Flavonoids on diabetic nephropathy: advances and therapeutic opportunities
Tóm tắt
With the advances in biomedical technologies, natural products have attracted substantial public attention in the area of drug discovery. Flavonoids are a class of active natural products with a wide range of pharmacological effects that are used for the treatment of several diseases, in particular chronic metabolic diseases. Diabetic nephropathy is a complication of diabetes with a particularly complicated pathological mechanism that affects at least 30% of diabetic patients and represents a great burden on public health. A large number of studies have shown that flavonoids can alleviate diabetic nephropathy. This review systematically summarizes the use of common flavonoids for the treatment of diabetic nephropathy. We found that flavonoids play a therapeutic role in diabetic nephropathy mainly by regulating oxidative stress and inflammation. Nrf-2/GSH, ROS production, HO-1, TGF-β1 and AGEs/RAGE are involved in the process of oxidative stress regulation. Quercetin, apigenin, baicalin, luteolin, hesperidin, genistein, proanthocyanidin and eriodictyol were found to be capable of alleviating oxidative stress related to the aforementioned factors. Regarding inflammatory responses, IL-1, IL-6β, TNF-α, SIRT1, NF-κB, and TGF-β1/smad are thought to be essential. Quercetin, kaempferol, myricetin, rutin, genistein, proanthocyanidin and eriodictyol were confirmed to influence the above targets. As a result, flavonoids promote podocyte autophagy and inhibit the overactivity of RAAS by suppressing the upstream oxidative stress and inflammatory pathways, ultimately alleviating DN. The above results indicate that flavonoids are promising drugs for the treatment of diabetic nephropathy. However, due to deficiencies in the effect of flavonoids on metabolic processes and their lack of structural stability in the body, further research is required to address these issues.
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Tài liệu tham khảo
Butler MS, Robertson AAB, Cooper MA. Natural product and natural product derived drugs in clinical trials. Nat Prod Rep. 2014;31:1612–61. https://doi.org/10.1039/c4np00064a.
Lu Z, Zhong Y, Liu W, Xiang L, Deng Y. The efficacy and mechanism of Chinese herbal medicine on diabetic kidney disease. J Diabetes Res. 2019;2019:2697672. https://doi.org/10.1155/2019/2697672.
Al-Waili N, Al-Waili H, Al-Waili T, Salom K. Natural antioxidants in the treatment and prevention of diabetic nephropathy; a potential approach that warrants clinical trials. Redox Rep. 2017;22:99–118. https://doi.org/10.1080/13510002.2017.1297885.
Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75:311–35. https://doi.org/10.1021/np200906s.
Li S, Zhang J, Li S, Liu C, Liu S, Liu Z. Extraction and separation of lactate dehydrogenase inhibitors from Poria cocos (Schw.) Wolf based on a hyphenated technique and in vitro methods. J Sep Sci. 2017;40:1773–83. https://doi.org/10.1002/jssc.201700054.
Qian Q, Zhou N, Qi P, Zhang Y, Mu X, Shi X, Wang Q. A UHPLC-QTOF-MS/MS method for the simultaneous determination of eight triterpene compounds from Poria cocos (Schw.) Wolf extract in rat plasma: application to a comparative pharmacokinetic study. J. Chromatogr B Anal Technol Biomed Life Sci. 2018;1102–1103:34–44. https://doi.org/10.1016/j.jchromb.2018.10.011.
Skyler JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, Groop PH, Handelsman Y, Insel RA, Mathieu C, McElvaine AT, Palmer JP, Pugliese A, Schatz DA, Sosenko JM, Wilding JPH, Ratner RE. Differentiation of diabetes by pathophysiology, natural history, and prognosis. Diabetes. 2017;66:241–55. https://doi.org/10.2337/db16-0806.
McElwain CJ, McCarthy FP, McCarthy CM. Gestational diabetes mellitus and maternal immune dysregulation: What we know so far. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22084261.
Kanter JE, Bornfeldt KE. Impact of diabetes mellitus. Arterioscler Thromb Vasc Biol. 2016;36:1049–53. https://doi.org/10.1161/ATVBAHA.116.307302.
Ene-Iordache B, Perico N, Bikbov B, Carminati S, Remuzzi A, Perna A, et al. Chronic kidney disease and cardiovascular risk in six regions of the world (ISN-KDDC): A cross-sectional study. Lancet Glob Heal. 2016;4:e307-19. https://doi.org/10.1016/S2214-109X(16)00071-1.
