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Liao Y, Zhang W, Huang Z, Yang L, Lu M. Diagnostic and prognostic value of miR-146b-5p in acute pancreatitis. Hereditas 2025; 162:93. [PMID: 40450371 DOI: 10.1186/s41065-025-00466-9] [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: 01/15/2025] [Accepted: 05/26/2025] [Indexed: 06/03/2025] Open
Abstract
OBJECTIVE MicroRNAs hold great potential as biomarkers for assessing the progression of acute pancreatitis (AP). This study aimed to explore the value of miR-146b-5p in the diagnosis and prognosis of AP patients. METHODS 110 AP patients were included and divided into 40 severe AP (SAP) patients and 70 non-SAP patients based on disease severity. Serum miR-146b-5p levels were measured using RT-qPCR. The diagnostic value of miR-146b-5p was evaluated utilizing ROC curves. Pearson correlation coefficient was employed to analyze the correlations between APACHEII, BISAP, and MCTSI scores and miR-146b-5p levels. The AP cell model was constructed by treating AR42J cells with deoxycholic acid (DCA), the proliferative capacity of cells was measured with CCK-8, apoptosis was measured by flow cytometry, and IL-6 and IL-8 protein levels were analyzed by ELISA. RESULTS Serum miR-146b-5p levels were decreased in SAP and unfavorable patients. Serum miR-146b-5p was able to effectively differentiate between SAP and non-SAP patients, and also effectively differentiate between unfavorable and favorable patients. MiR-146b-5p levels were significantly negatively correlated with APACHEII score (r=-0.6676), BISAP score (r=-0.5696), and MCTSI score (r=-0.5857). Furthermore, in the AP cell model, miR-146b-5p expression was down-regulated, proliferative capacity was diminished, apoptosis was increased, and IL-6 and IL-8 levels were elevated, but overexpression of miR-146b-5p partially reversed these changes. CONCLUSION miR-146b-5p expression is down-regulated in the serum of SAP patients and cells, and it has a good diagnostic effect. It may be a potential biomarker and therapeutic target for AP.
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Affiliation(s)
- Ying Liao
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Weiwei Zhang
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Zhenfei Huang
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Liu Yang
- Department of Critical Care Medicine, Ganzhou People's Hospital, Ganzhou City, Jiangxi Province, 341100, China
| | - Mingjin Lu
- Supply Room, The Fifth People's Hospital of Ganzhou, No. 666, Dongjiangyuan Avenue, Shuixi Town, Zhanggong District, Ganzhou City, Jiangxi Province, 341000, China.
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Wang Y, Ni Q, Xu S, Cui M, Wang R, Liu R. MiR-486-5p predicts the progression of severe acute pancreatitis by mediating the inflammatory response and ATG7/p38 MAPK pathway. Am J Med Sci 2025:S0002-9629(25)00982-6. [PMID: 40169118 DOI: 10.1016/j.amjms.2025.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/30/2024] [Accepted: 01/30/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND Acute pancreatitis (AP) is a serious disorder, and is frequently accompanied by shock or organ failure. The study aimed to investigate the predictive value of serum miR-486-5p for the prognosis of SAP patients and the underlying mechanism. METHODS The concentration of mRNAs was detected by Real-Time PCR reaction. The correlation between miRNA and each scoring system was analyzed via Pearson's correlation analysis. ROC curve was performed for diagnostic value evaluation. The predictive value of miRNA expression in the severity of AP was estimated by logistic regression analysis. HPDE6-C7 cells were treated with cerulein (Cer) to mimic AP in vitro. The cell apoptosis, viability, and inflammatory response were detected by flow cytometry, CCK-8, and ELISA, respectively. The targeting relationship was verified by DLR assay and RIP assay. RESULTS The expression of miR-486-5p was elevated in the serum of non-SAP and SAP groups (P < 0.001), which was interconnected with APACHE II, SOFA, and Ranson scores. MiR-486-5p can differentiate SAP patients from non-SAP with the AUC of 0.916, and it was an independent risk for the severity of AP patients. The miR-486-5p/ATG7 axis affected the apoptosis, viability, and inflammatory response of HPDE6-C7 cell models by the p38 MAPK pathway, thus involving the progression of AP. CONCLUSIONS Serum miR-486-5p may have a certain predictive value for the severity of AP and influence AP development through mediating cell inflammatory response via targeting ATG7.
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Affiliation(s)
- Yang Wang
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, PR China
| | - Qi Ni
- Department of Endocrinology, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, PR China
| | - Shuying Xu
- Department of Emergency, Binzhou Medical University Hospital, Binzhou, Shandong 256600, PR China
| | - Mingli Cui
- Department of Cardiovascular Medicine, Binzhou Medical University Hospital, Binzhou, Shandong 256600, PR China
| | - Ruixia Wang
- Department of Emergency, Binzhou Medical University Hospital, Binzhou, Shandong 256600, PR China.
| | - Rong Liu
- Faculty of Hepato-Biliary-Pancreatic Surgery, The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital, Beijing, PR China.
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Johnson-Pitt A, Catchpole B, Davison LJ. Exocrine pancreatic inflammation in canine diabetes mellitus - An active offender? Vet J 2024; 308:106241. [PMID: 39243807 DOI: 10.1016/j.tvjl.2024.106241] [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: 06/05/2024] [Revised: 08/27/2024] [Accepted: 09/01/2024] [Indexed: 09/09/2024]
Abstract
The purpose of this review is to examine the current scientific literature regarding the interplay between the exocrine and endocrine pancreas, specifically the role of the exocrine pancreas in the pathogenesis of canine diabetes mellitus. β-cell death caused by exocrine pancreatic inflammation is thought to be an under-recognised contributor to diabetes mellitus in dogs, with up to 30 % of canine diabetic patients with concurrent evidence of pancreatitis at post-mortem examination. Current diagnostics for pancreatitis are imprecise, and treatments for both diseases individually have their own limitations: diabetes through daily insulin injections, which has both welfare and financial implications for the stakeholders, and pancreatitis through treatment of clinical signs, such as analgesia and anti-emetics, rather than targeted treatment of the underlying cause. This review will consider the evidence for exocrine pancreatic inflammation making an active contribution to pancreatic β-cell loss and insulin-deficiency diabetes in the dog and explore current and potential future diagnostic and treatment avenues to improve outcomes for these patients.
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Affiliation(s)
- Arielle Johnson-Pitt
- Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire AL9 7TA, UK.
| | - Brian Catchpole
- Department of Pathobiology and Population Sciences, The Royal Veterinary College, Hertfordshire AL9 7TA, UK
| | - Lucy J Davison
- Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire AL9 7TA, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
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Chen H, Tu J, He L, Gao N, Yang W. Mmu_circ_0000037 inhibits the progression of acute pancreatitis by miR-92a-3p/Pias1 axis. Immun Inflamm Dis 2023; 11:e819. [PMID: 37102653 PMCID: PMC10091370 DOI: 10.1002/iid3.819] [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: 12/21/2022] [Revised: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is an inflammatory disease with high mortality. Previous study has suggested that circular RNAs are dysregulated and involved in the regulation of inflammatory responses in AP. This study aimed to investigate the function and regulatory mechanism underlying mmu_circ_0000037 in caerulein-induced AP cellular model. METHODS Caerulein-treated MPC-83 cells were used as an in vitro cellular model for AP. The expression levels of mmu_circ_0000037, microRNA (miR)-92a-3p, and protein inhibitor of activated STAT1 (Pias1) were detected by quantitative real-time polymerase chain reaction. Cell viability, amylase activity, apoptosis, and inflammatory response were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Amylase Assay Kit, flow cytometry, and enzyme-linked immunosorbent assays. The protein level was quantified by western blot analysis. The target interaction between miR-92a-3p and mmu_circ_0000037 or Pias1 were predicted by StarbaseV3.0 and validated by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS Mmu_circ_0000037 and Pias1 levels were decreased, whereas miR-92a-3p expression was elevated in caerulein-induced MPC-83 cells. Overexpression of mmu_circ_0000037 protected MPC-83 cells from caerulein-induced the decrease of cell viability, as well as the promotion of amylase activity, apoptosis and inflammation. MiR-92a-3p was targeted by mmu_circ_0000037, and miR-92a-3p overexpression rescued the effect of mmu_circ_0000037 on caerulein-induced MPC-83 cell injury. Pias1 was confirmed as a target of miR-92a-3p and mmu_circ_0000037 regulated the expression of Pias1 by sponging miR-92a-3p. CONCLUSION Mmu_circ_0000037 relieves caerulein-induced inflammatory injury in MPC-83 cells by targeting miR-92a-3p/Pias1 axis, providing a theoretical basis for the treatment of AP.
