Data mining and multi-omics profiling to reveal the mechanisms of cold/hot property of traditional Chinese medicine in Alzheimer’s disease treatment

i

This article has been updated. A Correction to this article was published on .

i

The Original Article was published on

i

The Original Article was published on

i

This article has been updated

i

This article was retracted on

i

This article has been updated

Abstract

Alzheimer’s disease (AD) is a severely debilitating condition that significantly hampers independent living, with no effective treatments currently available. Traditional Chinese medicine (TCM) has shown substantial promise in both preventing and alleviating AD symptoms. The medicinal properties-specifically hot, warm, cool, and cold-serve as a critical link between TCM theory and clinical application. However, the majority of research has concentrated on individual herbs for AD, with relatively few comprehensive studies exploring the biological mechanisms through which these herbs exert their medicinal properties. In this context, data mining, network pharmacology, and multi-omics approaches, including metabolomics, gut microbiota analysis, and proteomics, were employed to elucidate the effects and mechanisms of action of three hot/warm property herbs (THPH) and three cold/cool property herbs (TCPH) in the treatment of AD. Findings indicated that the herbs effective against AD primarily possess warm properties. THPH demonstrated a significant enhancement in cognitive, learning, and memory functions in AD rat models when compared to TCPH, potentially achieving therapeutic effects by boosting the synthesis of the neurotransmitter acetylcholine. Furthermore, THPH modulated energy metabolism, corrected metabolic imbalances in both brain and serum within AD rat models, inhibited oxidative stress, restored synaptic plasticity-related proteins and signaling pathways, and maintained intestinal microbiota homeostasis. Consequently, this study offers valuable insights into the therapeutic implications of the hot (warm) and cold (cool) properties of TCM in the management of Alzheimer’s disease.

Keywords

Alzheimer’s disease / Data mining / Multi-omics / Medicinal property / Traditional Chinese medicine

CHANGE HISTORY

A Correction to this paper has been published:
https://doi.org

The Retraction Note was updated to reflect reception of statements of disagreement from all authors.

This article has been retracted.Please see the Retraction Notice for more detail:
https://doi.org

References

[1] Wang YY, Sun YP, Yang BY, et al. Application of metabolomics and network analysis to reveal the ameliorating effect of four typical “hot” property herbs on hypothyroidism rats. Front Pharmacol. 2022; 13:955905. https://doi.org/10.3389/fphar.2022.955905.

[2] Wu JS, Luo Y, Deng DH, et al. Coptisine from Coptis chinensis exerts diverse beneficial properties: a concise review. J Cell Mol Med. 2019; 23(12):7946-7960. https://doi.org/10.1111/jcmm.14725.

[3] Wei GH, Fu XJ, Wang ZG . Multisolvent similarity measure of Chinese herbal medicine ingredients for cold-hot nature identification. J Chem Inf Model. 2019; 59(12):5065-5073. https://doi.org/10.1021/acs.jcim.9b00682.

[4] Wang YY, Sun YP, Yang BY, et al. Integrate metabolomics strategy and target prediction to reveal the ameliorate effect of four typical ‘cold’ property herbs on hyperthyroidism rats. J Ethnopharmacol. 2023; 301:115772. https://doi.org/10.1016/j.jep.2022.115772.

[5] Sultana OF, Bandaru M, Bushra MSTA, et al. Serotonin-mediated regulation of mitophagy in Alzheimer’s disease: mechanistic insights and therapeutic potential. Ageing Res Rev. 2026; 114:102957. https://doi.org/10.1016/j.arr.2025.102957.

[6] Xu LF, Liu R, Qin YK, et al. Brain metabolism in Alzheimer’s disease: biological mechanisms of exercise. Transl Neurodegener. 2023; 12(1):33. https://doi.org/10.1186/s40035-023-00364-y.

[7] Tang KS . The cellular and molecular processes associated with scopolamine-induced memory deficit: A model of Alzheimer’s biomarkers. Life Sci. 2019; 233:116695. https://doi.org/10.1016/j.lfs.2019.116695.

