Gene Expression Omnibus database analysis reveals comorbidity mechanisms of type 2 diabetes mellitus and vascular dementia and predicts potential herbal therapeutics

Abstract

Objective: This study aimed to investigate the comorbid mechanisms linking type 2 diabetes mellitus (T2DM) and vascular dementia (VaD), focusing on the roles of astrocytes and neurons, and to identify potential therapeutic traditional Chinese medicines (TCMs) and compounds.

Methods: T2DM (GSE161355) and VaD (GSE122063) transcriptomic datasets were retrieved from the Gene Expression Omnibus database. Differential expression analysis, functional enrichment, and druggability assessment were conducted to identify potential core targets. Corresponding TCMs and compounds were predicted by using the TCMSP and HERB databases, followed by analyses of their pharmacokinetics, toxicity, and binding affinity.

Results: In astrocytes, eight core genes (e.g., HSP90AA1, HIF1A, PTEN) were identified and primarily enriched in autophagy and inflammatory pathways. Eight TCMs, including Corydalis yanhusuo and Phellodendron chinense, were predicted to be relevant. Indigo exhibited a relatively strong binding affinity to HSP90AA1 (-10.0 kcal/mol). In neurons, eight core genes (e.g., NFKB1, CYCS, PTGS2) were enriched in apoptosis and neuro-inflammation pathways. Potential TCMs, such as Tripterygium wilfordii, were identified. Palmatine showed a relatively strong binding affinity to PTGS2 (-8.1 kcal/mol). Most predicted TCMs were characterized as bitter and cold in property, associated with the liver meridian, and attributed with heat-clearing effects.

Conclusion: Our findings suggest that the comorbidity of T2DM and VaD may involve dysregulated inflammatory and apoptotic pathways in astrocytes and neurons. The predicted TCMs and compounds represent multitarget intervention candidates, consistent with TCM theories of "Yin deficiency with internal heat" and "phlegm-stasis transforming into heat." These findings provide a theoretical basis for future experimental validation and the development of TCM-based therapies.

Keywords

astrocytes / neurons / traditional Chinese medicines / type 2 diabetes mellitus / vascular dementia

References

[1] Gorelick PB , Scuteri A , Black SE , et al. Vascular contributions to cognitive impairment and dementia:a statement for healthcare professionals from the American heart association/American stroke association. Stroke. 2011; 42 (9): 2672- 2713.

[2] Taylor R . Type 2 diabetes:etiology and reversibility. Diabetes Care. 2013; 36 (4): 1047- 1055.

[3] Alberti K , Eckel R , Grundy S , et al. Harmonizing the metabolic syndrome. Circulation. 2009; 120 (16): 1640- 1645.

[4] Biessels GJ , Whitmer RA . Cognitive dysfunction in diabetes: how to implement emerging guidelines. Diabetologia. 2020; 63 (1): 3- 9.

[5] Sutherland GT , Lim J , Srikanth V , Bruce DG . Epidemiological approaches to understanding the link between type 2 diabetes and dementia. J Alzheimers Dis. 2017; 59: 393- 403.

[6] Santello M , Toni N , Volterra A . Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci. 2019; 22 (2): 154- 166.

[7] Escartin C , Galea E , Lakatos A , et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021; 24 (3): 312- 325.

[8] Min LJ , Mogi M , Shudou M , et al. Peroxisome proliferator-activated receptor-γ activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice. Hypertension. 2012; 59 (5): 1079- 1088.

[9] Linnerbauer M , Wheeler MA , Quintana FJ . Astrocyte crosstalk in CNS inflammation. Neuron. 2020; 108 (4): 608- 622.

[10] Pellerin L , Magistretti PJ . Glutamate uptake into astrocytes stimulates aerobic glycolysis:a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci. 1994; 91 (22): 10625- 10629.

[11] Shi S , Yin HJ , Li J , Wang L , Wang W , Wang X . Studies of pathology and pharmacology of diabetic encephalopathy with KK-Ay mouse model. CNS Neurosci Ther. 2020; 26 (3): 332- 342.

[12] Chen F , Hu M , Du GT , et al. Research advances on mechanism of cognitive impairment in type 2 diabetes mellitus. Acta Neuropharmacologica. 2013; 3 (3): 27- 33.

