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1
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Zhang X, Xu C, Ji L, Zhang H. Endoplasmic reticulum stress in acute pancreatitis: Exploring the molecular mechanisms and therapeutic targets. Cell Stress Chaperones 2025; 30:119-129. [PMID: 40107566 PMCID: PMC11995708 DOI: 10.1016/j.cstres.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 03/22/2025] Open
Abstract
Acute pancreatitis (AP) is associated with multiple cellular mechanisms that trigger and or are triggered by the inflammatory injury and death of the acinar cells. One of the key mechanisms is the endoplasmic reticulum (ER) stress, which manifests as an accumulation of misfolded proteins within ER, an event that has proinflammatory and proapoptotic consequences. Hence, the degree of cell insult during AP could considerably depend on the signaling pathways that are upregulated during ER stress and its resulting dyshomeostasis such as C/EBP homologous protein (CHOP), cJUN NH2-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and NOD-like receptor protein 3 (NLRP3) inflammasome. Exploring these molecular pathways is an interesting area for translational medicine as it may lead to identifying new therapeutic targets in AP. This review of the literature aims to shed light on the different roles of ER stress in the etiopathogenesis and pathogenesis of AP. Then, it specifically focuses on the therapeutic implications of ER stress in this context.
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Affiliation(s)
- Xiaoliang Zhang
- Department of Gastroenterology, Weifang People's Hospital, Weifang, Shandong, China
| | - Chenchen Xu
- Department of Pediatrics, Weifang People's Hospital, Weifang, Shandong, China
| | - LiJuan Ji
- Department of Internal Medicine, Weicheng People's Hospital, Weifang, Shandong, China
| | - Haiwei Zhang
- Department of Gastroenterology, Weifang People's Hospital, Weifang, Shandong, China.
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Nordback I, Paajanen H, Pandol S. How Alcohol Induces Human Acute Alcoholic Pancreatitis-Problem Solved? THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00115-4. [PMID: 40254129 DOI: 10.1016/j.ajpath.2025.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/04/2025] [Accepted: 03/17/2025] [Indexed: 04/22/2025]
Abstract
It has been a puzzle why only a minority of heavy alcohol drinkers develop acute alcoholic pancreatitis. In this review, the sparse data available from published studies were collected and, based on them, a hypothesis was formed. Long-term high alcohol consumption results in lowered cholecystokinin and cholinergic stimulus of the pancreas, and causes concentration and acidification of pancreatic fluid, predisposing to protein secretion. Early during the withdrawal period when returning to a normal or high-fat nonalcoholic diet, there is a relative hyperstimulation of the pancreas, a well-established mechanism that results in experimental acute pancreatitis. Lower, physiological stimulation is enough to start acute pancreatitis, when the secretions cause temporary obstruction in the duct system; the stimulation against temporary obstruction is also well-known to result in experimental acute pancreatitis. The magnitude of alcohol-induced deficits in acinar cell defense mechanisms then finally determines the onset of pancreatitis.
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Affiliation(s)
- Isto Nordback
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
| | - Hannu Paajanen
- Department of Gastrointestinal Surgery, University of Eastern Finland, Kuopio, Finland
| | - Stephen Pandol
- Basic and Translational Pancreas Research, Cedars-Sinai Medical Center, Los Angeles, California.
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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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Srinivasan S, Mehra S, Jinka S, Bianchi A, Singh S, Dosch AR, Amirian H, Krishnamoorthy V, Silva IDC, Patel M, Box EW, Garrido V, Totiger TM, Zhou Z, Ban Y, Datta J, VanSaun M, Merchant N, Nagathihalli NS. Activation of CREB drives acinar cells to ductal reprogramming and promotes pancreatic cancer progression in animal models of alcoholic pancreatitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.01.05.574376. [PMID: 38903082 PMCID: PMC11188065 DOI: 10.1101/2024.01.05.574376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
BACKGROUND & AIMS Alcoholic chronic pancreatitis (ACP) exacerbates pancreatic damage through acinar cell injury, fibroinflammation, and cyclic adenosine monophosphate response element binding protein 1 (CREB) activation, surpassing the damage by alcohol (A) alone or cerulein-induced CP. The molecular cooperativity between CREB and oncogenic Kras G12D/+ (Kras*) in promoting pancreatic cancer progression within the context of ACP remains unclear. METHODS Experimental ACP induction was established in multiple mouse models, with euthanasia during the recovery stage to assess tumor latency. We established CREB deletion (Creb fl/fl ) in Ptf1a CreERTM/+ ;LSL-Kras G12D/+ (KC) genetic mouse models (KCC -/- ). Pancreata from Ptf1a CreERTM/+ , KC, and KCC -/- mice were analyzed using western blotting, phosphokinase array, and quantitative PCR. Single-cell RNA sequencing was performed in ACP-induced KC mice. Lineage tracing of acinar cell explant cultures and analysis of tissue samples from human pancreatic diseases (CP and pancreatic ductal adenocarcinoma [PDAC]) were conducted. RESULTS ACP induction in KC mice impaired the pancreas' repair mechanism. Acinar cell-derived ductal lesions demonstrated prolonged hyperactivated CREB in acinar-to-ductal metaplasia (ADM)/pancreatic intraepithelial neoplasia (PanIN) lesions associated with pancreatitis and in PDAC. Persistent CREB activation reprogrammed acinar cells, increasing profibrotic inflammation. In ACP-induced models, acinar-specific Creb ablation reduced advanced PanIN lesions, hindered tumor progression, and improved acinar cell function. Pharmacological targeting of CREB significantly reduced the primary tumor burden in a PDAC mouse model with ACP. CONCLUSIONS Our findings demonstrate that CREB and Kras* promote irreversible ADM, accelerating pancreatic cancer progression with ACP. Targeting CREB offers a promising strategy to address the clinical need for effective treatments for inflammation-driven pancreatic cancer.
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Affiliation(s)
- Supriya Srinivasan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Siddharth Mehra
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Sudhakar Jinka
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Anna Bianchi
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Samara Singh
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Austin R Dosch
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Haleh Amirian
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | | | - Iago De Castro Silva
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Manan Patel
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Edmond Worley Box
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Vanessa Garrido
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Tulasigeri M Totiger
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Zhiqun Zhou
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Yuguang Ban
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida
| | - Jashodeep Datta
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Michael VanSaun
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Nipun Merchant
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Nagaraj S Nagathihalli
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
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Ruiter-Lopez L, Khan MAS, Wang X, Song BJ. Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage. Antioxidants (Basel) 2025; 14:302. [PMID: 40227291 PMCID: PMC11939343 DOI: 10.3390/antiox14030302] [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: 02/01/2025] [Revised: 02/27/2025] [Accepted: 02/27/2025] [Indexed: 04/15/2025] Open
Abstract
Excessive alcohol consumption significantly impacts human health, particularly the brain, due to its susceptibility to oxidative stress, which contributes to neurodegenerative conditions. Alcohol metabolism in the brain occurs primarily via catalase, followed by CYP2E1 pathways. Excess alcohol metabolized by CYP2E1 generates reactive oxygen/nitrogen species (ROS/RNS), leading to cell injury via altering many different pathways. Elevated oxidative stress impairs autophagic processes, increasing post-translational modifications and further exacerbating mitochondrial dysfunction and ER stress, leading to cell death. The literature highlights that alcohol-induced oxidative stress disrupts autophagy and mitophagy, contributing to neuronal damage. Key mechanisms include mitochondrial dysfunction, ER stress, epigenetics, and the accumulation of oxidatively modified proteins, which lead to neuroinflammation and impaired cellular quality control. These processes are exacerbated by chronic alcohol exposure, resulting in the suppression of protective pathways like NRF2-mediated antioxidant responses and increased susceptibility to neurodegenerative changes in the brain. Alcohol-mediated neurotoxicity involves complex interactions between alcohol metabolism, oxidative stress, and autophagy regulation, which are influenced by various factors such as drinking patterns, nutritional status, and genetic/environmental factors, highlighting the need for further molecular studies to unravel these mechanisms and develop targeted interventions.
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Affiliation(s)
- Leon Ruiter-Lopez
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
| | - Mohammed A. S. Khan
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.A.S.K.); (X.W.)
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (M.A.S.K.); (X.W.)
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA
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Li H, Tan X, Li J, Zhang Q. New Progress in the Study of Pathogenesis of Alcoholic Pancreatitis. Digestion 2025:1-15. [PMID: 39827866 DOI: 10.1159/000542548] [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: 01/17/2024] [Accepted: 10/29/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Alcoholic pancreatitis is a progressive condition characterized by susceptibility to recurrence, progression to chronic pancreatitis, complications, and high morbidity. SUMMARY The main causes include long-term alcoholism, excessive drinking, the toxic effects of alcohol metabolites, interactions with biliary diseases, and genetic factors. Alcohol is the second leading cause of acute pancreatitis (AP) in the USA, accounting for one-third of all AP cases. A follow-up study on readmission revealed that the readmission rate of alcoholic acute pancreatitis (AAP) patients within 11 months was 43.1%, of which men dominated the admissions and readmissions of AAP. Among this population, 82.3% have alcohol use disorder, over half have tobacco use disorders, 6.7% have tobacco use disorder, 4.5% have opioid use disorder, and 18.5% of patients exhibit signs of potential alcoholic chronic pancreatitis. Numerous animal and clinical studies suggest that alcohol alone does not cause pancreatitis; rather, additional factors such as smoking, endotoxin lipopolysaccharide (LPS), genetic mutations, or other genetic predispositions - are necessary for the disease's progression. KEY MESSAGES Given the high rates of admission and readmission for alcoholic pancreatitis, it is essential to further investigate its pathogenesis and pathological processes to develop more effective treatment strategies. Therefore, this paper summarizes the current understanding of the pathogenesis and treatment status of alcoholic pancreatitis, drawing on recently published literature and data to provide insights and references for future research and treatment efforts.
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Affiliation(s)
- Hanhui Li
- Department of Gastroenterology, First Hospital of Yangtze University, Jingzhou, China,
- Digestive Disease Research Institution of Yangtze University, Jingzhou, China,
- Clinical medical college, Yangtze University, Jingzhou, China,
| | - Xiaoping Tan
- Digestive Disease Research Institution of Yangtze University, Jingzhou, China
- Jingzhou Hospital of Traditional Chinese Medicine, The Third Clinical Medical College of Yangtze University, Jingzhou, China
| | - Jie Li
- Department of Gastroenterology, First Hospital of Yangtze University, Jingzhou, China
- Digestive Disease Research Institution of Yangtze University, Jingzhou, China
| | - Qing Zhang
- Department of Gastroenterology, First Hospital of Yangtze University, Jingzhou, China
- Digestive Disease Research Institution of Yangtze University, Jingzhou, China
- Clinical medical college, Yangtze University, Jingzhou, China
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7
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Li X, Li X, Jinfeng Z, Yu T, Zhang B, Yang Y. Lysine acetylation and its role in the pathophysiology of acute pancreatitis. Inflamm Res 2025; 74:13. [PMID: 39775049 DOI: 10.1007/s00011-024-01989-z] [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: 09/18/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/11/2025] Open
Abstract
Acute pancreatitis (AP) represents a severe inflammatory condition of the exocrine pancreas, precipitating systemic organ dysfunction and potential failure. The global prevalence of acute pancreatitis is on an ascending trajectory. The condition carries a significant mortality rate during acute episodes. This underscores the imperative to elucidate the etiopathogenic pathways of acute pancreatitis, enhance comprehension of the disease's intricacies, and identify precise molecular targets coupled with efficacious therapeutic interventions. The pathobiology of acute pancreatitis encompasses not only the ectopic activation of trypsinogen but also extends to disturbances in calcium homeostasis, mitochondrial impairment, autophagic disruption, and endoplasmic reticulum stress responses. Notably, the realm of epigenetic regulation has garnered extensive attention and rigorous investigation in acute pancreatitis research over recent years. One of these modifications, lysine acetylation, is a reversible post-translational modification of proteins that affects enzyme activity, DNA binding, and protein stability by changing the charge on lysine residues and altering protein structure. Numerous studies have revealed the importance of acetylation modification in acute pancreatitis, and that it is a favorable target for the design of new drugs for this disease. This review centers on lysine acetylation, examining the strides made in acute pancreatitis research with a focus on the contributory role of acetylomic alterations in the pathophysiological landscape of acute pancreatitis, thereby aiming to delineate novel therapeutic targets and advance the development of more efficacious treatment modalities.