Tziomalos K, Athyros VG. Diabetic nephropathy: new risk factors and improvements in diagnosis. Rev Diabet Stud. 2015;12:110–8. https://doi.org/10.1900/RDS.2015.12.110.
Tung CW, Hsu YC, Shih YH, Chang PJ, Lin CL. Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology. 2018;23:32–7. https://doi.org/10.1111/nep.13451.
Qi SS, Shao ML, Ze S, Zheng HX. Salidroside from Rhodiola rosea L. attenuates diabetic nephropathy in STZ induced diabetic rats via anti-oxidative stress, anti-inflammation, and inhibiting TGF-β1/Smad pathway. J Funct Foods. 2021;77:104329. https://doi.org/10.1016/j.jff.2020.104329.
Qi SS, Zheng HX, Jiang H, Yuan LP, Dong LC. Protective effects of chromium picolinate against diabetic-induced renal dysfunction and renal fibrosis in streptozotocin-induced diabetic rats. Biomolecules. 2020;10:1–14.
Zheng HX, Qi SS, He J, Hu CY, Han H, Jiang H, et al. Cyanidin-3-glucoside from black rice ameliorates diabetic nephropathy via reducing blood glucose, suppressing oxidative stress and inflammation, and regulating transforming growth factor β1/Smad expression. J Agric Food Chem. 2020;68:4399–410.
Qi SS, He J, Dong LC, Yuan LP, Le WuJ, Zu YX, et al. Cyanidin-3-glucoside from black rice prevents renal dysfunction and renal fibrosis in streptozotocin-diabetic rats. J Funct Foods. 2020;72:104062. https://doi.org/10.1016/j.jff.2020.104062.
Vargas F, Romecín P, García-Guillén AI, Wangesteen R, Vargas-Tendero P, Paredes MD, Atucha NM, García-Estañ J. Flavonoids in kidney health and disease. Front Physiol. 2018;9:1–12. https://doi.org/10.3389/fphys.2018.00394.
Zeng H, Liu Q, Yu J, Jiang X, Wu Z, Wang M, Chen M, Chen X. One-step separation of nine structural analogues from Poria cocos (Schw.) Wolf. via tandem high-speed counter-current chromatography. J. Chromatogr B Anal Technol Biomed Life Sci. 2015;1004:10–6. https://doi.org/10.1016/j.jchromb.2015.09.017.
Tonneijck L, Muskiet MHA, Smits MM, Van Bommel EJ, Heerspink HJL, Van Raalte DH, Joles JA. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28:1023–39. https://doi.org/10.1681/ASN.2016060666.
Koszegi S, Molnar A, Lenart L, Hodrea J, Balogh DB, Lakat T, Szkibinszkij E, Hosszu A, Sparding N, Genovese F, Wagner L, Vannay A, Szabo AJ, Fekete A. RAAS inhibitors directly reduce diabetes-induced renal fibrosis via growth factor inhibition. J Physiol. 2019;597:193–209. https://doi.org/10.1113/JP277002.
Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update. Eur J Pharmacol. 2016;791:8–24. https://doi.org/10.1016/j.ejphar.2016.08.022.
Fakhruddin S, Alanazi W, Jackson KE. Diabetes-induced reactive oxygen species: mechanism of their generation and role in renal injury. J Diabetes Res. 2017. https://doi.org/10.1155/2017/8379327.
Platé M, Guillotin D, Chambers RC. The promise of mTOR as a therapeutic target pathway in idiopathic pulmonary fibrosis. Eur Respir Rev. 2020;29:1–7. https://doi.org/10.1183/16000617.0269-2020.
Zoja C, Xinaris C, Macconi D. Diabetic nephropathy: novel molecular mechanisms and therapeutic targets. Front Pharmacol. 2020;11:1–21. https://doi.org/10.3389/fphar.2020.586892.
Thomas MC, Brownlee M, Susztak K, Sharma K, Jandeleit-Dahm KAM, Zoungas S, Rossing P, Groop PH, Cooper ME. Diabetic kidney disease. Nat Rev Dis Prim. 2015;1:1–20. https://doi.org/10.1038/nrdp.2015.18.
Khursheed R, Singh SK, Wadhwa S, Kapoor B, Gulati M, Kumar R, Ramanunny AK, Awasthi A, Dua K. Treatment strategies against diabetes: success so far and challenges ahead. Eur J Pharmacol. 2019. https://doi.org/10.1016/j.ejphar.2019.172625.
