HDAC inhibitors promote pancreatic stellate cell apoptosis and relieve pancreatic fibrosis by upregulating miR-15/16 in
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RESEARCH ARTICLE
HDAC inhibitors promote pancreatic stellate cell apoptosis and relieve pancreatic fibrosis by upregulating miR‑15/16 in chronic pancreatitis Ting Ji1 · Weiguang Feng2 · Xiangcheng Zhang1 · Kui Zang1 · Xingxing Zhu1 · Futai Shang1 Received: 1 March 2020 / Accepted: 4 June 2020 © The Author(s) 2020
Abstract In chronic pancreatitis, PSCs are activated by proinflammatory cytokines to induce pancreatic fibrogenesis. HDAC inhibition protected against the pancreatic fibrosis and the apoptosis of PSCs through induced apoptosis and depressed inflammation. In our study, we found that miR-15 and miR-16 decreased significantly in chronic pancreatitis and HDAC inhibition could recover the levels of these two miRNAs. HDAC regulated the transcription of miR-15 and miR-16, which then modulate the apoptosis and fibrosis of PSCs. And we proved that Bcl-2 and Smad5 were the target genes of miR-15 and miR-16, which illustrated how HDAC inhibition alleviated the apoptosis and fibrogenesis of PSCs in chronic pancreatitis. These results suggested that HDAC inhibition protects against CP by promoting apoptosis and TGF-β/Smads signaling pathways, and indicated that HDAC inhibition is a potential therapy to alleviate CP patients in clinic, and these need to be explored further. Keywords Chronic pancreatitis · HDAC inhibition · Apoptosis · miR-15/miR-16
Introduction Chronic pancreatitis (CP) usually came from long-term damage to the pancreas, eventually caused endocrine and exocrine deficiency characterized by maldigestion and diabetes [1, 2]. The histologic features of CP include chronic inflammatory, fibrosis, acinar cell atrophy and distorted or blocked ducts [2–4]. Once damaged, pancreatic stellate cells (PSCs) are activated by proinflammatory cytokines to induce pancreatic fibrogenesis [5]. They can secrete excessive amounts of extracellular matrix (ECM) proteins which comprise fibrous tissue [6, 7]. Many researchers have attempted to identify how inflammation and apoptosis of the PSCs caused
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13577-020-00387-x) contains supplementary material, which is available to authorized users. * Futai Shang [email protected] 1
Intensive Care Unit, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, Beijing West Road, Huaiyin District, Huai’an 223300, Jiangsu, China
Intensive Care Unit, Huai’an No 4 People’s Hospital, 128 Yan’an East Road, Qingjiangpu District, Huai’an 223002, Jiangsu, China
2
chronic pancreatitis eventually, but the details of the mechanism were still unknown. HDAC enzymes involve removing the acetyl group from the histones comprising the nucleosome, and decreased levels of acetylation are usually associated with repression of gene expression [8, 9]. In recent years, HDAC inhibitors have emerged as a novel class of agents that regulate chromatin structure and gene expression, inducing growth inhibition, apoptosis, and differentiation, such as Vorinostat (SAHA) and Trichostatin
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