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. 2023 Oct 22;24(20):15457.
doi: 10.3390/ijms242015457.

Identification of Uncaria rhynchophylla in the Potential Treatment of Alzheimer's Disease by Integrating Virtual Screening and In Vitro Validation

Shuang Jiang  1 , Gilwa Borjigin  1 , Jiahui Sun  1 , Qi Li  1 , Qianbo Wang  1 , Yuanqiu Mu  1 , Xuepeng Shi  1 , Qian Li  1 , Xiaotong Wang  1 , Xiaodan Song  1 , Zhibin Wang  2 , Chunjuan Yang  1   3
Affiliations

Identification of Uncaria rhynchophylla in the Potential Treatment of Alzheimer's Disease by Integrating Virtual Screening and In Vitro Validation

Shuang Jiang et al. Int J Mol Sci. .

Abstract

Uncaria rhynchophylla (Gouteng in Chinese, GT) is the main medicine in many traditional recipes in China. It is commonly used to alleviate central nervous system (CNS) disorders, although its mechanism in Alzheimer's disease is still unknown. This study was designed to predict and validate the underlying mechanism in AD treatment, thus illustrating the biological mechanisms of GT in treating AD. In this study, a PPI network was constructed, KEGG analysis and GO analysis were performed, and an "active ingredient-target-pathway" network for the treatment of Alzheimer's disease was constructed. The active ingredients of GT were screened out, and the key targets were performed by molecular docking. UHPLC-Q-Exactive Orbitrap MS was used to screen the main active ingredients and was compared with the network pharmacology results, which verified that GT did contain the above ingredients. A total of targets were found to be significantly bound up with tau, Aβ, or Aβ and tau through the network pharmacology study. Three SH-SY5Y cell models induced by okadaic acid (OA), Na2S2O4, and H2O2 were established for in vitro validation. We first found that GT can reverse the increase in the hyperphosphorylation of tau induced by OA to some extent, protecting against ROS damage. Moreover, the results also indicated that GT has significant neuroprotective effects. This study provides a basis for studying the potential mechanisms of GT in the treatment of AD.

Keywords: Alzheimer’s disease; Uncaria rhynchophylla; network pharmacology; p-tau.

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Conflict of interest statement

We confirm that this work is original and has not been published elsewhere, nor is it currently under consideration for publication elsewhere. We have no conflict of interest to disclose.

Figures

Figure 1
Figure 1
Network analysis of the related targets of GT and AD. (a) Venn diagram of ingredient targets of GT- and AD-related targets. (b) The PPI network of the related targets of GT and AD. The size of circles represented the degree of value.
Figure 2
Figure 2
The “ingredient-targets-pathways” network. The blue V shapes represent the ingredients of GT. The green diamonds represent related targets of GT and AD, and the light blue ellipses represent pathways. GT: Uncaria rhynchophylla. The number of GT represents the ingredients of GT, and the names of the GT ingredients are shown in Table S1.
Figure 3
Figure 3
The enrichment analysis of GO and KEGG of GT and AD. (a) KEGG pathway, (b) biological process (BP), (c) cellular component (CC), and (d) molecular function (MF).
Figure 4
Figure 4
The UHPLC-Q-Exactive Orbitrap MS base peak intensity chromatograms of GT. (a) Positive mode. (b) Negative mode.
Figure 5
Figure 5
Schematic diagram of angustidine and angustoline docking with the core target. (a) PTGS2 docking with angustidine. (b) PTGS2 docking with angustoline.
Figure 6
Figure 6
Bioinformatics analysis of GT targets related to tau, Aβ, or Aβ and tau pathology. (a) The targets of GT alkaloids are related to tau, Aβ, or Aβ and tau. (b) PPI network of proteins associated with the pathology of tau, Aβ, or Aβ and tau. (c) The top 20 GO BP enrichment analysis related to tau, Aβ, or Aβ and tau. (d) KEGG pathway enrichment analysis related to tau, Aβ, or Aβ and tau.
Figure 7
Figure 7
(a–y) The expression of the targets of GT related to tau, Aβ, or Aβ and tau pathology against AD in the entorhinal cortex or hippocampus or temporal cortex in the control and AD groups of the GEO dataset. Entorhinal cortex (a–h), n = 39 in each group. Hippocampus (i–o), n = 66 in the healthy control group and n = 74 in the AD group. Temporal cortex (p–y), n = 39 in the healthy control group and n = 52 in the AD group (* p < 0.05, ** p < 0.01, *** p < 0.001 compared with control group).
Figure 8
Figure 8
Effect of different concentrations of GT extract (62.5, 125, 250 μg/mL) on tau phosphorylation in OA-induced tau hyperphosphorylation in SHSY-5Y cells. ## p < 0.01 compared with control group; ** p < 0.01 compared with model group.
Figure 9
Figure 9
Various concentrations of GT extract suppressed H2O2-induced cytotoxicity (a) and Na2S2O4-induced cytotoxicity (b) in SH-SY5Y cells. ## p < 0.01 compared with control group; ** p < 0.01 compared with model group.
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Supplementary concepts