Li Y, Xu G. Clinical efficacy and safety of Jinshuibao combined with ACEI/ARB in the treatment of diabetic kidney disease: a meta-analysis of randomized controlled trials. J Ren Nutr. 2020;30:92–100. https://doi.org/10.1053/j.jrn.2019.03.083.
Xu D, Hu MJ, Wang YQ, Cui YL. Antioxidant activities of quercetin and its complexes for medicinal application. Molecules. 2019. https://doi.org/10.3390/molecules24061123.
Costa LG, Garrick JM, Roquè PJ, Pellacani C. Mechanisms of neuroprotection by quercetin: counteracting oxidative stress and more. Oxid Med Cell Longev. 2016. https://doi.org/10.1155/2016/2986796.
Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, Frye SV, et al. Inhibition of inositol polyphosphate kinases by quercetin and related flavonoids: a structure-activity analysis. J Med Chem. 2019;62:1443–54.
Elbe H, Vardi N, Esrefoglu M, Ates B, Yologlu S, Taskapan C. Amelioration of streptozotocin-induced diabetic nephropathy by melatonin, quercetin, and resveratrol in rats. Hum Exp Toxicol. 2015;34:100–13. https://doi.org/10.1177/0960327114531995.
Iskender H, Dokumacioglu E, Sen TM, Ince I, Kanbay Y, Saral S. The effect of hesperidin and quercetin on oxidative stress, NF-κB and SIRT1 levels in a STZ-induced experimental diabetes model. Biomed Pharmacother. 2017;90:500–8. https://doi.org/10.1016/j.biopha.2017.03.102.
Anjaneyulu M, Chopra K. Quercetin, an anti-oxidant bioflavonoid, attenuates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol. 2004;31:244–8. https://doi.org/10.1111/j.1440-1681.2004.03982.x.
Wang C, Pan Y, Zhang QY, Wang FM, Kong LD. Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. PLoS ONE. 2012. https://doi.org/10.1371/journal.pone.0038285.
Gomes IBS, Porto ML, Santos MCLFS, Campagnaro BP, Pereira TMC, Meyrelles SS, Vasquez EC. Renoprotective, anti-oxidative and anti-apoptotic effects of oral low-dose quercetin in the C57BL/6J model of diabetic nephropathy. Lipids Health Dis. 2014;13:1–10. https://doi.org/10.1186/1476-511X-13-184.
Tang L, Li K, Zhang Y, Li H, Li A, Xu Y, Wei B. Quercetin liposomes ameliorate streptozotocin-induced diabetic nephropathy in diabetic rats. Sci Rep. 2020;10:1–8. https://doi.org/10.1038/s41598-020-59411-7.
Lai PB, Zhang L, Yang LY. Quercetin ameliorates diabetic nephropathy by reducing the expressions of transforming growth factor-β1 and connective tissue growth factor in streptozotocin-induced diabetic rats. Ren Fail. 2012;34:83–7. https://doi.org/10.3109/0886022X.2011.623564.
Wang HY, Zhao JG, Wei ZG, Zhang YQ. The renal protection of flavonoid-rich ethanolic extract from silkworm green cocoon involves in inhibiting TNF-α-p38 MAP kinase signalling pathway in type 2 diabetic mice. Biomed Pharmacother. 2019;2019: 109379. https://doi.org/10.1016/j.biopha.2019.109379.
Jiang X, Yu J, Wang X, Ge J, Li N. Quercetin improves lipid metabolism via SCAP-SREBP2-LDLr signaling pathway in early stage diabetic nephropathy. Diabetes Metab Syndr Obes Targets Ther. 2019;12:827–39. https://doi.org/10.2147/DMSO.S195456.
Lei D, Chengcheng L, Xuan Q, Yibing C, Lei W, Hao Y, Xizhi L, Yuan L, Xiaoxing Y, Qian L. Quercetin inhibited mesangial cell proliferation of early diabetic nephropathy through the Hippo pathway. Pharmacol Res. 2019;146: 104320. https://doi.org/10.1016/j.phrs.2019.104320.
Tong F, Liu S, Yan B, Li X, Ruan S, Yang S. Quercetin nanoparticle complex attenuated diabetic nephropathy via regulating the expression level of ICAM-1 on endothelium. Int J Nanomed. 2017;12:7799–813. https://doi.org/10.2147/IJN.S146978.
