EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis

Abstract Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1Tg) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1Tg AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1Tg mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases.

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EMC6 and APAF1 Promote Acinar Cell Injury in Acute and Chronic Pancreatitis

SSRN Electronic Journal ◽

10.2139/ssrn.3514634 ◽

2020 ◽

Author(s):

Jie-hui Tan ◽

Rong-chang Cao ◽

Lei Zhou ◽

Zhi-tao Zhou ◽

Huo-ji Chen ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Acinar Cell ◽

Cell Injury ◽

Acute And Chronic Pancreatitis

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Estradiol Alleviates Acinar Cell Apoptosis and Chronic Pancreatitis in Male Wistar Bonn/Kobori Rats

Pancreas ◽

10.1097/00006676-200304000-00024 ◽

2003 ◽

Vol 26 (3) ◽

pp. e59-e66 ◽

Cited By ~ 8

Author(s):

Soichi Nakamura ◽

Tamaki Yamada ◽

Takashi Hashimoto ◽

Satoru Takahashi ◽

Mitsue Sogawa ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Acinar Cell ◽

Cell Apoptosis

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HDAC inhibitors promote pancreatic stellate cell apoptosis and relieve pancreatic fibrosis by upregulating miR-15/16 in chronic pancreatitis

Human Cell ◽

10.1007/s13577-020-00387-x ◽

2020 ◽

Vol 33 (4) ◽

pp. 1006-1016

Author(s):

Ting Ji ◽

Weiguang Feng ◽

Xiangcheng Zhang ◽

Kui Zang ◽

Xingxing Zhu ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Proinflammatory Cytokines ◽

Cell Apoptosis ◽

Target Genes ◽

Stellate Cell ◽

Hdac Inhibitors ◽

Pancreatic Fibrosis ◽

Hdac Inhibition ◽

Pancreatic Stellate Cell ◽

Induced Apoptosis

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.

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K562 Cell Sensitization to 5-Fluorouracil- or Interferon-Alpha-Induced Apoptosis Via Cordycepin (3′-Deoxyadenosine): Fine Control of Cell Apoptosis Via Poly(A) Polymerase Upregulation

The International Journal of Biological Markers ◽

10.1177/172460080401900108 ◽

2004 ◽

Vol 19 (1) ◽

pp. 58-66

Author(s):

G.C. Lallas ◽

N. Courtis ◽

M. Havredaki

Keyword(s):

Drug Resistance ◽

Interferon Alpha ◽

Cell Apoptosis ◽

K562 Cell ◽

Classical Model ◽

K562 Cells ◽

Dapi Staining ◽

Mrna Maturation ◽

Apoptosis Pathways ◽

Induced Apoptosis

K562 cells represent a classical model for the study of drug resistance. Induction of apoptosis is accompanied by concomitant distinct modulations of poly(A) polymerase (PAP) and other proteins involved in mRNA maturation. Recent data suggest the involvement of mRNA stability in the induction of specific apoptosis pathways. In this study we used a specific polyadenylation inhibitor, cordycepin (3-deoxyadenosine), to investigate the involvement of polyadenylation in K562 cell apoptosis and drug resistance. The combination of cordycepin with either 5-fluorouracil or interferon-alpha sensitized chemoresistant K562 cells to apoptosis. This sensitization was followed by distinct PAP modulations before and after the appearance of characteristic apoptosis pointers (DNA laddering, DAPI staining, mitochondrial transmembrane potential). PAP modulations appeared essential for K562 sensitization. mRNA polyadenylation therefore seemed to be involved not only in apoptosis but also in drug resistance. Polyadenylation inhibition by cordycepin under certain conditions sensitized chemoresistant K562 cells to apoptosis and thus polyadenylation could prove to be a fine target for overcoming drug resistance.

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Inflammatory diseases of the pancreas: what new do we know about the mechanisms of their development in the 21st century?

Terapevticheskii arkhiv ◽

10.26442/00403660.2021.01.200595 ◽

2021 ◽

Vol 93 (1) ◽

pp. 66-70

Author(s):

Vadim A. Akhmedov ◽

Olga V. Gaus

Keyword(s):

Chronic Pancreatitis ◽

Tight Junctions ◽

21St Century ◽

Genetic Factors ◽

Inflammatory Diseases ◽

Adherens Junctions ◽

Transmembrane Proteins ◽

Laboratory Diagnostics ◽

Acute And Chronic Pancreatitis

Inflammatory diseases of the pancreas can range from acute to acute recurrent and chronic pancreatitis. With the improvement of laboratory diagnostics in the 21st century, the mechanisms of the pro-inflammatory and anti-inflammatory role of tight junctions, in particular the transmembrane proteins occludin, claudine and JAMs, cytoplasmic Zo-proteins, and adherens junctions, in particular -catenin, -catenin, E-cadherin, selectins and ICAMs in the pathogenesis of acute and chronic pancreatitis have become more clear. The study of genetic factors in the development of acute and chronic pancreatitis showed the role of mutations in the genes SPINK1 N34S, PRSS1, CEL-HYB in the progression of the disease.

