Saponins from Aralia taibaiensis protect against brain ischemia/reperfusion injuries by regulating the apelin/AMPK pathway

Abstract

Aralia taibaiensi, widely distributed in western China, particularly in the Qinba Mountains, has been utilized as a folk medicine for treating diabetes, gastropathy, rheumatism, and cardiovascular diseases. Saponins from A. taibaiensis (sAT) have demonstrated protective effects against oxidative stress and mitochondrial dysfunction induced by ischemia/reperfusion (I/R). However, the underlying mechanisms remain unclear. In vivo, middle cerebral artery occlusion/reperfusion (MCAO/R) induced inflammatory infiltration, neuronal injury, cell apoptosis, mitochondrial dysfunction, and oxidative stress in the ischaemic penumbra, which were effectively mitigated by sAT. sAT increased the mRNA and protein expression levels of apelin and its receptor apelin/apelin receptors (ARs) both in vivo and in vitro. (Ala13)-Apelin-13 (F13A) and small interfering RNA (siRNA) abolished the regulatory effects of sAT on neuroprotection mediated by adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/protein kinase B (Akt). Furthermore, sAT induced apelin/AR expression by simultaneously inhibiting P38 mitogen-activated protein kinase (P38 MAPK)/activating transcription factor 4 (ATF4) and upregulating hypoxia-inducible factor-1α (HIF-1α). Our findings indicate that sAT regulates apelin/AR/AMPK by inhibiting P38 MAPK/ATF4 and upregulating HIF-1a, thereby suppressing oxidative stress and mitochondrial dysfunction.

Keywords

Aralia taibaiensis / Apelin/apelin receptor / Stroke / P38 MAPK/ATF4 / HIF-1a

References

[1] Xu Y, Liu J, Zeng Y, et al. Traditional uses, phytochemistry, pharmacology, toxicity and quality control of medicinal genus Aralia: a review. J Ethnopharmacol. 2022; 284(298):114671. https://doi.org/10.3389/fphar.2021.726528.

[2] Clement JA, Clement ES. The medicinal chemistry of genus Aralia. Curr Top Med Chem. 2015; 14(24):2783-801. https://doi.org/10.2174/1568026615666141208110021.

[3] Weng Y, Yu L, Cui J, et al. Antihyperglycemic, hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis in experimental type 2 diabetic rats. J Ethnopharmacol. 2014; 152(3):553-560. https://doi.org/10.1016/j.jep.2014.02.001.

[4] Xi M, Hai C, Tang H, et al. Antioxidant and antiglycation properties of total saponins extracted from traditional Chinese medicine used to treat diabetes mellitus. Phytother Res. 2008; 22(2):228-237. https://doi.org/10.1002/ptr.2297.

[5] Duan J, Cui J, Yang Z, et al. Neuroprotective effect of Apelin 13 on ischemic stroke by activating AMPK/GSK-3β/Nrf2 signaling. J Neuroinflammation. 2019; 16(1):24. https://doi.org/10.1186/s12974-019-1406-7.

[6] Chen D, Lee J, Gu X, et al. Intranasal delivery of apelin-13 is neuroprotective and promotes angiogenesis after ischemic stroke in mice. ASN Neuro. 2015; 7(5):1759091415605114. https://doi.org/10.1177/1759091415605114.

[7] Duan J, Cui J, Zheng H, et al. Aralia taibaiensis protects against I/R-induced brain cell injury through the Akt/SIRT1/FOXO3a pathway. Oxid Med Cell Longev. 2019; 2019(284): 7609765. https://doi.org/10.1155/2019/7609765.

[8] Paul S, Candelario-Jalil E. Emerging neuroprotective strategies for the treatment of ischemic stroke: an overview of clinical and preclinical studies. Exp Neurol. 2021;335:113518. https://doi.org/10.1016/j.expneurol.2020.113518.

[9] Manuel Y. Fibrinolytic and non-fibrinolytic roles of tissue-type plasminogen activator in the ischemic brain. Neuroscience. 2024; 542:69-80. https://doi.org/10.1016/j.neuroscience.2023.08.011.

[10] Tao YY, et al.Ma JW, Feng. YZ, Tissue-type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease. MedComm. 2023; 4(5):e392-e392. https://doi.org/10.1002/mco2.392.

[11] Zhou X, Chen H, Wang L, et al. Mitochondrial dynamics: a potential therapeutic target for ischemic stroke. Front Aging Neurosci. 2021;13:721428. https://doi.org/10.3389/fnagi.2021.721428.

[12] Luo H, Gu X, Tong G, et al. Research progress of apelin in acute ischemic brain injury. Am J Transl Res. 2022; 14(10):7260-7267.

[13] Mughal A, O'Rourke ST. Vascular effects of apelin: mechanisms and therapeutic potential. Pharmacol Ther. 2018; 190(2018):139-147. https://doi.org/10.1016/j.pharmthera.2018.05.013.

[14] Hu J, Longmeng C, Dachao T, et al. Endogenous ligand of the APJ receptor apelin-13 inhibits cell apoptosis and oxidative stress of cardiomyocytes. Cell Mol Biol. 2023; 69(11):207-212.

[15] Razieh AZ, Hossein J, Saeed EM, et al. Effects of intracerebroventricular injection of apelin-13 on food intake in broiler chicks. Vet Res forum. 2023; 14(2):105-108.

[16] Zhang Y, Jiang WW, Sun WJ, et al. Neuroprotective roles of apelin-13 in neurological diseases. Neurochem Res. 2023; 48(6):1648-1662. https://doi.org/10.1007/s11064-023-03869-0.

