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Wang QW, Zheng H, Yang Y, Chang X, Du Z, Hang ZN, Li ZS, Liao Z. Distinct microbial signatures and their predictive value in recurrent acute pancreatitis: insights from 5-region 16S rRNA gene sequencing. Front Immunol 2025; 16:1558983. [PMID: 40093002 PMCID: PMC11906328 DOI: 10.3389/fimmu.2025.1558983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
Background Recurrent acute pancreatitis (RAP) poses significant clinical challenges, with 32.3% developing to chronic pancreatitis within 5 years. The underlying microbial factors contributing to RAP remain poorly understood. This study aims to identify blood microbial signatures associated with RAP and explore the potential microbial predictors for RAP. Methods In this prospective cohort, 90 acute pancreatitis patients are classified into non-recurrent acute pancreatitis (NRAP, n=68) and RAP (n=22) groups based on the number of pancreatitis episodes. Microbial composition of blood samples is analyzed using 5-region (5R) 16S rRNA gene sequencing. Key microbial taxa and functional predictions are made. A random forest model is used to assess the predictive value of microbial features for RAP. The impact of Staphylococcus hominis (S. hominis) on RAP is further evaluated in an experimental mouse model. Results Linear discriminant analysis effect size (LEfSe) analysis highlights significant microbial differences, with Paracoccus aminovorans, Corynebacterium glucuronolyticum and S. hominis being prominent in RAP. Functional predictions indicate enrichment of metabolic pathways in the RAP group. Random forest analysis identifies key microbial taxa with an AUC value of 0.759 for predicting RAP. Experimental validation shows that S. hominis exacerbates pancreatic inflammation in mice. Conclusions This study identifies distinct clinical and microbial features associated with RAP, emphasizing the role of specific bacterial taxa in pancreatitis recurrence. The findings suggest that microbial profiling could enhance the diagnosis and management of RAP, paving the way for personalized therapeutic approaches.
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Affiliation(s)
| | | | | | | | | | | | - Zhao-Shen Li
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhuan Liao
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, Naval Medical University, Shanghai, China
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Li Z, Du M, Wang J, Zhao X, Qu Y, Zhang D. Chaperone-Mediated Autophagy Reactivation Protects Against Severe Acute Pancreatitis-Associated Liver Injury Through Upregulating Keap1/Nrf2 Signaling Pathway and Inhibiting NLRP3 Inflammasome Activation. Cell Biochem Biophys 2025:10.1007/s12013-025-01677-7. [PMID: 39998716 DOI: 10.1007/s12013-025-01677-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2025] [Indexed: 02/27/2025]
Abstract
Acute liver injury (ALI) is a vital factor in the early progression of severe acute pancreatitis (SAP). It exacerbates systemic inflammation, impairs the liver's capacity to clear inflammatory mediators and cytokines, and contributes to systemic organ dysfunction syndrome (SODS). However, the mechanisms driving SAP-associated liver injury (SAP-ALI) are poorly understood, and effective therapeutic options remain limited. Chaperone-mediated autophagy (CMA), a selective form of autophagy, plays an essential role in reducing inflammation and oxidative stress by clearing damaged or dysfunctional proteins. This study examines the role of CMA in SAP-ALI and evaluates its therapeutic potential. In a sodium taurocholate-induced SAP-ALI rat model, CMA dysfunction was observed, characterized by reduced LAMP2A expression and the accumulation of CMA substrate proteins in pancreatic and hepatic tissues. The activator AR7 successfully restored CMA function, enhanced anti-inflammatory and antioxidant responses, and mitigated pancreatic and liver damage in SAP rat. In contrast, the CMA inhibitor PPD exacerbated liver injury, underscoring CMA's protective role in SAP-ALI. Mechanistic analyses demonstrated that CMA reactivation activated the Keap1/Nrf2 signaling pathway, leading to increased expression of antioxidant-related genes and suppression of NLRP3 inflammasome activation. Specifically, the protective effects of AR7-induced CMA activation were significantly reversed by the Nrf2 inhibitor ML385, which inhibited Nrf2 signaling and its associated protein levels. These findings show AR7-induced CMA reactivation as a promising therapeutic strategy for SAP-ALI, primarily through its enhancement of Keap1/Nrf2-regulated antioxidant pathways and inhibition of NLRP3 inflammasome activation.
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Affiliation(s)
- Zhongbiao Li
- Qingdao Medical College, Qingdao University, Qingdao, 266073, China
- Department of Gastrointestinal Surgery, Qingdao University Affiliated to Qingdao Municipal Hospital, Qingdao, 266011, China
| | - Min Du
- Department of Gastrointestinal Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266011, China
| | - Jiang Wang
- Department of Gastrointestinal Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266011, China
| | - Xihao Zhao
- Department of Gastrointestinal Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266011, China
| | - Yue Qu
- Imageing department, Qingdao University Affiliated Qingdao Haici Hospital, Qingdao, 266033, China.
| | - Dianliang Zhang
- Department of Gastrointestinal Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266011, China.
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Shen G, Wen H, Li H, Zhang X, Lan B, Dong X, Ge P, Luo Y, Chen H. Emodin protects against severe acute pancreatitis-associated acute lung injury by activating Nrf2/HO-1/GPX4 signal and inhibiting ferroptosis in vivo and in vitro. BMC Gastroenterol 2025; 25:57. [PMID: 39910464 PMCID: PMC11800461 DOI: 10.1186/s12876-025-03660-1] [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: 11/08/2024] [Accepted: 01/30/2025] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND Severe acute pancreatitis (SAP) has high morbidity, a complicated and dangerous course, and many complications, including severe pulmonary complications. SAP-associated acute lung injury (SAP-ALI) is still a significant challenge for surgeons because of its high mortality. Therefore, more effective treatment methods are urgently needed. Emodin (EMO) has shown tremendous potential in treating many refractory diseases. However, its protection mechanism in SAP-ALI needs to be further clarified. This study was undertaken to investigate the protective effects of EMO against lung injury in SAP rats and alveolar epithelial cells, with a particular focus on the classical ferroptosis pathway. METHODS In an in vivo study, forty SD rats were evenly split into five groups: sham operation (SO) group, the biliopancreatic duct was retrogradely injected with 5% sodium taurocholate (STC) to create the SAP group, SAP + EMO group was administered EMO via gavage to the rats following the modeling, SAP + ML385 group (a given inhibitor of nuclear factor erythroid 2-related factor 2 (Nrf2)), SAP + ML385 + EMO group. In an in vitro study, alveolar epithelial A549 cell lines were exposed to lipopolysaccharide (LPS) and treated with EMO. ML385 was also used to inhibit the expression of Nrf2. Pancreatic and lung tissue damage was evaluated using histological examination and molecular experiments. Enzyme-linked immunosorbent assays (ELISA) were used to assess the levels of pro-inflammatory cytokines, Fe2+, and associated oxidative stress indicators in the serum and cell supernatant. Real-time polymerase chain reaction (PCR), Western blot (WB), and immunofluorescence were used to find the expressions of related mRNAs and proteins in the lung tissue or A549 cells. RESULTS The findings demonstrated that suppressing Nrf2 expression exacerbated the inflammatory response brought on by SAP and the pathological alterations of SAP-ALI. Emodin treatment reversed this pathological change by activating the Nrf2/Heme Oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) signal path. Moreover, these results also showed that EMO, contrary to the effects of ML385, suppressed the ferroptosis response, which manifested as up-regulated glutathione (GSH) and GPX4 levels in vivo and in vitro and down-regulated malondialdehyde (MDA), superoxide dismutase (SOD), Fe2+, and reactive oxygen species (ROS) levels. CONCLUSIONS Our results demonstrated that EMO effectively inhibited ferroptosis both in vivo and in vitro, while also modulating the Nrf2/HO-1/GPX4 signaling pathway to provide protection against SAP-ALI.
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Affiliation(s)
- Gang Shen
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, People's Republic of China
- Dalian Women and Children's Medical Center (Group), Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
| | - Haiyun Wen
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, People's Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
| | - Huijuan Li
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People's Republic of China
| | - Xuetao Zhang
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, People's Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
| | - Bowen Lan
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, People's Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
| | - Xuanchi Dong
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, People's Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
| | - Peng Ge
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, People's Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
| | - Yalan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China
| | - Hailong Chen
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning Province, 116011, People's Republic of China.
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China.
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian Liaoning, 116011, People's Republic of China.
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Zhang T, Huang X, Feng S, Shao H. Lactate-Dependent HIF1A Transcriptional Activation Exacerbates Severe Acute Pancreatitis Through the ACSL4/LPCAT3/ALOX15 Pathway Induced Ferroptosis. J Cell Biochem 2025; 126:e30687. [PMID: 39676583 DOI: 10.1002/jcb.30687] [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: 07/19/2024] [Revised: 11/11/2024] [Accepted: 11/21/2024] [Indexed: 12/17/2024]
Abstract
Acute pancreatitis (AP) is a common emergency in the digestive system, and in severe cases, it can progress to severe acute pancreatitis (SAP), with a mortality rate of up to 30%, representing a dire situation. SAP in mice was induced by l-arginine (l-Arg). HE, IHC, WB and ELISA were used to study the role and regulation of HIF1A in SAP. At the same time, QPCR, WB, CHIP-QPCR and luciferase report were used to explore the specific mechanism of HIF1A regulation of SAP in vitro. The research results indicate that following SAP induction, the pancreatic tissue of mice exhibited significant glycolytic abnormalities, accompanied by a marked upregulation of HIF1A expression. This led to apparent damage in the pancreatic tissue, lungs, and kidneys. However, in sh-HIF1A mice, the degree of these injuries was significantly alleviated, along with a reduction in the production of inflammatory factors, oxidative products, and lipid peroxidation markers. This suggests that HIF1A plays a crucial role in the inflammatory and oxidative stress processes during SAP. Further exploration revealed that the absence or overexpression of HIF1A affects SAP by inducing ferroptosis through the ACSL4/LPCAT3/ALOX15 pathway. Notably, the elevated lactate level resulting from glycolytic abnormalities further enhances the histone lactylation in the HIF1A promoter region, thereby aggravating the expression of HIF1A. Lactate-dependent HIF1A transcriptional activation exacerbates severe acute pancreatitis through the ACSL4/LPCAT3/ALOX15 pathway induced ferroptosis.
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Affiliation(s)
- Tingyuan Zhang
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
| | - Xiaopei Huang
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
| | - Shengnan Feng
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
| | - Huanzhang Shao
- Department of ICU, Henan Provincial People's Hospital, Zhengzhou, China
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Wu CY, Wang KQ, Qin YY, Wang HW, Wu MM, Zhu XD, Lu XY, Zhu MM, Lu CS, Hu QQ. Micheliolide ameliorates severe acute pancreatitis in mice through potentiating Nrf2-mediated anti-inflammation and anti-oxidation effects. Int Immunopharmacol 2024; 143:113490. [PMID: 39467351 DOI: 10.1016/j.intimp.2024.113490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/19/2024] [Accepted: 10/21/2024] [Indexed: 10/30/2024]
Abstract
Severe acute pancreatitis (SAP) is an acute inflammatory injury disease with significant mortality rate and currently without effective strategy being available. Inflammation and oxidative stress play central roles in the etiology of SAP. Micheliolide (MCL), an active monomeric component isolated from Michelia champaca, has been proved its multiple therapeutic properties including anti-inflammatory, antioxidant and anti-cancer. Nevertheless, the therapeutic effect and underlying mechanism of MCL in SAP still remain unclear. Here, we found that caerulein with lipopolysaccharide (LPS)-induced SAP murine models exhibited severe pancreatic injury, including necrosis, edema, and vacuolation of acinar cells in the pancreas, elevated serum levels of amylase and lipase, and reduced number of the exocrine cells. As expected, MCL treatment alleviated these side effects. Mechanistically, MCL triggered nuclear factor erythroid 2-related factor 2 (Nrf2) activation, thereby activating Nrf2-regulated antioxidative pathways and inhibiting nuclear factor kappa B p65 (NF-κB p65)-mediated inflammatory response, resulting in protection against pancreatic injury in SAP mice. In addition, Nrf2 gene deficiency abolished the beneficial effects of MCL on SAP-induced pancreatic inflammation and oxidative stress and blocked the ability of MCL to alleviate the pancreatic injury in SAP mice. Collectively, these findings indicated that the suppression of SAP-induced pancreatic injury by MCL was at least in part due to Nrf2-mediated anti-oxidation effect and inhibition of inflammation.
