Research Progress on Pharmacological Activities of Neohesperidin Dihydrochalcone and Its Synthetic Precursors

WEI Jing; SONG Ruolan; CHEN Xiang; WANG Zhendong; DONG Ying; ZHONG Xiangjian; LÜ Fang; SHE Gaimei

doi:10.13386/j.issn1002-0306.2022010176

Volume 43 Issue 23

Nov. 2022

Turn off MathJax

Article Contents

Abstract

References

Science and Technology of Food Industry > 2022 > 43(23): 436-449. > DOI: 10.13386/j.issn1002-0306.2022010176

WEI Jing, SONG Ruolan, CHEN Xiang, et al. Research Progress on Pharmacological Activities of Neohesperidin Dihydrochalcone and Its Synthetic Precursors[J]. Science and Technology of Food Industry, 2022, 43(23): 436−449. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2022010176.

Citation:

PDF (4666 KB)

Research Progress on Pharmacological Activities of Neohesperidin Dihydrochalcone and Its Synthetic Precursors

1.
School of Chinnese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
2.
Huantai County Shishi Hospital, Zibo 256405, China
3.
Shandong Benyue Biological Technology Co., Ltd., Dongying 257000, China

More Information

Received Date: January 20, 2022
Available Online: September 25, 2022

Graphical Abstract

Abstract

Abstract

Neohesperidin dihydrochalcone (NHDC) is a sweetener with non-toxic, highly sweet and low-calorie characteristics. It has abilities of adding sweetness, adding fragrance and masking the bitterness, together with modifying flavours, as well as pharmacological activities such as antioxidant, anti-inflammatory, hypolipidemic and has potential for development in the fields of food and pharmaceutical. NHDC is usually obtained by hydrogenated reduction of neohesperidin (NHP) after hydrolysis under alkaline conditions, while neohesperidin is synthesized from hesperidin (HSD) and naringenin (NRG), they are called as synthesis precursors of NHDC. The synthetic precursors of NHDC have various biological activities, including antioxidant, liver and kidney protection, antibacterial and improving gastrointestinal function, etc. The pharmacological effects of NHDC are characterized by slow development process, lack of research systems and lack of depth of mechanisms compared to other dihydrochalcone compounds. In this paper, we searches the scientific databases including SciFinder, Web of Science and CNKI with the keywords of NHDC and its synthetic precursors, and reads its relevant literature. The pharmacological activity is systematically discussed and synthetic precursors mechanism is summarized for the NHDC, which will provide reference for the further utilization and development of NHDC and produce high value-added products in future.
- neohesperidin dihydrochalcone (NHDC),
- hesperidin (HSD),
- neohesperidin (NHP),
- naringin (NRG),
- pharmacological activities

FullText(HTML)

References (110)