[17] Duan J, Wei G, Guo C, et al. Aralia taibaiensis protects cardiac myocytes against high glucose-induced oxidative stress and apoptosis. Am J Chin Med. 2015; 43(6):1159-1175. https://doi.org/10.1142/S0192415X15500664.

[18] Vakili A, Zahedi khorasani M. Post-ischemic treatment of pentoxifylline reduces cortical not striatal infarct volume in transient model of focal cerebral ischemia in rat. Brain Res. 2007; 1144(2007):186-191. https://doi.org/10.1016/j.brainres.2007.01.096.

[19] Park SH, Lee AR, Choi K, et al. TOMM20 as a potential therapeutic target of colorectal cancer. BMB Rep. 2019; 52(12):712-717. https://doi.org/10.5483/BMBRep.2019.52.12.249.

[20] Biswas T, Dwivedi UN. Plant triterpenoid saponins: biosynthesis, in vitro production, and pharmacological relevance. Protoplasma. 2019; 256(6):1463-1486. https://doi.org/10.1007/s00709-019-01411-0.

[21] Fan C, Wang JX, Xiong ZE, et al. Saponins from Panax japonicus improve neuronal mitochondrial injury of aging rats. Pharm Biol. 2023; 61(1):1401-1412. https://doi.org/10.1080/13880209.2023.2244532.

[22] Sun A, Xu X, Lin J, et al. Neuroprotection by saponins. Phytother Res. 2015; 29(2):187-200. https://doi.org/10.1002/ptr.5246.

[23] Duan J, Yin Y, Wei G, et al. Chikusetsu saponin IVa confers cardioprotection via SIRT1/ERK1/2 and Homer1a pathway. Sci Rep. 2015; 5(1):18123. https://doi.org/10.1038/srep18123.

[24] Yan J, Duan J, Wu X, et al. Total saponins from Aralia taibaiensis protect against myocardial ischemia/reperfusion injury through AMPK pathway. Int J Mol Med. 2015; 36(6):1538-1546. https://doi.org/10.3892/ijmm.2015.2391.

[25] Xu W, Li T, Gao L, et al. Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats. J Neuroinflammation. 2019; 16(1):247. https://doi.org/10.1186/s12974-019-1620-3.

[26] Shao ZQ, Dou SS, Zhu JG, et al. Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury. Neural Regen Res. 2021; 16(6):1044-1051. https://doi.org/10.4103/1673-5374.300725.

[27] Stefania DA, Elena M, Federico DF, et al. Sirt1 activity in the brain: simultaneous effects on energy homeostasis and reproduction. Int J Environ Res Public Health. 2021; 18(3):1243-1243. https://doi.org/10.3390/IJERPH18031243.

[28] Meng XF, Tan J, Li MM, et al. Sirt1: role under the condition of ischemia/hypoxia. Cell Mol Neurobiol. 2017; 37(1):17-28. https://doi.org/10.1007/s10571-016-0355-2.

[29] Olmos Y, Sánchez-Gómez FJ, Wild B, et al. SirT1 regulation of antioxidant genes is dependent on the formation of a FoxO3a/PGC-1α complex. Antioxid Redox Signal. 2013; 19(13):1507-1521. https://doi.org/10.1089/ars.2012.4713.

[30] Halling JF, Pilegaard H. PGC-1α-mediated regulation of mitochondrial function and physiological implications. Appl Physiol Nutr Metab. 2020; 45(9):927-936. https://doi.org/10.1139/apnm-2020-0005.

[31] Wu Y, Wang X, Zhou X, et al. Temporal expression of apelin/apelin receptor in ischemic stroke and its therapeutic potential. Front Mol Neurosci. 2017;10:1. https://doi.org/10.3389/fnmol.2017.00001.

[32] Rastaldo R, Cappello S, Folino A, et al. Effect of apelin-apelin receptor system in postischaemic myocardial protection: a pharmacological postconditioning tool?. Antioxid Redox Signal. 2011; 14(5):909-922. https://doi.org/10.1089/ars.2010.3355.

[33] He L, Xu J, Chen L, et al.Apelin/APJ signaling in hypoxia-related diseases. Clin Chim Acta. 2015; 451(Pt B):191-198. https://doi.org/10.1016/j.cca.2015.09.029.

[34] Liang Z, Wu G, Fan C, et al. The emerging role of signal transducer and activator of transcription 3 in cerebral ischemic and hemorrhagic stroke. Prog Neurobiol. 2016; 137:1-16. https://doi.org/10.1016/j.pneurobio.2015.11.001.

[35] Morimoto N, Oida Y, Shimazawa M, et al. Involvement of endoplasmic reticulum stress after middle cerebral artery occlusion in mice. Neuroscience. 2007; 147(4):957-967. https://doi.org/10.1016/j.neuroscience.2007.04.017.

[36] Iwanaga Y, Kihara Y, Takenaka H, et al. Down-regulation of cardiac apelin system in hypertrophied and failing hearts: possible role of angiotensin II-angiotensin type 1 receptor system. J Mol Cell Cardiol. 2006; 41(5):798-806. https://doi.org/10.1016/j.yjmcc.2006.07.004.

[37] Jeong K, Oh Y, Kim SJ, et al. Apelin is transcriptionally regulated by ER stress-induced ATF4 expression via a p38 MAPK-dependent pathway. Apoptosis. 2014; 19(9):1399-1410. https://doi.org/10.1007/s10495-014-1013-0.

[38] Wang H, Qi J, Li L, et al. Inhibitory effects of chikusetsusaponin IVa on lipopolysaccharide-induced pro-inflammatory responses in THP-1 cells. Int J Immunopathol Pharmacol. 2015; 28(3):308-317. https://doi.org/10.1177/0394632015589519.