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Estradiol attenuated the induction of acinar cell apoptosis and development of chronic pancreatitis in wistar Bonn/Kobori rats

Gastroenterology ◽

10.1016/s0016-5085(08)83589-5 ◽

2001 ◽

Vol 120 (5) ◽

pp. A721

Author(s):

Tamaki Yamada ◽

Takashi Hashimoto ◽

Hirotaka Ohara ◽

Takahiro Nakazawa ◽

Hitoshi Sano ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Acinar Cell ◽

Cell Apoptosis

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LncRNA PFAL suppresses TNF-α-induced inflammation by upregulating miR-18a in WI-38 cells

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i12.5 ◽

2021 ◽

Vol 19 (12) ◽

pp. 2513-2520

Author(s):

Yichun Xie ◽

Hongqun Wang

Keyword(s):

Cell Viability ◽

Inflammatory Cytokines ◽

Cell Apoptosis ◽

Cell Injury ◽

Inflammatory Diseases ◽

Jnk Pathway ◽

Inflammatory Injury ◽

Mortality And Morbidity ◽

Injury Model ◽

Tnf Α

Purpose: Pneumonia is a serious respiratory disease among children with high mortality and morbidity all over the world. Long non-coding RNAs have been proven to play a vital role in many inflammatory diseases including pneumonia. In the present study, the protective impact of lncRNA PFAL on cell viability, cell apoptosis and secretion of inflammatory cytokines, as well as the underlying molecular mechanism in TNF-α-induced inflammatory injury model of pneumonia were investigated.Methods: WI-38 cell line was treated with 20 ng/ml TNF-α to establish an inflammatory injury model of pneumonia. LncRNA PFAL or miR-18a was up- or down-regulated in the WI-38 cells by transfection procedure. Cell viability was assessed using CCK-8 assay, while the rate of cell apoptosis was measured by utilizing flow cytometry. The mRNA expression levels of lncRNA PFAL, miR-18a, apoptosis-related and JNK pathway genes were determined with RT-qPCR. Moreover, the production of inflammatory cytokines such as IL-6 and MCP-1 were detected by using Western blot analysis.Results: The results indicated that cell viability was significantly (P<0.05) reduced, while the rate of cell apoptosis was increased in the TNF-α-induced WI-38 cells. Also, TNF-α treatment enhanced the expression of inflammatory cytokines that included IL-6 and MCP-1 in WI-38 cells. Overexpression of PFAL suppressed the injury induced by TNF-α and miR-18a was positively regulated by PFAL. Moreover, the inhibition of miR-18a weakens the effect of PFAL overexpression in TNF-α-induced cell injury. Furthermore, PFAL and miR-18a were involved in the regulation of JNK pathway.Conclusion: Overexpression of PFAL suppresses TNF-α-induced WI-38 cell injury by up-regulating miR-18a via the inactivation of JNK signaling pathway. Keywords: Inflammation, JNK pathway, miR-18a, PFAL, Pneumonia, TNF-α

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Role of T cells in development of chronic pancreatitis in male Wistar Bonn/Kobori rats: effects of tacrolimus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.281.6.g1397 ◽

2001 ◽

Vol 281 (6) ◽

pp. G1397-G1404 ◽

Cited By ~ 17

Author(s):

Tamaki Yamada ◽

Takashi Hashimoto ◽

Mitsue Sogawa ◽

Sawako Kobayashi ◽

Kenji Kaneda ◽

...

Keyword(s):

T Cells ◽

Chronic Pancreatitis ◽

T Cell ◽

Acinar Cell ◽

Cell Apoptosis ◽

Acinar Cells ◽

Plasma Corticosterone ◽

Fibrotic Tissue ◽

Cell Association

We assessed T cell association with acinar cell apoptosis and a preventive effect of tacrolimus, a T cell suppressant, on the development of chronic pancreatitis in male Wistar Bonn/Kobori rats. At 15 wk, cellular infiltrates composed of F4/80-positive cells (monocytes/macrophages), CD4-positive cells, and CD8-positive cells were extensive in the interlobular connective tissue and parenchyma. In particular, CD8-positive cells invaded pancreatic lobules and formed close associations with acinar cells, some of which demonstrated features of apoptosis. At 20 wk, CD8-positive cells were still abundant in the fibrotic tissue formed with loss of acinar cells. Repeated subcutaneous injection of 0.1 mg · kg−1 · day−1 but not 0.025 mg · kg−1 · day−1 of tacrolimus for 10 wk completely prevented the occurrence of acinar cell apoptosis, infiltration of CD4- and CD8-positive cells, and development of pancreatitis at the age of 20 wk, but these maneuvers did not recover the decreased plasma corticosterone levels, which may be responsible for the development of disease. We demonstrated that T cells, possibly CD8-positive cells, are involved in inducing apoptosis of acinar cells, raising the possibility that tacrolimus might find clinical application in the treatment of autoimmune chronic pancreatitis.

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