The Roles of Serine Protease Inhibitor Kazal Type 1 (SPINK1) in Pancreatic Diseases

Ohmuraya, Masaki; Yamamura, Ken Ichi

doi:10.1538/expanim.60.433

Cited by 42 publications

(33 citation statements)

References 73 publications

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“…Further, alternate mechanisms other than trypsinogen activation may be responsible for these associations. For example, PSTI and SPINK proteins have been shown to be important in cell death regulation (50), autophagy (51), growth (50, 52) and inflammation (52, 53). Such effects may explain amelioration of pancreatitis with PSTI overexpression (54, 55).…”

Section: Discussionmentioning

confidence: 99%

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

et al. 2013

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Background & Aims Premature activation of trypsinogen activation can cause pancreatic injury and has been associated with chronic pancreatitis (CP). Mice that lack intra-acinar activation of trypsinogen, such as trypsinogen-7–null (T−/−) and cathepsin B-null (CB−/−) mice, have been used to study trypsin-independent processes of CP development. We compared histological features and inflammatory response of pancreatic tissues from these mice to those from wild-type after development of CP. Methods CP was induced in wild-type, T−/−, and CB−/− mice by twice-weekly induction of acute pancreatitis for 10 weeks; acute pancreatitis was induced by hourly intraperitoneal injections of caerulein (50 μg/kg ×6). Pancreatic samples were collected and evaluated by histologic and immunohistochemical analyses. Normal human pancreas samples, obtained from the islet transplant program at the University of Minnesota, were used as controls and CP samples were obtained from surgical resections. Results Compared with pancreatic tissues from wild-type mice, those from T−/− and CB−/− mice had similar levels of atrophy, histo-morphologic features of CP, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF)-κB, a transcription factor that regulates the inflammatory response, immediately after injection of caerulein. Pancreatic tissues samples from patients CP had increased activation of NF-B (based on nuclear translocation p65 in acinar cells) compared with controls. Conclusion Induction of CP in mice by caerulein injection does not require intra-acinar activation of trypsinogen. Pancreatic acinar cells of patients with CP have increased levels of NF-κB activation, compared with controls; regulation of the inflammatory response by this transcription factor might be involved in pathogenesis of CP.

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Section: Discussionmentioning

confidence: 99%

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

et al. 2013

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“…Furthermore, many of these genes have additional functions that may explain their role as a risk factor. In particular, SPINK1 may be involved in basic cellular processes such as cell death regulation 21 , autophagy 22 , growth 23 and inflammation 24 , other than trypsinogen activation.…”

Section: Pathophysiology Of Chronic Pancreatitismentioning

confidence: 99%

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

et al. 2016

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A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to focus on research gaps and opportunities in chronic pancreatitis (CP) and its sequelae. This conference marked the 20th year anniversary of the discovery of the cationic trypsinogen (PRSS1) gene mutation for hereditary pancreatitis. The event was held on July 27, 2016, and structured into 4 sessions: (1) pathophysiology; (2) exocrine complications; (3) endocrine complications; and (4) pain. The current state of knowledge was reviewed; many knowledge gaps and research needs were identified that require further investigation. Common themes included the need to design better tools to diagnose CP and its sequelae early and reliably, identify predisposing risk factors for disease progression, develop standardized protocols to distinguish type 3c diabetes mellitus from other types of diabetes and design effective therapeutic strategies through novel cell culture technologies, animal models mimicking human disease, and pain management tools. Gene therapy and cystic fibrosis conductance regulator (CFTR) potentiators as possible treatments for CP were discussed. Importantly, the need for chronic pancreatitis endpoints and intermediate targets for future drug trials was emphasized.

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“…SPINK1, also known as pancreatic secretory trypsin inhibitor or tumor-associated trypsin inhibitor, encodes a 56 amino acid secreted peptide, which contains three disulfide bonds and a trypsin-specific binding site formed by Lys-Ile [4,5]. SPINK1 is usually with a signal peptide of approximately 20 amino acids at N-terminal.…”

Section: An Overview Of Spink1mentioning

confidence: 99%

Roles of Serine Protease Inhibitor Kazal type 1 (SPINK1) in Prostate Cancer

Shen¹,

Zhang²,

Qi³

et al. 2014

Med chem

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The Roles of Serine Protease Inhibitor Kazal Type 1 (SPINK1) in Pancreatic Diseases

Cited by 42 publications

References 73 publications

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

Chronic Pancreatitis in the 21st Century - Research Challenges and Opportunities

Roles of Serine Protease Inhibitor Kazal type 1 (SPINK1) in Prostate Cancer

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