The Journal of Korean Medicine (대한한의학회지)

The Society of Korean Medicine (대한한의학회)
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Exploration of the Potential and Mechanisms of Diabetic Cognitive Disorder Modulation by Daehwangmokdanpi-tang through a Network Pharmacological Approach

네트워크 약리학적 접근을 통한 대황목단피탕(大黃牧丹皮湯)의 당뇨병성 인지장애 조절 가능성 및 기전 탐색

  • Yebin Lim (Department of Pharmacology, College of Korean Medicine, Wonkwang University) ;
  • Bitna Kweon (Department of Pharmacology, College of Korean Medicine, Wonkwang University) ;
  • Dong-Uk Kim (Department of Pharmacology, College of Korean Medicine, Wonkwang University) ;
  • Do-Eun Lee (Department of Korean Neuropsychiatry Medicine, College of Korean Medicine, Wonkwang University) ;
  • Jungtae Leem (Research center of Traditional Korean medicine, Wonkwang University) ;
  • Dong-Gu Kim (Department of Herbology, College of Korean Medicine, Dong-Eui University) ;
  • Hyung Won Kang (Department of Korean Neuropsychiatry Medicine, College of Korean Medicine, Wonkwang University) ;
  • Gi-Sang Bae (Department of Pharmacology, College of Korean Medicine, Wonkwang University)
  • 임예빈 (원광대학교 한의과대학 약리학교실) ;
  • 권빛나 (원광대학교 한의과대학 약리학교실) ;
  • 김동욱 (원광대학교 한의과대학 약리학교실) ;
  • 이도은 (원광대학교 한의과대학 한방신경정신과학교실) ;
  • 임정태 (원광대학교 한국전통의학연구소) ;
  • 김동구 (동의대학교 한의과대학 본초학교실) ;
  • 강형원 (원광대학교 한의과대학 한방신경정신과학교실) ;
  • 배기상 (원광대학교 한의과대학 약리학교실)
  • Received : 2024.04.15
  • Accepted : 2024.05.07
  • Published : 2024.06.01
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Abstract

Objectives: This study utilized a network pharmacology approach to investigate the potential therapeutic effects and underlying mechanisms of Daehwangmokdanpi-tang (DHMDPT) in diabetic cognitive disorder (DCD). Methods: The compounds of DHMDPT and their target genes were obtained from the OASIS and PubChem databases. These putative target genes were compared with known targets of DCD to identify potential correlations. Using Cytoscape 3.10.2, a network was constructed to highlight key target genes. To further elucidate the underlying mechanisms, functional enrichment analysis was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Finally, CB-DOCK was used to assess binding affinities and confirm the interactions. Results: The results showed that a total of 27 compounds and 439 related genes were identified from DHMDPT. Among these, 373 genes interacted with the DCD gene set, indicating a close relationship between the effects of DHMDPT and DCD. Through GO enrichment analysis and KEGG pathways, 'Regulation of Apoptotic Process', 'Cytokine-Mediated signaling pathway', and 'AGE-RAGE signaling pathway in diabetic complications' were identified as the functional pathways of the 18 key target genes of DHMDPT on DCD. Additionally, molecular docking was performed to assess the binding affinities of the six most highly associated key target genes of DCD with active compounds. Conclusions: Using a network pharmacology approach, which included molecular docking, DHMDPT was found to be highly relevant to DCD. This study could serve as a foundation for further research on the cognitive enhancement effects of DHMDPT in DCD.

Keywords

Acknowledgement

본 연구는 보건복지부의 재원으로 한국보건산업진흥원의 보건의료기술(과제고유번호: HF20C0212)과 정부(교육부)의 재원으로 한국연구재단의 지원을 받아 수행된 연구임(NRF-2021R1I1A2053285/RS-2023-00248483).