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Affiliation(s)
- Xiaoqian Li
- Department of Immunology, School of Basic Medicine, Qingdao University, No. 308 Ningxia Road, Qingdao, 266021, 266071, Shandong, People's Republic of China
| | - Xiaolu Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao, 266021, Shandong, People's Republic of China
| | - Zhang Jinfeng
- Department of Surgery, Songshan Hospital of Qingdao University, Qingdao, 266071, Shandong, People's Republic of China
| | - Tao Yu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao, 266021, Shandong, People's Republic of China
| | - Bei Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, No. 308 Ningxia Road, Qingdao, 266021, 266071, Shandong, People's Republic of China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, No. 308 Ningxia Road, Qingdao, 266021, 266071, Shandong, People's Republic of China.
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Bassiouni W, Mahmud Z, Simmen T, Seubert JM, Schulz R. MMP-2 inhibition attenuates ER stress-mediated cell death during myocardial ischemia-reperfusion injury by preserving IRE1α. J Mol Cell Cardiol 2025; 198:74-88. [PMID: 39622369 DOI: 10.1016/j.yjmcc.2024.11.013] [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: 01/19/2024] [Revised: 09/23/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024]
Abstract
Endoplasmic reticulum (ER) stress is one of the major events accompanying myocardial ischemia-reperfusion (IR) injury, as hypoxia and oxidative stress disrupt protein folding in the ER. As a result, the unfolded protein response (UPR) is activated through different sensors including inositol-requiring enzyme 1α (IRE1α) and protein kinase R-like ER kinase (PERK). Failure of the UPR to reduce ER stress induces cellular dysfunction. Matrix metalloproteinase-2 (MMP-2) is a ubiquitous protease that is activated intracellularly in response to oxidative stress and partially localizes near the ER. However, its role in ER homeostasis is unknown. We hypothesized that MMP-2 is involved in the regulation of the UPR and ER stress-mediated apoptosis during IR injury. Isolated mouse hearts subjected to IR injury showed impaired recovery of post-ischemic contractile function compared to aerobically perfused controls. Ventricular extracts from IR hearts had higher levels of glucose-regulated protein-78 and protein disulfide isomerase and lower levels of IRE1α and PERK compared to aerobic controls. MMP-2 inhibitors, ARP-100 or ONO-4817, given 10 min before ischemia, improved cardiac post-ischemic recovery and preserved IRE1α level in hearts subjected to 30 min ischemia/40 min reperfusion. IR also increased the levels of CHOP and mitochondrial Bax and caspase-3 and -9 activities, indicating induction of apoptosis, all of which were attenuated by MMP-2 inhibitors, regardless of the reperfusion time. Immunoprecipitation showed an association between MMP-2 and IRE1α in aerobic and IR hearts. During myocardial IR injury MMP-2 may impair the UPR and induce apoptosis by proteolysis of IRE1α. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in part by preserving IRE1α and preventing the progression to myocardial cell death.
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Affiliation(s)
- Wesam Bassiouni
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Alexandria University, Egypt
| | - Zabed Mahmud
- Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Thomas Simmen
- Department of Cell Biology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
| | - John M Seubert
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada; Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
| | - Richard Schulz
- Department of Pharmacology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
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9
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Sandoval C, Canobbi L, Orrego Á, Reyes C, Venegas F, Vera Á, Torrens F, Vásquez B, Godoy K, Zamorano M, Caamaño J, Farías J. Application of Integrated Optical Density in Evaluating Insulin Expression in the Endocrine Pancreas During Chronic Ethanol Exposure and β-Carotene Supplementation: A Novel Approach Utilizing Artificial Intelligence. Pharmaceuticals (Basel) 2024; 17:1478. [PMID: 39598390 PMCID: PMC11597364 DOI: 10.3390/ph17111478] [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: 09/28/2024] [Revised: 10/29/2024] [Accepted: 11/01/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND β-carotene is an essential antioxidant, providing protection against type 2 diabetes mellitus, cardiovascular illnesses, obesity, and metabolic syndrome. This study investigates the impact of β-carotene on biochemical parameters and pancreatic insulin expression in mice exposed to ethanol. METHODS Thirty-six C57BL/6 mice (Mus musculus) were divided into six groups: 1. C (control), 2. LA (3% alcohol dose), 3. MA (7% alcohol dose), 4. B (0.52 mg/kg body weight/day β-carotene), 5. LA+B (3% alcohol dose + 0.52 mg/kg body weight/day β-carotene), and 6. MA+B (7% alcohol dose plus 0.52 mg/kg body weight/day β-carotene). After 28 days, the animals were euthanized for serum and pancreatic tissue collection. Biochemical analysis and pancreatic insulin expression were performed. One-way ANOVA was used. RESULTS The B, LA+B, and MA+B groups improved insulin levels and decreased HOMA-β versus the C group, with the LA+B and MA+B groups also showing lower ADH and ALDH levels than their nonsupplemented counterparts (p < 0.05). The B, LA+B, and MA+B groups showed a greater β-cell mass area compared to the unsupplemented groups. Additionally, the LA+B and MA+B groups demonstrated significantly increased β-cell area and integrated optical density compared to the LA and MA groups, respectively (p < 0.001). CONCLUSIONS In mice, β-cell loss led to increased glucose release due to decreased insulin levels. β-carotene appeared to mitigate ethanol's impact on these cells, resulting in reduced insulin degradation when integrated optical density was used. These findings suggest that antioxidant supplementation may be beneficial in treating ethanol-induced type 2 diabetes in animal models.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile;
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Luciano Canobbi
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Álvaro Orrego
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Camila Reyes
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Felipe Venegas
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Ángeles Vera
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile; (L.C.); (Á.O.); (C.R.); (F.V.); (Á.V.)
| | - Francisco Torrens
- Institut Universitari de Ciència Molecular, Universitat de València, 46071 València, Spain;
| | - Bélgica Vásquez
- Departamento de Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
- Centro de Excelencia en Estudios Morfológicos y Quirúrgicos (CEMyQ), Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Karina Godoy
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Mauricio Zamorano
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile;
| | - José Caamaño
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile;
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10
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Yang Z, Li S, Zhao C, Zhao Z, Tan J, Zhang L, Huang Y. X-Box binding protein 1 downregulates SIRT6 to promote injury in pancreatic ductal epithelial cells. Immun Inflamm Dis 2024; 12:e1301. [PMID: 38967361 PMCID: PMC11225082 DOI: 10.1002/iid3.1301] [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: 09/12/2023] [Revised: 04/19/2024] [Accepted: 05/19/2024] [Indexed: 07/06/2024] Open
Abstract
OBJECTIVE Acute pancreatitis (AP) stands as a frequent cause for clinical emergency hospital admissions. The X-box binding protein 1 (XBP1) was found to be implicated in pancreatic acinar cell apoptosis. The objective is to unveil the potential mechanisms governed by XBP1 and SIRT6 in the context of AP. METHODS Caerulein-treated human pancreatic duct epithelial (HPDE) cells to establish an in vitro research model. The levels and regulatory role of SIRT6 in the treated cells were evaluated, including its effects on inflammatory responses, oxidative stress, apoptosis, and endoplasmic reticulum stress. The relationship between XBP1 and SIRT6 was explored by luciferase and ChIP experiments. Furthermore, the effect of XBP1 overexpression on the regulatory function of SIRT6 on cells was evaluated. RESULTS Caerulein promoted the decrease of SIRT6 and the increase of XBP1 in HPDE cells. Overexpression of SIRT6 slowed down the secretion of inflammatory factors, oxidative stress, apoptosis level, and endoplasmic reticulum stress in HPDE cells. However, XBP1 negatively regulated SIRT6, and XBP1 overexpression partially reversed the regulation of SIRT6 on the above aspects. CONCLUSION Our study illuminates the role of XBP1 in downregulating SIRT6 in HPDE cells, thereby promoting cellular injury. Inhibiting XBP1 or augmenting SIRT6 levels holds promise in preserving cell function and represents a potential therapeutic avenue in the management of AP.
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Affiliation(s)
- Zhuo Yang
- Intensive Care Unit, Bazhong Hospital of Traditional Chinese MedicineBazhongSichuanChina
| | - Shaojun Li
- Acupuncture and Rehabilitation DepartmentBazhong Hospital of Traditional Chinese MedicineBazhongSichuanChina
| | - Chuan Zhao
- Intensive Care Unit, Bazhong Hospital of Traditional Chinese MedicineBazhongSichuanChina
| | - Zongzheng Zhao
- Intensive Care Unit, Bazhong Hospital of Traditional Chinese MedicineBazhongSichuanChina
| | - Juan Tan
- Intensive Care Unit, Bazhong Hospital of Traditional Chinese MedicineBazhongSichuanChina
| | - Lu Zhang
- Acupuncture and Rehabilitation DepartmentBazhong Hospital of Traditional Chinese MedicineBazhongSichuanChina
| | - Yuanqing Huang
- Intensive Care Unit, Bazhong Hospital of Traditional Chinese MedicineBazhongSichuanChina
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11
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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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12
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Ding WX, Ma X, Kim S, Wang S, Ni HM. Recent insights about autophagy in pancreatitis. EGASTROENTEROLOGY 2024; 2:e100057. [PMID: 38770349 PMCID: PMC11104508 DOI: 10.1136/egastro-2023-100057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Acute pancreatitis is a common inflammatory gastrointestinal disease without any successful treatment. Pancreatic exocrine acinar cells have high rates of protein synthesis to produce and secrete large amounts of digestive enzymes. When the regulation of organelle and protein homeostasis is disrupted, it can lead to endoplasmic reticulum (ER) stress, damage to the mitochondria and improper intracellular trypsinogen activation, ultimately resulting in acinar cell damage and the onset of pancreatitis. To balance the homeostasis of organelles and adapt to protect themselves from organelle stress, cells use protective mechanisms such as autophagy. In the mouse pancreas, defective basal autophagy disrupts ER homoeostasis, leading to ER stress and trypsinogen activation, resulting in spontaneous pancreatitis. In this review, we discuss the regulation of autophagy and its physiological role in maintaining acinar cell homeostasis and function. We also summarise the current understanding of the mechanisms and the role of defective autophagy at multiple stages in experimental pancreatitis induced by cerulein or alcohol.