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Affiliation(s)
- Chen-Yu Wu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Ke-Qi Wang
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yu-Ying Qin
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Hong-Wei Wang
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Min-Min Wu
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xian-Dong Zhu
- Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xin-Yu Lu
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The First Clinical Medical College of Wenzhou Medical University, Wenzhou 325000, China
| | - Mian-Mian Zhu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Chao-Sheng Lu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
| | - Qing-Qing Hu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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Sun HW, Bai YY, Qin ZL, Li RZ, Madzikatire TB, Akuetteh PDP, Li Q, Kong HR, Jin YP. Transfection of 12/15-lipoxygenase effectively alleviates inflammatory responses during experimental acute pancreatitis. World J Gastroenterol 2024; 30:4544-4556. [PMID: 39563743 PMCID: PMC11572619 DOI: 10.3748/wjg.v30.i42.4544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 08/26/2024] [Accepted: 10/08/2024] [Indexed: 10/31/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP), the initially triggered inflammatory process in the pancreas, can be life-threatening. It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components, maintain intracellular homeostasis, and promote apoptosis by upregulating the activity of caspases. Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases, the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined. AIM To investigate the effect of Alox15 expression in cerulein-induced AP in rats. METHODS Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP. The expression of Alox15 was then assessed at the mRNA and protein levels. RESULTS Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15-transfected rats. Further, the mRNA expression levels of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1, as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced. Additionally, we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells. The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP. CONCLUSION Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy, making it a potential therapeutic target for AP.
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Affiliation(s)
- Hong-Wei Sun
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yong-Yu Bai
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Zhen-Liu Qin
- Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Ri-Zhao Li
- Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | | | | | - Qiang Li
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Hong-Ru Kong
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yue-Peng Jin
- National Key Clinical Specialty (General Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Lee PJ, Papachristou GI, Speake C, Lacy-Hulbert A. Immune markers of severe acute pancreatitis. Curr Opin Gastroenterol 2024; 40:389-395. [PMID: 38967941 PMCID: PMC11305979 DOI: 10.1097/mog.0000000000001053] [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] [Indexed: 07/06/2024]
Abstract
PURPOSE OF REVIEW Acute pancreatitis is a common acute inflammatory disorder of the pancreas, and its incidence has been increasing worldwide. Approximately 10% of acute pancreatitis progresses to severe acute pancreatitis (SAP), which carries significant morbidity and mortality. Disordered immune response to pancreatic injury is regarded as a key event that mediates systemic injury in SAP. In this article, we review recent developments in immune biomarkers of SAP and future directions for research. RECENT FINDINGS Given the importance of the NLRP3-inflammasome pathway in mediating systemic inflammatory response syndrome and systemic injury, recent studies have investigated associations of SAP with systemic levels of activators of NLRP3, such as the damage associated molecular patterns (DAMPs) for the first time in human SAP. For example, circulating levels of histones, mitochondrial DNAs, and cell free DNAs have been associated with SAP. A panel of mechanistically relevant immune markers (e.g., panel of Angiopoeitin-2, hepatocyte growth factor, interleukin-8 (IL-8), resistin and sTNF-α R1) carried higher predictive accuracies than existing clinical scores and individual immune markers. Of the cytokines with established relevance to SAP pathogenesis, phase 2 trials of immunotherapies, including tumor necrosis factor (TNF)-alpha inhibition and stimulation of IL-10 production, are underway to determine if altering the immunologic response can reduce the severity of acute pancreatitis (AP). SUMMARY Circulating systemic levels of various DAMPs and a panel of immune markers that possibly reflect activities of different pathways that drive SAP appear promising as predictive biomarkers for SAP. But larger multicenter studies are needed for external validation. Studies investigating immune cellular pathways driving SAP using immunophenotyping techniques are scarce. Interdisciplinary efforts are also needed to bring some of the promising biomarkers to the bedside for validation and testing for clinical utility. Studies investigating the role of and characterization of altered gut-lymph and gut-microbiota in severe AP are needed.
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Affiliation(s)
- Peter J Lee
- Division of Gastroenterology, Hepatology, and Nutrition. Ohio State University Wexner Medical Center, Columbus, OH
| | - Georgios I Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition. Ohio State University Wexner Medical Center, Columbus, OH
| | - Cate Speake
- Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington
| | - Adam Lacy-Hulbert
- Center for Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington
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Liu M, Ma L, An W, Yang Y, Liu J, Jiang H, Yuan J, Sun X, Zhu J, Yan M, Wang L, Li Z, Liao Z, Sun C. Heterozygous Spink1 c.194+2T>C mutation promotes chronic pancreatitis after acute attack in mice. Pancreatology 2024; 24:677-689. [PMID: 38763786 DOI: 10.1016/j.pan.2024.05.514] [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: 01/15/2024] [Revised: 04/26/2024] [Accepted: 05/06/2024] [Indexed: 05/21/2024]
Abstract
BACKGROUND & AIMS Mutations in genes, including serine protease inhibitor Kazal-type 1 (SPINK1), influence disease progression following sentinel acute pancreatitis event (SAPE) attacks. SPINK1 c.194+2T > C intron mutation is one of the main mutants of SPINK1，which leads to the impairment of SPINK1 function by causing skipping of exon 3. Research on the pathogenesis of SAPE attacks would contribute to the understanding of the outcomes of acute pancreatitis. Therefore, the aim of the study was to clarify the role of SPINK1 c.194+2T > C mutation in the CP progression after an AP attack. METHODS SAPE attacks were induced in wildtype and SPINK mutant (Spink1 c.194+2T > C) mice by cerulein injection. The mice were sacrificed at 24 h, 14 d, 28 d, and 42 d post-SAPE. Data-independent acquisition (DIA) proteomic analysis was performed for the identification of differentially expressed protein in the pancreatic tissues. Functional analyses were performed using THP-1 and HPSCs. RESULTS Following SAPE attack, the Spink1 c.194+2T > C mutant mice exhibited a more severe acute pancreatitis phenotype within 24 h. In the chronic phase, the chronic pancreatitis phenotype was more severe in the Spink1 c.194+2T > C mutant mice after SAPE. Proteomic analysis revealed elevated IL-33 level in Spink1 c.194+2T > C mutant mice. Further in vitro analyses revealed that IL-33 induced M2 polarization of macrophages and activation of pancreatic stellate cells. CONCLUSION Spink1 c.194+2T > C mutation plays an important role in the prognosis of patients following SAPE. Heterozygous Spink1 c.194+2T > C mutation promotes the development of chronic pancreatitis after an acute attack in mice through elevated IL-33 level and the induction of M2 polarization in coordination with pancreatic stellate cell activation.
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Affiliation(s)
- Muyun Liu
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Department of Gastroenterology, NO. 905 Hospital of PLA Navy affiliated to Naval Medical University, Shanghai, 200050, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Lizhe Ma
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China; Department of Gastroenterology, No 988 Hospital of PLA Joint Logistics Support Force, Zhengzhou, 450000, China
| | - Wei An
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Yaying Yang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, China
| | - Juncen Liu
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Hui Jiang
- Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China; Department of Pathology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China
| | - Jihang Yuan
- Department of Medical Genetics, Naval Medical University, Shanghai, 200433, China
| | - Xiaoru Sun
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Jingyi Zhu
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Maoyun Yan
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Luowei Wang
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Zhaoshen Li
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China
| | - Zhuan Liao
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China.
| | - Chang Sun
- Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China; Shanghai Institute of Pancreatic Diseases, Shanghai, 200433, China.
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Cao Y, Li F, Sun Z, Liu J, Liu J, Yang Q, Ge P, Luo Y, Chen H. Regulation of Microtubule Stability in Pulmonary Microvascular Endothelial Cells in Rats with Severe Acute Pancreatitis: Qingyi Decoction is a Potential CDK5 Inhibitor. J Inflamm Res 2024; 17:2513-2530. [PMID: 38699595 PMCID: PMC11063490 DOI: 10.2147/jir.s451755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 04/16/2024] [Indexed: 05/05/2024] Open
Abstract
Purpose Explore the therapeutic effects and regulatory mechanism of Qingyi Decoction (QYD) on severe acute pancreatitis (SAP) associated acute lung injury (ALI). Methods We identified the constituents absorbed into the blood of QYD based on a network pharmacological strategy. The differentially expressed genes from the GEO database were screened to identify the critical targets of QYD treatment of SAP-ALI. The SAP-ALI rat model was constructed.Some methods were used to evaluate the efficacy and mechanism of QYD in treating SAP-ALI. LPS-stimulated pulmonary microvascular endothelial cell injury simulated the SAP-induced pulmonary endothelial injury model. We further observed the therapeutic effect of QYD and CDK5 plasmid transfection on endothelial cell injury. Results 18 constituents were absorbed into the blood, and 764 targets were identified from QYD, 25 of which were considered core targets for treating SAP-ALI. CDK5 was identified as the most critical gene. The results of differential expression analysis showed that the mRNA expression level of CDK5 in the blood of SAP patients was significantly up-regulated compared with that of healthy people. Animal experiments have demonstrated that QYD can alleviate pancreatic and lung injury inflammatory response and reduce the upregulation of CDK5 in lung tissue. QYD or CDK5 inhibitors could decrease the expression of NFAT5 and GEF-H1, and increase the expression of ACE-tub in SAP rat lung tissue. Cell experiments proved that QYD could inhibit the expression of TNF-α and IL-6 induced by LPS. Immunofluorescence results suggested that QYD could alleviate the cytoskeleton damage of endothelial cells, and the mechanism might be related to the inhibition of CDK5-mediated activation of NFAT5, GEF-H1, and ACE-tub. Conclusion CDK5 has been identified as a critical target for pulmonary endothelial injury of SAP-ALI. QYD may partially alleviate microtubule disassembly by targeting the CDK5/NFAT5/GEF-H1 signaling pathway, thus relieving SAP-induced pulmonary microvascular endothelial cell injury.
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Affiliation(s)
- Yinan Cao
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Fan Li
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Zhenxuan Sun
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Jin Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Jie Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Qi Yang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Peng Ge
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Yalan Luo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China
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10
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Yang L, Liu X, Yang J, Wang K, Ai Z, Shang J, Zhou M. Biomimetic delivery of emodin via macrophage membrane-coated UiO-66-NH 2 nanoparticles for acute pancreatitis treatment. Biochem Biophys Res Commun 2024; 702:149649. [PMID: 38341924 DOI: 10.1016/j.bbrc.2024.149649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 02/06/2024] [Indexed: 02/13/2024]
Abstract
Acute pancreatitis (AP) is a severe inflammatory condition with a rising incidence and high mortality rates, especially in severe cases. Emodin (ED), known for its potent anti-inflammatory properties, holds promise in addressing AP. However, its clinical application is hindered by limitations such as low bioavailability and insufficient target specificity. Herein, we developed a novel drug delivery system using macrophage membrane-coated UiO-66-NH2 nanoparticles loaded with ED (MVs-UiO-ED). UiO-66-NH2 was successfully synthesized and characterized, revealing an octahedral structure with a suitable size distribution. The successful loading of ED onto UiO-66-NH2 was confirmed by ultraviolet and infrared spectroscopy. Subsequently, MVs-UiO-ED was prepared by coating macrophage membrane-derived vesicles onto UiO-ED, resulting in a biomimetic delivery system. In vitro release studies demonstrated that MVs-UiO-ED exhibited a sustained-release profile, indicating its potential for prolonged drug circulation. An AP mouse model was established to evaluate the therapeutic efficacy of MVs-UiO-ED. Compared with the model group, MVs-UiO-ED significantly reduced serum levels of α-amylase and lipase, two indicators of pancreatitis severity. Furthermore, histopathological examinations revealed that MVs-UiO-ED ameliorated pancreatic tissue damage. This study underscores the potential of MVs-UiO-ED as an effective therapeutic approach for AP.