References

[1]	雷琳, 黄宝华, 卢宇靖, 等. 新橙皮苷二氢查耳酮的调味应用及其生理活性研究进展[J]. 中国调味品,2014,39(12):41−47. [LEI L, HUANG B H, LU Y J, et al. Research progress of flavor modifying and physiological activity of neohesperidin dihydrochalcone[J]. China Condiment,2014,39(12):41−47.
[2]	隗继浩. 新橙皮苷二氢查耳酮对OVA诱导口服耐受的影响[D]. 长春: 吉林大学, 2020 CHEN J H. Effect of neohesperidin dihydrochalcone on OVA-induced oral tolerance[D]. Changchun: Jilin University, 2020.
[3]	梁健丹, 李海梅, 罗华健, 等. 新橙皮甙二氢查尔酮与HSA/BSA的相互作用机制研究[J]. 南宁师范大学学报(自然科学版),2020,37(2):29−36. [LIANG J D, LI H M, LUO H J, et al. Study on the interaction mechanism between neohesperidin dihydrochalcone and different organisms (HSA/BSA)[J]. Journal of Nanning Normal University(Natural Scinence Edition),2020,37(2):29−36.
[4]	SHI Q, SONG X, FU J, et al. Artificial sweetener neohesperidin dihydrochalcone showed antioxidative, anti-inflammatory and anti-apoptosis effects against paraquat-induced liver injury in mice[J]. Int Immunopharmacol,2015,29(2):722−729. doi: 10.1016/j.intimp.2015.09.003
[5]	HU L, LI L, XU D, et al. Protective effects of neohesperidin dihydrochalcone against carbon tetrachloride-induced oxidative damage in vivo and in vitro[J]. Chem Biol Interact,2014,213:51−59. doi: 10.1016/j.cbi.2014.02.003
[6]	CHOI J M, YOON B S, LEE S K, et al. Antioxidant properties of neohesperidin dihydrochalcone: Inhibition of hypochlorous acid-induced DNA strand breakage, protein degradation, and cell death[J]. Biol Pharm Bull,2007,30(2):324. doi: 10.1248/bpb.30.324
[7]	SUAREZ J, HERRERA MD, MARHUENDA E. In vitro scavenger and antioxidant properties of hesperidin and neohesperidin dihydrochalcone[J]. Phytomedicine,1998,5(6):469−73. doi: 10.1016/S0944-7113(98)80044-5
[8]	XIA X M, FU J L, SONG X F, et al. Neohesperidin dihydrochalcone down-regulates MyD88-dependent and -independent signaling by inhibiting endotoxin-induced trafficking of TLR4 to lipid rafts[J]. Free Radic Biol Med,2015,89:522−532. doi: 10.1016/j.freeradbiomed.2015.08.023
[9]	BOK S H, JEONG T S, HWAN B K, et al. Use of neohesperidin dihydrochalcone for the manufacture of a medicament for preventing or treating elevated blood lipid levelrelated diseases: European, EP 1113726 Bl[P]. 2004-03-24.
[10]	王振东, 陈良, 王洋. 关于新甲基橙皮苷二氢查耳酮食品级产品标准和检测方法的研究[J]. 中国调味品,2016,41(11):135−139. [WANG Z D, CHEN L, WANG Y. Research on food-grade product standards and testing methods of neohesperidin dihydrochalcone[J]. China Condiment,2016,41(11):135−139.
[11]	李爱平. 新橙皮苷二氢查耳酮的制备及应用研究[D]. 广州: 华南理工大学, 2016 LI A P. Preparation and application of neosperidin dihydrochalcone[D]. Guangzhou: South China University of Technology, 2016.
[12]	TAN S, DAI L L, TAN P C, et al. Hesperidin administration suppresses the proliferation of lung cancer cells by promoting apoptosis via targeting the miR132/ZEB2 signalling pathway[J]. Int J Mol Med,2020,46(6):2069−2077. doi: 10.3892/ijmm.2020.4756
[13]	XU F, ZANG J, CHEN D Z, et al. Neohesperidin induces cellular apoptosis in human breast adenocarcinoma MDA-MB-231 cells via activating the Bcl-2/Bax-mediated signaling pathway[J]. Nat Prod Commun,2012,7(11):1475−1478.
[14]	CHEN M J, PENG W L, HU S F, et al. miR-126/VCAM-1 regulation by naringin suppresses cell growth of human non-small cell lung cancer[J]. Oncol Lett,2018,16(4):4754−4760.
[15]	AKSU E H, KANDEMIR F M, KÜCÜKLER S. The effects of hesperidin on colistin-induced reproductive damage, autophagy, and apoptosis by reducing oxidative stress[J]. Andrologia,2021,53(2):e13900.
[16]	徐坤勇, 郭建忠, 颜娟, 等. 响应曲面法优化枳壳中柚皮苷与新橙皮苷的提取工艺及抗氧化研究[J]. 现代中药研究与实践,2021,35(1):66−72. [XU K Y, GUO J Z, YAN J, et al. Optimization of extraction process of naringin and neohesperidin from Aurantii fructus by response surface methodology and anti-oxidant activity[J]. Research and Practice on Chinese Medicines,2021,35(1):66−72.