References

  1. Pranata S, Wu S-FV, Alizargar J, Liu J-H, Liang S-Y, Lu Y-Y. (2021) Precision health care elements, definitions, and strategies for patients with diabetes: A literature review. International Journal of Environmental Research and Public Health, 18(12), 6535. https://doi.org/10.3390/ijerph181265351.
  2. Kim J, Son C, Cho C, Kim C. (2010) Review of Randomized Controlled Clinical Trials Targeting Treatment of Diabetic Peripheral Neuropathy. Journal of Korean Medicine, 31(4), 164-170.
  3. Kang S-B. (1998) The Comparative Study between the Transformations of Sogal and the Complications of Diabetes Mellitus. Journal of Korean Oriental Medicine, 19(2), 137-152.
  4. Li H, Ren J, Li Y, Wu Q, Wei J. (2023) Oxidative stress: The nexus of obesity and cognitive dysfunction in diabetes. 14. https://doi.org/10.3389/fendo.2023.1134025
  5. Kodl CT, Seaquist ER. (2008) Cognitive Dysfunction and Diabetes Mellitus. Endocrine Reviews, 29(4), 494-511. https://doi.org/10.1210/er.2007-0034
  6. Ninomiya T. (2019) Epidemiological evidence of the relationship between diabetes and dementia. Diabetes Mellitus: A risk factor for Alzheimer's Disease, 13-25.
  7. Kawamura T, Umemura T, Hotta N. (2012) Cognitive impairment in diabetic patients: Can diabetic control prevent cognitive decline? Journal of Diabetes Investigation, 3(5), 413-423. https://doi.org/10.1111/j.2040-1124.2012.00234.x
  8. Sadeghi A, Hami J, Razavi S, Esfandiary E, Hejazi Z. (2016) The Effect of Diabetes Mellitus on Apoptosis in Hippocampus: Cellular and Molecular Aspects. International journal of preventive medicine, 7, 57. https://doi.org/10.4103/2008-7802.178531
  9. Guan D, Lewis MO, Li P, Zhang Y, Zhang P, Tang S et al. (2024) Incremental burden on health-related quality of life, health service utilization and direct medical expenditures associated with cognitive impairment among non-institutionalized people with diabetes aged 65 years and older. Diabetes, Obesity and Metabolism, 26(1), 275-282. https://doi.org/10.1111/dom.15313
  10. Chan-hee J, Ji-oh M. (2022) Cognitive Dysfuntion and Diabetes. The Journal of Korean Diabetes, 23(3), 165-177. https://doi.org/10.4093/jkd.2022.23.3.165
  11. Umegaki H. (2016) Therapeutic potential of antidiabetic medications in the treatment of cognitive dysfunction and dementia. Drugs & aging, 33, 399-409. https://doi.org/10.1007/s40266-016-0375-0
  12. Han SY, Kim YK. (2016) New approach for herbal formula research: Network pharmacology. The Physiological Society of Korean Medicine and The Society of Pathology in Korean Medicine, 30(6), 385-396. https://doi.org/10.15188/kjopp.2016.12.30.6.385
  13. Hopkins AL. (2008) Network pharmacology: the next paradigm in drug discovery. J Nature chemical biology, 4(11), 682-690.
  14. Nabirotchkin S, Peluffo AE, Rinaudo P, Yu J, Hajj R, Cohen D. (2020) Next-generation drug repurposing using human genetics and network biology. J Current Opinion in Pharmacology, 51, 78-92. https://doi.org/10.1016/j.coph.2019.12.004
  15. Rao RV, Subramaniam KG, Gregory J, Bredesen AL, Coward C, Okada S et al. (2023) Rationale for a multi-factorial approach for the reversal of cognitive decline in Alzheimer's disease and MCI: a review. J International Journal of Molecular Sciences, 24(2), 1659. https://doi.org/10.3390/ijms24021659
  16. Kumar B, Thakur A, Dwivedi AR, Kumar R, Kumar V. (2022) Multi-target-directed ligands as an effective strategy for the treatment of Alzheimer's disease. J Current Medicinal Chemistry, 29(10), 1757-1803. https://doi.org/10.2174/0929867328666210512005508
  17. Young-Gab Y.(1998). 東醫方劑와 處方解說.(vol. 1. Republic of Korea: Kim Jun-Su.
  18. Lee S-E. (2023) Antioxidative and Anti-inflammatory Effects of Daehwangmokdanphee-tang. Journal of the Korean Society of Cosmetology, 29, 1190-1198. https://doi.org/10.52660/JKSC.2023.29.5.1190
  19. Sung-Joo Park J-GJ, Sang-Wan Seo, Sang-Wook Hwang, Yong-Woo Kim, Dal-Soo Song, Young-Seok Chae, Min-Kyo Shin, Ho-Joon Song. (2005) Effects of Gami-Daehwangmokdanpi-Tang against CCK-induced acute pancreatitis. The Korea Journal of Herbology, 20(03), 59-65.
  20. Bitna K, Dong-uk K, Gabsik Y, Il-joo J. (2023) Prediction the efficacy and mechanism of action of Dawhwangmokdanpitang to treat psoriasis based on network pharmacology. The Korea Journal of Herbology, 38(6), 73-91. http://dx.doi.org/10.6116/kjh.2023.38.6.73
