Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64441110.2174/1573409920666230822110258ChemistryResearch ArticleBanxia Xiexin Decoction Prevents HT22 Cells from High Glucose-induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling PathwayShiYinliinfo@benthamscience.netShengPeiinfo@benthamscience.netGuoMinginfo@benthamscience.netChenKaiinfo@benthamscience.netZhaoYuninfo@benthamscience.netWangXuinfo@benthamscience.netWuMianhuainfo@benthamscience.netLiBoinfo@benthamscience.netThe First Clinical Medical College, Nanjing University of Chinese Medicine, Zhongda Hospital Southeast University, Southeast University0106202420691192707012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/644411

Background:Type 2 diabetes-associated cognitive dysfunction (DCD) is a chronic complication of diabetes that has gained international attention. The medicinal compound Banxia Xiexin Decoction (BXXXD) from traditional Chinese medicine (TCM) has shown potential in improving insulin resistance, regulating endoplasmic reticulum stress (ERS), and inhibiting cell apoptosis through various pathways. However, the specific mechanism of action and medical value of BXXXD remain unclear.

Methods:We utilized TCMSP databases to screen the chemical constituents of BXXXD and identified DCD disease targets through relevant databases. By using Stitch and String databases, we imported the data into Cytoscape 3.8.0 software to construct a protein-protein interaction (PPI) network and subsequently identified core targets through network topology analysis. The core targets were subjected to Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The results were further validated through in vitro experiments.

Results:Network pharmacology analysis revealed the screening of 1490 DCD-related targets and 190 agents present in BXXXD. The topological analysis and enrichment analysis conducted using Cytoscape software identified 34 core targets. Additionally, GO and KEGG pathway analyses yielded 104 biological targets and 97 pathways, respectively. BXXXD exhibited its potential in treating DCD by controlling synaptic plasticity and conduction, suppressing apoptosis, reducing inflammation, and acting as an antioxidant. In a high glucose (HG) environment, the expression of JNK, Foxo3a, SIRT1, ATG7, Lamp2, and LC3 was downregulated. BXXXD intervention on HT22 cells potentially involved inhibiting excessive oxidative stress, promoting neuronal autophagy, and increasing the expression levels of JNK, SIRT1, Foxo3a, ATG7, Lamp2, and LC3. Furthermore, the neuroprotective effect of BXXXD was partially blocked by SP600125, while quercetin enhanced the favorable role of BXXXD in the HG environment.

Conclusion:BXXXD exerts its effects on DCD through multiple components, targets, levels, and pathways. It modulates the JNK/SIRT1/Foxo3a signaling pathway to mitigate autophagy inhibition and apoptotic damage in HT22 cells induced by HG. These findings provide valuable perspectives and concepts for future clinical trials and fundamental research.