[17]	CHEN P, XIAO Z T, WU H, et al. The effects of naringin on cigarette smoke-induced dynamic changes in oxidation/antioxidant system in lung of mice[J]. Nat Prod Commun,2020,15(8):1−9.
[18]	LI Y S, ZHANG J, TIAN G H, et al. Kirenol, darutoside and hesperidin contribute to the anti-inflammatory and analgesic activities of siegesbeckia pubescens makino by inhibiting COX-2 expression and inflammatory cell infiltration[J]. J Ethnopharmacol,2021,268:113547. doi: 10.1016/j.jep.2020.113547
[19]	JAIN M, PARMAR H S. Evaluation of antioxidative and anti-inflammatory potential of hesperidin and naringin on the rat air pouch model of inflammation[J]. Inflamm Res,2011,60(5):483−491. doi: 10.1007/s00011-010-0295-0
[20]	REHMAN K, MUARWAR S M, AKASH MSH, et al. Hesperidin improves insulin resistance via down-regulation of inflammatory responses: Biochemical analysis and in silico validation[J]. PLoS One,2020,15(1):e0227637. doi: 10.1371/journal.pone.0227637
[21]	JIA S, HU Y, ZHANG W N, et al. Hypoglycemic and hypolipidemic effects of neohesperidin derived from Citrus aurantium L. in diabetic KK-A(y) mice[J]. Food Funct,2015,6(3):878−886. doi: 10.1039/C4FO00993B
[22]	WANG K, PENG S J, XIONG S F, et al. Naringin inhibits autophagy mediated by PI3K-Akt-mTOR pathway to ameliorate endothelial cell dysfunction induced by high glucose/high fat stress[J]. Eur J Pharmacol,2020,874:173003. doi: 10.1016/j.ejphar.2020.173003
[23]	AJA P M, EKPONO E U, AWOKE J N, et al. Hesperidin ameliorates hepatic dysfunction and dyslipidemia in male wistar rats exposed to cadmium chloride[J]. Toxicol Rep,2020,7:1331−1338. doi: 10.1016/j.toxrep.2020.09.014
[24]	LU J F, ZHU M Q, ZHANG H, et al. Neohesperidin attenuates obesity by altering the composition of the gut microbiota in high-fat diet-fed mice[J]. FASEB J,2020,34(9):12053−12071. doi: 10.1096/fj.201903102RR
[25]	BI C, JIANG Y N, FU Y N, et al. Naringin inhibits lipopolysaccharide-induced damage in human umbilical vein endothelial cells via attenuation of inflammation, apoptosis and MAPK pathways[J]. Cytotechnology,2016,68(4):1473−1487. doi: 10.1007/s10616-015-9908-3
[26]	ABDELAZIZ R M, ABDELAZEM A Z, HASHEM K S, et al. Protective effects of hesperidin against MTX-induced hepatotoxicity in male albino rats[J]. N-S Arch Pharmacol,2020,393(8):1405−1417. doi: 10.1007/s00210-020-01843-z
[27]	CAGLAYAN C, TEMEL Y, KANDEMIR F M, et al. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage[J]. Environ Sci Pollut Res Int,2018,25(21):20968−20984. doi: 10.1007/s11356-018-2242-5
[28]	HAN G E, KANG H T, CHUNG S, et al. Novel neohesperidin dihydrochalcone analogue inhibits adipogenic differentiation of human adipose-derived stem cells through the Nrf2 pathway[J]. Int J Mol Sci,2018,19(8):2215. doi: 10.3390/ijms19082215
[29]	IRANSHAHI M, REZAEE R, PARHIZ H, et al. Protective effects of flavonoids against microbes and toxins: The cases of hesperidin and hesperetin[J]. Life Sci,2015,137:125−132. doi: 10.1016/j.lfs.2015.07.014
[30]	PARHIZ H, ROOHBAKHSH A, SOLTANI F, et al. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: An updated review of their molecular mechanisms and experimental models[J]. Phytother Res,2015,29(3):323−331. doi: 10.1002/ptr.5256
[31]	DALY K, DARBY A C, HALL N, et al. Bacterial sensing underlies artificial sweetener-induced growth of gut Lactobacillus[J]. Environ Microbiol,2016,18(7):2159−2171. doi: 10.1111/1462-2920.12942
[32]	SHE G M, WANG S, LIU B. Dihydrochalcone glycosides from oxytropis myriophylla[J]. Chem Cent J,2011,5:71. doi: 10.1186/1752-153X-5-71
