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Almutary KH, Zaghloul MS, Nader MA, Elsheakh AR. Mechanistic insights into the protective potential of ambrisentan against L-arginine induced acute pancreatitis and multiorgan damage (role of NRF2/HO-1 and TXNIP/NLRP3 pathways). Biomed Pharmacother 2025; 187:118119. [PMID: 40319659 DOI: 10.1016/j.biopha.2025.118119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025] Open
Abstract
Acute pancreatitis (AP) is an abrupt inflammation of the pancreatic tissue. The severity of AP varies from mild and self-limiting to severe, potentially fatal, and can affect several organ systems. The most severe type of AP causes multiple organ damage (MOD) due to systemic inflammation. In this study, ambrisentan (AMB), an endothelin A receptor antagonist (ETA), was investigated for its potential to ameliorate L-arginine (L-Arg) induced AP and MOD in rats. AP was induced using L-Arg (100 mg/100 g). Two doses of AMB were tested and compared to N-acetylcystiene (NAC) effect. AMB restored the normal structure of the pancreatic, hepatic, pulmonary, and renal tissues. In addition, it normalized the levels of pancreatic enzymes, lactate dehydrogenase (LDH), serum liver enzymes, and kidney biomarkers. Furthermore, AMB corrected the imbalance in the levels of oxidants/antioxidants caused by L-Arg. In contrast, AMB (5 mg/kg) significantly upregulated the protein levels of adenosine monophosphate protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxidase-1(HO-1) and thioredoxin reductase 1 (TXNRD1) by approximately 69.59 %, 85.14 %, 688 % and 96 % respectively, compared with those in rats treated with L-Arg. Furthermore, AMB (5 mg/kg) significantly lowered the thioredoxin-interacting protein (TXNIP), nod-like Receptor Protein 3 (NLRP3), glycogen synthase kinase-3β (GSK-3β), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), CD68, autophagic markers (P62 and LC3) and apoptotic marker caspase 3 by around 62.43 %, 73.56 %, 62.5 %,70 %, 80.3 %, 93 %, 96.7 %, 95 %, 39.6 % respectively, compared to the group treated with L-Arg. AMB effectively improved the AP and MOD produced by L-Arg through its anti-inflammatory and antioxidant properties. NRF2/HO-1 and TXNIP/NLRP3 pathways play major roles in these protective effects.
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Affiliation(s)
- Khaled H Almutary
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Majmaah University, P.O.Box 66, Majmaah 11952, Saudi Arabia
| | - Marwa S Zaghloul
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt.
| | - Manar A Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt
| | - Ahmed R Elsheakh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa 7731168, Egypt; Future Studies and Risks Management & National Committee of Drugs, Academy of Scientific Research, Ministry of Higher Education, Elsayeda Zeinab, Egypt
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Yenice G, Ozkanlar S, Bolat I, Yildirim S. The Potential Ability of Betulinic Acid to Prevent Experimentally Induced Acute Pancreatitis in Rats. Basic Clin Pharmacol Toxicol 2025; 136:e70052. [PMID: 40344370 PMCID: PMC12061522 DOI: 10.1111/bcpt.70052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 04/15/2025] [Accepted: 04/22/2025] [Indexed: 05/11/2025]
Abstract
Acute pancreatitis (AP) is a serious pancreatic inflammatory disease that results in pancreatic enzyme activation and autodegradation. Betulinic acid (BA), a pentacyclic triterpene of natural origin that was isolated from several plants, has anti-inflammatory, immunomodulatory and antioxidant effects that can help with AP. With this study, we aimed to investigate the potential positive effects of BA on l-arginine-induced AP. A total of 24 male rats were divided into four groups (control, BA, AP and BA + AP). Animals in the BA group were given BA 50 mg/kg/day for 7 days. AP was induced by administering two doses of 250-mg/100-g l-arginine to animals in the AP group. The animals in the BA + AP group were administered 50-mg/kg/day BA (gavage) for 7 days and two doses of 250-mg/100-g l-arginine on the seventh day. BA pretreatment inhibited the increased lipase activity caused by AP and showed protective activity against oxidative damage to pancreatic tissue. It decreased the severity of inflammation by suppressing the release of pro-inflammatory cytokines while increasing the level of the anti-inflammatory cytokine IL-10. It showed a protective effect on pancreatic tissue by inhibiting tumour necrosis factor (TNF-α) and Bax expression. The findings of the study show that BA exhibits multifaceted protective activity in experimental AP induced with l-arginine.
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Affiliation(s)
- Guler Yenice
- Faculty of Veterinary Medicine, Department of Animal Nutrition and Nutritional DisordersAtaturk UniversityErzurumTurkey
| | - Seckin Ozkanlar
- Faculty of Veterinary Medicine, Department of BiochemistryAtaturk UniversityErzurumTurkey
| | - Ismail Bolat
- Faculty of Veterinary Medicine, Department of PathologyAtaturk UniversityErzurumTurkey
| | - Serkan Yildirim
- Faculty of Veterinary Medicine, Department of PathologyAtaturk UniversityErzurumTurkey
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Li J, Jia YC, Lu J, Zhang H, Wang Z, Xie X, Cao F, Li F. Inhibition of Zbp1-PANoptosome-mediated PANoptosis effectively attenuates acute pancreatitis. Cell Death Discov 2025; 11:180. [PMID: 40240343 PMCID: PMC12003674 DOI: 10.1038/s41420-025-02451-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/21/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025] Open
Abstract
Early acute pancreatitis is an acute inflammatory disease that involves multiple modes of cell death, including apoptosis, necrotic apoptosis, and pyroptosis in its disease process. PANoptosis, a type of cell death that includes pyroptosis, apoptosis, and necroptosis, has had an important role in a variety of infectious and inflammatory diseases in recent years. To judge the relationship between PANoptosis and AP, we first analyzed the data from pancreatic transcriptome data by bioinformatics techniques, and we found the enrichment of PANoptosis pathway in AP. Next, we screened the genes and identified differentially expressed genes (DEGs) associated with AP and PANoptosis. Finally, we found that Zbp1 may have a major role in the process of PANoptosis. For this purpose, we constructed AP models in mice and in vitro cell line 266-6 and intervened by inhibiting Zbp1. The final results showed that the PANoptosis in mice was significantly suppressed after inhibition of Zbp1. In conclusion, inflammatory injury in AP can be significantly improved by inhibiting Zbp1- PANoptosome-mediated PANoptosis.
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Affiliation(s)
- Jie Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Yu-Chen Jia
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Jiongdi Lu
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Haoyu Zhang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Zheng Wang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Xiaozhou Xie
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Feng Cao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China.
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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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Boggio V, Gonzalez CD, Zotta E, Ropolo A, Vaccaro MI. VMP1 Constitutive Expression in Mice Dampens Pancreatic and Systemic Histopathological Damage in an Experimental Model of Severe Acute Pancreatitis. Int J Mol Sci 2025; 26:3196. [PMID: 40243995 PMCID: PMC11988950 DOI: 10.3390/ijms26073196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/24/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
Acute pancreatitis (AP) an inflammatory condition caused by the premature activation of pancreatic proteases, leads to organ damage, systemic inflammation, and multi-organ failure. Severe acute pancreatitis (SAP) has high morbidity and mortality, affecting the liver, kidneys, and lungs. Autophagy maintains pancreatic homeostasis, with VMP1-mediated selective autophagy (zymophagy) preventing intracellular zymogen activation and acinar cell death. This study examines the protective role of VMP1 (Vacuole Membrane Protein 1)-induced autophagy using ElaI-VMP1 transgenic mice in a necrohemorrhagic SAP model (Hartwig's model). ElaI-VMP1 mice show significantly reduced pancreatic injury, including lower necrosis, edema, and inflammation, compared to wild-type (WT) mice. Biochemical markers (lactate dehydrogenase-LDH-, amylase, and lipase) and histopathology confirm that VMP1 expression mitigates pancreatic damage. Increased zymophagy negatively correlates with acinar necrosis, reinforcing its protective role. Beyond the pancreas, ElaI-VMP1 mice exhibit preserved liver, kidney, and lung histology, indicating reduced systemic organ damage. The liver maintains normal architecture, kidneys show minimal tubular necrosis, and lung inflammation features are reduced compared to WT mice. Our results confirm that zymophagy functions as a protective pathophysiological mechanism against pancreatic and extrapancreatic tissue injury in SAP. Further studies on the mechanism of VMP1-mediated selective autophagy in AP are necessary to determine its relevance and possible modulation to prevent the severity of AP.
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Affiliation(s)
- Veronica Boggio
- Instituto de Bioquímica y Biología Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina; (V.B.); (E.Z.)
| | - Claudio Daniel Gonzalez
- Centro de Educación Medica e Investigaciones Clínicas (CEMIC), Hospital Universitario Saavedra, Buenos Aires 1431, Argentina;
| | - Elsa Zotta
- Instituto de Bioquímica y Biología Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina; (V.B.); (E.Z.)
| | - Alejandro Ropolo
- Instituto de Bioquímica y Biología Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina; (V.B.); (E.Z.)
| | - Maria Ines Vaccaro
- Instituto de Bioquímica y Biología Molecular Prof. Alberto Boveris, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires 1113, Argentina; (V.B.); (E.Z.)
- Centro de Educación Medica e Investigaciones Clínicas (CEMIC), Hospital Universitario Saavedra, Buenos Aires 1431, Argentina;
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Chen X, Zhong R, Hu B. Mitochondrial dysfunction in the pathogenesis of acute pancreatitis. Hepatobiliary Pancreat Dis Int 2025; 24:76-83. [PMID: 38212158 DOI: 10.1016/j.hbpd.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 12/25/2023] [Indexed: 01/13/2024]
Abstract
The mechanism of cell damage during acute pancreatitis (AP) has not been fully elucidated, and there is still a lack of specific or effective treatments. Increasing evidence has implicated mitochondrial dysfunction as a key event in the pathophysiology of AP. Mitochondrial dysfunction is closely related to calcium (Ca2+) overload, intracellular adenosine triphosphate depletion, mitochondrial permeability transition pore openings, loss of mitochondrial membrane potential, mitophagy damage and inflammatory responses. Mitochondrial dysfunction is an early triggering event in the initiation and development of AP, and this organelle damage may precede the release of inflammatory cytokines, intracellular trypsin activation and vacuole formation of pancreatic acinar cells. This review provides further insight into the role of mitochondria in both physiological and pathophysiological aspects of AP, aiming to improve our understanding of the underlying mechanism which may lead to the development of therapeutic and preventive strategies for AP.
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Affiliation(s)
- Xia Chen
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Gastroenterology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Rui Zhong
- Department of Gastroenterology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu 610500, China
| | - Bing Hu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China.
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Mihoc T, Latcu SC, Secasan CC, Dema V, Cumpanas AA, Selaru M, Pirvu CA, Valceanu AP, Zara F, Dumitru CS, Novacescu D, Pantea S. Pancreatic Morphology, Immunology, and the Pathogenesis of Acute Pancreatitis. Biomedicines 2024; 12:2627. [PMID: 39595191 PMCID: PMC11591934 DOI: 10.3390/biomedicines12112627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Acute pancreatitis is a complex inflammatory disorder with significant morbidity and mortality. This review aims to integrate the current knowledge of pancreatic morphology and immunology with the pathogenesis of acute pancreatitis, providing a comprehensive understanding of this critical condition. We conducted an extensive literature review, synthesizing data from recent studies and authoritative sources on pancreatic anatomy, histology, immunology, and the pathophysiology of acute pancreatitis. We also incorporated epidemiological data, clinical features, diagnostic criteria, and prognostic factors. The pancreas exhibits a complex morphology with intricate interactions between its exocrine and endocrine components. Its unique immunological landscape plays a crucial role in maintaining homeostasis and orchestrating responses to pathological conditions. In acute pancreatitis, the disruption of intracellular calcium signaling leads to premature enzyme activation, triggering a cascade of events including mitochondrial dysfunction, ATP depletion, and the release of proinflammatory mediators. This process can escalate from localized inflammation to systemic complications. The interplay between pancreatic morphology, immune responses, and pathophysiological mechanisms contributes to the varied clinical presentations and outcomes observed in acute pancreatitis. Understanding the intricate relationships between pancreatic morphology, immunology, and the pathogenesis of acute pancreatitis is crucial for developing more effective diagnostic and therapeutic strategies. This integrated approach provides new insights into the complex nature of acute pancreatitis and may guide future research directions in pancreatic disorders.
