Background
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].
参考文献:
[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].
Protocol
| Cell experiment [1]: |
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Cell lines
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Colon cancer (SW480) and fibroblast (112CoN) cells
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Preparation Method
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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
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6.25, 12.5,25,50 and 100 μM for 24, 48, and 72 h
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Applications
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Maximum release of LDH into the medium was observed after 48 h of incubation with limonoids.
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| Animal experiment [2]: |
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Animal models
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Male Wistar rats
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Preparation Method
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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
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15 or 30 mg/kg, Miniature osmotic infusion pump
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Applications
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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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参考文献:
[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.
[2]:Mahmoud M F, Gamal S, El-Fayoumi H M. Limonin attenuates hepatocellular injury following liver ischemia and reperfusion in rats via toll-like receptor dependent pathway[J]. European Journal of Pharmacology, 2014, 740: 676-682.
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