[33]	王刚, 蔡才, 王亚珍, 等. 新橙皮苷二氢查耳酮的合成工艺及应用进展[J]. 江汉大学学报(自然科学版),2020,48(1):37−44. [WANG G, CAI C, WANG Y Z, et al. Synthesis and application of neohesperidin dihydrochalcone[J]. Journal of Jianghan University Natural Science Edition,2020,48(1):37−44.
[34]	ROOHBAKHSH A, PARHIZ H, SOLTANI F, et al. Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases[J]. Life Sci,2015,124:64−74. doi: 10.1016/j.lfs.2014.12.030
[35]	陈春玉, 李毅, 黄超明, 等. 新橙皮苷的制备工艺及应用进展[J]. 天然气化工(C1化学与化工),2014,39(3):81−87. [CHEN C Y, LI Y, HUANG C M, et al. Advances in preparation and application of neohesperidin[J]. Natural Gas Chemical Industry,2014,39(3):81−87.
[36]	SHIRANI K, YOUSEFSANI B S, SHIRANI M, et al. Protective effects of naringin against drugs and chemical toxins induced hepatotoxicity: A review[J]. Phytother Res,2020,34(8):1734−1744. doi: 10.1002/ptr.6641
[37]	刘坚, 王振, 蒋书歌, 等. 根皮乙酰苯-4′-β-新橙皮糖苷合成新橙皮苷工艺研究[J]. 中国野生植物资源,2020,39(8):1−5. [LIU J, WANG Z, JIANG S G, et al. Study on the synthesis of neohesperidin from phloroacetophenone-4'-β-neohesperidoside[J]. Chinese Wild Plant Resources,2020,39(8):1−5.
[38]	NIJVELDT R J, VAN NOOD E, VAN HOORN D E, et al. Flavonoids: A review of probable mechanisms of action and potential applications[J]. Am J Clin Nutr,2001,74(4):418−425. doi: 10.1093/ajcn/74.4.418
[39]	COS P, YING L, CALOMME M, et al. Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers[J]. J Nat Prod,1998,61(1):71−76. doi: 10.1021/np970237h
[40]	VAN ACKER S A, TROMP M N, HAENEN G R, et al. Flavonoids as scavengers of nitric oxide radical[J]. Biochem Biophys Res Commun,1995,214(3):755−759. doi: 10.1006/bbrc.1995.2350
[41]	LOTITO S B, FREI B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: Cause, consequence, or epiphenomenon?[J]. Free Radic Biol Med,2006,41(12):1727−1746. doi: 10.1016/j.freeradbiomed.2006.04.033
[42]	KUMAR R, AKHTAR F, RIZZVI S I. Hesperidin attenuates altered redox homeostasis in an experimental hyperlipidaemic model of rat[J]. Clin Exp Pharmacol Physiol,2020,47(4):571−582. doi: 10.1111/1440-1681.13221
[43]	ESTRUEL-AMADES S, MASSOT-CLADERA M, GARCIA-CERDÀ P, et al. Protective effect of hesperidin on the oxidative stress induced by an exhausting exercise in intensively trained rats[J]. Nutrients,2019,11(4):783. doi: 10.3390/nu11040783
[44]	ELHELALY A E, ALBASHER G, ALFARRAJ S, et al. Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats[J]. Environ Sci Pollut Res Int,2019,26(34):35151−35162. doi: 10.1007/s11356-019-06660-3
[45]	贾富霞, 王秀娟, 罗容. 酸橙枳实黄酮类抗氧化活性的药效组分研究[J]. 世界中医药,2017,16(15):46−55. [JIA F X, WANG X J, LUO R. Study on antioxidative active components alignment of flavonoids from Aurantii fructus immaturus[J]. World Chinese Medicine,2017,16(15):46−55.
[46]	龙江宜, 陈健民, 廖苑君, 等. 柚皮苷改善CCl₂所致大鼠学习记忆障碍及其机制[J]. 中国药理学通报,2020,36(3):372−379. [LONG J Y, CHEN J M, LIAO Y J, et al. Naringin improves learning and memory impairment induced by CCl₂ in rats and its mechanism[J]. Chinese Pharmacological Bulletin,2020,36(3):372−379.
[47]	张启焕, 严新, 许伟, 等. 超声波辅助醇溶剂法提取橙皮苷及体外抑菌活性分析[J]. 安徽农业科学,2015,43(31):33−34, 52. [ZHANG Q H, YAN X, XU W, et al. Study on extraction of hesperidin from ponkan peel and analysis of its bacteriostatic activity[J]. Journal of Anhui Agricultural Sciences,2015,43(31):33−34, 52.
[48]	JIN Y B, LIU P, LIU X G, et al. In vitro antioxidant and antimicrobial activities of the extract of Pericarpium Citri Reticulatae of a new Citrus cultivar and its main flavonoids[J]. LWT-Food Sci Technol,2008,41(4):597−603. doi: 10.1016/j.lwt.2007.04.008