Chen P, Shi Q, Xu X, Wang Y, Chen W, Wang H. Quercetin suppresses NF-κB and MCP-1 expression in a high glucose-induced human mesangial cell proliferation model. Int J Mol Med. 2012;30:119–25. https://doi.org/10.3892/ijmm.2012.955.
Huang T, Liu Y, Zhang C. Pharmacokinetics and bioavailability enhancement of baicalin: a review. Eur J Drug Metab Pharmacokinet. 2019;44:159–68. https://doi.org/10.1007/s13318-018-0509-3.
Hu Q, Zhang W, Wu Z, Tian X, Xiang J, Li L, Li Z, Peng X, Wei S, Ma X, Zhao Y. Baicalin and the liver-gut system: pharmacological bases explaining its therapeutic effects. Pharmacol Res. 2021;165: 105444. https://doi.org/10.1016/j.phrs.2021.105444.
Ma X, Jiang Y, Zhang W, Wang J, Wang R, Wang L, Wei S, Wen J, Li H, Zhao Y. Natural products for the prevention and treatment of cholestasis: a review. Phyther Res. 2020;34:1291–309. https://doi.org/10.1002/ptr.6621.
Zhang S, Xu L, Liang R, Yang C, Wang P. Baicalin suppresses renal fibrosis through microRNA-124/TLR4/NF-κB axis in streptozotocin-induced diabetic nephropathy mice and high glucose-treated human proximal tubule epithelial cells. J Physiol Biochem. 2020;76:407–16. https://doi.org/10.1007/s13105-020-00747-z.
Zheng XP, Nie Q, Feng J, Fan XY, Jin YL, Chen G, Du JW. Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin. BMC Nephrol. 2020;21:1–17. https://doi.org/10.1186/s12882-020-01833-6.
Yang M, Kan L, Wu L, Zhu Y, Wang Q. Effect of baicalin on renal function in patients with diabetic nephropathy and its therapeutic mechanism. Exp Ther Med. 2019. https://doi.org/10.3892/etm.2019.7181.
Ashrafizadeh M, Tavakol S, Ahmadi Z, Roomiani S, Mohammadinejad R, Samarghandian S. Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress. Phyther Res. 2020;34:911–23. https://doi.org/10.1002/ptr.6577.
Calderón-Montaño JM, Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M. A review on the dietary flavonoid kaempferol | BenthamScience. Mini Rev Med Chem. 2011;11:298–344.
Luo W, Chen X, Ye L, Chen X, Jia W, Zhao Y, Samorodov AV, Zhang Y, Hu X, Zhuang F, Qian J, Zheng C, Liang G, Wang Y. Kaempferol attenuates streptozotocin-induced diabetic nephropathy by downregulating TRAF6 expression: the role of TRAF6 in diabetic nephropathy. J Ethnopharmacol. 2021;268: 113553. https://doi.org/10.1016/j.jep.2020.113553.
Sharma D, Gondaliya P, Tiwari V, Kalia K. Kaempferol attenuates diabetic nephropathy by inhibiting RhoA/Rho-kinase mediated inflammatory signalling. Biomed Pharmacother. 2019;109:1610–9. https://doi.org/10.1016/j.biopha.2018.10.195.
Sharma D, Kumar Tekade R, Kalia K. Kaempferol in ameliorating diabetes-induced fibrosis and renal damage: An in vitro and in vivo study in diabetic nephropathy mice model. Phytomedicine. 2020;76: 153235. https://doi.org/10.1016/j.phymed.2020.153235.
Semwal DK, Semwal RB, Combrinck S, Viljoen A. Myricetin: a dietary molecule with diverse biological activities. Nutrients. 2016;8:1–31.
Song X, Tan L, Wang M, Ren C, Guo C, Yang B, Ren Y, Cao Z, Li Y, Pei J. Myricetin: a review of the most recent research. Biomed Pharmacother. 2021;134: 111017. https://doi.org/10.1016/j.biopha.2020.111017.
Jiang M, Zhu M, Wang L, Yu S. Anti-tumor effects and associated molecular mechanisms of myricetin. Biomed Pharmacother. 2019;120: 109506. https://doi.org/10.1016/j.biopha.2019.109506.
Ozcan F, Ozmen A, Akkaya B, Aliciguzel Y, Aslan M. Beneficial effect of myricetin on renal functions in streptozotocin-induced diabetes. Clin Exp Med. 2012;12:265–72. https://doi.org/10.1007/s10238-011-0167-0.
