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Stem bark of Fraxinus rhynchophylla ameliorates the severity of pancreatic fibrosis by regulating the TGF-β/Smad signaling pathway
  1. Ji-Won Choi1,2,
  2. Joon Yeon Shin1,
  3. Ziqi Zhou1,
  4. Dong-Uk Kim2,
  5. Bitna Kweon1,
  6. Hyuncheol Oh3,
  7. Youn-Chul Kim3,
  8. Ho-Joon Song1,
  9. Gi-Sang Bae2,4,5,
  10. Sung-Joo Park1,2
  1. 1 Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
  2. 2 Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
  3. 3 Institute of Pharmaceutical Research and Development, College of Pharmacy, WonkwangUniversity, Iksan, Jeollabuk-do, Republic of Korea
  4. 4 Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
  5. 5 Research Center of Traditional Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
  1. Correspondence to Professor Sung-Joo Park, Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea; parksj08{at}wku.ac.kr; Professor Gi-Sang Bae, Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea; baegs888{at}wku.ac.kr

Abstract

Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis. Fraxinus rhynchophylla (FR) reportedly exhibits anti-inflammatory, antioxidative and antitumor activities. Although FR possesses numerous properties associated with the regulation of diverse diseases, the effects of FR on CP remain unknown. Herein, we examined the effects of FR on CP. For CP induction, mice were intraperitoneally administered cerulein (50 μg/kg) 6 times a day, 4 days per week for 3 weeks. FR extract (100 or 400 mg/kg) or saline (control group) was intraperitoneally injected 1 hour before the first cerulein injection. After 3 weeks, the pancreas was harvested for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the antifibrogenic effects and regulatory mechanisms of FR. Administration of FR significantly inhibited histological damage in the pancreas, increased pancreatic acinar cell survival, decreased PSC activation and collagen deposition, and decreased pro-inflammatory cytokines. Moreover, FR treatment inhibited the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, fibronectin 1, and decreased pro-inflammatory cytokines in isolated PSCs stimulated with transforming growth factor (TGF)-β. Furthermore, FR treatment suppressed the phosphorylation of Smad 2/3 but not of Smad 1/5 in TGF-β-stimulated PSCs. Collectively, these results suggest that FR ameliorates pancreatic fibrosis by inhibiting PSC activation during CP.

  • pancreatitis
  • fibroblasts
  • transforming growth factors

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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Footnotes

  • J-WC, JYS and ZZ contributed equally.

  • Contributors J-WC, JYS, and ZZ: methodology, original draft writing. D-UK and BK: investigation. HO and Y-CK: resources. H-JS: data analysis. G-SB and S-JP: study design and data analysis. S-JP: supervision and guarantor. All authors revised and approved the final version of the manuscript.

  • Funding This research was supported by the National Research Foundation of Korea (NRF), grant funded by the Korean government (NRF-2019R1A2C2008814, NRF-2017R1A5A2015805, NRF-2020R1C1C1011297).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.