[49]	DU L H, JIANG Z P, XU L L, et al. Microfluidic reactor for lipase-catalyzed regioselective synthesis of neohesperidin ester derivatives and their antimicrobial activity research[J]. Carbohydr Res,2018,455:32−38. doi: 10.1016/j.carres.2017.11.008
[50]	左龙亚, 滕左, 王孝仕, 等. 不同溶剂柠檬果皮提取物抗氧化、抑菌活性比较及其与多酚组成的关系[J]. 园艺学报,2017,44(4):743−754. [ZUO L Y, TENG Z, WANG X S, et al. Comparsion of antioxidant and antifungal activities of various solvent extracts of lemon peel and analysis the relationship with polyphenol composition[J]. Acta Horticulturae Sinica,2017,44(4):743−754.
[51]	ZHAO Y, LIU S. Bioactivity of naringin and related mechanisms[J]. Pharmazie,2021,76(8):359−363.
[52]	FERRERO-MILIANI L, NIELSEN O H, ANDERSEN P S, et al. Chronic inflammation: Importance of NOD2 and NALP3 in interleukin-1beta generation[J]. Clin Exp Immunol,2010,147:227−235.
[53]	BENAVENTE-GARCÍA O, CASTILLO J. Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity[J]. J Agric Food Chem,2008,56(15):6185−6205. doi: 10.1021/jf8006568
[54]	WANG S Y, HE N, XING H Y, et al. Function of hesperidin alleviating inflammation and oxidative stress responses in COPD mice might be related to SIRT1/PGC-1α/NF-κB signaling axis[J]. J Recept Signal Transduct Res,2020,40(4):388−394. doi: 10.1080/10799893.2020.1738483
[55]	冯宝民, 蒋革, 贾景明, 等. 柚皮苷和新橙皮苷抗过敏作用的研究[J]. 大连大学学报,2005(4):63−64. [FENG B M, JIANG G, JIA J M, et al. Study on the anti-allergic activities of narigin and neohesperidin[J]. Journal of Dalian University,2005(4):63−64.
[56]	HAMDAN D I, MAHMOUD M F, WINK M, et al. Effect of hesperidin and neohesperidin from bittersweet orange (Citrus aurantium var. bigaradia) peel on indomethacin-induced peptic ulcers in rats[J]. Environ Toxicol Pharmacol,2014,37(3):907−915. doi: 10.1016/j.etap.2014.03.006
[57]	AHMAD S F, ATTIA S M, BAKHEET S A, et al. Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κB, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines[J]. Inflammation,2015,38(2):846−857. doi: 10.1007/s10753-014-9994-y
[58]	GIL M, KIM Y K, HONG S B, et al. Naringin decreases TNF-α and HMGB1 release from LPS-stimulated macrophages and improves survival in a CLP-induced sepsis mice[J]. PLoS One,2016,11(10):e0164186. doi: 10.1371/journal.pone.0164186
[59]	SU C Y, XIA X M, SHI Q, et al. Neohesperidin dihydrochalcone versus CCl₄-induced hepatic injury through different mechanisms: The implication of free radical scavenging and Nrf2 activation[J]. J Agric Food Chem,2015,63(22):5468−5475. doi: 10.1021/acs.jafc.5b01750
[60]	ABD-ELHAKIM Y M, GHONEIM M H, KHAIRY M H, et al. Single or combined protective and therapeutic impact of taurine and hesperidin on carbon tetrachloride-induced acute hepatic injury in rat[J]. Environ Sci Pollut Res Int,2020,27(12):13180−13193. doi: 10.1007/s11356-020-07895-1
[61]	隗世波, 刘青云, 石雅娴. 橙皮苷对脓毒症所致急性肾损伤大鼠的作用及其机制[J]. 中国新药与临床杂志,2020,39(8):494−498. [CHEN S B, LIU Q Y, SHI Y X. Effects and mechanism of hesperidin on sepsis-induced acute kidney injury in rats[J]. Chinese Journal of New Drugs and Clinical Remedies,2020,39(8):494−498.
[62]	PARK W S, PARK M S, KANG S W, et al. Hesperidin shows protective effects on renal function in ischemia-induced acute kidney injury (Sprague-Dawley Rats)[J]. Transplant Proc,2019,51(8):2838−2841. doi: 10.1016/j.transproceed.2019.02.055
[63]	WANG S W, SHENG H, BAI Y F, et al. Neohesperidin enhances PGC-1α-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice[J]. Nutr Diabetes,2020,10(1):27. doi: 10.1038/s41387-020-00130-3
[64]	ADIL M, KANDHARE A D, GHOSH P, et al. Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: Role of FXR and KIM-1[J]. Ren Fail,2016,38(6):1007−1020. doi: 10.3109/0886022X.2016.1163998
