Banxia Xiexin Decoction Prevents HT22 Cells from High Glucose-induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling Pathway


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Abstract

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.

About the authors

Yinli Shi

The First Clinical Medical College, Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Pei Sheng

The First Clinical Medical College, Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Ming Guo

, Zhongda Hospital Southeast University, Southeast University

Email: info@benthamscience.net

Kai Chen

The First Clinical Medical College, Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Yun Zhao

The First Clinical Medical College, Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Xu Wang

The First Clinical Medical College, Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Mianhua Wu

The First Clinical Medical College, Nanjing University of Chinese Medicine

Email: info@benthamscience.net

Bo Li

The First Clinical Medical College, Nanjing University of Chinese Medicine

Author for correspondence.
Email: info@benthamscience.net

References

  1. Brody, H. Diabetes. Nature, 2012, 485(7398), S1. doi: 10.1038/485S1a PMID: 22616093
  2. The Lancet. Diabetes: A dynamic disease. Lancet, 2017, 389(10085), 2163. doi: 10.1016/S0140-6736(17)31537-4 PMID: 28589879
  3. Banks, 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: 22820012
  4. Hamed, 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: 28276776
  5. Han, 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: 27766247
  6. Zhang, 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: 31707034
  7. Hu, 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: 29147649
  8. Chen, 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: 25794808
  9. Shinjyo, 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: 32005442
  10. Choi, 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: 23560064
  11. Chen, 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: 29873261
  12. Li, 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: 37274067
  13. Wang, 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: 25187824
  14. Ru, 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: 24735618
  15. Song, 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: 30478434
  16. Szklarczyk, 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: 30476243
  17. Zheng, 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: 32949888
  18. Huang, 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: 19131956
  19. Walter, 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: 25964631
  20. Murphy, 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: 2576375
  21. Bennett, 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: 11717429
  22. Costa, 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: 26904161
  23. Hu, 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: 35392573
  24. Yin, 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: 33053446
  25. Chen, 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: 30219731
  26. Cukierman-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: 32562683
  27. Wang, 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: 32418177
  28. Chornenkyy, 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: 30106209
  29. Wang, 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: 32807449
  30. Ebrahimpour, 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: 32994439
  31. Savage, 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: 12663460
  32. Enciu, 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: 23533687
  33. Yuan, 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: 19255142
  34. Sun, 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: 31081202
  35. Kitagishi, 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: 25031641
  36. Zalckvar, 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: 20150916
  37. Li, 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: 31969156
  38. Jing, 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: 32928514
  39. Lim, 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: 28822991
  40. Li, 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: 25450701
  41. Sang, 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: 27489133
  42. Zhu, 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

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