Influence of formononetin on oxidative stress injury in gestational diabetes mellitus rats

doi:10.11958/20221450

Abstract

Abstract:

Objective To explore the influence of formononetin on oxidative stress injury in gestational diabetes mellitus (GDM) rats by regulating nuclear factor erythroid-2-related factor 2 (Nrf2/hemeoxygenase-1 (HO-1)/NADPH quinone oxidoreductase-1 (NQO1) signaling pathway. Methods SD pregnant rats were injected intraperitoneally with streptozotocin to induce GDM model. Model rats were randomly grouped into the model group, the low-dose formononetin (50 mg/kg) group, the high-dose formononetin (100 mg/kg) group, the ML385 (Nrf2 inhibitor, 20 mg/kg) group, and the high-dose formononetin (100 mg/kg) + ML385 (20 mg/kg) group, 9 rats per group. Another 9 normal pregnant rats were regarded as the control group. After treatment with formononetin and ML385, body weight, serum fasting blood glucose (FSG), total cholesterol (TC), triglyceride (TG) levels, embryo survival rate, fetal body weight, the overall morphology and ultrastructure of placenta, levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and total antioxidant capacity (TAC) in serum and placental tissue were detected in rats of each group. The protein expression of Nrf2/HO-1/NQO1 pathway in placental tissue of rats was also detected in each group. Results Compared with the control group, the placental ultrastructure was damaged in the model group, and the embryonic survival rate, serum and placental tissue GSH, SOD, TAC levels, placental tissue Nrf2, HO-1, NQO1 protein expressions were significantly decreased (P<0.05). Body weight, FSG, TG, TC, fetal body weight, serum and placental tissue MDA levels were significantly increased in the model group (P<0.05). Compared with the model group, symptoms of placental ultrastructural damage were alleviated in the low-dose formononetin group and the high-dose formononetin group, and the embryonic survival rate, serum and placental tissue GSH, SOD, TAC levels, placental tissue Nrf2, HO-1, NQO1 protein expressions were all increased (P<0.05). The body weight, FSG, TG, TC, fetal body weight, serum and placental tissue MDA levels were all decreased (P<0.05), and the effect of high dose of formononetin was stronger. Changes of all indexes in the ML385 group were contrary to those in the formononetin treatment group, and formononetin can reverse the oxidative stress damage of ML385 on GDM rats, improve the placental damage and adverse pregnancy outcome of rats. Conclusion Formononetin can reduce oxidative stress injury in GDM rats by activating Nrf2/HO-1/NQO1 pathway, thereby improving placental damage and adverse pregnancy outcomes in rats.

Key words: diabetes, gestational, oxidative stress, anthocyanin, nuclear factor E2 related factor 2, heme monooxygenase-1, phosphatamide adenine dinucleotide quinone oxidoreductase-1

CLC Number:

