Lnc-PFAR facilitates autophagy and exacerbates pancreatic fibrosis by reducing pre-miR-141 maturation in chronic pancreatitis

AbstractChronic pancreatitis (CP) is described as progressive inflammatory fibrosis of pancreas, accompanied with irreversible impaired endocrine and exocrine insufficiency. Pancreatic stellate cells (PSCs) are widely distributed in the stroma of the pancreas and PSCs activation has been shown as one of the leading causes for pancreatic fibrosis. Our previous study has revealed that autophagy is dramatically activated in CP tissues, which facilitates PSCs activation and pancreatic fibrosis. Long non-coding RNAs (LncRNAs) have been recognized as crucial regulators for fibrosis-related diseases. LncRNAs interact with RNA binding protein or construct competitive endogenous RNA (ceRNA) hypothesis which elicited the fibrotic processes. Until now, the effects of lncRNAs on PSCs activation and pancreatic fibrosis have not been clearly explored. In this study, a novel lncRNA named Lnc-PFAR was found highly expressed in mouse and human CP tissues. Our data revealed that Lnc-PFAR facilitates PSCs activation and pancreatic fibrosis via RB1CC1-induced autophagy. Lnc-PFAR reduces miR-141 expression by suppressing pre-miR-141 maturation, which eventually upregulates the RB1CC1 and fibrosis-related indicators expression. Meanwhile, Lnc-PFAR enhanced PSCs activation and pancreatic fibrosis through trigging autophagy. Our study interrogates a novel lncRNA-induced mechanism in promoting the development of pancreatic fibrosis, and Lnc-PFAR is suggested to be a prospective therapeutic target in clinical scenarios.

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Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway

PLoS ONE ◽

10.1371/journal.pone.0141462 ◽

2015 ◽

Vol 10 (11) ◽

pp. e0141462 ◽

Cited By ~ 27

Author(s):

Wenqin Xiao ◽

Weiliang Jiang ◽

Jie Shen ◽

Guojian Yin ◽

Yuting Fan ◽

...

Keyword(s):

Retinoic Acid ◽

Chronic Pancreatitis ◽

Signaling Pathway ◽

Stellate Cells ◽

Pancreatic Fibrosis ◽

Pancreatic Stellate Cells ◽

Experimental Chronic Pancreatitis

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Rhein, a Natural Anthraquinone Derivative, Attenuates the Activation of Pancreatic Stellate Cells and Ameliorates Pancreatic Fibrosis in Mice with Experimental Chronic Pancreatitis

PLoS ONE ◽

10.1371/journal.pone.0082201 ◽

2013 ◽

Vol 8 (12) ◽

pp. e82201 ◽

Cited By ~ 30

Author(s):

Siu Wai Tsang ◽

Hongjie Zhang ◽

Chengyuan Lin ◽

Haitao Xiao ◽

Michael Wong ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Stellate Cells ◽

Pancreatic Fibrosis ◽

Pancreatic Stellate Cells ◽

Anthraquinone Derivative ◽

Experimental Chronic Pancreatitis

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NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00272.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. G99-G108 ◽

Cited By ~ 81

Author(s):

Atsushi Masamune ◽

Takashi Watanabe ◽

Kazuhiro Kikuta ◽

Kennichi Satoh ◽

Tooru Shimosegawa

Keyword(s):