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Affiliation(s)
- Liuxuan Yang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xianbin Liu
- Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, China
| | - Jing Yang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Ke Wang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhenghao Ai
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jinlu Shang
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Meiling Zhou
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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11
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Hu S, Lin T, Chen Y, Guo Y, Sun X, Shi L, Pan J. NLRC4-mediated pyroptosis was involved in coagulation disorders of acute pancreatitis. J Gene Med 2024; 26:e3683. [PMID: 38571451 DOI: 10.1002/jgm.3683] [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: 08/06/2023] [Revised: 11/29/2023] [Accepted: 03/03/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is a potentially lethal acute disease highly involved in coagulation disorders. Pyroptosis has been reported to exacerbate coagulation disorders, yet this implication has not been illustrated completely in AP. METHODS RNA sequencing data of peripheral blood of AP patients were downloaded from the Gene Expression Omnibus database. Gene set variation analysis and single sample gene set enrichment analysis were used to calculate the enrichment score of coagulation-related signatures and pyroptosis. Spearman and Pearson correlation analysis was used for correlation analysis. Peripheral blood samples and related clinical parameters were collected from patients with AP and healthy individuals. A severe AP (SAP) model of mice was established using caerulein and lipopolysaccharide. Enzyme-linked immunosorbent assay, chemiluminescence immunoassay and immunohistochemical analysis were employed to detect the level of coagulation indicators and pyroptosis markers in serum and pancreas tissues. Additionally, we evaluated the effect of pyroptosis inhibition and NLRC4 silence on the function of human umbilical vein endothelial cells (HUVECs). RESULTS Coagulation disorders were significantly positively correlated to the severity of AP, and they could be a predictor for AP severity. Further analyses indicated that six genes-DOCK9, GATA3, FCER1G, NLRC4, C1QB and C1QC-may be involved in coagulation disorders of AP. Among them, NLRC4 was positively related to pyroptosis that had a positive association with most coagulation-related signatures. Data from patients showed that NLRC4 and other pyroptosis markers, including IL-1β, IL-18, caspase1 and GSDMD, were significant correlation to AP severity. In addition, NLRC4 was positively associated with coagulation indicators in AP patients. Data from mice showed that NLRC4 was increased in the pancreas tissues of SAP mice. Treatment with a pyroptosis inhibitor effectively alleviated SAP and coagulation disorders in mice. Finally, inhibiting pyroptosis or silencing NLRC4 could relieve endothelial dysfunction in HUVECs. CONCLUSIONS NLRC4-mediated pyroptosis damages the function of endothelial cells and thereby exacerbates coagulation disorders of AP. Inhibiting pyroptosis could improve coagulation function and alleviate AP.
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Affiliation(s)
- Sunkuan Hu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou, China
- Wenzhou Key Laboratory of Critical Care and Artificial Intelligence, Wenzhou, China
| | - Tiesu Lin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yufeng Chen
- Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou, China
- Wenzhou Key Laboratory of Critical Care and Artificial Intelligence, Wenzhou, China
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yimo Guo
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xuecheng Sun
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lingyan Shi
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jingye Pan
- Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou, China
- Wenzhou Key Laboratory of Critical Care and Artificial Intelligence, Wenzhou, China
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Collaborative Innovation Center for Intelligence Medical Education, Wenzhou, China
- Zhejiang Engineering Research Center for Hospital Emergency and Process Digitization, Wenzhou, China
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12
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Liu J, Yan Q, Li S, Jiao J, Hao Y, Zhang G, Zhang Q, Luo F, Zhang Y, Lv Q, Zhang W, Zhang A, Song H, Xin Y, Ma Y, Owusu L, Ma X, Yin P, Shang D. Integrative metagenomic and metabolomic analyses reveal the potential of gut microbiota to exacerbate acute pancreatitis. NPJ Biofilms Microbiomes 2024; 10:29. [PMID: 38514648 PMCID: PMC10957925 DOI: 10.1038/s41522-024-00499-4] [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: 06/30/2023] [Accepted: 03/13/2024] [Indexed: 03/23/2024] Open
Abstract
Early dysbiosis in the gut microbiota may contribute to the severity of acute pancreatitis (AP), however, a comprehensive understanding of the gut microbiome, potential pathobionts, and host metabolome in individuals with AP remains elusive. Hence, we employed fecal whole-metagenome shotgun sequencing in 82 AP patients and 115 matched healthy controls, complemented by untargeted serum metabolome and lipidome profiling in a subset of participants. Analyses of the gut microbiome in AP patients revealed reduced diversity, disrupted microbial functions, and altered abundance of 77 species, influenced by both etiology and severity. AP-enriched species, mostly potential pathobionts, correlated positively with host liver function and serum lipid indicators. Conversely, many AP-depleted species were short-chain fatty acid producers. Gut microflora changes were accompanied by shifts in the serum metabolome and lipidome. Specifically, certain gut species, like enriched Bilophila wadsworthia and depleted Bifidobacterium spp., appeared to contribute to elevated triglyceride levels in biliary or hyperlipidemic AP patients. Through culturing and whole-genome sequencing of bacterial isolates, we identified virulence factors and clinically relevant antibiotic resistance in patient-derived strains, suggesting a predisposition to opportunistic infections. Finally, our study demonstrated that gavage of specific pathobionts could exacerbate pancreatitis in a caerulein-treated mouse model. In conclusion, our comprehensive analysis sheds light on the gut microbiome and serum metabolome in AP, elucidating the role of pathobionts in disease progression. These insights offer valuable perspectives for etiologic diagnosis, prevention, and intervention in AP and related conditions.
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Affiliation(s)
- Jianjun Liu
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Qiulong Yan
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | | | - Juying Jiao
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Yiming Hao
- Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Guixin Zhang
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qingkai Zhang
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Fei Luo
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Yue Zhang
- Puensum Genetech Institute, Wuhan, China
| | - Qingbo Lv
- Puensum Genetech Institute, Wuhan, China
| | - Wenzhe Zhang
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | | | - Huiyi Song
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yi Xin
- Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Yufang Ma
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Lawrence Owusu
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Xiaochi Ma
- Second Affiliated Hospital, Dalian Medical University, Dalian, China.
| | - Peiyuan Yin
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
- College of Integrative Medicine, Dalian Medical University, Dalian, China.
| | - Dong Shang
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
- College of Integrative Medicine, Dalian Medical University, Dalian, China.
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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13
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Yang H, Liu Y, Yao J, Wang Y, Wang L, Ren P, Bai B, Wen Q. Mesenchymal stem cells inhibit ferroptosis by activating the Nrf2 antioxidation pathway in severe acute pancreatitis-associated acute lung injury. Eur J Pharmacol 2024; 967:176380. [PMID: 38311279 DOI: 10.1016/j.ejphar.2024.176380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/24/2024] [Accepted: 02/01/2024] [Indexed: 02/10/2024]
Abstract
Severe acute pancreatitis-associated acute lung injury (SAP-ALI) remains a significant challenge for healthcare practitioners because of its high morbidity and mortality; therefore, there is an urgent need for an effective treatment. Mesenchymal stem cells (MSCs) have shown significant potential in the treatment of a variety of refractory diseases, including lung diseases. This study aimed to investigate the protective effects of MSCs against SAP-ALI and its underlying mechanisms. Our results suggest that MSCs mitigate pathological injury, hemorrhage, edema, inflammatory response in lung tissue, and lipopolysaccharide (LPS)-induced cell damage in RLE-6TN cells (a rat alveolar epithelial cell line). The results also showed that MSCs, similar to the effects of ferrostatin-1 (ferroptosis inhibitor), suppressed the ferroptosis response, which was manifested as down-regulated Fe2+, malondialdehyde, and reactive oxygen species (ROS) levels, and up-regulated glutathione peroxidase 4 (GPX4) and glutathione (GSH) levels in vivo and in vitro. The activation of ferroptosis by erastin (a ferroptosis agonist) reversed the protective effect of MSCs against SAP-ALI. Furthermore, MSCs activated the nuclear factor erythroid 2 associated factor 2 (Nrf2) transcription factor, and blocking the Nrf2 signaling pathway with ML385 abolished the inhibitory effect of MSCs on ferroptosis in vitro. Collectively, these results suggest that MSCs have therapeutic effects against SAP-ALI. The specific mechanism involves inhibition of ferroptosis by activating the Nrf2 transcription factor.
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Affiliation(s)
- Hongfang Yang
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Department of Anesthesiology, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Yan Liu
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Anesthesiology Department, Dalian Medical University, Dalian, China
| | - Jiaqi Yao
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yin Wang
- Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xian, China
| | - Lihong Wang
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Penghui Ren
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Anesthesiology Department, Dalian Medical University, Dalian, China
| | - Buyue Bai
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Anesthesiology Department, Dalian Medical University, Dalian, China
| | - Qingping Wen
- Department of Anesthesiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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14
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Rafaqat S, Sattar A, Anjum F, Gilani M, Rafaqat S. The role of predictive and prognostic values of inflammatory markers in acute pancreatitis: a narrative review. JOURNAL OF PANCREATOLOGY 2024; 7:72-85. [DOI: 10.1097/jp9.0000000000000145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
Abstract
Pancreatitis is an inflammatory condition affecting the pancreas and is classified into 2 types, acute and chronic, which can manifest in various forms. This review article summarizes the role of predictive and prognostic values of inflammatory markers in the pathogenesis of acute pancreatitis, mainly focused on preclinical and clinical studies. It includes serum amyloid A (SAA), monocyte chemotactic protein-1 (MCP-1), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), C-reactive protein (CRP), IL-10, myeloperoxidase, pentraxin 3, and plasminogen activator inhibitor 1. SAA3 plays a crucial role in developing acute pancreatitis by triggering a receptor-interacting protein 3–dependent necroptosis pathway in acinar cells. Targeting SAA3 could be a potential strategy for treating acute pancreatitis. The recruitment of monocytes/macrophages and the activation of the systemic MCP-1 signaling pathway play a role in the progression of pancreatitis, and blocking MCP-1 may have a suppressive effect on the development of pancreatic fibrosis. The ESR can predict severe acute pancreatitis with slightly lower accuracy than CRP. When ESR and CRP levels are combined at 24 hours, they predict severe acute pancreatitis accurately. IL-6 plays a crucial role in activating the Janus kinase/signal transducers and activators of the transcription pathway, exacerbating pancreatitis and contributing to the initiation and progression of pancreatic cancer. Endogenous IL-10 plays a crucial role in controlling the regenerative phase and limiting the severity of fibrosis and glandular atrophy induced by repeated episodes of acute pancreatitis in mice. The predictive and diagnostic roles of these inflammatory factors in pancreatitis were introduced in detail in this review.
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Affiliation(s)
- Saira Rafaqat
- Department of Zoology (Molecular Physiology), Lahore College for Women University, Lahore, Pakistan
| | - Aqsa Sattar
- Department of Zoology (Molecular Physiology), Lahore College for Women University, Lahore, Pakistan
| | - Farhan Anjum
- Institute of Zoology, University of the Punjab, Quaid-i-Azam Campus, Lahore, Pakistan
| | - Mahrukh Gilani
- Department of Zoology, Lahore College for Women University, Lahore, Pakistan
| | - Sana Rafaqat
- Department of Biotechnology (Human Genetics), Lahore College for Women University, Lahore, Pakistan
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15
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Liu Y, Cui H, Mei C, Cui M, He Q, Wang Q, Li D, Song Y, Li J, Chen S, Zhu C. Sirtuin4 alleviates severe acute pancreatitis by regulating HIF-1α/HO-1 mediated ferroptosis. Cell Death Dis 2023; 14:694. [PMID: 37865653 PMCID: PMC10590376 DOI: 10.1038/s41419-023-06216-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 09/26/2023] [Accepted: 10/10/2023] [Indexed: 10/23/2023]
Abstract
Acute pancreatitis (AP) is a common emergency of the digestive system and serious cases can develop into severe acute pancreatitis (SAP), which ortality rates up to 30%. Sirtuin4 (SIRT4) is a member of the sirtuin family, and plays a key role in inflammation and oxidative stress. However, the potential role of SIRT4 in SAP has yet to be elucidated. In the present study, we found that the expression level of SIRT4 in human AP was downregulated by screening a public database, suggesting that SIRT4 may play a role in AP. Subsequently, we used L-arginine (L-Arg) to induce SAP in SIRT4 knockout (SIRT4_KO) and SIRT4 overexpression (AAV_SIRT4) mice. The results showed that the pancreatic tissue injury and related lung and kidney injury were serious in SIRT4_KO mice after SAP induction, but were significantly reduced in AAV_SIRT4 mice. More importantly, we found that the levels of antioxidant factors GSH and SOD were decreased in SIRT4_KO mice, and the production of oxidative products and lipid peroxidation markers was increased, suggesting that SIRT4 was involved in inflammation and oxidative stress during SAP. Further studies showed that the absence or overexpression of SIRT4 affected the expression level of Hypoxia-inducible factor-1α (HIF-1α) after SAP induction, and regulated the expression of ferroptosis related proteins by mediating HIF-1α/HO-1 pathway. Collectively, our study revealed that SIRT4 plays a protective role in SAP by regulating the HIF-1α/HO-1 pathway to inhibit ferroptosis.
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Affiliation(s)
- Yanna Liu
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Huning Cui
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Chaopeng Mei
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Mengwei Cui
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Qianqian He
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Qiaofang Wang
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Dejian Li
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Yaodong Song
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Jiye Li
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China
| | - Sanyang Chen
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China.
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China.
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China.
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
| | - Changju Zhu
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, No 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China.
- Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China.
- Henan Emergency and Trauma Medicine Engineering Research Center, Zhengzhou, Henan, 450052, China.
