner [3]. Limonin has certain cytotoxicity to human colon cancer (Caco-2) cells [4]. Limonin has a good antiproliferative effect on lung cancer cells A549 (IC50 = 82.5 uM) [5].
In vivo, limonin (200 mg/kg) diets inhibited cell proliferation and promoted apoptosis through suppressing the levels of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in azoxymethane (AOM)-injected rats, therefore, it was considered that limonin has the effect of inhibiting colon cancer [6]. Limonin (50 mg/kg) has excellent antioxidant and therapeutic effects on N-nitroethylenediamine (DEN)-induced hepatocarcinoma rats by suppressing lipid peroxidation (LPO) and oxidative stress-mediated free radicals generation, and through modulating antioxidants` defense mechanism [7]. Limonin significantly decreased the levels of tumor necrosis factor-α (TNF-α), interleukin (IL-1β and IL-6), and inhibited the expression of inflammatory factors in lipopolysaccharide (LPS)-induced acute lung injury mice [8].
References:
[1].Fan S, Zhang C, Luo T, et al. Limonin: A review of its pharmacology, toxicity, and pharmacokinetics[J]. Molecules, 2019, 24(20): 3679.
[2].Gualdani R, Cavalluzzi M M, Lentini G, et al. The chemistry and pharmacology of citrus limonoids[J]. Molecules, 2016, 21(11): 1530.
[3].Zhang J J, Luo G, He R L, et al. Inhibiting effects of limonin on human hepatocarcinoma cells SMMC-7721 in vitro[J]. Sichuan J. Physiolog. Sci, 2007, 29: 157-160.
[4].Qian P, Jin H W, Yang X W. New limonoids from Coptidis Rhizoma–Euodiae Fructus couple[J]. Journal of Asian natural products research, 2014, 16(4): 333-344.
[5].Bai Y, Jin X, Jia X, et al. Two new apotirucallane-type isomeric triterpenoids from the root bark of Dictamnus dasycarpus with their anti-proliferative activity[J]. Phytochemistry Letters, 2014, 10: 118-122.
[6].Vanamala J, Leonardi T, Patil B S, et al. Suppression of colon carcinogenesis by bioactive compounds in grapefruit[J]. Carcinogenesis, 2006, 27(6): 1257-1265.
[7].Langeswaran K, Kumar S G, Perumal S, et al. Limonin–A citrus limonoid, establish anticancer potential by stabilizing lipid peroxidation and antioxidant status against N-nitrosodiethylamine induced experimental hepatocellular carcinoma[J]. Biomedicine & Preventive Nutrition, 2013, 3(2): 165-171.
[8].WANG D, ZHANG H, FANG J, et al. Effects of limoninon on LPS-induced acute lung injury in mice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(1): 8.
柠檬苦素是一种天然的四环三萜类化合物,广泛存在于桉树、黄柏和黄连[1]中。柠檬苦素具有抗肿瘤、抗炎镇痛、抗菌抗病毒、抗氧化、保护神经、保肝、调节血脂等药理作用。现代药理作用表明柠檬苦素对某些疾病具有防治价值,包括癌症、肠炎、肝炎、痔疮、骨质疏松、肥胖、过敏反应、脑老化等[2]。\n
柠檬苦素具有抗肝癌作用。在体外,柠檬苦素以浓度和时间依赖性方式抑制肝细胞癌细胞系 (SMMC-7721) 细胞的生长 (IC50 = 24.42 μg/mL) [3]。柠檬苦素对人结肠癌（Caco-2）细胞具有一定的细胞毒性[4]。柠檬苦素对肺癌细胞A549具有良好的抗增殖作用(IC50 = 82.5 uM)[5]。
在体内,柠檬苦素 (200 mg/kg) 饮食通过抑制偶氮甲烷 (AOM) 注射大鼠中诱导型一氧化氮合酶 (iNOS) 和环氧合酶 2 (COX-2) 的水平来抑制细胞增殖并促进细胞凋亡,因此,人们认为柠檬苦素具有抑制结肠癌的作用[6]。柠檬苦素 (50 mg/kg) 通过抑制脂质过氧化 (LPO) 和氧化应激介导的自由基生成,并通过调节抗氧化剂的防御机制,对 N-硝基乙二胺 (DEN) 诱导的肝癌大鼠具有出色的抗氧化和治疗作用 [7].柠檬苦素显着降低脂多糖（LPS）诱导的急性肺损伤小鼠肿瘤坏死因子-α（TNF-α）、白细胞介素（IL-1β和IL-6）的水平,并抑制炎症因子的表达[ 8].