[8] Zhang ML, Zhao X, Li WX, et al. Yin/Yang associated differential responses to Psoralea corylifolia Linn in rat models: an integrated metabolomics and transcriptomics study. Chin Med. 2023; 18(1):102. https://doi.org/10.1186/s13020-023-00793-x.

[9] Zhang M, Zhang X, Wei R, et al. Principles and strategies in cold/hot property studies of traditional Chinese medicine: an evolution from traditional theory to modern elucidation. J Pharm Anal. 2025; 16(6):101455. https://doi.org/10.1016/j.jpha.2025.101455.

[10] Luo YL, Zhou Y, Song MM, et al. Analyze the application and mechanism of Traditional Chinese Medicine in chronic urticaria based on data mining and network pharmacology. Chin J Anal Chem. 2025; 53(4):100512. https://doi.org/10.1016/J.CJAC.2025.100512.

[11] Chiroma SM, Mohd Moklas MA, Mat Taib CN, et al. D-galactose and aluminium chloride induced rat model with cognitive impairments. Biomed Pharmacother . 2018; 103:1602-1608. https://doi.org/10.1016/j.biopha.2018.04.152.

[12] Liu M, Zeng MN, Wang SC, et al. Thymidine and 2′-deoxyuridine reduce microglial activation and improve oxidative stress damage by modulating glycolytic metabolism on the Aβ_25-35-induced brain injury. Arch Biochem Biophys. 2022; 729:109377. https://doi.org/10.1016/j.abb.2022.109377.

[13] Ni HJ, Liu MQ, Cao MD, et al. Sinomenine regulates the cholinergic anti-inflammatory pathway to inhibit TLR4/NF-κB pathway and protect the homeostasis in brain and gut in scopolamine-induced Alzheimer’s disease mice. Biomed Pharmacother. 2024; 171:116190. https://doi.org/10.1016/j.biopha.2024.116190.

[14] Khan T, Waseem R, Shahid M, et al. Recent advancement in therapeutic strategies for Alzheimer’s disease: insights from clinical trials. Ageing Res Rev. 2023; 92:102113. https://doi.org/10.1016/j.arr.2023.102113.

[15] He ZJ, Li XQ, Wang Z, et al. Protective effects of luteolin against amyloid beta-induced oxidative stress and mitochondrial impairments through peroxisome proliferator-activated receptor γ-dependent mechanism in Alzheimer’s disease. Redox Biol. 2023; 66:102848. https://doi.org/10.1016/j.redox.2023.102848.

[16] Li DL, Cai CP, Liao YF, et al. Systems pharmacology approach uncovers the therapeutic mechanism of medicarpin against scopolamine-induced memory loss. Phytomedicine. 2021; 91:153662. https://doi.org/10.1016/j.phymed.2021.153662.

[17] Clarke JR, Ribeiro FC, Frozza RL, et al. Metabolic dysfunction in Alzheimer’s disease: from basic neurobiology to clinical approaches. J Alzheimers Dis. 2018; 64(s1):S405-S426. https://doi.org/10.3233/jad-179911.

[18] Zocchi L, Sassone-Corsi P . SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression. Epigenetics. 2014;7(7):695-700. https://doi.org/10.4161/epi.20733.

[19] Bélanger M, Allaman I, Magistretti PJ . Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 2011; 14(6):724-738. https://doi.org/10.1016/j.cmet.2011.08.016.

[20] Benaroya H. Brain energetics, mitochondria, and traumatic brain injury. Rev Neurosci. 2020; 31(4):363-390. https://doi.org/10.1515/revneuro-2019-0086.

[21] Gowda P, Reddy PH, Kumar S . Deregulated mitochondrial microRNAs in Alzheimer’s disease: focus on synapse and mitochondria. Ageing Res Rev. 2022; 73:101529. https://doi.org/10.1016/j.arr.2021.101529.