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
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16
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Glaubitz J, Asgarbeik S, Lange R, Mazloum H, Elsheikh H, Weiss FU, Sendler M. Immune response mechanisms in acute and chronic pancreatitis: strategies for therapeutic intervention. Front Immunol 2023; 14:1279539. [PMID: 37881430 PMCID: PMC10595029 DOI: 10.3389/fimmu.2023.1279539] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 10/02/2023] [Indexed: 10/27/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common inflammatory diseases of the gastrointestinal tract and a steady rising diagnosis for inpatient hospitalization. About one in four patients, who experience an episode of AP, will develop chronic pancreatitis (CP) over time. While the initiating causes of pancreatitis can be complex, they consistently elicit an immune response that significantly determines the severity and course of the disease. Overall, AP is associated with a significant mortality rate of 1-5%, which is caused by either an excessive pro-inflammation, or a strong compensatory inhibition of bacterial defense mechanisms which lead to a severe necrotizing form of pancreatitis. At the time-point of hospitalization the already initiated immune response is the only promising common therapeutic target to treat or prevent a severe disease course. However, the complexity of the immune response requires fine-balanced therapeutic intervention which in addition is limited by the fact that a significant proportion of patients is in danger of development or progress to recurrent and chronic disease. Based on the recent literature we survey the disease-relevant immune mechanisms and evaluate appropriate and promising therapeutic targets for the treatment of acute and chronic pancreatitis.
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Affiliation(s)
| | | | | | | | | | | | - Matthias Sendler
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany
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17
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Wiley MB, Mehrotra K, Bauer J, Yazici C, Bialkowska AB, Jung B. Acute Pancreatitis: Current Clinical Approaches, Molecular Pathophysiology, and Potential Therapeutics. Pancreas 2023; 52:e335-e343. [PMID: 38127317 PMCID: PMC11913250 DOI: 10.1097/mpa.0000000000002259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 06/28/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE Severe acute pancreatitis (SAP), pancreatic inflammation leading to multiorgan failure, is associated with high morbidity and mortality. There is a critical need to identify novel therapeutic strategies to improve clinical outcomes for SAP patients. MATERIALS AND METHODS A comprehensive literature review was performed to identify current clinical strategies, known molecular pathophysiology, and potential therapeutic targets for SAP. RESULTS Current clinical approaches focus on determining which patients will likely develop SAP. However, therapeutic options are limited to supportive care and fluid resuscitation. The application of a novel 5-cytokine panel accurately predicting disease outcomes in SAP suggests that molecular approaches will improve impact of future clinical trials in AP. CONCLUSIONS Inflammatory outcomes in acute pancreatitis are driven by several unique molecular signals, which compound to promote both local and systemic inflammation. The identification of master cytokine regulators is critical to developing therapeutics, which reduce inflammation through several mechanisms.
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Affiliation(s)
- Mark B Wiley
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Kunaal Mehrotra
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Jessica Bauer
- From the Department of Medicine, University of Washington, Seattle, WA
| | - Cemal Yazici
- Department of Medicine, University of Illinois Chicago, Chicago, IL
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY
| | - Barbara Jung
- From the Department of Medicine, University of Washington, Seattle, WA
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18
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Sheng LP, Han CQ, Ling X, Guo XW, Lin R, Ding Z. Proanthocyanidins suppress NLRP3 inflammasome and M1 macrophage polarization to alleviate severe acute pancreatitis in mice. J Biochem Mol Toxicol 2023; 37:e23242. [PMID: 36229953 DOI: 10.1002/jbt.23242] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 07/28/2022] [Accepted: 09/22/2022] [Indexed: 11/07/2022]
Abstract
The role of reactive oxygen species (ROS) is crucial for the pathogenesis of acute pancreatitis (AP). Proanthocyanidins (PAs) have been confirmed to exert antioxidant activity. Our study aimed to determine whether PAs alleviated SAP via reducing ROS, suppressing NLRP3 inflammasome, and inhibiting M1 macrophage polarization. Our study investigated the protective effects of PAs on pancreatic histopathological injury using SAP mice. The effects of PAs on macrophages were investigated in inflammatory RAW 264.7 cells or mouse bone marrow-derived macrophages (BMDMs) induced by lipopolysaccharide (LPS). Immunofluorescence staining and/or western blot assay were employed to evaluate NLRP3 inflammasome in macrophages and pancreatic tissue. Cell counting kit-8 (CCK-8) was used to access effects of PAs on cell viability and cytometry flow was used to determine the effects of the PAs on the ROS levels of the RAW 264.7 cells. Then, we evaluated M1 macrophage polarization using flow cytometry or real-time quantitative polymerase chain reaction (RT-qPCR). PAs administration alleviated pancreatic inflammation in SAP mice. The PAs depressed NLRP3 inflammasome and inhibited M1 macrophage polarization in pancreatic tissue. We also found that the PAs showed no cellular toxicity but decreased ROS levels in RAW 264.7 cells, downregulated the NLRP3 inflammasome in the macrophages, and inhibited cell M1 macrophage polarization. Our study indicates the anti-inflammatory properties of the PAs on SAP mice by decreasing ROS levels, suppressing NLRP3 inflammasome, and M1 macrophage polarization.
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Affiliation(s)
- Li-Ping Sheng
- Department of Gastroenterology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.,Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao-Qun Han
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Ling
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xian-Wen Guo
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhen Ding
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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19
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Zhang D, Li L, Li J, Wei Y, Tang J, Man X, Liu F. Colchicine improves severe acute pancreatitis-induced acute lung injury by suppressing inflammation, apoptosis and oxidative stress in rats. Biomed Pharmacother 2022; 153:113461. [DOI: 10.1016/j.biopha.2022.113461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/17/2022] [Accepted: 07/21/2022] [Indexed: 11/27/2022] Open
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20
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Wang GY, Shang D, Zhang GX, Song HY, Jiang N, Liu HH, Chen HL. Qingyi decoction attenuates intestinal epithelial cell injury via the calcineurin/nuclear factor of activated T-cells pathway. World J Gastroenterol 2022; 28:3825-3837. [PMID: 36157544 PMCID: PMC9367229 DOI: 10.3748/wjg.v28.i29.3825] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 12/15/2021] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent studies have demonstrated that dysfunction of the intestinal barrier is a significant contributing factor to the development of severe acute pancreatitis (SAP). A stable intestinal mucosa barrier functions as a major anatomic and functional barrier, owing to the balance between intestinal epithelial cell (IEC) proliferation and apoptosis. There is some evidence that calcium overload may trigger IEC apoptosis and that calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling might play an important role in calcium-mediated apoptosis.
AIM To investigate the potential mechanisms underlying the therapeutic effect of Qingyi decoction (QYD) in SAP.
METHODS A rat model of SAP was created via retrograde infusion of sodium deoxycholate. Serum levels of amylase, tumor necrosis factor (TNF-α), interleukin (IL)-6, D-lactic acid, and diamine oxidase (DAO); histological changes; and apoptosis of IECs were examined in rats with or without QYD treatment. The expression of the two subunits of CaN and NFAT in intestinal tissue was measured via quantitative real-time polymerase chain reaction and western blotting. For in vitro studies, Caco-2 cells were treated with lipopolysaccharide (LPS) and QYD serum, and then cell viability and intracellular calcium levels were detected.
RESULTS Retrograde infusion of sodium deoxycholate increased the severity of pancreatic and intestinal pathology and the levels of serum amylase, TNF-α, and IL-6. Both the indicators of intestinal mucosa damage (D-lactic acid and DAO) and the levels of IEC apoptosis were elevated in the SAP group. QYD treatment reduced the serum levels of amylase, TNF-α, IL-6, D-lactic acid, and DAO and attenuated the histological findings. IEC apoptosis associated with SAP was ameliorated under QYD treatment. In addition, the protein expression levels of the two subunits of CaN were remarkably elevated in the SAP group, and the NFATc3 gene was significantly upregulated at both the transcript and protein levels in the SAP group compared with the control group. QYD significantly restrained CaN and NFATc3 gene expression in the intestine, which was upregulated in the SAP group. Furthermore, QYD serum significantly decreased the LPS-induced elevation in intracellular free Ca2+ levels and inhibited cell death.
CONCLUSION QYD can exert protective effects against intestinal mucosa damage caused by SAP and the protective effects are mediated, at least partially, by restraining IEC apoptosis via the CaN/NFATc3 pathway.
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Affiliation(s)
- Guan-Yu Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
- Institute of Integrative Medicine of Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Dong Shang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
- Institute of Integrative Medicine of Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Gui-Xin Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
- Institute of Integrative Medicine of Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Hui-Yi Song
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
| | - Nan Jiang
- Institute of Integrative Medicine of Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Huan-Huan Liu
- Institute of Integrative Medicine of Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Hai-Long Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
- Institute of Integrative Medicine of Dalian Medical University, Dalian 116044, Liaoning Province, China
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21
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Takeo M, Nishio A, Masuda M, Aoi K, Okazaki T, Fukui T, Uchida K, Naganuma M, Okazaki K. Repeated Stimulation of Toll-Like Receptor 2 and Dectin-1 Induces Chronic Pancreatitis in Mice Through the Participation of Acquired Immunity. Dig Dis Sci 2022; 67:3783-3796. [PMID: 34424458 DOI: 10.1007/s10620-021-07186-w] [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: 12/10/2020] [Accepted: 07/20/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Stimulation of Toll-like receptor 3 (TLR3) induces autoimmune-mediated pancreatitis in susceptible mice, whereas stimulation of TLR4 causes nonautoimmune-mediated pancreatitis. However, the effects of TLR2 stimulation on the pancreas are unknown. AIMS We investigated the role of TLR2 stimulation on pancreatic damage by repeatedly stimulating mice with TLR2 ligands. METHODS Wild-type (WT) and interleukin 10-deficient (IL-10-knockout (KO)) mice were administered zymosan and lipoteichoic acid (LTA) intraperitoneally at various doses twice weekly for 4 weeks. Syngeneic T-cell-deficient mice, B-cell-deficient mice, recombination activating gene 2-deficient (RAG2-KO) mice and RAG2-KO mice that had been reconstituted with CD4+ or CD8+ T cells isolated from WT mice were treated with zymosan similarly. Mice were killed, the severity of pancreatitis was graded histologically, and serum cytokine levels were measured. RESULTS Repeated administration of zymosan induced pancreatitis dose dependently in both WT and IL-10-KO mice. Administration of LTA induced pancreatitis only in IL-10-KO mice. Adoptive transfer of splenocytes obtained from IL-10-KO mice with pancreatitis did not cause pancreatitis in recipient RAG2-KO mice. Pancreatitis was scarcely observed in RAG2-KO mice and was attenuated in T-cell-deficient and B-cell-deficient mice compared with WT mice. A single administration of zymosan significantly increased the serum level of monocyte chemoattractant protein 1 (MCP-1) in WT mice. CONCLUSIONS Repeated stimulation of TLR2 and dectin-1 induced nonautoimmune-mediated pancreatitis in mice. Participation of acquired immunity seems to play an important role in the pathogenesis of pancreatitis in association with the increase in serum MCP-1 level.
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Affiliation(s)
- Masahiro Takeo
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Akiyoshi Nishio
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan.
| | - Masataka Masuda
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Kazunori Aoi
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan
| | - Takashi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan
| | - Toshiro Fukui
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kochi Medical School, 185-1 Kohasu Okocho, Nankoku, Kochi, Japan
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
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22
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Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue. Nat Biomed Eng 2022; 6:882-897. [PMID: 34931077 PMCID: PMC9207157 DOI: 10.1038/s41551-021-00815-9] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 07/07/2021] [Indexed: 02/05/2023]
Abstract
Targeting the delivery of therapeutics specifically to diseased tissue enhances their efficacy and decreases their side effects. Here we show that mesenchymal stromal cells with their nuclei removed by density-gradient centrifugation following the genetic modification of the cells for their display of chemoattractant receptors and endothelial-cell-binding molecules are effective vehicles for the targeted delivery of therapeutics. The enucleated cells neither proliferate nor permanently engraft in the host, yet retain the organelles for energy and protein production, undergo integrin-regulated adhesion to inflamed endothelial cells, and actively home to chemokine gradients established by diseased tissues. In mouse models of acute inflammation and of pancreatitis, systemically administered enucleated cells expressing two types of chemokine receptor and an endothelial adhesion molecule enhanced the delivery of an anti-inflammatory cytokine to diseased tissue (with respect to unmodified stromal cells and to exosomes derived from bone-marrow-derived stromal cells), attenuating inflammation and ameliorating disease pathology. Enucleated cells retain most of the cells' functionality, yet acquire the cargo-carrying characteristics of cell-free delivery systems, and hence represent a versatile delivery vehicle and therapeutic system.
