Mechanism of Xiaozhong Zhitong Mixture against ischemia-reperfusion injury of skin flaps based on metabolomics

doi:10.12307/2023.591

Abstract

Abstract: BACKGROUND: Previous studies have confirmed that Xiaozhong Zhitong Mixture can alleviate ischemia-reperfusion injury of skin flaps, but its metabolomic mechanism has not been reported.
OBJECTIVE: To explore the mechanism of Xiaozhong Zhitong Mixture against ischemia-reperfusion injury of rat skin flaps.
METHODS: A rat skin flap ischemia-reperfusion injury model was established. Related metabolomics techniques were used to analyze the endogenous levels of metabolite samples from normal rats, model rats and rats after intervention with Xiaozhong Zhitong Mixture. Relevant biomarkers were retrieved and identified and metabolic pathways were then constructed.
RESULTS AND CONCLUSION: Xiaozhong Zhitong Mixture could significantly reduce the pathological changes of skin flap tissue in rats with skin flap ischemia-reperfusion injury. Significantly differential metabolites, including malonic acid and 3-(3-hydroxyphenyl)propionic acid, were identified and imported into MetaboAnalyst 4.0 and KEGG databases for metabolic pathway analysis. After intervention, the metabolic pathways of Xiaozhong Zhitong Mixture included pyrimidine metabolism and phenylalanine metabolism. To conclude, Xiaozhong Zhitong Mixture improves ischemia-reperfusion injury of rat skin flap by regulating the metabolic pathways such as pyrimidine and phenylalanine metabolic pathways, which thereby provides a theoretical basis for clarifying the mechanism of Xiaozhong Zhitong Mixture in the treatment of ischemia-reperfusion injury of rat skin flap.

Key words: Xiaozhong Zhitong Mixture, metabolomics, flap ischemia-reperfusion, malonic acid, 3-(3hydroxyphenyl)propionic acid

CLC Number:

He Bo, He Zhijun, Liu Tao, Ma Suilu. Mechanism of Xiaozhong Zhitong Mixture against ischemia-reperfusion injury of skin flaps based on metabolomics[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(23): 3653-3659.