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Affiliation(s)
- Tudorel Mihoc
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (T.M.); (V.D.)
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (T.M.); (V.D.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Cosmin-Ciprian Secasan
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Vlad Dema
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (T.M.); (V.D.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Alin Adrian Cumpanas
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Mircea Selaru
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Catalin Alexandru Pirvu
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Andrei Paul Valceanu
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Flavia Zara
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (C.-S.D.); (D.N.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Cristina-Stefania Dumitru
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (C.-S.D.); (D.N.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Dorin Novacescu
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (C.-S.D.); (D.N.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Stelian Pantea
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
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Wei X, Weng Z, Xu X, Yao J. Exploration of a miRNA-mRNA network shared between acute pancreatitis and Epstein-Barr virus infection by integrated bioinformatics analysis. PLoS One 2024; 19:e0311130. [PMID: 39546499 PMCID: PMC11567522 DOI: 10.1371/journal.pone.0311130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 09/10/2024] [Indexed: 11/17/2024] Open
Abstract
Acute pancreatitis (AP) stands out as a primary cause of hospitalization within gastrointestinal ailments, attributed to diverse factors, including Epstein-Barr virus (EBV) infection. Nevertheless, the common miRNAs and genes shared between AP and EBV infection remain unclear. In the present study, four datasets GSE194331, GSE42455, GSE45918 and GSE109220 were selected and downloaded from the Gene Expression Omnibus (GEO) database. Differential expression analysis was performed to screen for differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs). Target genes of overlapping DEMs were predicted, and intersections with overlapping DEGs were used to construct a miRNA-mRNA network. In addition, the enrichment analysis, drug prediction, diagnostic accuracy assessment, competitive endogenous RNA (ceRNA) network construction, transcription factor (TF)-miRNA-mRNA network construction, and immune cell infiltration analysis were also carried out. We found a total of 111 genes and 8 miRNAs shared between AP and EBV infection. A miRNA-mRNA network was constructed, which comprised 5 miRNAs and 10 genes exhibiting robust diagnostic performance. Histone deacetylase (HDAC) inhibitor was identified as a novel therapeutic intervention from drug prediction analysis. The results of immune cell infiltration analysis revealed that a consistent and significant difference could be found on activated B cell in AP and EBV-infected individuals in comparison to the controls. Taken together, our work, for the first time, revealed a miRNA-mRNA network shared between AP and EBV infection, thereby enriching a deeper comprehension of the intricate molecular mechanisms and potential therapeutic targets entwined in these two pathological conditions.
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Affiliation(s)
- Xing Wei
- Department of Infectious Disease, The Nantong First People’s Hospital and The Affiliated Hospital 2 of Nantong University, Nantong, China
| | - Zhen Weng
- MOE Engineering Center of Hematological Disease, Soochow University, Suzhou, China
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xia Xu
- Department of Gastroenterology, The Second People’s Hospital of Nantong and The Affiliated Rehabilitation Hospital of Nantong University, Nantong, China
| | - Jian Yao
- Department of Infectious Disease, The Nantong First People’s Hospital and The Affiliated Hospital 2 of Nantong University, Nantong, China
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Sun HW, Bai YY, Qin ZL, Li RZ, Madzikatire TB, Akuetteh PDP, Li Q, Kong HR, Jin YP. Transfection of 12/15-lipoxygenase effectively alleviates inflammatory responses during experimental acute pancreatitis. World J Gastroenterol 2024; 30:4544-4556. [PMID: 39563743 PMCID: PMC11572619 DOI: 10.3748/wjg.v30.i42.4544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/26/2024] [Accepted: 10/08/2024] [Indexed: 10/31/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP), the initially triggered inflammatory process in the pancreas, can be life-threatening. It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components, maintain intracellular homeostasis, and promote apoptosis by upregulating the activity of caspases. Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases, the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined. AIM To investigate the effect of Alox15 expression in cerulein-induced AP in rats. METHODS Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP. The expression of Alox15 was then assessed at the mRNA and protein levels. RESULTS Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15-transfected rats. Further, the mRNA expression levels of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1, as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced. Additionally, we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells. The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP. CONCLUSION Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy, making it a potential therapeutic target for AP.
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Affiliation(s)
- Hong-Wei Sun
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yong-Yu Bai
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Zhen-Liu Qin
- Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Ri-Zhao Li
- Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | | | | | - Qiang Li
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Hong-Ru Kong
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yue-Peng Jin
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Zhou Y, Huang X, Jin Y, Qiu M, Ambe PC, Basharat Z, Hong W. The role of mitochondrial damage-associated molecular patterns in acute pancreatitis. Biomed Pharmacother 2024; 175:116690. [PMID: 38718519 DOI: 10.1016/j.biopha.2024.116690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 06/03/2024] Open
Abstract
Acute pancreatitis (AP) is one of the most common gastrointestinal tract diseases with significant morbidity and mortality. Current treatments remain unspecific and supportive due to the severity and clinical course of AP, which can fluctuate rapidly and unpredictably. Mitochondria, cellular power plant to produce energy, are involved in a variety of physiological or pathological activities in human body. There is a growing evidence indicating that mitochondria damage-associated molecular patterns (mtDAMPs) play an important role in pathogenesis and progression of AP. With the pro-inflammatory properties, released mtDAMPs may damage pancreatic cells by binding with receptors, activating downstream molecules and releasing inflammatory factors. This review focuses on the possible interaction between AP and mtDAMPs, which include cytochrome c (Cyt c), mitochondrial transcription factor A (TFAM), mitochondrial DNA (mtDNA), cardiolipin (CL), adenosine triphosphate (ATP) and succinate, with focus on experimental research and potential therapeutic targets in clinical practice. Preventing or diminishing the release of mtDAMPs or targeting the mtDAMPs receptors might have a role in AP progression.
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Affiliation(s)
- Yan Zhou
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaoyi Huang
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Yinglu Jin
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Minhao Qiu
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Peter C Ambe
- Department of General Surgery, Visceral Surgery and Coloproctology, Vinzenz-Pallotti-Hospital Bensberg, Vinzenz-Pallotti-Str. 20-24, Bensberg 51429, Germany
| | | | - Wandong Hong
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
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11
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Bejjani J, Ramsey ML, Lee PJ, Phillips AE, Singh VK, Yadav D, Papachristou GI, Hart PA. Alterations in exocrine pancreatic function after acute pancreatitis. Pancreatology 2024; 24:505-510. [PMID: 38485543 PMCID: PMC11215795 DOI: 10.1016/j.pan.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/22/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024]
Abstract
Exocrine pancreatic dysfunction (EPD) is a malabsorptive complication of pancreatic disorders that can lead to a host of symptoms ranging from flatulence to diarrhea and contribute to weight loss and metabolic bone disease. It is increasingly recognized to occur after acute pancreatitis (AP), including episodes with mild severity. The risk of developing EPD after AP is influenced by a range of factors, including the degree of acinar cell destruction and inflammation during AP, and persistent structural derangements following AP. In this article, we discuss the epidemiology, pathophysiology, and clinical management of EPD after AP while highlighting key knowledge gaps.
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Affiliation(s)
- Joseph Bejjani
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Mitchell L Ramsey
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Peter J Lee
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Anna Evans Phillips
- Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Vikesh K Singh
- Division of Gastroenterology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Georgios I Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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12
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Zheng P, Li XY, Yang XY, Wang H, Ding L, He C, Wan JH, Ke HJ, Lu NH, Li NS, Zhu Y. Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models. World J Gastroenterol 2024; 30:2038-2058. [PMID: 38681131 PMCID: PMC11045495 DOI: 10.3748/wjg.v30.i14.2038] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/19/2024] [Accepted: 03/01/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure. Given the challenges associated with obtaining human pancreatic samples, research on AP predominantly relies on animal models. In this study, we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models. AIM To investigate the shared molecular changes underlying the development of AP across varying severity levels. METHODS AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide (LPS). Additionally, using Ptf1α to drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J- hM3/Ptf1α(cre) mice were administered Clozapine N-oxide to induce AP. Subsequently, we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus (GEO) database. RESULTS Caerulein-induced AP showed severe inflammation and edema, which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis. Compared with the control group, RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD-like receptor signaling pathway, TLR signaling pathway, and NF-κB signaling pathway, alongside elevated levels of apoptosis-related pathways, such as apoptosis, P53 pathway, and phagosome pathway. The significantly elevated genes in the TLR and NOD-like receptor signaling pathways, as well as in the apoptosis pathway, were validated through quantitative real-time PCR experiments in animal models. Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood, while TLR1, TLR7, RIPK3, and OAS2 genes exhibited marked elevation in human AP. The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP. The transgenic mouse model hM3/Ptf1α(cre) successfully validated significant differential genes in the TLR and NOD-like receptor signaling pathways as well as the apoptosis pathway, indicating that these pathways represent shared pathological processes in AP across different models. CONCLUSION The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP, notably the MYD88 gene. Apoptosis holds a central position in the necrotic processes of AP, with TUBA1A and GADD45A genes exhibiting prominence in human AP.
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Affiliation(s)
- Pan Zheng
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xue-Yang Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xiao-Yu Yang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Huan Wang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Ling Ding
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Cong He
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jian-Hua Wan
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hua-Jing Ke
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Nong-Hua Lu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Nian-Shuang Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
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Deng J, Song Z, Li X, Shi H, Huang S, Tang L. Role of lncRNAs in acute pancreatitis: pathogenesis, diagnosis, and therapy. Front Genet 2023; 14:1257552. [PMID: 37842644 PMCID: PMC10569178 DOI: 10.3389/fgene.2023.1257552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/18/2023] [Indexed: 10/17/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common acute abdominal diseases characterized by an injury and inflammatory disorder of the pancreas with complicated pathological mechanisms. Long non-coding RNAs (lncRNAs) have been shown to play an important role in various physiological and pathological processes in humans, and they have emerged as potential biomarkers of diagnosis and therapeutic targets in various diseases. Recently, accumulating evidence has shown significant alterations in the expression of lncRNAs, which are involved in the pathogenesis of AP, such as premature trypsinogen activation, impaired autophagy, inflammatory response, and acinar cell death. Moreover, lncRNAs can be the direct target of AP treatment and show potential as biomarkers for the diagnosis. Thus, in this review, we focus on the role of lncRNAs in the pathogenesis, diagnosis, and therapy of AP and emphasize the future directions to study lncRNAs in AP, providing new insight into understanding the cellular and molecular mechanisms of AP and seeking novel biomarkers for the diagnosis and therapeutic targets to improve clinical management in the future.