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Affiliation(s)
- Hua Chen
- Department of GastroenterologyFengxian District Central HospitalShanghaiChina
| | - Jun Tu
- Department of GastroenterologyFengxian District Central HospitalShanghaiChina
| | - Lei He
- Department of GastroenterologyFengxian District Central HospitalShanghaiChina
| | - Ning Gao
- Department of General Internal Medicine, Ping An Health InternetShanghai BranchShanghaiChina
| | - Weiqiang Yang
- Department of General SurgeryJiading District Central HospitalShanghaiChina
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Wang FJ, Mei X. Expression level of serum miR-347a-5p in patients with acute pancreatitis and its effect on viability, apoptosis, and inflammatory factors of pancreatic acinar cells induced by cerulein. Kaohsiung J Med Sci 2023. [PMID: 36912261 DOI: 10.1002/kjm2.12666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/20/2023] [Accepted: 02/02/2023] [Indexed: 03/14/2023] Open
Abstract
Acute pancreatitis (AP) is one of the life-threatening diseases of the digestive system. MicroRNA has been asserted to be a regulator of AP. This paper explored the miR-374a-5p expression in AP patients and investigated the efficacy of AR42J cells. In this study, 60 healthy people, 58 MAP patients and 58 SAP patients were included, and the serum miR-374a-5p levels of the subjects were detected by RT-qPCR technology. The pancreatitis cell model was structured by stimulating AR42J cells with cerulein. Next, cell viability and apoptosis were detected by CCK-8 assay and flow cytometry. ELISA was used to measure the concentration of cytokines, such as TNF-α, IL-6, and IL-1β. The data showed that miR-374a-5p was downregulated in samples from AP patients, while showing discriminative power for AP populations. Attenuated miR-374a-5p were negatively bound up with patients' Ranson score and APACHE II score. Besides, miR-374a-5p was declined in cerulein-treated AR42J cells and forced elevation of miR-374a-5p was beneficial to increase cell viability, and inhibit cell apoptosis and inflammation. The present study found that miR-374a-5p was reduced in AP serum samples, and up-regulated expression level of miR-374a-5p in cell models had a protective effect on cerulein-induced inhibition of cell function and inflammatory response.
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Affiliation(s)
- Fu-Jun Wang
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
| | - Xue Mei
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
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Patel HR, Diaz Almanzar VM, LaComb JF, Ju J, Bialkowska AB. The Role of MicroRNAs in Pancreatitis Development and Progression. Int J Mol Sci 2023; 24:1057. [PMID: 36674571 PMCID: PMC9862468 DOI: 10.3390/ijms24021057] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023] Open
Abstract
Pancreatitis (acute and chronic) is an inflammatory disease associated with significant morbidity, including a high rate of hospitalization and mortality. MicroRNAs (miRs) are essential post-transcriptional modulators of gene expression. They are crucial in many diseases' development and progression. Recent studies have demonstrated aberrant miRs expression patterns in pancreatic tissues obtained from patients experiencing acute and chronic pancreatitis compared to tissues from unaffected individuals. Increasing evidence showed that miRs regulate multiple aspects of pancreatic acinar biology, such as autophagy, mitophagy, and migration, impact local and systemic inflammation and, thus, are involved in the disease development and progression. Notably, multiple miRs act on pancreatic acinar cells and regulate the transduction of signals between pancreatic acinar cells, pancreatic stellate cells, and immune cells, and provide a complex interaction network between these cells. Importantly, recent studies from various animal models and patients' data combined with advanced detection techniques support their importance in diagnosing and treating pancreatitis. In this review, we plan to provide an up-to-date summary of the role of miRs in the development and progression of pancreatitis.
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Affiliation(s)
- Hetvi R. Patel
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Vanessa M. Diaz Almanzar
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph F. LaComb
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Agnieszka B. Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
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The Role of microRNAs in Inflammation. Int J Mol Sci 2022; 23:ijms232415479. [PMID: 36555120 PMCID: PMC9779565 DOI: 10.3390/ijms232415479] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammation is a biological response of the immune system to various insults, such as pathogens, toxic compounds, damaged cells, and radiation. The complex network of pro- and anti-inflammatory factors and their direction towards inflammation often leads to the development and progression of various inflammation-associated diseases. The role of small non-coding RNAs (small ncRNAs) in inflammation has gained much attention in the past two decades for their regulation of inflammatory gene expression at multiple levels and their potential to serve as biomarkers and therapeutic targets in various diseases. One group of small ncRNAs, microRNAs (miRNAs), has become a key regulator in various inflammatory disease conditions. Their fine-tuning of target gene regulation often turns out to be an important factor in controlling aberrant inflammatory reactions in the system. This review summarizes the biogenesis of miRNA and the mechanisms of miRNA-mediated gene regulation. The review also briefly discusses various pro- and anti-inflammatory miRNAs, their targets and functions, and provides a detailed discussion on the role of miR-10a in inflammation.
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8
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Wang L, Yuan N, Li Y, Ma Q, Zhou Y, Qiao Z, Li S, Liu C, Zhang L, Yuan M, Sun J. Stellate ganglion block relieves acute lung injury induced by severe acute pancreatitis via the miR-155-5p/SOCS5/JAK2/STAT3 axis. Eur J Med Res 2022; 27:231. [PMID: 36333771 PMCID: PMC9636723 DOI: 10.1186/s40001-022-00860-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 10/06/2022] [Indexed: 11/06/2022] Open
Abstract
Acute lung injury (ALI), a prevalent complication of severe acute pancreatitis (SAP), is also a leading contributor to respiratory failure and even death of SAP patients. Here, we intended to investigate the function and mechanism of stellate ganglion block (SGB) in ameliorating SAP-induced ALI (SAP-ALI). We engineered an SAP-ALI model in rats and treated them with SGB. HE staining and the dry and wet method were implemented to evaluate pathological alterations in the tissues and pulmonary edema. The rats serum changes of the profiles of TNF-α, IL-6, IL-1β, and IL-10 were examined. The profiles of miR-155-5p and SOCS5/JAK2/STAT3 were detected. Functional assays were performed for confirming the role of miR-155-5p in modulating the SOCS5/JAK2/STAT3 pathway in pulmonary epithelial cells. Our findings revealed that SGB vigorously alleviated SAP rat lung tissue damage and lung edema and lessened the generation of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. SGB enhanced SOCS5 expression, hampered miR-155-5p, and suppressed JAK2/STAT3 pathway activation. As evidenced by mechanism studies, miR-155-5p targeted the 3′UTR of SOCS5 and repressed its expression, hence resulting in JAK2/STAT3 pathway activation. During animal trials, we discovered that SGB ameliorated SAP-ALI, boosted SOCS5 expression, and mitigated the levels of pro-inflammatory factors and miR-155-5p in the plasma. In vitro, miR-155-5p overexpression substantially facilitated pulmonary epithelial cell apoptosis, inflammation, and JAK2/STAT3 pathway activation and restrained SOCS5 expression. All in all, our work hinted that SGB could modulate the miR-155-5p/SOCS5/JAK2/STAT3 axis to alleviate SAP-ALI.
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Lv H, Liu X, Zhou H. USP25 UPREGULATION BOOSTS GSDMD -MEDIATED PYROPTOSIS OF ACINAR CELLS IN ACUTE PANCREATITIS. Shock 2022; 58:408-416. [PMID: 36155610 DOI: 10.1097/shk.0000000000001992] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
ABSTRACT Acute pancreatitis (AP) is an inflammation-associated disorder in the digestive system. Ubiquitin-specific peptidase 25 ( USP25 ) can modulate inflammation in diseases. This study expounded on the role of USP25 in pyroptosis of acinar cells in AP. Acinar cells were treated with lipopolysaccharide (LPS) and caerulein (CRE) to induce AP. Afterward, the expression patterns of USP25 , microRNA (miR)-10a-5p, and Krüppel-like factor 4 ( KLF4 ) in acinar cells were examined. Then, acinar cell viability and levels of NLR family pyrin-domain containing 3 (NLRP3), cleaved caspase-1, cleaved N -terminal gasdermin D ( GSDMD - N ), interleukin (IL)-1β, and IL-18 were determined. We observed that USP25 was highly expressed in AP models, and silencing USP25 increased cell viability and inhibited pyroptosis of AP acinar cells. The bindings of USP25 to KLF4 and miR-10a-5p to KLF4 and the GSDMD 3'UTR sequence were validated. We found that USP25 binding to KLF4 inhibited ubiquitination degradation of KLF4 , KLF4 transcriptionally decreased miR-10a-5p expression, and miR-10a-5p targeted GSDMD expression. Finally, rescue experiments proved that KLF4 overexpression or miR-10a-5p suppression enhanced pyroptosis of AP acinar cells. Overall, USP25 stabilized KLF4 expression through deubiquitination, limited miR-10a-5p expression, and increased GSDMD expression, finally promoting pyroptosis of acinar cells in AP.
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Affiliation(s)
- Hui Lv
- Department of Gastroenterology, The Central Hospital of Zhoukou, Zhoukou, China
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Yang Q, Luo Y, Lan B, Dong X, Wang Z, Ge P, Zhang G, Chen H. Fighting Fire with Fire: Exosomes and Acute Pancreatitis-Associated Acute Lung Injury. Bioengineering (Basel) 2022; 9:615. [PMID: 36354526 PMCID: PMC9687423 DOI: 10.3390/bioengineering9110615] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 08/30/2023] Open
Abstract
Acute pancreatitis (AP) is a prevalent clinical condition of the digestive system, with a growing frequency each year. Approximately 20% of patients suffer from severe acute pancreatitis (SAP) with local consequences and multi-organ failure, putting a significant strain on patients' health insurance. According to reports, the lungs are particularly susceptible to SAP. Acute respiratory distress syndrome, a severe type of acute lung injury (ALI), is the primary cause of mortality among AP patients. Controlling the mortality associated with SAP requires an understanding of the etiology of AP-associated ALI, the discovery of biomarkers for the early detection of ALI, and the identification of potentially effective drug treatments. Exosomes are a class of extracellular vesicles with a diameter of 30-150 nm that are actively released into tissue fluids to mediate biological functions. Exosomes are laden with bioactive cargo, such as lipids, proteins, DNA, and RNA. During the initial stages of AP, acinar cell-derived exosomes suppress forkhead box protein O1 expression, resulting in M1 macrophage polarization. Similarly, macrophage-derived exosomes activate inflammatory pathways within endothelium or epithelial cells, promoting an inflammatory cascade response. On the other hand, a part of exosome cargo performs tissue repair and anti-inflammatory actions and inhibits the cytokine storm during AP. Other reviews have detailed the function of exosomes in the development of AP, chronic pancreatitis, and autoimmune pancreatitis. The discoveries involving exosomes at the intersection of AP and acute lung injury (ALI) are reviewed here. Furthermore, we discuss the therapeutic potential of exosomes in AP and associated ALI. With the continuous improvement of technological tools, the research on exosomes has gradually shifted from basic to clinical applications. Several exosome-specific non-coding RNAs and proteins can be used as novel molecular markers to assist in the diagnosis and prognosis of AP and associated ALI.
