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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2021, Vol. 15 Issue (2) : 313-329    https://doi.org/10.1007/s11684-020-0737-1
RESEARCH ARTICLE
H. sinensis mycelium inhibits epithelial--mesenchymal transition by inactivating the midkine pathway in pulmonary fibrosis
Li Lu1, Haiyan Zhu1, Hailin Wang1, Huaping Liang3(), Yayi Hou1,2,4(), Huan Dou1,2,4()
1. The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China
2. Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
3. State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Army Medical University, Chongqing 400042, China
4. Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China
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Abstract

The medical fungus Hirsutella sinensis has been used as a Chinese folk health supplement because of its immunomodulatory properties. Our previous studies established the antifibrotic action of Hirsutella sinensis mycelium (HSM) in the lung. The epithelial–mesenchymal transition (EMT) is involved in the pathogenesis of idiopathic pulmonary fibrosis. The present study investigates the role of HSM in mediating EMT during the development of pulmonary fibrosis. HSM significantly inhibits bleomycin (BLM)-induced pulmonary fibrosis by blocking the EMT. In addition, the expression levels of midkine are increased in the lungs of the BLM-induced group. Further analysis of the results indicates that the mRNA level of midkine correlated positively with EMT. HSM markedly abrogates the transforming growth factor β-induced EMT-like phenotype and behavior in vitro. The activation of midkine related signaling pathway is ameliorated following HSM treatment, whereas this extract also caused an effective attenuation of the induction of EMT (caused by midkine overexpression) in vitro. Results further confirm that oral medication of HSM disrupted the midkine pathway in vivo. Overall, findings suggest that the midkine pathway and the regulation of the EMT may be considered novel candidate therapeutic targets for the antifibrotic effects caused by HSM.

Keywords epithelial–mesenchymal transition      H. sinensis mycelium      midkine      pulmonary fibrosis     
Corresponding Author(s): Huaping Liang,Yayi Hou,Huan Dou   
Just Accepted Date: 27 September 2020   Online First Date: 12 November 2020    Issue Date: 23 April 2021
 Cite this article:   
Li Lu,Haiyan Zhu,Hailin Wang, et al. H. sinensis mycelium inhibits epithelial--mesenchymal transition by inactivating the midkine pathway in pulmonary fibrosis[J]. Front. Med., 2021, 15(2): 313-329.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0737-1
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I2/313
Forward (5′−3′) Reverse (5′−3′)
Midkine CGCGGTCGCCAAAAAGAAAG TACTTGCAGTCGGCTCCAAAC
h-NOX1 TTGTTTGGTTAGGGCTGAATGT GCCAATGTTGACCCAAGGATTTT
h-Notch2 CCTTCCACTGTGAGTGTCTGA AGGTAGCATCATTCTGGCAGG
h-ACE GGAGGAATATGACCGGACATCC TGGTTGGCTATTTGCATGTTCTT
h-vimentin GCCCTAGACGAACTGGGTC GGCTGCAACTGCCTAATGAG
h-E-cadherin CGAGAGCTACA-CGTTCACGG CGAGAGCTACACGTTCACGG
h-GAPDH AGAAGGCTGGGGCTCATTTG AGGGGCCATCCACAGTCTTC
h-N-cadherin TTTGATGGAGGTCTCCTAACACC ACGTTTAACACGTTGGAAATGTG
m-vimentin CGTCCACACGCACCTACAG GGGGGATGAGGAATAGAGGCT
m-E-cadherin GTGCAGGTGTCCGATGTCAA GGAGATTAACGAGGAGAGTGGC
m-N-cadherin AGGCTTCTGGTGAAATTGCAT GTCCACCTTGAAATCTGCTGG
m-NOX1 GCTGGATTTGAGAGCGTTGC GGTGGTATCTAGGGCTATGCT
mNotch2 GAGAAAAACCGCTGTCAGAATGG GGTGGAGTATTGGCAGTCCTC
mACE ATGACAAGCGACTTCTCCCC CCAAACCGAGGACCCCATAGA
mGAPDH AACGACCCCTTCATTGAC TCCACGACATACTCAGCAC
Tab.1  Primers used for q-PCR in this study
Fig.1  HSM alleviated EMT in BLM-treated mice with lung fibrosis. (A) The experimental plan was visualized. (B) Hydroxyproline analysis was performed to quantify the deposition of collagen. (C) H&E staining and Masson staining were used to determine the degree of fibrosis. The scale bar indicated 100 μm in the images (20×). (D) Immunohistochemical staining for the E-cadherin, α-SMA was performed. The scale bar indicated 10 μm in the images (100×). (E) The mRNA levels of vimentin, N-cadherin and E-cadherin in lung tissues were analyzed through qRT-PCR analyses. (F) The protein levels of vimentin, N-cadherin, and E-cadherin in the lung tissues were analyzed through Western blot analyses. Data represent the mean ± SD of three separate experiments. n = 6. *P<0.05, **P<0.01, *** P<0.005, vs. control group. #P<0.05, ##P<0.01, ###P<0.005, vs. BLM group.