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Affiliation(s)
- Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sydney Kim
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
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13
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Edwards D, Krishnan B, Jalal M. A case report of pancreatic exocrine insufficiency in a patient with Parkinson's disease: A coincidence or is there more to it than meets the eye? J R Coll Physicians Edinb 2024; 54:38-40. [PMID: 38396339 DOI: 10.1177/14782715241234078] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2024] Open
Abstract
Pancreatic exocrine insufficiency (PEI) is an under-diagnosed condition. Untreated PEI can result in developing gastrointestinal symptoms and long-term complications including weight loss, nutrient deficiencies, sarcopenia and osteoporosis. Current best practice recommends testing for PEI in certain disorders including chronic pancreatitis, cystic fibrosis, pancreatic cancer and post-pancreatic surgery. However, there is increasing evidence that PEI is associated with a number of conditions in addition to the aforementioned diseases. These 'at-risk' conditions are a heterogeneous group of diseases, for example, diabetes mellitus, people living with human immunodeficiency virus, high alcohol intake, and coeliac disease. The pathophysiology of some of 'at-risk' conditions is becoming increasingly recognised; therefore, the list of associated conditions are in evolving process. We present a case of a 60-year-old male with Parkinson's disease and persistent abdominal pain who was found to have low faecal elastase levels indicative of severe PEI. His past medical history included none of the known risk factors for PEI. After examining the literature, we report a similar pathophysiological process underlying the development of pancreatitis and Parkinson's disease which is dysfunction of the Unfolded Protein Response. We suggest further research to assess the prevalence of PEI in the population of patients with Parkinson's disease.
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Affiliation(s)
- David Edwards
- Department of Gastroenterology, Royal Bournemouth Hospital, Bournemouth, UK
| | - Babu Krishnan
- Department of Gastroenterology, Royal Bournemouth Hospital, Bournemouth, UK
| | - Mustafa Jalal
- Department of Gastroenterology, Royal Bournemouth Hospital, Bournemouth, UK
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14
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Sandoval C, Vera A, Birditt K, Godoy K, Carmine F, Caamaño J, Farías J. β-Carotene Supplementation Improves Pancreas Function during Moderate Ethanol Consumption: Initial Characterization from a Morphological Overview. Int J Mol Sci 2024; 25:1219. [PMID: 38279214 PMCID: PMC10815982 DOI: 10.3390/ijms25021219] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/28/2024] Open
Abstract
Alcohol is believed to harm acinar cells, pancreatic ductal epithelium, and pancreatic stellate cells. After giving ethanol and/or β-carotene to C57BL/6 mice, our goal was to evaluate their biochemistry, histology, and morpho-quantitative features. There were six groups of C57BL/6 mice: 1. Group C (control), 2. Group LA (low-dose alcohol), 3. Group MA (moderate-dose alcohol), 4. Group B (β-carotene), 5. Group LA + B (low-dose alcohol combined with β-carotene), and 6. Group MA + B (moderate-dose alcohol combined with β-carotene). After the animals were euthanized on day 28, each specimen's pancreatic tissue was taken. Lipase, uric acid, and amylase were assessed using biochemical assessment. Furthermore, the examination of the pancreatic structure was conducted using Ammann's fibrosis scoring system. Finally, the morpho-quantitative characteristics of the pancreatic islets and acinar cells were determined. In the serum of the MA + B group, there were higher amounts of total amylase (825.953 ± 193.412 U/L) and lower amounts of lipase (47.139 ± 6.099 U/L) (p < 0.05). Furthermore, Ammann's fibrosis punctuation in the pancreas revealed significant variations between the groups (p < 0.001). Finally, the stereological analysis of pancreatic islets showed that the groups were different (p < 0.001). These findings suggest that antioxidant treatments might help decrease the negative effects of ethanol exposure in animal models.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile;
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Angeles Vera
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Katherine Birditt
- Physiology Development and Neuroscience Department, University of Cambridge, Cambridge CB2 1TN, UK;
| | - Karina Godoy
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Florencia Carmine
- Carrera de Medicina, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - José Caamaño
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
- Laboratorio de Inmunohematología y Medicina Transfusional, Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
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15
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Qiu M, Cai F, Huang Y, Sun L, Li J, Wang W, Basharat Z, Zippi M, Goyal H, Pan J, Hong W. Fabp5 is a common gene between a high-cholesterol diet and acute pancreatitis. Front Nutr 2023; 10:1284985. [PMID: 38188879 PMCID: PMC10768664 DOI: 10.3389/fnut.2023.1284985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 12/08/2023] [Indexed: 01/09/2024] Open
Abstract
BACKGROUND AND AIMS Hypercholesterolemia has been identified as risk factor for severe acute pancreatitis (AP). We aimed to identify the common differentially expressed genes (DEGs) between a high-cholesterol diet and AP. METHODS We retrived gene expression profiles from the GEO database. DEGs were assessed using GEO2R. For AP hub genes, we conducted functional enrichment analysis and protein-protein interaction (PPI) analysis. GeneMANIA and correlation analysis were employed to predict potential DEG mechanisms. Validation was done across various healthy human tissues, pancreatic adenocarcinoma, peripheral blood in AP patients, and Sprague-Dawley rats with AP. RESULTS The gene "Fabp5" emerged as the sole common DEG shared by a high-cholesterol diet and AP. Using the 12 topological analysis methods in PPI network analysis, Rela, Actb, Cdh1, and Vcl were identified as hub DEGs. GeneMANIA revealed 77.6% physical interactions among Fabp5, TLR4, and Rela, while genetic correlation analysis indicated moderate associations among them. Peripheral blood analysis yielded area under the ROC curve (AUC) values of 0.71, 0.63, 0.74, 0.64, and 0.91 for Fabp5, TLR4, Actb, Cdh1 genes, and artificial neural network (ANN) model respectively, in predicting severe AP. In vivo immunohistochemical analysis demonstrated higher Fabp5 expression in the hyperlipidemia-associated AP group compared to the AP and control groups. CONCLUSION Fabp5 emerged as the common DEG connecting a high-cholesterol diet and AP. Rela was highlighted as a crucial hub gene in AP. Genetic interactions were observed among Fabp5, TLR4, and Rela. An ANN model consisting of Fabp5, TLR4, Actb, and Cdh1 was helpful in predicting severe AP.
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Affiliation(s)
- Minhao Qiu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fangfang Cai
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | - Yining Huang
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liang Sun
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jianmin Li
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou, China
| | | | - Maddalena Zippi
- Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, Rome, Italy
| | - Hemant Goyal
- Borland Groover Clinic, Baptist Medical Center, Jacksonville, FL, United States
| | - Jingye Pan
- Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wandong Hong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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16
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Mareninova OA, Gretler SR, Lee GE, Pimienta M, Qin Y, Elperin JM, Ni J, Razga Z, Gukovskaya AS, Gukovsky I. Ethanol inhibits pancreatic acinar cell autophagy through upregulation of ATG4B, mediating pathological responses of alcoholic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2023; 325:G265-G278. [PMID: 37431575 PMCID: PMC10511161 DOI: 10.1152/ajpgi.00053.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/23/2023] [Accepted: 07/01/2023] [Indexed: 07/12/2023]
Abstract
Excessive alcohol intake is a major risk factor for pancreatitis, sensitizing the exocrine pancreas to stressors by mechanisms that remain obscure. Impaired autophagy drives nonalcoholic pancreatitis, but the effects of ethanol (EtOH) and alcoholic pancreatitis on autophagy are poorly understood. Here, we find that ethanol reduces autophagosome formation in pancreatic acinar cells, both in a mouse model of alcoholic pancreatitis induced by a combination of EtOH diet and cerulein (a CCK ortholog) and in EtOH+CCK-treated acinar cells (ex vivo model). Ethanol treatments decreased pancreatic level of LC3-II, a key mediator of autophagosome formation. This was caused by ethanol-induced upregulation of ATG4B, a cysteine protease that, cell dependently, regulates the balance between cytosolic LC3-I and membrane-bound LC3-II. We show that ATG4B negatively regulates LC3-II in acinar cells subjected to EtOH treatments. Ethanol raised ATG4B level by inhibiting its degradation, enhanced ATG4B enzymatic activity, and strengthened its interaction with LC3-II. We also found an increase in ATG4B and impaired autophagy in a dissimilar, nonsecretagogue model of alcoholic pancreatitis induced by EtOH plus palmitoleic acid. Adenoviral ATG4B overexpression in acinar cells greatly reduced LC3-II and inhibited autophagy. Furthermore, it aggravated trypsinogen activation and necrosis, mimicking key responses of ex vivo alcoholic pancreatitis. Conversely, shRNA Atg4B knockdown enhanced autophagosome formation and alleviated ethanol-induced acinar cell damage. The results reveal a novel mechanism, whereby ethanol inhibits autophagosome formation and thus sensitizes pancreatitis, and a key role of ATG4B in ethanol's effects on autophagy. Enhancing pancreatic autophagy, particularly by downregulating ATG4B, could be beneficial in mitigating the severity of alcoholic pancreatitis.NEW & NOTEWORTHY Ethanol sensitizes mice and humans to pancreatitis, but the underlying mechanisms remain obscure. Autophagy is important for maintaining pancreatic acinar cell homeostasis, and its impairment drives pancreatitis. This study reveals a novel mechanism, whereby ethanol inhibits autophagosome formation through upregulating ATG4B, a key cysteine protease. ATG4B upregulation inhibits autophagy in acinar cells and aggravates pathological responses of experimental alcoholic pancreatitis. Enhancing pancreatic autophagy, particularly by down-regulating ATG4B, could be beneficial for treatment of alcoholic pancreatitis.
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Affiliation(s)
- Olga A Mareninova
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States
- Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, United States
| | - Sophie R Gretler
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States
- Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, United States
| | - Grace E Lee
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
| | - Michael Pimienta
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
| | - Yueqiu Qin
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
- Division of Gastroenterology and Hepatology, Youjiang Medical University for Nationalities, Baise, China
| | - Jason M Elperin
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
| | - Jinliang Ni
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
- First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Zsolt Razga
- Institute of Pathology, University of Szeged, Szeged, Hungary
| | - Anna S Gukovskaya
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States
- Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, United States
| | - Ilya Gukovsky
- David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, United States
- Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, United States
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17
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Abudayyak M, Karaman EF, Guler ZR, Ozden S. Effects of perfluorooctanoic acid on endoplasmic reticulum stress and lipid metabolism-related genes in human pancreatic cells. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 98:104083. [PMID: 36804611 DOI: 10.1016/j.etap.2023.104083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 01/24/2023] [Accepted: 02/17/2023] [Indexed: 06/18/2023]
Abstract
Perfluorooctanoic acid (PFOA) is environmentally persistent and has been classified by The International Cancer Research Agency (IARC) as a possible human pancreatic carcinogen. In this study, the epigenetic alteration, the changes in the expression levels of endoplasmic reticulum stress-related and metabolism-related genes, as well as DNA methyltransferase expression were investigated using RT-PCR and ELISA assays. PFOA induced a significant increase in the methylation ratio (5-mC%), impacted DNA methylation maintenance gene expression and decreased lipid metabolism-related genes except for PPARγ (≥ 13-fold increase). While PFOA induced the expression of ATF4 (≥ 5.41-folds), CHOP (≥ 5.41-folds) genes, it inhibited the expression of ATF6 (≥ 67.2%), GRP78 (≥ 64.3%), Elf2α (≥ 95.8%), IRE1 (≥ 95.5%), and PERK (≥ 91.7%) genes. It is thought that epigenetic mechanisms together with disruption in the glucose-lipid metabolism and changes in endoplasmic reticulum stress-related genes may play a key role in PFOA-induced pancreatic toxicity.