  21. APA.(2015). Diagnostic and Statistical Manual of Mental Disorders.(5th ed.). Korea: Hakjisa.
  22. Yang W, Kim JK, Park KW, Suh S, Lee H-J, Park M-K. (2020) Correlation between Peripheral Neuropathy and Cognitive Factors in Type 2 Diabetic Patients. Journal of Life Science, 30(3), 250-259. https://doi.org/10.5352/JLS.2020.30.3.250
  23. Sims-Robinson C, Kim B, Feldman EL: Diabetes and cognitive dysfunction. In: Neurobiology of Brain Disorders. Elsevier; 2015: 189-201.
  24. Varghese SM, Joy N, John AM, George G, Chandy GM, Benjamin AI. (2022) Sweet memories or not? A comparative study on cognitive impairment in diabetes mellitus. Frontiers in Public Health, 10, 822062. https://doi.org/10.3389/fpubh.2022.822062
  25. Han E, Lee J-Y, Han K-d, Cho H, Kim KJ, Lee B-W et al. (2020) Gamma glutamyltransferase and risk of dementia in prediabetes and diabetes. Scientific reports, 10(1), 6800. https://doi.org/10.1038/s41598-020-63803-0
  26. Lee YJ, Kang HM, Kim NK, Yang JY, Noh JH, Ko KS et al. (2014) Factors associated for mild cognitive impairment in older Korean adults with type 2 diabetes mellitus. Diabetes & Metabolism Journal, 38(2), 150. https://doi.org/10.4093/dmj.2014.38.2.150
  27. Biessels GJ, Whitmer RA. (2020) Cognitive dysfunction in diabetes: how to implement emerging guidelines. Diabetologia, 63(1), 3-9. https://doi.org/10.1007/s00125-019-04977-9
  28. Yin Q, Gao Y, Wang X, Li S, Hou X, Bi W. (2023) China should emphasize understanding and standardized management in diabetic cognitive dysfunction. Frontiers in Endocrinology, 14. https://doi.org/10.3389/fendo.2023.1195962
  29. Pan G, Chai L, Chen R, Yuan Q, Song Z, Feng W et al. (2024) Potential mechanism of Qinggong Shoutao pill alleviating age-associated memory decline based on integration strategy. Pharm Biol, 62(1), 105-119. http://doi.org/10.1080/13880209.2023.2291689
  30. Chen J, Zhang T, Luo Q, Wang R, Dai Y, Chen Z et al. (2024) Network pharmacology combined with experimental validation to investigate the effect of Rongjin Niantong Fang on chondrocyte apoptosis in knee osteoarthritis. Mol Med Rep, 29(6). https://doi.org/10.3892/mmr.2024.13226
  31. Wu T, Zhang H, Jin Y, Zhang M, Zhao Q, Li H et al. (2024) The active components and potential mechanisms of Wuji Wan in the treatment of ethanol-induced gastric ulcer: An integrated metabolomics, network pharmacology and experimental validation. Journal of ethnopharmacology, 326, 117901. https://doi.org/10.1016/j.jep.2024.117901
  32. Sung-Ha Myung Y-SK. (2005) Anti-Oxidative and Neuroprotective Effects of Rhei Rhizoma on BV-2 Microglia Cells and Hippocampal Neurons. The Korean Journal of Oriental Physiology & Pathology, 19(03), 647-655.
  33. Won-Chul L. (2003) Effect of Rhei Rhizoma on HSP70 Expression and Ischemic Damaged Hippocampus of the Aged BCAO Rats. J of Oriental Chr Dis, 91, 21-29.
  34. Moon S, Seon K, Lim J, Song B. (2009) The Effect of the Moutan Radicis Cortex on Expression of CD81 and GFAP in Injured Astrocyte. the Journal of Internal Korean Medicine, 30(1), 24-35.
  35. Chen W, Liu Q, Gao X, Geng Y, Kan H. (2024) Observational study on the potential mechanism of Sanao decoction in the treatment of asthma based on network pharmacology and molecular docking. Medicine, 103(12), e37592. https://doi.org/10.1097/MD.0000000000037592
  36. Piperi C, Goumenos A, Adamopoulos C, Papavassiliou AG. (2015) AGE/RAGE signalling regulation by miRNAs: associations with diabetic complications and therapeutic potential. J The international journal of biochemistry cell biology, 60, 197-201. https://doi.org/10.1016/j.biocel.2015.01.009
  37. Derk J, MacLean M, Juranek J, Schmidt AM. (2018) The receptor for advanced glycation endproducts (RAGE) and mediation of inflammatory neurodegeneration. J Journal of Alzheimer's disease Parkinsonism, 8(1). https://doi.org/10.4172/2161-0460.1000421
  38. Erekat NS. (2022) Apoptosis and its therapeutic implications in neurodegenerative diseases. J Clinical Anatomy, 35(1), 65-78. https://doi.org/10.1002/ca.23792
  39. Waghela BN, Vaidya FU, Ranjan K, Chhipa AS, Tiwari BS, Pathak C. (2021) AGE-RAGE synergy influences programmed cell death signaling to promote cancer. J Molecular & Cellular Biochemistry, 476, 585-598. https://doi.org/10.1007/s11010-020-03928-y