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Affiliation(s)
- Jie Deng
- Department of Clinical Pharmacy, The General Hospital of Western Theater Command, Chengdu, China
| | - Ziying Song
- Department of Emergency Medicine, The General Hospital of Western Theater Command, Chengdu, China
| | - Xiaolan Li
- Department of Pain Medicine, The General Hospital of Western Theater Command, Chengdu, China
| | - Huiqing Shi
- Department of Clinical Pharmacy, The General Hospital of Western Theater Command, Chengdu, China
| | - Shangqing Huang
- Department of General Surgery, Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China
- School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Lijun Tang
- Department of General Surgery, Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, China
- School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, China
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14
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Hegde SG, Kashyap S, Devi S, Kumar P, Michael Raj A J, Kurpad AV. Estimation of exocrine pancreatic insufficiency in children with acute pancreatitis using the 13C mixed triglyceride breath test. Pancreatology 2023; 23:601-606. [PMID: 37481340 DOI: 10.1016/j.pan.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/10/2023] [Accepted: 07/16/2023] [Indexed: 07/24/2023]
Abstract
BACKGROUND /Objective: The extent of exocrine pancreatic insufficiency (EPI) in the paediatric population with acute pancreatitis (AP) is unknown. The primary objective was to use a 6 h stable-isotope breath test to determine the prevalence of EPI in children with AP. The secondary objective was to determine the diagnostic ability of a 4 h abbreviated breath test in the detection of EPI. METHODS 13C-mixed triglyceride (MTG) breath test was used to measure fat digestibility in 12 children with AP and 12 normal children. EPI was diagnosed based on a cumulative dose percentage recovery (cPDR) cut-off value < 26.8% present in literature. To reduce the test burden, the diagnostic accuracy of an abbreviated 4 h test was evaluated, using a cPDR cut-off that was the 2.5th percentile of its distribution in control children. RESULTS The cPDR of cases was significantly lower than that of controls (27.71 ± 7.88% vs 36.37 ± 4.70%, p = 0.005). The cPDR during acute illness was not significantly different to that at 1 month follow up (24.69 ± 6.83% vs 26.98 ± 11.10%, p = 0.52). The 4 h and 6 h breath test results correlated strongly (r = 0.93, p < 0.001) with each other. The new 4 h test had 87.5% sensitivity and 93.8% specificity for detecting EPI. CONCLUSION Two-thirds (66.7%) of this sample of children with AP had EPI during admission, which persisted at 1 month follow up. The 4 h abbreviated 13C-MTG breath test has good diagnostic ability to detect EPI in children and may improve its clinical utility in this age group.
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Affiliation(s)
- Shalini G Hegde
- Department of Paediatric Surgery, St. John's Medical College Hospital, India
| | - Sindhu Kashyap
- Division of Nutrition, St. John's Research Institute, Bangalore, India
| | - Sarita Devi
- Division of Nutrition, St. John's Research Institute, Bangalore, India
| | - Prasanna Kumar
- Department of Paediatric Surgery, St. John's Medical College Hospital, India
| | | | - Anura V Kurpad
- Department of Physiology, St. John's Medical College Hospital, India.
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15
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Li H, Wu D, Zhang H, Li P. New insights into regulatory cell death and acute pancreatitis. Heliyon 2023; 9:e18036. [PMID: 37519748 PMCID: PMC10372241 DOI: 10.1016/j.heliyon.2023.e18036] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 07/01/2023] [Accepted: 07/05/2023] [Indexed: 08/01/2023] Open
Abstract
Acute pancreatitis (AP) may be associated with both local and systemic complications. Although it is usually self-limiting, up to 20% of patients develop severe acute pancreatitis (SAP), which leads to systemic inflammatory response syndrome (SIRS) and multiorgan dysfunction and failure affecting the lung, kidney, liver and heart. Patients who survive the condition frequently develop devastating long-term consequences such as diabetes mellitus, exocrine pancreatic insufficiency, chronic pancreatitis (CP) and poor quality of life. A lack of specific targeted treatments is the main reason for high mortality and morbidity, indicating that more research on the pathogenesis of AP is needed. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of AP, including mechanisms of calcium-mediated acinar cell injury and death, the cytoprotective role of the unfolded protein response (UPR) and autophagy in preventing sustained endoplasmic reticulum stress (ERs); however, the mechanism of parenchymal cell death is relatively poorly understood. This paper reviews the research progress of the regulatory cell death (RCD) mode in the pathogenesis of AP, providing some new insights and regulatory targets for the pathogenesis and treatment of AP, facilitating better targeted drug development.
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16
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Wei B, Su Z, Yang H, Feng Y, Meng C, Liang Z. Inhibition of TRAF6 improves hyperlipidemic acute pancreatitis by alleviating pyroptosis in vitro and in vivo rat models. Biol Direct 2023; 18:23. [PMID: 37165439 PMCID: PMC10170794 DOI: 10.1186/s13062-023-00380-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 05/01/2023] [Indexed: 05/12/2023] Open
Abstract
OBJECTIVE Hypertriglyceridemia (HTG) is one of the common causes of acute pancreatitis (AP). Hyperlipidemic acute pancreatitis (HTG-AP) is associated with higher mortality owing to its tendency for greater severity and rapid progression. The purpose of this study was to explore the mechanism of involvement of tumor necrosis factor receptor-related factor 6 (TRAF6) in pyroptosis during HTG-AP. METHODS The HTG environment was simulated with palmitic acid treatment in vitro and a high-fat diet in vivo. Cerulein was used to establish the HTG-AP model, followed by genetic and pharmacological inhibition of TRAF6. Pyroptosis activation, inflammatory reaction, and the interaction between TRAF6 and pyroptosis in HTG-AP were assessed. RESULTS HTG was found to aggravate the development of pancreatitis, accompanied by increased pyroptosis and enhanced inflammatory response in HTG-AP models. Mechanistically, TRAF6 downregulation decreased the activation of pyroptosis in cerulein-induced HTG-AP. CONCLUSION Collectively, inhibition of TRAF6 improved HTG-AP and the associated inflammation by alleviating pyroptosis.
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Affiliation(s)
- Biwei Wei
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, 530021, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Zhou Su
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, 530021, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Huiying Yang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, 530021, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yong Feng
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, 530021, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Chunmei Meng
- Life Sciences Institute, Guangxi Medical University, Nanning, China
| | - Zhihai Liang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, 530021, Nanning, Guangxi Zhuang Autonomous Region, China.
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17
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Song Q, Gao H, Wu W, Gao Y, Yang J, Jiao Z, Luo Y. Gabexate Mesylate-Poloxamer 407 Conjugate Alleviates Sodium Taurocholate-Induced Severe Acute Pancreatitis in an Optimized Rat Model. Dig Dis Sci 2023; 68:138-146. [PMID: 35451710 DOI: 10.1007/s10620-022-07497-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/16/2021] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND AIMS We have previously shown that gabexate mesylate-poloxamer 407 conjugate (GMTI) alleviates traumatic pancreatitis in rats. In this study, we evaluated the therapeutic effect of GMTI on sodium taurocholate-induced severe acute pancreatitis (SAP) in an optimized rat model. METHODS An SAP rat model was established via microinjection of 3.5% sodium taurocholate and retention in the bile duct for 1 min. SAP rats were administered GMTI via tail vein injection (i.v.) or tail vein injection + intraperitoneal injection (i.v. + i.p.). All rats were sacrificed at 12 h after treatment. Biochemical approach and enzyme-linked immunosorbent assay were performed to measure the serum levels of amylase (AMY), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Hematoxylin and eosin staining and TUNEL assay were conducted to examine histopathology and acinar cell apoptosis in the rat pancreas. RESULTS SAP was successfully induced in all model rats, as evidenced by progressively aggravating SAP symptoms and signs, pancreatic histopathological abnormalities, as well as elevated serum levels of TNF-α, IL-6, and AMY. The mortality rates at 1 h, 6 h, and 12 h were 0%, 0%, and 25%, respectively. GMTI therapy via i.v. or i.v. + i.p. significantly reduced pancreatic wet weights, ascites amounts, pathological scores, and circulating levels of TNF-α and IL-6 while promoting acinar cell apoptosis in SAP rats. GMTI therapy via i.v. + i.p. outperformed i.v. in improving pancreatic histology and reducing TNF-α and IL-6 serum levels in SAP rats. CONCLUSIONS Our optimized SAP rat model is reliable and reproducible. GMTI therapy is a promising approach against SAP.
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Affiliation(s)
- Qing Song
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Hanjing Gao
- Department of Ultrasound, Second Medical Center, General Hospital of Chinese PLA, Beijing, 100853, China
| | - Wen Wu
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Yu Gao
- Department of Ultrasound, General Hospital of Chinese PLA, Seventh medical center, Beijing, 100700, China
| | - Jihua Yang
- Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Ziyu Jiao
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China
| | - Yukun Luo
- Department of Ultrasound, First Medical Center of General Hospital of Chinese PLA, Middle Street of 4th West Ring Road, Beijing, 100853, China.
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Jia A, Yang ZW, Shi JY, Liu JM, Zhang K, Cui YF. MiR-325-3p Alleviates Acute Pancreatitis via Targeting RIPK3. Dig Dis Sci 2022; 67:4471-4483. [PMID: 35094251 DOI: 10.1007/s10620-021-07322-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/08/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS Acute pancreatitis (AP) is an acute inflammatory disease that can lead to death. Mir-325-3p is strongly and abnormally expressed in many diseases, necessitating exploration of its function and mechanism in AP. METHODS Blood samples from AP patients and mice were analyzed. The expression levels of miR-325-3p in AP patients and mouse were detected. Whether miR-325-3p targets RIPK3 gene was predicted by TargetScan online database and dual luciferase reporter assay. In vitro experiments verified the effect of miR-325-3p overexpression on caerulein-induced MPC83 pancreatic acinar cancer cell line. In vivo experiments verified the effect of overexpression of miR-325-3p on the disease degree of pancreatic tissues in AP mice. RESULTS Analysis of blood samples from AP patients and experiments in mice demonstrated that expression of miR-325-3p was significantly reduced during the process of AP in humans and mice. Predicted using the TargetScan online database and through dual luciferase reporter assay detection, miR-325-3p directly targets the RIPK3 gene. In vitro experiments revealed that overexpression of miR-325-3p reversed caerulein-induced apoptosis and necroptosis in MPC83 pancreatic acinar cancer cell line. We used Z-VAD-FMK to assess necroptosis and demonstrated that miR-325-3p targets necroptosis to reduce cell damage. In subsequent experiments in mice, we verified that overexpression of miR-325-3p reduces inflammation, edema, hemorrhage, and necrosis in acute pancreatitis. Characteristic western blot, immunohistochemistry, and transmission electron microscopy results revealed that overexpression of miR-325-3p reduces the severity of acute pancreatitis by inhibiting pancreatic necroptosis in AP mice. CONCLUSIONS The current research results indicate that miR-325-3p directly targets RIPK3 and exerts a protective role in mouse AP. Necroptosis is still the primary mechanism of RIPK3 regulation. MiR-325-3p inhibits acute pancreatitis by targeting RIPK3-dependent necroptosis, which may represent a novel treatment method for acute pancreatitis.
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Affiliation(s)
- Ao Jia
- Tianjin Medical University, Tianjin, 300070, China
| | | | - Ji-Yu Shi
- Tianjin Medical University, Tianjin, 300070, China
| | - Jia-Ming Liu
- Tianjin Medical University, Tianjin, 300070, China
| | - Kun Zhang
- Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, 122 Sanwei Road, Nankai District, Tianjin, 300110, China
| | - Yun-Feng Cui
- Tianjin Medical University, Tianjin, 300070, China. .,Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, 122 Sanwei Road, Nankai District, Tianjin, 300110, China.