[13] Chen WJ , Huang XB . Research progress of traditional Chinese and Western medicine on cognitive dysfunction in type 2 diabetes. Chinese Journal of Information on TCM. 2012; 19 (7): 106- 110.

[14] Wang LL . Traditional Chinese and Western Medicine Research on Cognitive Dysfunction in Type 2 Diabetes. Master's thesis. Beijing University of Chinese Medicine; CNKI. 2015.

[15] Ming SP , Liu L , Qu YQ . The progress of integrated traditional Chinese and Western medicine on the pathogenesis of diabetic cognitive impairment. Lishizhen Medicine And Materia Medica Research. 2018; 29 (1): 164- 167.

[16] Zhang MR , Zhang M , Jing GC . Influence of naofucong on cognitive function and expressions of NF-κB and GFAP in hippocampus of STZ-induced diabetic rats. Chinese Archives Of Traditional Chinese Medicine. 2014; 32 (8): 1991- 1994.

[17] Zeng WY , Suo YR , Li HH , et al. Research progress of active components of traditional Chinese medicine on prevention of diabetic cognitive deficits. Liaoning Journal Of Traditional Chinese Medicine. 2017; 44 (12): 2667- 2671.

[18] Ru J , Li P , Wang J , et al. TCMSP:a database of systems pharmacology for drug discovery from herbal medicines. J Cheminf. 2014; 6 (1): 13.

[19] Fang S , Dong L , Liu L , et al. HERB:a high-throughput experiment- and reference-guided database of traditional Chinese medicine. Nucleic Acids Res. 2021; 49 (D1): D1197- D1206.

[20] Fu L , Shi S , Yi J , et al. ADMETlab 3.0:an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support. Nucleic Acids Res. 2024; 52 (W1): W422- W431.

[21] Lefterov I , Bookout A , Wang Z , Staufenbiel M , Mangelsdorf D , Koldamova R . Expression profiling in APP23 mouse brain:inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener. 2007; 2 (1): 20.

[22] Yao Y , Li X , Yang X , Mou H , Wei L . Indirubin, an active component of Indigo Naturalis, exhibits inhibitory effects on leukemia cells via targeting HSP90AA1 and PI3K/Akt pathway. Anti Cancer Agents Med Chem. 2024; 24 (9): 718- 727.

[23] Yang L , Li X , Huang W , Rao X , Lai Y . Pharmacological properties of indirubin and its derivatives. Biomed Pharmacother. 2022; 151: 113112.

[24] Alberti G , Paladino L , Vitale AM , et al. Functions and therapeutic potential of extracellular Hsp60, Hsp70, and Hsp90 in neuroinflammatory disorders. Appl Sci. 2021; 11 (2): 736.

[25] Long J , Song J , Zhong L , Liao Y , Liu L , Li X . Palmatine:a review of its pharmacology, toxicity and pharmacokinetics. Biochimie. 2019; 162: 176- 184.

[26] Moran C , Phan TG , Chen J , et al. Brain atrophy in type 2 diabetes:regional distribution and influence on cognition. Diabetes. 2013; 62 (9): 3073- 3080.

[27] Yau PL , Javier DC , Ryan CM , et al. Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus. Diabetes. 2009; 58 (4): 1259- 1267.

[28] O'Brien JT , Desmond P , Ames D , Schweitzer I , Chiu E , Tress B . Temporal lobe magnetic resonance imaging can differentiate Alzheimer's disease from normal ageing, depression, vascular dementia and other causes of cognitive impairment. Psychol Med. 1997; 27 (6): 1267- 1275.

[29] Deng YS , Zheng YF , Zhou Q , et al. Pathogenesis and treatment of diabetes mellitus and its complications "glycoconjugate stasis in collaterals" based on glucotoxicity and inflammation interaction. China J Chin Mater Med. 2025: 1- 12.

[30] Chapouly C , Tadesse Argaw A , Horng S , et al. Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain. 2015; 138 (Pt 6): 1548- 1567.

[31] Saggu R , Schumacher T , Gerich F , et al. Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. Acta Neuropathol Commun. 2016; 4 (1): 76.

[32] Jiao XH , Wan J , Wu WF , et al. GLT-1 downregulation in hippocampal astrocytes induced by type 2 diabetes contributes to postoperative cognitive dysfunction in adult mice. CNS Neurosci Ther. 2024; 30 (9): e70024.

