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Ruan K, Zhang J, Chu Z, Wang X, Zhang X, Liu Q, Yang J. Exosomes in acute pancreatitis: Pathways to cellular death regulation and clinical application potential. Int Immunopharmacol 2025; 153:114491. [PMID: 40117803 DOI: 10.1016/j.intimp.2025.114491] [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: 01/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/23/2025]
Abstract
Acute pancreatitis (AP) is a severe inflammatory condition of the digestive system which, in severe cases, can lead to persistent organ failure (POF). Developing novel therapeutic interventions and diagnostic biomarkers is critical to improve the management and prognosis of this disease. Exosomes, small extracellular vesicles, can reflect the inflammatory state of the pancreas, providing valuable insights into disease progression. Moreover, these vesicles are essential mediators of intercellular communication, modulating inflammatory responses by affecting patterns of cell death and macrophage polarization-key factors in determining AP clinical outcomes. Their stability, bioavailability, and capacity to transport various bioactive molecules render exosomes promising tools for early diagnosis and precision therapy, potentially enhancing patient outcomes. This review highlights the innovative potential of exosomes in transforming the management of AP, providing a foundation for more accurate diagnostics and targeted treatments with clinical applicability.
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Affiliation(s)
- Kaiyi Ruan
- Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Jinglei Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhuohuan Chu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiang Wang
- Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Xiaofeng Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China; Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310006, China.
| | - Qiang Liu
- Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310006, China.
| | - Jianfeng Yang
- Department of Gastroenterology, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310006, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310006, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou 310006, China.
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Cattane N, Mazzelli M, Begni V, Mombelli E, Papp M, Maj C, Riva MA, Cattaneo A. Molecular mechanisms underlying stress vulnerability and resilience in the chronic mild stress model: New insights from mRNA and miRNAs data combining. Brain Behav Immun 2024; 121:340-350. [PMID: 39074628 DOI: 10.1016/j.bbi.2024.07.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/23/2024] [Accepted: 07/20/2024] [Indexed: 07/31/2024] Open
Abstract
Stress is a major risk factor for the development of psychiatric disorders, including depression. However, its effects are not the same in all the subjects as only a portion of individuals exposed to stress will eventually develop negative mental outcomes, while others can be considered resilient. However, the biological processes underlying the development of a vulnerable or resilient phenotype are still poor understood. In order to cover this, we here used both transcriptomic and miRNomic based approaches in the ventral hippocampus of control (CON) and rats exposed to the chronic mild stress (CMS) paradigm, which were then divided into vulnerable (VULN) or resilient (RES) animals according to the sucrose consumption test. Transcriptomic analyses in VULN rats, compared to both the group of CON and RES animals, revealed the activation of inflammatory/immune-related pathways, specifically involved in antibodies and cytokine production, and the inhibition of pathways involved in protein synthesis. Conversely, transcriptomic data in RES animals suggested the activation of several pathways involved in neurotransmission. We then performed a mRNA-miRNA integration analysis by using miRComb R package, and we found that the most significant mRNA-miRNA pairs were involved in promoting the inflammatory status in VULN animals and, vice versa, by decreasing it in RES rats. Moreover, in VULN animals, the mRNA-miRNA combining analyses revealed the modulation of the olfactory sensory system, a key biological process that has been already found involved in the etiology of stress related disorders such as depression. Overall, our mRNA-miRNA integration-based approach identified distinct biological processes that are relevant for the development of a vulnerable or resilient phenotype in response to the negative effects of CMS exposure, which could allow the identification of novel targets for prevention or treatment.
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Affiliation(s)
- Nadia Cattane
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Monica Mazzelli
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Veronica Begni
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Elisa Mombelli
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Mariusz Papp
- Behavioral Pharmacology Laboratory, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
| | - Carlo Maj
- Center for Human Genetics, University of Marburg, Marburg, Germany
| | - Marco Andrea Riva
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Annamaria Cattaneo
- Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
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Wang L, Wang G, Song J, Yao D, Wang Y, Chen T. A comprehensive analysis of the prognostic characteristics of microRNAs in breast cancer. Front Genet 2024; 15:1293824. [PMID: 38572416 PMCID: PMC10987719 DOI: 10.3389/fgene.2024.1293824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 03/07/2024] [Indexed: 04/05/2024] Open
Abstract
Both overall survival (OS) and disease-specific survival (DSS) are significant when determining a patient's prognosis for breast cancer (BC). The effect of DSS-related microRNAs on BC susrvival, however, is not well understood. Here, we spotted differentially expressed miRNAs (DEMs) in the TCGA database of BC DSS, identified eight DSS-related miRNAs, and constructed a risk model. AUC values at 1, 3, and 5 years were 0.852, 0.861, and 0.868, respectively, indicating a risk model's excellent prognostic prediction ability. Then, we validated miRNA roles in BC OS and finally defined miR-551b as an independently prognostic miRNA in BC. According to function analysis, miR-551b is strongly linked with the emergence and spread of cancer, including protein ubiquitination, intracellular protein transport, metabolic pathways, and cancer pathways. Moreover, we confirmed the low expression of miR-551b in BC tissue and cells. After miR-551b inhibition or overexpression, cell function was either dramatically increased or diminished, respectively, indicating that miR-551b could regulate BC proliferation, invasion, and migration. In conclusion, we thoroughly clarified BC-related miRNAs on DSS and OS and verified miR-551b as a crucial regulator in the development and prognosis of cancer. These results can offer fresh ideas for BC therapy.