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19
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Wang M, Gorelick F. Ovariectomy Affects Acute Pancreatitis in Mice. Dig Dis Sci 2022; 67:2971-2980. [PMID: 34169436 PMCID: PMC8702581 DOI: 10.1007/s10620-021-07116-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/14/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Serum estradiol levels in severe acute injury are correlated with in hospital mortality. In acute pancreatitis, serum estradiol levels are strong predictors of disease severity. Studies of whether changes in estradiol levels play a causative role in acute pancreatitis severity are limited. The ovariectomized mouse model has been used to study the effects of estradiol in health and disease. AIMS We assessed whether the ovariectomized mouse model could be used to assess the effects of estradiol on pancreatitis severity. METHODS C57BL/6 mice with their ovaries removed were used to simulate low circulating estradiol conditions. Ovariectomized mice were treated with six hourly injections of cerulein to induce mild acute pancreatitis and compared to ovariectomized mice pre-treated with subcutaneous estradiol injections. RESULTS Findings suggest ovariectomized model is a problematic preparation to study pancreatitis. At baseline, ovariectomy leads to prominent acinar cell ultrastructure changes as well as changes in other select morphologic and biomarkers of pancreatitis. In addition, ovariectomy changed select acute pancreatitis responses that were only partially rescued by estradiol pre-treatment. CONCLUSIONS These findings suggest that the ovariectomized mouse as a model of estradiol depletion should be used with caution in pancreatic studies. Future studies should explore whether derangements in other female hormones produced by the ovaries can lead to changes in pancreatic studies.
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Affiliation(s)
- Melinda Wang
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Fred Gorelick
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
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20
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Sun S, Han Y, Zhang C, Liu H, Wang B, Cao S, Yuan Q, Wei S, Chen Y. Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis. Front Cell Dev Biol 2022; 10:827714. [PMID: 35281076 PMCID: PMC8904929 DOI: 10.3389/fcell.2022.827714] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/07/2022] [Indexed: 12/14/2022] Open
Abstract
Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein–induced inflammation and necroptotic cell death. Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein–treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist. Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.
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Affiliation(s)
- Shukun Sun
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Yu Han
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Chuanxin Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Han Liu
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Bailu Wang
- Clinical Trial Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shengchuan Cao
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Qiuhuan Yuan
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
| | - Shujian Wei
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- *Correspondence: Shujian Wei, ; Yuguo Chen,
| | - Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Shandong University, Jinan, China
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Chinese Ministry of Education, Qilu Hospital, Cheeloo College of Medicine, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Shandong University, Jinan, China
- *Correspondence: Shujian Wei, ; Yuguo Chen,
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21
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Parte S, Nimmakayala RK, Batra SK, Ponnusamy MP. Acinar to ductal cell trans-differentiation: A prelude to dysplasia and pancreatic ductal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2022; 1877:188669. [PMID: 34915061 DOI: 10.1016/j.bbcan.2021.188669] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer (PC) is the deadliest neoplastic epithelial malignancies and is projected to be the second leading cause of cancer-related mortality by 2024. Five years overall survival being ~10%, mortality and incidence rates are disturbing. Acinar to ductal cell metaplasia (ADM) encompasses cellular reprogramming and phenotypic switch-over, making it a cardinal event in tumor initiation. Differential cues and varied regulatory factors drive synchronous functions of metaplastic cell populations leading to multiple cell fates and physiological outcomes. ADM is a precursor for developing early pre-neoplastic lesions further progressing into PC due to oncogenic signaling. Hence delineating molecular events guiding tumor initiation may provide cues for regenerative medicine and precision onco-medicine. Therefore, understanding PC pathogenesis and early diagnosis are crucial. We hereby provide a timely overview of the current progress in this direction and future perspectives we foresee unfolding in the best interest of patient well-being and better clinical management of PC.
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Affiliation(s)
- Seema Parte
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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22
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Assessment the Effect of Ficus carica Leaf Extract on B16F10 Melanoma Cancer Cells: The Roles of p53, Caspase-3 & Caspase-9 on Induction of Intrinsic Apoptosis Cascade. Jundishapur J Nat Pharm Prod 2021. [DOI: 10.5812/jjnpp.117429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Melanoma is the most serious kind of skin cancer which has significantly increased in recent decades, and the importance of its primary treatment is increased widely. Ficus carica leaves have various therapeutic impact such as anti-inflammatory, anti-proliferative and apoptotic activity. Objectives: Hence, regarding the F. carica effect on the treatment of various diseases, the present research was conducted to identify the effect of methanolic extract of F. carica leaf on apoptosis induction in B16F10 melanoma cancer cells. Methods: Cell survival was estimated by MTT assay after treatment of B16F10 cells in various concentrations of F. carica leaf extract (150, 250, 350, 450, 550, 650, 750 and 850 μg /mL) for 24 and 48 h. Cell apoptosis was analysed by AO/PI and DAPI staining, Annexin V/Propidium Iodide flow cytometry. Moreover, Real-time PCR was utilized to evaluate the expression of apoptotic genes including p53, Bax, caspase-3 and caspase-9 genes. Results: MTT assay results indicated that methanolic extract of F. carica leaf prevented the proliferation of B16F10 cells in a dose and time dependent manner. AO/PI staining results showed an elevation in apoptotic cells in treated groups and DAPI indicated that F. carica extract resulted in chromatin condensation and fragmentation. Annexin V revealed the increasing percentage of apoptotic cells after treatment. In addition, the up-regulation of apoptotic genes confirmed the apoptosis inducing potential of F. carica leaves in B16F10 cells by Real-time PCR. Conclusions: Thus, methanolic extract of F. carica leaves could be suggested as an effective anti-cancer agent for further studies on melanoma cancer.
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23
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New-Aaron M, Ganesan M, Dagur RS, Kharbanda KK, Poluektova LY, Osna NA. Pancreatogenic Diabetes: Triggering Effects of Alcohol and HIV. BIOLOGY 2021; 10:108. [PMID: 33546230 PMCID: PMC7913335 DOI: 10.3390/biology10020108] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Multiorgan failure may not be completely resolved among people living with HIV despite HAART use. Although the chances of organ dysfunction may be relatively low, alcohol may potentiate HIV-induced toxic effects in the organs of alcohol-abusing, HIV-infected individuals. The pancreas is one of the most implicated organs, which is manifested as diabetes mellitus or pancreatic cancer. Both alcohol and HIV may trigger pancreatitis, but the combined effects have not been explored. The aim of this review is to explore the literature for understanding the mechanisms of HIV and alcohol-induced pancreatotoxicity. We found that while premature alcohol-inducing zymogen activation is a known trigger of alcoholic pancreatitis, HIV entry through C-C chemokine receptor type 5(CCR5)into pancreatic acinar cells may also contribute to pancreatitis in people living with HIV (PLWH). HIV proteins induce oxidative and ER stresses, causing necrosis. Furthermore, infiltrative immune cells induce necrosis on HIV-containing acinar cells. When necrotic products interact with pancreatic stellate cells, they become activated, leading to the release of both inflammatory and profibrotic cytokines and resulting in pancreatitis. Effective therapeutic strategies should block CCR5 and ameliorate alcohol's effects on acinar cells.
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Affiliation(s)
- Moses New-Aaron
- Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
| | - Murali Ganesan
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Raghubendra Singh Dagur
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Natalia A. Osna
- Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Veteran Affairs Nebraska—Western Iowa Health Care System, Omaha, NE 68105, USA; (M.G.); (R.S.D.); (K.K.K.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA;
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Ren Y, Liu W, zhang L, Zhang J, Bi J, Wang T, Wang M, Du Z, Wang Y, zhang L, Wu Z, Lv Y, Meng L, Wu R. Milk fat globule EGF factor 8 restores mitochondrial function via integrin-medicated activation of the FAK-STAT3 signaling pathway in acute pancreatitis. Clin Transl Med 2021; 11:e295. [PMID: 33634976 PMCID: PMC7828261 DOI: 10.1002/ctm2.295] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Acute pancreatitis (AP) remains a significant clinical challenge. Mitochondrial dysfunction contributes significantly to the pathogenesis of AP. Milk fat globule EGF factor 8 (MFG-E8) is an opsonizing protein, which has many biological functions via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining a normal mitochondrial function. However, MFG-E8's role in AP has not been evaluated. METHODS Blood samples were acquired from 69 healthy controls and 134 AP patients. Serum MFG-E8 levels were measured by ELISA. The relationship between serum concentrations of MFG-E8 and disease severity were analyzed. The role of MFG-E8 was evaluated in experimental models of AP. RESULTS Serum concentrations of MFG-E8 were lower in AP patients than healthy controls. And serum MFG-E8 concentrations were negatively correlated with disease severity in AP patients. In mice, MFG-E8 administration decreased L-arginine-induced pancreatic injury and mortality. MFG-E8's protective effects in experimental AP were associated with improvement in mitochondrial function and reduction in oxidative stress. MFG-E8 knockout mice suffered more severe pancreatic injury and greater mitochondrial damage after l-arginine administration. Mechanistically, MFG-E8 activated the FAK-STAT3 pathway in AP mice. Cilengitide, a specific αvβ3/5 integrin inhibitor, abolished MFG-E8's beneficial effects in AP. PF00562271, a specific FAK inhibitor, blocked MFG-E8-induced STAT3 phosphorylation. APTSTAT3-9R, a specific STAT3 antagonist, also eliminated MFG-E8's beneficial effects under such a condition. CONCLUSIONS MFG-E8 acts as an endogenous protective mediator in the pathogenesis of AP. MFG-E8 administration protects against AP possibly by restoring mitochondrial function via activation of the integrin-FAK-STAT3 signaling pathway. Targeting the action of MFG-E8 may present a potential therapeutic option for AP.
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Affiliation(s)
- Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Wuming Liu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Lin zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Zhaoqing Du
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Yawen Wang
- BiobankFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Laboratory MedicineFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi ProvinceChina
| | - Lin zhang
- Department of Laboratory MedicineFirst Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi ProvinceChina
| | - Zheng Wu
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
- Department of Hepatobiliary SurgeryFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
| | - Lingzhong Meng
- Department of AnesthesiologyYale University School of MedicineNew HavenConnecticutUSA
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative MedicineShaanxi Provincial Center for Regenerative Medicine and Surgical EngineeringFirst Affiliated Hospital of Xi'an Jiaotong University.Xi'anShaanxi ProvinceChina
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Abdominal paracentesis drainage attenuates severe acute pancreatitis by enhancing cell apoptosis via PI3K/AKT signaling pathway. Apoptosis 2021; 25:290-303. [PMID: 32100210 PMCID: PMC7181427 DOI: 10.1007/s10495-020-01597-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Our previous studies have shown that abdominal paracentesis drainage (APD) is a safe and effective strategy for patients with severe acute pancreatitis (SAP). However, the underlying mechanisms behind APD treatment remain poorly understood. Given that apoptosis is a critical pathological response of SAP, we here aim to investigate the effect of APD on cell apoptosis in pancreatic tissues during SAP and to explore its potential molecular mechanism. SAP was induced by 5% sodium-taurocholate retrograde while APD group was inserted a drainage tube into the right lower abdomen of rats immediately after SAP induction. Histopathological staining, serum amylase, endotoxin and inflammatory mediators were measured. Cell apoptosis, apoptosis-related proteins and signaling pathway were also evaluated. Our results demonstrated that APD treatment significantly attenuated pancreatic damage and decreased the serum levels of amylase, endotoxin, TNF-α, IL-1 and IL-6 in rats with SAP. Notably, APD treatment enhanced cell apoptosis and reduced necrosis in pancreatic tissues, as evidenced by Tunnel staining, the increased pro-apoptosis proteins (Cleaved-caspase-3 and bax) and decreased anti-apoptosis protein (Bcl-2). Moreover, the effect of APD on cell apoptosis was further confirmed by the regulatory pathway of PI3K/AKT and NF-kB signaling pathway. These results suggest that APD attenuates the severity of SAP by enhancing cell apoptosis via suppressing PI3K/AKT signaling pathway. Our findings provide new insights for understanding the effectiveness of APD in patients with SAP.