Kandasamy N, Ashokkumar N. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin-cadmium induced diabetic nephrotoxic rats. Toxicol Appl Pharmacol. 2014;279:173–85. https://doi.org/10.1016/j.taap.2014.05.014.
Kandasamy N, Ashokkumar N. Renoprotective effect of myricetin restrains dyslipidemia and renal mesangial cell proliferation by the suppression of sterol regulatory element binding proteins in an experimental model of diabetic nephropathy. Eur J Pharmacol. 2014;743:53–62. https://doi.org/10.1016/j.ejphar.2014.09.014.
Ganeshpurkar A, Saluja AK. The pharmacological potential of rutin. Saudi Pharm J. 2017;25:149–64. https://doi.org/10.1016/j.jsps.2016.04.025.
Dogra A, Gour A, Bhatt S, Sharma P, Sharma A, Kotwal P, Wazir P, Mishra P, Singh G, Nandi U. Effect of rutin on pharmacokinetic modulation of diclofenac in rats. Xenobiotica. 2020;50:1332–40. https://doi.org/10.1080/00498254.2020.1773008.
Lu N, Ding Y, Yang Z, Gao P. Effects of rutin on the redox reactions of hemoglobin. Int J Biol Macromol. 2016;89:175–80. https://doi.org/10.1016/j.ijbiomac.2016.04.066.
Kamalakkannan N, Prince PSM. The influence of rutin on the extracellular matrix in streptozotocin-induced diabetic rat kidney. J Pharm Pharmacol. 2010;58:1091–8. https://doi.org/10.1211/jpp.58.8.0010.
Hao HH, Shao ZM, Tang DQ, Lu Q, Chen X, Yin XX, Wu J, Chen H. Preventive effects of rutin on the development of experimental diabetic nephropathy in rats. Life Sci. 2012;91:959–67. https://doi.org/10.1016/j.lfs.2012.09.003.
Wang X, Zhao X, Feng T, Jin G, Li Z. Rutin prevents high glucose-induced renal glomerular endothelial hyperpermeability by inhibiting the ROS/Rhoa/ROCK signaling pathway. Planta Med. 2016;82:1252–7. https://doi.org/10.1055/s-0042-110859.
Han CS, Liu K, Zhang N, Li SW, Gao HC. Rutin suppresses high glucose-induced ACTA2 and P38 protein expression in diabetic nephropathy. Exp Ther Med. 2017;14:181–6. https://doi.org/10.3892/etm.2017.4509.
Ganesan D, Albert A, Paul E, Ananthapadmanabhan K, Andiappan R, Sadasivam SG. Rutin ameliorates metabolic acidosis and fibrosis in alloxan induced diabetic nephropathy and cardiomyopathy in experimental rats. Mol Cell Biochem. 2020;471:41–50. https://doi.org/10.1007/s11010-020-03758-y.
Ganesan D, Holkar A, Albert A, Paul E, Mariakuttikan J, Sadasivam Selvam G. Combination of ramipril and rutin alleviate alloxan induced diabetic nephropathy targeting multiple stress pathways in vivo. Biomed Pharmacother. 2018;108:1338–46. https://doi.org/10.1016/j.biopha.2018.09.142.
Salehi B, Venditti A, Sharifi-Rad M, Kręgiel D, Sharifi-Rad J, Durazzo A, Lucarini M, Santini A, Souto EB, Novellino E, Antolak H, Azzini E, Setzer WN, Martins N. The therapeutic potential of Apigenin. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20061305.
He M, Min JW, Kong WL, He XH, Li JX, Peng BW. A review on the pharmacological effects of vitexin and isovitexin. Fitoterapia. 2016;115:74–85. https://doi.org/10.1016/j.fitote.2016.09.011.
Malik S, Suchal K, Khan SI, Bhatia J, Kishore K, Dinda AK, Arya DS. Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-ĸB-TNF-α and TGF-β1-MAPK-fibronectin pathways. Am J Physiol Ren Physiol. 2017;313:F414–22. https://doi.org/10.1152/ajprenal.00393.2016.
Lv J, Zhou D, Wang Y, Sun W, Zhang C, Xu J, Yang H, Zhou T, Li P. Effects of luteolin on treatment of psoriasis by repressing HSP90. Int Immunopharmacol. 2020;79: 106070. https://doi.org/10.1016/j.intimp.2019.106070.
Aziz N, Kim MY, Cho JY. Anti-inflammatory effects of luteolin: a review of in vitro, in vivo, and in silico studies. J Ethnopharmacol. 2018;225:342–58. https://doi.org/10.1016/j.jep.2018.05.019.
