Abstract
The widely used Radix Astragali (RA) has significant therapeutic effects on cognitive impairment (CI) caused by type 2 diabetes (T2DM). However, the effective active ingredients and the precise mechanism underly RA alleviation of T2DM-induced CI still require further study. In this study, we aim to elucidate whether and how jaranol, a key effective active ingredient in RA, influences CI in db/db mice. We used various online databases and Cytoscape to screen jaranol as the most active ingredient of RA in the treatment of T2DM-induced CI. The fear conditioning experiment, new object recognition (NOR) test, and Morris water maze (MWM) test were conducted to assess the improvement effect of jaranol on CI in diabetic mice. The protein-protein interaction (PPI) network, Cytoscape, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify key genes. The levels of AKT and caspase-3 were determined by Western blotting. The number of surviving hippocampal neurons was verified through Nissl staining. AutoDock was utilized for predicting potential binding sites between jaranol and key genes.As a result, jaranol attenuated CI in db/db mice probably through activation of PI3K-AKT signaling pathway by inhibiting cell apoptosis in hippocampus. Furthermore, A329 near the active site of AKT1 had hydrogen bond with jaranol. In conclusion, we suggest that jaranol may have therapeutic applications in T2DM-induced CI by targeting the PI3K-AKT signaling pathway directly via key sites. Our study provides alternative drugs and potential therapeutic targets for the prevention and treatment of T2DM-induced CI.
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References
Al-Khayri JM, Sahana GR, Nagella P, Joseph BV, Alessa FM, Al-Mssallem MQ (2022) Flavonoids as potential anti-inflammatory molecules: a review. Molecules 27(9):2901. https://doi.org/10.3390/molecules27092901
Arenbaoligao, Guo X, Xiong J, Zhang S, Yang Y, Chen D, Xie Y (2023) Kumatakenin inhibited iron-ferroptosis in epithelial cells from colitis mice by regulating the Eno3-IRP1-axis. Front Pharmacol 14:1127931. https://doi.org/10.3389/fphar.2023.1127931
Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, Craft S, Gandy S, Buettner C, Stoeckel LE, Holtzman DM, Nathan DM (2018) Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol 14(3):168–181. https://doi.org/10.1038/nrneurol.2017.185
Auyeung KK, Han QB, Ko JK (2016) Astragalus membranaceus: a review of its Protection Against inflammation and gastrointestinal cancers. Am J Chin Med 44(1):1–22. https://doi.org/10.1142/S0192415X16500014
Balu DT, Carlson GC, Talbot K, Kazi H, Hill-Smith TE, Easton RM, Birnbaum MJ, Lucki I (2012) Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function. Hippocampus 22(2):230–240. https://doi.org/10.1002/hipo.20887
Bian YQ, Li J, Peng S, Lyu TY, Zhang YL, Qiao YJ (2020) Exploration of potential efficacy markers of Astragali Radix for invigorating Qi based on systematic traditional Chinese medicine. Zhongguo Zhongyao Zazhi 45(14):3266–3274. https://doi.org/10.19540/j.cnki.cjcmm.20200210.405
Biessels GJ, Despa F (2018) Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 14(10):591–604. https://doi.org/10.1038/s41574-018-0048-7
Chen Z, Liu L, Gao C, Chen W, Vong CT, Yao P, Yang Y, Li X, Tang X, Wang S, Wang Y (2020) Astragali Radix (Huangqi): a promising edible immunomodulatory herbal medicine. J Ethnopharmacol 258:112895. https://doi.org/10.1016/j.jep.2020.112895
