Spautin-A41 Attenuates Cerulein-Induced Acute Pancreatitis through Inhibition of Dysregulated Autophagy

Kai Dong; Xia Chen; Liping Xie; Lanting Yu; Mengjun Shen; Yanping Wang; Shanshan Wu; Jiajia Wang; Junxi Lu; Gang Wei; Dongliang Xu; Liu Yang

doi:10.1248/bpb.b19-00132

Regular Articles

Spautin-A41 Attenuates Cerulein-Induced Acute Pancreatitis through Inhibition of Dysregulated Autophagy

Kai Dong, Xia Chen, Liping Xie, Lanting Yu, Mengjun Shen, Yanping Wang, Shanshan Wu, Jiajia Wang, Junxi Lu, Gang Wei, Dongliang Xu, Liu Yang

Author information

Kai Dong
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Xia Chen
Department of Endocrinology and Metabolism, Shanghai Fourth People’s Hospital, Tongji University
Liping Xie
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Lanting Yu
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Mengjun Shen
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Yanping Wang
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Shanshan Wu
Shandong University Affiliated Shandong Provincial Hospital Affiliated, Department of Endocrinology and Metabolism
Jiajia Wang
Department of Endocrinology, Medical College of Soochow University
Junxi Lu
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Gang Wei
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Dongliang Xu
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Department of Urology, Changzheng Hospital, Second Military Medical University
Liu Yang Corresponding author
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital

Keywords: spautin-A41, pancreatitis, autophagy, spautin-1, Class III phosphatidylinositol 3 (PI3) kinase

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Supplementary material

2019 Volume 42 Issue 11 Pages 1789-1798

DOI https://doi.org/10.1248/bpb.b19-00132

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Abstract

Autophagy plays key roles in the development of acute pancreatitis (AP) and the regulation of impaired autophagy has therapeutic potential. The objective of the present study was to investigate whether pharmacological inhibition of autophagy could ameliorate AP in mice and examine the underlying mechanisms. In current study, by imaging-based high-throughput screening, a novel spautin-1 derivative spautin-A41 was identified as a potent autophagy inhibitor. Mice treated with spautin-A41 were resistant to the cerulein-induced elevation of serum pancreatic enzyme activities and pancreatic apoptosis. Mechanistically, spautin-A41 effectively reduced the expression levels of Class III phosphatidylinositol 3 (PI3) kinase complexes and subsequently ameliorated pancreatitis by inhibiting the formation of autophagosome. Therefore, pharmacological inhibition of autophagy by spautin-A41 may serve as new target for treating or lessening the severity of AP.

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