Abstract：Objective: To explore the impact of hesperetin on D-galactose-induced oxidative stress injury in rats with cataract and its mechanism of regulating Keap1/Nrf2/ARE signaling pathway. Methods: Seventy-two SPF Wistar male rats were randomly separated into sham operation group, model group, positive group, low and high dose hesperetin groups, and high dose hesperetin + Nrf2 inhibitor ATRA group. Cataract rat models were established by subcutaneous injection of 200mg/kg of D-galactose in all groups except the sham-operation group. The positive control group was treated with fuming capsule (30mg/kg), the low and high dose groups were treated with hesperetin (50mg/kg, 150mg/kg) respectively, and the high dose +ATRA group was treated with hesperetin (100mg/kg) first, and then ATRA(10mg/kg) was injected intraperitoneally. Slit lamp was used to observe the degree of opacity of the lens tissue in both eyes; HE was applied to observe the morphological changes of lens epithelium in each group; TUNEL method was applied to detect the apoptosis rate of lens epithelial tissue; ELISA was applied to measure superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities in the lens; Western blotting was applied to detect the expression levels of Keap1, Nrf2, and HO-1 proteins in the lens. Results: Compared with the sham-operation group, the lens epithelial tissue of the model group had disordered cell arrangement, edema, and enlarged gaps, the degree of lens opacity, epithelial cell apoptosis rate, Keap1 and cytoplasmic Nrf2 protein expression increased (P<0.05), SOD, CAT, GSH-Px activity, nuclear Nrf2, HO-1 protein expressions decreased (P<0.05). Compared with the model group, the damage of the lens epithelium of the rats in the positive group and the low and high-dose hesperetin groups was alleviated, the degree of lens opacity, epithelial cell apoptosis rate, Keap1 and cytoplasmic Nrf2 protein expression decreased (P<0.05), SOD, CAT, GSH-Px activity, nuclear Nrf2, HO-1 protein expressions increased (P<0.05). The Nrf2 inhibitor ATRA could greatly attenuate the ameliorating effect of high-dose hesperetin on lens damage in cataract rats. Conclusion: Hesperetin can alleviate D-galactose-induced oxidative stress injury in cataract rats, which may be achieved by inhibiting the expression of Keap1 and promoting the activation of Nrf2/ARE pathway.
[1] Kanada F,Takamura Y,Miyake S,et al.Histone acetyltransferase and Polo-like kinase 3 inhibitors prevent rat galactose-induced cataract[J].Sci Rep,2019,9(1):20085-20095. [2] Chen YY,Wu TT,Ho CY,et al.Dapagliflozin prevents NOX and SGLT2-dependent oxidative stress in lens cells exposed to fructose-induced diabetes mellitus[J].Int Mol Sci,2019,20(18):4357-4371. [3] Tu W,Wang H,Li S,et al.The anti-Inflammatory and anti-Oxidant mechanisms of the keap1/Nrf2/ARE signaling pathway in chronic diseases[J].Aging Dis,2019,10(3):637-651. [4] Chen X,Zou D,Chen X,et al.Hesperetin inhibits foam cell formation and promotes cholesterol efflux in THP-1-derived macrophages by activating LXRα signal in an AMPK-dependent manner[J].Physiol Biochem,2021,77(3):405-417. [5] Lee A,Gu H,Gwon MH,et al.Hesperetin suppresses LPS/high glucose-induced inflammatory responses via TLR/MyD88/NF-κB signaling pathways in THP-1 cells[J].Nutr Res Pract,2021,15(5):591-603. [6] Nakazawa Y,Aoki M,Ishiwa S,et al.Oral intake of αglucosylhesperidin ameliorates seleniteinduced cataract formation[J].Mol Med Rep,2020,21(3):1258-1266. [7] Feng W,Yang X,Feng M,et al.Alginate oligosaccharide prevents against D-galactose-mediated cataract in C57BL/6J mice via regulating oxidative stress and antioxidant system[J].Curr Eye Res,2021,46(6):802-810. [8] Zhu X,Zhang YM,Zhang MY,et al.Hesperetin ameliorates diabetes-associated anxiety and depression-like behaviors in rats via activating Nrf2/ARE pathway[J].Metab Brain Dis,2021,36(7):1969-1983. [9] Lim JC,Caballero Arredondo M,Braakhuis AJ,et al.Vitamin C and the lens:new insights into delaying the onset of cataract[J].Nutrients,2020,12(10):3142-3163. [10] Cai ZY,Fu MD,Liu K,et al.Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress[J].Int Ophthalmol,2021,14(8):1260-1273. [11] Serafini MM,Catanzaro M,Fagiani F,et al.Modulation of keap1/Nrf2/ARE signaling pathway by curcuma and garlic-derived hybrids[J].Front Pharmacol,2020,10(1):1597-1609. [12] 赵勇洁,尚利晓,李琰.大黄素对白内障大鼠晶状体氧化应激和炎症影响的机制研究[J].医学研究杂志,2021,50(7):72-76. [13] Lin X,Bai D,Wei Z,et al.Curcumin attenuates oxidative stress in RAW264.7 cells by increasing the activity of antioxidant enzymes and activating the Nrf2-Keap1 pathway[J].PLoS One,2019,14(5):1-13.
2023, Vol. 29 
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