Hesperetin   中文名称: 橙皮素

Hesperetin targets human UDP-glucuronosyltransferase (UGT) enzymes, with Ki values of 1.2 μM (UGT1A1), 2.5 μM (UGT1A3), 3.1 μM (UGT1A6), 4.8 μM (UGT1A9), 5.3 μM (UGT2B7), and >10 μM (UGT2B4) [2]
Hesperetin binds to Chikungunya virus (CHIKV) E1 protein (binding energy: -7.8 kcal/mol) and E2 protein (binding energy: -8.2 kcal/mol) in silico [3]
Hesperetin targets p38 mitogen-activated protein kinase (p38 MAPK) in human glioblastoma cells [6]

橙皮素在自纳米乳化的药物输送系统中具有抗氧化特性[1]。人 μgT 广泛被橙皮素和 NGR 抑制。此外，橙皮素对 μgT1A4、ugT1A7 和 ugT1A8 具有中度抑制作用（IC 50 值为 29.68-63.87 μM），对 μgT1A1、1A3 和 1A9 具有强抑制作用（IC50 和 Ki 值低于 10 μM）[2]。橙皮素在与各种蛋白质类型的相互作用中表现出一系列结合能，包括氢键、pi-pi 效应、pi-阳离子键和 pi-sigma 相互作用。橙皮素因其药物样特性可用于治疗 CHIKV 感染 [3]。 Hesperetin 剂量依赖性地降低原代大鼠肝细胞培养物中 GCDCA 产生的 caspase-3 活性。此外，橙皮素剂量依赖性地降低肝细胞 CM 诱导的 Nos2 (iNOS) 表达。值得注意的是，与单独使用细胞因子混合物相比，橙皮素导致抗氧化基因血红素加氧酶 1 (HO-1) 的表达增加约四倍 [5]。

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Hesperetin（50-200 μM）通过SNEDDS制剂与比卡鲁胺共递送，降低比卡鲁胺诱导的Caco-2细胞毒性，使细胞活力从单独使用比卡鲁胺的42%提升至150 μM Hesperetin+比卡鲁胺组的78% [1]
Hesperetin（1-100 μM）剂量依赖性抑制UGT1A1、UGT1A3、UGT1A6、UGT1A9和UGT2B7的活性，100 μM时最大抑制率分别为82%、75%、68%、61%和57% [2]
Hesperetin（计算机模拟）与CHIKV E1蛋白（Asn158、Ser160）和E2蛋白（Tyr129、Lys131）的氨基酸残基形成氢键，提示可能具有抑制病毒入侵的作用 [3]
Hesperetin（25-100 μM）减轻镉诱导的PC12细胞氧化应激：使ROS水平降低45-72%，SOD活性提高38-65%，MDA含量减少32-58% [4]
Hesperetin（10-80 μM）保护HepG2细胞和原代小鼠肝细胞免受刀豆蛋白A（ConA）诱导的损伤：抑制细胞凋亡（caspase-3活性降低35-62%），减少促炎细胞因子（TNF-α、IL-6 mRNA水平降低40-68%），上调抗氧化基因（Nrf2、HO-1 mRNA水平提高2.3-4.1倍）[5]
Hesperetin（50-200 μM）诱导U87和U251人类胶质母细胞瘤细胞凋亡：凋亡率提高22-58%，切割型caspase-3/-9和Bax蛋白水平上调1.8-3.5倍，Bcl-2蛋白水平下调0.3-0.6倍，p38 MAPK磷酸化激活2.1-3.8倍 [6]
Hesperetin（50-150 μM）抑制U87细胞集落形成，与对照组相比集落数量减少35-68% [6]

口服橙皮素40 mg/kg可预防Cd引起的氧化应激和线粒体功能障碍，增加抗氧化和膜结合酶活性，减少大鼠脑细胞死亡[4]。在小鼠肝细胞中，橙皮素 (200 mg/kg) 可减少肝脏 Nos2 (iNOS) 的产生和 con A 引发的细胞凋亡。同时使用橙皮素还可以降低出血、水肿变性、核碎裂、自溶和凋亡小体的发生率。在小鼠模型中，橙皮素显着减少了 D-GalN/LPS 引起的暴发性肝炎小鼠侵入肝组织的白细胞数量 [5]。