[65]	BOK S H, JEONG T S, CHOI M S, et al. Bioflavonoids as plasma high density lipoprotein level increasing agent: Canadian, CA 2346325 Al[P]. 2001-04-07.
[66]	XIONG H J, WANG J, RAN Q, et al. Hesperidin: A therapeutic agent for obesity[J]. Drug Des Devel Ther,2019,13:3855−3866. doi: 10.2147/DDDT.S227499
[67]	SUNDARAM R, NANDHAKUMAR E, HASEENA B H. Hesperidin, a citrus flavonoid ameliorates hyperglycemia by regulating key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats[J]. Toxicol Mech Methods,2019,29(9):644−653. doi: 10.1080/15376516.2019.1646370
[68]	PRASATTHONG P, MEEPHAT S, RATTANAKANOKCHAI S, et al. Hesperidin ameliorates signs of the metabolic syndrome and cardiac dysfunction via IRS/Akt/GLUT4 signaling pathway in a rat model of diet-induced metabolic syndrome[J]. Eur J Nutr,2021,60(2):833−848. doi: 10.1007/s00394-020-02291-4
[69]	ZHANG J K, SUN C D, YAN Y Y, et al. Purification of naringin and neohesperidin from Huyou (Citrus changshanensis) fruit and their effects on glucose consumption in human HepG2 cells[J]. Food Chem,2012,135(3):1471−1478. doi: 10.1016/j.foodchem.2012.06.004
[70]	YANG Y, GONG W Y, JIN C X, et al. Naringin ameliorates experimental diabetic renal fibrosis by inhibiting the ERK1/2 and JNK MAPK signaling pathways[J]. J Funct Foods,2018,50:53−62. doi: 10.1016/j.jff.2018.09.020
[71]	PENGNET S, PROMMAOUAN S, SUMARITHUM P, et al. Naringin reverses high-cholesterol diet-induced vascular dysfunction and oxidative stress in rats via regulating LOX-1 and NADPH oxidase subunit expression[J]. Biomed Res Int,2019:3708497.
[72]	ZOPUN M, LIEDER B, HOLIK A K, et al. Noncaloric sweeteners induce peripheral serotonin secretion via the T1R3-dependent pathway in human gastric parietal tumor cells (HGT-1)[J]. J Agric Food Chem,2018,66(27):7044−7053. doi: 10.1021/acs.jafc.8b02071
[73]	DALY K, DARBY A C, HALL N, et al. Dietary supplementation with lactose or artificial sweetener enhances swine gut Lactobacillus population abundance[J]. Br J Nutr,2014,111(Suppl 1):S30−S35.
[74]	SHI Z, LEI H, CHEN G, et al. Impaired intestinal Akkermansia muciniphila and aryl hydrocarbon receptor ligands contribute to nonalcoholic fatty liver disease in mice[J]. mSystems,2021,6(1):20.
[75]	WU M N, LI Y R, GU Y F. Hesperidin improves colonic motility in loeramide-induced constipation rat model via 5-hydroxytryptamine 4R/cAMP signaling pathway[J]. Digestion,2020,101:692−705. doi: 10.1159/000501959
[76]	ESTRUEL-AMADES S, MASSOT-CLADERA M, PÉREZ-CANO F J, et al. Hesperidin effects on gut microbiota and gut-associated lymphoid tissue in healthy rats[J]. Nutrients,2019,11(2):324. doi: 10.3390/nu11020324
[77]	GUO K, REN J, GU G, et al. Hesperidin protects against intestinal inflammation by restoring intestinal barrier function and up-regulating treg cells[J]. Mol Nutr Food Res,2020,64(10):e1970058. doi: 10.1002/mnfr.201970058
[78]	GONG Y, DONG R, GAO X, et al. Neohesperidin prevents colorectal tumorigenesis by altering the gut microbiota[J]. Pharmacol Res,2019,148:104460. doi: 10.1016/j.phrs.2019.104460
[79]	袁菱, 陈彦, 辛然, 等. 柚皮苷、橙皮苷、新橙皮苷与芍药苷配伍的肠吸收研究[J]. 中国医院药学杂志,2013,33(15):1256−1260. [YUAN L, CHEN Y, XIN R, et al. Study on intestinal absorption of main components after naringin, hesperidin, neohesperidin co-administration with paeoniflorin, respectively[J]. Chinese Journal of Hospital Pharmacy,2013,33(15):1256−1260. doi: 10.13286/j.cnki.chinhosppharmacyj.2013.15.011
[80]	LEE J H, LEE S H, KIM Y S, et al. Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease[J]. Phytother Res,2009,23(12):1748−1753. doi: 10.1002/ptr.2840