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Affiliation(s)
- Lingying Wang
- Department of Thoracic Surgery, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
| | - Gui Wang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jiahong Song
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Di Yao
- Department of Thoracic Surgery, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
| | - Yong Wang
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Tianyou Chen
- Department of Thoracic Surgery, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan, China
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Wei H, Zhao H, Cheng D, Zhu Z, Xia Z, Lu D, Yu J, Dong R, Yue J. miR-148a and miR-551b-5p regulate inflammatory responses via regulating autophagy in acute pancreatitis. Int Immunopharmacol 2024; 127:111438. [PMID: 38159552 DOI: 10.1016/j.intimp.2023.111438] [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: 08/26/2023] [Revised: 12/08/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024]
Abstract
Acute pancreatitis (AP) is a common inflammatory response that occurs in the pancreas with mortality rates as high as 30 %. However, there is still no consistent and effective treatment for AP now. MicroRNA-148 was reported to be involved in AP through IL-6 signaling pathway. Therefore, we aimed to further explore the detailed mechanisms of AP, to develop more therapeutic approach for AP. Exosomes were isolated from peripheral blood mononuclear cells of 20 AP patients and 20 healthy volunteers to evaluate the abnormally expressed miRNA. Then pancreatic acinar cells (PACs) were transfected with retrovirus to overexpress miR-148a/miR-551b-5p to evaluate their function. Both miR-148a and miR-551b-5p were highly expressed in AP patients than these in healthy cases. Then overexpressing miR-551b-5p in PACs could regulate autophagy through directly binding to Baculoviral IAP Repeat Containing 6, leading to the increased secretions of interleukin-1β (IL-1β) and interleukin-18 (IL-18) through interleukin-1 (IL-1) signaling pathway. Moreover, overexpressing miR-148a in PACs could decrease the secretions of IL-1β and IL-18 to modulate autophagy. The exosomal miRNA-148a and miRNA-551b-5p derived from peripheral blood mononuclear cells of AP patients may two-way mediate autophagy damage through IL-6/STAT3 signaling pathway, which participated in the AP pathogenesis. Our findings may provide new targets for the diagnosis and treatment of AP.
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Affiliation(s)
- Huiping Wei
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Hui Zhao
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China.
| | - Dongliang Cheng
- Pediatric Intensive Care Unit, Henan Provincial People's Hospital, No. 7 Weiwu Road, Jinshui District, Zhengzhou 450000, Henan Province, China
| | - Zhenni Zhu
- Pediatric Gastroenterology Department, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Zhi Xia
- Pediatric Intensive Care Unit, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Dan Lu
- Department of Clinical Examination, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Jing Yu
- Department of General Surgery, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Ran Dong
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
| | - Jing Yue
- Department of Emergency, Hubei Maternal and Child Health Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 745 Wuluo Road, Hongshan District, Wuhan 430070, Hubei, China
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Miao J, Kang L, Lan T, Wang J, Wu S, Jia Y, Xue X, Guo H, Wang P, Li Y. Identification of optimal reference genes in golden Syrian hamster with ethanol- and palmitoleic acid-induced acute pancreatitis using quantitative real-time polymerase chain reaction. Animal Model Exp Med 2023; 6:609-618. [PMID: 37202901 PMCID: PMC10757205 DOI: 10.1002/ame2.12321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 03/28/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND Acute pancreatitis (AP) is a severe disorder that leads to high morbidity and mortality. Appropriate reference genes are important for gene analysis in AP. This study sought to study the expression stability of several reference genes in the golden Syrian hamster, a model of AP. METHODS AP was induced in golden Syrian hamster by intraperitoneal injection of ethanol (1.35 g/kg) and palmitoleic acid (2 mg/kg). The expression of candidate genes, including Actb, Gapdh, Eef2, Ywhaz, Rps18, Hprt1, Tubb, Rpl13a, Nono, and B2m, in hamster pancreas at different time points (1, 3, 6, 9, and 24 h) posttreatment was analyzed using quantitative polymerase chain reaction. The expression stability of these genes was calculated using BestKeeper, Comprehensive Delta CT, NormFinder, and geNorm algorithms and RefFinder software. RESULTS Our results show that the expression of these reference genes fluctuated during AP, of which Ywhaz and Gapdh were the most stable genes, whereas Tubb, Eef2, and Actb were the least stable genes. Furthermore, these genes were used to normalize the expression of TNF-α messenger ribonucleic acid in inflamed pancreas. CONCLUSIONS In conclusion, Ywhaz and Gapdh were suitable reference genes for gene expression analysis in AP induced in Syrian hamster.
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Affiliation(s)
- Jinxin Miao
- Academy of Chinese Medicine ScienceHenan University of Chinese MedicineZhengzhouChina
| | - Le Kang
- Academy of Chinese Medicine ScienceHenan University of Chinese MedicineZhengzhouChina
| | - Tianfeng Lan
- Sino‐British Research Centre for Molecular Oncology, National Center for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Jianyao Wang
- Sino‐British Research Centre for Molecular Oncology, National Center for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Siqing Wu
- Academy of Chinese Medicine ScienceHenan University of Chinese MedicineZhengzhouChina
| | - Yifan Jia
- Academy of Chinese Medicine ScienceHenan University of Chinese MedicineZhengzhouChina
| | - Xia Xue
- Henan Key Laboratory of Helicobacter pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research CenterThe Fifth Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Haoran Guo
- Sino‐British Research Centre for Molecular Oncology, National Center for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Pengju Wang
- Sino‐British Research Centre for Molecular Oncology, National Center for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical SciencesZhengzhou UniversityZhengzhouChina
| | - Yan Li
- Academy of Chinese Medicine ScienceHenan University of Chinese MedicineZhengzhouChina
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Soffritti I, Gravelsina S, D'Accolti M, Bini F, Mazziga E, Vilmane A, Rasa-Dzelzkaleja S, Nora-Krukle Z, Krumina A, Murovska M, Caselli E. Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci 2023; 24:10582. [PMID: 37445763 DOI: 10.3390/ijms241310582] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/15/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multifactorial disease that causes increasing morbidity worldwide, and many individuals with ME/CFS symptoms remain undiagnosed due to the lack of diagnostic biomarkers. Its etiology is still unknown, but increasing evidence supports a role of herpesviruses (including HHV-6A and HHV-6B) as potential triggers. Interestingly, the infection by these viruses has been reported to impact the expression of microRNAs (miRNAs), short non-coding RNA sequences which have been suggested to be epigenetic factors modulating ME/CFS pathogenic mechanisms. Notably, the presence of circulating miRNAs in plasma has raised the possibility to use them as valuable biomarkers for distinguishing ME/CFS patients from healthy controls. Thus, this study aimed at determining the role of eight miRNAs, which were selected for their previous association with ME/CFS, as potential circulating biomarkers of the disease. Their presence was quantitatively evaluated in plasma from 40 ME/CFS patients and 20 healthy controls by specific Taqman assays, and the results showed that six out of the eight of the selected miRNAs were differently expressed in patients compared to controls; more specifically, five miRNAs were significantly upregulated (miR-127-3p, miR-142-5p, miR-143-3p, miR-150-5p, and miR-448), and one was downmodulated (miR-140-5p). MiRNA levels directly correlated with disease severity, whereas no significant correlations were observed with the plasma levels of seven pro-inflammatory cytokines or with the presence/load of HHV-6A/6B genome, as judged by specific PCR amplification. The results may open the way for further validation of miRNAs as new potential biomarkers in ME/CFS and increase the knowledge of the complex pathways involved in the ME/CFS development.
