Monocrotaline (Crotaline)   中文名称: 野百合碱

OCT1 (IC50 = 36.8 μM); OCT2 (IC50 = 1852.6 μM)

野百合碱是一种天然存在的配体，具有很强的抗肿瘤作用和剂量依赖性细胞毒性。在 HepG2 细胞上测试时，野百合碱的 IC50 为 24.966 µg/mL，体外遗传毒性为 IC50 的 2 倍 [2]。

高血压大鼠模型可以通过使用野百合碱的动物建模来创建。在大鼠中，MCT 会导致肺血管综合征，其典型表现为肺心病、肺动脉高压 (PH) 和增殖性肺血管炎 [3]。野百合碱诱导的动物模型的优点是与临床前模型中人类肺动脉高压（PAH）的几个重要方面非常相似，例如血管重塑、平滑肌细胞增殖、内皮功能障碍、炎症细胞因子上调和右心室衰竭。 [4]。野百合碱的施用导致与外周出血（PH）发病机制相关的多个途径发生改变，例如刺激糖酵解、增殖标记物升高、肉碱稳态紊乱、炎症和纤维化生物标记物升高以及谷胱甘肽产生。减少[5]。给予单剂量野百合碱（60 mg/kg ip）的大鼠肺动脉压力显着升高，右心室肥厚和肺动脉结构重塑也增加。然后，给予黄芪甲苷 IV (ASIV)，剂量为 10 和 30 mg/kg/d，持续 21 天。通过增强肺动脉重塑和炎症，ASIV可以预防肺动脉高压[7]。野百合碱（60 mg/kg；腹腔注射；单剂量）3-4 周后诱导大鼠肺动脉高压 (PAH) 模型 [7]。在左肺切除大鼠模型中，野百合碱（60 mg/kg；腹腔注射；单剂量）表现出显着的抗肿瘤功效以及剂量依赖性细胞毒性[9]。使用 1 N HCl 溶解野百合碱，然后用无菌盐水稀释，并使用 1 N NaOH 将 pH 调至 7.4 [7]。

本研究利用体外稳定转染的HEK293细胞，系统地研究了山莨菪碱和野百合碱两种生物碱与有机阳离子转运蛋白OCT1、2、3、MATE1和MATE2-K的相互作用。山莨菪碱和野百合碱均抑制OCTs和MATE转运蛋白。对OCT1的最低IC50为12.9µmol·L-1的山莨菪碱，对OCT2的最高IC50为1.8 mmol·L-1野百合碱。Anisodine是OCT2的底物（Km=13.3±2.6µmol·L-1和Vmax=286.8±53.6 pmol/mg蛋白质/min）。Monocrotaline被确定为OCT1（Km=109.1±17.8µmol·L-1，Vmax=576.5±87.5 pmol/mg蛋白质/min）和OCT2（Km=64.7±14.8µmol•L-1，V max=180.7±22.0 pmol/mg蛋白/min）的底物，而不是OCT3和MATE转运蛋白。结果表明，OCT2可能对肾清除山莨菪碱很重要，OCT1负责野百合碱进入肝脏。然而，MATE1和MATE2-K都不能促进山莨菪碱和野百合碱的跨细胞转运。这些药物可能会在高OCT1表达（肝脏）和高OCT2表达（肾脏）的器官中积聚[8]。

细胞活力测定[2]
细胞类型： HepG2 细胞
测试浓度： 25、50、100 和 200 µg/mL
孵育时间：48小时
实验结果：诱导凋亡率呈剂量依赖性。

Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling[7]
Male Sprague-Dawley rats, 8 weeks old weighing 200-230 g, were obtained from the Animal Center of Qiqihar Medical University. The protocol for the present study was approved by the Qiqihar Medical University Institutional Review Board (no. QMU-AECC-2018-27). The rats were housed in a temperature- and humidity-controlled environment with 12-h light/dark cycles. Food and water were available ad libitum. The experiments conformed to the National Institutes of Health guidelines concerning the care and use of laboratory animals, and all animal procedures were approved by the Animal Care and Use Committee of the Qiqihar Medical University. The rats were randomly assigned to 4 groups (8 rats per group) as follows: The control group, the monocrotaline (MCT) group, the MCT + 10 mg/kg/dahy ASIV (ASIV10) group, and the MCT + 30 mg/kg/day ASIV (ASIV30) group. To establish MCT-induced PAH, the rats were administered a single intraperitoneal injection of MCT (60 mg/kg), while the control group received the same volume of saline. MCT was dissolved in 1 N HCl, diluted in sterile saline and adjusted to pH 7.4 with 1 N NaOH. ASIV was initially dissolved in DMSO as a stock solution and further diluted in saline immediately prior to use; the final DMSO concentration was 0.5%. Within hours of the MCT injection, there were signs of pulmonary vascular endothelial damage, but without an increase in pulmonary artery pressure. By 2 weeks, pulmonary artery pressure began to increase, as previously described. At 2 days following the MCT administration, ASIV or the vehicle (0.5% DMSO in saline) were administered intraperitoneally once a day for 21 days.