[81]	LIU P, BIAN Y, FAN Y, et al. Protective effect of naringin on in vitro gut-vascular barrier disruption of intestinal microvascular endothelial cells induced by TNF-α[J]. J Agric Food Chem,2020,68(1):168−175. doi: 10.1021/acs.jafc.9b06347
[82]	MANEESAI P, BUNBUPHA S, POTUE P, et al. Hesperidin prevents nitric oxide deficiency-induced cardiovascular remodeling in rats via suppressing TGF-β1 and MMPs protein expression[J]. Nutrients,2018,10(10):1549. doi: 10.3390/nu10101549
[83]	LI X F, HU X R, WANG J C, et al. Inhibition of autophagy via activation of PI3K/Akt/mTOR pathway contributes to the protection of hesperidin against myocardial ischemia/reperfusion injury[J]. Int J Mol Med,2018,42(4):1917−1924.
[84]	KUZU M, KANDEMIR F M, YILDIRIM S, et al. Attenuation of sodium arsenite-induced cardiotoxicity and neurotoxicity with the antioxidant, anti-inflammatory, and antiapoptotic effects of hesperidin[J]. Environ Sci Pollut Res Int,2021,28(9):10818−10831. doi: 10.1007/s11356-020-11327-5
[85]	ZHANG J S, FU X D, YANG L, et al. Neohesperidin inhibits cardiac remodeling induced by Ang II in vivo and in vitro[J]. Biomed Pharmacother,2020,129:110364. doi: 10.1016/j.biopha.2020.110364
[86]	CHEN J, GUO R, YAN H, et al. Naringin inhibits ROS-activated MAPK pathway in high glucose-induced injuries in H9c2 cardiac cells[J]. Basic Clin Pharmacol Toxicol,2014,114(4):293−304. doi: 10.1111/bcpt.12153
[87]	刘丹, 熊书, 马羚, 等. 柚皮苷对缺氧/复氧损伤心肌细胞Caspase-3活性及IRE1α表达的影响[J]. 中国生物制品学杂志,2020,33(8):904−907. [LIU D, XIONG S, MA L, et al. Effect of naringin on Caspase-3 activity and IRE1α expression in myocardial cells injured by hypoxia/reoxygenation[J]. Chinese Journal of Biologicals,2020,33(8):904−907.
[88]	HAJIALYANI M, HOSEIN F M, ECHEVERRÍA J, et al. Hesperidin as a neuroprotective agent: A review of animal and clinical evidence[J]. Molecules,2019,24(3):648. doi: 10.3390/molecules24030648
[89]	TAMILSELVAM K, BRAIDY N, MANIVASAGAM T, et al. Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxidative stress and apoptosis in a cellular model for Parkinson's disease[J]. Oxid Med Cell Longev,2013:102741.
[90]	ANTUNES M S, LADD F V L, LADD A A B L, et al. Hesperidin protects against behavioral alterations and loss of dopaminergic neurons in 6-OHDA-lesioned mice: The role of mitochondrial dysfunction and apoptosis[J]. Metab Brain Dis,2021,36(1):153−167. doi: 10.1007/s11011-020-00618-y
[91]	WELBAT J U, NAEWLA S, PANNANGRONG W, et al. Neuroprotective effects of hesperidin against methotrexate-induced changes in neurogenesis and oxidative stress in the adult rat[J]. Biochem Pharmacol,2020,178:114083. doi: 10.1016/j.bcp.2020.114083
[92]	WANG J J, CUI P. Neohesperidin attenuates cerebral ischemia-reperfusion injury via inhibiting the apoptotic pathway and activating the Akt/Nrf2/HO-1 pathway[J]. J Asian Nat Prod Res,2013,15(9):1023−1037. doi: 10.1080/10286020.2013.827176
[93]	WANG J, YUAN Y, ZHANG P, et al. Neohesperidin prevents Aβ25-35-induced apoptosis in primary cultured hippocampal neurons by blocking the s-nitrosylation of protein-disulphide isomerase[J]. Neurochem Res,2018,43(9):1736−1744. doi: 10.1007/s11064-018-2589-5
[94]	KULASEKARAN G, GANAPASAM S. Neuroprotective efficacy of naringin on 3-nitropropionic acid-induced mitochondrial dysfunction through the modulation of Nrf2 signaling pathway in PC12 cells[J]. Mol Cell Biochem,2015,409(1-2):199−211. doi: 10.1007/s11010-015-2525-9
[95]	MENG X D, FU M M, WANG S F, et al. Naringin ameliorates memory deficits and exerts neuroprotective effects in a mouse model of Alzheimer's disease by regulating multiple metabolic pathways[J]. Mol Med Rep,2021,23(5):332. doi: 10.3892/mmr.2021.11971