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23
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Jiao J, Liu J, Li Q, Zhang G, Pan C, Luo F, Zhang Q, Qi B, Zhao L, Yin P, Shang D. Gut Microbiota-Derived Diaminopimelic Acid Promotes the NOD1/RIP2 Signaling Pathway and Plays a Key Role in the Progression of Severe Acute Pancreatitis. Front Cell Infect Microbiol 2022; 12:838340. [PMID: 35811665 PMCID: PMC9257083 DOI: 10.3389/fcimb.2022.838340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/02/2022] [Indexed: 11/18/2022] Open
Abstract
Impaired intestinal barrier function and gut microbiota dysbiosis are believed to be related to exacerbation of acute pancreatitis (AP). As a bacterial cell wall peptidoglycan component, diaminopimelic acid (DAP) is a specific ligand of NOD1 that regulates the NOD1/RIP2/NF-kB signaling pathway. Here, we investigated the role of DAP in the crosstalk between the gut microbiota and pancreas during the occurrence of AP. Upregulation of NOD1/RIP2/NF-kB and elevated serum DAP levels were found in severe AP (SAP) model rats. The accumulation of DAP in SAP patients corroborated its ability to serve as an indicator of disease severity. Subsequently, SAP rats were treated with oral administration of the traditional Chinese medicine Qingyi Keli (QYKL) as well as neomycin, which can widely eliminate DAP-containing bacteria. Both QYKL and neomycin intervention ameliorated intestinal and pancreatic damage and systemic inflammation in SAP rats. Through 16S rDNA sequencing, we found that QYKL could rehabilitate the gut microbiota structure and selectively inhibit the overgrowth of enteric bacteria, such as Helicobacter and Lactobacillus, in SAP rats without affecting some protective strains, including Romboutsia and Allobaculum. Interestingly, we demonstrated that the decrease in serum DAP was accompanied by suppression of the NOD1/RIP2/NF-kB signaling pathway in both the intestine and pancreas of the two intervention groups. Taken together, these results suggested that the gut microbiota-DAP-NOD1/RIP2 signaling pathway might play a critical role in the progression of AP and that SAP could be alleviated via intervention in the signaling pathway. Our work provides new potential early warning indicators of SAP and targets for intervention.
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Affiliation(s)
- Juying Jiao
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
- Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianjun Liu
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Qi Li
- Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Guixin Zhang
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Chen Pan
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Fei Luo
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Qingkai Zhang
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bing Qi
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Liang Zhao
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Peiyuan Yin
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
- *Correspondence: Dong Shang, ; Peiyuan Yin,
| | - Dong Shang
- Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
- Pancreaticobiliary Centre, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Dong Shang, ; Peiyuan Yin,
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24
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Xia W, Lu Z, Chen W, Zhou J, Zhao Y. Excess fatty acids induce pancreatic acinar cell pyroptosis through macrophage M1 polarization. BMC Gastroenterol 2022; 22:72. [PMID: 35183119 PMCID: PMC8858517 DOI: 10.1186/s12876-022-02146-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 02/01/2022] [Indexed: 12/24/2022] Open
Abstract
AbstractFree fatty acid derived from hyperlipidemia contributes to the development of inflammation in the pancreas. Here we explore the molecular mechanisms of fatty acid-induced pancreatitis through cellular experiments and the construction of a mouse model of hyperlipidemic pancreatitis. We found that palmitic acid stimulation leads to M1 polarization of macrophage, which secretes cathepsin S via exosomes to pancreatic acinar cells and leads to activation of the caspase1-mediated classical pyrolysis pathway, resulting in inflammation and pancreatic tissue damage. In vivo experiments have also demonstrated that the high levels of fatty acids induced by hyperlipidaemia exacerbate the development of pancreatitis, and that cathepsin S inhibitors significantly alleviate hyperlipidemic pancreatitis. Therefore, cathepsin S may be a new target for the clinical treatment of hyperlipidemic pancreatitis.
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25
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Mohamed MZ, Mohammed HH, Khalaf HM. Therapeutic effect of rupatadine against l-arginine-induced acute pancreatitis in rats: role of inflammation. Can J Physiol Pharmacol 2022; 100:176-183. [PMID: 35050802 DOI: 10.1139/cjpp-2021-0330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Acute pancreatitis (AP) is an abrupt inflammatory disorder causing high morbidity and mortality. As AP is an insidious medical emergency, a curative modality is required instead of a preventive measure. Thus, we investigated the possible curative effect of rupatadine on a rat model of AP. Rupatadine is a potent histamine receptor 1 (H1R) and platelet-activating factor (PAF) blocker. We used four groups of six Wistar rats as follows: the control group received vehicle; the rupatadine control group received rupatadine as 6 mg/kg orally; the AP group received l-arginine intraperitoneally, and the treatment group received rupatadine at 1, 6, and 24 h after l-arginine injection. The levels of serum amylase, pancreatic oxidative parameters, and pancreatic cytokines were measured. PAF, histamine, and myeloperoxidase levels were determined in the pancreas. Histopathological and immunohistochemical examinations were performed to determine nuclear factor kappa-B (NF-κB) and caspase 3 expressions. Oxidative damage and severe inflammation were detected in the pancreas of the AP group. Rupatadine reduced the oxidative damage and the levels of proinflammatory cytokines, PAF, histamine, myeloperoxidase, NF-κB, and caspase 3 expressions. It restored the pancreatic acini to almost normal condition. Rupatadine induced important anti-inflammatory and antiapoptotic effects against l-arginine-induced AP.
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Affiliation(s)
- Mervat Z Mohamed
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Hanaa H Mohammed
- Department of Histology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Hanaa M Khalaf
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
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26
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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: 4] [Impact Index Per Article: 1.3] [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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Li H, Yang W, Liu MW, Wan LJ, Wang YQ. Protective effects of Baicalin injection on severe acute pancreatitis through regulating follistatin-like-1 signaling pathway by down-regulating miR-429 expression in mice. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e19791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Hui Li
- Kunming Medical University, China
| | - Wei Yang
- Kunming Medical, University, China
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28
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Patel A, Zhang M, Liao G, Karkache W, Montroy J, Fergusson DA, Khadaroo RG, Tran DTT, McIsaac DI, Lalu MM. A Systematic Review and Meta-Analysis Examining the Impact of Age on Perioperative Inflammatory Biomarkers. Anesth Analg 2021; 134:751-764. [PMID: 34962902 DOI: 10.1213/ane.0000000000005832] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Dysregulation of immune responses to surgical stress in older patients and those with frailty may manifest as differences in inflammatory biomarkers. We conducted a systematic review and meta-analysis to examine differences in perioperative inflammatory biomarkers between older and younger patients, and between patients with and without frailty. METHODS MEDLINE, Embase, Cochrane, and CINAHL databases were searched (Inception to June 23, 2020). Observational or experimental studies reporting the perioperative level or activity of biomarkers in surgical patients stratified by age or frailty status were included. The primary outcome was inflammatory biomarkers (grouped by window of ascertainment: pre-op; post-op: <12 hours, 12-24 hours, 1-3 days, 3 days to 1 week, and >1 week). Quality assessment was conducted using the Newcastle-Ottawa Scale. Inverse-variance, random-effects meta-analysis was conducted. RESULTS Forty-five studies (4263 patients) were included in the review, of which 36 were pooled for meta-analysis (28 noncardiac and 8 cardiac studies). Two studies investigated frailty as the exposure, while the remaining investigated age. In noncardiac studies, older patients had higher preoperative levels of interleukin (IL)-6 and C-reactive protein (CRP), lower preoperative levels of lymphocytes, and higher postoperative levels of IL-6 (<12 hours) and CRP (12-24 hours) than younger patients. In cardiac studies, older patients had higher preoperative levels of IL-6 and CRP and higher postoperative levels of IL-6 (<12 hours and >1 week). CONCLUSIONS Our findings demonstrate a paucity of frailty-specific studies; however, the presence of age-associated differences in the perioperative inflammatory response is consistent with age-associated states of chronic systemic inflammation and immunosenescence. Additional studies assessing frailty-specific changes in the systemic biologic response to surgery may inform the development of targeted interventions.
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Affiliation(s)
- Abhilasha Patel
- From the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - MengQi Zhang
- From the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Gary Liao
- From the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Wassim Karkache
- From the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Dean A Fergusson
- From the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.,Clinical Epidemiology Program.,Blueprint Translational Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Rachel G Khadaroo
- Department of Surgery and Critical Care Medicine, University of Alberta, Walter C Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada
| | - Diem T T Tran
- Clinical Epidemiology Program.,Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Daniel I McIsaac
- Clinical Epidemiology Program.,Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Manoj M Lalu
- Clinical Epidemiology Program.,Blueprint Translational Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.,Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Zhu CJ, Yang WG, Li DJ, Song YD, Chen SY, Wang QF, Liu YN, Zhang Y, Cheng B, Wu ZW, Cui ZC. Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1 - induced inflammation. World J Gastroenterol 2021; 27:7669-7686. [PMID: 34908806 PMCID: PMC8641048 DOI: 10.3748/wjg.v27.i44.7669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/09/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined.
AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.
METHODS SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.
RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.
CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.
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Affiliation(s)
- Chang-Ju Zhu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Wan-Guang Yang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - De-Jian Li
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yao-Dong Song
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - San-Yang Chen
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qiao-Fang Wang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan-Na Liu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan Zhang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bo Cheng
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhong-Wei Wu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zong-Chao Cui
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Kong L, Zhang H, Lu C, Shi K, Huang H, Zheng Y, Wang Y, Wang D, Wang H, Huang W. AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation. Front Pharmacol 2021; 12:724514. [PMID: 34531748 PMCID: PMC8438129 DOI: 10.3389/fphar.2021.724514] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
Acute pancreatitis (AP) is a highly fatal acute inflammation and is often accompanied by multiple organ dysfunction syndrome (MODS). The liver, one of the most vulnerable extrapancreatic organs in AP, is the major organ involved in the evolution of the disease and correlates strongly with the occurrence of MODS. However, the etiology of pancreatitis-associated liver injury (PALI) has not been clarified and currently lacks an effective treatment. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is a cell permeable nucleoside with pleiotropic effects on anti-inflammatory and antioxidant stress that binds with adenosine monophosphate protein kinase (AMPK) and induces AMPK activation. However, the role of AICAR in PALI remains elusive. Here, we show that activation of AMPK by AICAR, a direct AMPK agonist, significantly ameliorates sodium taurocholate-induced PALI in rats, whereas treatment of PALI rats with the AMPK antagonist Compound C profoundly exacerbates the degree of liver injury, suggesting that hepatic AMPK activation exerts an essential protective role in PALI. Mechanistically, AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2(Nrf2) -regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyrolysis, protecting rats from sodium taurocholate-induced PALI. In addition, Nrf2 deficiency strikingly weakens the beneficial effects of AICAR on alleviation of liver injury, oxidative stress and NLRP3 inflammasome activation in L-arginine-induced PALI mice. Thus, AICAR protects against PALI in rodents by triggering AMPK, which is mediated at least in part by Nrf2-modulated antioxidant effects and NLRP3 inflammasome activation.
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Affiliation(s)
- Lijun Kong
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hewei Zhang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chaosheng Lu
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongjian Huang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yushu Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yongqiang Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dan Wang
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hongwei Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Huang
- Department of Nutrition, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Kandikattu HK, Venkateshaiah SU, Mishra A. Chronic Pancreatitis and the Development of Pancreatic Cancer. Endocr Metab Immune Disord Drug Targets 2021; 20:1182-1210. [PMID: 32324526 DOI: 10.2174/1871530320666200423095700] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/31/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023]
Abstract
Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-κB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.
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Affiliation(s)
- Hemanth K Kandikattu
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Sathisha U Venkateshaiah
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Anil Mishra
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA 70112, United States
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32
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Randhi R, Damon M, Dixon KJ. Selective inhibition of soluble TNF using XPro1595 relieves pain and attenuates cerulein-induced pathology in mice. BMC Gastroenterol 2021; 21:243. [PMID: 34049483 PMCID: PMC8161932 DOI: 10.1186/s12876-021-01827-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/19/2021] [Indexed: 11/12/2022] Open
Abstract
Background Symptoms associated with acute pancreatitis can be debilitating, and treatment remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of acute pancreatitis. Methods Acute pancreatitis was induced in adult male C57Bl/6J mice by administering cerulein (8 injections of 50 µg/kg I.P., spaced an hour apart), with XPro1595 (10 mg/kg, S.C.) or vehicle being administered approximately 18 h after the last injection. Serum was collected 6 or 18 h after the last cerulein injection, pancreatic tissue was collected 2 and 7 days post-induction, and brain hippocampal tissue was collected at 7 days post-induction. The animal’s pain level was assessed 3, 5 and 7 days post-induction. Results The induction of acute pancreatitis promoted a strong increase in serum amylase levels, which had receded back to baseline levels by the next morning. XPro1595 treatment began after amylase levels had subsided at 18 h, and prevented pancreatic immune cell infiltration, that subsequently prevented tissue disruption and acinar cell death. These improvements in pathology were associated with a significant reduction in mechanical hypersensitivity (neuropathic pain). XPro1595 treatment also prevented an increase in hippocampal astrocyte reactivity, that may be associated with the prevention of neuropathic pain in this mouse model. Conclusion Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of cerulein-induced pancreatitis in mice, which provides support of its use in patients with pancreatitis.