Cheng Q, Wang J, Li M, Fang J, Ding H, Meng J, Zhang J, Fang X, Liu H, Ma C, Chen C, Zhang W (2022) CircSV2b participates in oxidative stress regulation through mir-5107-5p-Foxk1-Akt1 axis in Parkinson’s disease. Redox Biol 56:102430. https://doi.org/10.1016/j.redox.2022.102430
Cole JB, Florez JC (2020) Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 16(7):377–390. https://doi.org/10.1038/s41581-020-0278-5
Dove A, Shang Y, Xu W, Grande G, Laukka EJ, Fratiglioni L, Marseglia A (2021) The impact of diabetes on cognitive impairment and its progression to dementia. Alzheimer’s Dement 17(11):1769–1778. https://doi.org/10.1002/alz.12482
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2):193–204. https://doi.org/10.1016/j.ctrv.2003.07.007
Ge XH, Zhu GJ, Geng DQ, Zhang HZ, He JM, Guo AZ, Ma LL, Yu DH (2017) Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats. Physiol Behav 170:115–123. https://doi.org/10.1016/j.physbeh.2016.12.021
Hamed SA (2017) Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications. Expert Rev Clin Pharmacol 10(4):409–428. https://doi.org/10.1080/17512433.2017.1293521
Hers I, Vincent EE, Tavare JM (2011) Akt signalling in health and disease. Cell Signal 23(10):1515–1527. https://doi.org/10.1016/j.cellsig.2011.05.004
Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 3(11):935–949. https://doi.org/10.1038/nrd1549
Kumar P, Raman T, Swain MM, Mishra R, Pal A (2017) Hyperglycemia-Induced oxidative-nitrosative stress induces inflammation and neurodegeneration via augmented tuberous sclerosis Complex-2 (TSC-2) activation in neuronal cells. Mol Neurobiol 54(1):238–254. https://doi.org/10.1007/s12035-015-9667-3
Li X, Zhao T, Gu J, Wang Z, Lin J, Wang R, Duan T, Li Z, Dong R, Wang W, Hong K-F, Liu Z, Huang W, Gui D, Zhou H, Xu Y (2022) Intake of flavonoids from Astragalus membranaceus ameliorated brain impairment in diabetic mice via modulating brain-gut axis. Chin Med 17(1). https://doi.org/10.1186/s13020-022-00578-8
Liu T, Zhang Y, Liu J, Peng J, Jia X, Xiao Y, Zheng L, Dong Y (2022) Evaluation of the acute and sub-acute oral toxicity of Jaranol in Kunming Mice. Front Pharmacol 13:903232. https://doi.org/10.3389/fphar.2022.903232
Maleki SJ, Crespo JF, Cabanillas B (2019) Anti-inflammatory effects of flavonoids. Food Chem 299:125124. https://doi.org/10.1016/j.foodchem.2019.125124
Mo J, Tong Y, Ma J, Wang K, Feng Y, Wang L, Jiang H, Jin C, Li J (2023) The mechanism of flavonoids from Cyclocarya paliurus on inhibiting liver cancer based on in vitro experiments and network pharmacology. Front Pharmacol 14:1049953. https://doi.org/10.3389/fphar.2023.1049953
Ong KL, Stafford LK, McLaughlin SA, Boyko EJ, Vollset SE, Smith AE, Dalton BE, Duprey J, Cruz JA, Hagins H, Lindstedt PA, Aali A, Abate YH, Abate MD, Abbasian M, Abbasi-Kangevari Z, Abbasi-Kangevari M, Abd ElHafeez S, Abd-Rabu R, Abdulah DM et al (2023) Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the global burden of Disease Study 2021. Lancet 402(10397):203–234. https://doi.org/10.1016/s0140-6736(23)01301-6
Pugazhenthi S, Qin L, Reddy PH (2017) Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 1863(5):1037–1045. https://doi.org/10.1016/j.bbadis.2016.04.017
Qi DS, Tao JH, Zhang LQ, Li M, Wang M, Qu R, Zhang SC, Liu P, Liu F, Miu JC, Ma JY, Mei XY, Zhang F (2016) Neuroprotection of Cilostazol against ischemia/reperfusion-induced cognitive deficits through inhibiting JNK3/caspase-3 by enhancing Akt1. Brain Res 1653:67–74. https://doi.org/10.1016/j.brainres.2016.10.017
Rom S, Zuluaga-Ramirez V, Gajghate S, Seliga A, Winfield M, Heldt NA, Kolpakov MA, Bashkirova YV, Sabri AK, Persidsky Y (2019) Hyperglycemia-driven neuroinflammation compromises BBB leading to memory loss in both diabetes Mellitus (DM) type 1 and type 2 mouse models. Mol Neurobiol 56(3):1883–1896. https://doi.org/10.1007/s12035-018-1195-5
