Ditan Decoction ameliorates vascular dementia-induced cognitive dysfunction through anti-ferroptosis via the HIF1α pathway: Integrating network pharmacology and experimental validation

被引：0

作者：

Gu, Mengyu ^{[1
,2
]}

Sun, Lieqian ^{[1
,2
]}

Yang, Jie ^{[3
,5
]}

Wang, Kaiyi ^{[1
,2
]}

Wu, Fan ^{[1
,2
]}

Zheng, Li ^{[1
,2
]}

Shen, Xiangzhong ^{[1
,2
]}

Lai, Xing ^{[2
]}

Gong, Lili ^{[2
]}

Peng, Ying ^{[2
]}

Xu, Shujie ^{[2
]}

Yang, Jia ^{[4
]}

Yang, Chao ^{[2
]}

机构：

[1] Hubei Univ Chinese Med, Wuhan 430065, Peoples R China

[2] Hubei Prov Hosp Integrated Chinese & Western Med, Dept Gerontol, Wuhan 430022, Peoples R China

[3] Hubei Univ Chinese Med, Hubei Prov Hosp Tradit Chinese Med, Affiliated Hosp, Wuhan 430061, Peoples R China

[4] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Integrated Tradit Chinese & Western Med, Wuhan 430022, Peoples R China

[5] Hubei Shizhen Lab, Wuhan 430065, Peoples R China

来源：

JOURNAL OF ETHNOPHARMACOLOGY | 2025年 / 344卷

基金：

中国国家自然科学基金;

关键词：

Ditan Decoction; Vascular dementia; Ferroptosis; Oxidative stress; HIF1 alpha pathway; CELL-DEATH; OXIDATIVE STRESS; IRON UPTAKE; METABOLISM; MECHANISMS;

D O I：

10.1016/j.jep.2025.119459

中图分类号：

Q94 [植物学];

学科分类号：

071001 ;

摘要：

Ethnopharmacological relevance: Vascular dementia (VaD) represents a frequently seen cognitive dysfunction syndrome and has ranks second among dementia subtypes following Alzheimer's disease. At present, Ditan Decoction (DTD), the traditional Chinese herbal prescription, is clinically applied in treating VaD. However, the material basis of its efficacy and therapeutic mechanism still remain unknown. Aim of the study: This experiment investigated the protection induced by DTD against VaD and the associated mechanism through network pharmacology, mass spectrometry analysis, and in vivo validation. Materials and methods: We induced VaD in a rat model using bilateral common carotid artery ligation method (2VO) and administered DTD at doses of 2.14, 4.28 and 8.55 g/kg, with Memantine (0.9 mg/kg) being the positive control. Following oral administration with DTD or Memantine for 4 weeks, behavioral tests were used for assessing cognitive function. H&E and Nissl staining was used for evaluating hippocampal pathology. TEM was used to visualize the ultrastructure of the hippocampal tissue. ELISA was carried out for measuring inflammatory factor levels in rat serum, and biochemical assays were employed to assess oxidative stress levels. Ferroptosis in the hippocampus was examined through analyzing corresponding biomarkers and protein expression. Additionally, HPLC-Q-Exactive-MS technology was employed for identifying DTD components, whereas network pharmacology was conducted for predicting DTD's targets for treating VaD. HIF1 alpha expression levels were assessed by Western blotting and immunofluorescence. We also further validated whether the protective effects of DTD on VaD were mediated through the HIF1 alpha-regulated ferroptosis signaling pathway by using an HIF1 alpha inhibitor in rats. Results: DTD demonstrated protective effects against 2VO-induced hippocampal injury through alleviating oxidative stress, lowering systemic inflammation, while preventing ferroptosis of hippocampal tissue. As revealed by network pharmacology, DTD probably executes its function in VaD by activating HIF1 alpha pathway. According to immunofluorescence and Western blotting, DTD activated HIF1 alpha within hippocampal tissue. Furthermore, DTD's protection against VaD and ferroptosis was reversed when an HIF1 alpha inhibitor was applied. Conclusion: These findings suggested that DTD rescued cognitive dysfunction in VaD by inhibiting ferroptosis via activating HIF1 alpha pathway.

引用

页数：15

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[1]

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[2]

Bogdan A.R., Miyazawa M., Hashimoto K., Tsuji Y., Regulators of iron homeostasis: new players in metabolism, cell death, and disease, Trends Biochem. Sci., 41, pp. 274-286, (2016)

[3]

Cheng L., Zhang H., Wu F., Liu Z., Cheng Y., Wang C., Role of Nrf2 and its activators in cardiocerebral vascular disease, Oxid. Med. Cell. Longev., (2020)

[4]

Chiang S.K., Chen S.E., Chang L.C., The role of HO-1 and its crosstalk with oxidative stress in cancer cell survival, Cells, 10, (2021)

[5]

Cui Y., Zhang Y., Zhao X., Shao L., Liu G., Sun C., Xu R., Zhang Z., ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation, Brain Behav. Immun., 93, pp. 312-321, (2021)

[6]

Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M., Gleason C.E., Patel D.N., Bauer A.J., Cantley A.M., Yang W.S., Morrison B., Stockwell B.R., Ferroptosis: an iron-dependent form of nonapoptotic cell death, Cell, 149, pp. 1060-1072, (2012)

[7]

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[8]

Forman H.J., Zhang H., Rinna A., Glutathione: overview of its protective roles, measurement, and biosynthesis, Mol. Aspect. Med., 30, pp. 1-12, (2009)

[9]

Fukai T., Ushio-Fukai M., Superoxide dismutases: role in redox signaling, vascular function, and diseases, Antioxidants Redox Signal., 15, pp. 1583-1606, (2011)

[10]

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