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Affiliation(s)
- Qi Yang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, China
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Yalan Luo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Bowen Lan
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Xuanchi Dong
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Zhengjian Wang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Peng Ge
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Guixin Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Hailong Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian 116044, China
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
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11
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Jia A, Yang ZW, Shi JY, Liu JM, Zhang K, Cui YF. MiR-325-3p Alleviates Acute Pancreatitis via Targeting RIPK3. Dig Dis Sci 2022; 67:4471-4483. [PMID: 35094251 DOI: 10.1007/s10620-021-07322-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/08/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS Acute pancreatitis (AP) is an acute inflammatory disease that can lead to death. Mir-325-3p is strongly and abnormally expressed in many diseases, necessitating exploration of its function and mechanism in AP. METHODS Blood samples from AP patients and mice were analyzed. The expression levels of miR-325-3p in AP patients and mouse were detected. Whether miR-325-3p targets RIPK3 gene was predicted by TargetScan online database and dual luciferase reporter assay. In vitro experiments verified the effect of miR-325-3p overexpression on caerulein-induced MPC83 pancreatic acinar cancer cell line. In vivo experiments verified the effect of overexpression of miR-325-3p on the disease degree of pancreatic tissues in AP mice. RESULTS Analysis of blood samples from AP patients and experiments in mice demonstrated that expression of miR-325-3p was significantly reduced during the process of AP in humans and mice. Predicted using the TargetScan online database and through dual luciferase reporter assay detection, miR-325-3p directly targets the RIPK3 gene. In vitro experiments revealed that overexpression of miR-325-3p reversed caerulein-induced apoptosis and necroptosis in MPC83 pancreatic acinar cancer cell line. We used Z-VAD-FMK to assess necroptosis and demonstrated that miR-325-3p targets necroptosis to reduce cell damage. In subsequent experiments in mice, we verified that overexpression of miR-325-3p reduces inflammation, edema, hemorrhage, and necrosis in acute pancreatitis. Characteristic western blot, immunohistochemistry, and transmission electron microscopy results revealed that overexpression of miR-325-3p reduces the severity of acute pancreatitis by inhibiting pancreatic necroptosis in AP mice. CONCLUSIONS The current research results indicate that miR-325-3p directly targets RIPK3 and exerts a protective role in mouse AP. Necroptosis is still the primary mechanism of RIPK3 regulation. MiR-325-3p inhibits acute pancreatitis by targeting RIPK3-dependent necroptosis, which may represent a novel treatment method for acute pancreatitis.
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Affiliation(s)
- Ao Jia
- Tianjin Medical University, Tianjin, 300070, China
| | | | - Ji-Yu Shi
- Tianjin Medical University, Tianjin, 300070, China
| | - Jia-Ming Liu
- Tianjin Medical University, Tianjin, 300070, China
| | - Kun Zhang
- Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, 122 Sanwei Road, Nankai District, Tianjin, 300110, China
| | - Yun-Feng Cui
- Tianjin Medical University, Tianjin, 300070, China. .,Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, 122 Sanwei Road, Nankai District, Tianjin, 300110, China.
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Huang H, Chen W, Lu J, Zhang S, Xiang X, Wang X, Tang G. Circ_0000284 Promoted Acute Pancreatitis Progression through the Regulation of miR-10a-5p/Wnt/β-Catenin Pathway. Chem Biodivers 2022; 19:e202101006. [PMID: 35581162 DOI: 10.1002/cbdv.202101006] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/30/2022] [Indexed: 12/17/2022]
Abstract
Circular RNAs (circRNAs) have been found to be involved in the progression of acute pancreatitis (AP). The objective of our study was to investigate the effects of circ_0000284 on caerulein-induced AR42J cell injury. To mimic AP in vitro, rat pancreatic acinar AR42J cells were treated with caerulein. The expression of circ_0000284 and miR-10a-5p was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Enzyme-linked immunosorbent assay (ELISA) was employed to determine the content of inflammatory cytokines interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor α (TNF-α). Western blotting was applied to analyze the levels of Wnt/β-catenin pathway-related and apoptosis-related proteins. Cell viability and apoptosis were monitored by Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. The target connection between circ_0000284 and miR-10a-5p was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. AP induced inflammation in patients, and caerulein treatment increased apoptosis and inflammation in AR42J cells. Circ_0000284 was upregulated in serum of AP patients and caerulein-induced AR42J cells, while Wnt/β-catenin pathway was inactivated. Knockdown of circ_0000284 could decrease apoptosis and inflammation in caerulein-induced AR42J cells, which was attenuated by miR-10a-5p inhibition or Wnt signaling pathway antagonist Dickkopf-related protein 1 (DKK1). MiR-10a-5p was sponged by circ_000028 and was downregulated in caerulein-induced AR42J cells. Circ_0000284 depletion could protect caerulein-induced AR42J cells from apoptosis and inflammation by upregulating miR-10a-5p expression and activating Wnt/β-catenin pathway, underscoring a potential target for AP therapy.
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Affiliation(s)
- Huali Huang
- Department of Gastroenterology, The First People's Hospital of Nanning, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530022, P. R., China
| | - Wenjing Chen
- Guangxi Medical University, Nanning, Guangxi, 530021, P. R. China
| | - Jiefu Lu
- Department of Gastroenterology, The First People's Hospital of Nanning, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530022, P. R., China
| | - Shiyu Zhang
- Guangxi Medical University, Nanning, Guangxi, 530021, P. R. China
| | - Xuelian Xiang
- Guangxi Medical University, Nanning, Guangxi, 530021, P. R. China
| | - Xianmo Wang
- Department of clinical laboratory, The First People's Hospital of ingzhou, Hubei Province, P. R., China
| | - Guodu Tang
- Guangxi Medical University, Guangxi International Zhuang Medicine Hospital, No. 22 Shuangcong Road, Qingxiu District, Nanning, 530021, P. R. China
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13
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New challenges for microRNAs in acute pancreatitis: progress and treatment. J Transl Med 2022; 20:192. [PMID: 35509084 PMCID: PMC9066850 DOI: 10.1186/s12967-022-03338-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/06/2022] [Indexed: 12/17/2022] Open
Abstract
Acute pancreatitis (AP) is a common clinical abdominal emergency, with a high and increasing incidence each year. Severe AP can easily cause systemic inflammatory response syndrome, multiple organ dysfunction and other complications, leading to higher hospitalization rates and mortality. Currently, there is no specific treatment for AP. Thus, we still need to understand the exact AP pathogenesis to effectively cure AP. With the rise of transcriptomics, RNA molecules, such as microRNAs (miRNAs) transcribed from nonprotein-coding regions of biological genomes, have been found to be of great significance in the regulation of gene expression and to be involved in the occurrence and development of many diseases. Increasing evidence has shown that miRNAs, as regulatory RNAs, can regulate pancreatic acinar necrosis and apoptosis and local and systemic inflammation and play an important role in the development and thus potentially the diagnosis and treatment of AP. Therefore, here, the current research on the relationship between miRNAs and AP is reviewed.
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14
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Yao Q, Ke HJ, Yang Q, Liao GY, Liu P. Study on the Mechanism of MicroRNA551b-5p in Severe Acute Pancreatitis Capillary Leakage Syndrome. DISEASE MARKERS 2022; 2022:6373757. [PMID: 35256892 PMCID: PMC8898106 DOI: 10.1155/2022/6373757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/26/2022] [Accepted: 01/31/2022] [Indexed: 11/30/2022]
Abstract
Objective This study focused on investigating the effects of microRNA551b-5p (miR-551b-5p) on severe acute pancreatitis. Methods Initially, quantitative real-time polymerase chain reaction (qPCR) is employed to determine the expression of miR-551b-5p in differentiated human umbilical vein endothelial cells (HUVECs). Further, the effects of aberrantly expressed miR-551b-5p in HUVECs Transwell assay. The expressions of proteins associated with severe acute pancreatitis capillary leakage syndrome are determined by Western blot, FITC-phalloidin, and immunofluorescence stainings. Finally, the correlative factor and the target genes of miR-551b-5p, as well as their contributions, are assessed. Results We observed that overexpression of miR-551b-5p distinctly promoted the expression of EGFR, AKT3, and AQP5, while it suppressed the expression of JAM3, AQP1, and occludin. Functionally, the cytoskeleton of the miR-551b-5p overexpression was relatively loose with apparent vacuoles, and overexpression of miR-551b-5p increased the permeability of HUVECs. Conclusion miR-551b-5p overexpression promoted changes in vascular endothelial permeability via upregulation of the EGFR/AKT3 pathway and downregulation of occludin and JAM3.