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Affiliation(s)
- Irene Soffritti
- Department of Chemical, Pharmaceutical and Agricultural Sciences, and LTTA, University of Ferrara, 44121 Ferrara, Italy
| | - Sabine Gravelsina
- Institute of Microbiology and Virology, Rīga Stradiņš University, LV-1067 Riga, Latvia
| | - Maria D'Accolti
- Department of Chemical, Pharmaceutical and Agricultural Sciences, and LTTA, University of Ferrara, 44121 Ferrara, Italy
| | - Francesca Bini
- Department of Chemical, Pharmaceutical and Agricultural Sciences, and LTTA, University of Ferrara, 44121 Ferrara, Italy
| | - Eleonora Mazziga
- Department of Chemical, Pharmaceutical and Agricultural Sciences, and LTTA, University of Ferrara, 44121 Ferrara, Italy
| | - Anda Vilmane
- Institute of Microbiology and Virology, Rīga Stradiņš University, LV-1067 Riga, Latvia
| | | | - Zaiga Nora-Krukle
- Institute of Microbiology and Virology, Rīga Stradiņš University, LV-1067 Riga, Latvia
| | - Angelika Krumina
- Faculty of Medicine, Department of Infectology, Rīga Stradiņš University, LV-1006 Riga, Latvia
| | - Modra Murovska
- Institute of Microbiology and Virology, Rīga Stradiņš University, LV-1067 Riga, Latvia
| | - Elisabetta Caselli
- Department of Chemical, Pharmaceutical and Agricultural Sciences, and LTTA, University of Ferrara, 44121 Ferrara, Italy
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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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Venkatesh K, Glenn H, Delaney A, Andersen CR, Sasson SC. Fire in the belly: A scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol 2023; 13:1077414. [PMID: 36713404 PMCID: PMC9874226 DOI: 10.3389/fimmu.2022.1077414] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Introduction Acute pancreatitis (AP) is characterised by an inflammatory response that in its most severe form can cause a systemic dysregulated immune response and progression to acute multi-organ dysfunction. The pathobiology of the disease is unclear and as a result no targeted, disease-modifying therapies exist. We performed a scoping review of data pertaining to the human immunology of AP to summarise the current field and to identify future research opportunities. Methods A scoping review of all clinical studies of AP immunology was performed across multiple databases. Studies were included if they were human studies of AP with an immunological outcome or intervention. Results 205 studies met the inclusion criteria for the review. Severe AP is characterised by significant immune dysregulation compared to the milder form of the disease. Broadly, this immune dysfunction was categorised into: innate immune responses (including profound release of damage-associated molecular patterns and heightened activity of pattern recognition receptors), cytokine profile dysregulation (particularly IL-1, 6, 10 and TNF-α), lymphocyte abnormalities, paradoxical immunosuppression (including HLA-DR suppression and increased co-inhibitory molecule expression), and failure of the intestinal barrier function. Studies including interventions were also included. Several limitations in the existing literature have been identified; consolidation and consistency across studies is required if progress is to be made in our understanding of this disease. Conclusions AP, particularly the more severe spectrum of the disease, is characterised by a multifaceted immune response that drives tissue injury and contributes to the associated morbidity and mortality. Significant work is required to develop our understanding of the immunopathology of this disease if disease-modifying therapies are to be established.