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Hyperbaric Oxygen Ameliorated Acute Pancreatitis in Rats via the Mitochondrial Pathway. Dig Dis Sci 2020; 65:3558-3569. [PMID: 32006213 DOI: 10.1007/s10620-020-06070-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 01/12/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Acute pancreatitis (AP) is a common disease of the digestive system. The mechanism of hyperbaric oxygen (HBO) therapy for AP is not completely clear. AIMS This study investigated the effects of HBO in AP and whether it acts through the mitochondria-mediated apoptosis pathway. METHODS Eighty male Sprague-Dawley rats were randomly assigned to four groups: control (8 rats), sham (24 rats), AP (24 rats), or AP + HBO (24 rats). AP was induced by ligating the pancreatic duct. The AP + HBO group was given HBO therapy starting at 6 h postinduction. Eight rats in each group were killed on days 1, 2, and 3 postinduction to assess pancreatic injury, mitochondrial membrane potential, ATP level, and expression levels of BAX, Bcl-2, caspase-3, caspase-9, and PARP in pancreatic tissue and blood levels of amylase, lipase, and pro-inflammatory cytokines. RESULTS HBO therapy alleviated the severity of AP and decreased histopathological scores and levels of serum amylase, lipase, and pro-inflammatory cytokines. Compared to AP induction alone, HBO therapy increased expression of the apoptotic protein BAX, caspase-3, caspase-9, and PARP and ATP levels in tissues and decreased antiapoptotic protein Bcl-2 expression levels and the mitochondrial membrane potential on the first day; the results on the second day were partly consistent with those on the first day, while there was no obvious difference on the third day. CONCLUSIONS HBO therapy could induce caspase-dependent apoptosis in AP rats to alleviate pancreatitis, which was possibly triggered by mitochondrial apoptosis pathway regulation of Bcl-2 family members.
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Sun H, Tian J, Li J. MiR-92b-3p ameliorates inflammation and autophagy by targeting TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells. Int Immunopharmacol 2020; 88:106691. [PMID: 32822908 DOI: 10.1016/j.intimp.2020.106691] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/20/2020] [Accepted: 06/08/2020] [Indexed: 02/08/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disease with high morbidity and mortality. Dysregulation of microRNAs (miRNAs) was involved in human diseases, including AP. However, the effects of miR-92b-3p on AP process and its mechanism remain not been fully clarified. The expression levels of miR-92b-3p and tumor necrosis factor receptor-associated factor-3 (TRAF3) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of TRAF3, tumor necrosis factor α (TNF-α) TNF-α, interleukin-6 (IL-6), phosphorylated mitogen-activated protein kinase kinase 3 (p-MKK3), MKK3, p38 and phosphorylated p38 (p-p38) were detected by western blot. The concentration of TNF-α and IL-6 in the medium was measured using ELISA kits. The possible binding sites of miR-92b-3p and TRAF3 were predicted by TargetScan and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The expression level of miR-92b-3p was decreased and TRAF3 expression was increased in AR42J cells stimulated with caerulein. Moreover, the protein levels of pro-inflammatory cytokines (TNF-α and IL-6) were markedly elevated, and the expression levels of autophagy-related markers Beclin1 as well as the ratio of LC3-II/I were obviously increased in AR42J cells treated with caerulein. In addition, overexpression of miR-92b-3p or knockdown of TRAF3 significantly suppressed the release of pro-inflammatory cytokines and autophagy in caerulein-induced AR42J cells. Furthermore, TRAF3 was a direct target of miR-92b-3p and its upregulation reversed the effects of miR-92b-3p overexpression on inflammatory response and autophagy. Besides, overexpression of miR-92b-3p inhibited the activation of the MKK3-p38 pathway by affecting TRAF3 expression. In conclusion, miR-92b-3p attenuated inflammatory response and autophagy by downregulating TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells, providing a novel avenue for treatment of AP.
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Affiliation(s)
- Hongzhi Sun
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China
| | - Jiakun Tian
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China
| | - Jinliang Li
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China.
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Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis. Cell Death Dis 2020; 11:889. [PMID: 33087696 PMCID: PMC7578033 DOI: 10.1038/s41419-020-03050-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 12/11/2022]
Abstract
Chronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.
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Yuan J, Chheda C, Piplani H, Geng M, Tan G, Thakur R, Pandol SJ. Pancreas-specific deletion of protein kinase D attenuates inflammation, necrosis, and severity of acute pancreatitis. Biochim Biophys Acta Mol Basis Dis 2020; 1867:165987. [PMID: 33039594 DOI: 10.1016/j.bbadis.2020.165987] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 10/01/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Protein kinase D (PKD) family, which includes PKD/PKD1, PKD2, and PKD3, has been increasingly implicated in the regulation of multiple cellular functions and human diseases. We recently reported that pharmacologic inhibition of PKD ameliorated the pathologic responses and severity of pancreatitis. However, to further investigate the importance of PKD family members in pancreatitis, it is necessary to explore the effects of pancreas-specific genetic inhibition of PKD isoform on pathology of pancreatitis. METHODS We generated a mouse model (referred as PKD3Δpanc mice) with pancreas-specific deletion of PKD3, the predominant PKD isoform in mouse pancreatic acinar cells, by crossing Pkd3flox/flox mice with Pdx1-Cre transgenic mice which express Cre recombinase under the control of the mouse Pdx1 promoter. Pancreas-specific deletion of the PKD3 gene and PKD3 protein was confirmed by PCR and Western blot analysis. Experimental pancreatitis was induced in PKD3Δpanc and Pkd3flox/flox (control mice) littermates by intraperitoneal injections of cerulein or L-arginine. RESULTS Compared to the control mice, PKD3Δpanc mice displayed significant attenuation in inflammation, necrosis, and severity of pancreatitis in both experimental models. PKD3Δpanc mice had markedly decreased NF-κB and trypsinogen activation, pancreatic mRNA expression of multiple inflammatory molecules, and the receptor-interacting protein kinase 1 (RIP1) activation in pancreatitis. PKD3Δpanc mice also had less pancreatic ATP depletion, increased pro-survival Bcl-2 family protein expression, and autophagy promotion. CONCLUSION With PKD3Δpanc mouse model, we further demonstrated that PKD plays a critical role in pathobiological process of pancreatitis and PKD constitutes a novel therapeutic target to treat this disorder.
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Affiliation(s)
- Jingzhen Yuan
- Cedars-Sinai Medical Center, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA.
| | | | | | - Meng Geng
- Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA; Frank Netter H. School of Medicine at Quinnipiac University, CT, USA
| | - Grace Tan
- Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA; Loma Linda Medical School, Los Angeles, CA, United States of America
| | - Reetu Thakur
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stephen J Pandol
- Cedars-Sinai Medical Center, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, South California Research Center for Alcoholic Liver and Pancreatic Diseases, California, USA
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Yang X, Li R, Xu L, Qian F, Sun L. Serum amyloid A3 is required for caerulein-induced acute pancreatitis through induction of RIP3-dependent necroptosis. Immunol Cell Biol 2020; 99:34-48. [PMID: 32725692 DOI: 10.1111/imcb.12382] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/28/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023]
Abstract
Serum amyloid A (SAA) is an early and sensitive biomarker of inflammatory diseases, but its role in acute pancreatitis (AP) is still unclear. Here, we used a caerulein-induced mouse model to investigate the role of SAA in AP and other related inflammatory responses. In our study, we found that the expression of a specific SAA isoform, SAA3, was significantly elevated in a caerulein-induced AP animal model. In addition, SAA3-knockout (Saa3-/- ) mice showed lower serum levels of amylase and lipase, tissue damage and proinflammatory cytokine production in the pancreas compared with those of wild-type mice in response to caerulein administration. AP-associated acute lung injury was also significantly attenuated in Saa3-/- mice. In our in vitro experiments, treatment with cholecystokinin and recombinant SAA3 significantly induced necroptosis and cytokine production. Moreover, we found that the regulatory effect of SAA3 on acinar cell necroptosis was through a receptor-interacting protein 3 (RIP3)-dependent manner. Collectively, our findings indicate that SAA3 is required for AP by inducing an RIP3-dependent necroptosis pathway in acinar cells and is a potential drug target for AP.
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Affiliation(s)
- Xinyi Yang
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Runsheng Li
- Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, PR China
| | - Lu Xu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Feng Qian
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China.,Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Anhui Province, Bengbu, 233003, PR China
| | - Lei Sun
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, PR China
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Wang H, Jiang Y, Li H, Wang J, Li C, Zhang D. Carbachol protects the intestinal barrier in severe acute pancreatitis by regulating Cdc42/F-actin cytoskeleton. Exp Ther Med 2020; 20:2828-2837. [PMID: 32765779 PMCID: PMC7401956 DOI: 10.3892/etm.2020.8985] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 12/06/2019] [Indexed: 12/17/2022] Open
Abstract
The present study aimed to investigate the effect of carbachol on the intestinal tight-junction barrier in a rat model of severe acute pancreatitis (SAP) without aggravating pancreatic injury, and to determine whether cell division cycle 42 (Cdc42)/F-actin could have a regulatory role. Rats were separated into a sham-operation (SO) group (n=10), SO + carbachol group (n=10), SAP group (n=60) and SAP + carbachol group (n=60). Sodium taurocholate (5%) was retrogradely injected into the biliopancreatic duct of rats to induce SAP. Subsequently, 16S rRNA sequencing was used to detect bacterial translocation (BT) in the gut of surviving animals. Hematoxylin and eosin staining was used to detect morphological changes in the pancreas and intestine. The expression of F-actin and tight junction proteins was analyzed by western blotting and immunofluorescence, and Cdc42 expression was analyzed by immunohistochemistry and western blotting. The results demonstrated that the intestinal injury in SO and SO + carbachol groups was lower than that in the SAP + carbachol group (P<0.05); however, the intestinal injury was similar in the SO and SO + carbachol groups (P>0.05), and was significantly more severe in the SAP group compared with the SAP + carbachol group (P<0.05). Similarly, pancreatic injury in the SAP and SAP + carbachol groups was significantly higher compared with the SO and SO + carbachol groups (P<0.05); however, pancreatic injury was similar in the SAP and SAP + carbachol groups (P>0.05), and in the SO and SO + carbachol groups (P>0.05). Furthermore, the mortality rate and BT in the SAP group were significantly higher compared with the SAP + carbachol group (mortality rate, 50% vs. 30%, P<0.05; BT, 60% vs. 33.3%, P<0.05). In addition, the expression of Cdc42, F-actin and claudin-2 was significantly higher in the SAP and SAP + carbachol groups compared with the SO and SO + carbachol groups (P<0.05), and the expression of occludin and zonula occludens-1 were significantly higher in the SO and SO + carbachol groups compared with the SAP and SAP + carbachol groups (P<0.05). In conclusion, these findings demonstrated that carbachol may protect the intestinal barrier in the SAP rat model without aggravating pancreatic injury via regulation of Cdc42/F-actin expression.
