Abstract:
:Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and chronic pancreatitis. Mutations in human cationic trypsinogen (PRSS1) are associated with HP and have provided some insight into the pathogenesis of pancreatitis, but mechanisms responsible for the initiation of pancreatitis have not been elucidated and the role of apoptosis and necrosis has been much debated. However, it has been generally accepted that trypsinogen, prematurely activated within the pancreatic acinar cell, has a major role in the initiation process. Functional studies of HP have been limited by the absence of an experimental system that authentically mimics disease development. We therefore developed a novel transgenic murine model system using wild-type (WT) human PRSS1 or two HP-associated mutants (R122H and N29I) to determine whether expression of human cationic trypsinogen in murine acinar cells promotes pancreatitis. The rat elastase promoter was used to target transgene expression to pancreatic acinar cells in three transgenic strains that were generated: Tg(Ela-PRSS1)NV, Tg(Ela-PRSS1*R122H)NV and Tg(Ela-PRSS1*N29I)NV. Mice were analysed histologically, immunohistochemically and biochemically. We found that transgene expression is restricted to pancreatic acinar cells and transgenic PRSS1 proteins are targeted to the pancreatic secretory pathway. Animals from all transgenic strains developed pancreatitis characterised by acinar cell vacuolisation, inflammatory infiltrates and fibrosis. Transgenic animals also developed more severe pancreatitis upon treatment with low-dose cerulein than controls, displaying significantly higher scores for oedema, inflammation and overall histopathology. Expression of PRSS1, WT or mutant, in acinar cells increased apoptosis in pancreatic tissues and isolated acinar cells. Moreover, studies of isolated acinar cells demonstrated that transgene expression promotes apoptosis rather than necrosis. We therefore conclude that expression of WT or mutant human PRSS1 in murine acinar cells induces apoptosis and is sufficient to promote spontaneous pancreatitis, which is enhanced in response to cellular insult.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Athwal T,Huang W,Mukherjee R,Latawiec D,Chvanov M,Clarke R,Smith K,Campbell F,Merriman C,Criddle D,Sutton R,Neoptolemos J,Vlatković Ndoi
10.1038/cddis.2014.120subject
Has Abstractpub_date
2014-04-10 00:00:00pages
e1165issn
2041-4889pii
cddis2014120journal_volume
5pub_type
杂志文章abstract::Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0804-6
更新日期:2018-07-03 00:00:00
abstract::We sought to identify miRNAs that can efficiently induce apoptosis in ovarian cancer cells by overcoming BCL-X(L) and MCL1 anti-apoptotic activity, using combined computational and experimental approaches. We found that miR-491-5p efficiently induces apoptosis in IGROV1-R10 cells by directly inhibiting BCL-X(L) expres...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.389
更新日期:2014-10-09 00:00:00
abstract::Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays a crucial role in human malignancies. Here, we showed that microRNA-422a (miR-422a) expression was dramatically downregulated in gastric cancer (GC) samples and cell lines compared with normal controls, and that its expression level was inver...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0564-3
更新日期:2018-05-01 00:00:00
abstract::After axotomy of embryonic hippocampal neurons in vitro, some of the axotomized axons lose their identity, and new axons arise and grow. This axotomy-induced axonogenesis requires importin, suggesting that some injury-induced signals are transported via axons to elicit axonogenesis after axotomy. In this study, we sho...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2011.59
更新日期:2011-06-23 00:00:00
abstract::The aim of our study was to investigate the role of autophagy, a homeostatic process involved in the lysosomal degradation of damaged cell organelles and proteins, in regulating the survival of mesangial cells treated with advanced glycation end products (AGEs). In the present study, AGEs induced mitochondrial depolar...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.322
更新日期:2016-11-03 00:00:00
abstract::Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca2+ overload, and neur...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1979-1
更新日期:2019-10-10 00:00:00
abstract::Chemoresistance is one of the leading causes that contributes to tumor relapse and poor patient outcome after several rounds of drug therapy. The causes of chemoresistance are multi-factorial. Ultimately, it is the balance of pro- and anti-apoptotic activities in the cells. We have previously reported links between PO...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.443
更新日期:2017-09-14 00:00:00
abstract::Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis is associated with, and exacerbated by, obesity and the concomitant-elevated free fatty acid concentrations typically found in these patients. Hyperglycaemia and hyperlipidaemia together contribute to a decline in in...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.203