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Affiliation(s)
- Karthik Venkatesh
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
| | - Hannah Glenn
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Anthony Delaney
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Christopher R. Andersen
- Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Division of Critical Care, The George Institute for Global Health, Newtown, NSW, Australia
| | - Sarah C. Sasson
- The Kirby Institute, The University of New South Wales, Kensington, NSW, Australia
- Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW, Australia
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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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Gu H, Peng J, Wang M, Guo Z, Huang H, Yan L. MicroRNA-320-3p promotes the progression of acute pancreatitis by blocking DNMT3a-mediated MMP8 methylation in a targeted manner. Mol Immunol 2022; 151:84-94. [PMID: 36113364 DOI: 10.1016/j.molimm.2022.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 08/05/2022] [Accepted: 09/05/2022] [Indexed: 11/24/2022]
Abstract
In this research, we screened out two genes upregulated in mice with acute pancreatitis (AP) by gene sequencing: microRNA (miR)-320-3p and matrix metalloprotease 8 (MMP8). This study was designed to determine whether miR-320-3p and MMP8 participate in AP development and explore the mechanisms, with a new idea for clinical diagnosis and treatment of AP. Expression of miR-320-3p, DNA methyltransferase 3a (DNMT3a), and MMP8 in mouse pancreatic tissues and AR42J cells was tested by RT-qPCR and western blot assays. Pancreatic pathological changes, serum amylase and lipase, and inflammatory factors in mouse serum and cell supernatant were measured by hematoxylin-eosin staining, automation analyzer, and enzyme-linked immunosorbent assay, respectively. Cell proliferation and apoptosis were determined by CCK-8 assay and flow cytometry. The interaction between miR-320-3p, DNMT3a, and MMP8 was verified by luciferase activity assay, ChIP-qPCR, and MSP assay. High expression of miR-320-3p and MMP8, and low expression of DNMT3a were observed in pancreatic tissues of AP mice and caerulein-induced AP cellular model. Downregulation of miR-320-3p alleviated injury of mouse pancreas, reduced the levels of serum amylase and lipase, and blocked inflammatory factor levels in AP mice. In caerulein-induced AP cellular models, inhibiting miR-320-3p facilitated proliferation and inhibited apoptosis. Upregulation of MMP8 resulted in the opposite results, which could be reversed by simultaneous inhibition of miR-320-3p. miR-320-3p targeted DNMT3a, and downregulating miR-320-3p promoted DNMT3a expression. Moreover, DNMT3a promoted DNA methylation in MMP8 promoter region, thereby inhibiting MMP8 expression in AP mouse and cellular models. This research suggests that miR-320-3p inhibits DNMT3a to reduce MMP8 methylation and increase MMP8 expression, thereby promoting AP progression.
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Affiliation(s)
- Huan Gu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Jie Peng
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Meng Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Zimeng Guo
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Haosu Huang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
| | - Lu Yan
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
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12
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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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13
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Wang X, Qian J, Meng Y, Wang P, Cheng R, Zhou G, Zhu S, Liu C. Salidroside alleviates severe acute pancreatitis-triggered pancreatic injury and inflammation by regulating miR-217-5p/YAF2 axis. Int Immunopharmacol 2022; 111:109123. [PMID: 35963157 DOI: 10.1016/j.intimp.2022.109123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/28/2022] [Accepted: 07/31/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Our previous studies have shown that salidroside (Sal) exerted a protective effect in severe acute pancreatitis (SAP) via inhibiting the inflammatory response. However, the molecular mechanism has not been fully elucidated. METHODS Using SAP rat model and miRNA microarray, the effect of Sal on miRNA expression profiling was determined and then validated their changes by quantitative Real-time PCR (qRT-PCR). Then, SAP cell model, enzyme-linked immunosorbent assay (ELISA) and Cell Counting Kit-8 (CCK-8) assay were used to explore the biological function of miR-217-5p in vitro. Bioinformatics analysis, luciferase reporter assay and miRNA pulldown assay were performed to investigate the underlying mechanism of miR-217-5p in the protection of Sal against SAP. RESULTS Compared with SAP group, 21 differentially expressed miRNAs were identified in SAP + Sal group. The target genes of these miRNAs were strongly associated with regulation of transcription, Axon guidance, Pathways in cancer and MAPK signaling pathway. Among these miRNAs, miR-217-5p was the most downregulated miRNA. Sal treatment alleviated cell injury and reduced the production of pro-inflammatory cytokines. Whereas overexpression of miR-217-5p reversed the effects of Sal. We identified YY1 associated factor 2 (YAF2) as a direct target gene of miR-217-5p and Sal treatment could upregulate YAF2 expression via targeting miR-217-5p. Furthermore, knockdown of YAF2 counteracted Sal-induced alleviation of cell injury and inflammation. Moreover, Sal could suppress the activation of p38 MAPK pathway by regulating miR-217-5p/YAF2 axis. CONCLUSIONS Our findings for the first time highlighted that Sal alleviated pancreatic injury and inhibited inflammation by regulating miR-217-5p/YAF2 axis, which might provide new therapeutic strategies for SAP treatment.
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Affiliation(s)
- Xiaohong Wang
- Department of Gastroenterology, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, Jiangsu, China.
| | - Jing Qian
- Department of General Surgery, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, Jiangsu, China
| | - Yun Meng
- Department of Gastroenterology, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, Jiangsu, China
| | - Ping Wang
- Department of Gastroenterology, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, Jiangsu, China
| | - Ruizhi Cheng
- Department of Gastroenterology, Yizheng Hospital of Nanjing Drum Tower Hospital Group, Yizheng 211900, Jiangsu, China
| | - Guoxiong Zhou
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, China
| | - Shunxing Zhu
- Laboratory Animal Center of Nantong University, Nantong 226001, Jiangsu, China
| | - Chun Liu
- Laboratory Animal Center of Nantong University, Nantong 226001, Jiangsu, China
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14
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Fernandez GJ, Ramírez-Mejia JM, Urcuqui-Inchima S. Vitamin D boosts immune response of macrophages through a regulatory network of microRNAs and mRNAs. J Nutr Biochem 2022; 109:109105. [PMID: 35858666 DOI: 10.1016/j.jnutbio.2022.109105] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 10/31/2022]
Abstract
Vitamin D is associated with the stimulation of innate immunity, inflammation, and host defense against pathogens. Macrophages express receptors of Vitamin D, regulating transcription of genes related to immune processes. However, the transcriptional and post-transcriptional strategies controlling gene expression in differentiated macrophages, and how they are influenced by Vitamin D are not well understood. We studied whether Vitamin D enhances immune response by regulating the expression of microRNAs and mRNAs. Analysis of the transcriptome showed differences in expression of 199 genes, of which 68% were up-regulated, revealing the cell state of monocyte-derived macrophages differentiated with Vitamin D (D3-MDMs) as compared to monocyte-derived macrophages (MDMs). The differentially expressed genes appear to be associated with pathophysiological processes, including inflammatory responses, and cellular stress. Transcriptional motifs in promoter regions of up- or down-regulated genes showed enrichment of VDR motifs, suggesting possible roles of transcriptional activator or repressor in gene expression. Further, microRNA-Seq analysis indicated that there were 17 differentially expressed miRNAs, of which, 7 were up-regulated and 10 down-regulated, suggesting that Vitamin D plays a critical role in the regulation of miRNA expression during macrophages differentiation. The miR-6501-3p, miR-1273h-5p, miR-665, miR-1972, miR-1183, miR-619-5p were down-regulated in D3-MDMs compared to MDMs. The integrative analysis of miRNA and mRNA expression profiles predict that miR-1972, miR-1273h-5p, and miR-665 regulate genes PDCD1LG2, IL-1B, and CD274, which are related to the inflammatory response. Results suggest an essential role of Vitamin D in macrophage differentiation that modulates host response against pathogens, inflammation, and cellular stress.