Figures/Tables 15

References

[1] SCHMIDT Y, BANNASCH H, EISENHARDT SU. Ischemia-reperfusion injury leads to significant tissue damage in free flap surgery. Plast Reconstr Surg. 2012;129(1):174e-175e.
[2] BIAN F, XIAO Y, ZAHEER M, et al. Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn. Int J Mol Sci. 2017;18(3):562.
[3] YIN XF, ZHANG Q, CHEN ZY, et al. NLRP3 in human glioma is correlated with increased WHO grade, and regulates cellular proliferation, apoptosis and metastasis via epithelial-mesenchymal transition and the PTEN/AKT signaling pathway. Int J Oncol. 2018;53(3):973-986.
[4] HAN Y, XU X, TANG C, et al. Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis. Redox Biol. 2018;16:32-46.
[5] SHARMA A, TATE M, MATHEW G, et al. Oxidative Stress and NLRP3-Inflammasome Activity as Significant Drivers of Diabetic Cardiovascular Complications: Therapeutic Implications. Front Physiol. 2018;9:114.
[6] 单海民,程春生,马文龙,等.川芎嗪对岛状皮瓣缺血再灌注损伤血液流变学影响的研究[J].世界中西医结合杂志,2012,7(10): 846-849.
[7] HONG P, GU RN, LI FX, et al. NLRP3 inflammasome as a potential treatment in ischemic stroke concomitant with diabetes. J Neuroinflammation. 2019;16(1):121.
[8] 毕军伟,李盛华,米仲祥,等.陇中消肿止痛合剂的实验研究与临床应用[J].西部中医药,2016,29(4):51-53.
[9] 王海刚.基于 p38MAPK-PPARγ/NF-κB 信号通路探讨消肿止痛合剂对皮瓣缺血再灌注损伤的干预机制研究[D].兰州:甘肃中医药大学,2021.
[10] 姚兴璋,刘涛,何志军,等.消肿止痛合剂对大鼠缺血皮瓣血管再生及VEGF-Dll4/Notch 信号通路的影响[J].暨南大学学报(自然科学与医版),2021,42(2):164-171.
[11] TAN B, MA Y, ZHANG L, et al. The application of metabolomics analysis in the research of gestational diabetes mellitus and preeclampsia. J Obstet Gynaecol Res. 2020;46(8):1310-1318.
[12] SCHMAUSS D, WEINZIERL A, SCHMAUSS V, et al. Common Rodent Flap Models in Experimental Surgery. Eur Surg Res. 2018;59(3-4):255-264.
[13] CHEN D, ZHONG L, LI Y, et al. Changes in serum inflammatory factor interleukin-6 levels and pathology of carotid vessel walls of rats with chronic periodontitis and diabetes mellitus after the periodontal intervention. Saudi J Biol Sci. 2020;27(6):1679-1684.
[14] LIU X, ZHANG M, CHENG X, et al. LC-MS-Based Plasma Metabolomics and Lipidomics Analyses for Differential Diagnosis of Bladder Cancer and Renal Cell Carcinoma. Front Oncol. 2020;10:717.
[15] WEBB JL. Enzyme and metabolism inhibitors. New York: Academic Press, 1966.
[16] BRAND MD. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Med. 2016;100:14-31.
[17] HAUSENLOY DJ, YELLON DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123(1):92-100.
[18] QUINLAN CL, ORR AL, PEREVOSHCHIKOVA IV, et al. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. 2012;287(32):27255-27264.
[19] KONSTAM MA, KIERNAN MS, BERNSTEIN D, et al. Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2018;137(20):e578-e622.
[20] HARJOLA VP, MEBAZAA A, ČELUTKIENĖ J, et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail. 2016;18(3):226-241.
[21] MILLS EL, KELLY B, LOGAN A, et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell. 2016;167(2):457-470.e13.
[22] BAILIS W, SHYER JA, ZHAO J, et al. Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. Nature. 2019;571(7765):403-407.
[23] PELL VR, CHOUCHANI ET, FREZZA C, et al. Succinate metabolism: a new therapeutic target for myocardial reperfusion injury. Cardiovasc Res. 2016;111(2):134-141.
[24] CHOUCHANI ET, PELL VR, GAUDE E, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014;515(7527):431-435.
[25] ZHANG J, WANG YT, MILLER JH, et al. Accumulation of Succinate in Cardiac Ischemia Primarily Occurs via Canonical Krebs Cycle Activity. Cell Rep. 2018;23(9):2617-2628.
[26] PELL VR, SPIROSKI AM, MULVEY J, et al. Ischemic preconditioning protects against cardiac ischemia reperfusion injury without affecting succinate accumulation or oxidation. J Mol Cell Cardiol. 2018;123:88-91.
[27] MARTIN JL, COSTA ASH, GRUSZCZYK AV, et al. Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation. Nat Metab. 2019;1:966-974.
[28] KOHLHAUER M, PELL VR, BURGER N, et al. Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive. Basic Res Cardiol. 2019;114(3):18.
[29] PRAG HA, PALA L, KULA-ALWAR D, et al. Ester Prodrugs of Malonate with Enhanced Intracellular Delivery Protect Against Cardiac Ischemia-Reperfusion Injury In Vivo. Cardiovasc Drugs Ther. 2022;36(1):1-13.
[30] CHENG D, SONG Q, DING Y, et al. Comparative Study on the Protective Effect of Chlorogenic Acid and 3-(3-Hydroxyphenyl) Propionic Acid against Cadmium-Induced Erythrocyte Cytotoxicity: In Vitro and In Vivo Evaluation. J Agric Food Chem. 2021;69(13):3859-3870.
[31] WAHYUNI WT, ROHAETI E, SARI DR. Graphene modified screen printed carbon electrode for voltammetric detection of glutathione as oxidative stress biomarker[A]//IOP Conference Series: Earth and Environmental Science[C]. Bogor: The 4th International Seminar on Sciences, 2018.
[32] 聂春霞,何盼,郝艳艳,等.基于1H-NMR代谢组学的山楂不同炮制品对高脂血症大鼠模型的影响研究[J].中草药,2019,50(10): 2362-2370.
[33] 彭琳秀,谢彤,单进军.基于气相色谱-质谱联用的抗结核药致肾损伤代谢组学及谷胱甘肽治疗作用研究[J].分析化学,2020,48(9): 1160-1168.