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Affiliation(s)
- Qian Yao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hua-Jing Ke
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qin Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Gen-You Liao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Pi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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15
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Protective Effect of miR-193a-5p and miR-320-5p on Caerulein-Induced Injury in AR42J Cells. Dig Dis Sci 2021; 66:4333-4343. [PMID: 33405047 DOI: 10.1007/s10620-020-06800-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 12/16/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Acute pancreatitis is a common inflammatory disease. MicroRNAs have been implicated in the pathogenesis of acute pancreatitis. AIMS The purpose of this study was to investigate the precise roles of miR-193a-5p and miR-320-5p in AP. METHODS The levels of miR-193a-5p, miR-320-5p and tumor necrosis factor receptor-associated factor 3 were detected by quantitative real-time polymerase chain reaction. Cell apoptosis was determined using flow cytometry. Enzyme-linked immunosorbent assay was performed to measure TNF-α, IL-6, IL-1β and IL-8 production, amylase activity, and malondialdehyde content. Targeted relationship between miR-193a-5p or miR-320-5p and TRAF3 was confirmed by the dual-luciferase reporter and RNA immunoprecipitation assays. RESULTS Our data showed that miR-193a-5p and miR-320-5p were down-regulated in acute pancreatitis serum and caerulein-treated AR42J cells. The increased expression of miR-193a-5p or miR-320-5p alleviated caerulein-induced cell injury in AR42J cells. Tumor necrosis factor receptor-associated factor 3 was a direct target of miR-193a-5p and miR-320-5p in AR42J cells. Moreover, miR-193a-5p and miR-320-5p regulated caerulein-induced AR42J cells injury through targeting tumor necrosis factor receptor-associated factor 3. CONCLUSION The present findings demonstrated that miR-193a-5p and miR-320-5p protected AR42J cells against caerulein-induced cell injury by targeting tumor necrosis factor receptor-associated factor 3, highlighting their roles as potential therapeutic targets for acute pancreatitis treatment.
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16
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Patel BK, Patel KH, Bhatia M, Iyer SG, Madhavan K, Moochhala SM. Gut microbiome in acute pancreatitis: A review based on current literature. World J Gastroenterol 2021; 27:5019-5036. [PMID: 34497432 PMCID: PMC8384740 DOI: 10.3748/wjg.v27.i30.5019] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/04/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
The gut microbiome is a complex microbial community, recognized for its potential role in physiology, health, and disease. The available evidence supports the role of gut dysbiosis in pancreatic disorders, including acute pancreatitis (AP). In AP, the presence of gut barrier damage resulting in increased mucosal permeability may lead to translocation of intestinal bacteria, necrosis of pancreatic and peripancreatic tissue, and infection, often accompanied by multiple organ dysfunction syndrome. Preserving gut microbial homeostasis may reduce the systemic effects of AP. A growing body of evidence suggests the possible involvement of the gut microbiome in various pancreatic diseases, including AP. This review discusses the possible role of the gut microbiome in AP. It highlights AP treatment and supplementation with prebiotics, synbiotics, and probiotics to maintain gastrointestinal microbial balance and effectively reduce hospitalization, morbidity and mortality in an early phase. It also addresses novel therapeutic areas in the gut microbiome, personalized treatment, and provides a roadmap of human microbial contributions to AP that have potential clinical benefit.
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Affiliation(s)
- Bharati Kadamb Patel
- Department of Surgery, National University of Singapore, Singapore 119228, Singapore
| | - Kadamb H Patel
- School of Applied Sciences, Temasek Polytechnic, Singapore 529757, Singapore
| | - Madhav Bhatia
- Department of Pathology, University of Otago, Christchurch 8140, New Zealand
| | - Shridhar Ganpati Iyer
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- National University Hospital, National University of Singapore, Singapore 119228, Singapore
| | - Krishnakumar Madhavan
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- National University Hospital, National University of Singapore, Singapore 119228, Singapore
| | - Shabbir M Moochhala
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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Zhang K, Zhang X. MiR-146b-3p protects against AR42J cell injury in cerulein-induced acute pancreatitis model through targeting Anxa2. Open Life Sci 2021; 16:255-265. [PMID: 33817317 PMCID: PMC7968541 DOI: 10.1515/biol-2021-0028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 11/17/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Background Acute pancreatitis (AP) is a common inflammatory disorder. MicroRNAs play crucial roles in the pathogenesis of AP. In this article, we explored the detailed role and molecular mechanisms of miR-146b-3p in AP progression. Methods The rat AR42J cells were treated with cerulein to establish the AP model in vitro. The miR-146b-3p and Annexin A2 (Anxa2) mRNA levels were assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Cell viability and apoptosis were tested using the Cell Counting Kit-8 (CCK-8) and flow cytometry assays, respectively. Caspase-3 activity and the production of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay and qRT-PCR. Targeted interaction between miR-146b-3p and Anxa2 was verified by the dual-luciferase reporter and RNA immunoprecipitation assays. Western blot analysis was performed to detect the expression of Anxa2 protein. Results Our data revealed that miR-146b-3p was significantly downregulated in AP samples. The enforced expression of miR-146b-3p alleviated cerulein-induced injury in AR42J cells, as evidenced by the promotion in cell viability and the repression in cell apoptosis, as well as the reduction in IL-1β, IL-6, and TNF-α production. Anxa2 was directly targeted and inhibited by miR-146b-3p. Moreover, the alleviative effect of miR-146b-3p overexpression on cerulein-induced AR42J cell injury was mediated by Anxa2. Conclusions The current work had led to the identification of miR-146b-3p overexpression that protected against cerulein-induced injury in AR42J cells at least in part by targeting Anxa2, revealing a promising target for AP diagnosis and treatment.
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Affiliation(s)
- Kunpeng Zhang
- Department of Hepatobiliary Surgery, Xingtai People's Hospital, Xingtai, Hebei, 054001, China.,Department of Neurology, Xingtai People's Hospital, 16 Hongxing Street, Qiaodong District, Xingtai, Hebei, 054001, China
| | - Xiaoyu Zhang
- Department of Neurology, Xingtai People's Hospital, 16 Hongxing Street, Qiaodong District, Xingtai, Hebei, 054001, China
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18
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Huang P, Xu M, He XY. Correlations between microRNA-146a and immunoglobulin and inflammatory factors in Guillain-Barré syndrome. J Int Med Res 2021; 48:300060520904842. [PMID: 32223661 PMCID: PMC7133091 DOI: 10.1177/0300060520904842] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Objective To study correlations between expression of microRNA-146a (miR-146a) and immunoglobulin and inflammatory cytokines in serum of patients with Guillain–Barré syndrome (GBS). Methods Eighty-four patients with GBS were selected as the experimental group and 50 healthy individuals as controls. Reverse transcription-PCR was used to detect expression of miR-146a in peripheral blood of all participants. Immunoturbidometric assay was used to detect immunoglobulins (Ig)G, IgA, and IgM in peripheral blood of all participants. The levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor α (TNF-α) were measured by ELISA in peripheral blood. The expression of miR-146a was compared between the two groups and Pearson correlation analysis was used to analyze correlations between miR-146a and immunoglobulin and inflammatory factors. Results Expression of miR-146a was higher in the GBS group than in controls. Expression of IL-6, CRP, TNF-α, and IgG was significantly higher in the GBS group than in controls. miR-146a was significantly and positively correlated with IL-6, CRP, TNF-α, and IgG but not with IgA and IgM. Conclusion The expression profile of miR-146a in patients with GBS differs from that in healthy individuals. Thus, miR-146a may participate in the pathogenesis of GBS by regulating immune and inflammatory responses.
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Affiliation(s)
- Pan Huang
- Department of Neurology, People's Hospital of Deyang City, DeYang, Sichuan, China
| | - Min Xu
- Department of Neurology, The second People's Hospital of Deyang City, DeYang, Sichuan, China
| | - Xiao-Ying He
- Department of Neurology, The Affiliated Hospital of Southwest Medical University, Cangzhou City, Sichuan Province, LuZhou, SiChuan, China
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19
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Sun H, Tian J, Li J. MiR-92b-3p ameliorates inflammation and autophagy by targeting TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells. Int Immunopharmacol 2020; 88:106691. [PMID: 32822908 DOI: 10.1016/j.intimp.2020.106691] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 05/20/2020] [Accepted: 06/08/2020] [Indexed: 02/08/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disease with high morbidity and mortality. Dysregulation of microRNAs (miRNAs) was involved in human diseases, including AP. However, the effects of miR-92b-3p on AP process and its mechanism remain not been fully clarified. The expression levels of miR-92b-3p and tumor necrosis factor receptor-associated factor-3 (TRAF3) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of TRAF3, tumor necrosis factor α (TNF-α) TNF-α, interleukin-6 (IL-6), phosphorylated mitogen-activated protein kinase kinase 3 (p-MKK3), MKK3, p38 and phosphorylated p38 (p-p38) were detected by western blot. The concentration of TNF-α and IL-6 in the medium was measured using ELISA kits. The possible binding sites of miR-92b-3p and TRAF3 were predicted by TargetScan and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The expression level of miR-92b-3p was decreased and TRAF3 expression was increased in AR42J cells stimulated with caerulein. Moreover, the protein levels of pro-inflammatory cytokines (TNF-α and IL-6) were markedly elevated, and the expression levels of autophagy-related markers Beclin1 as well as the ratio of LC3-II/I were obviously increased in AR42J cells treated with caerulein. In addition, overexpression of miR-92b-3p or knockdown of TRAF3 significantly suppressed the release of pro-inflammatory cytokines and autophagy in caerulein-induced AR42J cells. Furthermore, TRAF3 was a direct target of miR-92b-3p and its upregulation reversed the effects of miR-92b-3p overexpression on inflammatory response and autophagy. Besides, overexpression of miR-92b-3p inhibited the activation of the MKK3-p38 pathway by affecting TRAF3 expression. In conclusion, miR-92b-3p attenuated inflammatory response and autophagy by downregulating TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells, providing a novel avenue for treatment of AP.