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Affiliation(s)
- Geysson Javier Fernandez
- Grupo Inmunovirología, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Julieta M Ramírez-Mejia
- Research group CIBIOP, Department of Biological Sciences, Universidad EAFIT, Medellín, Antioquia, Colombia
| | - Silvio Urcuqui-Inchima
- Grupo Inmunovirología, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia.
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15
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Liu D, Wen L, Wang Z, Hai Y, Yang D, Zhang Y, Bai M, Song B, Wang Y. The Mechanism of Lung and Intestinal Injury in Acute Pancreatitis: A Review. Front Med (Lausanne) 2022; 9:904078. [PMID: 35872761 PMCID: PMC9301017 DOI: 10.3389/fmed.2022.904078] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/10/2022] [Indexed: 12/12/2022] Open
Abstract
Acute pancreatitis (AP), as a common cause of clinical acute abdomen, often leads to multi-organ damage. In the process of severe AP, the lungs and intestines are the most easily affected organs aside the pancreas. These organ damages occur in succession. Notably, lung and intestinal injuries are closely linked. Damage to ML, which transports immune cells, intestinal fluid, chyle, and toxic components (including toxins, trypsin, and activated cytokines to the systemic circulation in AP) may be connected to AP. This process can lead to the pathological changes of hyperosmotic edema of the lung, an increase in alveolar fluid level, destruction of the intestinal mucosal structure, and impairment of intestinal mucosal permeability. The underlying mechanisms of the correlation between lung and intestinal injuries are inflammatory response, oxidative stress, and endocrine hormone secretion disorders. The main signaling pathways of lung and intestinal injuries are TNF-α, HMGB1-mediated inflammation amplification effect of NF-κB signal pathway, Nrf2/ARE oxidative stress response signaling pathway, and IL-6-mediated JAK2/STAT3 signaling pathway. These pathways exert anti-inflammatory response and anti-oxidative stress, inhibit cell proliferation, and promote apoptosis. The interaction is consistent with the traditional Chinese medicine theory of the lung being connected with the large intestine (fei yu da chang xiang biao li in Chinese). This review sought to explore intersecting mechanisms of lung and intestinal injuries in AP to develop new treatment strategies.
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Affiliation(s)
- Dongling Liu
- School of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Linlin Wen
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
- County People’s Hospital, Pingliang, China
| | - Zhandong Wang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yang Hai
- Gansu University of Chinese Medicine/Scientific Research and Experimental Center, Lanzhou, China
| | - Dan Yang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yanying Zhang
- Gansu University of Chinese Medicine/Scientific Research and Experimental Center, Lanzhou, China
- Gansu Provincial Engineering Laboratory for Research and Promotion of Quality Standardization of Authentic Medicinal Materials in Gansu Province/Provincial Key Laboratory of Pharmaceutical Chemistry and Quality Research in Colleges and Universities in Gansu Province/Gansu Provincial Laboratory Animal Industry Technology Center, Lanzhou, China
| | - Min Bai
- Gansu Provincial Engineering Laboratory for Research and Promotion of Quality Standardization of Authentic Medicinal Materials in Gansu Province/Provincial Key Laboratory of Pharmaceutical Chemistry and Quality Research in Colleges and Universities in Gansu Province/Gansu Provincial Laboratory Animal Industry Technology Center, Lanzhou, China
| | - Bing Song
- Gansu University of Chinese Medicine/Scientific Research and Experimental Center, Lanzhou, China
- Gansu Provincial Engineering Laboratory for Research and Promotion of Quality Standardization of Authentic Medicinal Materials in Gansu Province/Provincial Key Laboratory of Pharmaceutical Chemistry and Quality Research in Colleges and Universities in Gansu Province/Gansu Provincial Laboratory Animal Industry Technology Center, Lanzhou, China
| | - Yongfeng Wang
- Gansu Provincial Engineering Laboratory for Research and Promotion of Quality Standardization of Authentic Medicinal Materials in Gansu Province/Provincial Key Laboratory of Pharmaceutical Chemistry and Quality Research in Colleges and Universities in Gansu Province/Gansu Provincial Laboratory Animal Industry Technology Center, Lanzhou, China
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Thapa R, Iqbal Z, Garikipati A, Siefkas A, Hoffman J, Mao Q, Das R. Early prediction of severe acute pancreatitis using machine learning. Pancreatology 2022; 22:43-50. [PMID: 34690046 DOI: 10.1016/j.pan.2021.10.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 09/27/2021] [Accepted: 10/12/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute pancreatitis (AP) is one of the most common causes of gastrointestinal-related hospitalizations in the United States. Severe AP (SAP) is associated with a mortality rate of nearly 30% and is distinguished from milder forms of AP. Risk stratification to identify SAP cases needing inpatient treatment is an important aspect of AP diagnosis. METHODS We developed machine learning algorithms to predict which patients presenting with AP would require treatment for SAP. Three models were developed using logistic regression, neural networks, and XGBoost. Models were assessed in terms of area under the receiver operating characteristic (AUROC) and compared to the Harmless Acute Pancreatitis Score (HAPS) and Bedside Index for Severity in Acute Pancreatitis (BISAP) scores for AP risk stratification. RESULTS 61,894 patients were used to train and test the machine learning models. With an AUROC value of 0.921, the model developed using XGBoost outperformed the logistic regression and neural network-based models. The XGBoost model also achieved a higher AUROC than both HAPS and BISAP for identifying patients who would be diagnosed with SAP. CONCLUSIONS Machine learning may be able to improve the accuracy of AP risk stratification methods and allow for more timely treatment and initiation of interventions.
