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Saadh MJ, Saeed TN, Alfarttoosi KH, Sanghvi G, Roopashree R, Thakur V, Lakshmi L, Kubaev A, Taher WM, Alwan M, Jawad MJ, Al-Nuaimi AMA. Exosomes and MicroRNAs: key modulators of macrophage polarization in sepsis pathophysiology. Eur J Med Res 2025; 30:298. [PMID: 40247413 PMCID: PMC12007276 DOI: 10.1186/s40001-025-02561-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 04/06/2025] [Indexed: 04/19/2025] Open
Abstract
Sepsis is a highly dangerous and complex condition that can result in death. It is characterized by a strong reaction to an infection, causing dysfunction in multiple bodily systems and a high risk of mortality. The transformation of macrophages is a vital stage in the procedure as they possess the capability to interchange between two separate types: M1, which promotes inflammation, and M2, which inhibits inflammation. The choice greatly affects the immune response of the host. This analysis underscores the rapidly expanding roles of exosomes and microRNAs (miRNAs) in regulating the trajectory of macrophage polarization during episodes of sepsis. Exosomes, extremely small extracellular vesicles, facilitate cellular communication by transferring biologically active compounds, including miRNAs, proteins, and lipids. We investigate the impact of changes in exosome production and composition caused by sepsis on macrophage polarization and function. Unique microRNAs present in exosomes play a significant role in controlling crucial signaling pathways that govern the phenotype of macrophages. Through thorough examination of recent progress in this area, we clarify the ways in which miRNAs derived from exosomes can either aggravate or alleviate the inflammatory reactions that occur during sepsis. This revelation not only deepens our comprehension of the underlying mechanisms of sepsis, but it also reveals potential new biomarkers and targets for treatment. This assessment aims to amalgamate diverse research investigations and propose potential avenues for future investigations on the influence that exosomes and miRNAs have on macrophage polarization and the body's response to sepsis. These entities are essential for controlling the host's reaction to sepsis and hold important functions in this mechanism.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Tamara Nazar Saeed
- Department of Medical Laboratory Technics, College of Health and Medical Technology, Alnoor University, Mosul, Iraq.
| | | | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
| | - R Roopashree
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Vishal Thakur
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - L Lakshmi
- Department of Nursing, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, 18 Amir Temur Street, 140100, Samarkand, Uzbekistan
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Al-Rawaf HA, Gabr SA, Alghadir T, Alghadir F, Iqbal A, Alghadir AH. Correlation between circulating microRNAs and vascular biomarkers in type 2 diabetes based upon physical activity: a biochemical analytic study. BMC Endocr Disord 2025; 25:55. [PMID: 40016689 PMCID: PMC11866858 DOI: 10.1186/s12902-025-01855-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/21/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND This research investigated how physical activity (PA) might impact the expression of several microRNAs, specifically miR-126, miR-146a, miR-34a, miR-124a, miR-155, and miR-221, in the blood of elderly individuals with type 2 diabetes (T2D). Additionally, the study examined the relationship between these microRNAs and markers of vascular endothelial dysfunction, including vascular endothelial growth factor (VEGF), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB), to assess their potential in the prevention, early detection, and treatment of diabetes. METHODS This correlational observational study involved 100 male participants, aged between 18 and 65 years, all of whom had been living with type 2 diabetes (T2D) for over six years. The participants were divided into three groups: inactive, moderate, and active, depending on their level of physical activity (PA). Real-time PCR and immunoassays were employed to measure the expression of selected miRNAs, as well as VEGF, apoA-I, apoB, and diabetic management indicators. PA levels were determined using ACTi graph GT1M accelerometer (model WAM 7164; Fort Walton Beach, FL) and energy expenditure was measured in the form of metabolic equivalent (MET) by indirect calorimetry method. RESULTS The expression levels of miR-146a, miR-34a, and miR-124a were significantly higher in patients with higher physical activity, while no such increase was observed for the other miRNAs in less active participants. Additionally, PA-active individuals showed a more pronounced decrease in fasting blood sugar (FBS), insulin resistance (IR), fasting insulin (FINS), HOMA-IR, HbA1c (%), and levels of VEGF, apoAI, apoB, and the apoB/apoA-I ratio. The alteration in miRNA expression was positively associated with physical activity, VEGF, apoAI, apoB, the apoB/apoA-I ratio, and diabetes-related metrics, while being inversely related to BMI. CONCLUSIONS In diabetic patients with higher physical activity levels, circulating miR-146a, miR-34a, and miR-124a showed elevated expression, accompanied by a notable decrease in vascular biomarkers, including apoAI, apoB, and the apoB/apoA-I ratio. The findings revealed a strong correlation between these vascular biomarkers and the physiological responses of miR-146a, miR-34a, and miR-124a, though larger studies are required to validate these results further. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Hadeel A Al-Rawaf
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, 11433, Saudi Arabia
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | - Sami A Gabr
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | - Talal Alghadir
- College of Medicine, King Saud University, Riyadh, 11433, Saudi Arabia
| | - Faisal Alghadir
- College of Medicine, King Saud University, Riyadh, 11433, Saudi Arabia
| | - Amir Iqbal
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia.