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Affiliation(s)
- Hanlin Wang
- Center of Colon and Rectum, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266011, P.R. China
| | - Yingjian Jiang
- Center of Colon and Rectum, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266011, P.R. China
| | - Hongbo Li
- Center of Colon and Rectum, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266011, P.R. China
| | - Jiang Wang
- Center of Colon and Rectum, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266011, P.R. China
| | - Chang Li
- Center of Colon and Rectum, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266011, P.R. China
| | - Dianliang Zhang
- Center of Colon and Rectum, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266011, P.R. China
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El Morsy EM, Ahmed MA. Carvedilol attenuates l-arginine induced acute pancreatitis in rats through modulation of oxidative stress and inflammatory mediators. Chem Biol Interact 2020; 327:109181. [DOI: 10.1016/j.cbi.2020.109181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 05/29/2020] [Accepted: 06/15/2020] [Indexed: 12/18/2022]
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Chen L, Chen Y, Yun H, Jianli Z. Tetramethylpyrazine (TMP) protects rats against acute pancreatitis through NF-κB pathway. Bioengineered 2019; 10:172-181. [PMID: 31034353 PMCID: PMC6527080 DOI: 10.1080/21655979.2019.1613103] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Acute pancreatitis (AP) is a digestive disease characterized by pancreatic inflammation. Tetramethylpyrazine (TMP) has been effectively used to ameliorate the damage on intestinal mucosa injury in rats with acute necrotizing pancreatitis (ANP). We aim to study the protective effect of TMP on caerulein-induced AP and to explore the possible mechanism. The mice randomized into control and different experimental groups. AP was induced in mice by 6-hourly intraperitoneal (i.p) injections of caerulein (50 μg/kg at 1 h interval). TMP (i.p, 10 mg/kg, 1 h interval) was administered 3 h before caerulein injection. Administration of TMP attenuated the severity of AP as shown by the histopathology, reduced serum amylase activity and pro-inflammatory cytokines TNF-α and IL-6. Further, TMP enhances the beneficial effect by reducing caerulein-induced NF-κB activation and inducing cell apoptosis in pancreas. Therefore, inhibition of nuclear factor-kappa B(NF-κB) signals by TMP represents a potential therapeutic strategy for the treatment of acute pancreatitis.
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Affiliation(s)
- Longying Chen
- a Department of Internal medicine intensive care , the central hospital of Linyi , Yishui , Shandong , China
| | - Yongjun Chen
- b Department of Traditional Chinese medicine , the affiliated hospital of Qingdao University , Shandong , China
| | - Hao Yun
- c Department of General Surgery , The Affiliated Hospital of Qingdao University , Shandong , China
| | - Zhang Jianli
- c Department of General Surgery , The Affiliated Hospital of Qingdao University , Shandong , China
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Lv C, Jin Q. Maresin-1 Inhibits Oxidative Stress and Inflammation and Promotes Apoptosis in a Mouse Model of Caerulein-Induced Acute Pancreatitis. Med Sci Monit 2019; 25:8181-8189. [PMID: 31671079 PMCID: PMC6844145 DOI: 10.12659/msm.917380] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background This study aimed to investigate the effects of maresin-1 (MaR1) in a mouse model of caerulein-induced acute pancreatitis (AP). Material/Methods Fifty C57BL/6 mice with caerulein-induced AP were divided into the untreated control group (N=10), the untreated AP model group (N=10), the MaR1-treated (low-dose, 0.1 μg) AP model group (N=10), the MaR1-treated (middle-dose, 0.5 μg) AP model group (N=10), and the MaR1-treated (high-dose, 1 μg) AP model group (N=10). Enzyme-linked immunoassay (ELISA) measured serum levels of amylase, lipase, tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 and mRNA was measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Malondialdehyde (MDA), protein carbonyls, superoxide dismutase (SOD), and the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) were measured. Histology of the pancreas included measurement of acinar cell apoptosis using the terminal-deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) assay. Western blot measured Toll-like receptor 4 (TLR4), MyD88, and phospho-NF-κB p65, and apoptosis-associated proteins Bcl-2, Bax, cleaved caspase-3, and cleaved caspase-9. Results Following treatment with MaR1, serum levels of amylase, lipase, TNF-α, IL-1β, and IL-6 decreased, MDA and protein carbonyl levels decreased, SOD and the GSH/GSSG ratio increased in a dose-dependent manner. In the MaR1-treated AP mice, inflammation of the pancreas and the expression of inflammatory cytokines, pancreatic acinar cell apoptosis, Bcl-2 expression, and expression of TLR4, MyD88, and p-NF-κB p65 were reduced, but Bax, cleaved caspase-3, and cleaved caspase-9 expression increased. Conclusions In a mouse model of caerulein-induced AP, treatment with MaR1 reduced oxidative stress and inflammation and reduced apoptosis.
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Affiliation(s)
- Chengjie Lv
- Department of Neonatal Surgery, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
| | - Qi Jin
- Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China (mainland)
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El-Kashef DH, Shaaban AA, El-Agamy DS. Protective role of pirfenidone against experimentally-induced pancreatitis. Pharmacol Rep 2019; 71:774-781. [PMID: 31376587 DOI: 10.1016/j.pharep.2019.04.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 03/02/2019] [Accepted: 04/08/2019] [Indexed: 01/19/2023]
Abstract
BACKGROUND Pirfenidone (PFD) is an orally active antifibrotic agent that has anti-inflammatory activity in diverse animal models. Its effect against acute pancreatitis (AP) has not been elucidated. Hence, the present investigation was carried out to assess the potential protective role of PFD against l-arginine-induced AP in mice. METHODS AP was induced in adult male Swiss albino mice via intraperitoneal injections of l-arginine (4 g/kg, twice each 1 h apart). PFD (250 mg/kg, orally) was administered one day before and on the day of l-arginine challenge. Twenty-four hours after l-arginine injection, the severity of AP was evaluated using biochemical and histological analyses. Indices of oxidative stress, inflammation and apoptosis were evaluated using ELISA and immunohistochemistry (IHC). RESULTS PFD suppressed the development of l-arginine-induced AP as revealed by the improvement of histopathological lesions of pancreatic specimen and the significant reduction of serum amylase and lipase levels. Notably, PFD reduced the lipid peroxidation and enhanced the antioxidants such as reduced glutathione (GSH) and superoxide dismutase (SOD) in pancreatic tissue. Importantly, PFD suppressed AP-associated elevation of inflammatory cytokines along with depression of nuclear factor kappa-B (NF-κB) immuno-expression in pancreatic tissue. Lastly, PFD efficiently ameliorated AP-induced elevation of the pro-apoptotic protein (Bax) and increased AP-induced reduction of the anti-apoptotic protein (Bcl2). CONCLUSIONS PFD protected against l-arginine-induced AP in mice through anti-oxidative, anti-inflammatory and anti-apoptotic properties.
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Affiliation(s)
- Dalia H El-Kashef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ahmed A Shaaban
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Faculty of Pharmacy, Aqaba University of Technology, Aqaba, Jordan
| | - Dina S El-Agamy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.
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Yang Y, Huang Q, Luo C, Wen Y, Liu R, Sun H, Tang L. MicroRNAs in acute pancreatitis: From pathogenesis to novel diagnosis and therapy. J Cell Physiol 2019; 235:1948-1961. [PMID: 31552677 DOI: 10.1002/jcp.29212] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 09/03/2019] [Indexed: 02/06/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disorder initiated by activation of pancreatic zymogens, leading to pancreatic injury and systemic inflammatory response. MicroRNAs (miRNAs) have emerged as important regulators of gene expression and key players in human physiological and pathological processes. Discoveries over the past decade have confirmed that altered expression of miRNAs is implicated in the pathogenesis of AP. Indeed, a number of miRNAs have been found to be dysregulated in various cell types involved in AP such as acinar cells, macrophages, and lymphocytes. These aberrant miRNAs can regulate acinar cell necrosis and apoptosis, local and systemic inflammatory response, thereby contributing to the initiation and progression of AP. Moreover, patients with AP possess unique miRNA signatures when compared with healthy individuals or those with other diseases. In view of their stability and easy detection, therefore, miRNAs have the potential to act as biomarkers for the diagnosis and assessment of patients with AP. In this review, we provide an overview of the novel cellular and molecular mechanisms underlying the roles of miRNAs during the disease processes of AP, as well as the potential diagnosis and therapeutic biomarkers of miRNAs in patients with AP.
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Affiliation(s)
- Yi Yang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Qilin Huang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Chen Luo
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Yi Wen
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Ruohong Liu
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Hongyu Sun
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Lijun Tang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
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Zarkasi KA, Jen-Kit T, Jubri Z. Molecular Understanding of the Cardiomodulation in Myocardial Infarction and the Mechanism of Vitamin E Protections. Mini Rev Med Chem 2019; 19:1407-1426. [DOI: 10.2174/1389557519666190130164334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 11/10/2018] [Accepted: 01/12/2019] [Indexed: 12/13/2022]
Abstract
:
Myocardial infarction is a major cause of deaths globally. Modulation of several molecular
mechanisms occurs during the initial stages of myocardial ischemia prior to permanent cardiac tissue
damage, which involves both pathogenic as well as survival pathways in the cardiomyocyte. Currently,
there is increasing evidence regarding the cardioprotective role of vitamin E in alleviating the disease.
This fat-soluble vitamin does not only act as a powerful antioxidant; but it also has the ability to regulate
several intracellular signalling pathways including HIF-1, PPAR-γ, Nrf-2, and NF-κB that influence
the expression of a number of genes and their protein products. Essentially, it inhibits the molecular
progression of tissue damage and preserves myocardial tissue viability. This review aims to summarize
the molecular understanding of the cardiomodulation in myocardial infarction as well as the
mechanism of vitamin E protection.
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Affiliation(s)
- Khairul Anwar Zarkasi
- Department of Biochemistry, Faculty of Medicine, UKM Medical Centre, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia
| | - Tan Jen-Kit
- Department of Biochemistry, Faculty of Medicine, UKM Medical Centre, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia
| | - Zakiah Jubri
- Department of Biochemistry, Faculty of Medicine, UKM Medical Centre, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia
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Song HY, Kim HM, Mushtaq S, Kim WS, Kim YJ, Lim ST, Byun EB. Gamma-Irradiated Chrysin Improves Anticancer Activity in HT-29 Colon Cancer Cells Through Mitochondria-Related Pathway. J Med Food 2019; 22:713-721. [PMID: 31158040 DOI: 10.1089/jmf.2018.4320] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Irradiation technology can improve the biological activities of natural molecules through a structural modification. This study was conducted to investigate the enhancement of the anticancer effects of chrysin upon exposure to gamma irradiation. Gamma irradiation induces the production of new radiolytic peaks simultaneously with the decrease of the chrysin peak, which increases the cytotoxicity in HT-29 human colon cancer cells. An isolated chrysin derivative (CM1) exhibited a stronger apoptotic effect in HT-29 cells than intact chrysin. The apoptotic characteristics induced by CM1 in HT-29 cells was mediated through the intrinsic signaling pathway, including the excessive production of included reactive oxygen species, the dissipation of the mitochondrial membrane potential, regulation of the B cell lymphoma-2 family, activation of caspase-9, 3, and cleavage of poly (adenosine diphosphate-ribose) polymerase. Our findings suggest that CM1 can be a potential anticancer candidate for the treatment of colon cancer.
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Affiliation(s)
- Ha-Yeon Song
- 1 Department of Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Korea.,2 Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, Korea
| | - Hye-Min Kim
- 3 Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Sajid Mushtaq
- 1 Department of Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Korea.,4 Department of Radiation Biotechnology and Applied Radioisotope Science, Korea University of Science and Technology, Deajeon, Korea
| | - Woo Sik Kim
- 1 Department of Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Korea
| | - Young Jun Kim
- 3 Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Seung-Taik Lim
- 2 Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, Korea
| | - Eui-Baek Byun
- 1 Department of Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Korea
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Zhan X, Wan J, Zhang G, Song L, Gui F, Zhang Y, Li Y, Guo J, Dawra RK, Saluja AK, Haddock AN, Zhang L, Bi Y, Ji B. Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 2019; 316:G816-G825. [PMID: 30943050 PMCID: PMC6620583 DOI: 10.1152/ajpgi.00004.2019] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 01/31/2023]
Abstract
Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW & NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.