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17
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Tang GX, Yang MS, Xiang KM, Yang BC, Liu ZL, Zhao SP. MiR-20b-5p modulates inflammation, apoptosis and angiogenesis in severe acute pancreatitis through autophagy by targeting AKT3. Autoimmunity 2021; 54:460-470. [PMID: 34402705 DOI: 10.1080/08916934.2021.1953484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a common acute abdominal disease with high morbidity and mortality. However, the mechanism underlying SAP is still unclear. METHODS Cerulean and LPS (Cer-LPS) was used to establish a rat model and an in vitro model of SAP. qRT-PCR, western blot and IHC were determined to analyse the expression of mRNA and proteins. IL-1β, TNF-α and IL-6 levels were measured applying ELISA. H&E staining was determined to observe the pathological changes. Apoptosis was tested by AV-PI staining using flow cytometry. CCK8 assay was taken to detect cell viability. Cell migration was assessed by transwell assay. Tube formation assay was conducted to evaluate angiogenesis. Luciferase assay was used to detect relationship of miR-20b-5p and AKT3. RESULTS MiR-20b-5p was lowly expressed in SAP models both in vivo and in vitro. Overexpression of miR-20b-5p restrained inflammation and apoptosis in Cer-LPS treated pancreatic acinar cells. Furthermore, miR-20b-5p promoted the angiogenesis of vascular endothelial cells, since the viability, migration and the capability of tube formation were increased by miR-20b-5p. Mechanically, miR-20b-5p directly targeted AKT3 to promote autophagy. Furthermore, miR-20b-5p could prevent the inflammation, apoptosis and enhance angiogenesis via enhancing autophagy, which was verified in vivo. CONCLUSION This study demonstrated miR-20b-5p attenuates SAP through directly targeting AKT3 to regulate autophagy, subsequently inhibit inflammation and apoptosis, and promote angiogenesis. Our findings suggested a novel target of miR-20b-5p for the therapy of SAP.
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Affiliation(s)
- Guan-Xiu Tang
- Department of Geriatric Medicine, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Ming-Shi Yang
- Department of Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Kai-Min Xiang
- Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Bing-Chang Yang
- Department of Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Zuo-Liang Liu
- Department of Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
| | - Shang-Ping Zhao
- Department of Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, P.R. China
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18
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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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19
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Shen Y, Xue C, You G, Liu C. miR-9 alleviated the inflammatory response and apoptosis in caerulein-induced acute pancreatitis by regulating FGF10 and the NF-κB signaling pathway. Exp Ther Med 2021; 22:795. [PMID: 34093751 PMCID: PMC8170642 DOI: 10.3892/etm.2021.10227] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRs) have been implicated in the development of acute pancreatitis (AP). However, the role and potential mechanism of miR-9 in AP progression remains unclear. Caerulein-treated AR42J cells were used as a cellular model of AP. Results revealed caerulein triggered an inflammatory response by promoting the secretion of inflammatory cytokines [tumor necrosis factor-α, interleukin (IL) 1β and IL-6], as evidenced by ELISA. Furthermore, caerulein-induced apoptosis was reported by flow cytometry and western blot assays. Additionally, miR-9 expression was downregulated by caerulein treatment, as demonstrated by reverse transcription quantitative PCR. However, miR-9 overexpression reduced the inflammatory response and apoptosis in caerulein-treated AR42J cells. miR-9 knockdown resulted in opposite effects. Furthermore, fibroblast growth factor (FGF) 10 was validated to be targeted via miR-9 by luciferase, RNA immunoprecipitation and RNA pull-down assays. Results demonstrated increased FGF10 expression in caerulein-treated AR42J cells and that FGF10 overexpression exacerbated the caerulein-induced inflammatory response and apoptosis, while its knockdown had the opposite effect. Additionally, FGF10 reversed the effect of miR-9 on caerulein-induced injury in AR42J cells. Results demonstrated that miR-9 inhibited the expression of the nuclear factor κB (NF-κB) pathway-related proteins by downregulating FGF10. As a result, miR-9 decreased inflammatory response and apoptosis in caerulein-treated AR42J cells by targeting FGF10 and blocking NF-κB signaling, suggesting that miR-9 may serve as a novel target for AP treatment.