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Affiliation(s)
- Mahmoud Abudayyak
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Ecem Fatma Karaman
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Biruni University, Istanbul, Turkey
| | - Zeynep Rana Guler
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey; Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Turkey
| | - Sibel Ozden
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.
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18
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Caldwell NJ, Li H, Bellizzi AM, Luo J. Altered MANF Expression in Pancreatic Acinar and Ductal Cells in Chronic Alcoholic Pancreatitis: A Cross-Sectional Study. Biomedicines 2023; 11:biomedicines11020434. [PMID: 36830970 PMCID: PMC9953319 DOI: 10.3390/biomedicines11020434] [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: 01/13/2023] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress response protein that plays an important role in pancreatic functions. As both alcohol and ER stress response proteins are involved in the pathogenesis of pancreatitis, we sought to investigate the expression of MANF in chronic alcoholic pancreatitis (CAP) and chronic non-alcoholic pancreatitis (CNP). METHODS A cohort of chronic pancreatitis tissues was gathered from routine surgical pathology (n = 77) and autopsy (n = 10) cases and tissue microarrays were created. Sampled tissues were reviewed and designated as representing CAP (n = 15), CNP (n = 58), or normal pancreatic tissue (NPT) (n = 27). MANF immunohistochemistry (IHC) and digital image analysis were performed to obtain an estimation of tissue fibrosis and an optical density (OD) of MANF IHC in ducts and acini for each case. The averaged values for these variables among histologic designations were compared. RESULTS The amount of fibrous tissue of the combined CAP and CNP group (chronic alcoholic and non-alcoholic pancreatitis, CANP) exceeded that of the NPT group (70% vs. 34%, p < 0.0001). The MANF OD in ducts of CANP was significantly higher than that of NPT (0.19 vs. 0.10, p < 0.05). The MANF OD in ducts of CAP was significantly higher than that of CNP (0.27 vs. 0.17, p < 0.05). The MANF OD in acini of CAP was significantly lower than that in CNP (0.81 vs. 1.05, p < 0.05). Finally, there was a statistically significant positive relationship between the amount of fibrosis and MANF OD in ducts (p < 0.001). CONCLUSIONS MANF expression was higher in ducts of CAP than CNP. In contrast, MANF expression in acini was lower in CAP than CNP and NPT. There was a positive correlation between fibrosis and MANF levels in the ducts.
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Affiliation(s)
- Nicholas J. Caldwell
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Hui Li
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Andrew M. Bellizzi
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Jia Luo
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Iowa City VA Health Care System, Iowa City, IA 52246, USA
- Correspondence: ; Tel.: +1-319-335-2256
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19
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Effects of Berberine against Pancreatitis and Pancreatic Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27238630. [PMID: 36500723 PMCID: PMC9738201 DOI: 10.3390/molecules27238630] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/28/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022]
Abstract
The pancreas is a glandular organ with endocrine and exocrine functions necessary for the maintenance of blood glucose homeostasis and secretion of digestive enzymes. Pancreatitis is characterized by inflammation of the pancreas leading to temporary or permanent pancreatic dysfunction. Inflammation and fibrosis caused by chronic pancreatitis exacerbate malignant transformation and significantly increase the risk of developing pancreatic cancer, the world's most aggressive cancer with a 5-year survival rate less than 10%. Berberine (BBR) is a naturally occurring plant-derived polyphenol present in a variety of herbal remedies used in traditional medicine to treat ulcers, infections, jaundice, and inflammation. The current review summarizes the existing in vitro and in vivo evidence on the effects of BBR against pancreatitis and pancreatic cancer with a focus on the signalling mechanisms underlying the effects of BBR.
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20
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Tang Y, Zhou X, Cao T, Chen E, Li Y, Lei W, Hu Y, He B, Liu S. Endoplasmic Reticulum Stress and Oxidative Stress in Inflammatory Diseases. DNA Cell Biol 2022; 41:924-934. [PMID: 36356165 DOI: 10.1089/dna.2022.0353] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Yun Tang
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xiangping Zhou
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ting Cao
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - En Chen
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yumeng Li
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Wenbo Lei
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yibao Hu
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Bisha He
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Shuangquan Liu
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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21
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Bhatia R, Thompson CM, Clement EJ, Ganguly K, Cox JL, Rauth S, Siddiqui JA, Mashiana SS, Jain M, Wyatt TA, Mashiana HS, Singh S, Woods NT, Kharbanda KK, Batra SK, Kumar S. Malondialdehyde-Acetaldehyde Extracellular Matrix Protein Adducts Attenuate Unfolded Protein Response During Alcohol and Smoking-Induced Pancreatitis. Gastroenterology 2022; 163:1064-1078.e10. [PMID: 35788346 PMCID: PMC9796922 DOI: 10.1053/j.gastro.2022.06.071] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/20/2022] [Accepted: 06/27/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the molecular players responsible for the progressive loss of pancreatic parenchyma and fibroinflammatory response are poorly characterized. METHODS Tandem mass tag-based proteomic and bioinformatics analyses were performed on the pancreata of mice exposed to alcohol, cigarette smoke, or a combination of alcohol and cigarette smoke. Biochemical, immunohistochemistry, and transcriptome analyses were performed on the pancreatic tissues and primary acinar cells treated with cerulein in combination with ethanol (50 mmol/L) and cigarette smoke extract (40 μg/mL) for the mechanistic studies. RESULTS A unique alteration in the pancreatic proteome was observed in mice exposed chronically to the combination of alcohol and cigarette smoke (56.5%) compared with cigarette smoke (21%) or alcohol (17%) alone. The formation of toxic metabolites (P < .001) and attenuated unfolded protein response (P < .04) were the significantly altered pathways on combined exposure. The extracellular matrix (ECM) proteins showed stable malondialdehyde-acetaldehyde (MAA) adducts in the pancreata of the combination group and chronic pancreatitis patients with a history of smoking and alcohol consumption. Interestingly, MAA-ECM adducts significantly suppressed expression of X-box-binding protein-1, leading to acinar cell death in the presence of alcohol and smoking. The stable MAA-ECM adducts persist even after alcohol and smoking cessation, and significantly delay pancreatic regeneration by abrogating the expression of cyclin-dependent kinases (CDK7 and CDK5) and regeneration markers. CONCLUSIONS The combined alcohol and smoking generate stable MAA-ECM adducts that increase endoplasmic reticulum stress and acinar cell death due to attenuated unfolded protein response and suppress expression of cell cycle regulators. Targeting aldehyde adducts might provide a novel therapeutic strategy for the management of recurrent acute pancreatitis and chronic pancreatitis.
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Affiliation(s)
- Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Christopher M Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Emalie J Clement
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Jesse L Cox
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Simran S Mashiana
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
| | - Todd A Wyatt
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, Nebraska
| | - Harmeet S Mashiana
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Shailender Singh
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Nicholas T Woods
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska
| | - Kusum K Kharbanda
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
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22
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Han X, Li B, Bao J, Wu Z, Chen C, Ni J, Shen J, Song P, Peng Q, Wan R, Wang X, Wu J, Hu G. Endoplasmic reticulum stress promoted acinar cell necroptosis in acute pancreatitis through cathepsinB-mediated AP-1 activation. Front Immunol 2022; 13:968639. [PMID: 36059491 PMCID: PMC9438943 DOI: 10.3389/fimmu.2022.968639] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 08/01/2022] [Indexed: 11/25/2022] Open
Abstract
Acinar cell death and inflammatory response are two important events which determine the severity of acute pancreatitis (AP). Endoplasmic reticulum (ER) stress and necroptosis are involved in this process, but the relationships between them remain unknown. Here, we analyzed the interaction between ER stress and necroptosis and the underlying mechanisms during AP. Experimental pancreatitis was induced in Balb/C mice by caerulein (Cae) and lipopolysaccharide (LPS) or L-arginine (L-Arg) in vivo, and pancreatic acinar cells were also used to follow cellular mechanisms during cholecystokinin (CCK) stimulation in vitro. AP severity was assessed by serum amylase, lipase levels and histological examination. Changes in ER stress, trypsinogen activation and necroptosis levels were analyzed by western blotting, enzyme-linked immunosorbent assay (ELISA), adenosine triphosphate (ATP) analysis or lactate dehydrogenase (LDH) assay. The protein kinase C (PKC)α -mitogen-activated protein kinase (MAPK) -cJun pathway and cathepsin B (CTSB) activation were evaluated by western blotting. Activating protein 1 (AP-1) binding activity was detected by electrophoretic mobility shift assay (EMSA). We found that ER stress is initiated before necroptosis in CCK-stimulated acinar cells in vitro. Inhibition of ER stress by 4-phenylbutyrate (4-PBA) can significantly alleviate AP severity both in two AP models in vivo. 4-PBA markedly inhibited ER stress and necroptosis of pancreatic acinar cells both in vitro and in vivo. Mechanistically, we found that 4-PBA significantly reduced CTSB maturation and PKCα-JNK-cJun pathway -mediated AP-1 activation during AP. Besides, CTSB inhibitor CA074Me markedly blocked PKCα-JNK-cJun pathway -mediated AP-1 activation and necroptosis in AP. However, pharmacologic inhibition of trypsin activity with benzamidine hydrochloride had no effect on PKCα-JNK-cJun pathway and necroptosis in CCK-stimulated pancreatic acinar cells. Furthermore, SR11302, the inhibitor of AP-1, significantly lowered tumor necrosis factor (TNF) α levels, and its subsequent receptor interacting protein kinases (RIP)3 and phosphorylated mixed lineagekinase domain-like (pMLKL) levels, ATP depletion and LDH release rate in CCK-stimulated pancreatic acinar cells. To sum up, all the results indicated that during AP, ER stress promoted pancreatic acinar cell necroptosis through CTSB maturation, thus induced AP-1 activation and TNFα secretion via PKCα-JNK-cJun pathway, not related with trypsin activity. These findings provided potential therapeutic target and treatment strategies for AP or other cell death-related diseases.
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Affiliation(s)
- Xiao Han
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingpiao Bao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zengkai Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Congying Chen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianbo Ni
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Shen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Pengli Song
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Peng
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Wan
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianghong Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Guoyong Hu, ; Jianghong Wu,
| | - Guoyong Hu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Guoyong Hu, ; Jianghong Wu,
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Wen W, Li H, Luo J. Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity. Mol Neurobiol 2022; 59:2992-3015. [PMID: 35254650 PMCID: PMC10928853 DOI: 10.1007/s12035-022-02786-7] [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: 11/12/2021] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
- Iowa City VA Health Care System, Iowa City, IA, 52246, USA.