更新日期:2016-08-11 00:00:00
abstract::Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent stat...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03074-9
更新日期:2020-10-14 00:00:00
abstract::Homeodomain-interacting protein kinase 2 (HIPK2) is a multitalented coregulator of an increasing number of transcription factors and cofactors involved in cell death and proliferation in several organs and systems. As Hipk2(-/-) mice show behavioral abnormalities consistent with cerebellar dysfunction, we investigated...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.298
更新日期:2015-12-03 00:00:00
abstract::Colorectal cancer (CRC) is the second major cause of tumor-related deaths. MicroRNAs (miRNAs) have pivotal roles in CRC progression. Here, we describe the effect of miR-181d on CRC cell metabolism and underlying molecular mechanism. Our data firmly demonstrated that knockdown of miR-181d suppressed CRC cell proliferat...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.300
更新日期:2017-07-27 00:00:00
abstract::Since publication of this paper, the authors have noticed that there were errors in Fig. 2A (the GAPDH of Mel-CV, Mel-CV.S, Mel-RMu and Mel-RMu.S), Fig. 2C (the GAPDH of Mel-CV.S and Mel-RMu.S), Fig. 3F (the GAPDH of Mel-CV.S and Mel-RMu.S), Fig. 3J(the GAPDH of Mel-RMu.S), Fig. 5C (the ERK1/2 of patient#3(post)), and...
journal_title:Cell death & disease
pub_type: 已发布勘误
doi:10.1038/s41419-019-1301-2
更新日期:2019-03-05 00:00:00
abstract::The serine protease hepsin is frequently overexpressed in human prostate cancer (PCa) and is associated with matrix degradation and PCa progression in mice. Curiously, low expression of hepsin is associated with poor survival in different cancer types, and transgenic overexpression of hepsin leads to loss of viability...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1830-8
更新日期:2019-08-09 00:00:00
abstract::Inhibitors of apoptosis (IAP) proteins contribute to cell death resistance in malignancies and emerged as promising targets in cancer therapy. Currently, small molecules mimicking the IAP-antagonizing activity of endogenous second mitochondria-derived activator of caspases (SMAC) are evaluated in phase 1/2 clinical tr...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.355
更新日期:2017-08-03 00:00:00
abstract::Tumor-associated macrophages (TAMs) are frequently found near pancreatic cancer cells, but it is uncertain whether they are involved in pancreatic cancer progression and the Warburg effect. Here, we show that CCL18 secreted by TAMs facilitates malignant progression and induced a glycolytic phenotype in pancreatic canc...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0486-0
更新日期:2018-05-01 00:00:00
abstract::Accumulating evidence has highlighted the potential role of non-coding RNAs (ncRNAs) and upstream open-reading frames (uORFs) in the biological behaviors of glioblastoma. Here, we elucidated the function and possible molecular mechanisms of the effect of some ncRNAs and NR2C2-uORF on the biological behaviors of glioma...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1149-x
更新日期:2018-12-05 00:00:00
abstract::A number of microRNAs have been shown to regulate skeletal muscle development and differentiation. MicroRNA-222 is downregulated during myogenic differentiation and its overexpression leads to alteration of muscle differentiation process and specialized structures. By using RNA-induced silencing complex (RISC) pulldow...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.10
更新日期:2016-02-04 00:00:00
abstract::Therapeutic resistance of neoplasms is mainly attributed to gradual evolution of mutational profile1. Here, we demonstrate a microRNA-mediated mechanism that effectively improves fitness of SKBR3 mammary carcinoma cells by cytoplasmic reprogramming. The reprogramming is triggered by endogenous miR4673 transcribed from...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1088-6
更新日期:2018-10-19 00:00:00
abstract::The clinical use of the antineoplastic drug cisplatin is limited by its deleterious nephrotoxic side effect. Cisplatin-induced nephrotoxicity is associated with an increase in oxidative stress, leading ultimately to renal cell death and irreversible kidney dysfunction. Oxidative stress could be modified by the cystic ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.355
更新日期:2013-10-03 00:00:00
abstract::Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) has been implicated in diverse kidney diseases, yet its in vivo significance in diabetic nephropathy (DN) is largely unknown. In the present study, we demonstrated a podocyte-specific Rac1-deficient mouse strain and showed that specific inhibition of Rac1...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0353-z
更新日期:2018-03-01 00:00:00
abstract::As a key member of the forkhead box transcription factors, forkhead box F2 (FOXF2) serves as a transcriptional regulator and regulates downstream gene expression in embryonic development, metabolism and in some common diseases, such as stroke and gastroparesis. Recent studies have shown that aberrant expression of FOX...
