Study on the potential molecular mechanism of <i>Rhodiola crenulata</i> for type 2 diabetes mellitus and Alzheimer’s disease based on network pharmacology and molecular docking_West China Medical Journal

Authors：

LUO Ling , HUANG Jialu , YANG Zihua , ZHAO Le , HUANG Ruixian , YU Haibing ,  KONG Danli ,  DING Yuanlin

School of Public Health, Guangdong Medical University, Dongguan, Guangdong, 523808, P. R. China;

Corresponding author：

KONG Danli, Email: kdlgdmu@gdmu.edu.cn; DING Yuanlin, Email: gdmusbd@gdmu.edu.cn

Keywords：

Network pharmacology; molecular docking; Rhodiola Crenulata; type 2 diabetes mellitus; Alzheimer's disease

DOI：

10.7507/1002-0179.202211164

Video：

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Objective To explore the potential molecular mechanism of Rhodiola crenulata (RC) for type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) by network pharmacology and molecular docking. Methods The target genes of T2DM and AD, the effective active components and targets of RC were identified through multiple public databases during March to August, 2022. The main active components and core genes of RC anti T2DM-AD were screened. The key genes were enrichment analyzed by gene ontology function and Kyoto gene and Kyoto Encyclopedia of Genes and Genomes. AutoDock Vina was used for molecular docking and binding energy calculation. Results A total of 5189 T2DM related genes and 1911 AD related genes were obtained, and the intersection result showed that there were 1418 T2DM-AD related genes. There were 48 active components of RC and 617 corresponding target genes. There were 220 crossing genes between RC and T2DM-AD. The main active components of RC anti T2DM-AD included kaempferol, velutin, and crenulatin. The key genes for regulation include ESR1, EGFR, and AKT1, which were mainly enriched in the hypoxia-inducible factor-1 signal pathway, estrogen signal pathway, and vascular endothelial growth factor signal pathway. The docking binding energies of the main active components of RC and key gene molecules were all less than −1.2 kcal/mol (1 kcal=4.2 kJ). Conclusions RC may play a role in influencing T2DM and AD by regulating the hypoxia-inducible factor-1 signaling pathway, estrogen signaling pathway, and vascular endothelial growth factor signaling pathway.

Citation： LUO Ling, HUANG Jialu, YANG Zihua, ZHAO Le, HUANG Ruixian, YU Haibing, KONG Danli, DING Yuanlin. Study on the potential molecular mechanism of Rhodiola crenulata for type 2 diabetes mellitus and Alzheimer’s disease based on network pharmacology and molecular docking. West China Medical Journal, 2023, 38(4): 567-573. doi: 10.7507/1002-0179.202211164 Copy

