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. 2024 Oct 10:15:1472146.
doi: 10.3389/fendo.2024.1472146. eCollection 2024.

Protective effects of arecanut seed phenols in retinoic acid induced osteoporosis and the potential mechanisms explored by network pharmacology

Min-Min Tang  1   2 , Li-Ping Sun  3 , Fei Song  1   2 , Hua Chen  1   2
Affiliations

Protective effects of arecanut seed phenols in retinoic acid induced osteoporosis and the potential mechanisms explored by network pharmacology

Min-Min Tang et al. Front Endocrinol (Lausanne). .

Abstract

Background: Arecanut seed is an important traditional medicine in Southeast Asia. It has been presented in a clinical formula to treat osteoporosis (OP) in China. Arecanut seed is abundant in phenols. However, most of current studies mainly focused on estrogen-deficient osteoporosis (OP) model of arecanut seed phenols (ASP), there is still a lack of roundly research about molecular mechanism of ASP therapy on OP and its influence on in drug-induced bone loss.

Materials and methods: To explore potential molecular mechanisms and the effects of ASP on OP, network pharmacology, molecular docking methods and a retinoic acid-induced OP rat model were employed in this study. According to the network pharmacology method, OP related targets and ASP compound related targets were collected from databases to obtain hub targets and top active chemicals in ASP treating OP. The potential therapic pathways were also calculated. Binding capacities of top active chemicals to hub targets were analyzed by molecular dock assay. In the animal experiment, osteocalcin (OCN) levels and alkaline phosphatase (ALP) activity in serum of all the rats were determined. The views of bone section were stained to observe the bone micro-structure of ASP affects. Bone mineral density (BMD), cortical bone thickness (CBT), area ratio of bone cortex (CAR) and area ratio of bone trabecula (TAR) were obtained from micro computed tomography to evaluate the effectiveness of ASP on bone loss.

Conclusion: Three hub genes and three top active compounds were screened by network pharmacology analysis and they combined well with each other. ASP had positive effects on alleviating RA-induced bone loss by regulating the expression of the hub genes. Signals in IL-17 pathway were predicted and primarily verified being potential targets in ASP treating OP.

Keywords: arecanut seed; molecular docking; network pharmacology; osteoporosis; phenols.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Network pharmacology predicts mechanisms and targets of ASP therapy for OP. (A) Network pharmacology procedures. (B) Interaction network between ASP compounds and potential targets (The green rectangle is active compounds of ASP; The red to light red oval is the intersection of target disease and ASP). (C) Construction of a PPI network of all overlapped potential target proteins (The darker the color, the larger node, indicating that the node plays a central role in the PPI network).
Figure 2
Figure 2
The GO analysis of interacting targets.
Figure 3
Figure 3
The KEGG analysis of interacting targets.
Figure 4
Figure 4
Molecular docking analysis of active compounds and core targets. (A-C) Kaempferol-TNF-α, Isorhamnetin-TNF-α, Acacetin-TNF-α; (D-F) Kaempferol-IL-6, Isorhamnetin IL-6, Acacetin IL-6; (G-I) Kaempferol-TP53, Isorhamnetin-TP53, Acacetin-TP53. Note: Data are mean ± SD, different lowercases mean there is significant difference between the corresponding groups at p<0.05. Lowercases have the same meaning in the following figures.
Figure 5
Figure 5
Effects of ASP on serum parameters in retinoic acid-induced osteoporosis rats. (A) Effects of ASP on serum calcium and phosphorus contents in retinoic acid-induced osteoporosis rats. (B) Effects of ASP on serum OCN content and activities of ALP and TRAP in retinoic acid-induced osteoporosis rats. Different lowercases mean there is significant difference between the corresponding groups at p<0.05. Lowercases have the same meaning in the following figures.
Figure 6
Figure 6
Effects of ASP on bone histomorphometry parameters in retinoic acid-induced osteoporosis rats. (A) Effects of ASP on length and diameter of femur and tibia in retinoic acid-induced osteoporosis rats. (B) Effects of ASP on bone weight and BMD of femur and tibia in retinoic acid-induced osteoporosis rats. (C) Effects of ASP on bone calcium and phosphorous contents in retinoic acid-induced osteoporosis rats.
Figure 7
Figure 7
Effects of ASP on bone histopathology of retinoic acid-induced osteoporosis rats. (A) Effects of ASP on osteoclastogenesis in left tibias of rats (magnification of 100×). (B) Effects of ASP on trabecular microarchitectures of the left femur of rats (magnification 400×). (C) Effects of ASP on cortical microarchitectures of the left femur of rats (magnification 400×).
Figure 8
Figure 8
Effects of ASP on micro-CT views of femur and tibia of retinoic acid-induced osteoporosis rats. (A) Micro-CT views of left femur. (B) Micro-CT views of right tibia. (C) TAR, CBT and CAR calculated based on the mirco-CT views.
Figure 9
Figure 9
Effects of ASP on genes of right femur in in retinoic acid-induced osteoporosis rats.
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