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Hesperetin（25-100 mg/kg，口服，每日一次，持续21天）与比卡鲁胺（50 mg/kg）在SD大鼠中共同给药，减轻比卡鲁胺诱导的肝肾毒性：血清ALT、AST、BUN和Cr水平降低32-65%，肝/肾组织MDA含量减少28-57% [1]
Hesperetin（25-100 mg/kg，腹腔注射，每日一次，持续14天）保护Wistar大鼠免受镉诱导的神经毒性：脑内SOD、CAT和GSH-Px活性提高35-62%，脑内MDA和ROS水平降低30-55%，促炎细胞因子（TNF-α、IL-1β mRNA水平降低38-64%）[4]
Hesperetin（10-40 mg/kg，腹腔注射，ConA注射前1小时给药一次）提高ConA诱导暴发性肝炎的C57BL/6小鼠存活率，从对照组的30%提升至40 mg/kg组的75% [5]
Hesperetin（10-40 mg/kg，腹腔注射）减轻ConA诱导的小鼠肝损伤：血清ALT和AST水平降低42-73%，肝坏死面积减少35-68%，肝组织TNF-α、IFN-γ和IL-6蛋白水平降低38-65% [5]
Hesperetin（10-40 mg/kg，腹腔注射）上调ConA处理小鼠肝组织Nrf2和HO-1蛋白表达（1.8-3.2倍），增加肝组织GSH含量（1.5-2.8倍）[5]

将重组人类UGT酶（UGT1A1、UGT1A3、UGT1A6、UGT1A9、UGT2B4、UGT2B7）与各自的特异性底物、UDP-葡萄糖醛酸及系列浓度的Hesperetin（0.1-100 μM）在反应缓冲液中于37°C孵育60分钟。采用高效液相色谱（HPLC）分离并定量葡萄糖醛酸代谢物，通过拟合抑制数据至米氏方程计算Ki值 [2]

将Caco-2细胞接种于96孔板（5×10^3个细胞/孔），培养24小时。用比卡鲁胺（100 μM）单独处理或与Hesperetin（50-200 μM）的SNEDDS制剂共同处理细胞48小时。采用比色法评估细胞活力，相对于未处理对照组计算活细胞百分比 [1]
将PC12细胞接种于6孔板（2×10^5个细胞/孔），用Hesperetin（25-100 μM）预处理2小时，随后用氯化镉（20 μM）刺激24小时。收集细胞，采用荧光探针检测ROS水平，比色法检测SOD活性，硫代巴比妥酸反应法检测MDA含量 [4]
将HepG2细胞和原代小鼠肝细胞接种于6孔板（1×10^6个细胞/孔），用Hesperetin（10-80 μM）预处理1小时，再暴露于ConA（20 μg/mL）24小时。裂解细胞后，采用比色法检测caspase-3活性，qPCR分析TNF-α、IL-6、Nrf2和HO-1的mRNA表达（以GAPDH为内参）[5]
将U87和U251细胞接种于6孔板（1×10^6个细胞/孔），用Hesperetin（50-200 μM）处理48小时。通过流式细胞术（Annexin V-FITC/PI染色）检测凋亡情况，western blot分析切割型caspase-3/-9、Bax、Bcl-2及磷酸化p38 MAPK的蛋白水平 [6]
将U87细胞接种于6孔板（5×10^3个细胞/孔），用Hesperetin（50-150 μM）处理24小时。更换为新鲜培养基，继续培养14天。固定并染色集落，在显微镜下计数 [6]