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Affiliation(s)
- Rajasa Randhi
- Department of Surgery, Virginia Commonwealth University, 1101 E. Marshall St, Richmond, VA, 23298, USA
| | - Melissa Damon
- Department of Surgery, Virginia Commonwealth University, 1101 E. Marshall St, Richmond, VA, 23298, USA
| | - Kirsty J Dixon
- Department of Surgery, Virginia Commonwealth University, 1101 E. Marshall St, Richmond, VA, 23298, USA.
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Knezevic M, Gojkovic S, Krezic I, Zizek H, Malekinusic D, Vrdoljak B, Vranes H, Knezevic T, Barisic I, Horvat Pavlov K, Drmic D, Staroveski M, Djuzel A, Rajkovic Z, Kolak T, Kocman I, Lovric E, Milavic M, Sikiric S, Tvrdeic A, Patrlj L, Strbe S, Kokot A, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Occlusion of the Superior Mesenteric Artery in Rats Reversed by Collateral Pathways Activation: Gastric Pentadecapeptide BPC 157 Therapy Counteracts Multiple Organ Dysfunction Syndrome; Intracranial, Portal, and Caval Hypertension; and Aortal Hypotension. Biomedicines 2021; 9:biomedicines9060609. [PMID: 34073625 PMCID: PMC8229949 DOI: 10.3390/biomedicines9060609] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric pentadecapeptide BPC 157 therapy counteracts multiple organ dysfunction syndrome in rats, which have permanent occlusion of the superior mesenteric artery close to the abdominal aorta. Previously, when confronted with major vessel occlusion, its effect would rapidly activate collateral vessel pathways and resolve major venous occlusion syndromes (Pringle maneuver ischemia, reperfusion, Budd-Chiari syndrome) in rats. This would overwhelm superior mesenteric artery permanent occlusion, and result in local, peripheral, and central disturbances. Methods: Assessments, for 30 min (gross recording, angiography, ECG, pressure, microscopy, biochemistry, and oxidative stress), included the portal hypertension, caval hypertension, and aortal hypotension, and centrally, the superior sagittal sinus hypertension; systemic arterial and venous thrombosis; ECG disturbances; MDA-tissue increase; and multiple organ lesions and disturbances, including the heart, lung, liver, kidney, and gastrointestinal tract, in particular, as well as brain (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus). BPC 157 therapy (/kg, abdominal bath) (10 µg, 10 ng) was given for a 1-min ligation time. Results: BPC 157 rapidly recruits collateral vessels (inferior anterior pancreaticoduodenal artery and inferior mesenteric artery) that circumvent occlusion and ascertains blood flow distant from the occlusion in the superior mesenteric artery. Portal and caval hypertension, aortal hypotension, and, centrally, superior sagittal sinus hypertension were attenuated or eliminated, and ECG disturbances markedly mitigated. BPC 157 therapy almost annihilated venous and arterial thrombosis. Multiple organ lesions and disturbances (i.e., heart, lung, liver, and gastrointestinal tract, in particular, as well as brain) were largely attenuated. Conclusions: Rats with superior mesenteric artery occlusion may additionally undergo BPC 157 therapy as full counteraction of vascular occlusion-induced multiple organ dysfunction syndrome.
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Affiliation(s)
- Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Dominik Malekinusic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Borna Vrdoljak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Tamara Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Miro Staroveski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Antonija Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Zoran Rajkovic
- Department of Surgery, Faculty of Dental Medicine and Health, University of Osijek, 31000 Osijek, Croatia;
| | - Toni Kolak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivica Kocman
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Ante Tvrdeic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Leonardo Patrlj
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
- Correspondence: ; Tel.: +385-1-4566-833; Fax: +385-1-492-0050
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Wei TF, Zhao L, Huang P, Hu FL, Jiao JY, Xiang KL, Wang ZZ, Qu JL, Shang D. Qing-Yi Decoction in the Treatment of Acute Pancreatitis: An Integrated Approach Based on Chemical Profile, Network Pharmacology, Molecular Docking and Experimental Evaluation. Front Pharmacol 2021; 12:590994. [PMID: 33995005 PMCID: PMC8117095 DOI: 10.3389/fphar.2021.590994] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Qing-Yi Decoction (QYD) is a classic precompounded prescription with satisfactory clinical efficacy on acute pancreatitis (AP). However, the chemical profile and overall molecular mechanism of QYD in treating AP have not been clarified. Methods: In the present study, a rapid, simple, sensitive and reliable ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS)-based chemical profile was first established. An integration strategy of network pharmacology analysis and molecular docking based identified ingredients was further performed to screen out the potential targets and pathways involved in the treatment of QYD on AP. Finally, SD rats with acute pancreatitis were constructed to verify the predicted results through a western blot experiment. Results: A total of 110 compounds, including flavonoids, phenolic acids, alkaloids, monoterpenes, iridoids, triterpenes, phenylethanoid glycosides, anthraquinones and other miscellaneous compounds were identified, respectively. Eleven important components, 47 key targets and 15 related pathways based on network pharmacology analysis were obtained. Molecular docking simulation indicated that ERK1/2, c-Fos and p65 might play an essential role in QYD against AP. Finally, the western blot experiments showed that QYD could up-regulate the expression level of ERK1/2 and c-Fos, while down-regulate the expression level of p65. Conclusion: This study predicted and validated that QYD may treat AP by inhibiting inflammation and promoting apoptosis, which provides directions for further experimental studies.
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Affiliation(s)
- Tian-Fu Wei
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Liang Zhao
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Peng Huang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Feng-Lin Hu
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Ju-Ying Jiao
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Kai-Lai Xiang
- Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhi-Zhou Wang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Jia-Lin Qu
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China.,Department of General Surgery, Pancreatic-Biliary Center, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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Xu Q, Wang M, Guo H, Liu H, Zhang G, Xu C, Chen H. Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1 β/CXCL1 Signaling. Front Pharmacol 2021; 12:655372. [PMID: 33967799 PMCID: PMC8103163 DOI: 10.3389/fphar.2021.655372] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Objective: Severe acute pancreatitis (SAP) can lead to acute lung injury (ALI). This study investigated the therapeutic effect of emodin and its molecular mechanisms in a rat model of SAP-ALI. Methods: Forty male Sprague-Dawley rats were randomly divided into the groups: Control (CON), SAP (SAP), emodin (EMO), and C23 (C23). The latter three groups of rats were induced for SAP-ALI by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and were treated with vehicle, emodin or C23, respectively. One day post induction, their pancreatic and lung injury was assessed by histology and arterial blood gas analysis. In vitro, rat alveolar macrophages (NR8383 cells) were treated with recombinant rat CIRP in the presence or absence of TAK242 (a TLR4 inhibitor), C23 or emodin. The CIRP-mediated activation of the NLRP3/IL-1β/CXCL1 signaling in rat lungs and NR8383 cells was determined. Similarly, the role of IL-1β in the CIRP-induced CXCL1 expression was investigated. Results: Emodin treatment significantly reduced inflammation and tissue damages in the pancreatic and lung tissues in rats with SAP-ALI, accompanied by decreasing serum amylase, CIRP and IL-1β levels and improving lung function. Furthermore, emodin significantly mitigated the SAP-up-regulated CIRP expression in the pancreatic islets and lung tissues, and attenuated the SAP-activated NF-κB signaling, NLRP3 inflammasome formation and CXCL1 expression in lung resident macrophages as well as neutrophil infiltration in the lungs of rats. In addition, treatment with CIRP significantly activated the NF-κB signaling and NLRP3 inflammasome formation and induced IL-1β and CXCL1 expression and pyroptosis in NR8383 cells, which were abrogated by TAK242 and significantly mitigated by C23 or emodin. Moreover, CIRP only induced very lower levels of CXCL1 expression in IL-1β-silencing NR8383 cells and treatment with IL-1β induced CXCL1 expression in NR8383 cells in a dose and time-dependent manner. Conclusion: Emodin may inhibit the CIRP-activated NLRP3/IL-1β/CXCL1signaling to decrease neutrophil infiltration and ameliorate the SAP-ALI in rats.
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Affiliation(s)
- Qiushi Xu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Mengfei Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Haoya Guo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Huanhuan Liu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Guixin Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Caiming Xu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.,Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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Tan Y, Zhang W, Wu HY, Xia J, Zhang HB, Liu MW, Qian CY. Effects of emodin on intestinal mucosal barrier by the upregulation of miR-218a-5p expression in rats with acute necrotizing pancreatitis. Int J Immunopathol Pharmacol 2021; 34:2058738420941765. [PMID: 32664763 PMCID: PMC7364802 DOI: 10.1177/2058738420941765] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Emodin is an effective component in rhubarb to cure intestinal dysfunction, but the specific mechanism remains unknown. This study aimed to evaluate the protective effects of emodin on intestinal dysfunction caused by acute severe pancreatitis and reveal the functional mechanism of emodin in the treatment of this condition. An acute severe pancreatitis model was prepared using taurocholate. In the treatment group, 50 mg/kg emodin was injected intravenously 2 h before the induction of acute severe pancreatitis at an interval of 8 h. After 24 h, the gene expression and protein levels of miR-218a-5p, RhoA, ROCK1, Akt, Notch1, Bax, Bcl-2, Fas, FasL, caspase-3, and caspase-9 were determined through reverse transcription polymerase chain reaction and Western blot analysis. The protein levels of occludin, zonula occludens-1 (ZO-1), and E-cadherin in the intestinal tract were also determined through Western blot analysis. The effects of miR-218a-5p on the apoptosis of rat intestinal epithelial cell-18 were observed through flow cytometry. The effects of emodin on intestinal cell apoptosis induced by acute severe pancreatitis were observed via TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling). Pathological changes in the pancreas and intestine of rats in each group were observed through hematoxylin and eosin staining. After 24 h of acute severe pancreatitis induced by taurocholate, emodin reduced the expression of miR-218a-5p in the intestinal tract; increased the expression of Notch1 and Bcl-2; decreased the expression levels of RhoA, ROCK1, Akt, Bax, Fas, FasL, caspase-3, and caspase-9; inhibited the intestinal cell apoptosis caused by acute severe pancreatitis; increased the protein expression levels of occludin, zonula occludens-1 (ZO-1), and E-cadherin in the intestinal tract; and alleviated intestinal dysfunction caused by acute severe pancreatitis. Emodin could regulate Notch1 and RhoA/ROCK pathways by regulating the miR-218a-5p expression in the intestine. It could also inhibit intestinal cell apoptosis induced by acute severe pancreatitis and improve the intestinal dysfunction caused by severe acute pancreatitis.
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Affiliation(s)
- Yang Tan
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wei Zhang
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hai-Ying Wu
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Jing Xia
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Huang-Bo Zhang
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ming-Wei Liu
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chuan-Yun Qian
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, China
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Bu HF, Subramanian S, Geng H, Wang X, Liu F, Chou PM, Du C, De Plaen IG, Tan XD. MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice. Cells 2021; 10:728. [PMID: 33806041 PMCID: PMC8064467 DOI: 10.3390/cells10040728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/18/2021] [Accepted: 03/22/2021] [Indexed: 11/23/2022] Open
Abstract
Milk fat globule-EGF factor 8 (MFG-E8) is a secreted glycoprotein that regulates tissue homeostasis, possesses potent anti-inflammatory properties, and protects against tissue injury. The human pancreas expresses MFG-E8; however, the role of MFG-E8 in the pancreas remains unclear. We examined the expression of MFG-E8 in the pancreas at baseline and during cerulein-induced acute pancreatitis in mice and determined whether MFG-E8 attenuates the progression of pancreatitis, a serious inflammatory condition that can be life-threatening. We administered cerulein to wild-type (WT) and Mfge8 knockout (KO) mice to induce pancreatitis. Immunoblot analysis showed that MFG-E8 is constitutively expressed in the murine pancreas and is increased in mice with cerulein-induced acute pancreatitis. In situ hybridization revealed that ductal epithelial cells in the mouse pancreas express Mfge8 transcripts at baseline. During pancreatitis, Mfge8 transcripts were abundantly expressed in acinar cells and endothelial cells in addition to ductal epithelial cells. Knocking out Mfge8 in mice exacerbated the severity of cerulein-induced acute pancreatitis and delayed its resolution. In contrast, administration of recombinant MFG-E8 attenuated cerulein-induced acute pancreatitis and promoted repair of pancreatic injury in Mfge8 KO mice. Taken together, our study suggests that MFG-E8 protects the pancreas against inflammatory injury and promotes pancreatic tissue repair. MFG-E8 may represent a novel therapeutic target in acute pancreatitis.