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24
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Jia W, Xu L, Xu W, Yang M, Zhang Y. Application of nanotechnology in the diagnosis and treatment of acute pancreatitis. NANOSCALE ADVANCES 2022; 4:1949-1961. [PMID: 36133408 PMCID: PMC9419146 DOI: 10.1039/d2na00020b] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 03/16/2022] [Indexed: 06/16/2023]
Abstract
Acute pancreatitis (AP) is a common digestive system disease. The severity of AP ranges from mild edema in the pancreas to severe systemic inflammatory responses leading to peripancreatic/pancreatic necrosis, multi-organ failure and death. Improving the sensitivity of AP diagnosis and developing alternatives to traditional methods to treat AP have gained the attention of researchers. With the continuous rise of nanotechnology, it is being widely used in daily life, biomedicine, chemical energy and many other fields. Studies have demonstrated the effectiveness of nanotechnology in the diagnosis and treatment of AP. Nanotechnology has the advantages of simplicity, rapidity and sensitivity in detecting biomarkers of AP, as well as enhancing imaging, which helps in the early diagnosis of AP. On the other hand, nanoparticles (NPs) have oxidative stress inhibiting and anti-inflammatory effects, and can also be loaded with drugs as well as being used in anti-infection therapy, providing a new approach for the treatment of AP. In this article, we elaborate and summarize on the potential of nanoparticles for diagnostic and therapeutic applications in AP from the current reported literature and experimental results to provide useful guidelines for further research on the application of nanotechnology.
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Affiliation(s)
- WeiLu Jia
- Medical School, Southeast University Nanjing 210009 China
| | - LinFeng Xu
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University Nanjing 210009 China
| | - WenJing Xu
- Medical School, Southeast University Nanjing 210009 China
| | - Meng Yang
- Department of Ultrasound, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing 100730 China
| | - YeWei Zhang
- Medical School, Southeast University Nanjing 210009 China
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University Nanjing 210009 China
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25
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Srinivasan MP, Bhopale KK, Caracheo AA, Kaphalia L, Gong B, Popov VL, Boor PJ, Shakeel Ansari GA, Kaphalia BS. Exposure to binge ethanol and fatty acid ethyl esters exacerbates chronic ethanol-induced pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice. Am J Physiol Gastrointest Liver Physiol 2022; 322:G327-G345. [PMID: 34984929 PMCID: PMC8816639 DOI: 10.1152/ajpgi.00263.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase-deficient (ADH-) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP. Hepatic ADH- and ADH normal (ADH+) deer mice were fed Lieber-DeCarli liquid diet containing 3% (wt/vol) EtOH for 3 mo. One week before the euthanization, chronic EtOH-fed mice were further administered with an oral gavage of binge EtOH with/without FAEEs. Blood alcohol concentration (BAC), pancreatic injury, and inflammatory markers were measured. Pancreatic morphology, ultrastructural changes, and endoplasmic reticulum (ER)/oxidative stress were examined using H&E staining, electron microscopy, immunostaining, and/or Western blot, respectively. Overall, BAC was substantially increased in chronic EtOH-fed groups of ADH- versus ADH+ deer mice. A significant change in pancreatic acinar cell morphology, with mild to moderate fibrosis and ultrastructural changes evident by dilatations and disruption of ER cisternae, ER/oxidative stress along with increased levels of inflammatory markers were observed in the pancreas of chronic EtOH-fed groups of ADH- versus ADH+ deer mice. Furthermore, chronic plus binge EtOH and FAEEs exposure elevated BAC, enhanced ER/oxidative stress, and exacerbated chronic EtOH-induced pancreatic injury in ADH- deer mice suggesting a role of increased body burden of EtOH and its metabolism under reduced hepatic ADH in initiation and progression of ACP.NEW & NOTEWORTHY We established a chronic EtOH feeding model of hepatic alcohol dehydrogenase-deficient (ADH-) deer mice, which mimics several fibroinflammatory features of human alcoholic chronic pancreatitis (ACP). The fibroinflammatory and morphological features exacerbated by chronic plus binge EtOH and FAEEs exposure provide a strong case for metabolic basis of ACP. Most importantly, several pathological and molecular targets identified in this study provide a much broader understanding of the mechanism and avenues to develop therapeutics for ACP.
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Affiliation(s)
- Mukund P. Srinivasan
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Kamlesh K. Bhopale
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Anna A. Caracheo
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Lata Kaphalia
- 2Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas
| | - Bin Gong
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Vsevolod L. Popov
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - Paul J. Boor
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
| | - G. A. Shakeel Ansari
- 1Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
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Li H, Wen W, Luo J. Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis. Biomedicines 2022; 10:biomedicines10010108. [PMID: 35052788 PMCID: PMC8773075 DOI: 10.3390/biomedicines10010108] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/04/2023] Open
Abstract
Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.
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Affiliation(s)
- Hui Li
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Wen Wen
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Jia Luo
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
- Iowa City VA Health Care System, Iowa City, IA 52246, USA
- Correspondence: ; Tel.: +1-319-335-2256
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27
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Borrello MT, Martin MB, Pin CL. The unfolded protein response: An emerging therapeutic target for pancreatitis and pancreatic ductal adenocarcinoma. Pancreatology 2022; 22:148-159. [PMID: 34774415 DOI: 10.1016/j.pan.2021.10.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 12/11/2022]
Abstract
Pancreatitis is a debilitating disease involving inflammation and fibrosis of the exocrine pancreas. Recurrent or chronic forms of pancreatitis are a significant risk factor for pancreatic ductal adenocarcinoma. While genetic factors have been identified for both pathologies, environmental stresses play a large role in their etiology. All cells have adapted mechanisms to handle acute environmental stress that alters energy demands. A common pathway involved in the stress response involves endoplasmic reticulum stress and the unfolded protein response (UPR). While rapidly activated by many external stressors, in the pancreas the UPR plays a fundamental biological role, likely due to the high protein demands in acinar cells. Despite this, increased UPR activity is observed in response to acute injury or following exposure to risk factors associated with pancreatitis and pancreatic cancer. Studies in animal and cell cultures models show the importance of affecting the UPR in the context of both diseases, and inhibitors have been developed for several specific mediators of the UPR. Given the importance of the UPR to normal acinar cell function, efforts to affect the UPR in the context of disease must be able to specifically target pathology vs. physiology. In this review, we highlight the importance of the UPR to normal and pathological conditions of the exocrine pancreas. We discuss recent studies suggesting the UPR may be involved in the initiation and progression of pancreatitis and PDAC, as well as contributing to chemoresistance that occurs in pancreatic cancer. Finally, we discuss the potential of targeting the UPR for treatment.
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Affiliation(s)
- M Teresa Borrello
- Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Mickenzie B Martin
- Depts. of Physiology and Pharmacology, Paediatrics, and Oncology, Schulich School of Medicine and Dentistry, The University of Western Ontario, Canada; Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Christopher L Pin
- Depts. of Physiology and Pharmacology, Paediatrics, and Oncology, Schulich School of Medicine and Dentistry, The University of Western Ontario, Canada; Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada.
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28
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Elnagar GM, Elseweidy MM, Elkomy NMIM, Al-Gabri NA, Shawky M. 10-Dehydrogingerdione ameliorates renal endoplasmic reticulum/oxidative stress and apoptosis in alcoholic nephropathy induced in experimental rats. Life Sci 2021; 279:119673. [PMID: 34081991 DOI: 10.1016/j.lfs.2021.119673] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/04/2021] [Accepted: 05/27/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Chronic alcoholism induces kidney injury (KI), leading to increased mortality in alcoholic hepatitis patients. Endoplasmic reticulum stress (ER) represents the main initiator of kidney diseases and alcoholic nephropathy. AIMS We used alcoholic nephropathy rat model followed by 10-dehydrogingerdione (10-DHGD) intake as potential modulator. This is to focus on ER/oxidative stress/inflammatory and apoptotic pathways involvement. MAIN METHOD Alcoholic nephropathy was induced by alcohol administration (3.7 g/kg/body weight) orally and daily for 45 days. 10-DHGD (10 mg/kg/day) was administered either alone or along with alcohol. KEY FINDINGS Our results demonstrated significant increase in kidney function parameters like f creatinine, urea, uric acid, and blood urea nitrogen (BUN) levels. Renal ER/oxidative stress markers such as cytochrome P450 family two subfamily E member 1 (CYP2E1), C/EBP homologous protein (CHOP), and endoplasmic glucose-regulated protein 78 (GRP-78) demonstrated also significant increase. Inflammatory mediators like nuclear factor-kappa B (NF-kB), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β along with apoptotic marker caspase-3 behaved similarly. Antioxidant molecules like reduced glutathione (GSH), superoxide dismutase (SOD), and catalase demonstrated marked decrease. SIGNIFICANCE 10-DHGD administration resulted in significant modulation represented by an enhancement in the kidney functions and the histopathological patterns in a conclusion of its potential to ameliorate the pathological changes (kidney injury) induced by alcohol intake.
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Affiliation(s)
- Gehad M Elnagar
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Egypt
| | | | - Nesreen M I M Elkomy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Egypt
| | - Naif A Al-Gabri
- Department of Pathology, Faculty of Veterinary Medicine, Thamar University, Yemen; Laboratory of Regional Djibouti Livestock Quarantine, Abu Yasar international Est. 1999, Djibouti
| | - Mohamed Shawky
- Department of Biochemistry, Faculty of Pharmacy, Horus University, Egypt
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29
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Ren C, Zhou X, Bao X, Zhang J, Tang J, Zhu Z, Zhang N, Bai Y, Xi Y, Zhang Q, Ma B. Dioscorea zingiberensis ameliorates diabetic nephropathy by inhibiting NLRP3 inflammasome and curbing the expression of p66Shc in high-fat diet/streptozotocin-induced diabetic mice. J Pharm Pharmacol 2021; 73:1218-1229. [PMID: 34061184 DOI: 10.1093/jpp/rgab053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 03/01/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Diabetic nephropathy (DN) is a severe diabetic complication. Dioscorea zingiberensis (DZ) possesses excellent pharmacological properties with lower toxicity. The purpose of this study was to investigate the efficacy and mechanism of DZ in DN. METHODS DN was established by the high-fat diet combining intraperitoneal injection of streptozotocin in mice. The DZ (125 and 250 mg/kg/day) were intragastrical administered for 8 consecutive weeks. After treatment, blood, urine and kidney tissue were collected for biological detection, renal morphology, fibrosis and molecular mechanism research, respectively. KEY FINDINGS This study has shown that DZ significantly ameliorated kidney hypertrophy, renal structural damage and abnormal function of the kidney indicators (creatinine, urinary protein and blood urea nitrogen). Further molecular mechanism data suggested that the NLRP3/Cleaved-caspase-1 signal pathway was remarkably activated in DN, and DZ treatment reversed these changes, which indicated that it effectively attenuated inflammatory response caused by hyperglycaemia. In addition, DN inhibits hyperglycaemia-induced activation of oxidative stress by suppressing the expression of p66Shc proteins. CONCLUSIONS DZ could efficiently suppress oxidative stress and inflammatory responses to postpone the development of DN, and its mechanism might be related to inhibition of NLRP3 and p66Shc activities. Thus, DZ could be developed into a new therapeutic agent for DN.