Banxia Xiexin decoctionbioinformaticsautophagyapoptosisdiabetic cognitive dysfunctionJNK/SIRT1/Foxo3a.Brody, H. Diabetes. Nature, 2012, 485(7398), S1. doi: 10.1038/485S1a PMID: 22616093The Lancet. Diabetes: A dynamic disease. Lancet, 2017, 389(10085), 2163. doi: 10.1016/S0140-6736(17)31537-4 PMID: 28589879Banks, W.A.; Owen, J.B.; Erickson, M.A. Insulin in the brain: There and back again. Pharmacol. Ther., 2012, 136(1), 82-93. doi: 10.1016/j.pharmthera.2012.07.006 PMID: 22820012Hamed, S.A. Brain injury with diabetes mellitus: Evidence, mechanisms and treatment implications. Expert Rev. Clin. Pharmacol., 2017, 10(4), 409-428. doi: 10.1080/17512433.2017.1293521 PMID: 28276776Han, N.; Kim, Y.J.; Park, S.M.; Kim, S.M.; Lee, J.S.; Jung, H.S.; Lee, E.J.; Kim, T.K.; Kim, T.N.; Kwon, M.J.; Lee, S.H.; Kim, M.; Rhee, B.D.; Park, J.H. Repeated glucose deprivation/reperfusion induced PC-12 cell death through the involvement of foxo transcription factor. Diabetes Metab. J., 2016, 40(5), 396-405. doi: 10.4093/dmj.2016.40.5.396 PMID: 27766247Zhang, Y.; Wu, Q.; Zhang, L.; Wang, Q.; Yang, Z.; Liu, J.; Feng, L. Caffeic acid reduces A53T α-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson’s disease. Pharmacol. Res., 2019, 150(12), 104538. doi: 10.1016/j.phrs.2019.104538 PMID: 31707034Hu, Q.; Wang, G.; Peng, J.; Qian, G.; Jiang, W.; Xie, C.; Xiao, Y.; Wang, X. Knockdown of SIRT1 suppresses bladder cancer cell proliferation and migration and induces cell cycle arrest and antioxidant response through FOXO3a-mediated pathways. BioMed Res. Int., 2017, 2017(9), 1-14. doi: 10.1155/2017/3781904 PMID: 29147649Chen, G.; Yang, Y.; Liu, M.; Teng, Z.; Ye, J.; Xu, Y.; Cai, X.; Cheng, X.; Yang, J.; Hu, C.; Wang, M.; Cao, P. Banxia xiexin decoction protects against dextran sulfate sodium-induced chronic ulcerative colitis in mice. J. Ethnopharmacol., 2015, 166(5), 149-156. doi: 10.1016/j.jep.2015.03.027 PMID: 25794808Shinjyo, N.; Parkinson, J.; Bell, J.; Katsuno, T.; Bligh, A. Berberine for prevention of dementia associated with diabetes and its comorbidities: A systematic review. J. Integr. Med., 2020, 18(2), 125-151. doi: 10.1016/j.joim.2020.01.004 PMID: 32005442Choi, J.; Kim, T.H.; Choi, T.Y.; Lee, M.S. Ginseng for health care: A systematic review of randomized controlled trials in Korean literature. PLoS One, 2013, 8(4), e59978. doi: 10.1371/journal.pone.0059978 PMID: 23560064Chen, F.; He, Y.; Wang, P.; Wei, P.; Feng, H.; Rao, Y.; Shi, J.; Tian, J. Banxia Xiexin decoction ameliorated cognition via the regulation of insulin pathways and glucose transporters in the hippocampus of APPswe/PS1dE9 mice. Int. J. Immunopathol. Pharmacol., 2018, 32(12) doi: 10.1177/2058738418780066 PMID: 29873261Li, X.H.; Xu, J.Y.; Wang, X.; Liao, L.J.; Huang, L.; Huang, Y.Q.; Zhang, Z.F. BanXiaXieXin decoction treating gastritis mice with drug-resistant Helicobacter pylori and its mechanism. World J. Gastroenterol., 2023, 29(18), 2818-2835. doi: 10.3748/wjg.v29.i18.2818 PMID: 37274067Wang, X.; Yang, J.; Cao, Q.; Tang, J. Therapeutic efficacy and mechanism of water-soluble extracts of Banxiaxiexin decoction on BALB/c mice with oxazolone-induced colitis. Exp. Ther. Med., 2014, 8(4), 1201-1204. doi: 10.3892/etm.2014.1890 PMID: 25187824Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6(1), 13. doi: 10.1186/1758-2946-6-13 PMID: 24735618Song, W.; Ni, S.; Fu, Y.; Wang, Y. Uncovering the mechanism of Maxing Ganshi Decoction on asthma from a systematic perspective: A network pharmacology study. Sci. Rep., 2018, 8(1), 17362. doi: 10.1038/s41598-018-35791-9 PMID: 30478434Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; Mering, C. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res., 2019, 47(D1), D607-D613. doi: 10.1093/nar/gky1131 PMID: 30476243Zheng, S.; Baak, J.P.; Li, S.; Xiao, W.; Ren, H.; Yang, H.; Gan, Y.; Wen, C. Network pharmacology analysis of the therapeutic mechanisms of the traditional Chinese herbal formula Lian Hua Qing Wen in Corona virus disease 2019 (COVID-19), gives fundamental support to the clinical use of LHQW. Phytomedicine, 2020, 79(12), 153336. doi: 10.1016/j.phymed.2020.153336 PMID: 32949888Huang, D.W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57. doi: 10.1038/nprot.2008.211 PMID: 19131956Walter, W.; Sánchez-Cabo, F.; Ricote, M. GOplot: An R package for visually combining expression data with functional analysis. Bioinformatics, 2015, 31(17), 2912-2914. doi: 10.1093/bioinformatics/btv300 PMID: 25964631Murphy, T.H.; Miyamoto, M.; Sastre, A.; Schnaar, R.L.; Coyle, J.T. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron, 1989, 2(6), 1547-1558. doi: 10.1016/0896-6273(89)90043-3 PMID: 2576375Bennett, B.L.; Sasaki, D.T.; Murray, B.W.; O’Leary, E.C.; Sakata, S.T.; Xu, W.; Leisten, J.C.; Motiwala, A.; Pierce, S.; Satoh, Y.; Bhagwat, S.S.; Manning, A.M.; Anderson, D.W. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci., 2001, 98(24), 13681-13686. doi: 10.1073/pnas.251194298 PMID: 11717429Costa, L.G.; Garrick, J.M.; Roquè, P.J.; Pellacani, C. Mechanisms of neuroprotection by quercetin: Counteracting oxidative stress and more. Oxid. Med. Cell. Longev., 2016, 2016(1), 1-10. doi: 10.1155/2016/2986796 PMID: 26904161Hu, Y.; Zhou, Y.; Yang, Y.; Tang, H.; Si, Y.; Chen, Z.; Shi, Y.; Fang, H. Metformin protects against diabetes-induced cognitive dysfunction by inhibiting mitochondrial fission protein DRP1. Front. Pharmacol., 2022, 13(3), 832707. doi: 10.3389/fphar.2022.832707 PMID: 35392573Yin, Q.; Ma, J.; Han, X.; Zhang, H.; Wang, F.; Zhuang, P.; Zhang, Y. Spatiotemporal variations of vascular endothelial growth factor in the brain of diabetic cognitive impairment. Pharmacol. Res., 2021, 163(1), 105234. doi: 10.1016/j.phrs.2020.105234 PMID: 33053446Chen, J.L.; Luo, C.; Pu, D.; Zhang, G.Q.; Zhao, Y.X.; Sun, Y.; Zhao, K.X.; Liao, Z.Y.; Lv, A.K.; Zhu, S.Y.; Zhou, J.; Xiao, Q. Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance. Exp. Neurol., 2019, 311(1), 44-56. doi: 10.1016/j.expneurol.2018.09.008 PMID: 30219731Cukierman-Yaffe, T.; Gerstein, H.C.; Colhoun, H.M.; Diaz, R.; García-Pérez, L.E.; Lakshmanan, M.; Bethel, A.; Xavier, D.; Probstfield, J.; Riddle, M.C.; Rydén, L.; Atisso, C.M.; Hall, S.; Rao-Melacini, P.; Basile, J.; Cushman, W.C.; Franek, E.; Keltai, M.; Lanas, F.; Leiter, L.A.; Lopez-Jaramillo, P.; Pirags, V.; Pogosova, N.; Raubenheimer, P.J.; Shaw, J.E.; Sheu, W.H.H.; Temelkova-Kurktschiev, T. Effect of dulaglutide on cognitive impairment in type 2 diabetes: An exploratory analysis of the REWIND trial. Lancet Neurol., 2020, 19(7), 582-590. doi: 10.1016/S1474-4422(20)30173-3 PMID: 32562683Wang, B.; Zeng, K.W.; Hong, Z.F.; Ti, G.X.; Wang, L.Y.; Lu, P.; Liu, Z. Banxia xiexin decoction () treats diabetic gastroparesis through PLC-IP3-Ca2+/NO-cGMP-PKG signal pathway. Chin. J. Integr. Med., 2020, 26(11), 833-838. doi: 10.1007/s11655-020-3077-8 PMID: 32418177Chornenkyy, Y.; Wang, W.X.; Wei, A.; Nelson, P.T. Alzheimer’s disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline. Brain Pathol., 2019, 29(1), 3-17. doi: 10.1111/bpa.12655 PMID: 30106209Wang, Q.S.; Luo, X.Y.; Fu, H.; Luo, Q.; Wang, M.Q.; Zou, D.Y. MiR-139 protects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced nerve injury through targeting c-Jun to inhibit NLRP3 inflammasome activation. J. Stroke Cerebrovasc. Dis., 2020, 29(9), 105037. doi: 10.1016/j.jstrokecerebrovasdis.2020.105037 PMID: 32807449Ebrahimpour, S.; Shahidi, S.B.; Abbasi, M.; Tavakoli, Z.; Esmaeili, A. Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) increases Nrf2 expression via miR-27a mediation to prevent memory dysfunction in diabetic rats. Sci. Rep., 2020, 10(1), 15957. doi: 10.1038/s41598-020-71971-2 PMID: 32994439Savage, D.B.; Tan, G.D.; Acerini, C.L.; Jebb, S.A.; Agostini, M.; Gurnell, M.; Williams, R.L.; Umpleby, A.M.; Thomas, E.L.; Bell, J.D.; Dixon, A.K.; Dunne, F.; Boiani, R.; Cinti, S.; Vidal-Puig, A.; Karpe, F.; Chatterjee, V.K.K.; O’Rahilly, S. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes, 2003, 52(4), 910-917. doi: 10.2337/diabetes.52.4.910 PMID: 12663460Enciu, A.M.; Gherghiceanu, M.; Popescu, B.O. Triggers and effectors of oxidative stress at blood-brain barrier level: Relevance for brain ageing and neurodegeneration. Oxid. Med. Cell. Longev., 2013, 2013(3), 1-12. doi: 10.1155/2013/297512 PMID: 23533687Yuan, Z.; Gong, S.; Luo, J.; Zheng, Z.; Song, B.; Ma, S.; Guo, J.; Hu, C.; Thiel, G.; Vinson, C.; Hu, C.D.; Wang, Y.; Li, M. Opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis. Mol. Cell. Biol., 2009, 29(9), 2431-2442. doi: 10.1128/MCB.01344-08 PMID: 19255142Sun, Q.; Zeng, Q.C.; Chen, Y.Q.; Zhang, M.; Wei, L.L.; Chen, P. Long intergenic noncoding RNA p21 suppresses the apoptosis of hippocampus neurons in streptozotocin-diabetic mice by sponging microRNA-221 through upregulation of FOS. J. Cell. Physiol., 2019, 234(11), 21113-21125. doi: 10.1002/jcp.28714 PMID: 31081202Kitagishi, Y.; Nakanishi, A.; Ogura, Y.; Matsuda, S. Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease. Alzheimers Res. Ther., 2014, 6(3), 35. doi: 10.1186/alzrt265 PMID: 25031641Zalckvar, E.; Yosef, N.; Reef, S.; Ber, Y.; Rubinstein, A.D.; Mor, I.; Sharan, R.; Ruppin, E.; Kimchi, A. A systems level strategy for analyzing the cell death network: Implication in exploring the apoptosis/autophagy connection. Cell Death Differ., 2010, 17(8), 1244-1253. doi: 10.1038/cdd.2010.7 PMID: 20150916Li, X.; He, S.; Ma, B. Autophagy and autophagy-related proteins in cancer. Mol. Cancer, 2020, 19(1), 12. doi: 10.1186/s12943-020-1138-4 PMID: 31969156Jing, G.C.; Liu, D.; Liu, Y.Q.; Zhang, M.R. Nao-Fu-Cong ameliorates diabetic cognitive dysfunction by inhibition of JNK/CHOP/Bcl2-mediated apoptosis in vivo and in vitro. Chin. J. Nat. Med., 2020, 18(9), 704-713. doi: 10.1016/S1875-5364(20)60009-7 PMID: 32928514Lim, C.J.; Lee, Y.M.; Kang, S.G.; Lim, H.W.; Shin, K.O.; Jeong, S.K.; Huh, Y.H.; Choi, S.; Kor, M.; Seo, H.S.; Park, B.D.; Park, K.; Ahn, J.K.; Uchida, Y.; Park, K. Aquatide activation of SIRT1 reduces cellular senescence through a SIRT1-FOXO1-autophagy axis. Biomol. Ther., 2017, 25(5), 511-518. doi: 10.4062/biomolther.2017.119 PMID: 28822991Li, Y.; Shen, G.; Yu, C.; Li, G.; Shen, J.; Gong, J.; Xu, Y. Angiotensin II induces mitochondrial oxidative stress and mtDNA damage in osteoblasts by inhibiting SIRT1–FoxO3a–MnSOD pathway. Biochem. Biophys. Res. Commun., 2014, 455(1-2), 113-118. doi: 10.1016/j.bbrc.2014.10.123 PMID: 25450701Sang, Y.; Li, W.; Zhang, G. The protective effect of resveratrol against cytotoxicity induced by mycotoxin, zearalenone. Food Funct., 2016, 7(9), 3703-3715. doi: 10.1039/C6FO00191B PMID: 27489133Zhu, Y.; Ding, A.; Yang, D.; Cui, T.; Yang, H.; Zhang, H.; Wang, C. CYP2J2-produced epoxyeicosatrienoic acids attenuate ischemia/reperfusion-induced acute kidney injury by activating the SIRT1-FoxO3a pathway. Life Sci., 2020, 246(4), 117327. doi: 10.1016/j.lfs.2020.117327 PMID: 31954161