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Affiliation(s)
- Heng-Fu Bu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (H.-F.B.); (S.S.); (H.G.); (X.W.); (F.L.); (C.D.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Saravanan Subramanian
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (H.-F.B.); (S.S.); (H.G.); (X.W.); (F.L.); (C.D.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Hua Geng
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (H.-F.B.); (S.S.); (H.G.); (X.W.); (F.L.); (C.D.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Xiao Wang
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (H.-F.B.); (S.S.); (H.G.); (X.W.); (F.L.); (C.D.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Fangyi Liu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (H.-F.B.); (S.S.); (H.G.); (X.W.); (F.L.); (C.D.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Pauline M. Chou
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Chao Du
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (H.-F.B.); (S.S.); (H.G.); (X.W.); (F.L.); (C.D.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Isabelle G. De Plaen
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
- Division of Neonatology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA
| | - Xiao-Di Tan
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611, USA; (H.-F.B.); (S.S.); (H.G.); (X.W.); (F.L.); (C.D.)
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
- Department of Research & Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA
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Elshemy MM, Asem M, Allemailem KS, Uto K, Ebara M, Nabil A. Antioxidative Capacity of Liver- and Adipose-Derived Mesenchymal Stem Cell-Conditioned Media and Their Applicability in Treatment of Type 2 Diabetic Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8833467. [PMID: 33623636 PMCID: PMC7875634 DOI: 10.1155/2021/8833467] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/08/2021] [Accepted: 01/21/2021] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is mainly characterized by insulin resistance and impaired insulin secretion, which cannot be reversed with existing therapeutic strategies. Using mesenchymal stem cells (MSCs), cell-based therapy has been demonstrated in displaying therapeutic effects in T2DM for their self-renewable, differentiation potential, and immunosuppressive properties and higher levels of angiogenic factors. Stem cell therapies are complicated and have a serious adverse effect including tumor formation and immunogenicity, while using mesenchymal stem cell-conditioned media (MSC-CM) significantly reduces stem cell risk, maintaining efficacy and showing significantly higher levels of growth factors, cytokines, and angiogenic factors that stimulate angiogenesis and promote fracture healing in diabetes. In the present study, we investigated the therapeutic potential of the liver and adipose MSC-CM in diabetic endothelial dysfunction compared with standard insulin therapy. Fifty adult male Sprague Dawley rats were divided equally into 5 groups as follows: control, diabetic, diabetic+insulin, diabetic+liver MSC-CM, and diabetic+adipose MSC-CM; all treatments continued for 4 weeks. Finally, we observed that liver MSC-CM therapy had the most apparent improvement in levels of blood glucose; HbA1c; AGEs; lipid panel (cholesterol, TG, LDL, HDL, and total lipids); renal function (urea, uric acid, creatinine, and total protein); liver function (AST, ALT, ALP, bilirubin, and albumin); CPK; C-peptide; HO-1; inflammatory markers including IL-6, TNF-α, and CRP; growth factors (liver and serum IGF-1); amylase; histopathological changes; pancreatic cell oxidative stress; and antioxidant markers (MDA, GSH, ROS, CAT, SOD, HO-1, and XO) toward the normal levels compared with insulin and adipose MSCs-CM. Moreover, both the liver and adipose MSC-CM relieved the hyperglycemic status by improving pancreatic islet β cell regeneration, promoting the conversion of alpha cells to beta cells, reducing insulin resistance, and protecting pancreatic tissues against oxidative stress-induced injury as well as possessing the ability to modulate immunity and angiogenesis. These results indicated that MSC-CM infusion has therapeutic effects in T2DM rats and may be a promising novel therapeutic target.
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Affiliation(s)
| | - Medhat Asem
- Faculty of Science, Menoufia University, Menoufia, Egypt
| | - Khaled S. Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Koichiro Uto
- Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
| | - Mitsuhiro Ebara
- Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
- Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
- Graduate School of Industrial Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo 125-8585, Japan
| | - Ahmed Nabil
- Research Center for Functional Materials, National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, Egypt
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Ferrero-Andrés A, Panisello-Roselló A, Roselló-Catafau J, Folch-Puy E. Polyethylene glycol 35 ameliorates pancreatic inflammatory response in cerulein-induced acute pancreatitis in rats. World J Gastroenterol 2020; 26:5970-5982. [PMID: 33132648 PMCID: PMC7584060 DOI: 10.3748/wjg.v26.i39.5970] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/12/2020] [Accepted: 09/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is a sudden inflammatory process of the pancreas that may also involve surrounding tissues and/or remote organs. Inflammation and parenchymal cell death are common pathological features of this condition and determinants of disease severity. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic water-soluble polymers widely used in biological, chemical, clinical and pharmaceutical settings.
AIM To evaluate the protective effect of a 35-kDa molecular weight PEG (PEG35) on the pancreatic damage associated to cerulein-induced acute pancreatitis in vivo and in vitro.
METHODS Wistar rats were assigned at random to a control group, a cerulein–induced AP group and a PEG35 treatment group. AP was induced by five hourly intraperitoneal injections of cerulein (50 μg/kg/bw), while the control animals received saline solution. PEG35 was administered intraperitoneally 10 minutes before each cerulein injection in a dose of 10 mg/kg. After AP induction, samples of pancreatic tissue and blood were collected for analysis. AR42J pancreatic acinar cells were treated with increasing concentrations of PEG35 prior to exposure with tumor necrosis factor α (TNFα), staurosporine or cerulein. The severity of AP was determined on the basis of plasma levels of lipase, lactate dehydrogenase activity, pancreatic edema and histological changes. To evaluate the extent of the inflammatory response, the gene expression of inflammation-associated markers was determined in the pancreas and in AR42J-treated cells. Inflammation-induced cell death was also measured in models of in vivo and in vitro pancreatic damage.
RESULTS Administration of PEG35 significantly improved pancreatic damage through reduction on lipase levels and tissue edema in cerulein-induced AP rats. The increased associated inflammatory response caused by cerulein administration was attenuated by a decrease in the gene expression of inflammation-related cytokines and inducible nitric oxide synthase enzyme in the pancreas. In contrast, pancreatic tissue mRNA expression of interleukin 10 was markedly increased. PEG35 treatment also protected against inflammation-induced cell death by attenuating lactate dehydrogenase activity and modulating the pancreatic levels of apoptosis regulator protein BCL-2 in cerulein hyperstimulated rats. Furthermore, the activation of pro-inflammatory markers and inflammation-induced cell death in pancreatic acinar cells treated with TNFα, cerulein or staurosporine was significantly reduced by PEG35 treatment, in a dose-dependent manner.
CONCLUSION PEG35 ameliorates pancreatic damage in cerulein-induced AP and AR42J-treated cells through the attenuation of the inflammatory response and associated cell death. PEG35 may be a valuable option in the management of AP.
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Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Barcelona 08036, Catalonia, Spain
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Barcelona 08036, Catalonia, Spain
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Catalonia, Spain
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Catalonia, Spain
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Zhang FH, Liu Y, Dong XB, Hao H, Fan KL, Meng XQ, Kong L. Shenmai Injection Upregulates Heme Oxygenase-1 to Confer Protection Against Severe Acute Pancreatitis. J Surg Res 2020; 256:295-302. [PMID: 32712444 DOI: 10.1016/j.jss.2020.06.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 06/01/2020] [Accepted: 06/16/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND To explore the mechanism of Shenmai injection (SMI) on severe acute pancreatitis (SAP) through heme oxygenase-1 (HO-1) signaling. METHODS A total of 40 male Sprague-Dawley (SD) rats (220-260 g) were grouped into the following four categories (n = 10): SAP + SMI + Zinc protoporphyrin (ZnPP), SAP + SMI, SAP, and sham surgery groups. ZnPP is a specific inhibitor of HO-1. Four percent of sodium taurocholate (1 mL/kg) was retrogradely injected via the pancreatic duct to induce the SAP model. The SAP group rats received 1.6 mL/kg saline by intravenous injection 30 min after the induction of SAP. The SAP + SMI group rats received 1.6 mL/kg SMI by intravenous injection 30 min after the induction of SAP. The SAP + SMI + ZnPP group rats received an intravenous injection of 1.6 mL/kg SMI and intraperitoneal administration of 30 mg/kg ZnPP 30 min after the SAP induction. Twenty-four hours after the SAP induction, blood samples were collected for the measurement of amylase, lipase, creatinine, myeloperoxidase, interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and HO-1 level, while tissue specimens were harvested for the determination of HO-1, TNF-α, and IL-10 mRNA level. Meanwhile, histopathological changes in organs (pancreas, lung, and kidney) were stored. RESULTS The serum concentration of amylase, lipase, creatinine, and myeloperoxidase was higher in the SAP group than in the SAP + SMI group. Treatment with SMI increased HO-1 and IL-10 level and reduced TNF-α level in serum and tissues compared to the SAP group (P < 0.05). Treatment with SMI abolished the organ-damaging effects of SAP (P < 0.05). Furthermore, suppression of HO-1 expression by ZnPP canceled the aforementioned effects. CONCLUSIONS SMI confers protection against the SAP-induced systemic inflammatory response and multiple organs damage via HO-1 upregulation.
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Affiliation(s)
- Fei-Hu Zhang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China; Department of Emergency Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Yang Liu
- Department of Emergency Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao-Bin Dong
- Department of Emergency Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hao Hao
- Department of Emergency Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Kai-Liang Fan
- Department of Emergency Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xian-Qing Meng
- Department of Emergency Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Li Kong
- Department of Emergency Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Zhang PY, Yu B, Men WJ, Bai RY, Chen MY, Wang ZX, Zeng T, Zhou K. Acetyl-α-boswellic acid and Acetyl-β-boswellic acid protects against caerulein-induced pancreatitis via down-regulating MAPKs in mice. Int Immunopharmacol 2020; 86:106682. [PMID: 32563781 DOI: 10.1016/j.intimp.2020.106682] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 05/31/2020] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
This study is to investigate the protective effect of Acetyl-α-boswellic acid and Acetyl-β-boswellic mixture(α/β-ABA), which is the active ingredients isolated from Frankincense, on actue pancreatitis and its mechanism. Our experimental results showed that 2 μM α/β-ABA reduced production of NO, TNF-α, IL-6, IL-10 and IL-1β in RAW264.7 cells that were stimulated with lipopolysaccharide (LPS) which indicates its anti-inflammatory role. In pancreatitis model induced by caerulein, intra-gastrical administration of 100 mg/kg α/β-ABA relieved inflammatory cells infiltration significantly and attenuated the serum elevation of amylase TNF-α and IL-6 remarkably in mice. Furthermore, α/β-ABA down-regulated mitogen-activated protein kinase (MAPK) family phosphorylated proteins in pancreas, including phosphorylated p38, ERK1/2 and JNK, to reduce the serum inflammatory factors. Finally, α/β-ABA alleviated the pancreatic edema and inflammatory cell infiltration in pancreatitis mice model. This study suggests that α/β-ABA may be targeted for drug development against pancreatitis via modulating MAPKs pathway.
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Affiliation(s)
- Pan-Yang Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Bin Yu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Wei-Jie Men
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ru-Yu Bai
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Meng-Ying Chen
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Zhao-Xin Wang
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Tao Zeng
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Kun Zhou
- Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin 301617, China.
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Abdel-Aziz AM, Rifaai RA, Abdel-Gaber SA. Possible mechanisms mediating the protective effect of cilostazol in L-arginine induced acute pancreatitis in rats: role of cGMP, cAMP, and HO-1. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1859-1870. [PMID: 32424476 DOI: 10.1007/s00210-020-01897-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 05/06/2020] [Indexed: 12/22/2022]
Abstract
Acute pancreatitis (AP) is an inflammatory disorder with a high mortality rate. Cilostazol is a selective phosphodiesterase-3 inhibitor drug that is commonly used as an antiplatelet, antithrombotic, and vasodilator drug. It exhibits antioxidant, anti-inflammatory, and anti-apoptotic activities, but its effect on AP has not been fully elucidated yet. The present study aimed to investigate the effects of cilostazol on L-arginine-induced AP and the possible protective mechanisms. A rat model of AP was established by a single i.p. injection of 3-g/kg L-arginine on day 13 of the experiment. The treated groups received a single daily oral dose of either 100 or 300 mg/kg/day for 14 consecutive days. Rats with AP showed histopathological changes of pancreatic tissue injury together with increased serum amylase enzyme activity and decreased serum insulin, pancreatic adiponectin, and cGMP levels. Moreover, AP rats showed increased pancreatic inflammatory biomarker (TNF-α, VCAM-1, and MPO) levels with decreased anti-inflammatory IL-10 levels. In addition, oxidative stress biomarkers (MDA and NO) were increased in AP with decreased antioxidant SOD activity and GSH level. Moreover, HO-1 immunostaining was increased in the AP group. Cilostazol pretreatment reversed the histopathological change; decreased the amylase activity and the levels of TNF-α, VCAM-1, and MPO; and increased the levels of insulin, adiponectin, cGMP, cAMP, and IL-10. Moreover, cilostazol decreased MDA and NO but increased SOD and GSH. Lastly, cilostazol increased the HO-1 immunostaining more than in the AP group. These data suggest that cilostazol protects against L-arginine-induced AP, which may be related to an increase in cGMP, cAMP, and upregulation of HO-1 with subsequent anti-inflammatory and antioxidant properties.