journal_title:Cell death & disease
pub_type: 杂志文章,评审
doi:10.1038/s41419-020-2604-z
更新日期:2020-06-05 00:00:00
abstract::The glutamate-induced excitotoxicity pathway has been reported in several neurodegenerative diseases. Molecules that inhibit the release of glutamate or cause the overactivation of glutamate receptors can minimize neuronal cell death in these diseases. Osmotin, a homolog of mammalian adiponectin, is a plant protein fr...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.538
更新日期:2014-01-30 00:00:00
abstract::Hypertension-induced cardiac hypertrophy and attenuated cardiac function are the major characteristics of early stage heart failure. Cardiomyocyte death in pathological cardiac conditions is the primary cause of heart failure and mortality. Our previous studies found that heat shock factor 1 (HSF1) protected cardiomyo...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.320
更新日期:2017-08-10 00:00:00
abstract::Although accumulating evidence has linked mesenchymal stem cells (MSCs) with tumor growth, the underlying mechanisms are poorly understood. Here, we demonstrated for the first time that human umbilical cord MSCs (hUCMSCs) dramatically increased the growth of lung adenocarcinoma (LUAD) cancer cells in a xenograft tumor...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0323-5
更新日期:2018-02-13 00:00:00
abstract::Aberrant de novo lipogenesis (DNL) results in excessive hepatic lipid accumulation and liver steatosis, the causative factors of many liver diseases, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). However, the underlying mechanism of DNL dys...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-03075-8
更新日期:2020-10-10 00:00:00
abstract::Pyroptosis is a highly inflammatory form of programmed cell death that is caused by infection with intracellular pathogens and activation of canonical or noncanonical inflammasomes. The purinergic receptor P2X7 is activated by the noncanonical inflammasome and contributes essentially to pyroptotic cell death. The Ca2+...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0373-8
更新日期:2018-02-20 00:00:00
abstract::The proteins of the Bcl-2 family have a crucial role in mitochondrial outer membrane permeabilization during apoptosis and in the regulation of mitochondrial dynamics. Current models consider that Bax forms toroidal pores at mitochondria that are responsible for the release of cytochrome c, whereas Bcl-xL inhibits por...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.34
更新日期:2016-02-25 00:00:00
abstract::Melatonin, an endogenous hormone molecule, has a variety of biological functions, but a functional role of melatonin in the infection of Gram-negative bacterium Vibrio vulnificus has yet to be described. In this study, we investigated the molecular mechanism of melatonin in the apoptosis of human intestinal epithelial...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-017-0083-7
更新日期:2018-01-19 00:00:00
abstract::Acute pancreatitis (AP) is an acute inflammatory process of the pancreas that is characterized by inflammation, edema, vacuolization and necrosis, which has significant morbidity and lethality. The pathogenesis of AP has not been established completely. An early and critical feature of AP is the aberrant signaling of ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-017-0073-9
更新日期:2018-01-19 00:00:00
abstract::In the healthcare sector, phytocompounds are known to be beneficial by contributing or alleviating a variety of diseases. Studies have demonstrated the progressive effects of phytocompounds on immune-related diseases and to exhibit anticancer effects. Graviola tree is an evergreen tree with its extracts (leafs and see...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0772-x
更新日期:2018-07-09 00:00:00