Mitochondrial dysfunction and apoptosis of acinar cells in chronic pancreatitis

Singh, Lipi; Bakshi, Dapinder Kaur; Majumdar, S.; Arora, Sunil; Vasishta, Rakesh Kumar; Wig, Jai Dev

doi:10.1007/s00535-008-2179-4

Cited by 15 publications

(10 citation statements)

References 40 publications

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“…In addition, ER stress induced by mutation and misfolding of the carboxyl ester lipase (CEL) protein is also involved in CP development by regulating acinar cell apoptosis 17 . Consistently, pancreatic tissues from patients with CP exhibit significant DNA fragmentation, apoptotic nuclei, and increased p53 expression, as well as substantial alterations in other apoptosis-regulating factors 18 . These observations suggest that ER stress and apoptosis might be involved in the development of CP.…”

Section: Introductionmentioning

confidence: 65%

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis

et al. 2019

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Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.

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Section: Introductionmentioning

confidence: 65%

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis

et al. 2019

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“…[20][21][22][23] In the acinar cells of CP, Bateman et al showed a statistically significant increase in apoptotic index compared with that in controls. In a recent report, Schrader et al 24 showed a lack of increased b-cells turnover in CP patients, despite an B10-fold increase in the number of apoptotic acinar cells, suggesting that the damage to the pancreas somehow specifically targets the exocrine compartment and affects the endocrine islets to a lesser extent.…”

Section: Pancreatic Stellate Cellsmentioning

confidence: 99%

Mechanisms of parenchymal injury and signaling pathways in ectatic ducts of chronic pancreatitis: implications for pancreatic carcinogenesis

Bhanot

Möller

2009

Laboratory Investigation

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The pathobiology of chronic pancreatitis (CP) remains enigmatic despite remarkable progress made recently in uncovering key mechanisms involved in the initiation and progression of the disease. CP is increasingly thought of as a multifactorial disorder. Apoptosis plays a role in parenchymal destruction, the pathological hallmark of CP. The apoptotic mechanisms preferentially target the exocrine compartment, leaving endocrine islets relatively intact for a prolonged period. Exocrine cells shed their 'immunoprivileged' status, express death receptors, and are rendered susceptible to apoptosis induced by death ligands on infiltrating lymphocytes, and released locally by activated pancreatic stellate cells. Islet cells retain their 'immunoprivileged' status and activate anti-apoptotic programs through NF-kB. Ductal changes, including distortion, dilatation, and pancreatic ductal hypertension in the setting of CP, induce genomic damage and increased cell turnover. In addition, signaling mechanisms that play a role in the development of embryonic pancreas are reinstated, thus, playing a role in repair, regeneration, and transformation. This, in turn, leads to acino-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Some of these pathways are activated in pancreatic cancer. We attempt to integrate the current knowledge and major concepts in the pathogenesis of CP and to explain the mechanism of differential cell loss. We also discuss the possible implications of signaling pathway activation in pancreatic inflammation, relevant to the cellular transformation that leads to pancreatic neoplasia.

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“…TP53, the regulatory factor of apoptosis, could interact with Bcl 2 family proteins in the cytoplasm that causing mitochondrial outer membrane permeability increased and cell apoptosis [32]. In clinical, pancreatic tissues from patients with pancreatitis exhibited apoptotic nuclei, and increased p53 expression [33]. Consistently, Lei Zhou et al found that TP53 suppressed on mouse pancreatitis model obviously inhibited pancreatic acinar cell apoptosis and the in ammation [34].…”

Section: Discussionmentioning

confidence: 86%

Uncovering the Pharmacological of Xiaochaihu Decoction in the Treatment of Pancreatitis Based on the Network Pharmacology

Zhan

et al. 2020

Preprint

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BackgroundXiaochaihu Decoction (XD) was a traditional prescription, has been demonstrated the pharmacodynamic on pancreatitis. But the underline mechanism remained to be explored. Therefore, this study was aimed to combined network pharmacology method and molecular docking technology to demonstrate the potential mechanism of XD treated with pancreatitis.MethodsFirstly, compounds of seven herbs containing XD were collected from TCMSP Database and the putative targets of Pancreatitis were obtained from OMIM, TTD, Genecards Database. Then PPI network was constructed according to the matching results between XD potential targets and pancreatic neoplasms targets. Furthermore, enrichment analysis on GO and KEGG by DAVID utilized bioinformatics resources. Finally, Molecular Docking was performed to simulate the interaction between the active compound of XD and putative targets.ResultsA total of 196 active ingredients and 91 putative targets were selected out. The PPI interaction network analysis demonstrated that Quercetin was the candidate agents and MAPK3, IL-6 and TP53 were the potential targets for the XD treatment of pancreatitis. The KEGG analysis revealed that pathways in cancers, TNF signaling way, MAPK signaling way might play an important role in pancreatitis therapy. And Molecular Docking results showed that Quercetin combined well with MAPK3, IL-6 and TP53.ConclusionThis study illustrated that Quercetin containing in XD might played an important role in pancreatitis therapy by acting the key genes of MPAK3, IL-6 and TP53. And it also provided a strategy to elucidate the mechanisms of Traditional Chinese Medicine (TCM) at the level of network pharmacology.

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Mitochondrial dysfunction and apoptosis of acinar cells in chronic pancreatitis

Abstract: Apoptosis plays an important role both in the initial stages and during the progression of CP, as evident in all tissue grades. Increased DeltaPsim, loss of ATP, and activation of caspases suggests the involvement of intrinsic pathways.

Cited by 15 publications

References 40 publications

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis

Mechanisms of parenchymal injury and signaling pathways in ectatic ducts of chronic pancreatitis: implications for pancreatic carcinogenesis

Uncovering the Pharmacological of Xiaochaihu Decoction in the Treatment of Pancreatitis Based on the Network Pharmacology

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