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Affiliation(s)
- Chaoxing Ren
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
| | - Xiaowei Zhou
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
| | - Xiaowen Bao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
| | - Jie Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
| | - Jun Tang
- Jiangsu Huanghe Pharmaceutical Co., Ltd, Yancheng, People's Republic of China
| | - Zhiming Zhu
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
| | - Nan Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
- School of Chemical and Molecular Engineering, Nanjing Tech University, Nanjing, People's Republic of China
| | - Yu Bai
- Department of Biological Sciences, University of Toronto Scarborough, ON, Canada
| | - Youli Xi
- Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, People's Republic of China
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
| | - Bo Ma
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, People's Republic of China
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Wu H, Li H, Wen W, Wang Y, Xu H, Xu M, Frank JA, Wei W, Luo J. MANF protects pancreatic acinar cells against alcohol-induced endoplasmic reticulum stress and cellular injury. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:883-892. [PMID: 33644980 DOI: 10.1002/jhbp.928] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 01/31/2021] [Accepted: 02/09/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND/PURPOSE Heavy alcohol drinking is associated with pancreatitis. Pancreatitis is initiated by the damage to the pancreatic acinar cells. The endoplasmic reticulum (ER) stress has been shown to play an important role in alcohol-induced pancreatic damage. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible protein. The aim of the study was to determine whether MANF can ameliorate alcohol-induced ER stress and cellular damages to pancreatic acinar cells. METHODS Alcohol-induced damage to mouse pancreatic 266-6 acinar cells was determined by MTT and flow cytometry. MANF expression was downregulated by MANF siRNA using the Neon Transfection System. The overexpression of MANF was performed by the infection with the adenoviral vector carrying mouse MANF gene. The expression of ER stress markers was determined by immunoblotting and immunofluorescence. RESULTS Alcohol caused ER stress, oxidative stress and induced apoptosis of 266-6 acinar cells. Recombinant human MANF alleviated alcohol-induced ER stress and cell death by inhibiting IRE1-caspase 12-caspase 3 apoptotic pathway. Overexpression of mouse MANF also protected cells against alcohol-induced apoptosis. In contrast, inhibiting MANF by siRNA exacerbated alcohol-induced cellular damage. CONCLUSIONS MANF was protective against alcohol-induced ER stress and cellular injury in pancreatic acinar cells. The findings suggest a potential therapeutic value of MANF for alcoholic pancreatitis.
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Affiliation(s)
- Huaxun Wu
- Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Yongchao Wang
- Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Jacqueline A Frank
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Wei Wei
- Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Wei J, Fang D. Endoplasmic Reticulum Stress Signaling and the Pathogenesis of Hepatocarcinoma. Int J Mol Sci 2021; 22:ijms22041799. [PMID: 33670323 PMCID: PMC7918477 DOI: 10.3390/ijms22041799] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC), also known as hepatoma, is a primary malignancy of the liver and the third leading cause of cancer mortality globally. Although much attention has focused on HCC, its pathogenesis remains largely obscure. The endoplasmic reticulum (ER) is a cellular organelle important for regulating protein synthesis, folding, modification and trafficking, and lipid metabolism. ER stress occurs when ER homeostasis is disturbed by numerous environmental, physiological, and pathological challenges. In response to ER stress due to misfolded/unfolded protein accumulation, unfolded protein response (UPR) is activated to maintain ER function for cell survival or, in cases of excessively severe ER stress, initiation of apoptosis. The liver is especially susceptible to ER stress given its protein synthesis and detoxification functions. Experimental data suggest that ER stress and unfolded protein response are involved in HCC development, aggressiveness and response to treatment. Herein, we highlight recent findings and provide an overview of the evidence linking ER stress to the pathogenesis of HCC.
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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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Wang Y, Wen W, Li H, Clementino M, Xu H, Xu M, Ma M, Frank J, Luo J. MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress. Neurobiol Dis 2021; 148:105216. [PMID: 33296727 PMCID: PMC7856049 DOI: 10.1016/j.nbd.2020.105216] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/18/2020] [Accepted: 12/03/2020] [Indexed: 12/23/2022] Open
Abstract
Fetal alcohol spectrum disorders (FASD) are a spectrum of developmental disorders caused by prenatal alcohol exposure. Neuronal loss or neurodegeneration in the central nervous system (CNS) is one of the most devastating features in FASD. It is imperative to delineate the underlying mechanisms to facilitate the treatment of FASD. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases, including ethanol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) responds to ER stress and has been identified as a protein upregulated in response to ethanol exposure during the brain development. To investigate the role of MANF in ethanol-induced neurodegeneration and its association with ER stress regulation, we established a CNS-specific Manf knockout mouse model and examined the effects of MANF deficiency on ethanol-induced neuronal apoptosis and ER stress using a third-trimester equivalent mouse model. We found MANF deficiency exacerbated ethanol-induced neuronal apoptosis and ER stress and that blocking ER stress abrogated the harmful effects of MANF deficiency on ethanol-induced neuronal apoptosis. Moreover, using an animal model of ER-stress-induced neurodegeneration, we demonstrated that MANF deficiency potentiated tunicamycin (TM)-induced ER stress and neurodegeneration. A whole transcriptome RNA sequencing also supported the functionality of MANF in ER stress modulation and revealed targets that may mediate the ER stress-buffering capacity of MANF. Collectively, these results suggest that MANF is a neurotrophic factor that can protect neurons against ethanol-induced neurodegeneration by ameliorating ER stress.
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Affiliation(s)
- Yongchao Wang
- Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America
| | - Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America
| | - Marco Clementino
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Murong Ma
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Jacqueline Frank
- Department of Neurology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America; Iowa City VA Health Care System, Iowa City, IA 52246, United States of America.
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Dolai S, Takahashi T, Qin T, Liang T, Xie L, Kang F, Miao YF, Xie H, Kang Y, Manuel J, Winter E, Roche PA, Cattral MS, Gaisano HY. Pancreas-specific SNAP23 depletion prevents pancreatitis by attenuating pathological basolateral exocytosis and formation of trypsin-activating autolysosomes. Autophagy 2020; 17:3068-3081. [PMID: 33213278 DOI: 10.1080/15548627.2020.1852725] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Intrapancreatic trypsin activation by dysregulated macroautophagy/autophagy and pathological exocytosis of zymogen granules (ZGs), along with activation of inhibitor of NFKB/NF-κB kinase (IKK) are necessary early cellular events in pancreatitis. How these three pancreatitis events are linked is unclear. We investigated how SNAP23 orchestrates these events leading to pancreatic acinar injury. SNAP23 depletion was by knockdown (SNAP23-KD) effected by adenovirus-shRNA (Ad-SNAP23-shRNA/mCherry) treatment of rodent and human pancreatic slices and in vivo by infusion into rat pancreatic duct. In vitro pancreatitis induction by supraphysiological cholecystokinin (CCK) or ethanol plus low-dose CCK were used to assess SNAP23-KD effects on exocytosis and autophagy. Pancreatitis stimuli resulted in SNAP23 translocation from its native location at the plasma membrane to autophagosomes, where SNAP23 would bind and regulate STX17 (syntaxin17) SNARE complex-mediated autophagosome-lysosome fusion. This SNAP23 relocation was attributed to IKBKB/IKKβ-mediated SNAP23 phosphorylation at Ser95 Ser120 in rat and Ser120 in human, which was blocked by IKBKB/IKKβ inhibitors, and confirmed by the inability of IKBKB/IKKβ phosphorylation-disabled SNAP23 mutant (Ser95A Ser120A) to bind STX17 SNARE complex. SNAP23-KD impaired the assembly of STX4-driven basolateral exocytotic SNARE complex and STX17-driven SNARE complex, causing respective reduction of basolateral exocytosis of ZGs and autolysosome formation, with consequent reduction in trypsinogen activation in both compartments. Consequently, pancreatic SNAP23-KD rats were protected from caerulein and alcoholic pancreatitis. This study revealed the roles of SNAP23 in mediating pathological basolateral exocytosis and IKBKB/IKKβ's involvement in autolysosome formation, both where trypsinogen activation would occur to cause pancreatitis. SNAP23 is a strong candidate to target for pancreatitis therapy.
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Affiliation(s)
- Subhankar Dolai
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | | | - Tairan Qin
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Tao Liang
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Li Xie
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Fei Kang
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yi-Fan Miao
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Huanli Xie
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Youhou Kang
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Justin Manuel
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Erin Winter
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Paul A Roche
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Mark S Cattral
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Herbert Y Gaisano
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Cooley MM, Thomas DDH, Deans K, Peng Y, Lugea A, Pandol SJ, Puglielli L, Groblewski GE. Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis. Cell Mol Gastroenterol Hepatol 2020; 11:725-738. [PMID: 33080365 PMCID: PMC7841443 DOI: 10.1016/j.jcmgh.2020.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/14/2020] [Accepted: 10/05/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways plays a central role in the development and progression of pancreatitis. Less is known, however, of the consequence of perturbing ER-associated post-translational protein modifications on pancreatic outcomes. Here, we examined the role of the ER acetyl-CoA transporter AT-1 on pancreatic homeostasis. METHODS We used an AT-1S113R/+ hypomorphic mouse model, and generated an inducible, acinar-specific, AT-1 knockout mouse model, and performed histologic and biochemical analyses to probe the effect of AT-1 loss on acinar cell physiology. RESULTS We found that AT-1 expression is down-regulated significantly during both acute and chronic pancreatitis. Furthermore, acinar-specific deletion of AT-1 in acinar cells induces chronic ER stress marked by activation of both the spliced x-box binding protein 1 and protein kinase R-like ER kinase pathways, leading to spontaneous mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis. Induction of acute-on-chronic pancreatitis in the AT-1 model led to acinar cell loss and glad atrophy. CONCLUSIONS These results indicate a key role for AT-1 in pancreatic acinar cell homeostasis, the unfolded protein response, and that perturbations in AT-1 function leads to pancreatic disease.
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Affiliation(s)
| | | | | | - Yajing Peng
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin
| | - Aurelia Lugea
- Pancreatic Research Group, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephen J Pandol
- Pancreatic Research Group, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Luigi Puglielli
- Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin; Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin
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Srinivasan MP, Bhopale KK, Caracheo AA, Amer SM, Khan S, Kaphalia L, Loganathan G, Balamurugan AN, Kaphalia BS. Activation of AMP-activated protein kinase attenuates ethanol-induced ER/oxidative stress and lipid phenotype in human pancreatic acinar cells. Biochem Pharmacol 2020; 180:114174. [PMID: 32717227 DOI: 10.1016/j.bcp.2020.114174] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 12/18/2022]
Abstract
Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved β-oxidation of fatty acids). These cells also showed significant ER stress as evidenced by the increased expression for GRP78, IRE1α, and PERK/CHOP arm of unfolded protein response promoting apoptosis and activating p-JNK1/2 and p-ERK1/2 with increased secretion of cytokines. AR42J cells treated with EtOH showed increased oxidative stress, impaired mitochondrial biogenesis, and decreased ATP production rate. However, AMPKα activation by AICAR attenuated EtOH-induced ER/oxidative stress, lipogenesis, and inflammatory responses as well as the formation of FAEEs and restored mitochondrial function in hPACs as well as AR42J cells. Therefore, it is likely that EtOH-induced inactivation of AMPKα plays a crucial role in acinar cell injury leading to pancreatitis. Findings from this study also suggest that EtOH-induced inactivation of AMPKα is closely related to ER/oxidative stress and synthesis of FAEEs, as activation of AMPKα by AICAR attenuates formation of FAEEs, ER/oxidative stress and lipogenesis, and improves inflammatory responses and mitochondrial bioenergetics.
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Affiliation(s)
- Mukund P Srinivasan
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Kamlesh K Bhopale
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Anna A Caracheo
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Samir M Amer
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA; Department of Forensic Medicine and Clinical Toxicology, Tanta University, Tanta, Egypt
| | - Shamis Khan
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | - Lata Kaphalia
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77550, USA
| | | | - Appakalai N Balamurugan
- Department of Surgery, University of Louisville, Louisville, KY 40202, USA; Islet Biology Laboratory, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Department of Surgery, University of Cincinnati, Cincinnati, OH 45229, USA
| | - Bhupendra S Kaphalia
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA.