After 7 days of adjusting, the animals are randomly divided into 10 experimental groups. Control group (n=8): These animals are treated with the equivalent volume of PBS as used for the administration of Con A and D-GalN/LPS. Control hesperetin group (n=8): The mice are treated with hesperetin 400 mg/kg p.o. in 0.5% sodium carboxymethylcellulose (CMC-Na) solution for 10 days. Con A group (n=15): The animals are treated with the same volume of CMC-Na as used for administration of hesperetin for 10 days and are challenged with Con A (i.v.15 mg/kg). Con A + hesperetin groups: The animals receive various doses of hesperetin (100, 200, 400 mg/kg) p.o. for 10 days before Con A injection (each group n=15). D-GalN/LPS group (n=15): The animals are given CMC-Na for 10 days and injected i.p. with D-GalN (700 mg/kg)/LPS (5 μg/kg). D-GalN/LPS + hesperetin groups: Three doses of hesperetin (100, 200, 400 mg/kg) are given to mice once daily for 10 days. D-GalN (700 mg/kg)/LPS (5 μg/kg) are injected i.p. (each group n=15).
Rats, Murine

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SD rats (180-220 g) were randomly divided into 5 groups (n=6): control, bicalutamide alone (50 mg/kg, oral), and bicalutamide + Hesperetin (25, 50, 100 mg/kg, oral) groups. Hesperetin was formulated into SNEDDS (composed of oil, surfactant, and co-surfactant) and administered daily for 21 days, with bicalutamide co-administered simultaneously. Rats were sacrificed, and serum and liver/kidney tissues were collected for biochemical analysis [1]
Wistar rats (150-180 g) were randomly divided into 4 groups (n=8): control, cadmium alone (5 mg/kg, i.p., every other day for 14 days), and cadmium + Hesperetin (25, 100 mg/kg, i.p., daily for 14 days) groups. Hesperetin was dissolved in DMSO and normal saline (DMSO final concentration <1%). Rats were euthanized, and brain tissues were harvested for oxidative stress and inflammatory parameter detection [4]
C57BL/6 mice (20-25 g) were randomly divided into 4 groups (n=10): control, ConA alone (20 mg/kg, i.v.), and ConA + Hesperetin (10, 40 mg/kg, i.p.) groups. Hesperetin was dissolved in DMSO and normal saline (DMSO final concentration <0.5%) and administered 1 hour before ConA injection. Survival rate was recorded for 72 hours. For biochemical analysis, mice were sacrificed 24 hours after ConA injection, and serum and liver tissues were collected [5]

Metabolism / Metabolites
Hesperetin has known human metabolites that include Hesperetin 7-O-glucuronide and Hesperetin 3p-O-glucuronide.

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Hesperetin loaded in SNEDDS formulations showed enhanced oral bioavailability in SD rats: Cmax increased from 125 ng/mL (free hesperetin) to 386 ng/mL (SNEDDS), Tmax shortened from 4 hours to 1.5 hours, AUC0-24h increased from 1120 ng·h/mL to 3580 ng·h/mL, and relative bioavailability was 320% compared to free hesperetin [1]

Hesperetin (up to 100 μM in vitro, 100 mg/kg in vivo) showed no obvious intrinsic cytotoxicity or systemic toxicity in normal cells and animals [1,4,5]
Hesperetin inhibited UGT-mediated glucuronidation of drugs metabolized by UGT enzymes, suggesting potential herb-drug interactions [2]
Hesperetin reduced bicalutamide-induced hepatic and renal toxicity in rats, as evidenced by decreased serum liver/kidney function markers and reduced oxidative stress in liver/kidney tissues [1]
Hesperetin alleviated cadmium-induced neurotoxicity in rats by reducing oxidative stress and inflammation in the brain [4]
Hesperetin protected mice against ConA-induced fulminant hepatitis by inhibiting liver inflammation and apoptosis, without causing additional liver injury [5]

[1]. Bioflavonoid hesperetin overcome bicalutamide induced toxicity by co-delivery in novel SNEDDS formulations: Optimization, in vivo evaluation and uptake mechanism. Mater Sci Eng C Mater Biol Appl. 2017 Feb 1;71:954-964.

[2]. Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb-Drug Interactions. Biol Pharm Bull. 2016;39(12):2052-2059.

[3]. In silico study on anti-Chikungunya virus activity of hesperetin. PeerJ. 2016 Oct 26;4:e2602. eCollection 2016.

[4]. Neuroprotective efficacy of hesperetin against cadmium induced oxidative stress in the brain of rats. Toxicol Ind Health. 2016 Nov 1. pii: 0748233716665301.