Xiong C, Wu Q, Fang M, Li H, Chen B, Chi T. Protective effects of luteolin on nephrotoxicity induced by long-term hyperglycaemia in rats. J Int Med Res. 2020. https://doi.org/10.1177/0300060520903642.
Zhang M, He L, Liu J, Zhou L. Luteolin attenuates diabetic nephropathy through suppressing inflammatory response and oxidative stress by inhibiting STAT3 pathway. Exp Clin Endocrinol Diabetes. 2020. https://doi.org/10.1055/a-0998-7985.
Yu Q, Zhang M, Qian L, Wen D, Wu G. Luteolin attenuates high glucose-induced podocyte injury via suppressing NLRP3 inflammasome pathway. Life Sci. 2019;225:1–7. https://doi.org/10.1016/j.lfs.2019.03.073.
Wang GG, Lu XH, Li W, Zhao X, Zhang C. Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evid Based Complement Altern Med. 2011. https://doi.org/10.1155/2011/323171.
Alam MA, Subhan N, Rahman MM, Uddin SJ, Reza HM, Sarker SD. Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv Nutr. 2014;5:404–17. https://doi.org/10.3945/an.113.005603.
Nyane NA, Tlaila TB, Malefane TG, Ndwandwe DE, Owira PMO. Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: molecular and pharmacological insights. Eur J Pharmacol. 2017;803:103–11. https://doi.org/10.1016/j.ejphar.2017.03.042.
Chen F, Wei G, Xu J, Ma X, Wang Q. Naringin ameliorates the high glucose-induced rat mesangial cell inflammatory reaction by modulating the NLRP3 Inflammasome. BMC Complement Altern Med. 2018;18:1–11. https://doi.org/10.1186/s12906-018-2257-y.
Zhang J, Yang S, Li H, Chen F, Shi J. Naringin ameliorates diabetic nephropathy by inhibiting NADPH oxidase 4. Eur J Pharmacol. 2017;804:1–6. https://doi.org/10.1016/j.ejphar.2017.04.006.
Roy S, Ahmed F, Banerjee S, Saha U. Naringenin ameliorates streptozotocin-induced diabetic rat renal impairment by downregulation of TGF-β1 and IL-1 via modulation of oxidative stress correlates with decreased apoptotic events. Pharm Biol. 2016;54:1616–27. https://doi.org/10.3109/13880209.2015.1110599.
Yan N, Wen L, Peng R, Li H, Liu H, Peng H, Sun Y, Wu T, Chen L, Duan Q, Sun Y, Zhou Q, Wei L, Zhang Z. Naringenin ameliorated kidney injury through Let-7a/TGFBR1 signaling in diabetic nephropathy. J Diabetes Res. 2016. https://doi.org/10.1155/2016/8738760.
Ding S, Qiu H, Huang J, Chen R, Zhang J, Huang B, Zou X, Cheng O, Jiang Q. Activation of 20-HETE/PPARs involved in reno-therapeutic effect of naringenin on diabetic nephropathy. Chem Biol Interact. 2019;307:116–24. https://doi.org/10.1016/j.cbi.2019.05.004.
Muhammad T, Ikram M, Ullah R, Rehman SU, Kim MO. Hesperetin, a citrus flavonoid, attenuates LPS-induced neuroinflammation, apoptosis and memory impairments by modulating TLR4/NF-κB signaling. Nutrients. 2019;11:1–20. https://doi.org/10.3390/nu11030648.
Li C, Schluesener H. Health-promoting effects of the citrus flavanone hesperidin. Crit Rev Food Sci Nutr. 2017;57:613–31. https://doi.org/10.1080/10408398.2014.906382.
Mas-Capdevila A, Teichenne J, Domenech-Coca C, Caimari A, Bas JMD, Escoté X, et al. Effect of hesperidin on cardiovascular disease risk factors: the role of intestinal microbiota on hesperidin bioavailability. Nutrients. 2020;12:1–27.
Chen YJ, Kong L, Tang ZZ, Zhang YM, Liu Y, Wang TY, Liu YW. Hesperetin ameliorates diabetic nephropathy in rats by activating Nrf2/ARE/glyoxalase 1 pathway. Biomed Pharmacother. 2019;111:1166–75. https://doi.org/10.1016/j.biopha.2019.01.030.