Shahzad M, Shabbir A, Wojcikowski K, Wohlmuth H, Gobe GC (2016) The antioxidant effects of Radix Astragali (Astragalus Membranaceus and related species) in protecting tissues from Injury and Disease. Curr Drug Targets 17(12):1331–1340. https://doi.org/10.2174/1389450116666150907104742
Singh AK, Kashyap MP, Tripathi VK, Singh S, Garg G, Rizvi SI (2017) Neuroprotection through Rapamycin-Induced activation of Autophagy and PI3K/Akt1/mTOR/CREB Signaling against Amyloid-beta-Induced Oxidative Stress, Synaptic/Neurotransmission dysfunction, and neurodegeneration in adult rats. Mol Neurobiol 54(8):5815–5828. https://doi.org/10.1007/s12035-016-0129-3
Su HF, Shaker S, Kuang Y, Zhang M, Ye M, Qiao X (2021) Phytochemistry and cardiovascular protective effects of Huang-Qi (Astragali Radix). Med Res Rev 41(4):1999–2038. https://doi.org/10.1002/med.21785
Sun G, Ding XA, Argaw Y, Guo X, Montell DJ (2020) Akt1 and dCIZ1 promote cell survival from apoptotic caspase activation during regeneration and oncogenic overgrowth. Nat Commun 11(1):5726. https://doi.org/10.1038/s41467-020-19068-2
Tao J, Cui Y, Duan Y, Zhang N, Wang C, Zhang F (2017) Puerarin attenuates locomotor and cognitive deficits as well as hippocampal neuronal injury through the PI3K/Akt1/GSK-3beta signaling pathway in an in vivo model of cerebral ischemia. Oncotarget 8(63):106283–106295. https://doi.org/10.18632/oncotarget.22290
Unver Saraydin S, Ozdenoglu Kutlu B, Saraydin D (2021) Effects of diabetes on apoptosis and mitosis in rat hippocampus. Biotech Histochem 96(6):460–467. https://doi.org/10.1080/10520295.2020.1818827
van Sloten TT, Sedaghat S, Carnethon MR, Launer LJ, Stehouwer CDA (2020) Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol 8(4):325–336. https://doi.org/10.1016/S2213-8587(19)30405-X
Wang X, Zhao L (2016) Calycosin ameliorates diabetes-induced cognitive impairments in rats by reducing oxidative stress via the PI3K/Akt/GSK-3beta signaling pathway. Biochem Biophys Res Commun 473(2):428–434. https://doi.org/10.1016/j.bbrc.2016.03.024
Wang R, Wang M, Zhou J, Wu D, Ye J, Sun G, Sun X (2020a) Saponins in Chinese Herbal Medicine exerts Protection in Myocardial Ischemia-Reperfusion Injury: possible mechanism and target analysis. Front Pharmacol 11:570867. https://doi.org/10.3389/fphar.2020.570867
Wang X, Xu W, Chen H, Li W, Li W, Zhu G (2020b) Astragaloside IV prevents Aβ1–42 oligomers-induced memory impairment and hippocampal cell apoptosis by promoting PPARγ/BDNF signaling pathway. Brain Res 1747:147041. https://doi.org/10.1016/j.brainres.2020.147041
Woo JH, Ahn JH, Jang DS, Lee KT, Choi JH (2017) Effect of Kumatakenin isolated from cloves on the apoptosis of Cancer cells and the alternative activation of Tumor-Associated macrophages. J Agric Food Chem 65(36):7893–7899. https://doi.org/10.1021/acs.jafc.7b01543
Xu W, Shao X, Tian L, Gu L, Zhang M, Wang Q, Wu B, Wang L, Yao J, Xu X, Mou S, Ni Z (2014) Astragaloside IV ameliorates renal fibrosis via the inhibition of mitogen-activated protein kinases and antiapoptosis in vivo and in vitro. J Pharmacol Exp Ther 350(3):552–562. https://doi.org/10.1124/jpet.114.214205
Xu Y, Xiong J, Zhao Y, He B, Zheng Z, Chu G, Zhu Q (2015) Calycosin rebalances Advanced Glycation End products-Induced glucose uptake dysfunction of hepatocyte in Vitro. Am J Chin Med 43(6):1191–1210. https://doi.org/10.1142/S0192415X15500688