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2.	Jayaraj RL, Azimullah S, Beiram R. Diabetes as a risk factor for Alzheimer’s disease in the Middle East and its shared pathological mediators. Saudi J Biol Sci, 2020, 27(2): 736-750.
3.	刘敏, 谭丽阳, 张军, 等. 2 型糖尿病与阿尔茨海默病相关性机制的研究进展. 中国老年学杂志, 2019, 34(3): 746-749.
4.	Michailidis M, Moraitou D, Tata DA, et al. Alzheimer’s disease as type 3 diabetes: common pathophysiological mechanisms between Alzheimer’s disease and type 2 diabetes. Int J Mol Sci, 2022, 23(5): 2687.
5.	Takeishi J, Tatewaki Y, Nakase T, et al. Alzheimer’s disease and type 2 diabetes mellitus: the use of MCT oil and a ketogenic diet. Int J Mol Sci, 2021, 22(22): 12310.
6.	Watson GS, Peskind ER, Asthana S, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology, 2003, 60(12): 1899-1903.
7.	中华人民共和国国家药典委员会. 中国药典. 北京: 中国医药科技出版社, 2015: 154-155.
8.	Ma D, Wang L, Jin Y, et al. Application of UHPLC fingerprints combined with chemical pattern recognition analysis in the differentiation of six rhodiola species. Molecules, 2021, 26(22): 6855.
9.	Wang L, Wang Y, Yang W, et al. Network pharmacology and molecular docking analysis on mechanisms of Tibetan Hongjingtian (Rhodiola crenulata) in the treatment of COVID-19. J Med Microbiol, 2021, 70(7): 001374.
10.	Huang LY, Yen IC, Tsai WC, et al. Rhodiola crenulata suppresses high glucose-induced matrix metalloproteinase expression and inflammatory responses by inhibiting ROS-related HMGB1-TLR4 signaling in endothelial cells. Am J Chin Med, 2020, 48(1): 91-105.
11.	王琦, 刘瑜琦. 中药红景天干预阿尔茨海默发病机制的研究进展. 中国中西医结合杂志, 2012, 32(12): 1706-1709.
12.	Zhuang W, Yue L, Dang X, et al. Rosenroot (Rhodiola): potential applications in aging-related diseases. Aging Dis, 2019, 10(1): 134-146.
13.	马韫楠, 吴娅丽, 钟宛凌, 等. 基于网络药理学的地龙平喘作用机制研究. 中国现代中药, 2021, 23(10): 1737-1746.
14.	Wang YY, Huang ZT, Yuan MH, et al. Role of hypoxia inducible factor-1α in Alzheimer’s disease. J Alzheimers Dis, 2021, 80(3): 949-961.
15.	Mitroshina EV, Savyuk MO, Ponimaskin E, et al. Hypoxia-inducible factor (HIF) in ischemic stroke and neurodegenerative disease. Front Cell Dev Biol, 2021, 9: 703084.
16.	Ashok BS, Ajith TA, Sivanesan S. Hypoxia-inducible factors as neuroprotective agent in Alzheimer’s disease. Clin Exp Pharmacol Physiol, 2017, 44(3): 327-334.
17.	Liu N, Cai X, Liu T, et al. Hypoxia-inducible factor-1α mediates the expression of mature β cell-disallowed genes in hypoxia-induced β cell dedifferentiation. Biochem Biophys Res Commun, 2020, 523(2): 382-388.
18.	Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med, 2013, 19(3): 197-209.
19.	Weigt C, Hertrampf T, Flenker U, et al. Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats. J Steroid Biochem Mol Biol, 2015, 154: 12-22.
20.	Martin L, Bouvet P, Chounlamountri N, et al. VEGF counteracts amyloid-β-induced synaptic dysfunction. Cell Rep, 2021, 35(6): 109121.
21.	Yu WY, Sun W, Yu DJ, et al. Adipose-derived stem cells improve neovascularization in ischemic flaps in diabetic mellitus through HIF-1α/VEGF pathway. Eur Rev Med Pharmacol Sci, 2018, 22(1): 10-16.
22.	范羽丰, 谭蓉, 江铃. 大花红景天以生活方式对 27 例 2 型糖尿病患者的治疗评价. 中国现代药物应用, 2007, 1(6): 10-11.
23.	Zhang X, Wang X, Hu X, et al. Neuroprotective effects of a Rhodiola crenulata extract on amyloid-β peptides (Aβ1-42) -induced cognitive deficits in rat models of Alzheimer’s disease. Phytomedicine, 2019, 57: 331-338.
24.	Babaei P, Eyvani K, Kouhestani S. Sex-independent cognition improvement in response to kaempferol in the model of sporadic Alzheimer’s disease. Neurochem Res, 2021, 46(6): 1480-1486.
25.	Zhang N, Xu H, Wang Y, et al. Protective mechanism of kaempferol against Aβ25-35-mediated apoptosis of pheochromocytoma (PC-12) cells through the ER/ERK/MAPK signalling pathway. Arch Med Sci, 2020, 17(2): 406-416.
26.	吴巧敏, 卢笑, 倪海祥. 山奈酚防治 2 型糖尿病研究进展. 浙江中西医结合杂志, 2017, 27(4): 344-349.
27.	Xie C, Kang J, Li Z, et al. The açaí flavonoid velutin is a potent anti-inflammatory agent: blockade of LPS-mediated TNF-α and IL-6 production through inhibiting NF-κB activation and MAPK pathway. J Nutr Biochem, 2012, 23(9): 1184-1191.
28.	Lee D, Imm JY. Antiobesity effect of tricin, a methylated cereal flavone, in high-fat-diet-induced obese mice. J Agric Food Chem, 2018, 66(38): 9989-9994.
29.	Habtemariam S. Protective effects of caffeic acid and the Alzheimer’s brain: an update. Mini Rev Med Chem, 2017, 17(8): 667-674.
30.	Nagao A, Kobayashi M, Koyasu S, et al. HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int J Mol Sci, 2019, 20(2): 238.
31.	Gabryelska A, Karuga FF, Szmyd B, et al. HIF-1α as a mediator of insulin resistance, T2DM, and its complications: potential links with obstructive sleep apnea. Front Physiol, 2020, 11: 1035.
32.	Viña J, Lloret A. Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-beta peptide. J Alzheimers Dis, 2010, 20(Suppl 2): S527-S533.
33.	Chen LH, Fan YH, Kao PY, et al. Genetic polymorphisms in estrogen metabolic pathway associated with risks of Alzheimer’s disease: evidence from a southern Chinese population. J Am Geriatr Soc, 2017, 65(2): 332-339.
34.	Santos RS, Frank AP, Fátima LA, et al. Activation of estrogen receptor alpha induces beiging of adipocytes. Mol Metab, 2018, 18: 51-59.
35.	Singh Angom R, Wang Y, Wang E, et al. VEGF receptor-1 modulates amyloid β 1-42 oligomer-induced senescence in brain endothelial cells. FASEB J, 2019, 33(3): 4626-4637.
36.	Tchaikovski V, Olieslagers S, Böhmer FD, et al. Diabetes mellitus activates signal transduction pathways resulting in vascular endothelial growth factor resistance of human monocytes. Circulation, 2009, 120(2): 150-159.