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Affiliation(s)
| | - Rehab Ahmed Rifaai
- Departments of Histology and cell biology, Faculty of Medicine, Minia University, Minia, 61511, Egypt
| | - Seham A Abdel-Gaber
- Departments of Pharmacology, Faculty of Medicine, Minia University, Minia, 61511, Egypt.
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Steen EH, Wang X, Balaji S, Butte MJ, Bollyky PL, Keswani SG. The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis. Adv Wound Care (New Rochelle) 2020; 9:184-198. [PMID: 32117582 PMCID: PMC7047112 DOI: 10.1089/wound.2019.1032] [Citation(s) in RCA: 241] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 06/18/2019] [Indexed: 02/06/2023] Open
Abstract
Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cell-based therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis.
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Affiliation(s)
- Emily H. Steen
- Department of Surgery, Baylor College of Medicine, Houston, Texas
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
| | - Xinyi Wang
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
| | - Swathi Balaji
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
| | - Manish J. Butte
- Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, California
| | - Paul L. Bollyky
- Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Sundeep G. Keswani
- Department of Surgery, Baylor College of Medicine, Houston, Texas
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
- Division of Pediatric Surgery, Department of Surgery, Texas Children's Hospital, Houston, Texas
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Shah J, Rana SS. Acute respiratory distress syndrome in acute pancreatitis. Indian J Gastroenterol 2020; 39:123-132. [PMID: 32285399 DOI: 10.1007/s12664-020-01016-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 01/14/2020] [Indexed: 02/07/2023]
Abstract
Development of organ failure is one of the major determinants of mortality in patients with acute pancreatitis (AP). Acute respiratory distress syndrome (ARDS) is an important cause of respiratory failure in AP and is associated with high mortality. Pathogenesis of ARDS in AP is incompletely understood. Release of various cytokines plays an important role in development of ARDS in AP. Increased gut permeability due to various toxins, inflammatory mediators, and pancreatic enzymes potentiates lung injury by gut-lymph-lung axis leading on to increased translocation of bacterial endotoxins. Various scoring systems, serum levels of various cytokines and lung ultrasound have been evaluated for prediction of development of ARDS in AP with varying results. Various drugs have shown encouraging results in prevention of ARDS in animal models but these encouraging results in animal models are yet to be confirmed in clinical studies. There is no specific effective treatment for ARDS. Treatment of sepsis and local complications of AP should be done according to the standard management strategies. Lung protective ventilatory strategies are of paramount importance to improve outcome of patients of AP with ARDS and therefore effective coordination between gastroenterologists and intensivists is needed for effective management of these patients.
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Affiliation(s)
- Jimil Shah
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, 160 012, India
| | - Surinder S Rana
- Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, 160 012, India.
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Yan Z, Zang B, Gong X, Ren J, Wang R. MiR-214-3p exacerbates kidney damages and inflammation induced by hyperlipidemic pancreatitis complicated with acute renal injury. Life Sci 2020; 241:117118. [PMID: 31790686 DOI: 10.1016/j.lfs.2019.117118] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/15/2019] [Accepted: 11/27/2019] [Indexed: 12/11/2022]
Abstract
AIMS Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. MAIN METHODS Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. KEY FINDINGS MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. SIGNIFICANCE MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.
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Affiliation(s)
- Zhaopeng Yan
- Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Bin Zang
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Xiaoying Gong
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Jiangyue Ren
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Rui Wang
- Department of Critical Care Medicine, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China.
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Park JS, Jeong S, Kim JM, Lee BH, Kim JM, Lee DH. Development of an acute pancreatitis porcine model based on endoscopic retrograde infusion of contrast medium or sodium taurocholate. Korean J Intern Med 2019; 34:1244-1251. [PMID: 30428647 PMCID: PMC6823576 DOI: 10.3904/kjim.2017.367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 05/22/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND/AIMS A reproducible, endoscope-based, large animal model, of acute pancreatitis was developed to meet the need for a suitable means of preclinically testing treatments. The aim of this study was to develop an endoscope-based animal model of acute pancreatitis. METHODS This experimental study was conducted on six mini-pigs. The pancreatitis model was induced by infusing contrast medium (CM) or sodium taurocholate (TCA) under high pressure (100 mmHg) into the main pancreatic duct by endoscopic retrograde pancreatography. Animals were randomly allocated to three groups: a CM group, a 10% TCA group, and a 20% TCA group. Pancreatic injuries were evaluated histologically, and serum amylase and lipase levels were measured. RESULTS Acute pancreatitis was observed in all animals during hematologic and histologic examinations. Serum amylase and lipase levels were significantly higher (> 10 times baseline), and pancreatic edema, vacuolization of acinar cells, and hemorrhagic necrosis were observed. Severity of pancreatitis tended to be greater in the TCA groups than in the CM group as assessed using histologic scores, and degrees of pancreatitis were found to be dose-dependently related to TCA concentration. CONCLUSION The two endoscopic procedures described are effective and safe for creating a swine model of acute pancreatitis. The authors hope the described endoscopic methods will assist in the development of a suitable treatment strategy.
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Affiliation(s)
- Jin-Seok Park
- Digestive Disease Center, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Seok Jeong
- Digestive Disease Center, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
- The National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorders (NCEED), Incheon, Korea
- Correspondence to Seok Jeong, M.D. Department of Internal Medicine, Inha University Hospital, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea Tel: +82-32-890-2548 Fax: +82-32-890-2549 E-mail:
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Bum Hei Lee
- The National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorders (NCEED), Incheon, Korea
| | - Jae Min Kim
- The National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorders (NCEED), Incheon, Korea
| | - Don Haeng Lee
- Digestive Disease Center, Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
- The National Center of Efficacy Evaluation for the Development of Health Products Targeting Digestive Disorders (NCEED), Incheon, Korea
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Dong K, Chen X, Xie L, Yu L, Shen M, Wang Y, Wu S, Wang J, Lu J, Wei G, Xu D, Yang L. Spautin-A41 Attenuates Cerulein-Induced Acute Pancreatitis through Inhibition of Dysregulated Autophagy. Biol Pharm Bull 2019; 42:1789-1798. [DOI: 10.1248/bpb.b19-00132] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Kai Dong
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Xia Chen
- Department of Endocrinology and Metabolism, Shanghai Fourth People’s Hospital, Tongji University
| | - Liping Xie
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Lanting Yu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Mengjun Shen
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yanping Wang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Shanshan Wu
- Shandong University Affiliated Shandong Provincial Hospital Affiliated, Department of Endocrinology and Metabolism
| | - Jiajia Wang
- Department of Endocrinology, Medical College of Soochow University
| | - Junxi Lu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Gang Wei
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Dongliang Xu
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
- Department of Urology, Changzheng Hospital, Second Military Medical University
| | - Liu Yang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
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Sun Z, Li L, Qu J, Li H, Chen H. Proteomic analysis of therapeutic effects of Qingyi pellet on rodent severe acute pancreatitis-associated lung injury. Biomed Pharmacother 2019; 118:109300. [DOI: 10.1016/j.biopha.2019.109300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/25/2019] [Accepted: 07/31/2019] [Indexed: 12/13/2022] Open
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Munir F, Jamshed MB, Shahid N, Muhammad SA, Bhandari A, Zhang Q. Protective effects of maresin 1 against inflammation in experimentally induced acute pancreatitis and related lung injury. Am J Physiol Gastrointest Liver Physiol 2019; 317:G333-G341. [PMID: 31125268 DOI: 10.1152/ajpgi.00078.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Severe acute pancreatitis (SAP) is an inflammatory disorder that progresses with local and systemic difficulties accompanied by a relatively high mortality rate. In recent years, maresin 1 (MaR1) has been shown to be a macrophage mediator with effective proresolving and anti-inflammatory properties that prevents the occurrence of various inflammatory conditions. The purpose of this study was to investigate the role of MaR1 in SAP and related lung injury. Experimental SAP was induced in mice with a combination of cerulean and lipopolysaccharide. MaR1 was administered 30 min before the primary injection of cerulean. Biochemical markers and histological injury scores were used to evaluate the severity of acute pancreatitis. To determine the degree of inflammation, serum cytokines and myeloperoxidase activity in pancreas and lung tissues were measured. Western blot analysis detected the activation of NF-κB. After MaR1 pretreatment, the activities of amylase, lipase, TNF-α, IL-1β, and IL-6 were decreased in serum, and the myeloperoxidase activity both in pancreas and in lung tissues significantly decreased, whereas the activity of anti-inflammatory cytokine IL-10 in serum was increased. MaR1-pretreated mice reduced the activation of pancreatic NF-κB and decreased the severity of pancreatic and lung-related injuries. These results confirm that MaR1 alleviated inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimentally induced acute pancreatitis and exerted anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of SAP.NEW & NOTEWORTHY These results provided us evidence to confirm that maresin 1 (MaR1) can alleviate inflammation of the pancreas and lung by inhibiting the activity of NF-κB in experimental induced acute pancreatitis and exerts certain anti-inflammatory effects. These findings suggest that MaR1 could be a new and useful drug in the treatment of severe acute pancreatitis.
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Affiliation(s)
- Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Muhammad Babar Jamshed
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Numan Shahid
- Department of General Surgery, The School of International Studies of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahaudin Zakariya University, Multan, Punjab, Pakistan
| | - Adheesh Bhandari
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - QiYu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
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Pekgöz M. Post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review for prevention and treatment. World J Gastroenterol 2019; 25:4019-4042. [PMID: 31413535 PMCID: PMC6689803 DOI: 10.3748/wjg.v25.i29.4019] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/19/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Post endoscopic retrograde cholangiopancreatography (ERCP) is comparatively complex application. Researchers has been investigated prevention of post-ERCP pancreatitis (PEP), since it has been considered to be the most common complication of ERCP. Although ERCP can lead various complications, it can also be avoided.
AIM To study the published evidence and systematically review the literature on the prevention and treatment for PEP.
METHODS A systematic literature review on the prevention of PEP was conducted using the electronic databases of ISI Web of Science, PubMed and Cochrane Library for relevant articles. The electronic search for the review was performed by using the search terms “Post endoscopic retrograde cholangiopancreatography pancreatitis” AND “prevention” through different criteria. The search was restricted to randomized controlled trials (RCTs) performed between January 2009 and February 2019. Duplicate studies were detected by using EndNote and deleted by the author. PRISMA checklist and flow diagram were adopted for evaluation and reporting. The reference lists of the selected papers were also scanned to find other relevant studies.
RESULTS 726 studies meeting the search criteria and 4 relevant articles found in the edited books about ERCP were identified. Duplicates and irrelevant studies were excluded by screening titles and abstracts and assessing full texts. 54 studies were evaluated for full text review. Prevention methods were categorized into three groups as (1) assessment of patient related factors; (2) pharmacoprevention; and (3) procedural techniques for prevention. Most of studies in the literature showed that young age, female gender, absence of chronic pancreatitis, suspected Sphincter of Oddi dysfunction, recurrent pancreatitis and history of previous PEP played a crucial role in posing high risks for PEP. 37 studies designed to assess the impact of 24 different pharmacologic agents to reduce the development of PEP delivered through various administration methods were reviewed. Nonsteroidal anti-inflammatory drugs are widely used to reduce risks for PEP. Rectal administration of indomethacin immediately prior to or after ERCP in all patients is recommended by European Society for Gastrointestinal Endoscopy guidelines to prevent the development of PEP. The majority of the studies reviewed revealed that rectally administered indomethacin had efficacy to prevent PEP. Results of the other studies on the other pharmacological interventions had both controversial and promising results. Thirteen studies conducted to evaluate the efficacy of 4 distinct procedural techniques to prevent the development of PEP were reviewed. Pancreatic Stent Placement has been frequently used in this sense and has potent and promising benefits in the prevention of PEP. Studies on the other procedural techniques have had inconsistent results.
CONCLUSION Prevention of PEP involves multifactorial aspects, including assessment of patients with high risk factors for alternative therapeutic and diagnostic techniques, administration of pharmacological agents and procedural techniques with highly precise results in the literature.
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Affiliation(s)
- Murat Pekgöz
- Department of Gastroenterology, VM Medical Park Bursa Hospital, Bursa 16022, Turkey
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