R285.5

Figures/Tables 6

References 20

[1]	MOON J H, JANG H C. Gestational diabetes mellitus:Diagnostic approaches and maternal-offspring complications[J]. Diabetes Metab J, 2022, 46(1):3-14. doi:10.4093/dmj.2021.0335.
[2]	WANG Y, HUANG Y, WU P, et al. Plasma lipidomics in early pregnancy and risk of gestational diabetes mellitus:A prospective nested case-control study in Chinese women[J]. Am J Clin Nutr, 2021, 114(5):1763-1773. doi:10.1093/ajcn/nqab242.
[3]	HUANG T T, SUN W J, LIU H Y, et al. p66Shc-mediated oxidative stress is involved in gestational diabetes mellitus[J]. World J Diabetes, 2021, 12(11):1894-1907. doi:10.4239/wjd.v12.i11.1894.
[4]	JOO E H, KIM Y R, KIM N, et al. Effect of endogenic and exogenic oxidative stress triggers on adverse pregnancy outcomes:Preeclampsia,fetal growth restriction,gestational diabetes mellitus and preterm birth[J]. Int J Mol Sci, 2021, 22(18):10122-10134. doi:10.3390/ijms221810122.
[5]	LIANG Y, YU H, KE X, et al. Vitamin D deficiency worsens maternal diabetes induced neurodevelopmental disorder by potentiating hyperglycemia-mediated epigenetic changes[J]. Ann N Y Acad Sci, 2021, 1491(1):74-88. doi:10.1111/nyas.14535.
[6]	LIM J O, SONG K H, LEE I S, et al. Cimicifugae rhizoma extract attenuates oxidative stress and airway inflammation via the upregulation of Nrf2/HO-1/NQO1 and downregulation of NF-κB phosphorylation in ovalbumin-induced asthma[J]. Antioxidants(Basel), 2021, 10(10):1626-1637. doi:10.3390/antiox10101626.
[7]	HOU X, ZHANG J, MA H, et al. Hypoxia-reoxygenation treatment attenuates gestational diabetes mellitus[J]. Endocr Connect, 2021, 10(1):84-91. doi:10.1530/EC-20-0555.
[8]	白月, 王红芳, 黄怀鹏. 芒柄花素药理作用的研究进展[J]. 现代药物与临床, 2022, 37(2):425-432.
	BAI Y, WANG H F, HUANG H P, et al. Advance on pharmacological action of formononetin[J]. Drugs & Clinic, 2022, 37(2):425-432.
[9]	张馨允, 郭启仓, 张景义, 等. 刺芒柄花素对糖尿病肾病大鼠肾脏氧化应激损伤的作用及机制[J]. 中成药, 2021, 43(12):3326-3332.
	ZHANG X Y, GUO Q C, ZHANG J Y, et al. Effects and mechanism of formononetin on oxidative damage in the kidneys of rats with diabetic nephropathy[J]. Chinese Traditional Patent Medicine, 2021, 43(12):3326-3332.
[10]	杨春荣, 张莉莉, 韩曦. 妊娠期糖尿病大鼠子宫内膜组织中NF-κB及GLUT4表达与胰岛素抵抗发生的相关性[J]. 临床和实验医学杂志, 2021, 20(13):1365-1369.
	YANG C R, ZHANG L L, HAN X. Correlation between the expression of NF-κB and GLUT4 in the endometrium of gestational diabetic rats and the occurrence of insulin resistance[J]. Journal of Clinical and Experimental Medicine, 2021, 20(13):1365-1369. doi:10.3969/j.issn.1671-4695.2021.13.006.
[11]	胡志平, 马俊, 陈彦蓉, 等. 刺芒柄花素激活脑外伤小鼠Nrf2/HO-1通路减轻脑水肿并改善行为障碍[J]. 中国实验诊断学, 2021, 25(6):887-893.
	HU Z P, MA J, CHEN Y R, et al. Formononetin activates Nrf2/HO-1 pathway to reduce brain edema and improve behavior disorder in mice with traumatic brain injury[J]. Chinese Journal of Laboratory Diagnosis, 2021, 25(6):887-893. doi:10.3969/j.issn.1007-4287.2021.06.027.
[12]	杨丽, 赵岗, 樊秀梅, 等. 基于Nrf2/HO-1通路研究芹菜素改善妊娠期糖尿病大鼠氧化应激损伤[J]. 中国医药导报, 2020, 17(13):27-31.
	YANG L, ZHAO G, FAN X M, et al. Study on apigenin improvement of oxidative stress injury in diabetic rats based on Nrf2/HO-1 pathway[J]. China Medical Herald, 2020, 17(13):27-31. doi:CNKI:SUN:YYCY.0.2020-13-008.
[13]	VIOLANTE-CUMPA J R, LAVALLE-GONZÁLEZ F J, MANCILLAS-ADAME L G, et al. Gestational diabetes mellitus and COVID-19,clinical characteristics and review of the literature[J]. Prim Care Diabetes, 2021, 15(5):887-889. doi:10.1016/j.pcd.2021.07.016.
[14]	ZHANG L, ZHANG J, HAN B, et al. Gestational diabetes mellitus-induced changes in proteomes and glycated/glycosylated proteomes of human colostrum[J]. J Agric Food Chem, 2021, 69(36):10749-10759. doi:10.1021/acs.jafc.1c03791.
[15]	GAUTAM S, ALAM F, MOIN S, et al. Role of ferritin and oxidative stress index in gestational diabetes mellitus[J]. J Diabetes Metab Disord, 2021, 20(2):1615-1619. doi:10.1007/s40200-021-00911-2.
[16]	FENG Y, FENG Q, YIN S, et al. Stress adaptation disorders play a role in rat gestational diabetes with oxidative stress and glucose transporter-4 expression[J]. Gynecol Endocrinol, 2020, 36(9):786-790. doi:10.1080/09513590.2019.1707797.
[17]	周海银, 罗兰, 陈艳瑛, 等. 刺芒柄花素通过调控SIRT1/PGC-1α通路对脓毒症诱导的大鼠急性肾损伤的影响[J]. 中医药导报, 2022, 28(1):6-11.
	ZHOU H Y, LUO L, CHEN Y Y, et al. Effects of formononetin on sepsis induced acute kidney injury in rats by regulating the SIRT1/PGC-1α pathway[J]. Guiding Journal of Traditional Chinese Medicine and Pharmacy, 2022, 28(1):6-11. doi:10.13862/j.cnki.cn43-1446/r.2022.01.046.
[18]	王锦淳, 王蕾, 秦爱萍, 等. 芒柄花黄素对糖尿病小鼠认知功能障碍的改善作用研究[J]. 临床合理用药杂志, 2022, 15(9):1-5,9.
	WANG J C, WANG L, QIN A P, et al. Improvement of formononetin on cognitive dysfunction in diabetic mice[J]. Guiding Journal of Traditional Chinese Medicine and Pharmacy, 2022, 15(9):1-5,9. doi:10.15887/j.cnki.13-1389/r.2022.09.001.
[19]	HE Y, JIANG K, ZHAO X. Taraxasterol protects hippocampal neurons from oxygen-glucose deprivation-induced injury through activation of Nrf2 signalling pathway[J]. Artif Cells Nanomed Biotechnol, 2020, 48(1):252-258. doi:10.1080/21691401.2019.1699831.
[20]	CHEN Y, TANG J, ZHANG Y, et al. Astaxanthin alleviates gestational diabetes mellitus in mice through suppression of oxidative stress[J]. Naunyn Schmiedebergs Arch Pharmacol, 2020, 393(12):2517-2527. doi:10.1007/s00210-020-01861-x.

