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| Discussion of mechanism of Compound Qiying Granules based on PERK/Nrf2 pathway in treating diabetic peripheral neuropathy |
| CHEN Chen1 HU Yan1 LIU Tao2 HU Xiaoling2 |
1.The Fourth Clinical Medical College, Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China;
2.Xinjiang Uygur Autonomous Region Hospital of Traditional Chinese Medicine, Xinjiang Uygur Autonomous Region, Urumqi 830000, China
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Abstract Objective To investigate the mechanism of Compound Qiying Granules on diabetic peripheral neuropathy (DPN) rats based on PERK/Nrf2 pathway. Methods A total of 72 SPF male Wistar rats weight 180-220 g and aged eight weeks were divided into normal control group, model group, positive drug group, and Compound Qiying Granules low-dose, medium-dose, high-dose groups by random number table method, with 12 rats in each group. Except the normal control group, the other five groups were continuously fed high-fat diet, and streptozotocin (30 mg/kg) was injected eight weeks later, and then rats with fasting blood glucose ＞11.1 mol/L were selected to continue high-fat diet for four weeks to build DPN model. After the DPN modeling was successful, Compound Qiying Granules low-dose, medium-dose, high-dose groups were given 1.17, 2.34, 4.68 g/kg Compound Qiying Granules, respectively, the positive drug group was given Trimethylamine Oxide (110 mg/kg), 2 ml/time, once a day, the normal control group and model group were given the same amount of double steaming water. After four weeks of intervention, blood glucose changes before and after intervention in the six groups were compared, and hematoxylin-eosin staining of sciatic nerve in the six groups was observed. Glucose regulatory protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), phosphorylated PERK (p-PERK), activating transcription factor 4 (ATF4), nuclear factor-erythroid 2-related factor 2 (Nrf2), C/EBP homologous protein (CHOP), cysteine aspartic acid specific protease-3 (caspase-3) in six groups of sciatic nerves were detected by Western blot. Results In the normal control group, the structure of myelinated nerve fibers was complete, the distribution was uniform, the arrangement was regular, the shape and structure of axons, myelin sheath, and nerve membranes were good and complete, and the shape and structure of endoneurals were normal. In the model group, there were loss and decrease of myelinated nerve fibers, partial disordered arrangement, partial axonal degeneration, segmental demyelination, thickening of nerve membrane, and hyperplasia of endoneural collagen fibers. The degree of degeneration, demyelination, thickening of nerve membrane, and hyperplasia of nerve intima in Compound Qiying Granules low-dose, medium-dose, high-dose groups were less than those in model group. After the successful DPN modeling, the blood glucose of the model group was higher than that of the normal control group (P＜0.05), and there was no statistical significance in blood glucose of Compound Qiying Granules low-dose, medium-dose, high-dose groups compared with the model group (P＞0.05). After four weeks of drug intervention, the blood glucose of model group was higher than that of normal control group, and those of Compound Qiying Granules low-dose, medium-dose, high-dose groups were lower than those of model group, and those of Compound Qiying Granules medium-dose, high-dose groups were lower than those in Compund Qiying Granules low-dose group (P＜0.05). GRP78, p-PERK, ATF4, CHOP, and caspase-3 of sciatic nerve tissues in model group were higher than those in normal control group, and Nrf2 was lower than that in normal control group (P＜0.05). GRP78, ATF4, and CHOP in Compound Qiying Granules medium-dose, high-dose groups were lower than those in model group, and Nrf2 were higher than those in model group; p-PERK and caspase-3 in Compound Qiying Granules high-dose group were lower than those in model group (P＜0.05). ATF4 and CHOP of Compound Qiying Granules high-dose group were lower than those of Compound Qiying Granules low-dose group, CHOP of Compound Qiying Granules medium-dose group was lower than that of Compound Qiying Granules low-dose group (P＜0.05). Conclusion Compound Qiying Granules has certain hypoglycemic and neuroprotective effects, and its mechanism may be to relieve endoplasmic reticulum stress by inhibiting PERK/Nrf2 pathway.
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[1] Patel YR，Gadiraju TV，Gaziano JM，et al. Adherence to healthy lifestyle factors and risk of death in men with diabetes mellitus：The Physicians’ Health Study [J]. Clin Nutr，2018，37（1）： 139-143.
[2] Elafros MA，Andersen H，Bennett DL，et al. Towards prevention of diabetic peripheral neuropathy：clinical presentation，pathogenesis，and new treatments [J]. Lancet Neurol，2022，21（10）：922-936.
[3] Chang MC，Yang S. Diabetic peripheral neuropathy essentials：a narrative review [J]. Ann Palliat Med，2023，12（2）：390- 398.
[4] 徐园园，魏迎凤，卢学超，等.血清CTRP3水平对2型糖尿病周围神经病变的作用[J].微循环学杂志，2022，61（2）： 45-49，53.
[5] 史爱贤，侯辉，刘慧.硫辛酸联合甘舒霖30R胰岛素治疗2型糖尿病周围神经病变的效果[J].中国实用医药，2022，17（12）：116-119.