[33] Feng L , Gao L . The role of neurovascular coupling dysfunction in cognitive decline of diabetes patients. Front Neurosci. 2024; 18: 1375908.

[34] Son SM , Song H , Byun J , et al. Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions. Autophagy. 2012; 8 (12): 1842- 1844.

[35] Abner EL , Nelson PT , Kryscio RJ , et al. Diabetes is associated with cerebrovascular but not Alzheimer's disease neuropathology. Alzheimer's Dement. 2016; 12 (8): 882- 889.

[36] Nelson PT , Smith CD , Abner EA , et al. Human cerebral neuropathology of type 2 diabetes mellitus. Biochim Biophys Acta. 2009; 1792 (5): 454- 469.

[37] Wang JQ , Yin J , Song YF , et al. Brain aging and AD-like pathology in streptozotocin-induced diabetic rats. J Diabetes Res. 2014; 2014: 796840- 12.

[38] Erickson JR , Pereira L , Wang L , et al. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature. 2013; 502 (7471): 372- 376.

[39] Montgomery SL , Bowers WJ . Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 2012; 7 (1): 42- 59.

[40] Campbell IL , Erta M , Lim SL , et al. Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J Neurosci. 2014; 34 (7): 2503- 2513.

[41] Biessels GJ , Despa F . Cognitive decline and dementia in diabetes mellitus:mechanisms and clinical implications. Nat Rev Endocrinol. 2018; 14 (10): 591- 604.

[42] Lazaro I , Oguiza A , Recio C , et al. Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice. Diabetes. 2015; 64 (10): 3600- 3613.

[43] Wu ZH , Wong ET , Shi Y , et al. ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Mol Cell. 2010; 40 (1): 75- 86.

[44] Mousavi S , Khazeei Tabari MA , Bagheri A , Samieefar N , Shaterian N , Kelishadi R . The role of p66Shc in diabetes:a comprehensive review from bench to bedside. J Diabetes Res. 2022; 2022: 7703520- 15.

[45] Gary DS , Mattson MP . PTEN regulates Akt kinase activity in hippocampal neurons and increases their sensitivity to glutamate and apoptosis. NeuroMolecular Med. 2002; 2 (3): 261- 269.

[46] Shi GD , OuYang YP , Shi JG , Liu Y , Yuan W , Jia L . PTEN deletion prevents ischemic brain injury by activating the mTOR signaling pathway. Biochem Biophys Res Commun. 2011; 404 (4): 941- 945.

[47] Wang J , Xu X , Elliott MH , Zhu M , Le YZ . Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes. 2010; 59 (9): 2297- 2305.

[48] Minghetti L . Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol. 2004; 63 (9): 901- 910.

[49] Enzmann G , Mysiorek C , Gorina R , et al. The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury. Acta Neuropathol. 2013; 125 (3): 395- 412.

[50] Zenaro E , Pietronigro E , Della Bianca V , et al. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med. 2015; 21 (8): 880- 886.

[51] Zafar A , Ng HP , Chan ER , Dunwoodie SL , Mahabeleshwar GH . Myeloid-CITED2 deficiency exacerbates diet-induced obesity and pro-inflammatory macrophage response. Cells. 2023; 12 (17): 2136.

[52] Vaishnav RA , Singh IN , Miller DM , Hall ED . Lipid peroxidation- derived reactive aldehydes directly and differentially impair spinal cord and brain mitochondrial function. J Neurotrauma. 2010; 27 (7): 1311- 1320.

[53] Jeong SY , Seol DW . The role of mitochondria in apoptosis. BMB Rep. 2008; 41 (1): 11- 22.

[54] Liang QZ , Peng X , Fu XX , et al. Exploring the turbidity poison theory of traditional Chinese medicine and herbal intervention strategy for type 2 diabetes mellitus based on pyroptosis. Journal of Nanjing University of Traditional Chinese Medicine. 2025: 1- 9.

[55] Chen W , Liu FY , Hu XH , et al. Treat vascular dementia based on the theory of liver depression and blood stasis. Liaoning Journal Of Traditional Chinese Medicine. 2010; 37 (8): 1462- 1463.