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Hocevar SE, Kamendulis LM, Hocevar BA. Perfluorooctanoic acid activates the unfolded protein response in pancreatic acinar cells. J Biochem Mol Toxicol 2020; 34:e22561. [PMID: 32578922 DOI: 10.1002/jbt.22561] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/21/2020] [Accepted: 06/11/2020] [Indexed: 01/09/2023]
Abstract
Perfluoroalkyl substances, such as perfluorooctanoic acid (PFOA), are widely used in consumer and industrial applications. Human epidemiologic and animal studies suggest that PFOA exposure elicits adverse effects on the pancreas; however, little is known about the biological effects of PFOA in this organ. In this study, we show that PFOA treatment of mouse pancreatic acinar cells results in endoplasmic reticulum (ER) stress and activation of the protein kinase-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase/endonuclease 1α (IRE1α), and activating transcription factor 6 arms of the unfolded protein response (UPR) pathway. PFOA-stimulated activation of the UPR was blocked by pretreatment with specific PERK and IRE1α inhibitors and the chemical chaperone 4-phenyl butyrate, but not the antioxidants N-acetyl- l-cysteine and Tiron. PFOA treatment led to increased cytosolic Ca+2 levels and induction of the UPR was blocked by an inhibitor of the inositol 1,4,5-trisphosphate receptor. These findings indicate that PFOA-induced ER stress may be the mechanistic trigger leading to oxidative stress in the pancreas.
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Affiliation(s)
- Sarah E Hocevar
- Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, Indiana
| | - Lisa M Kamendulis
- Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, Indiana
| | - Barbara A Hocevar
- Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, Indiana
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Żorniak M, Sirtl S, Mayerle J, Beyer G. What Do We Currently Know about the Pathophysiology of Alcoholic Pancreatitis: A Brief Review. Visc Med 2020; 36:182-190. [PMID: 32775348 PMCID: PMC7383280 DOI: 10.1159/000508173] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/21/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Alcoholic pancreatitis is a serious medical concern worldwide and remains to be one of the common causes of pancreatic disease. SUMMARY While alcohol consumption causes direct damage to pancreatic tissue, only a small percentage of active drinkers will develop pancreatitis. An explanation of this phenomenon is probably that alcohol increases pancreatic vulnerability to damage; however, the simultaneous presence of additional risk factors and pancreatic costressors is required to increase the risk of pancreatitis and its complications caused by alcohol misuse. Recently, a number of important genetic as well as environmental factors influencing the risk of alcoholic pancreatitis have been described. KEY MESSAGES In brief, this review reports established factors for the development of alcoholic pancreatitis and summarizes recent progress made in basic and clinical research.
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Affiliation(s)
- Michał Żorniak
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
- Department of Gastroenterology, Medical University of Silesia, Katowice, Poland
| | - Simon Sirtl
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
| | - Julia Mayerle
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
| | - Georg Beyer
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
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Riaz TA, Junjappa RP, Handigund M, Ferdous J, Kim HR, Chae HJ. Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation. Cells 2020; 9:E1160. [PMID: 32397116 PMCID: PMC7290600 DOI: 10.3390/cells9051160] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 04/27/2020] [Accepted: 05/06/2020] [Indexed: 12/14/2022] Open
Abstract
Inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1α signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1α along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1α function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1α are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.
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Affiliation(s)
- Thoufiqul Alam Riaz
- Department of Pharmacology, School of Medicine, Institute of New Drug Development, Jeonbuk National University, Jeonju 54907, Korea; (T.A.R.); (R.P.J.)
| | - Raghu Patil Junjappa
- Department of Pharmacology, School of Medicine, Institute of New Drug Development, Jeonbuk National University, Jeonju 54907, Korea; (T.A.R.); (R.P.J.)
| | - Mallikarjun Handigund
- Department of Laboratory Medicine, Jeonbuk National University, Medical School, Jeonju 54907, Korea;
| | - Jannatul Ferdous
- Department of Radiology and Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea;
| | - Hyung-Ryong Kim
- College of Dentistry, Dankook University, Cheonan 31116, Korea
| | - Han-Jung Chae
- Department of Pharmacology, School of Medicine, Institute of New Drug Development, Jeonbuk National University, Jeonju 54907, Korea; (T.A.R.); (R.P.J.)
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Rasineni K, Srinivasan MP, Balamurugan AN, Kaphalia BS, Wang S, Ding WX, Pandol SJ, Lugea A, Simon L, Molina PE, Gao P, Casey CA, Osna NA, Kharbanda KK. Recent Advances in Understanding the Complexity of Alcohol-Induced Pancreatic Dysfunction and Pancreatitis Development. Biomolecules 2020; 10:669. [PMID: 32349207 PMCID: PMC7277520 DOI: 10.3390/biom10050669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/13/2020] [Accepted: 04/15/2020] [Indexed: 02/05/2023] Open
Abstract
Chronic excessive alcohol use is a well-recognized risk factor for pancreatic dysfunction and pancreatitis development. Evidence from in vivo and in vitro studies indicates that the detrimental effects of alcohol on the pancreas are from the direct toxic effects of metabolites and byproducts of ethanol metabolism such as reactive oxygen species. Pancreatic dysfunction and pancreatitis development are now increasingly thought to be multifactorial conditions, where alcohol, genetics, lifestyle, and infectious agents may determine the initiation and course of the disease. In this review, we first highlight the role of nonoxidative ethanol metabolism in the generation and accumulation of fatty acid ethyl esters (FAEEs) that cause multi-organellar dysfunction in the pancreas which ultimately leads to pancreatitis development. Further, we discuss how alcohol-mediated altered autophagy leads to the development of pancreatitis. We also provide insights into how alcohol interactions with other co-morbidities such as smoking or viral infections may negatively affect exocrine and endocrine pancreatic function. Finally, we present potential strategies to ameliorate organellar dysfunction which could attenuate pancreatic dysfunction and pancreatitis severity.
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Affiliation(s)
- Karuna Rasineni
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (C.A.C.); (N.A.O.); (K.K.K.)
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Mukund P. Srinivasan
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555-0419, USA; (M.P.S.); (B.S.K.)
| | - Appakalai N. Balamurugan
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Department of Surgery, University of Cincinnati, Cincinnati, OH 45229, USA;
| | - Bhupendra S. Kaphalia
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555-0419, USA; (M.P.S.); (B.S.K.)
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, MO 66160, USA; (S.W.); (W.-X.D.)
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, MO 66160, USA; (S.W.); (W.-X.D.)
| | - Stephen J. Pandol
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (S.J.P.); (A.L.)
| | - Aurelia Lugea
- Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (S.J.P.); (A.L.)
| | - Liz Simon
- Department of Physiology, Louisiana State University Health Sciences Center-New Orleans, New Orleans, LA 70112, USA; (L.S.); (P.E.M.)
| | - Patricia E. Molina
- Department of Physiology, Louisiana State University Health Sciences Center-New Orleans, New Orleans, LA 70112, USA; (L.S.); (P.E.M.)
| | - Peter Gao
- Program Director, Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-6902, USA;
| | - Carol A. Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (C.A.C.); (N.A.O.); (K.K.K.)
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Natalia A. Osna
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (C.A.C.); (N.A.O.); (K.K.K.)
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
| | - Kusum K. Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; (C.A.C.); (N.A.O.); (K.K.K.)
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
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Orekhova A, Geisz A, Sahin-Tóth M. Ethanol feeding accelerates pancreatitis progression in CPA1 N256K mutant mice. Am J Physiol Gastrointest Liver Physiol 2020; 318:G694-G704. [PMID: 32116022 PMCID: PMC7191466 DOI: 10.1152/ajpgi.00007.2020] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. Alcohol initiates pancreatitis and promotes its progression in the context of genetic susceptibility and/or other environmental risk factors such as smoking. Genetic mutations can cause digestive enzyme misfolding, which induces endoplasmic reticulum (ER) stress and elicits pancreatitis. Here, we tested the hypothesis that alcohol synergizes with misfolding in promoting ER stress and thereby accelerates chronic pancreatitis progression. To this end, we fed an ethanol-containing diet to CPA1 N256K mice, which carry the human p.N256K CPA1 mutation and develop spontaneous chronic pancreatitis. Inexplicably, CPA1 N256K mice suffered generalized seizures after 2-3 wk of ethanol feeding, which resulted in high mortality and the early termination of the study. Analysis of CPA1 N256K mice euthanized after 3-3.5 wk of ethanol feeding revealed more severe chronic pancreatitis associated with significantly increased Hspa5 [ER chaperone immunoglobulin heavy chain-binding protein (BiP)] mRNA levels when compared with CPA1 N256K mice on a control liquid diet. In contrast, ethanol feeding of C57BL/6N mice for 4 wk increased Hspa5 levels to a lesser degree and caused no pancreatitis. We conclude that ethanol feeding synergizes with the misfolding CPA1 mutant in promoting ER stress and thereby accelerates progression of chronic pancreatitis in CPA1 N256K mice.NEW & NOTEWORTHY Alcoholic pancreatitis is a multifactorial, progressive, inflammatory disorder of the pancreas. This study demonstrates that alcohol synergizes with digestive enzyme misfolding in promoting endoplasmic reticulum stress and thereby accelerates progression of chronic pancreatitis.
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Affiliation(s)
- Anna Orekhova
- 1Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, Massachusetts
| | - Andrea Geisz
- 1Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, Massachusetts
| | - Miklós Sahin-Tóth
- 1Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, Massachusetts,2Department of Surgery, University of California Los Angeles, Los Angeles, California
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42
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Takahashi T, Miao Y, Kang F, Dolai S, Gaisano HY. Susceptibility Factors and Cellular Mechanisms Underlying Alcoholic Pancreatitis. Alcohol Clin Exp Res 2020; 44:777-789. [PMID: 32056245 DOI: 10.1111/acer.14304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022]
Abstract
Alcohol is a major cause of acute and chronic pancreatitis. There have been some recent advances in the understanding of the mechanisms underlying alcoholic pancreatitis, which include perturbation in mitochondrial function and autophagy and ectopic exocytosis, with some of these cellular events involving membrane fusion soluble N-ethylmaleimide-sensitive factor receptor protein receptor proteins. Although new insights have been unraveled recently, the precise mechanisms remain complex, and their finer details have yet to be established. The overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also the stellate cells and duct cells. Why only some are more susceptible to pancreatitis and with increased severity, while others are not, would suggest that there may be undefined protective factors or mechanisms that enhance recovery and regeneration after injury. Furthermore, there are confounding influences of lifestyle factors such as smoking and diet, and genetic background. Whereas alcohol and smoking cessation and a generally healthy lifestyle are intuitively the advice given to these patients afflicted with alcoholic pancreatitis in order to reduce disease recurrence and progression, there is as yet no specific treatment. A more complete understanding of the pathogenesis of pancreatitis from which novel therapeutic targets could be identified will have a great impact, particularly with the stubbornly high fatality (>30%) of severe pancreatitis. This review focuses on the susceptibility factors and underlying cellular mechanisms of alcohol injury on the exocrine pancreas.