[22] Zhao X, Fang JK, Li S, et al. Artemisinin attenuated hydrogen peroxide (H₂O₂)-induced oxidative injury in SH-SY5Y and hippocampal neurons via the activation of AMPK Pathway. Int J Mol Sci. 2019; 20(11):2680. https://doi.org/10.3390/ijms20112680.

[23] Theparambil SM, Kopach O, Braga A, et al. Adenosine signalling to astrocytes coordinates brain metabolism and function. Nature. 2024; 632(8023):139-146. https://doi.org/10.1038/s41586-024-07611-w.

[24] Duran-Aniotz C, Hetz C . Glucose metabolism: s sweet relief of Alzheimer’s disease. Curr Biol. 2016; 26(17):R806-R809. https://doi.org/10.1016/j.cub.2016.07.060.

[25] Bekdash RA . The cholinergic system, the adrenergic system and the neuropathology of Alzheimer’s disease. Int J Mol Sci. 2021; 22(3):1273. https://doi.org/10.3390/ijms22031273.

[26] Gu X, Wang XY . An overview of recent analysis and detection of acetylcholine. Anal Biochem. 2021; 632:114381. https://doi.org/10.1016/j.ab.2021.114381.

[27] Tabner BJ, El-Agnaf OMA, Turnbull S, et al. Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. J Biol Chem. 2005; 280(43):35789-35792. https://doi.org/10.1074/jbc.C500238200.

[28] Kowalska M, Piekut T, Prendecki M, et al. Mitochondrial and nuclear DNA oxidative damage in physiological and pathological aging. DNA Cell Biol. 2020; 39(8):1410-1420. https://doi.org/10.1089/dna.2019.5347.

[29] Dewanjee S, Chakraborty P, Bhattacharya H, et al. Altered glucose metabolism in Alzheimer’s disease: role of mitochondrial dysfunction and oxidative stress. Free Radic Biol Med. 2022; 193:134-157. https://doi.org/10.1016/j.freeradbiomed.2022.09.032.

[30] Lachkar F, Ferré P, Foufelle F, et al. Dihydroceramides: their emerging physiological roles and functions in cancer and metabolic diseases. Am J Physiol Endocrinol Metab. 2021; 320(1):E122-E130. https://doi.org/10.1152/ajpendo.00330.2020.

[31] Hatanaka H, Hanyu H, Fukasawa R, et al. Differences in peripheral oxidative stress markers in Alzheimer’s disease, vascular dementia and mixed dementia patients. Geriatr Gerontol Int. 2015; 15(S1):53-58. https://doi.org/10.1111/ggi.12659.

[32] Xia CR, Tian QY, Kong LY, et al. Metabolomics analysis for nitrite degradation by the metabolites of limosilactobacillus fermentum RC4. Foods. 2022; 11(7):1009-1009. https://doi.org/10.3390/foods11071009.

[33] Carvalho-Silva M, Gomes LM, de Prá SD-T, et al. Evidence of hippocampal astrogliosis and antioxidant imbalance after L-tyrosine chronic administration in rats. Metab Brain Dis. 2019; 35(1):193-200. https://doi.org/10.1007/s11011-019-00511-3.

[34] Lin CC, Yang CC, Chen YW, et al. Arachidonic acid induces ARE/Nrf2-dependent heme oxygenase-1 transcription in rat brain astrocytes. Mol Neurobiol. 2017; 55(4):3328-3343. https://doi.org/10.1007/s12035-017-0590-7.

[35] Cao XF, Guo HX, Dai YJ, et al. Excessive linoleic acid induces muscle oxidative stress through 5-lipoxygenase-dependent peroxidation. Redox Biol. 2024; 71:103096. https://doi.org/10.1016/j.redox.2024.103096.

[36] Liu Q, Wang SC, Ding K . Research advances in the treatment of Alzheimer’s disease with polysaccharides from traditional Chinese medicine. Chin J Nat Med. 2017; 15(9):641-652. https://doi.org/10.1016/s1875-5364(17)30093-6.