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Affiliation(s)
- Hongzhi Sun
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China
| | - Jiakun Tian
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China
| | - Jinliang Li
- Department of Critical Care Medicine, The Second Hospital of Jilin University, No 218 Ziqiang Street, Nanguan District 130041, Changchun, China.
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20
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Jotatsu T, Izumi H, Morimoto Y, Yatera K. Selection of microRNAs in extracellular vesicles for diagnosis of malignant pleural mesothelioma by in vitro analysis. Oncol Rep 2020; 44:2198-2210. [PMID: 33000251 PMCID: PMC7551269 DOI: 10.3892/or.2020.7778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 09/04/2020] [Indexed: 12/12/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a malignant tumor which is a challenge for diagnosis and is associated with a poor patient prognosis. Thus, early diagnostic interventions will improve the quality of life and life expectancy of these patients. Recently, cellular microRNAs (miRNAs) have been found to be involved in maintaining homeostasis, and abnormal miRNA expression has often been observed in various diseases including cancer. Extracellular vesicles (EVs) released by many cells contain proteins and nucleic acids. miRNAs are secreted from all cells via EVs and circulate throughout the body. In this study, culture media were passed sequentially through membrane filters 220–50 nm in size, and EVs with diameters of 50 to 220 nm (EVcap50/220) were collected. miRNAs (EV50-miRNAs) in EVcap50/220 were purified, and microarray analysis was performed. EV50-miRNA expression profiles were compared between MPM cells and a normal pleural mesothelial cell line, and six EV50-miRNAs were selected for further investigation. Of these, hsa-miR-193a-5p and hsa-miR-551b-5p demonstrated higher expression in MPM-derived EVcap50/220. These miRNAs reduced the expression of several genes involved in cell-cell interactions and cell-matrix interactions in normal pleural mesothelial cells. Our data suggest that hsa-miR-193a-5p and hsa-miR-551b-5p in EVcap50/220 could be diagnostic markers for MPM.
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Affiliation(s)
- Takanobu Jotatsu
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807‑8555, Japan
| | - Hiroto Izumi
- Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807‑8555, Japan
| | - Yasuo Morimoto
- Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807‑8555, Japan
| | - Kazuhiro Yatera
- Department of Respiratory Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807‑8555, Japan
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Chen X, Song D. LncRNA MEG3 Participates in Caerulein-Induced Inflammatory Injury in Human Pancreatic Cells via Regulating miR-195-5p/FGFR2 Axis and Inactivating NF-κB Pathway. Inflammation 2020; 44:160-173. [PMID: 32856219 DOI: 10.1007/s10753-020-01318-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Acute pancreatitis (AP) is a dysfunctional pancreas disease marked by severe inflammation. Long non-coding RNAs (lncRNAs) involving in the regulation of inflammatory responses have been frequently mentioned. The purpose of this study was to ensure the function and action mode of lncRNA maternally expressed gene 3 (MEG3) in caerulein-induced AP cell model. HPDE cells were treated with caerulein to establish an AP model in vitro. The expression of MEG3, miR-195-5p, and fibroblast growth factor receptor 2 (FGFR2) was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation and apoptosis were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry assay, respectively. The expression of CyclinD1, B cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (Bax), FGFR2, P65, phosphorylated P65 (p-P65), alpha inhibitor of nuclear factor kappa beta (NF-κB) (IκB-α), and phosphorylated IκB-α (p-IκB-α) at the protein level was quantified by western blot. The concentrations of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were monitored by enzyme-linked immunosorbent assay (ELISA). The targeted relationship between miR-195-5p and MEG3 or FGFR2 was forecasted by the online software starBase v2.0 and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. As a result, the expression of MEG3 and FGFR2 was decreased in caerulein-induced HPDE cells, while the expression of miR-195-5p was increased. MEG3 overexpression inhibited cell apoptosis and inflammatory responses that were induced by caerulein. Mechanically, miR-195-5p was targeted by MEG3 and abolished the effects of MEG3 overexpression. FGFR2 was a target of miR-195-5p, and MEG3 regulated the expression of FGFR2 by sponging miR-195-5p. FGFR2 overexpression abolished miR-195-5p enrichment-aggravated inflammatory injuries. Moreover, the NF-κB signaling pathway was involved in the MEG3/miR-195-5p/FGFR2 axis. Collectively, MEG3 participates in caerulein-induced inflammatory injuries by targeting the miR-195-5p/FGFR2 regulatory axis via mediating the NF-κB pathway in HPDE cells.
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Affiliation(s)
- Xinghai Chen
- Department of Emergency and Critical Medicine, The Second Hospital of Jilin University, No. 218, Nanguan District, Ziqiang Street, Changchun, Jilin, 130041, China
| | - Debiao Song
- Department of Emergency and Critical Medicine, The Second Hospital of Jilin University, No. 218, Nanguan District, Ziqiang Street, Changchun, Jilin, 130041, China.
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22
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Zeng J, Chen JY, Meng J, Chen Z. Inflammation and DNA methylation coregulate the CtBP-PCAF-c-MYC transcriptional complex to activate the expression of a long non-coding RNA CASC2 in acute pancreatitis. Int J Biol Sci 2020; 16:2116-2130. [PMID: 32549759 PMCID: PMC7294942 DOI: 10.7150/ijbs.43557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are emerging as important regulators involved in the pathogenesis of many diseases. However, it is still unknown if they contribute to the occurrence of acute pancreatitis (AP). Here, we identified a lncRNA CASC2 (Cancer Susceptibility Candidate 2) was significantly upregulated in the pancreatic tissues from AP patients. Knockdown or overexpression of CASC2 in vitro could specifically repress or induce the expression of two proinflammatory cytokines including IL6 (Interleukin 6) and IL17, respectively. Changing the expression levels of several transcription factors that were predicted to bind to the promoter of CASC2, we found c-MYC could specifically regulate the expression of CASC2. Using immunoprecipitation, mass spectrometry, and co-immunoprecipitation assays, we proved that c-MYC assembled a transcriptional complex with PCAF (p300/CBP-associated Factor) and CtBP1/2 (C-terminal Binding Protein 1 and 2), terming as the CtBP-PCAF-c-MYC (CPM) complex. Further investigation revealed that CtBPs were amplified in the pancreatic tissues from AP patients and they functioned as coactivators to induce the expression of CASC2 and thus led to the upregulation of IL6 and IL17. Moreover, we identified that decreased DNA methylation levels in the promoters of CtBPs and inflammatory stimuli coactivated the expression of CtBPs. Collectively, we identified a new signaling pathway in which DNA methylation and inflammatory stimuli coregulate the CPM complex to activate CASC2 expression, whose induction further activates the expression of IL6 and IL17, eventually aggravating inflammation response and causing the pathology of AP.
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Affiliation(s)
- Jun Zeng
- Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China
| | - Jian-Yong Chen
- Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China
| | - Jun Meng
- Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China
| | - Zhi Chen
- Department of critical care medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, China.,Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
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Elevated hsa_circRNA_101015, hsa_circRNA_101211, and hsa_circRNA_103470 in the Human Blood: Novel Biomarkers to Early Diagnose Acute Pancreatitis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2419163. [PMID: 32149089 PMCID: PMC7049409 DOI: 10.1155/2020/2419163] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 10/24/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
Objective To explore potential biomarkers to accurately diagnose patients with acute pancreatitis (AP) at early stage and to auxiliary clinicians implement the best treatment options. Methods We selected 3 patients with AP and 3 healthy controls for microarray analysis to obtain differentially expressed circular RNAs (circRNAs). To further verify the results of the microarray analysis, the six differentially expressed circRNAs were confirmed by quantitative polymerase chain reaction (qPCR). The diagnostic accuracy and sensitivity of differentially expressed circRNAs were assessed using the receiver operating characteristic (ROC) curve. A ceRNA network was constructed based on the 6 differentially expressed circRNAs. Results There were 25 upregulated circRNAs and 26 downregulated circRNAs in the blood of patients with AP. Next, the qPCR verification results further confirmed three downregulated circRNAs, including hsa_circRNA_002532, has_circRNA_059665, and hsa_circRNA_104156, and three upregulated circRNAs including hsa_circRNA_101015, hsa_circRNA_101211, and hsa_circRNA_103470. Among them, hsa_circRNA_101015, hsa_circRNA_101211, and hsa_circRNA_103470 increased with the severity of the disease. ROC analysis showed that the three circRNA models show promise to diagnose AP. And a ceRNA network revealed that above six circRNAs could participate in complex regulated network. Conclusions Elevated hsa_circRNA_101015, hsa_circRNA_101211, and hsa_circRNA_103470 could be used as novel biomarkers to diagnose AP patients.