组别	母体体质量/g	FSG/ （mmol/L）	TG/ （mmol/L）	TC/ （mmol/L）
对照组	306.85±6.20	3.54±0.38	0.75±0.08	2.70±0.24
模型组	356.34±7.14^a	17.42±3.13^a	1.48±0.14^a	5.15±0.56^a
芒柄花素低剂量组	332.68±5.25^b	10.83±2.34^b	1.13±0.10^b	3.89±0.40^b
芒柄花素高剂量组	310.02±4.39^bc	4.02±0.54^bc	0.81±0.09^bc	2.78±0.29^bc
ML385组	372.69±7.81^b	26.79±3.48^b	1.95±0.19^b	6.26±0.48^b
芒柄花素高剂量+ ML385组	351.73±6.92^d	15.21±2.95^d	1.43±0.12^d	5.08±0.41^d
F	154.591^＊＊	115.158^＊＊	117.919^＊＊	108.771^＊＊

组别	母体体质量/g	FSG/ （mmol/L）	TG/ （mmol/L）	TC/ （mmol/L）
对照组	306.85±6.20	3.54±0.38	0.75±0.08	2.70±0.24
模型组	356.34±7.14^a	17.42±3.13^a	1.48±0.14^a	5.15±0.56^a
芒柄花素低剂量组	332.68±5.25^b	10.83±2.34^b	1.13±0.10^b	3.89±0.40^b
芒柄花素高剂量组	310.02±4.39^bc	4.02±0.54^bc	0.81±0.09^bc	2.78±0.29^bc
ML385组	372.69±7.81^b	26.79±3.48^b	1.95±0.19^b	6.26±0.48^b
芒柄花素高剂量+ ML385组	351.73±6.92^d	15.21±2.95^d	1.43±0.12^d	5.08±0.41^d
F	154.591^＊＊	115.158^＊＊	117.919^＊＊	108.771^＊＊

组别	胚胎存活率/%	胎鼠体质量/g
对照组	98.87±1.12	4.14±0.18
模型组	73.12±4.80^a	5.81±0.33^a
芒柄花素低剂量组	83.84±2.15^b	5.04±0.23^b
芒柄花素高剂量组	95.03±1.96^bc	4.25±0.14^bc
ML385组	64.01±2.07^b	6.53±0.29^b
芒柄花素高剂量+ML385组	75.74±3.39^d	5.74±0.21^d
F	200.071^＊＊	141.104^＊＊

组别	胚胎存活率/%	胎鼠体质量/g
对照组	98.87±1.12	4.14±0.18
模型组	73.12±4.80^a	5.81±0.33^a
芒柄花素低剂量组	83.84±2.15^b	5.04±0.23^b
芒柄花素高剂量组	95.03±1.96^bc	4.25±0.14^bc
ML385组	64.01±2.07^b	6.53±0.29^b
芒柄花素高剂量+ML385组	75.74±3.39^d	5.74±0.21^d
F	200.071^＊＊	141.104^＊＊

组别	MDA/ （nmol/L）	GSH/ （U/L）	SOD/ （U/L）	TAC/ （μmol/L）
对照组	2.81±0.32	64.62±5.31	91.12±7.54	15.21±1.43
模型组	4.93±0.45^a	40.85±3.08^a	60.78±4.65^a	8.16±0.64^a
芒柄花素低剂量组	3.87±0.38^b	49.97±3.53^b	73.89±5.31^b	11.08±0.91^b
芒柄花素高剂量组	2.95±0.31^bc	60.11±4.12^bc	88.67±6.24^bc	14.74±1.30^bc
ML385组	6.01±0.48^b	31.53±1.85^b	48.93±3.86^b	4.85±0.46^b
芒柄花素高剂量+ ML385组	4.82±0.43^d	42.04±2.98^d	63.51±4.38^d	8.74±0.65^d
F	87.584^＊＊	106.674^＊＊	82.515^＊＊	156.001^＊＊