Dokumacioglu E, Iskender H, Musmul A. Effect of hesperidin treatment on α-Klotho/FGF-23 pathway in rats with experimentally-induced diabetes. Biomed Pharmacother. 2019;109:1206–10. https://doi.org/10.1016/j.biopha.2018.10.192.
Zhang YH, Wang B, Guo F, Li ZZ, Qin GJ. Involvement of the TGFβ1-ILK-Akt signaling pathway in the effects of hesperidin in type 2 diabetic nephropathy. Biomed Pharmacother. 2018;105:766–72. https://doi.org/10.1016/j.biopha.2018.06.036.
Ganai AA, Farooqi H. Bioactivity of genistein: A review of in vitro and in vivo studies. Biomed Pharmacother. 2015;76:30–8. https://doi.org/10.1016/j.biopha.2015.10.026.
Mukund V, Mukund D, Sharma V, Mannarapu M, Alam A. Genistein: its role in metabolic diseases and cancer. Crit Rev Oncol Hematol. 2017;119:13–22. https://doi.org/10.1016/j.critrevonc.2017.09.004.
Elmarakby AA, Ibrahim AS, Faulkner J, Mozaffari MS, Liou GI, Abdelsayed R. Tyrosine kinase inhibitor, genistein, reduces renal inflammation and injury in streptozotocin-induced diabetic mice. Vascul Pharmacol. 2011;55:149–56. https://doi.org/10.1016/j.vph.2011.07.007.
Kim MJ, Lim Y. Protective effect of short-term genistein supplementation on the early stage in diabetes-induced renal damage. Mediators Inflamm. 2013. https://doi.org/10.1155/2013/510212.
Wang Y, Li Y, Zhang T, Chi Y, Liu M, Liu Y. Genistein and myd88 activate autophagy in high glucose-induced renal podocytes in vitro. Med Sci Monit. 2018:24: 4823–4831. https://doi.org/10.12659/MSM.910868
Smeriglio A, Barreca D, Bellocco E, Trombetta D. Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects. Br J Pharmacol. 2017;174:1244–62. https://doi.org/10.1111/bph.13630.
Rodríguez-Pérez C, García-Villanova B, Guerra-Hernández E, Verardo V. Grape seeds proanthocyanidins: an overview of in vivo bioactivity in animal models. Nutrients. 2019;11:1–18. https://doi.org/10.3390/nu11102435.
Ding Y, Li H, Li Y, Liu D, Zhang L, Wang T, Liu T, Ma L. Protective effects of grape seed proanthocyanidins on the kidneys of diabetic rats through the Nrf2 signalling pathway. Evid Based Complement Altern Med. 2020. https://doi.org/10.1155/2020/5205903.
Gao Z, Liu G, Hu Z, Shi W, Chen B, Zou P, Li X. Grape seed proanthocyanidins protect against streptozotocin-induced diabetic nephropathy by attenuating endoplasmic reticulum stress-induced apoptosis. Mol Med Rep. 2018;18:1447–54. https://doi.org/10.3892/mmr.2018.9140.
Li X, Gao Z, Gao H, Li B, Peng T, Jiang B, Yang X, Hu Z. Nephrin loss is reduced by grape seed proanthocyanidins in the experimental diabetic nephropathy rat model. Mol Med Rep. 2017;16:9393–400. https://doi.org/10.3892/mmr.2017.7837.
Bao L, Cai X, Dai X, Ding Y, Jiang Y, Li Y, Zhang Z, Li Y. Grape seed proanthocyanidin extracts ameliorate podocyte injury by activating peroxisome proliferator-activated receptor-γ coactivator 1α in low-dose streptozotocin-and high-carbohydrate/high-fat diet-induced diabetic rats. Food Funct. 2014;5:1872–80. https://doi.org/10.1039/c4fo00340c.
Li X, Xiao Y, Gao H, Li B, Xu L, Cheng M, Jiang B, Ma Y. Grape seed proanthocyanidins ameliorate diabetic nephropathy via modulation of levels of AGE, RAGE and CTGF. Nephron Exp Nephrol. 2009;111:31–42. https://doi.org/10.1159/000191103.
Islam A, Islam MS, Rahman MK, Uddin MN, Akanda MR. The pharmacological and biological roles of eriodictyol. Arch Pharm Res. 2020;43:582–92. https://doi.org/10.1007/s12272-020-01243-0.