[6] Griebeler ML，Morey-Vargas OL，Brito JP，et al. Pharmacologic interventions for painful diabetic neuropathy：An umbrella systematic review and comparative effectiveness network meta-analysis [J]. Ann Intern Med，2014，161（9）：639-649.
[7] Waldfogel JM，Nesbit SA，Sharma R，et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life：A systematic review [J]. Neurology，2017，89（8）：875.
[8] Panthi S，Jing X，Gao C，et al. Yang-warming method in the treatment of diabetic peripheral neuropathy：an updated systematic review and meta-analysis [J]. BMC Complement Altern Med，2017，17（1）：424.
[9] 庄晓芳，胡晓灵.复方芪鹰颗粒对DPN患者血管内皮生长因子的影响及临床疗效观察[J].科技导报，2009，27（12）：23-27.
[10] 张文佳，胡晓灵.复方芪鹰颗粒对DPN患者胰岛素样生长因子-1影响的临床研究[J].山西中医杂志，2010， 26（3）：17-19.
[11] 陶天琪，王晓礽，徐菲菲，等.MR-1通过抑制PERK/Nrf2途径减轻缺氧/复氧诱导的心肌细胞凋亡[J].中国病理生理杂志，2014，30（2）：193-202.
[12] Yang XW，Yao WJ，Liu HL，et al. Tangluoning，a traditional Chinese medicine，attenuates in vivo and in vitro diabetic peripheral neuropathy through modulation of PERK/Nrf2 pathway [J]. Sci Rep，2017，7（1）：1014.
[13] 马丽，胡晓灵.络必通颗粒对DPN大鼠神经电生理及Na+-K+-ATP酶活性的影响[J].中成药，2010，32（9）：1587-1589.
[14] 刘涛，卢军，石莹莹，等.复方芪鹰颗粒对糖尿病周围神经病变大鼠Hsp70表达影响[J].中国医药导报，2017， 14（1）：28-31.
[15] Liu T，Zhou J，Cui HJ，et al. iTRAQ-based quantitative proteomics reveals the neuroprotection of rhubarb in experimental intracerebral hemorrhage [J]. J Ethnopharmacol，2019，232：244-254.
[16] 王清全，汤秀华.当归拈痛汤治疗糖尿病周围神经病变临床观察[J].中国中医药现代远程教育，2023，21（4）：95-97.
[17] 洪挺，胡咏梅.参芪降糖颗粒治疗2型糖尿病周围神经病变临床研究[J].新中医，2023，55（2）：81-84.
[18] 李江敏子，刘殿池，尚菊菊，等.温经散寒法联合甲钴胺治疗糖尿病周围神经病变的疗效及对血清胱抑素C水平的影响[J].中国临床研究，2022，35（7）：932-937.
[19] 郎金飞，赵伟河，李陈芳.益气通络汤治疗糖尿病周围神经病变临床研究[J].新中医，2022，54（7）：102-106.
[20] 邹晓霞.益气活血通痹汤治疗糖尿病周围神经病变临床观察[J].中国中医药现代远程教育，2021，19（24）：84-85.
[21] 杨丽，高怀林.从“络”论治糖尿病周围神经病变研究进展[J].疑难病杂志，2022，21（4）：428-431.
[22] 李桂云，张雅琼，刘攀云，等.针灸结合常规西药治疗糖尿病周围神经病变的临床效益探讨[J].中国医药，2021， 16（6）：861-864.
[23] 李楠，杜娜，王玉莹，等.α-硫辛酸注射液联合中药湿敷护理对糖尿病周围神经病变患者的影响[J].中国医药科学，2021，11（12）：110-112.
[24] 丁琦，阿布都沙拉木·阿布都热衣木，沈玉国，等.复方芪鹰颗粒对糖尿病周围神经病变患者SOD、MDA、8-OHdG的影响[J].光明中医，2022，37（3）：425-428.
[25] Back SH，Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes [J]. Annu Rev Biochem，2012，81：767-793.
[26] Diaz-Morales N，Iannantuoni F，Escribano-Lopez I，et al. Does metformin modulate endoplasmic reticulum stress and autophagy in type 2 diabetic PBMCs？[J]. Antioxid Redox Signal，2018，28（17）：1562-1569.
[27] Wu YB，Li HQ，Ren MS，et al. CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress：A New Mechanism for Diabetic Peripheral Neuropathy [J]. Cell Physiol Biochem，2013， 32：367-379.
[28] 张亮，徐敏，庄向华，等.内质网应激与凋亡在糖尿病周围神经病变中的表达变化[J].山东大学学报（医学版），2017，55（8）：13-17.
[29] 史浩田，姚伟洁，杨鑫伟，等.糖络宁对糖尿病周围神经病变大鼠PERK-CHOP-Caspase-12通路的影响[J].环球中医，2017，10（3）：269-274.
[30] Liu YP，Shao SJ，Guo HD. Schwann Cells Apoptosis Is Induced by High Glucose in Diabetic Peripheral Neuropathy [J]. Life Sci，2020，248：117459. |
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