  40. Piras S, Furfaro A, Domenicotti C, Traverso N, Marinari U, Pronzato M, Nitti M. (2016) RAGE expression and ROS generation in neurons: differentiation versus damage. J Oxidative medicine cellular longevity, 2016. https://doi.org/10.1155/2016/9348651
  41. Taguchi K, Fukami K. (2023) RAGE signaling regulates the progression of diabetic complications. J Frontiers in Pharmacology, 14, 1128872. https://doi.org/10.3389/fphar.2023.1128872
  42. Marioni RE, Strachan MW, Reynolds RM, Lowe GD, Mitchell RJ, Fowkes FGR et al. (2010) Association between raised inflammatory markers and cognitive decline in elderly people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. J Diabetes, 59(3), 710-713. https://doi.org/10.2337/db09-1163
  43. Geng J, Wang L, Zhang L, Qin C, Song Y, Ma Y et al. (2018) Blood-brain barrier disruption induced cognitive impairment is associated with increase of inflammatory cytokine. J Frontiers in aging neuroscience, 10, 129. https://doi.org/10.3389/fnagi.2018.00129
  44. Liu H, Guo D, Wang J, Zhang W, Zhu Z, Zhu K et al. (2024) Aloe-emodin from Sanhua Decoction inhibits neuroinflammation by regulating microglia polarization after subarachnoid hemorrhage. Journal of ethnopharmacology, 322, 117583. https://doi.org/10.1016/j.jep.2023.117583
  45. Hu B, Zhang H, Meng X, Wang F, Wang P. (2014) Aloe-emodin from rhubarb (Rheum rhabarbarum) inhibits lipopolysaccharide-induced inflammatory responses in RAW264. 7 macrophages. Journal of ethnopharmacology, 153(3), 846-853. https://doi.org/10.1016/j.jep.2014.03.059
  46. Kuhad A, Bishnoi M, Tiwari V, Chopra K. (2009) Suppression of NF-κβ signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacology Biochemistry and Behavior, 92(2), 251-259. https://doi.org/10.1016/j.pbb.2008.12.012
  47. Ghasemi R, Zarifkar A, Rastegar K, Moosavi M. (2014) Insulin protects against Aβ-induced spatial memory impairment, hippocampal apoptosis and MAPKs signaling disruption. Neuropharmacology, 85, 113-120. https://doi.org/10.1016/j.neuropharm.2014.01.036
  48. Maiti P, Singh SB, Mallick B, Muthuraju S, Ilavazhagan G. (2008) High altitude memory impairment is due to neuronal apoptosis in hippocampus, cortex and striatum. J Journal of chemical neuroanatomy, 36(3-4), 227-238. https://doi.org/10.1016/j.jchemneu.2008.07.003
  49. Jafari Anarkooli I, Sankian M, Ahmadpour S, Varasteh A-R, Haghir H. (2008) Evaluation of Bcl-2 family gene expression and Caspase-3 activity in hippocampus STZ-induced diabetic rats. Journal of Diabetes Research, 2008. https://doi.org/10.1155/2008/638467
  50. Liu Z, Kumar M, Kabra A. (2022) Cucurbitacin B exerts neuroprotection in a murine Alzheimer's disease model by modulating oxidative stress, inflammation, and neurotransmitter levels. J Frontiers in Bioscience-Landmark, 27(2), 71. https://doi.org/10.31083/j.fbl2702071
  51. Zhao W-Q, Chen H, Quon MJ, Alkon DL. (2004) Insulin and the insulin receptor in experimental models of learning and memory. European journal of pharmacology, 490(1-3), 71-81. https://doi.org/10.1016/j.ejphar.2004.02.045
  52. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang H-Y, Ahima RS et al. (2018) Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nature Reviews Neurology, 14(3), 168-181. https://doi.org/10.1038/nrneurol.2017.185
  53. Kim B, Feldman EL. (2015) Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome. J Experimental molecular medicine, 47(3), e149-e149. https://doi.org/10.1038/emm.2015.3
  54. Banu GS. (2017) Cucurbitacin augments insulin sensitivity and glucose uptake through translocation and activation of GLUT-4 in PI3K/ALT signalling pathway. J World Journal of Pharmaceutical Research, 6, 1078-1096. https://doi.org/10.20959/wjpr20178-8924
  55. Cao Y, Chang S, Dong J, Zhu S, Zheng X, Li J et al. (2016) Emodin ameliorates high-fat-diet induced insulin resistance in rats by reducing lipid accumulation in skeletal muscle. J European Journal of Pharmacology, 780, 194-201. https://doi.org/10.1016/j.ejphar.2016.03.049
  56. Naowaboot J, Piyabhan P, Tingpej P, Munkong N, Parklak W, Pannangpetch P. (2018) Anti-insulin resistant effect of ferulic acid on high fat diet-induced obese mice. J Asian Pacific Journal of Tropical Biomedicine, 8(12), 604-608. http://doi.org/10.4103/2221-1691.248098