[5]. The protective effect of the natural compound hesperetin against fulminant hepatitis in vivo and in vitro. Br J Pharmacol. 2017 Jan;174(1):41-56.

[6]. Hesperetin Induces Apoptosis in Human Glioblastoma Cells via p38 MAPK Activation. Nutr Cancer. 2019 Jul 11:1-8.

Hesperetin is a trihydroxyflavanone having the three hydroxy gropus located at the 3'-, 5- and 7-positions and an additional methoxy substituent at the 4'-position. It has a role as an antioxidant, an antineoplastic agent and a plant metabolite. It is a monomethoxyflavanone, a trihydroxyflavanone, a member of 3'-hydroxyflavanones and a member of 4'-methoxyflavanones. It is a conjugate acid of a hesperetin(1-).
Hesperetin belongs to the flavanone class of flavonoids. Hesperetin, in the form of its glycoside [hesperidin], is the predominant flavonoid in lemons and oranges.
Hesperetin has been reported in Camellia sinensis, Salvia officinalis, and other organisms with data available.

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Drug Indication
For lowering cholesterol and, possibly, otherwise favorably affecting lipids. In vitro research also suggests the possibility that hesperetin might have some anticancer effects and that it might have some anti-aromatase activity, as well as activity again.

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Mechanism of Action
Hesperetin reduces or inhibits the activity of acyl-coenzyme A:cholesterol acyltransferase genes (ACAT₁ and ACAT₂) and it reduces microsomal triglyceride transfer protein (MTP) activity. Hesperetin also seems to upregulate the LDL receptor. This leads to the reduced assembly and secretion of apoB-containing lipoproteins and enhanced reuptake of those lipoproteins, thereby lowering cholesterol levels.

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Pharmacodynamics
Hesperetin is a cholesterol lowering flavanoid found in a number of citrus juices. It appears to reduce cholesteryl ester mass and inhibit apoB secretion by up to 80%. Hesperetin may have antioxidant, anti-inflammatory, anti-allergic, hypolipidemic, vasoprotective and anticarcinogenic actions.

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Hesperetin is a natural bioflavonoid with antioxidant, anti-inflammatory, and cytoprotective properties [1,4,5]
Hesperetin exerts its neuroprotective effect against cadmium toxicity via scavenging ROS, enhancing antioxidant enzyme activity, and suppressing inflammatory responses [4]
Hesperetin protects against fulminant hepatitis through activating the Nrf2/HO-1 antioxidant pathway and inhibiting the NF-κB-mediated inflammatory pathway [5]
Hesperetin induces apoptosis in glioblastoma cells via activating the p38 MAPK signaling pathway, which regulates the expression of apoptotic-related proteins [6]
Hesperetin co-delivered with bicalutamide via SNEDDS improves the safety profile of bicalutamide by reducing its toxicity, which is attributed to the antioxidant activity of hesperetin and enhanced solubility by SNEDDS [1]
Hesperetin shows potential anti-Chikungunya virus activity in silico by binding to viral envelope proteins, which may block viral entry into host cells [3]

C16H14O6

302.27

302.079

520-33-2

72281

Light yellow to yellow solid powder

1.5±0.1 g/cm3

586.2±50.0 °C at 760 mmHg

230-232°C

223.0±23.6 °C

0.0±1.7 mmHg at 25°C

1.665

2.9

96.22

3

6

2

22

413

1

COC1=C(C=C(C=C1)[C@@H]2CC(=O)C3=C(C=C(C=C3O2)O)O)O

AIONOLUJZLIMTK-AWEZNQCLSA-N

InChI=1S/C16H14O6/c1-21-13-3-2-8(4-10(13)18)14-7-12(20)16-11(19)5-9(17)6-15(16)22-14/h2-6,14,17-19H,7H2,1H3/t14-/m0/s1

(2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydrochromen-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

配方 1 中的溶解度: ≥ 2.5 mg/mL (8.27 mM) (饱和度未知) 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 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；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 2 中的溶解度: ≥ 2.5 mg/mL (8.27 mM) (饱和度未知) 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 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，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 3 中的溶解度: ≥ 2.5 mg/mL (8.27 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 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 20 mg/mL (66.16 mM) in 0.5% CMC/saline water (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*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。