Fig.2  HSM inhibited the expression levels of midkine in the lung tissues of BLM-induced mice. (A) The mRNA levels of midkine was performed using qRT-PCR analyses. (B) The protein level of midkine was determined using Western blot analyses. (C) The immunohistochemical staining was performed to determine the expression and location of midkine. The scale bar indicated 10 mm in the images (10×). Data represent the mean ± SD of three separate experiments. n = 6. *P<0.05, **P<0.01, *** P<0.005, vs. control group. #P<0.05, ##P<0.01, ###P<0.005, vs. BLM group.
Fig.3  The expression levels of midkine were positively associated with EMT activation. (A) The correlation between midkine and EMT markers (a-SMA, vimentin, N-cadherin, and E-cadherin) in the lung tissue. (B) A549 cells were transfected with pcDNA3.1/midkine plasmid, and mRNA expression levels of midkine, vimentin, N-cadherin and E-cadherin were determined using qRT-PCR analyses. (C) The protein levels of midkine, vimentin, N-cadherin, and E-cadherin were analyzed by Western blot analyses. (D) The expression of N-cadherin and α-SMA were analyzed by immunofluorescence staining. The scale bar indicated 100 μm in the images (40×). Data represent the mean±SD of three separate experiments. n = 6. *P<0.05, **P<0.01, *** P<0.005, vs. Vehicle group.
Fig.4  HSM inhibited TGF-β1-induced EMT in A549 cells. (A) A549 cells were treated with various concentrations of HSM and cultured for 24 hours. The cell viability was analyzed by the CCK8 assay. A549 cells were pretreated with HSM for 2 hours and were subsequently treated with or without TGF-β1 (5 ng/mL) for 24 hours. (B) The mRNA levels of vimentin, E-cadherin, and N-cadherin were analyzed through qRT-PCR analyses. (C) The protein levels of vimentin, E-cadherin, and N-cadherin were performed using Western blot analyses. (D) The protein levels of α-SMA and collagen were performed using Western blot analyses. (E) The expression of EMT markers (vimentin and α-SMA) were analyzed by immunofluorescence staining. The scale bar indicated 100 μm in the images (100×). Data represent the mean±SD of three separate experiments *P<0.05, **P<0.01, ***P<0.005, vs. control group. #P<0.05, ##P<0.01, ###P<0.005, vs. BLM group.
Fig.5  HSM inhibited the expression of midkine and its downstream signaling proteins in the TGF-β1-induced EMT model. A549 cells were pretreated with HSM for 2 hours and treated with or without TGF-β (5 ng/mL) for 24 hours. The mRNA levels of midkine (A), NOX1, Notch2, and ACE (C) were analyzed through qRT-PCR analyses. The protein levels of midkine (B), NOX1, Notch2, and ACE (D) were analyzed by Western blot analyses. Data represent the mean ± SD of three separate experiments. *P<0.05, **P<0.01, *** P<0.005, vs. control group. #P<0.05, ##P<0.01, ###P<0.005, vs. BLM group.
Fig.6  HSM inhibited induction of EMT by midkine overexpression in A549 cells. A549 cells were pretreated with HSM for 2 hours and then transfected with pcDNA3.1/midkine plasmid. (A) The mRNA expression of midkine was analyzed through qRT-PCR analyses. (B) The protein levels of midkine was analyzed using western blot analyses. (C) The expression of midkine was analyzed by immunofluorescence staining. The scale bar indicated 100 μm in the images (100×). (D) The mRNA expression of NOX1, Notch2, and ACE were analyzed using qRT-PCR analyses. (E) The protein levels of NOX1, Notch2, and ACE were performed by Western blot analyses. Data represent the mean ± SD of three separate experiments. #P<0.05, ##P<0.01, ###P<0.005, vs. vehicle group without HSM treatment. *P<0.05, **P<0.01, ***P<0.005, vs. transfected with pcDNA/midkine but without HSM treatment group.
Fig.7  HSM inhibited BLM-induced midkine signaling pathway activation in vivo. A549 cells were pretreated with HSM for 2 hours and were subsequently transfected with pcDNA3.1/midkine plasmid. (A) The mRNA expression of vimentin, N-cadherin, and E-cadherin were analyzed using qRT-PCR analyses. (B) The protein levels of vimentin, N-cadherin, and E-cadherin were performed using Western blot analyses. (C) The expression of vimentin and α-SMA were analyzed by immunofluorescence staining. The scale bar indicated 100 mm in the images (40×). Data represent the mean±SD of three separate experiments. #P<0.05, ##P<0.01, ###P<0.005, vs. vehicle group without HSM treatment. *P<0.05, **P<0.01, *** P<0.005, vs. transfected with pcDNA/midkine but without HSM treatment group.
Fig.8  HSM inhibited BLM-induced midkine signaling pathway activation in vivo. (A) The mRNA levels of NOX1, Notch2, and ACE in mouse lung tissue were analyzed using real-time PCR. (B) The protein levels of NOX1, Notch2, and ACE in the mouse lung tissue were analyzed by Western blot analyses. Data represent the mean ± SD of three separate experiments. *P<0.05, **P<0.01, *** P<0.005, vs. control group. #P<0.05, ##P<0.01, ###P<0.005, vs. BLM group.
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[1] Qiuxia Han, Hanyu Zhu, Xiangmei Chen, Zhangsuo Liu. Non-genetic mechanisms of diabetic nephropathy[J]. Front. Med., 2017, 11(3): 319-332.
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