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Affiliation(s)
- Yang Shen
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
| | - Chengjun Xue
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
| | - Guoli You
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
| | - Cui Liu
- Department of Gastroenterology, Jiangsu Hospital, Nantong University, Nantong, Jiangsu 224700, P.R. China
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Dysregulation of miR-192-5p in acute pancreatitis patients with nonalcoholic fatty liver and its functional role in acute pancreatitis progression. Biosci Rep 2021; 40:224146. [PMID: 32406504 PMCID: PMC7256679 DOI: 10.1042/bsr20194345] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 05/06/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a frequent metabolic disease and has been demonstrated to contribute to the severity of acute pancreatitis (AP). The present study aimed to investigate the aberrant expression of microRNA-192-5p (miR-192-5p) in AP patients with NAFLD, and further analyze the clinical significance and biological function of miR-192-5p in AP progression. METHODS Expression of miR-192-5p was estimated using quantitative real-time PCR (qRT-PCR). Diagnostic value of miR-192-5p was evaluated by the receiver operating characteristic curve (ROC). The effects of miR-192-5p on cell proliferation, apoptosis and inflammatory response of pancreatic acinar cells were further assessed by CCK-8 assay, flow cytometry and enzyme-linked immunosorbent assay (ELISA). RESULTS Circulating miR-192-5p was decreased in AP patients with NAFLD compared with those patients without NAFLD and healthy controls (P<0.05). The down-regulated expression of miR-192-5p had a relative high diagnostic accuracy to distinguish the AP patients with NAFLD from the cases without NAFLD. Furthermore, the overexpression of miR-192-5p in pancreatic acinar cells led to the decreased cell proliferation, increased cell apoptosis and suppressed inflammatory reaction (all P<0.05). CONCLUSION Collectively, all data indicated that serum expression of miR-192-5p in AP patients with NAFLD is significantly decreased and serves as a candidate diagnostic biomarker. The up-regulation of miR-192-5p in pancreatic acinar cell leads to increased cell apoptosis and decreased inflammatory response, suggesting the potential of miR-192-5p as a therapeutic target of AP.
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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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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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Sell SL, Widen SG, Prough DS, Hellmich HL. Principal component analysis of blood microRNA datasets facilitates diagnosis of diverse diseases. PLoS One 2020; 15:e0234185. [PMID: 32502186 PMCID: PMC7274418 DOI: 10.1371/journal.pone.0234185] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 05/19/2020] [Indexed: 12/11/2022] Open
Abstract
Early, ideally pre-symptomatic, recognition of common diseases (e.g., heart disease, cancer, diabetes, Alzheimer’s disease) facilitates early treatment or lifestyle modifications, such as diet and exercise. Sensitive, specific identification of diseases using blood samples would facilitate early recognition. We explored the potential of disease identification in high dimensional blood microRNA (miRNA) datasets using a powerful data reduction method: principal component analysis (PCA). Using Qlucore Omics Explorer (QOE), a dynamic, interactive visualization-guided bioinformatics program with a built-in statistical platform, we analyzed publicly available blood miRNA datasets from the Gene Expression Omnibus (GEO) maintained at the National Center for Biotechnology Information at the National Institutes of Health (NIH). The miRNA expression profiles were generated from real time PCR arrays, microarrays or next generation sequencing of biologic materials (e.g., blood, serum or blood components such as platelets). PCA identified the top three principal components that distinguished cohorts of patients with specific diseases (e.g., heart disease, stroke, hypertension, sepsis, diabetes, specific types of cancer, HIV, hemophilia, subtypes of meningitis, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s disease, mild cognitive impairment, aging, and autism), from healthy subjects. Literature searches verified the functional relevance of the discriminating miRNAs. Our goal is to assemble PCA and heatmap analyses of existing and future blood miRNA datasets into a clinical reference database to facilitate the diagnosis of diseases using routine blood draws.
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Affiliation(s)
- Stacy L. Sell
- Department of Anesthesiology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America
| | - Steven G. Widen
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America
| | - Donald S. Prough
- Department of Anesthesiology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America
| | - Helen L. Hellmich
- Department of Anesthesiology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America
- * E-mail:
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24
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Shan Y, Kong W, Zhu A, Zhang J, Ying R, Zhu W. Increased levels of miR-372 correlate with disease progression in patients with hyperlipidemic acute pancreatitis. Exp Ther Med 2020; 19:3845-3850. [PMID: 32346449 DOI: 10.3892/etm.2020.8609] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/23/2020] [Indexed: 12/13/2022] Open
Abstract
The aim of the present study was to investigate the expression of microRNA (miRNA)-372 in the serum of patients with hyperlipidemic acute pancreatitis (HTGAP), and its clinical significance. Patients with a serum lipid concentration ≥11.3 or 5.65-11.3 mmol/l with chylous serum were included in group A (n=40). The remaining patients did not have HTGAP and were included in group B (B). A further 25 patients with hyperlipidemia, but not AP (group C), and 30 healthy volunteers (group D) were recruited as controls. The level of miR-372 in the serum of group A (4.76±2.60) was significantly increased compared with groups B (0.98±0.80), C (0.85±0.62) and D (0.76±0.44); however, there was no significant difference in the expression of miR-372 between groups B, C and D. The expression level of miR-372 was significantly increased in the severe HTGAP group (6.45±2.20) compared with the mild HTGAP group (3.08±1.74). Further experiments suggested that the expression level of miR-372 was positively correlated with the level of triacylglycerol (r=0.666; P<0.001) but not with the level of amylase (r=-0.145; P>0.05). ROC analysis indicated that the combined use of miR-372 expression levels and Acute Physiology and Chronic Health Evaluation II scoring improved the diagnostic value for HTGAP. In summary, the expression of miR-372 in HTGAP was significantly upregulated and increased with the severity of the disease. The results of the present study may provide a novel strategy for the diagnosis and severity assessment of HTGAP in the clinic.