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Affiliation(s)
- Xianbao Zhan
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
- Department of Oncology, Changhai Hospital, Second Military Medical University , Shanghai , China
| | - Jianhua Wan
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Guowei Zhang
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University , Guangzhou , China
| | - Lele Song
- Department of Oncology, Changhai Hospital, Second Military Medical University , Shanghai , China
| | - Fu Gui
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Yuebo Zhang
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Yinghua Li
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Jia Guo
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Rajinder K Dawra
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami , Miami, Florida
| | - Ashok K Saluja
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami , Miami, Florida
| | - Ashley N Haddock
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Lizhi Zhang
- Department of Pathology, Mayo Clinic , Rochester, Minnesota
| | - Yan Bi
- Department of Gastroenterology and Hepatology, Mayo Clinic , Jacksonville, Florida
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
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Hu Y, Dai J, Zong G, Xiao J, Guo X, Dai Y, Lu Z, Wan R. Restoration of p53 acetylation by HDAC inhibition permits the necrosis/apoptosis switch of pancreatic ainar cell during experimental pancreatitis in mice. J Cell Physiol 2019; 234:21988-21998. [PMID: 31058328 DOI: 10.1002/jcp.28761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/07/2019] [Accepted: 04/10/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Yangyang Hu
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Juanjuan Dai
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Guanzhao Zong
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Jingbo Xiao
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Xingya Guo
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Yiqi Dai
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Zhanjun Lu
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Rong Wan
- Shanghai Key Laboratory of Pancreatic Disease, Department of Gastroenterology, Shanghai General Hospital Shanghai Jiaotong University School of Medicine Shanghai China
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Seo JY, Pandey RP, Lee J, Sohng JK, Namkung W, Park YI. Quercetin 3-O-xyloside ameliorates acute pancreatitis in vitro via the reduction of ER stress and enhancement of apoptosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 55:40-49. [PMID: 30668442 DOI: 10.1016/j.phymed.2018.07.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 07/01/2018] [Accepted: 07/16/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND AND PURPOSE Glycosylation of phenolic compounds has been reported to increase water-solubility, reduce toxicity, and sometimes give improved or novel pharmacological activities. Present study was aimed to evaluate and compare the beneficial effects of quercetin aglycone (Quer) and its glycosylated derivative, quercetin 3-O-xyloside (Quer-Xyl), against acute pancreatitis (AP). METHODS The cellular acute pancreatitis model was established by treating the rat pancreatic acinar cells (AR42J) with lipopolysaccharide (10 µg/ml) and cerulein (10-7 M). The cytotoxicity of Quer or Quer-Xyl on AR42J cells was assessed by MTT assay. Calcium and ROS levels were fluorometrically determined. The ER stress levels (PERK, GRP78), expression levels of amylase and lipase, and apoptotic markers (caspase-3 and -9) were measured by RT-PCR, western blotting, or fluorometric assay. RESULTS While Quer increased the mRNA expressions of AP marker enzymes, amylase and lipase, Quer-Xyl dose-dependently reversed their expressions. Quer-Xyl suppressed intracellular ROS production and both mRNA and protein levels of GRP78 and PERK, which were significantly elevated in cerulein and LPS-treated AR42J cells. Further, RT-PCR and fluorescence assay revealed that Quer-Xyl dose-dependently augmented the mRNA expressions and activities of caspase-3 and -9. CONCLUSION These results showed that Quer-Xyl, but not Quer, has a significant anti-pancreatitis activity through attenuating intracellular ROS production and ER stress response and enhancing apoptotic cell death, suggesting that it might be useful as a potent functional ingredient in health-beneficial foods or as a therapeutic agent to prevent or treat AP.
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Affiliation(s)
- Jeong Yeon Seo
- Department of Biotechnology, Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Republic of Korea
| | - Ramesh Prasad Pandey
- Department of BT-Convergent Pharmaceutical Engineering, Institute of Biomolecule Reconstruction, Sun Moon University, Asan, Chungnam 31460, Republic of Korea
| | - Jisun Lee
- Department of Biotechnology, Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Republic of Korea
| | - Jae Kyung Sohng
- Department of BT-Convergent Pharmaceutical Engineering, Institute of Biomolecule Reconstruction, Sun Moon University, Asan, Chungnam 31460, Republic of Korea
| | - Wan Namkung
- Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul 21983, Republic of Korea
| | - Yong Il Park
- Department of Biotechnology, Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Republic of Korea.
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Xia S, Wang J, Kalionis B, Zhang W, Zhao Y. Genistein protects against acute pancreatitis via activation of an apoptotic pathway mediated through endoplasmic reticulum stress in rats. Biochem Biophys Res Commun 2018; 509:421-428. [PMID: 30594397 DOI: 10.1016/j.bbrc.2018.12.108] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 12/14/2018] [Indexed: 12/20/2022]
Abstract
Acute pancreatitis (AP) is a severe and frequently lethal disorder, but the precise mechanisms are not well understood and there is lack of effective drugs. Therefore, our study examined the in vivo intervention effects of genistein and elucidated its mechanism in acute experimental pancreatitis models. We used cerulein or taurocholate to induce acute pancreatitis (AP) in Sprague-Dawley rats with prior genistein treatment. Histological examination of the pancreas was performed and the expression of unfolded protein response (UPR) components and apoptotic mediators like caspase 12 and c-Jun N-terminal protein kinase (JNK) were measured. The amount of apoptosis in pancreatic acinar cells was also determined. Our studies found that the severity of cerulein- or taurocholate-induced AP was rescued by prior genistein treatment. Genistein stimulated the activation of multiple endoplasmic reticulum (ER) stress-related regulators like GRP78, PERK, eIF2α, and upregulated the expression of the apoptotic genes, caspase 12 and CHOP. Moreover, TUNEL assays showed that genistein treatment promoted acinar cell apoptosis. Taken together, we speculated that ER stress-associated apoptotic pathways in AP are induced by genistein, which showed cytoprotective capacity in the exocrine pancreas. These data suggest novel therapeutic strategies that employ genistein in the prevention of AP.
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Affiliation(s)
- Shijin Xia
- Shanghai Institute of Geriatrics, Huadong Hospital, Fudan University, Shanghai, 200040, PR China.
| | - Jian Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200030, PR China.
| | - Bill Kalionis
- Department of Maternal-Fetal Medicine Pregnancy Research Centre and University of Melbourne Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, Victoria, 3052, Australia.
| | - Wei Zhang
- Department of Gastroenterology, Huadong Hospital, Fudan University, 200040, Shanghai, PR China.
| | - Yun Zhao
- Department of Emergency Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, PR China.
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Fu Q, Liu CJ, Zhang X, Zhai ZS, Wang YZ, Hu MX, Xu XL, Zhang HW, Qin T. Glucocorticoid receptor regulates expression of microRNA-22 and downstream signaling pathway in apoptosis of pancreatic acinar cells. World J Gastroenterol 2018; 24:5120-5130. [PMID: 30568389 PMCID: PMC6288647 DOI: 10.3748/wjg.v24.i45.5120] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/12/2018] [Accepted: 11/13/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the underlying mechanism that microRNA-22 (miR-22) promotes the apoptosis of rat pancreatic acinar cells (AR42J) and the elements that regulate the expression of miR-22.
METHODS One hundred nanomoles per liter of caerulein (Cae) was administrated to induce the apoptosis of AR42J cells and the apoptosis rate was detected by flow cytometry analysis. An amylase assay kit was used to measure the amylase expression level in the supernatant. Quantitative real-time PCR (qRT-PCR) was adopted to measure miR-22 expression. We used online tools to predict the potential transcription promoter of miR-22 and the binding sites, which was further identified by using luciferase reporter analysis, chromatin immunoprecipitation (ChIP) and ChIP-qPCR assays. Then, a mimic of miR-22, Nr3c1 plasmid encoding the glucocorticoid receptor (GR), and si-Nr3c1 were used to transfect AR42J cells, respectively. The mRNA expression of miR-22, Nr3c1, and Erb-b2 receptor tyrosine kinase 3 (ErbB3) was confirmed by qRT-PCR and the apoptosis rate of AR42J cells was detected by flow cytometry analysis. Western blot was used to detect the expression of ErbB3, GR, PI3k, PI3k-p85α, Akt, p-Akt, Bad, Bax, Bcl-xl, Bcl-2, and cleaved caspase3.
RESULTS After inducing apoptosis of AR42J cells in vitro, the expression of miR-22 was significantly increased by 2.20 ± 0.26 and 4.19 ± 0.54 times, respectively, at 3 h and 6 h in comparison with the control group. As revealed by qRT-PCR assay, the expression of miR-22 was 78.25 ± 6.61 times higher in the miR-22 mimic group relative to the miRNA control group, accompanied with an obviously increased acinar cell apoptosis rate (32.53 ± 1.15 vs 18.07 ± 0.89, P = 0.0006). The upregulation of miR-22 could suppress its target gene, ErbB3, and the phosphorylation of PI3k and Akt. Furthermore, we predicted the potential transcription promoter of miR-22 and the binding sites using online tools. Luciferase reporter analysis and site-directed mutagenesis indicated that the binding site (GACAGCCATGTACA) of the GR, which is encoded by the Nr3c1 gene. Downregulation of the expression of GR could upregulate the expression of miR-22, which further promoted the apoptosis of AR42J cells.
CONCLUSION GR transcriptionally represses the expression of miR-22, which further promotes the apoptosis of pancreatic acinar cells by downregulating the downstream signaling pathway.
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Affiliation(s)
- Qiang Fu
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Chuan-Jiang Liu
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Xu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Zhen-Sheng Zhai
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Yu-Zhu Wang
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Ming-Xing Hu
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Xian-Ling Xu
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Hong-Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
| | - Tao Qin
- Department of Hepatobiliary and Pancreatic Surgery, People’s Hospital of Zhengzhou University (Henan Provincial People’s Hospital), School of Medicine, Zhengzhou University, Zhengzhou 450003, Henan Province, China
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Courreges AP, Najenson AC, Vatta MS, Bianciotti LG. Atrial natriuretic peptide attenuates endoplasmic reticulum stress in experimental acute pancreatitis. Biochim Biophys Acta Mol Basis Dis 2018; 1865:485-493. [PMID: 30529145 DOI: 10.1016/j.bbadis.2018.12.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 11/19/2018] [Accepted: 12/05/2018] [Indexed: 12/30/2022]
Abstract
Increasing evidence shows that the endoplasmic reticulum (ER) stress is an early event that injures pancreatic acinar cells and contributes to the pathogenesis of acute pancreatitis. In the present work we sought to establish whether atrial natriuretic peptide (ANP) alleviated ER stress in rats with cerulein-induced pancreatitis. The major components of the unfolded protein response (UPR) and their downstream effectors were assessed by immunoblotting or fluorimetry and the ultrastructure of ER evaluated by electron transmission microscopy. Cross-talk with autophagy was evaluated by beclin-1 expression. ANP reduced binding immunoglobulin protein (Bip) expression (UPR major controller) which under non-stress conditions keeps inactive the stress sensor proteins: protein kinase-like ER kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6). Although ANP did not change PERK expression it decreased p-eIF2α and enhanced downstream effector CHOP, suggesting that ANP stimulates ER-dependent apoptosis. In accordance, ANP also decreased Bcl2 expression and enhanced proapoptotic proteins Bax and Bak. The atrial peptide enhanced ATF6 expression and although it did not affect IRE1/sXBP1 signaling, it increased caspase-2 activity, also involved in ER-dependent apoptosis. Furthermore, ANP decreased beclin-1 expression. The ultrastructure of the RE revealed decreased swelling and conserved ribosomes in the presence of ANP. Present findings support that ANP alleviates ER stress in acute pancreatitis by modulating the three branches of the UPR and stimulates ER-dependent apoptosis. Gaining insights into the modulation of ER stress may help to develop specific therapeutic strategies for acute pancreatitis and/or medical interventions at risk of its developing like endoscopic retrograde cholangiopancreatography.