| Cas No. | 1180-71-8 | SDF | |
| 别名 | 柠檬苦素; Limonoic acid 3,19 | ||
| 化学名 | 12-(furan-3-yl)-6,6,8a,12a-tetramethyldecahydrooxireno[2,3-d]pyrano[4',3':3,3a]isobenzofuro[5,4-f]isochromene-3,8,10(1H,6H,8aH)-trione | ||
| Canonical SMILES | CC1(C2CC(=O)C3(C(C24COC(=O)CC4O1)CCC5(C36C(O6)C(=O)OC5C7=COC=C7)C)C)C | ||
| 分子式 | C26H30O8 | 分子量 | 470.51 |
| 溶解度 | ≥ 23.9 mg/mL in DMSO | 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 | 2.1254 mL | 10.6268 mL | 21.2535 mL |
| 5 mM | 0.4251 mL | 2.1254 mL | 4.2507 mL |
| 10 mM | 0.2125 mL | 1.0627 mL | 2.1254 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics
Limonin is a natural tetracyclic triterpenoid compound, which widely exists in Euodia rutaecarpa (Juss.) Benth., Phellodendron chinense Schneid., and Coptis chinensis Franch. Its extensive pharmacological effects have attracted considerable attention in recent years. However, there is no systematic review focusing on the pharmacology, toxicity, and pharmacokinetics of limonin. Therefore, this review aimed to provide the latest information on the pharmacology, toxicity, and pharmacokinetics of limonin, exploring the therapeutic potential of this compound and looking for ways to improve efficacy and bioavailability. Limonin has a wide spectrum of pharmacological effects, including anti-cancer, anti-inflammatory and analgesic, anti-bacterial and anti-virus, anti-oxidation, liver protection properties. However, limonin has also been shown to lead to hepatotoxicity, renal toxicity, and genetic damage. Moreover, limonin also has complex impacts on hepatic metabolic enzyme. Pharmacokinetic studies have demonstrated that limonin has poor bioavailability, and the reduction, hydrolysis, and methylation are the main metabolic pathways of limonin. We also found that the position and group of the substituents of limonin are key in affecting pharmacological activity and bioavailability. However, some issues still exist, such as the mechanism of antioxidant activity of limonin not being clear. In addition, there are few studies on the toxicity mechanism of limonin, and the effects of limonin concentration on pharmacological effects and toxicity are not clear, and no researchers have reported any ways in which to reduce the toxicity of limonin. Therefore, future research directions include the mechanism of antioxidant activity of limonin, how the concentration of limonin affects pharmacological effects and toxicity, finding ways to reduce the toxicity of limonin, and structural modification of limonin-one of the key methods necessary to enhance pharmacological activity and bioavailability.
Limonin ameliorates acute pancreatitis by suppressing JAK2/STAT3 signaling pathway
Acute pancreatitis (AP) is one of the most common acute abdomen of digestive system and has the characteristics of dangerous condition and rapid development. Limonin has been confirmed to hold anti-inflammatory and antioxidant effects in various diseases. However, its potential beneficial effect on AP and the concrete mechanisms have never been revealed. Here, two mouse models were used to investigate the protective effects of limonin on AP, the caerulein-induced mild acute pancreatitis (MAP) model and L-arginine-induced severe AP (SAP) model. Firstly, it was found that limonin administration attenuated lipase and serum amylase levels and ameliorated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. Additionally, the amelioration of AP by limonin was associated with reduced levels of inflammation initiators (IL-6, IL-1β, CCL2, and TNF-α). Mechanistically, we found that limonin suppressed the Janus Activating Kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway, as evident by the decreased levels of JAK2 and p-STAT3. And activation of JAK2 using JAK2 activator rescued the protective effects of limonin on AP. Thus, our results demonstrate that limonin can ameliorate AP in two mice models via suppressing JAK2/STAT3 signaling pathway.
Limonin Inhibits IL-1 β-Induced Inflammation and Catabolism in Chondrocytes and Ameliorates Osteoarthritis by Activating Nrf2
Osteoarthritis (OA), a degenerative disorder, is considered to be one of the most common forms of arthritis. Limonin (Lim) is extracted from lemons and other citrus fruits. Limonin has been reported to have anti-inflammatory effects, while inflammation is a major cause of OA; thus, we propose that limonin may have a therapeutic effect on OA. In this study, the therapeutic effect of limonin on OA was assessed in chondrocytes in vitro in IL-1β induced OA and in the destabilization of the medial meniscus (DMM) mice in vivo. The Nrf2/HO-1/NF-κB signaling pathway was evaluated to illustrate the working mechanism of limonin on OA in chondrocytes. In this study, it was found that limonin can reduce the level of IL-1β induced proinflammatory cytokines such as INOS, COX-2, PGE2, NO, TNF-α, and IL-6. Limonin can also diminish the biosynthesis of IL-1β-stimulated chondrogenic catabolic enzymes such as MMP13 and ADAMTS5 in chondrocytes. The research on the mechanism study demonstrated that limonin exerts its protective effect on OA through the Nrf2/HO-1/NF-κB signaling pathway. Taken together, the present study shows that limonin may activate the Nrf2/HO-1/NF-κB pathway to alleviate OA, making it a candidate therapeutic agent for OA.
Limonin ameliorates acetaminophen-induced hepatotoxicity by activating Nrf2 antioxidative pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1
Background: Limonin, a bioactive compound from citrus plants, exerts antioxidant activities, however its therapeutic potential in acetaminophen (APAP)-induced hepatotoxicity remains unclear.