[96]	HELMY H S, SENOUSY M A, EL-SAHAR A E, et al. Aberrations of miR-126-3p, miR-181a and sirtuin1 network mediate Di-(2-ethylhexyl) phthalate-induced testicular damage in rats: The protective role of hesperidin[J]. Toxicology,2020,433-434:152406. doi: 10.1016/j.tox.2020.152406
[97]	OLAYINKA E T, ADEWOLE K E. In vivo andin silico evaluation of the ameliorative effect of hesperidin on finasteride-induced testicular oxidative stress in wistar rats[J]. Toxicol Mech Methods,2021,31(2):81−89. doi: 10.1080/15376516.2020.1831123
[98]	ABD-ELHAKIM Y M, GHONEIM M H, EBRAHEIM L L M, et al. Taurine and hesperidin rescues carbon tetrachloride-triggered testicular and kidney damage in rats via modulating oxidative stress and inflammation[J]. Life Sci,2020,254:117782. doi: 10.1016/j.lfs.2020.117782
[99]	STANISIC D, COSTA A F, CRUZ G, et al. Applications of flavonoids, with an emphasis on hesperidin, as anticancer prodrugs: Phytotherapy as an alternative to chemotherapy[J]. Studies in Natural Products Chemistry,2018,58:161−212.
[100]	KONGTAWELERT P, WUDTIWAI B, SHWE T H, et al. Inhibitory effect of hesperidin on the expression of programmed death ligand (PD-L1) in breast cancer[J]. Molecules,2020,25(2):252. doi: 10.3390/molecules25020252
[101]	ZENG L, ZHEN Y, CHEN Y, et al. Naringin inhibits growth and induces apoptosis by a mechanism dependent on reduced activation of NF-κB/COX-2-caspase-1 pathway in HeLa cervical cancer cells[J]. Int J Oncol,2014,45(5):1929−1936. doi: 10.3892/ijo.2014.2617
[102]	KASHANI-AMIN E, EBRAHIM-HABIBI A, LARIJANI B, et al. Effect of neohesperidin dihydrochalcone on the activity and stability of alpha-amylase: A comparative study on bacterial, fungal, and mammalian enzymes[J]. J Mol Recognit,2015,28(10):605−613. doi: 10.1002/jmr.2473
[103]	LEE H J, IM A R, KIM S M, et al. The flavonoid hesperidin exerts anti-photoaging effect by downregulating matrix metalloproteinase (MMP)-9 expression via mitogen activated protein kinase (MAPK)-dependent signaling pathways[J]. BMC Complement Altern Med,2018,18(1):39. doi: 10.1186/s12906-017-2058-8
[104]	VENTURA-MARTINEZ R, MARES-SÁNchez J J, AVILÉS-HERRERA J, et al. Antinociceptive synergy between metamizole and hesperidin in a model of visceral pain in mice[J]. Arch Med Res,2021,52(4):389−396. doi: 10.1016/j.arcmed.2020.12.011
[105]	GUO J, FANG Y, JIANG F, et al. Neohesperidin inhibits TGF-β1/Smad3 signaling and alleviates bleomycin-induced pulmonary fibrosis in mice[J]. Eur J Pharmacol,2019,864:172712. doi: 10.1016/j.ejphar.2019.172712
[106]	TAN Z, CHENG J, LIU Q, et al. Neohesperidin suppresses osteoclast differentiation, bone resorption and ovariectomised-induced osteoporosis in mice[J]. Mol Cell Endocrinol,2017,439:369−378. doi: 10.1016/j.mce.2016.09.026
[107]	GUO C, ZHANG H, GUAN X, et al. The anti-aging potential of neohesperidin and its synergistic effects with other citrus flavonoids in extending chronological lifespan of saccharomyces cerevisiae BY4742[J]. Molecules,2019,24(22):4093. doi: 10.3390/molecules24224093
[108]	LI F B, SUN X L, MA J X, et al. Naringin prevents ovariectomy-induced osteoporosis and promotes osteoclasts apoptosis through the mitochondria-mediated apoptosis pathway[J]. Biochem Biophys Res Commun,2014,452(3):629−635. doi: 10.1016/j.bbrc.2014.08.117
[109]	LI N, JIANG Y, WOOLEY P H, et al. Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis[J]. J Orthop Sci,2013,18(3):478−485. doi: 10.1007/s00776-013-0362-9
[110]	YUE W, YUN L, LUO M, et al. Evaluation of pharmacological relaxation effect of the natural product naringin on in vitro cultured airway smooth muscle cells and in vivo ovalbumin-induced asthma Balb/c mice[J]. Biomedical Reports,2016,5(6):715. doi: 10.3892/br.2016.797