1. Lynn J, Park M, Ogunwale C, et al. A tale of two diseases: exploring mechanisms linking diabetes mellitus with Alzheimer’s disease. J Alzheimers Dis, 2022, 85(2): 485-501.
2. Jayaraj RL, Azimullah S, Beiram R. Diabetes as a risk factor for Alzheimer’s disease in the Middle East and its shared pathological mediators. Saudi J Biol Sci, 2020, 27(2): 736-750.
3. 刘敏, 谭丽阳, 张军, 等. 2 型糖尿病与阿尔茨海默病相关性机制的研究进展. 中国老年学杂志, 2019, 34(3): 746-749.
4. Michailidis M, Moraitou D, Tata DA, et al. Alzheimer’s disease as type 3 diabetes: common pathophysiological mechanisms between Alzheimer’s disease and type 2 diabetes. Int J Mol Sci, 2022, 23(5): 2687.
5. Takeishi J, Tatewaki Y, Nakase T, et al. Alzheimer’s disease and type 2 diabetes mellitus: the use of MCT oil and a ketogenic diet. Int J Mol Sci, 2021, 22(22): 12310.
6. Watson GS, Peskind ER, Asthana S, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology, 2003, 60(12): 1899-1903.
7. 中华人民共和国国家药典委员会. 中国药典. 北京: 中国医药科技出版社, 2015: 154-155.
8. Ma D, Wang L, Jin Y, et al. Application of UHPLC fingerprints combined with chemical pattern recognition analysis in the differentiation of six rhodiola species. Molecules, 2021, 26(22): 6855.
9. Wang L, Wang Y, Yang W, et al. Network pharmacology and molecular docking analysis on mechanisms of Tibetan Hongjingtian (Rhodiola crenulata) in the treatment of COVID-19. J Med Microbiol, 2021, 70(7): 001374.
10. Huang LY, Yen IC, Tsai WC, et al. Rhodiola crenulata suppresses high glucose-induced matrix metalloproteinase expression and inflammatory responses by inhibiting ROS-related HMGB1-TLR4 signaling in endothelial cells. Am J Chin Med, 2020, 48(1): 91-105.
11. 王琦, 刘瑜琦. 中药红景天干预阿尔茨海默发病机制的研究进展. 中国中西医结合杂志, 2012, 32(12): 1706-1709.
12. Zhuang W, Yue L, Dang X, et al. Rosenroot (Rhodiola): potential applications in aging-related diseases. Aging Dis, 2019, 10(1): 134-146.
13. 马韫楠, 吴娅丽, 钟宛凌, 等. 基于网络药理学的地龙平喘作用机制研究. 中国现代中药, 2021, 23(10): 1737-1746.
14. Wang YY, Huang ZT, Yuan MH, et al. Role of hypoxia inducible factor-1α in Alzheimer’s disease. J Alzheimers Dis, 2021, 80(3): 949-961.
15. Mitroshina EV, Savyuk MO, Ponimaskin E, et al. Hypoxia-inducible factor (HIF) in ischemic stroke and neurodegenerative disease. Front Cell Dev Biol, 2021, 9: 703084.
16. Ashok BS, Ajith TA, Sivanesan S. Hypoxia-inducible factors as neuroprotective agent in Alzheimer’s disease. Clin Exp Pharmacol Physiol, 2017, 44(3): 327-334.
17. Liu N, Cai X, Liu T, et al. Hypoxia-inducible factor-1α mediates the expression of mature β cell-disallowed genes in hypoxia-induced β cell dedifferentiation. Biochem Biophys Res Commun, 2020, 523(2): 382-388.
18. Cui J, Shen Y, Li R. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med, 2013, 19(3): 197-209.
19. Weigt C, Hertrampf T, Flenker U, et al. Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats. J Steroid Biochem Mol Biol, 2015, 154: 12-22.
20. Martin L, Bouvet P, Chounlamountri N, et al. VEGF counteracts amyloid-β-induced synaptic dysfunction. Cell Rep, 2021, 35(6): 109121.