Chronic Pancreatitis ◽

Nadph Oxidase ◽

Stellate Cells ◽

Pancreatic Fibrosis ◽

Pancreatic Stellate Cells ◽

Human Pancreas ◽

Ros Production ◽

Chemokine Production ◽

Cell Functions ◽

Diphenylene Iodonium

Activated pancreatic stellate cells (PSCs) play an important role in pancreatic fibrosis and inflammation, where oxidative stress is implicated in the pathogenesis. NADPH oxidase might be a source of reactive oxygen species (ROS) in the injured pancreas. This study aimed to clarify the expression and regulation of cell functions by NADPH oxidase in PSCs. PSCs were isolated from rat and human pancreas tissues. Expression of NADPH oxidase was assessed by reverse transcription-PCR and immunostaining. Intracellular ROS production was assessed using 2′,7′-dichlorofluorescin diacetate. The effects of diphenylene iodonium (DPI) and apocynin, inhibitors of NADPH oxidase, on key parameters of PSC activation were evaluated in vitro. In vivo, DPI (at 1 mg·kg body wt−1·day−1) was administered in drinking water to 10-wk-old male Wistar Bonn/Kobori rats for 10 wk and to rats with chronic pancreatitis induced by dibutyltin dichloride (DBTC). PSCs expressed key components of NADPH oxidase (p22phox, p47phox, NOX1, gp91phox/NOX2, NOX4, and NOX activator 1). PDGF-BB, IL-1β, and angiotensin II induced ROS production, which was abolished by DPI and apocynin. DPI inhibited PDGF-induced proliferation, IL-1β-induced chemokine production, and expression of α-smooth muscle actin and collagen. DPI inhibited transformation of freshly isolated cells to a myofibroblast-like phenotype. In addition, DPI inhibited the development of pancreatic fibrosis in Wistar Bonn/Kobori rats and in rats with DBTC-induced chronic pancreatitis. In conclusion, PSCs express NADPH oxidase to generate ROS, which mediates key cell functions and activation of PSCs. NADPH oxidase might be a potential target for the treatment of pancreatic fibrosis.

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Baicalin Ameliorates Pancreatic Fibrosis by Inhibiting the Activation of Pancreatic Stellate Cells in Mice with Chronic Pancreatitis

Frontiers in Pharmacology ◽

10.3389/fphar.2020.607133 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jianwei Fan ◽

Lifang Duan ◽

Nan Wu ◽

Xiaofan Xu ◽

Jiaqi Xin ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Stellate Cells ◽

Pancreatic Fibrosis ◽

Pancreatic Stellate Cells ◽

Type I ◽

Alpha Smooth Muscle Actin

Pancreatic inflammation and fibrosis are typical pathological features in chronic pancreatitis (CP). Activated pancreatic stellate cells (PSCs) have been regarded as the core event in the development of pancreatic fibrosis and are considered to be the key target for treatment of CP. Baicalin (C21H18O11), the main chemical composition of Baikal skullcap in the traditional Chinese medicines Dachaihu decoction (DCHD) and Xiaochaihu decoction (XCHD), has shown significant effects in the treatment of pancreatic fibrosis in CP mice; however, whether baicalin can inhibit the activation of PSCs and its underlying mechanism remain unclear. In this study, the influence of baicalin on activated PSCs in vitro and in vivo was investigated, and the results showed that Baicalin could significantly ameliorate the degree of pancreatic inflammation and fibrosis, while decreasing the levels of alpha-smooth muscle actin (α-SMA), F4/80 (surface markers of mouse macrophages), nuclear factor kappa-B (NF-κB), monocyte chemotactic protein 1 (MCP-1), and collagen type I alpha 1 (COL1A1)in the pancreas. Moreover, NF-κB and α-SMA were co-expressed in the pancreas of CP mice. Baicalin treatment markedly reduced the expression of co-location of α-SMA and NF-κB. In vitro, the protein expression levels of transforming growth factor-β receptor 1 (TGF-βR1), phosphorylated TGF-β activated kinase 1 p-TAK 1, and NF-κBp65 in PSCs were all remarkably reduced after treatment with baicalin. In addition, baicalin could inhibit MCP-1 mRNA expression in supernatant of activated PSCs, as well as the excessive migration of macrophages. Taken together, our findings indicated that baicalin could inhibit the TGF-β1/TGF-βR1/TAK1/NF-κB signaling pathway of activated PSCs, reduce the secretion of MCP-1, and further decrease the infiltration of macrophages and inflammation cells of the local microenvironment of the pancreas. Thus, this study provides a reliable experimental basis for baicalin in the prevention and treatment of CP.

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Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis

Scientific Reports ◽

10.1038/s41598-020-76095-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Lin Gao ◽

Xiao-Feng Lei ◽

Aya Miyauchi ◽

Masahito Noguchi ◽

Tomokatsu Omoto ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Smooth Muscle Actin ◽

Stellate Cells ◽

Matrix Proteins ◽

Pancreatic Fibrosis ◽

Pancreatic Stellate Cells ◽

Pathological Conditions ◽

Potential Marker ◽

Actin Expression ◽

Tgf Β1

Abstract Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.