Xu S, Yang J, Wan H, Yu L, He Y (2023) Combination of Radix Astragali and Safflower promotes angiogenesis in rats with ischemic stroke via silencing PTGS2. Int J Mol Sci 24(3):2126. https://doi.org/10.3390/ijms24032126
Yan X, Yu A, Zheng H, Wang S, He Y, Wang L (2019) Calycosin-7-O-β-D-glucoside attenuates OGD/R-Induced damage by preventing oxidative stress and neuronal apoptosis via the SIRT1/FOXO1/PGC-1α pathway in HT22 cells. Neural Plast 2019(1–11). https://doi.org/10.1155/2019/8798069
Yang WC, Gong DH, Hong W, Gao YY, Hao GF (2023) Grasping cryptic binding sites to neutralize drug resistance in the field of anticancer. Drug Discov Today 28(9):103705. https://doi.org/10.1016/j.drudis.2023.103705
Ying C, Li Y, Wu S, Gao L, Zhu Y, Qian Y, Wen X, Li H, Huang C, Hu B, Song Y, Zhou X (2024) MKK3 K329 mutation attenuates Diabetes-Associated Cognitive Dysfunction by blocking the MKK3-RAGE Interaction and Inhibiting Neuroinflammation. Aging Dis. https://doi.org/10.14336/AD.2024.0222
Zhang J, Wu C, Gao L, Du G, Qin X (2020) Astragaloside IV derived from Astragalus membranaceus: a research review on the pharmacological effects. Adv Pharmacol 87:89–112. https://doi.org/10.1016/bs.apha.2019.08.002
Zhang CH, Yang X, Wei JR, Chen NM, Xu JP, Bi YQ, Yang M, Gong X, Li ZY, Ren K, Han QH, Zhang L, Li X, Ji MY, Wang CC, Li MH (2021) Ethnopharmacology, Phytochemistry, Pharmacology, Toxicology and clinical applications of Radix Astragali. Chin J Integr Med 27(3):229–240. https://doi.org/10.1007/s11655-019-3032-8
Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2):88–98. https://doi.org/10.1038/nrendo.2017.151
Zhou Z, Wang M, Huang C, Li Y, Gao L, Zhu Y, Ying C, Zhou X (2022) Treadmill exercise training alleviates diabetes-induced depressive-like behavior and cognitive impairment by improving hippocampal CA1 neurons injury in db/db mice. Brain Res Bull 190:84–96. https://doi.org/10.1016/j.brainresbull.2022.09.018
Acknowledgements
We are grateful to all the staff in the Public Experimental Research Center and Experimental Animal Center of Xuzhou Medical University for their support and help during the experiments.
Funding
This work was supported by grants from the National Natural Science Foundation of China, Grant/Award Number: 82271205; The Jiangsu Province graduate student innovation project, Grant/Award Number: KYCX23-2925.
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Ye Qian, Yue Xu, Qiuyu Zhang, and Changjiang Ying conceived and designed the study. Ye Qian, Yue Xu, Qiuyu Zhang, and Chengyu Huang performed the bioinformatics analysis and data processing. Hui Li, Lin Gao, Shidi Wu, and Chengyu Qi analyzed the data and prepared figures. Ye Qian wrote the first draft of the manuscript. Ye Qian and Changjiang Ying revised the final version of the manuscript. Xiaoyan Zhou, Xiangru Wen, and Changjiang Ying supervised the entire study. All authors read and approved the final manuscript.
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Animal experimental procedures were carried out in accordance with the guidelines described in the 2011 revised Regulations on the Administration of Laboratory Animal Affairs in China and approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University (protocol: 202207S074).
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Qian, Y., Xu, Y., Zhang, Q. et al. Jaranol alleviates cognitive impairment in db/db mice through the PI3K/AKT pathway. Metab Brain Dis 40, 88 (2025). https://doi.org/10.1007/s11011-024-01527-0
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DOI: https://doi.org/10.1007/s11011-024-01527-0