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Wang L, Zhao X, Wang Y. The pivotal role and mechanism of long non-coding RNA B3GALT5-AS1 in the diagnosis of acute pancreatitis. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:2307-2315. [PMID: 31177837 DOI: 10.1080/21691401.2019.1623231] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The present study planned to dig the potential impacts of long non-coding RNA B3GALT5-AS1 in acute pancreatitis (AP). A total of 66 patients who were diagnosed with AP using ultrasonic imaging were enrolled in the study. Expression levels of B3GALT5-AS1 in the serum of AP patients were determined. Afterwards, rat pancreatic AR42J acinar cells were disposed with caerulein to produce AP-like injury. The role and molecular mechanisms of B3GALT5-AS1 in AP were explored through in vitro cell experiments. The levels of lncRNA B3GALT5-AS1 were observed to be lessened in patients with AP relative to healthy controls. In addition, caerulein was observed to induce injuries in the AR42J cells (depressed cell viability, enhanced cell apoptosis, cytokines production, and levels of amylase). Overexpression of B3GALT5-AS1 alleviated the caerulein-produced injury in the AR42J cells. Moreover, it was determined that miR-203 showed a downside expression by B3GALT5-AS1 regulation, and the overexpression of B3GALT5-AS1 retrained caerulein-produced injury through the suppression of miR-203. In addition, it was observed that miR-203 lessened the level of nuclear factor interleukin-3 (NFIL3) and that NFIL3 was targeted by miR-203. Lastly, the impacts of B3GALT5-AS1 on caerulein-induced cell injury were manifested through the NF-κB signalling pathway. The data from the present study revealed that in patients with AP, B3GALT5-AS1 is expressed in reduced amounts. Overexpression of B3GALT5-AS1 may alleviate caerulein-induced cell injury in AR42J cells through the regulation of miR-203/NFIL3 axis and by inhibiting the activation of the NF-κB signals.
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Affiliation(s)
- Linlin Wang
- a Department of Ultrasound, China-Japan Union Hospital, Jilin University , Changchun , Jilin , China
| | - Xiaonan Zhao
- b Infectious Department of China-Japan Union Hospital, Jilin University , Changchun , China
| | - Ye Wang
- c Department of Pediatrics, China-Japan Union Hospital, Jilin University , Changchun , Jilin , China
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Yang Y, Huang Q, Luo C, Wen Y, Liu R, Sun H, Tang L. MicroRNAs in acute pancreatitis: From pathogenesis to novel diagnosis and therapy. J Cell Physiol 2019; 235:1948-1961. [PMID: 31552677 DOI: 10.1002/jcp.29212] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 09/03/2019] [Indexed: 02/06/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disorder initiated by activation of pancreatic zymogens, leading to pancreatic injury and systemic inflammatory response. MicroRNAs (miRNAs) have emerged as important regulators of gene expression and key players in human physiological and pathological processes. Discoveries over the past decade have confirmed that altered expression of miRNAs is implicated in the pathogenesis of AP. Indeed, a number of miRNAs have been found to be dysregulated in various cell types involved in AP such as acinar cells, macrophages, and lymphocytes. These aberrant miRNAs can regulate acinar cell necrosis and apoptosis, local and systemic inflammatory response, thereby contributing to the initiation and progression of AP. Moreover, patients with AP possess unique miRNA signatures when compared with healthy individuals or those with other diseases. In view of their stability and easy detection, therefore, miRNAs have the potential to act as biomarkers for the diagnosis and assessment of patients with AP. In this review, we provide an overview of the novel cellular and molecular mechanisms underlying the roles of miRNAs during the disease processes of AP, as well as the potential diagnosis and therapeutic biomarkers of miRNAs in patients with AP.
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Affiliation(s)
- Yi Yang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Qilin Huang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Chen Luo
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Yi Wen
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Ruohong Liu
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Hongyu Sun
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China
| | - Lijun Tang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, China.,College of Medicine, Southwest Jiaotong University, Chengdu, China
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Lou YB, Wang XH, Fu ZC. Effects of miR-7a-5p expression on proliferation and apoptosis of acinar cells in acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2019; 27:991-998. [DOI: 10.11569/wcjd.v27.i16.991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic acinar cell proliferation and apoptosis are closely related to the development of acute pancreatitis (AP). MicroRMAs (miRNAs) participate in cell proliferation and apoptosis by regulating target gene expression, and identification of miRNA molecules related to pancreatic acinar cell proliferation and apoptosis is important for clinical diagnosis and treatment of AP.
AIM To investigate the effect of miRNA-7a-5p on the proliferation and apoptosis of acinar cells in AP and the underlying mechanism.
METHODS A caerulin-induced AP model was constructed using pancreatitis acinar AR42J cells. qRT-PCR and Western blot were used to detect the expression of miR-7a-5p and protein inhibitor of activated signal transducer and activator of transcription 1 (PIAS1) in control AR42J cells and cerulein induced AR42J cells. After anti-miR-7a-5p and pcDNA-PIAS1 were transfected into AR42J cells, the proliferation of AR42J cells was detected by MTT assay, and the apoptosis of AR42J cells was detected by flow cytometry. The luciferase reporter system was used to detect the targeted regulation of PIAS1 gene by miR-7a-5p, and Western blot was used to detect the regulation of PIAS1 protein expression by miR-7a-5p. To silence PIAS1 expression by RNA interference, si-PIAS1 and its negative control plasmid were transfected into anti-miR-7a-5p treated AR42J cells, and the proliferation and apoptosis of AR42J cells were detected.
RESULTS Compared with control AR42J cells, the expression level of miR-7a-5p was significantly increased in cerulein induced AR42J cells (P < 0.05), and the expression of PIAS1 protein was significantly decreased (P < 0.05). Inhibition of miR-7a-5p expression promoted proliferation and inhibited apoptosis of AR42J cells. MiR-7a-5p could negatively regulate the expression of its target gene PIAS1. Overexpression of PIAS1 promoted proliferation and inhibited apoptosis of AR42J cells. Compared with the anti-miR-7a-5p + si-NC group, the activity of AR42J cells in the anti-miR-7a-5p + si-PIAS1 group was significantly decreased (P < 0.05), and the apoptosis rate was significantly increased (P < 0.05).
CONCLUSION MiR-7a-5p can promote the apoptosis of acinar cells and reduce the proliferation of cells in AP by inhibiting the expression of PIAS1.
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Affiliation(s)
- Yi-Bo Lou
- Department of Emergency Medicine, Yiwu Central Hospital, Yiwu 322000, Zhejiang Province, China
| | - Xiao-Hua Wang
- Department of Emergency Medicine, Yiwu Central Hospital, Yiwu 322000, Zhejiang Province, China
| | - Zhi-Cheng Fu
- Department of Gastroenterology, Yiwu Central Hospital, Yiwu 322000, Zhejiang Province, China
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Evaluation of Circulating MicroRNA Biomarkers in the Acute Pancreatic Injury Dog Model. Int J Mol Sci 2018; 19:ijms19103048. [PMID: 30301227 PMCID: PMC6212914 DOI: 10.3390/ijms19103048] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 09/22/2018] [Accepted: 10/03/2018] [Indexed: 12/22/2022] Open
Abstract
This study aimed to evaluate the usefulness of four microRNAs (miRNAs) in an acute pancreatic injury dog model. Acute pancreatitis was induced by infusion of cerulein for 2 h (7.5 μg/kg/h). The levels of well-known miRNAs, microRNA-216a (miR-216a) and microRNA-375 (miR-375), and new candidates microRNA-551b (miR-551b), and microRNA-7 (miR-7), were measured at 0, 0.5, 1, 2, 6, 12, and 24 h with serum amylase and lipase, and histopathological examination was performed. Among the four miRNAs, miR-216a and miR-375, and serum enzymes were significantly increased by cerulein treatment. The expression levels of miRNAs and serum enzymes peaked at 2–6 h with a similar pattern; however, the overall increases in miR-216a and miR-375 levels were much higher than those of the serum enzyme biomarkers. Increased levels of miR-216a and miR-375 were most highly correlated to the degree of individual histopathological injuries of the pancreas, and showed much greater dynamic response than serum enzyme biomarkers. Twenty-four-hour time-course analysis in this study revealed time-dependent changes of miRNA expression levels, from initial increase to decrease by predose level in acute pancreatitis. Our findings demonstrate that, in dogs, miR-216a and miR-375 have the potential to sensitively detect pancreatitis and reflect well the degree of pancreatic injury, whereas miR-551b and miR-7 do not.
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Zhang Y, Yan L, Han W. Elevated Level of miR-551b-5p is Associated With Inflammation and Disease Progression in Patients With Severe Acute Pancreatitis. Ther Apher Dial 2018; 22:649-655. [PMID: 29989302 DOI: 10.1111/1744-9987.12720] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 05/03/2018] [Accepted: 05/30/2018] [Indexed: 12/30/2022]
Abstract
Circulating microRNAs have the potential to be noninvasive biomarkers for assessing disease progression. MicroRNA-551b-5p (miR-551b-5p) was previously reported to be differentially expressed in pancreatic patients. The serum miR-551b-5p level was measured in patients with mild acute pancreatitis (MAP), severe acute pancreatitis (SAP), and healthy controls using quantitative real-time polymerase chain reaction (RT-PCR) analysis to evaluate its impact on inflammatory response. Acute Physiology and Chronic Health Evaluation II (APACHE II), Multiple Organ Dysfunction Score (MODS), Sequential Organ Assessment Score (SOFA), and Ranson's scores were recorded. Inflammatory cytokines, IL-6, IL-17, IL-1β, and Tumor Necrosis Factor-α (TNF-α), were detected in serum samples obtained from MAP and SAP patients on admission day 1, day 3, and day 5 using Enzyme Linked Immunosorbent Assay (ELISA). Inflammatory cytokines were analyzed in peripheral blood mononuclear cells (PBMCs), which were transfected with miR-551b-5p-negative controls and inhibitors. The serum miR-551b-5p level was significantly higher in MAP and SAP patients compared to controls (P < 0.001). An elevated miR-551b-5p level is positively associated with APACHE II, MODS, SOFA, and Ranson's scores (P < 0.001). Serum cytokines levels were significantly elevated in MAP and SAP patients compared to controls (P < 0.05). In addition, the level of these inflammatory cytokines was increased in PBMCs of SAP patients in comparison with those of healthy controls (P < 0.05), and this rise was significantly reduced with the addition of an miR-551b-5p inhibitor. In conclusion, serum miR-551b-5p is elevated in patients with MAP and SAP and is involved in the regulation of inflammatory response. It may be a useful biomarker for assessing the severity of SAP.