Bai J, Wang Y, Zhu X, Shi J. Eriodictyol inhibits high glucose-induced extracellular matrix accumulation, oxidative stress, and inflammation in human glomerular mesangial cells. Phyther Res. 2019;33:2775–82. https://doi.org/10.1002/ptr.6463.
Kuzu M, Yıldırım S, Kandemir FM, Küçükler S, Çağlayan C, Türk E, Dörtbudak MB. Protective effect of morin on doxorubicin-induced hepatorenal toxicity in rats. Chem Biol Interact. 2019;308:89–100. https://doi.org/10.1016/j.cbi.2019.05.017.
Yang J, Zeng J, Wen L, Zhu H, Jiang Y, John A, Yu L, Yang B. Effect of morin on the degradation of water-soluble polysaccharides in banana during softening. Food Chem. 2019;287:346–53. https://doi.org/10.1016/j.foodchem.2019.02.100.
Ke YQ, Liu C, Hao JB, Lu L, Lu NN, Wu ZK, Zhu SS, Chen XL. Morin inhibits cell proliferation and fibronectin accumulation in rat glomerular mesangial cells cultured under high glucose condition. Biomed Pharmacother. 2016;84:622–7. https://doi.org/10.1016/j.biopha.2016.09.088.
Lee YY, Lee EJ, Park JS, Jang SE, Kim DH, Kim HS. Anti-inflammatory and antioxidant mechanism of tangeretin in activated microglia. J Neuroimmune Pharmacol. 2016;11:294–305. https://doi.org/10.1007/s11481-016-9657-x.
Kang MK, Kim SI, Oh SY, Na W, Kang YH. Tangeretin ameliorates glucose-induced podocyte injury through blocking epithelial to mesenchymal transition caused by oxidative stress and hypoxia. Int J Mol Sci. 2020;21:1–17. https://doi.org/10.3390/ijms21228577.
Chen F, Ma Y, Sun Z, Zhu X. Tangeretin inhibits high glucose-induced extracellular matrix accumulation in human glomerular mesangial cells. Biomed Pharmacother. 2018;102:1077–83. https://doi.org/10.1016/j.biopha.2018.03.169.
Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol Adv. 2015;33:1582–614. https://doi.org/10.1016/j.biotechadv.2015.08.001.
Murota K, Nakamura Y, Uehara M. Flavonoid metabolism: The interaction of metabolites and gut microbiota. Biosci Biotechnol Biochem. 2018;82:600–10. https://doi.org/10.1080/09168451.2018.1444467.
Ghorbani A. Mechanisms of antidiabetic effects of flavonoid rutin. Biomed Pharmacother. 2017;96:305–12. https://doi.org/10.1016/j.biopha.2017.10.001.
Sajid M, Channakesavula CN, Stone SR, Kaur P. Synthetic biology towards improved flavonoid pharmacokinetics. Biomolecules. 2021;11:754. https://doi.org/10.3390/biom11050754.
Wong YK, Xu C, Kalesh KA, He Y, Lin Q, Wong WSF, Shen HM, Wang J. Artemisinin as an anticancer drug: recent advances in target profiling and mechanisms of action. Med Res Rev. 2017;37:1492–517. https://doi.org/10.1002/med.21446.
Yang MH, Wan WQ, Luo JS, Zheng MC, Huang K, Yang LH, Mai HR, Li J, Chen HQ, Sun XF, Liu RY, Chen GH, Feng X, Ke ZY, Li B, Tang YL, Huang LB, Luo XQ. Multicenter randomized trial of arsenic trioxide and Realgar-Indigo naturalis formula in pediatric patients with acute promyelocytic leukemia: interim results of the SCCLG-APL clinical study. Am J Hematol. 2018;93:1467–73. https://doi.org/10.1002/ajh.25271.
Xie T, Song S, Li S, Ouyang L, Xia L, Huang J. Review of natural product databases. Cell Prolif. 2015;48:398–404. https://doi.org/10.1111/cpr.12190.
Testa R, Bonfigli AR, Genovese S, De Nigris V, Ceriello A. The possible role of flavonoids in the prevention of diabetic complications. Nutrients. 2016;8:1–13. https://doi.org/10.3390/nu8050310.
Hu Q, Wei S, Wen J, Zhang W, Jiang Y, Qu C, Xiang J, Zhao Y, Peng X, Ma X. Network pharmacology reveals the multiple mechanisms of Xiaochaihu decoction in the treatment of non-alcoholic fatty liver disease. BioData Min. 2020;13:1–14. https://doi.org/10.1186/s13040-020-00224-9.