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Affiliation(s)
- Yuqiang Shan
- Department of General Surgery, Jinling Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China.,Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Wencheng Kong
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Akao Zhu
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Jian Zhang
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Rongchao Ying
- Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Weiming Zhu
- Department of General Surgery, Jinling Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China
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Lapitz A, Arbelaiz A, O’Rourke CJ, Lavin JL, La Casta A, Ibarra C, Jimeno JP, Santos-Laso A, Izquierdo-Sanchez L, Krawczyk M, Perugorria MJ, Jimenez-Aguero R, Sanchez-Campos A, Riaño I, Gónzalez E, Lammert F, Marzioni M, Macias RI, Marin JJ, Karlsen TH, Bujanda L, Falcón-Pérez JM, Andersen JB, Aransay AM, Rodrigues PM, Banales JM. Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis. Cells 2020; 9:721. [PMID: 32183400 PMCID: PMC7140677 DOI: 10.3390/cells9030721] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/06/2020] [Accepted: 03/09/2020] [Indexed: 12/11/2022] Open
Abstract
: Cholangiocarcinoma (CCA) comprises a group of heterogeneous biliary cancers with dismal prognosis. The etiologies of most CCAs are unknown, but primary sclerosing cholangitis (PSC) is a risk factor. Non-invasive diagnosis of CCA is challenging and accurate biomarkers are lacking. We aimed to characterize the transcriptomic profile of serum and urine extracellular vesicles (EVs) from patients with CCA, PSC, ulcerative colitis (UC), and healthy individuals. Serum and urine EVs were isolated by serial ultracentrifugations and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting. EVs transcriptome was determined by Illumina gene expression array [messenger RNAs (mRNA) and non-coding RNAs (ncRNAs)]. Differential RNA profiles were found in serum and urine EVs from patients with CCA compared to control groups (disease and healthy), showing high diagnostic capacity. The comparison of the mRNA profiles of serum or urine EVs from patients with CCA with the transcriptome of tumor tissues from two cohorts of patients, CCA cells in vitro, and CCA cells-derived EVs, identified 105 and 39 commonly-altered transcripts, respectively. Gene ontology analysis indicated that most commonly-altered mRNAs participate in carcinogenic steps. Overall, patients with CCA present specific RNA profiles in EVs mirroring the tumor, and constituting novel promising liquid biopsy biomarkers.
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Affiliation(s)
- Ainhoa Lapitz
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
| | - Ander Arbelaiz
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
| | - Colm J. O’Rourke
- Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), 2200 Copenhagen, Denmark; (C.J.O.); (J.B.A.)
| | - Jose L. Lavin
- CIC bioGUNE, Genome Analysis Platform, 48160 Derio, Spain; (J.L.L.); (A.M.A.)
| | - Adelaida La Casta
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
| | - Cesar Ibarra
- Hospital of Cruces, 48903 Bilbao, Spain; (C.I.); (A.S.-C.)
| | - Juan P. Jimeno
- “Complejo Hospitalario de Navarra”, 31008 Pamplona, Spain;
| | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
| | - Laura Izquierdo-Sanchez
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Centre, Saarland University, 66421 Homburg, Germany; (M.K.); (F.L.)
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, 02-091 Warsaw, Poland
| | - Maria J. Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
| | - Raul Jimenez-Aguero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
| | | | - Ioana Riaño
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
| | - Esperanza Gónzalez
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Exosomes Laboratory, 48160 Derio, Spain;
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Centre, Saarland University, 66421 Homburg, Germany; (M.K.); (F.L.)
| | - Marco Marzioni
- Department of Gastroenterology, “Università Politecnica delle Marche”, 60121 Ancona, Italy;
| | - Rocio I.R. Macias
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
- Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain; (R.I.R.M.); (J.J.G.M.)
| | - Jose J.G. Marin
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
- Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain; (R.I.R.M.); (J.J.G.M.)
| | - Tom H. Karlsen
- Division of Cancer Medicine, Surgery and Transplantation, Norwegian PSC Research Center, Oslo University Hospital, 0372 Oslo, Spain;
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
| | - Juan M. Falcón-Pérez
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
- Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Exosomes Laboratory, 48160 Derio, Spain;
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
| | - Jesper B. Andersen
- Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), 2200 Copenhagen, Denmark; (C.J.O.); (J.B.A.)
| | - Ana M. Aransay
- CIC bioGUNE, Genome Analysis Platform, 48160 Derio, Spain; (J.L.L.); (A.M.A.)
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
| | - Pedro M. Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; (A.L.); (A.A.); (A.L.C.); (A.S.-L.); (L.I.-S.); (M.J.P.); (R.J.-A.); (I.R.); (L.B.)
- Carlos III National Institute of Health, Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), 28220 Madrid, Spain;
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
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Lipoxin A4 Ameliorates Acute Pancreatitis-Associated Acute Lung Injury through the Antioxidative and Anti-Inflammatory Effects of the Nrf2 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2197017. [PMID: 31781326 PMCID: PMC6875318 DOI: 10.1155/2019/2197017] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/08/2019] [Accepted: 09/12/2019] [Indexed: 02/08/2023]
Abstract
Acute lung injury (ALI) is a critical event involved in the pathophysiological process of acute pancreatitis (AP). Many methods have been widely used for the treatment of AP-ALI, but few are useful during early inflammation. Lipoxin A4 (LXA4), a potent available anti-inflammatory and novel antioxidant mediator, has been extensively studied in AP-ALI, but its underlying mechanism as a protective mediator is not clear. This research was conducted to identify the possible targets and mechanisms involved in the anti-AP-ALI effect of LXA4. First, we confirmed that LXA4 strongly inhibited AP-ALI in mice. Next, using ELISA, PCR, and fluorescence detection to evaluate different parameters, LXA4 was shown to reduce the inflammatory cytokine production induced by AP and block reactive oxygen species (ROS) generation in vivo and in vitro. In addition, TNF-α treatment activated the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream gene heme oxygenase-1 (HO-1) in human pulmonary microvascular endothelial cells (HPMECs), and LXA4 further promoted their expression. This study also provided evidence that LXA4 phosphorylates Ser40 and triggers its nuclear translocation to activate Nrf2. Moreover, when Nrf2-knockout (Nrf2−/−) mice and cells were used to further assess the effect of the Nrf2/HO-1 pathway, we found that Nrf2 expression knockdown partially eliminated the effect of LXA4 on the reductions in inflammatory factor levels while abrogating the inhibitory effect of LXA4 on the ROS generation stimulated by AP-ALI. Overall, LXA4 attenuated the resolution of AP-induced inflammation and ROS generation to mitigate ALI, perhaps by modulating the Nrf2/HO-1 pathway. These findings have laid a foundation for the treatment of AP-ALI.
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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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