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Affiliation(s)
- Ana Paula Courreges
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Genética, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM), Buenos Aires, Argentina
| | - Ana Clara Najenson
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Genética, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM), Buenos Aires, Argentina
| | - Marcelo S Vatta
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, Argentina
| | - Liliana G Bianciotti
- CONICET-Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Fisiopatología, Buenos Aires, Argentina.
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Wang D, Tang M, Zong P, Liu H, Zhang T, Liu Y, Zhao Y. MiRNA-155 Regulates the Th17/Treg Ratio by Targeting SOCS1 in Severe Acute Pancreatitis. Front Physiol 2018; 9:686. [PMID: 29937734 PMCID: PMC6002743 DOI: 10.3389/fphys.2018.00686] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 05/17/2018] [Indexed: 12/11/2022] Open
Abstract
Acute pancreatitis (AP) is a serious condition associated with intestinal barrier disruption or inflammation of the pancreatic tissue. Specific microRNAs are involved in the pathogenesis of AP, during which IL-17-producing CD4+ T helper (Th17) cells accumulate in the pancreas. In this study, significantly increased levels of miR-155 were detected in clinical samples from patients with AP, and overexpression of miR-155 correlated with severe AP (SAP). To identify the effect of miR-155 on T cell differentiation, we isolated CD4+ T lymphocytes and in vitro experiments showed that inhibition of miR-155 significantly reversed the stress-induced increase in the Th17/Treg ratio. The results also showed that miR-155 increased the Th17-mediated inflammatory response by targeting SOCS1. The interaction between miR-155 and the 3′-UTR of SOCS1 was confirmed by a dual luciferase reporter assay and RT-PCR. Experimental AP of varying severity was induced in BALB/c mice by caerulein hyperstimulation and miR-155 expression was found to increase with disease progression. Inhibition of miR-155 expression significantly improved the pathology of the pancreas. We also observed downregulation of expression of inflammatory factors, IL-17, SOCS1 and phosphorylated STAT1 after miR-155 inhibition. In summary, miR-155 regulates the Th17/Treg ratio by targeting SOCS1, most probably via direct binding to its 3′-UTR region, indicating that this microRNA may be a potential biomarker and/or therapeutic target for AP.
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Affiliation(s)
- Dongyan Wang
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Maochun Tang
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Pengfei Zong
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Hua Liu
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Ting Zhang
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Yu Liu
- The Community Health Service Center of Nanxiang Town, Shanghai, China
| | - Yan Zhao
- Department of Gastroenterology, Tenth People's Hospital of Tongji University, Shanghai, China
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Phytoceuticals in Acute Pancreatitis: Targeting the Balance between Apoptosis and Necrosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:5264592. [PMID: 29686719 PMCID: PMC5857302 DOI: 10.1155/2018/5264592] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/29/2017] [Accepted: 12/20/2017] [Indexed: 12/11/2022]
Abstract
Despite recent advances in understanding the complex pathogenesis of pancreatitis, the management of the disease remains suboptimal. The use of phytoceuticals (plant-derived pleiotropic multitarget molecules) represents a new research trend in pancreatology. The purpose of this review is to discuss the phytoceuticals with pancreatoprotective potential in acute pancreatitis and whose efficacy is based, at least in part, on their capacity to modulate the acinar cell death. The phytochemicals selected, belonging to such diverse classes as polyphenols, flavonoids, lignans, anthraquinones, sesquiterpene lactones, nitriles, and alkaloids, target the balance between apoptosis and necrosis. Activation of apoptosis via various mechanisms (e.g., inhibition of X-linked inhibitor of apoptosis proteins by embelin, upregulation of FasL gene expression by resveratrol) and/or inhibition of necrosis seem to represent the essential key for decreasing the severity of the disease. Apart from targeting the apoptosis/necrosis balance, the phytochemicals displayed other specific protective activities: inhibition of inflammasome (e.g., rutin), suppression of neutrophil infiltration (e.g., ligustrazine, resveratrol), and antioxidant activity. Even though many of the selected phytoceuticals represent a promising therapeutic alternative, there is a shortage of human evidence, and further studies are required to provide solid basis to justify their use in the treatment of pancreatitis.
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Xiang H, Tao X, Xia S, Qu J, Song H, Liu J, Shang D. Targeting MicroRNA Function in Acute Pancreatitis. Front Physiol 2017; 8:726. [PMID: 28983256 PMCID: PMC5613139 DOI: 10.3389/fphys.2017.00726] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/07/2017] [Indexed: 12/11/2022] Open
Abstract
Acute pancreatitis (AP) is a common gastrointestinal disorder that featured by acute inflammatory responses leading to systemic inflammatory response syndrome (SIRS) or multiple organ failure. A worldwide increase in annual incidence has been observed during the past decade with high acute hospitalization and mortality. Lack of any specific treatment for AP, even to this day, is a reminder that there is much to be learned about the exact pathogenesis of AP. Fortunately, the discovery of microRNA (miRNA) has started an entirely new thought process regarding the molecular mechanism associated with the disease processes. Given the extensive effort made on miRNA research, certain types of miRNA have been identified across a variety of biological processes, including cell differentiation, apoptosis, metabolism, and inflammatory responses. Mutations in miRNA sequences or deregulation of miRNA expression may contribute to the alteration of a pivotal physiological function leading to AP. Designing miRNA-related tools for AP diagnosis and treatment presents a novel and potential research frontier. In this mini-review, we summarize the current knowledge of various miRNAs closely interacting with AP and the possible development of targeted miRNA therapies in this disease, which may benefit the development of potential disease biomarkers and novel treatment targets for future medical implications.
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Affiliation(s)
- Hong Xiang
- College of Integrative Medicine, Dalian Medical UniversityDalian, China.,Department of General Surgery, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Xufeng Tao
- College of Pharmacy, Dalian Medical UniversityDalian, China
| | - Shilin Xia
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Jialin Qu
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Huiyi Song
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Jianjun Liu
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Dong Shang
- College of Integrative Medicine, Dalian Medical UniversityDalian, China.,Department of General Surgery, First Affiliated Hospital of Dalian Medical UniversityDalian, China
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Xie Q, Fei M, Fa Z, Wang L, Wang J, Zhang Y, Wang J, Deng X. Methane-rich saline alleviates cerulein-induced acute pancreatitis by inhibiting inflammatory response, oxidative stress and pancreatic apoptosis in mice. Int Immunopharmacol 2017; 51:17-24. [PMID: 28759809 DOI: 10.1016/j.intimp.2017.07.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 06/26/2017] [Accepted: 07/21/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease involving intracellular activation of digestive enzymes and pancreatic acinar cell injury. The present study was performed to investigate whether methane-rich saline (MS) was involved in the regulation of AP. METHODS MS (16ml/kg) was administered at different dosing frequencies on mice with cerulein-induced AP. Serum amylase, lipase and histopathological changes in the pancreas tissue were measured. Serum cytokine TNFα, IL-6, IFNγ and IL-10 were detected by ELISA. The mRNA levels of these inflammatory cytokines in the pancreas were detected by real time-PCR. Myeloperoxidase (MPO) and superoxide dismutase (SOD) were determined using commercial kits. Apoptosis was assessed by immunohistochemistry and Western blot. RESULTS MS treatment reversed the increased serum level of amylase and lipase, alleviated the pathological damage in the pancreas, and decreased the expression of TNFα, IL-6, IFNγ and IL-10 in cerulean-induced AP mice. In addition, MPO was down-regulated and SOD was up-regulated in the MS treated pancreas, indicating that MS had an anti-oxidant effect against AP. Furthermore, MS protected pancreatic cells against cerulean-induced apoptosis and abolished cleaved caspase-3. CONCLUSION MS exerted anti-inflammatory, anti-oxidant and anti-apoptotic effects on cerulein-induced AP in mice and may proved to be a promising therapeutic agent for the clinical treatment of pancreatitis.
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Affiliation(s)
- Qun Xie
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Miaomiao Fei
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Zhenzong Fa
- Shanghai Key Laboratory of Molecular Mycology, Department of Dermatology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Liping Wang
- Department of Anesthesiology, Fuzhou General Hospital of Nanjing Military Region, Fuzhou 350025, Fujian Province, China
| | - Jun Wang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Yan Zhang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jiafeng Wang
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
| | - Xiaoming Deng
- Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
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Abstract
The PMCA is an ATP-driven Ca2+ pump critical for the maintenance of low cytosolic calcium. The PMCA has an important but paradoxical role in cell death and survival. The PMCA can be differentially regulated by caspase/calpain cleavage. Glycolytic ATP supply may be sufficient to fuel the PMCA during metabolic stress. The ATP sensitivity of the PMCA can be regulated by acidic phospholipids. The plasma membrane Ca2+-ATPase (PMCA) is a ubiquitously expressed, ATP-driven Ca2+ pump that is critical for maintaining low resting cytosolic Ca2+ ([Ca2+]i) in all eukaryotic cells. Since cytotoxic Ca2+ overload has such a central role in cell death, the PMCA represents an essential “linchpin” for the delicate balance between cell survival and cell death. In general, impaired PMCA activity and reduced PMCA expression leads to cytotoxic Ca2+ overload and Ca2+ dependent cell death, both apoptosis and necrosis, whereas maintenance of PMCA activity or PMCA overexpression is generally accepted as being cytoprotective. However, the PMCA has a paradoxical role in cell death depending on the cell type and cellular context. The PMCA can be differentially regulated by Ca2+-dependent proteolysis, can be maintained by a localised glycolytic ATP supply, even in the face of global ATP depletion, and can be profoundly affected by the specific phospholipid environment that it sits within the membrane. The major focus of this review is to highlight some of the controversies surrounding the paradoxical role of the PMCA in cell death and survival, challenging the conventional view of ATP-dependent regulation of the PMCA and how this might influence cell fate.
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Affiliation(s)
- Jason I E Bruce
- Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom.
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50
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Gao E, Jiang Y, Li Z, Xue D, Zhang W. Association between high mobility group box‑1 protein expression and cell death in acute pancreatitis. Mol Med Rep 2017; 15:4021-4026. [PMID: 28440506 PMCID: PMC5436195 DOI: 10.3892/mmr.2017.6496] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 02/20/2017] [Indexed: 01/03/2023] Open
Abstract
The present study used caerulein stimulation of AR42J rat pancreatic cells as an in vitro acute pancreatitis (AP) model to investigate proteins differentially expressed in apoptosis and necrosis. AR42J cells were stimulated with 10‑8mol/l caerulein and incubated for 24 h. Apoptosis and necrosis were detected using flow cytometry. The sorted Annexin V‑positive cells (apoptotic) and the Annexin V/propidium iodide double‑positive cells (necrotic) were analysed using proteomics. Results showed that numerous proteins were differentially expressed in these 2 groups. Functional enrichment analysis was performed on the differentially expressed genes using the Database for Annotation, Visualization and Integrated Discovery. High mobility group box‑1 protein (HMGB1) was specifically expressed in the necrosis group. Models of varying degrees of AP were established using caerulein at concentrations of 10‑9, 10‑8, 10‑7, 10‑6 and 10‑5 mol/l. The percentage of apoptotic and necrotic cells in each group was determined using flow cytometry. Protein expression levels of HMGB1 were detected by western blot analysis. The present study showed that as the concentration of caerulein increased, the percentage of necrotic cells and the protein expression levels of HMGB1 increased. HMGB1 is involved in many biological processes, including the chromosomal protein glycyl lysine isopeptide cross‑link. HMGB1 may be involved in the early stage of pancreatitis, potentially by inducing the development of cell death by necrosis. These results provide an experimental basis for clinical intervention in AP.
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Affiliation(s)
- Enjun Gao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Yanfeng Jiang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Zhituo Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Weihui Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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