21. Yu WY, Sun W, Yu DJ, et al. Adipose-derived stem cells improve neovascularization in ischemic flaps in diabetic mellitus through HIF-1α/VEGF pathway. Eur Rev Med Pharmacol Sci, 2018, 22(1): 10-16.
22. 范羽丰, 谭蓉, 江铃. 大花红景天以生活方式对 27 例 2 型糖尿病患者的治疗评价. 中国现代药物应用, 2007, 1(6): 10-11.
23. Zhang X, Wang X, Hu X, et al. Neuroprotective effects of a Rhodiola crenulata extract on amyloid-β peptides (Aβ1-42) -induced cognitive deficits in rat models of Alzheimer’s disease. Phytomedicine, 2019, 57: 331-338.
24. Babaei P, Eyvani K, Kouhestani S. Sex-independent cognition improvement in response to kaempferol in the model of sporadic Alzheimer’s disease. Neurochem Res, 2021, 46(6): 1480-1486.
25. Zhang N, Xu H, Wang Y, et al. Protective mechanism of kaempferol against Aβ25-35-mediated apoptosis of pheochromocytoma (PC-12) cells through the ER/ERK/MAPK signalling pathway. Arch Med Sci, 2020, 17(2): 406-416.
26. 吴巧敏, 卢笑, 倪海祥. 山奈酚防治 2 型糖尿病研究进展. 浙江中西医结合杂志, 2017, 27(4): 344-349.
27. Xie C, Kang J, Li Z, et al. The açaí flavonoid velutin is a potent anti-inflammatory agent: blockade of LPS-mediated TNF-α and IL-6 production through inhibiting NF-κB activation and MAPK pathway. J Nutr Biochem, 2012, 23(9): 1184-1191.
28. Lee D, Imm JY. Antiobesity effect of tricin, a methylated cereal flavone, in high-fat-diet-induced obese mice. J Agric Food Chem, 2018, 66(38): 9989-9994.
29. Habtemariam S. Protective effects of caffeic acid and the Alzheimer’s brain: an update. Mini Rev Med Chem, 2017, 17(8): 667-674.
30. Nagao A, Kobayashi M, Koyasu S, et al. HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int J Mol Sci, 2019, 20(2): 238.
31. Gabryelska A, Karuga FF, Szmyd B, et al. HIF-1α as a mediator of insulin resistance, T2DM, and its complications: potential links with obstructive sleep apnea. Front Physiol, 2020, 11: 1035.
32. Viña J, Lloret A. Why women have more Alzheimer’s disease than men: gender and mitochondrial toxicity of amyloid-beta peptide. J Alzheimers Dis, 2010, 20(Suppl 2): S527-S533.
33. Chen LH, Fan YH, Kao PY, et al. Genetic polymorphisms in estrogen metabolic pathway associated with risks of Alzheimer’s disease: evidence from a southern Chinese population. J Am Geriatr Soc, 2017, 65(2): 332-339.
34. Santos RS, Frank AP, Fátima LA, et al. Activation of estrogen receptor alpha induces beiging of adipocytes. Mol Metab, 2018, 18: 51-59.
35. Singh Angom R, Wang Y, Wang E, et al. VEGF receptor-1 modulates amyloid β 1-42 oligomer-induced senescence in brain endothelial cells. FASEB J, 2019, 33(3): 4626-4637.
36. Tchaikovski V, Olieslagers S, Böhmer FD, et al. Diabetes mellitus activates signal transduction pathways resulting in vascular endothelial growth factor resistance of human monocytes. Circulation, 2009, 120(2): 150-159.

West China Medical Journal

Study on the potential molecular mechanism of Rhodiola crenulata for type 2 diabetes mellitus and Alzheimer’s disease based on network pharmacology and molecular docking

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