Purpose: Our study aims to investigate the protective effect of limonin on APAP-induced hepatotoxicity and illuminate the underlying mechanisms.
Study: design In vitro, we chose L-02 cells to establish in vitro APAP-induced liver injury model. L-02 cells were treated with APAP (7.5 mM) for 24 h after pre-incubation with limonin (10, 25, 50 μM) or NAC (250 μM) for 2 h. In vivo, we used C57BL/6 mice as an in vivo APAP-induced liver injury model. C57BL/6 mice with pre-treatment of limonin (40, 80 mg/kg) or NAC (150 mg/kg) for 1 h, were given with a single dose of APAP (300 mg/kg).
Methods: After pre-incubation with limonin (10, 25, 50 μM) for 2 h, L-02 cells were treated with APAP (7.5 mM) for 24 h.The experiments in vitro included MTT assay, Annexin V/PI staining, measurement of reactive oxygen species (ROS), quantitative real-time PCR analysis, Western blot analysis, immunofluorescence microscopy and analysis of LDH activity. Transfection of Nrf2 or Sirt1 siRNA was also conducted in vitro. In vivo, C57BL/6 mice with pre-treatment of limonin (40, 80 mg/kg) or NAC (150 mg/kg) for 1 h, were given with a single dose of APAP (300 mg/kg). Mice were sacrificed at 4, 12 h after APAP poisoning, and analysis of ALT and AST in serum, GSH level in liver tissues, liver histological observation and immunohistochemistry were performed.
Results: Limonin increased the cell viability and alleviated APAP-induced apoptosis in hepatocytes. Limonin also inhibited APAP-induced mitochondrial-mediated apoptosis by decreasing the ratio of Bax/Bcl-2, recovery of mitochondrial membrane potential (MMP), inhibiting ROS production and cleavage of caspase-3 in L-02 cells. Moreover, limonin induced activation of Nrf2 and increased protein expression and mRNA levels of its downstream targets, including HO-1, NQO1 and GCLC/GCLM. The inhibition of limonin on apoptosis and promotion on Nrf2 antioxidative pathway were lessened after the application of Nrf2 siRNA. In addition, limonin inhibited NF-κB transcriptional activation, NF-κB-regulated genes and protein expression of inflammatory related proteins iNOS and COX2. Furthermore, limonin increased the protein expression of Sirt1. Sirt1 siRNA transfection confirmed that limonin activated Nrf2 antioxidative pathway and inhibited NF-κB inflammatory response by upregulating Sirt1. Finally, we established APAP-induced liver injury in vivo and demonstrated that limonin alleviated APAP-induced hepatotoxicity by activating Nrf2 antioxidative signals and inhibiting NF-κB inflammatory response via upregulating Sirt1.
Conclusion: In summary, this study documented that limonin mitigated APAP-induced hepatotoxicity by activating Nrf2 antioxidative pathway and inhibiting NF-κB inflammatory response via upregulating Sirt1, and demonstrated that limonin had therapeutic promise in APAP-induced liver injury.
Limonin stabilises sirtuin 6 (SIRT6) by activating ubiquitin specific peptidase 10 (USP10) in cardiac hypertrophy
Background and purpose: Limonin, a naturally occurring tetracyclic triterpenoid, has extensive pharmacological effects. Its role in cardiac hypertrophy remains to be elucidated. We investigated its effects on cardiac hypertrophy along with the potential mechanisms involved.
Experimental approach: The effects of limonin on cardiac hypertrophy in C57/BL6 mice caused by aortic banding, plus neonatal rat cardiac myocytes (NRCMs) stimulated with phenylephrine to induce cardiomyocyte hypertrophy in vitro were investigated.
Key results: Limonin markedly improved the cardiac function and heart weight in aortic banded mice. Limonin-treated mice and NRCMs also produced fewer cardiac hypertrophy markers than those treated with the vehicle in the hypertrophic groups. Sustained aortic banding- or phenylephrine-stimulation impaired cardiac sirtuin 6 (SIRT6) protein levels, which were partially reversed by limonin associated with enhanced activity of PPARα. Sirt6 siRNA inhibited the anti-hypertrophic effects of limonin in vitro. Interestingly, limonin did not influence Sirt6 mRNA levels, but regulated ubiquitin levels. Thus, the protein biosynthesis inhibitor, cycloheximide and proteasome inhibitor, MG-132, were used to determine SIRT6 protein expression levels. Under phenylephrine stimulation, limonin increased SIRT6 protein levels in the presence of cycloheximide, but it did not influence SIRT6 expression in the presence of MG-132, suggesting that limonin promotes SIRT6 levels by inhibiting its ubiquitination degradation. Furthermore, limonin inhibited the degradation of SIRT6 by activating ubiquitin-specific peptidase 10 (USP10), while Usp10 siRNA prevented the beneficial effects of limonin.
Conclusion and implications: Limonin mediates the ubiquitination and degradation of SIRT6 by activating USP10, providing an attractive therapeutic target for cardiac hypertrophy.