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Affiliation(s)
- Yongpeng Zhang
- Department of Emergency, People's Hospital of Dongying, Dongying, Shandong, China
| | - Liying Yan
- Department of Emergency, People's Hospital of Dongying, Dongying, Shandong, China
| | - Wang Han
- Department of Emergency, People's Hospital of Dongying, Dongying, Shandong, China
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Tahamtan A, Teymoori-Rad M, Nakstad B, Salimi V. Anti-Inflammatory MicroRNAs and Their Potential for Inflammatory Diseases Treatment. Front Immunol 2018; 9:1377. [PMID: 29988529 PMCID: PMC6026627 DOI: 10.3389/fimmu.2018.01377] [Citation(s) in RCA: 259] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 06/04/2018] [Indexed: 12/27/2022] Open
Abstract
Inflammation is a complicated biological and pathophysiological cascade of responses to infections and injuries, and inflammatory mechanisms are closely related to many diseases. The magnitude, the complicated network of pro- and anti-inflammatory factors, and the direction of the inflammatory response can impact on the development and progression of various disorders. The currently available treatment strategies often target the symptoms and not the causes of inflammatory disease and may often be ineffective. Since the onset and termination of inflammation are crucial to prevent tissue damage, a range of mechanisms has evolved in nature to regulate the process including negative and positive feedback loops. In this regard, microRNAs (miRNAs) have emerged as key gene regulators to control inflammation, and it is speculated that they are fine-tune signaling regulators to allow for proper resolution and prevent uncontrolled progress of inflammatory reactions. In this review, we discuss recent findings related to significant roles of miRNAs in immune regulation, especially the potential utility of these molecules as novel anti-inflammatory agents to treat inflammatory diseases. Furthermore, we discuss the possibilities of using miRNAs as drugs in the form of miRNA mimics or miRNA antagonists.
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Affiliation(s)
- Alireza Tahamtan
- Infectious Diseases Research Centre, Golestan University of Medical Sciences, Gorgan, Iran.,Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Teymoori-Rad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Britt Nakstad
- Department of Pediatric and Adolescent Medicine, Akershus University Hospital, Lørenskog, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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30
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Is MicroRNA-127 a Novel Biomarker for Acute Pancreatitis with Lung Injury? DISEASE MARKERS 2017; 2017:1204295. [PMID: 29434409 PMCID: PMC5757136 DOI: 10.1155/2017/1204295] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/23/2017] [Accepted: 10/15/2017] [Indexed: 02/05/2023]
Abstract
Background and Aims The aim of this study was to determine the expression of microRNA-127 (miR-127) in both rat models and patients of acute pancreatitis (AP) with lung injury (LI). Methods Rats were administrated with retrograde cholangiopancreatography injection of 0.5% or 3.5% sodium taurocholate to induce AP with mild or severe LI and were sacrificed at 6, 12, and 24 h. Rats from the control group received a laparotomy only. Plasma from a prospective cohort of AP patients was collected. The levels of miR-127 in the tissues and plasma were detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results The upregulation of miR-127 in the lungs of rats was detected in the groups of AP with severe LI at 6 h and 24 h, whereas it was scarcely detectable in plasma. In the pilot study that included 18 AP patients and 5 healthy volunteers, the plasma miR-127 level was significantly downregulated in AP patients with respiratory failure compared with the healthy volunteers (P = 0.014) and those without respiratory failure (P = 0.043). Conclusion miR-127 might serve as a potential marker for the identification of AP with LI.
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Elevated Serum miR-7, miR-9, miR-122, and miR-141 Are Noninvasive Biomarkers of Acute Pancreatitis. DISEASE MARKERS 2017; 2017:7293459. [PMID: 29332987 PMCID: PMC5733206 DOI: 10.1155/2017/7293459] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 11/08/2017] [Accepted: 11/12/2017] [Indexed: 12/20/2022]
Abstract
Background It has been reported that several microRNAs (miRNAs), such as miR-141, miR-9, and miR-122, are involved in the regulation of pancreatitis-related proteins or that their levels change in acute pancreatitis (AP) animal models. However, the serum levels, as well as the clinical diagnostic and prognostic values, of these miRNAs in AP patients remain unclear. Furthermore, as a pancreas- (islet) enriched miRNA, miR-7 was reported to be downregulated in AP patients, which requires further verification. Methods The levels of miR-7, miR-9, miR-122, and miR-141 were examined and compared using qRT-PCR among 80 severe AP patients, 80 mild AP patients, and 74 healthy controls. Results The serum levels of these four miRNAs were increased markedly in the AP patients compared with the controls, and these levels decreased significantly after effective therapy. Particularly, the level of miR-7 was higher in severe AP patients than in mild AP patients. ROC curve analysis demonstrated that four miRNAs could be used as potential biomarkers for AP. Moreover, these miRNAs showed strong positive correlations with CRP, which may be associated with inflammation. Conclusions The serum miR-7, miR-9, miR-122, and miR-141 levels were increased in AP patients. These 4 miRNAs may represent diagnostic and prognostic biomarkers for AP.
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32
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Xiang H, Tao X, Xia S, Qu J, Song H, Liu J, Shang D. Targeting MicroRNA Function in Acute Pancreatitis. Front Physiol 2017; 8:726. [PMID: 28983256 PMCID: PMC5613139 DOI: 10.3389/fphys.2017.00726] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/07/2017] [Indexed: 12/11/2022] Open
Abstract
Acute pancreatitis (AP) is a common gastrointestinal disorder that featured by acute inflammatory responses leading to systemic inflammatory response syndrome (SIRS) or multiple organ failure. A worldwide increase in annual incidence has been observed during the past decade with high acute hospitalization and mortality. Lack of any specific treatment for AP, even to this day, is a reminder that there is much to be learned about the exact pathogenesis of AP. Fortunately, the discovery of microRNA (miRNA) has started an entirely new thought process regarding the molecular mechanism associated with the disease processes. Given the extensive effort made on miRNA research, certain types of miRNA have been identified across a variety of biological processes, including cell differentiation, apoptosis, metabolism, and inflammatory responses. Mutations in miRNA sequences or deregulation of miRNA expression may contribute to the alteration of a pivotal physiological function leading to AP. Designing miRNA-related tools for AP diagnosis and treatment presents a novel and potential research frontier. In this mini-review, we summarize the current knowledge of various miRNAs closely interacting with AP and the possible development of targeted miRNA therapies in this disease, which may benefit the development of potential disease biomarkers and novel treatment targets for future medical implications.
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Affiliation(s)
- Hong Xiang
- College of Integrative Medicine, Dalian Medical UniversityDalian, China.,Department of General Surgery, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Xufeng Tao
- College of Pharmacy, Dalian Medical UniversityDalian, China
| | - Shilin Xia
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Jialin Qu
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Huiyi Song
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Jianjun Liu
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical UniversityDalian, China
| | - Dong Shang
- College of Integrative Medicine, Dalian Medical UniversityDalian, China.,Department of General Surgery, First Affiliated Hospital of Dalian Medical UniversityDalian, China
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Xin L, Gao J, Wang D, Lin JH, Liao Z, Ji JT, Du TT, Jiang F, Hu LH, Li ZS. Novel blood-based microRNA biomarker panel for early diagnosis of chronic pancreatitis. Sci Rep 2017; 7:40019. [PMID: 28074846 PMCID: PMC5225423 DOI: 10.1038/srep40019] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 12/01/2016] [Indexed: 12/11/2022] Open
Abstract
Chronic pancreatitis (CP) is an inflammatory disease characterized by progressive fibrosis of pancreas. Early diagnosis will improve the prognosis of patients. This study aimed to obtain serum miRNA biomarkers for early diagnosis of CP. In the current study, we analyzed the differentially expressed miRNAs (DEmiRs) of CP patients from Gene Expression Omnibus (GEO), and the DEmiRs in plasma of early CP patients (n = 10) from clinic by miRNA microarrays. Expression levels of DEmiRs were further tested in clinical samples including early CP patients (n = 20), late CP patients (n = 20) and healthy controls (n = 18). The primary endpoints were area under curve (AUC) and expression levels of DEmiRs. Four DEmiRs (hsa-miR-320a-d) were obtained from GEO CP, meanwhile two (hsa-miR-221 and hsa-miR-130a) were identified as distinct biomarkers of early CP by miRNA microarrays. When applied on clinical serum samples, hsa-miR-320a-d were accurate in predicting late CP, while hsa-miR-221 and hsa-miR-130a were accurate in predicting early CP with AUC of 100.0% and 87.5%. Our study indicates that miRNA expression profile is different in early and late CP. Hsa-miR-221 and hsa-miR-130a are biomarkers of early CP, and the panel of the above 6 serum miRNAs has the potential to be applied clinically for early diagnosis of CP.