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Affiliation(s)
- Toshimasa Takahashi
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Yifan Miao
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Fei Kang
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Subhankar Dolai
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Herbert Y Gaisano
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
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Wang S, Ni HM, Chao X, Ma X, Kolodecik T, De Lisle R, Ballabio A, Pacher P, Ding WX. Critical Role of TFEB-Mediated Lysosomal Biogenesis in Alcohol-Induced Pancreatitis in Mice and Humans. Cell Mol Gastroenterol Hepatol 2020; 10:59-81. [PMID: 31987928 PMCID: PMC7210479 DOI: 10.1016/j.jcmgh.2020.01.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Alcohol abuse is the major cause of experimental and human pancreatitis but the molecular mechanisms remain largely unknown. We investigated the role of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, in the pathogenesis of alcoholic pancreatitis. METHODS Using a chronic plus acute alcohol binge (referred to as Gao-binge) mouse model, we analyzed pancreas injury, autophagic flux, zymogen granule removal, TFEB nuclear translocation and lysosomal biogenesis in GFP-LC3 transgenic mice, acinar cell-specific Atg5 knockout (KO) and TFEB KO mice as well as their matched wild type mice. RESULTS We found that Gao-binge alcohol induced typical features of pancreatitis in mice with increased serum amylase and lipase activities, pancreatic edema, infiltration of inflammatory cells, accumulation of zymogen granules (ZGs) and expression of inflammatory cytokines. While Gao-binge alcohol increased the number of autophagosomes, it also concurrently inhibited TFEB nuclear translocation and TFEB-mediated lysosomal biogenesis resulting in insufficient autophagy. Acinar cell-specific Atg5 KO and acinar cell-specific TFEB KO mice developed severe inflammatory and fibrotic pancreatitis in both Gao-binge alcohol and control diet-fed mice. In contrast, TFEB overexpression inhibited alcohol-induced pancreatic edema, accumulation of zymogen granules and serum amylase and lipase activities. In line with our findings in mice, decreased LAMP1 and TFEB nuclear staining were also observed in human alcoholic pancreatitis tissues. CONCLUSIONS our results indicate that TFEB plays a critical role in maintaining pancreatic acinar cell homeostasis. Impairment of TFEB-mediated lysosomal biogenesis by alcohol may lead to insufficient autophagy and promote alcohol-induced pancreatitis.
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Affiliation(s)
- Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Thomas Kolodecik
- Digestive Diseases Section, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut; West Haven VA Medical Center, VA Connecticut Health System, West Haven, Connecticut
| | - Robert De Lisle
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Andrew Ballabio
- Telethon Institute of Genetics and Medicine, Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Medical Genetics, Department of Translational Medicine, Federico II University, Naples, Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
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44
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Cheng L, Yang Z, Sun Z, Zhang W, Ren Y, Wang M, Han X, Fei L, Zhao Y, Pan H, Xie J, Nie S. Schizandrin B Mitigates Rifampicin-Induced Liver Injury by Inhibiting Endoplasmic Reticulum Stress. Biol Pharm Bull 2020; 43:145-152. [DOI: 10.1248/bpb.b19-00725] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Ling Cheng
- Nanjing University of Chinese Medicine
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
- The First Affiliated Hospital of Anhui University of Chinese Medicine
| | - Zhizhou Yang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Zhaorui Sun
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Wei Zhang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Yi Ren
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Mengmeng Wang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Xiaoqin Han
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Libo Fei
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Yang Zhao
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Hui Pan
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Ji Xie
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
| | - Shinan Nie
- Nanjing University of Chinese Medicine
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University
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Abstract
The risks, measurements of severity, and management of severe acute pancreatitis and its complications have evolved rapidly over the past decade. Evidence suggests that initial goal directed therapy, nutritional support, and vigilance for pancreatic complications are best practice. Patients can develop pancreatic fluid collections including acute pancreatic fluid collections, pancreatic pseudocysts, acute necrotic collections, and walled-off necrosis. Several randomized controlled trials and cohort studies have recently highlighted the advantage of managing these conditions with a progressive approach, with initial draining for infection followed by less invasive techniques. Surgery is no longer an early intervention and may not be needed. Instead, interventional radiologic and endoscopic methods seem to be safer with at least as good survival outcomes. Newly developed evidence based quality indicators are available to assess and improve performance. Development and clinical testing of drugs to target the mechanisms of disease are necessary for further advancements.
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Affiliation(s)
- O Joe Hines
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-6904, USA
| | - Stephen J Pandol
- Department of Medicine, Cedar-Sinai Medical Center, Los Angeles, CA 90048, USA
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Ren Y, Qiu M, Zhang J, Bi J, Wang M, Hu L, Du Z, Li T, Zhang L, Wang Y, Lv Y, Wu Z, Wu R. Low Serum Irisin Concentration Is Associated with Poor Outcomes in Patients with Acute Pancreatitis, and Irisin Administration Protects Against Experimental Acute Pancreatitis. Antioxid Redox Signal 2019; 31:771-785. [PMID: 31250660 DOI: 10.1089/ars.2019.7731] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Aims: Severe acute pancreatitis (AP) is a serious condition without specific treatment. Mitochondrial dysfunction plays a crucial role in the pathogenesis of AP. Irisin, a novel exercise-induced hormone, contributes to many health benefits of physical activity. We and others have shown that irisin protects against ischemia reperfusion-induced organ injury by alleviating mitochondrial damage. However, the role of irisin in AP has not been evaluated. The purpose of this study was to investigate the role of serum irisin levels in patients with AP and the effect of irisin administration in experimental AP. Results: Serum irisin levels were decreased in AP patients, and low serum irisin levels were associated with worse outcomes in these patients. Treatment with exogenous irisin increased survival and mitigated pancreatic injury in experimental AP. The protective effects of irisin in AP were associated with improvement in mitochondrial function and reduction in ER stress. Moreover, irisin upregulated UCP2 expression in the pancreas, and administration of genipin, a specific UCP2 antagonist, abolished irisin's beneficial effects in L-arginine-induced AP. Innovation and Conclusion: Low serum irisin was associated with poor outcomes in AP patients, and irisin administration protected against experimental AP by restoring mitochondrial function via activation of UCP2. Restoration of mitochondrial function by irisin may offer therapeutic potential for patients with AP. Antioxid. Redox Signal. 31, 771-785.
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Affiliation(s)
- Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Minglong Qiu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liangshuo Hu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhaoqing Du
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Teng Li
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Lin Zhang
- Department of Laboratory Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yawen Wang
- Department of Laboratory Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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47
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Role of endoplasmic reticulum stress and protein misfolding in disorders of the liver and pancreas. Adv Med Sci 2019; 64:315-323. [PMID: 30978662 DOI: 10.1016/j.advms.2019.03.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/17/2018] [Accepted: 03/21/2019] [Indexed: 12/24/2022]
Abstract
The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. The fraction of protein passing through the ER represents a large proportion of the total protein in the cell. Protein folding, glycosylation, sorting and transport are essential tasks of the ER and a compromised ER folding network has been recognized to be a key component in the disease pathogenicity of common neurodegenerative, metabolic and malignant diseases. On the other hand, the ER protein folding machinery also holds significant potential for therapeutic interventions. Many causes can lead to ER stress. A disturbed calcium homeostasis, the generation of reactive oxygen species (ROS) and a persistent overload of misfolded proteins within the ER can drive the course of adisease. In this review the role of ER-stress in diseases of the liver and pancreas will be examined using pancreatitis and Wilson´s disease as examples. Potential therapeutic targets in ER-stress pathways will also be discussed.
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48
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Abstract
The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.
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49
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Sun S, Kelekar S, Kliewer SA, Mangelsdorf DJ. The orphan nuclear receptor SHP regulates ER stress response by inhibiting XBP1s degradation. Genes Dev 2019; 33:1083-1094. [PMID: 31296559 PMCID: PMC6672048 DOI: 10.1101/gad.326868.119] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/07/2019] [Indexed: 02/06/2023]
Abstract
In this study, Sun et al. investigated the role of the orphan nuclear receptor SHP, a well-known transcriptional corepressor of bile acid and lipid metabolism in the liver, in other tissues. They report that SHP functions as a regulator of ER stress in the exocrine pancreas, specifically via the regulation of XBP1s stability. The orphan nuclear receptor SHP (small heterodimer partner) is a well-known transcriptional corepressor of bile acid and lipid metabolism in the liver; however, its function in other tissues is poorly understood. Here, we report an unexpected role for SHP in the exocrine pancreas as a modulator of the endoplasmic reticulum (ER) stress response. SHP expression is induced in acinar cells in response to ER stress and regulates the protein stability of the spliced form of X-box-binding protein 1 (XBP1s), a key mediator of ER stress response. Loss of SHP reduces XBP1s protein level and transcriptional activity, which in turn attenuates the ER stress response during the fasting–feeding cycle. Consequently, SHP-deficient mice also are more susceptible to cerulein-induced pancreatitis. Mechanistically, we show that SHP physically interacts with the transactivation domain of XBP1s, thereby inhibiting the polyubiquitination and degradation of XBP1s by the Cullin3–SPOP (speckle-type POZ protein) E3 ligase complex. Together, our data implicate SHP in governing ER homeostasis and identify a novel posttranslational regulatory mechanism for the key ER stress response effector XBP1.
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Affiliation(s)
- Shengyi Sun
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Sherwin Kelekar
- Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Steven A Kliewer
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.,Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - David J Mangelsdorf
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
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50
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Saloman JL, Albers KM, Cruz-Monserrate Z, Davis BM, Edderkaoui M, Eibl G, Epouhe AY, Gedeon JY, Gorelick FS, Grippo PJ, Groblewski GE, Husain SZ, Lai KK, Pandol SJ, Uc A, Wen L, Whitcomb DC. Animal Models: Challenges and Opportunities to Determine Optimal Experimental Models of Pancreatitis and Pancreatic Cancer. Pancreas 2019; 48:759-779. [PMID: 31206467 PMCID: PMC6581211 DOI: 10.1097/mpa.0000000000001335] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
At the 2018 PancreasFest meeting, experts participating in basic research met to discuss the plethora of available animal models for studying exocrine pancreatic disease. In particular, the discussion focused on the challenges currently facing the field and potential solutions. That meeting culminated in this review, which describes the advantages and limitations of both common and infrequently used models of exocrine pancreatic disease, namely, pancreatitis and exocrine pancreatic cancer. The objective is to provide a comprehensive description of the available models but also to provide investigators with guidance in the application of these models to investigate both environmental and genetic contributions to exocrine pancreatic disease. The content covers both nongenic and genetically engineered models across multiple species (large and small). Recommendations for choosing the appropriate model as well as how to conduct and present results are provided.
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Affiliation(s)
- Jami L. Saloman
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Kathryn M. Albers
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Brian M. Davis
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Mouad Edderkaoui
- Basic and Translational Pancreas Research, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Ariel Y. Epouhe
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Jeremy Y. Gedeon
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Fred S. Gorelick
- Department of Internal Medicine, Section of Digestive Diseases & Department of Cell Biology Yale University School of Medicine; Veterans Affairs Connecticut Healthcare, West Haven, CT
| | - Paul J. Grippo
- Department of Medicine, Division of Gastroenterology and Hepatology, UI Cancer Center, University of Illinois at Chicago, Chicago, IL
| | - Guy E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI
| | | | - Keane K.Y. Lai
- Department of Pathology (National Medical Center), Department of Molecular Medicine (Beckman Research Institute), and Comprehensive Cancer Center, City of Hope, Duarte, CA
| | - Stephen J. Pandol
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Aliye Uc
- Stead Family Department of Pediatrics, University of Iowa, Stead Family Children’s Hospital, Iowa City, IA
| | - Li Wen
- Department of Pediatrics, Stanford University, Palo Alto, CA
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