[56] Tang PL , Wang F . Treating cognitive dysfunction in diabetes based on liver Yang deficiency. Jiangxi Journal Of Traditional Chinese Medicine. 2018; 49 (4): 22- 23.

[57] Yi PR , Lin XL , Bu J , et al. Progression of research on traditional Chinese medicine in prevention and treatment diabetic encephalopathy with different symptoms. Tianjin Journal of Traditional Chinese Medicine. 2024; 41 (6): 795- 801.

[58] Wu HH . Research on the correlation between liver depression grade and blood glucose level in type 2 diabetes patients. Chinese Medicine Modern Distance Education of China. 2021; 19 (4): 46- 47.

[59] Chen Rui , Zhou XQ , Shang XL . Exploration on ideas of differentiating and treating diabetic encephalopathy based on the method of tonifying kidney, detoxification and dredging collaterals. Jilin Journal of Chinese Medicine. 2022; 42 (6): 644- 646.

[60] Li SY , Li JC , Song Q , et al. Mechanism of alkaloids from wine steamed Coptidis Rhizoma-volatile oil from Acori Tatarinowii rhizoma on prevention and treatment of diabetic cognitive impairment based on interactive network of "key components- potential targets-core pathway". Chin Tradit Herb Drugs. 2021; 52 (19): 5910- 5921.

[61] Sun N , Huang Y , Zhou WX , et al. A preliminary study on the effect of Uncaria alkaloids on cognitive impairment induced by LPS. Chin J Pharmacol Toxicol. 2019; 33 (6): 463- 464.

[62] Liu B . Effect and mechanism of Dendrobium nobile Lindl. alkaloids on improving learning and memory impairment in senescence-accelerated mice. Doctoral dissertation. Shanghai University of Traditional Chinese Medicine; CNKI. 2020.

[63] Hao Y , Li J , Yue S , Wang S , Hu S , Li B . Neuroprotective effect and possible mechanisms of berberine in diabetes-related cognitive impairment:a systematic review and meta-analysis of animal studies. Front Pharmacol. 2022; 13: 917375.

[64] Paudel YN , Angelopoulou E , Semple B , Piperi C , Othman I , Shaikh MF . Potential neuroprotective effect of the HMGB1 inhibitor glycyrrhizin in neurological disorders. ACS Chem Neurosci. 2020; 11 (4): 485- 500.

[65] Hu C , He M , Chen M , et al. Amelioration of neuropathic pain and attenuation of neuroinflammation responses by tetrahydropalmatine through the p38MAPK/NF-κB/iNOS signaling pathways in animal and cellular models. Inflammation. 2022; 45 (2): 891- 903.

[66] Zhang L , Xu J , Guo J , Wang Y , Wang Q . Elucidation of pharmacological mechanism underlying the anti-Alzheimer's disease effects of Evodia rutaecarpa and discovery of novel lead molecules:an in silico study. Molecules. 2023; 28 (15): 5846.

[67] Chen YR , Niu YS , Zhou HL . Achyranthes bidentata Blume (Amaranthaceae):a review of its botany, traditional uses, phytochemistry, pharmacology, and toxicology. J Pharm Pharmacol. 2024; 76 (8): 930- 966.

[68] Zheng Y , Zhang WJ , Wang XM . Triptolide with potential medicinal value for diseases of the central nervous system. CNS Neurosci Ther. 2013; 19 (2): 76- 82.

[69] Lee S , Jung IC , Lee SR . The effects of Dichroa febrifuga (DIF) extract on the Alzheimer's disease model. Journal of Oriental Neuropsychiatry. 2005; 16 (1): 81- 96.

[70] Loerch PM , Lu T , Dakin KA , et al. Evolution of the aging brain transcriptome and synaptic regulation. PLoS One. 2008; 3 (10): e3329.

[71] Glorioso C , Sibille E . Between destiny and disease:genetics and molecular pathways of human central nervous system aging. Prog Neurobiol. 2011; 93 (2): 165- 181.

[72] Yankner BA , Lu T , Loerch P . The aging brain. Annu Rev Pathol. 2008; 3 (1): 41- 66.

[73] Bishop NA , Lu T , Yankner BA . Neural mechanisms of ageing and cognitive decline. Nature. 2010; 464 (7288): 529- 535.

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