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Affiliation(s)
- Lei Xin
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Jun Gao
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Dan Wang
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Jin-Huan Lin
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Zhuan Liao
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Jun-Tao Ji
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Ting-Ting Du
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Fei Jiang
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Liang-Hao Hu
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
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Zhang XX, Deng LH, Chen WW, Shi N, Jin T, Lin ZQ, Ma Y, Jiang K, Yang XN, Xia Q. Circulating microRNA 216 as a Marker for the Early Identification of Severe Acute Pancreatitis. Am J Med Sci 2016; 353:178-186. [PMID: 28183420 DOI: 10.1016/j.amjms.2016.12.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 12/04/2016] [Accepted: 12/08/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND To study the value of circulating microRNA 216 (miR-216) as a marker for the severity of acute pancreatitis (AP) in both murine models and patients. MATERIALS AND METHODS Mice with AP were induced by intraperitoneal injection of 50μg/kg/hour cerulean either 7 times, sacrificed at 8, 9, 10, 11 or 12 hours after the first injection, or 12 times, sacrificed at 24 hours after the first injection. Plasma samples and data from patients with AP were obtained from a prospective cohort. Quantitative reverse transcription polymerase chain reaction was used to determine the miR-216a and miR-216b level. RESULTS The upregulation of miR-216a and miR-216b in the serum of mice was induced by cerulean injection in both the 7- and 12-injection groups (P < 0.05). The downregulation of miR-216a in pancreatic tissues of mice with AP was detected (P < 0.05), but no difference was observed in pancreatic miR-216b levels among any of the groups (all P > 0.05). The serum miR-216a level was positively correlated with pancreatic histopathology severity scores, and was negatively correlated with pancreatic miR-216a (r = -0.483, P = 0.009). The plasma miR-216a level was significantly upregulated in patients with severe AP (SAP) compared with patients with mild AP (MAP) or moderate severe AP (MSAP) (SAP versus MAP, P = 0.04; SAP versus MSAP, P = 0.00), but no difference was seen between patients with MAP and those with MSAP (P = 0.73). CONCLUSIONS Circulating miR-216a might be a potential biomarker for the early identification of SAP.
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Affiliation(s)
- Xiao-Xin Zhang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Li-Hui Deng
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China.
| | - Wei-Wei Chen
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Na Shi
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Tao Jin
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Zi-Qi Lin
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Yun Ma
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Kun Jiang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Xiao-Nan Yang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Qing Xia
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China.
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35
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Deng LH, Xia Q. MicroRNAs in acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2016; 24:3128-3134. [DOI: 10.11569/wcjd.v24.i20.3128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis is an acute inflammatory condition of the pancreas that can develop into a complicated clinical course with severe local and systemic complications, resulting in a prolonged clinical course with considerable mortality. MicroRNAs (miRNAs), a class of small non-coding RNA molecules that negatively regulate gene expression, have potential value in clinical research and biomarker discovery. In recent years, accumulating evidence suggests that miRNAs may act as potential biomarkers for pancreatic tissue injury, and much attention has been paid to those miRNAs involved in acute pancreatitis. However, the role of miRNAs in acute pancreatitis has been validated in very few clinical studies. A better understanding of the role that miRNAs play in acute pancreatitis can lead to the development of new diagnostic and prognostic tools for future clinical applications.
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Chen WQ, Hu L, Chen GX, Deng HX. Role of microRNA-7 in digestive system malignancy. World J Gastrointest Oncol 2016; 8:121-127. [PMID: 26798443 PMCID: PMC4714141 DOI: 10.4251/wjgo.v8.i1.121] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 11/19/2015] [Indexed: 02/05/2023] Open
Abstract
There are several malignancies of the digestive system (including gastric, pancreatic and colorectal cancers, and hepatocellular carcinoma), which are the most common types of cancer and a major cause of death worldwide. MicroRNA (miR)-7 is abundant in the pancreas, playing an important role in pancreatic development and endocrine function. Expression of miR-7 is downregulated in digestive system malignancies compared with normal tissue. Although there are contrasting results for miR-7 expression, almost all research reveals that miR-7 is a tumor suppressor, by targeting various genes in specific pathways. Moreover, miR-7 can target different genes simultaneously in different malignancies of the digestive system. By acting on many cytokines, miR-7 is also involved in many gastrointestinal inflammatory diseases as a significant carcinogenic factor. Consequently, miR-7 might be a biomarker or therapeutic target gene in digestive system malignancies.
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Kuśnierz-Cabala B, Nowak E, Sporek M, Kowalik A, Kuźniewski M, Enguita FJ, Stępień E. Serum levels of unique miR-551-5p and endothelial-specific miR-126a-5p allow discrimination of patients in the early phase of acute pancreatitis. Pancreatology 2015; 15:344-51. [PMID: 26094040 DOI: 10.1016/j.pan.2015.05.475] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 04/08/2015] [Accepted: 05/26/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Vascular dysfunction is a severe complication which can cause organ ischemia and damage during acute pancreatitis (AP). Laboratory assessment of AP is based on several routine parameters and does not reflect endothelial dysfunction or organ injury. Recently, small non-protein-coding RNAs (miRNAs) have been introduced to laboratory diagnostics as new biomarkers or predictive parameters. Candidate miRNAs (hsa-miR-16-5p, -103a-3p, -122-5p, -126-5p, -148a-5p, -216a-5p, -375, and -551b-5b) were selected to check their possible clinical application in stratification of patients with different AP severity. METHODS In this observational study, 62 patients with mild (MAP) and 26 with moderate and severe (SAP) acute pancreatitis were included. The control group consisted of 10 age and sex matched subjects. Circulating miRNAs were analyzed in serum using a quantitative real-time PCR method (q-RT-PCR) by means of 3'-locked-nucleic-acid primers. RESULTS In SAP patients, a significant increase in most of the selected miRNAs (miR-126-5p, -148a-3p, -216a-5p and -551b-5p, and miR-375) was observed when compared to control subjects. In MAP patients, three miRNAs were significantly elevated: endothelial-specific miR-216a-5p, -551b-5p, as well as miR-375 that is highly abundant in pancreas. ROC analysis revealed that miR-126-p and miR-551b-5p can predict AP severity (AUC 0.748, sensitivity 60.0%, specificity 87.1%, p < 0.001) and (AUC 0.716; sensitivity 69.2%, specificity 72.6%, p < 0.001). miR-375 was not relevant (AUC 0.458; sensitivity 55.%, specificity 44.4%). CONCLUSIONS A pancreatic miRNA signature can be useful for assessment of pancreatic injury in the acute phase of AP. Endothelial dysfunction during AP is reflected by levels of specific circulating miRNAs and may help in patient stratification.
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Affiliation(s)
- Beata Kuśnierz-Cabala
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
| | - Ewelina Nowak
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Mateusz Sporek
- Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland; Surgery Department of the District Hospital in Sucha Beskidzka, Poland
| | - Artur Kowalik
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Marek Kuźniewski
- Department of Nephrology, Jagiellonian University Medical College, Krakow, Poland
| | - Francisco J Enguita
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ewa Stępień
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland; Department of Medical Physics, M. Smoluchowski Institute of Physics, Jagiellonian University, Krakow, Poland.
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Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs. Blood 2015; 125:3202-12. [PMID: 25838349 DOI: 10.1182/blood-2014-11-611046] [Citation(s) in RCA: 220] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 03/30/2015] [Indexed: 12/25/2022] Open
Abstract
The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-κB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease.
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Distinct miRNA signatures associate with subtypes of cholangiocarcinoma from infection with the tumourigenic liver fluke Opisthorchis viverrini. J Hepatol 2014; 61:850-8. [PMID: 25017828 DOI: 10.1016/j.jhep.2014.05.035] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/07/2014] [Accepted: 05/21/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Intrahepatic cholangiocarcinoma (ICC) is a significant public health problem in East Asia, where it is strongly associated with chronic infection by the food-borne parasite Opisthorchis viverrini (OV). We report the first comprehensive miRNA expression profiling by microarray of the most common histologic grades and subtypes of ICC: well differentiated, moderately differentiated, and papillary ICC. METHODS MicroRNA expression profiles from FFPE were compared among the following: ICC tumour tissue (n = 16), non-tumour tissue distally macrodissected from the same ICC tumour block (n = 15), and normal tissue (n = 13) from individuals undergoing gastric bypass surgery. A panel of deregulated miRNAs was validated by qPCR. RESULTS Each histologic grade and subtype of ICC displayed a distinct miRNA profile, with no cohort of miRNAs emerging as commonly deregulated. Moderately differentiated ICC showed the greatest miRNA deregulation in quantity and magnitude, followed by the papillary subtype, and then well differentiated ICC. Moreover, when ICC tumour tissues were compared to adjacent non-tumour tissue, similar miRNA dysregulation profiles were observed. CONCLUSIONS We show that common histologic grades and subtypes of ICC have distinct miRNA profiles. As histological grade and subtypes are associated with ICC aggressiveness, these profiles could be used to enhance the early detection and improve the personalised treatment for ICC. These findings also suggest the involvement of specific miRNAs during ICC tumour progression and differentiation. We plan to use these insights to (a) detect these profiles in circulation and (b) conduct functional analyses to decipher the roles of miRNAs in ICC tumour differentiation.
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