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Radix Scrophulariae Extracts Exert Effect on Hyperthyroidism via MST1/Hippo Signaling Pathway

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Abstract

Objective

To explore the mechanism of Radix Scrophulariae (RS) extracts in the treatment of hyperthyroidism rats by regulating proliferation, apoptosis, and autophagy of thyroid cell through the mammalian sterile 20-like kinase 1 (MST1)/Hippo pathway.

Methods

Twenty-four rats were randomly divided into 4 groups according to a random number table: control, model group, RS, and RS+Hippo inhibitor (XMU-MP-1) groups (n=6 per group). Rats were gavaged with levothyroxine sodium tablet suspension (LST, 8 μ g/kg) for 21 days except for the control group. Afterwards, rats in the RS group were gavaged with RS extracts at the dose of 1,350 mg/kg, and rats in the RS+XMU-MP-1 group were gavaged with 1,350 mg/kg RS extracts and 1 mg/kg XMU-MP-1. After 15 days of administration, thyroid gland was taken for gross observation, and histopathological changes were observed by hematoxylin-eosin staining. The structure of Golgi secretory vesicles in thyroid tissues was observed by transmission electron microscopy. The expression of thyrotropin receptor (TSH-R) was observed by immunohistochemistry. Terminal-deoxynucleoitidyl transferase mediated nick end labeling assay was used to detect cell apoptosis in thyroid tissues. Real-time quantity primer chain reaction and Western blot were used to detect the expressions of MST1, p-large tumor suppressor gene 1 (LATS1), p-Yes1 associated transcriptional regulator (YAP), proliferating cell nuclear antigen (PCNA), G1/S-specific cyclin-D1 (Cyclin D1), B-cell lymphoma-2 (Bcl-2), Caspase-3, microtubule-associated proeins light chain 3 II/I (LC3-II/I), and recombinant human autophagy related 5 (ATG5). Thyroxine (T4) level was detected by enzyme-linked immunosorbent assay.

Results

The thyroid volume of rats in the model group was significantly increased compared to the normal control group (P<0.01), and pathological changes such as uneven size of follicular epithelial cells, disorderly arrangement, and irregular morphology occurred. The secretion of small vesicles by Golgi apparatus was reduced, and the expressions of receptor protein TSH-R and T4 were significantly increased (P<0.01), while the expressions of MST1, p-LATS1, p-YAP, Caspase-3, LC3-II/I, and ATG5 were significantly decreased (P<0.01). The expressions of Bcl-2, PCNA, and cyclin D1 were significantly increased (P<0.01). Compared with the model group, RS extracts reduced the volume of thyroid gland, improved pathological condition of the thyroid gland, promoted secretion of the secretory vesicles with double-layer membrane structure in thyroid Golgi, significantly inhibited the expression of TSH-R and T4 levels (P<0.01), upregulated MST1, p-LATS1, p-YAP, Caspase-3, LC3-II/I, and ATG5 expressions (P<0.01), and downregulated Bcl-2, PCNA, and Cyclin D1 expressions (P<0.01). XMU-MP-1 inhibited the intervention effects of RS extracts (P<0.01).

Conclusion

RS extracts could inhibit proliferation and promote apoptosis and autophagy in thyroid tissues through MST1/Hippo pathway for treating hyperthyroidism.

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Authors and Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 50001, China

    Ning Zhang & Ling Li

  2. Department of Chinese Medicine Rehabilitation, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 50001, China

    Tao Ye

  3. College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China

    Xu Lu

  4. College of Life and Health, Dalian University, Dalian, Liaoning Province, 116622, China

    Zi-hui Li

Authors
  1. Ning Zhang
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  2. Tao Ye
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  3. Xu Lu
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  4. Zi-hui Li
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  5. Ling Li
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Contributions

Zhang N and Ye T contributed equally to this work. Zhang N was involved in the conception, design, and operation of the research. Ye T and Lu X drafted the manuscript. Lu X and Li ZH carried out the animal experiments. Ye T performed statistical analysis. Li L participated in the design and operation of the research. All authors are involved in reviewing the final draft.

Corresponding author

Correspondence to Ling Li.

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The authors declare there is no conflicts of interest regarding the publication of this paper.

Additional information

Supported by the National Natural Science Foundation of China (No. 82060830), Guizhou Province Traditional Chinese Medicine, Ethnic Medicine Science, and Technology Research Poject (No. QZYY-2021-113), and Science and Technology Fund Project of Guizhou Provincial Health Commission (No. gzwkj2021-457)

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Zhang, N., Ye, T., Lu, X. et al. Radix Scrophulariae Extracts Exert Effect on Hyperthyroidism via MST1/Hippo Signaling Pathway. Chin. J. Integr. Med. 29, 998–1006 (2023). https://doi.org/10.1007/s11655-023-3744-7

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