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A total of 36 male specific-pathogen free Sprague-Dawley rats (age, 6–8 weeks; weight, 300–350 g) were kept in a conventional room at 22±2°C, a relative humidity of 55±10% and a 12-h light/dark cycle. Rats had access to food and water ad libitum. The rats were divided into the following three equal groups at random: Control group, where rats received no treatment; model group, where rats underwent a left pneumonectomy plus subcutaneous injection of 60 mg/kg monocrotaline (MCT), a natural ligand exhibiting dose-dependent cytotoxicity with potent antineoplastic activity, at 7 days following the procedure; PTX group, where rats underwent the same procedure as those in the model group plus administration of 2 mg/kg PTX via the caudal vein (21) daily for 1 week at 3 weeks following injection of MCT[9].

[1]. Gomez-Arroyo JG, et al. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol. 2012 Feb 15;302(4):L363-9.
[2]. Kusuma SS, et al. Antineoplastic activity of monocrotaline against hepatocellular carcinoma. Anticancer Agents Med Chem. 2014;14(9):1237-48.
[3]. Wilson DW, et, al. Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol. 1992;22(5-6):307-25.
[4]. Nogueira-Ferreira R, et al. Exploring the monocrotaline animal model for the study of pulmonary arterial hypertension: A network approach. Pulm Pharmacol Ther. 2015 Dec;35:8-16.
[5]. Rafikova O,et al. Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed RatLung. PLoS One. 2016 Mar 3;11(3):e0150480.
[6]. Wu XH, et al. Experimental animal models of pulmonary hypertension: Development and challenges. Animal Model Exp Med. 2022 Sep; 5(3):207-216.
[7]. Jin H, et al. Astragaloside IV blocks monocrotaline‑induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling. Int J Mol Med. 2021 Feb;47(2):595-606.
[8]. Chen JY, et al. An in vitro study on interaction of anisodine and monocrotaline with organic cation transporters of the SLC22 and SLC47 families. Chin J Nat Med. 2019 Jul;17(7):490-497.
[9]. Zhao J, et al. Effects of paclitaxel intervention on pulmonary vascular remodeling in rats with pulmonary hypertension. Exp Ther Med. 2019 Feb;17(2):1163-1170.

C16H23NO6

325.36

325.15252

C, 59.07; H, 7.13; N, 4.31; O, 29.50

315-22-0

Typically exists as solids (or liquids in special cases) at room temperature

-0.37

96.3

O=C(O[C@]1([H])CCN2[C@]1([H])C(CO3)=CC2)[C@H](C)[C@@](C)(O)[C@@](C)(O)C3=O

QVCMHGGNRFRMAD-XFGHUUIASA-N

InChI=1S/C16H23NO6/c1-9-13(18)23-11-5-7-17-6-4-10(12(11)17)8-22-14(19)16(3,21)15(9,2)20/h4,9,11-12,20-21H,5-8H2,1-3H3/t9-,11+,12+,15+,16-/m0/s1

20-Norcrotalanan-11,15-dione, 14,19-dihydro-12,13-dihydroxy-, (13-alpha,14-alpha)- (9CI)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

1M HCl : 200 mg/mL (~614.70 mM)
DMSO : ~25 mg/mL (~76.84 mM)
H2O : ~2 mg/mL (~6.15 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.68 mM) (饱和度未知) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.68 mM) (饱和度未知) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浮液。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (6.39 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 4 中的溶解度: ≥ 2.08 mg/mL (6.39 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100μL 20.8mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 5 中的溶解度: ≥ 2.08 mg/mL (6.39 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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配方 6 中的溶解度: ≥ 0.5 mg/mL (1.54 mM)(饱和度未知) in 1% DMSO 99% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。

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配方 7 中的溶解度: 4.17 mg/mL (12.82 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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配方 8 中的溶解度: 21 mg/mL (64.54 mM) in 20% HP-β-CD in Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 需要超声波和加温并加热至 53°C。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。