[37] Zhou H, Yin XH, Zhang GQ, et al. Advancing nanomaterial-based strategies for Alzheimer’s disease: a perspective. JACS Au. 2025; 5(4):1519-1537. https://doi.org/10.1021/jacsau.5c00002.

[38] Shi HS, Yu YH, Lin DH, et al. β-Glucan attenuates cognitive impairment via the gut-brain axis in diet-induced obese mice. Microbiome. 2020; 8(1):143. https://doi.org/10.1186/s40168-020-00920-y.

[39] Ren TY, Chen Z, Xie J, et al. Studies on the role of Rosa roxburghii Tratt quercetin in improving intestinal metabolism and the microbiome in mice with Alzheimer’s disease. J Funct Foods. 2024; 114:106046. https://doi.org/10.1016/j.jff.2024.106046.

[40] Chen YY, Chen SY, Chang HY, et al. Phyllanthus emblica L. polysaccharides ameliorate colitis via microbiota modulation and dual inhibition of the RAGE/NF-κB and MAPKs signaling pathways in rats. Int J Biol Macromol. 2024; 258:129043. https://doi.org/10.1016/j.ijbiomac.2023.129043.

[41] Feng RB, Wang Q, Yu TT, et al. Quercetin ameliorates bone loss in OVX rats by modulating the intestinal flora-SCFAs-inflammatory signaling axis. Int Immunopharmacol. 2024; 136:112341. https://doi.org/10.1016/j.intimp.2024.112341.

[42] Hu ZM, Chu ZX, Ling XK, et al. Sinensetin from citrus peel alleviates DSS-induced inflammation by regulating gut microbiota and serum metabolism in mice. Food Biosci. 2024; 62:105066. https://doi.org/10.1016/j.fbio.2024.105066.

[43] Zhang Q, Wu GR, Shen SM, et al. Dioscoreae persimilis polysaccharide ameliorates DSS-induced ulcerative colitis in mice through modulation of microbiota composition. JHIP. 2023; 4(2):157-165. https://doi.org/10.1016/j.jhip.2023.09.004.

[44] Kang J, Li CQ, Gao XH, et al. Metformin inhibits tumor growth and affects intestinal flora in diabetic tumor-bearing mice. Eur J Pharmacol. 2021; 912:174605. https://doi.org/10.1016/j.ejphar.2021.174605.

[45] Hahn R. Treatment of neuropsychiatric symptoms in Alzheimer’s disease with traditional Chinese medicine: an integrative medicine case report. Adv Integr Med. 2024; 11(4):240-246. https://doi.org/10.1016/j.aimed.2024.08.008.

[46] Xiong R, Liu HX, Zhang SP, et al. Acorus tatarinowii Schott attenuates Alzheimer’s disease via neuronal ferroptosis inhibition: a synergistic network pharmacology and multi-omics profiling study. J Ethnopharmacol. 2026; 356:120829. https://doi.org/10.1016/j.jep.2025.120829.

[47] Garg A, Agrawal R, Deshmukh R . Pharmacology of polygala tenuifolia and its significance in traditional Chinese medicine. Pharmacol Res Modern Chin Med. 2024; 10:100341. https://doi.org/10.1016/j.prmcm.2023.100341.

[48] Hwang J, Keum M, Choe YM, et al. Panax ginseng: a modulator of amyloid, tau pathology, and cognitive function in Alzheimer’s disease. J Ginseng Res. 2025; 49(4):348-355. https://doi.org/10.1016/j.jgr.2025.03.011.

[49] Maitre M, Jeltsch-David H, Okechukwu NG, et al. Myelin in Alzheimer’s disease: culprit or bystander? Acta Neuropathol Commun. 2023; 11(1):56. https://doi.org/10.1186/s40478-023-01554-5.

[50] Sen MK, Mahns DA, Coorssen JR, et al. The roles of microglia and astrocytes in phagocytosis and myelination: insights from the cuprizone model of multiple sclerosis. Glia. 2022; 70(7):1215-1250. https://doi.org/10.1002/glia.24148.