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New aspects of formation and progression of pancreatic fibrosis in pancreatitis

Herald of Pancreatic Club ◽

10.33149/vkp.2019.02.03 ◽

2019 ◽

Vol 43 (2) ◽

pp. 20-24

Author(s):

V. A. Akhmedov ◽

O. V. Gaus

Keyword(s):

Extracellular Matrix ◽

Chronic Pancreatitis ◽

Growth Factor ◽

Transforming Growth Factor ◽

Stellate Cells ◽

Transforming Growth Factor Β ◽

Pancreatic Fibrosis ◽

Pancreatic Stellate Cells ◽

Main Components ◽

Acute And Chronic Pancreatitis

Fibrosis formation is a dynamic process during which the formation of an extracellular matrix takes place in interstitial spaces and areas where the main components of exocrine pancreatic function (acinar cells) are damaged. According to studies, the biggest role in the formation of pancreatic fibrosis upon chronic pancreatitis is played by various types of effector cells, such as fibroblasts, myofibroblasts and fibrocytes, while fibroblasts and myofibroblasts are the key fibrosis cells responsible for the secretion of extracellular matrix. Activated pancreatic stellate cells become main components of fibrosis formation in patients with chronic pancreatitis, synthesizing transforming growth factor-β, fibroblast growth factor, which leads to enhanced synthesis of extracellular matrix. The presented review highlights molecular mechanisms (Rho-kinase, mitogen-activating protein kinase, transforming growth factor-β, associated with the protein encoded by SMAD in humans, phosphatidylinositol-3 kinase), which play an important role in the activation of pancreatic stellate cells and launching the phenomenon of pancreatic fibrogenesis. The presented data opens up prospects for the development of diagnostic areas with the search for new markers for the diagnosis of acute and chronic pancreatitis along with development of new therapeutic options for the pathogenetic therapy of patients with acute and chronic pancreatitis based on the results obtained.

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Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

Autophagy ◽

10.1080/15548627.2018.1503146 ◽

2018 ◽

Vol 14 (12) ◽

pp. 2083-2103 ◽

Cited By ~ 70

Author(s):

Zili Zhang ◽

Zhen Yao ◽

Ling Wang ◽

Hai Ding ◽

Jiangjuan Shao ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Stellate Cells

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Activated Pancreatic Stellate Cells Promote Acinar Duct Metaplasia by Disrupting Mitochondrial Respiration and Releasing Reactive Oxygen Species

Current Chinese Science ◽

10.2174/2210298101666210928122952 ◽

2021 ◽

Vol 01 ◽

Author(s):

Hong Xiang ◽

Fangyue Guo ◽

Qi Zhou ◽

Xufeng Tao ◽

Deshi Dong

Keyword(s):

Reactive Oxygen Species ◽

Mitochondrial Respiration ◽

Reactive Oxygen ◽

Acinar Cells ◽

Stellate Cells ◽

Pancreatic Fibrosis ◽

Pancreatic Stellate Cells ◽

Pancreatic Acinar Cells ◽

Oxygen Species

Background: Chronic pancreatitis (CP) is a long-term risk factor for pancreatic ductal adenocarcinoma (PDAC), and both diseases share a common etiology. The activation of Pancreatic stellate cells (PaSCs) caused by inflammation of the chronic pancreas plays a pivotal role in the pathology of pancreatic fibrosis and the malignant phenotype of PDAC. However, the central role of activated PaSCs in acinar-to-ductal metaplasia (ADM) remains unknown. Objective: In the present study, we investigated the link between pancreatic fibrosis and ADM and the possible underlying mechanism. Methods: A caerulein-treated mouse CP model was established, and Masson trichrome histochemical stain and transmission electron microscope (TEM) were used to observe stromal fibrosis and cell ultrastructure, respectively. The expression of amylase and cytokeratin 19 (CK19), mitochondria respiration, and reactive oxygen species (ROS) were detected in vitro in the co-culture model of primary pancreatic acinar cells and PaSCs. Results: The activation of PaSCs and pancreatic fibrosis were accompanied by ADM in pancreatic parenchyma in caerulein-treated mice, which was verified by the co-cultivation experiment in vitro. Furthermore, we showed that activated PaSCs promote ADM by disrupting mitochondrial respiration and releasing ROS. The expression of inflammation-and ADM-related genes, including S100A8, S100A9, and CK19, was observed to be up-regulated in pancreatic acinar cells in the presence of activated PaSCs. The expression of S100A9 and CK19 proteins was also up-regulated in acinar cells co-cultured with activated PaSCs. Conclusion: The manipulation of mitochondrial respiration and ROS release is a promising preventive and/or therapeutic strategy for PDAC, and S100A9 is expected to be a therapeutic target to block the ADM process induced by the activation of PaSCs.

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