| | - Ahmad H Alghadir
- Rehabilitation Research Chair, Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
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Khidr EG, El-Sayyad GS, Abulsoud AI, Rizk NI, Zaki MB, Raouf AA, Elrebehy MA, Abdel Hady MMM, Elballal MS, Mohammed OA, Abdel-Reheim MA, El-Dakroury WA, Abdel Mageed SS, Al-Noshokaty TM, Doghish AS. Unlocking the Potential of miRNAs in Sepsis Diagnosis and Prognosis: From Pathophysiology to Precision Medicine. J Biochem Mol Toxicol 2025; 39:e70156. [PMID: 39871533 DOI: 10.1002/jbt.70156] [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: 11/23/2024] [Revised: 12/25/2024] [Accepted: 01/16/2025] [Indexed: 01/29/2025]
Abstract
The clinical syndrome appears as a dysregulated host response to infection that results in life-threatening organ dysfunction known as Sepsis. Sepsis is a serious public health concern where for every five deaths in ICU there is one patient who dies with sepsis worldwide. Sepsis is featured as unbalanced inflammation and immunosuppression which is sustained and profound, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and the deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based diagnosis and therapies for sepsis. Yet, the picture is not so straightforward because of miRNAs' versatile and dynamic features. More research is needed to clarify the expression and role of miRNAs in sepsis and promote the use of miRNAs for sepsis management. This study provides an extensive, current, and thorough analysis of the involvement of miRNAs in sepsis. Its purpose is to encourage future research in this area, as tiny miRNAs have the potential to be used for rapid diagnosis, prognosis, and treatment of sepsis.
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Affiliation(s)
- Emad Gamil Khidr
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Gharieb S El-Sayyad
- Medical Laboratory Technology Department, Faculty of Applied Health Sciences Technology, Badr University in Cairo (BUC), Cairo, Egypt
- Drug Microbiology Lab., Drug Radiation Research Department, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Menoufia National University, Menofia, Egypt
| | - Ahmed Amr Raouf
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Mahmoud A Elrebehy
- Biochemistry Department, Faculty of Pharmacy, Galala University, Suez, Egypt
| | - Manal M M Abdel Hady
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Goyang, Republic of Korea
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, Saudi Arabia
| | | | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
| | | | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo, Egypt
- Biochemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
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Loi MV, Sultana R, Nguyen TM, Tia ST, Lee JH, O’Connor D. The Diagnostic Utility of Host RNA Biosignatures in Adult Patients With Sepsis: A Systematic Review and Meta-Analysis. Crit Care Explor 2025; 7:e1212. [PMID: 39888601 PMCID: PMC11789890 DOI: 10.1097/cce.0000000000001212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2025] Open
Abstract
OBJECTIVES Sepsis is a life-threatening medical emergency, with a profound healthcare burden globally. Its pathophysiology is complex, heterogeneous and temporally dynamic, making diagnosis challenging. Medical management is predicated on early diagnosis and timely intervention. Transcriptomics is one of the novel "-omics" technologies being evaluated for recognition of sepsis. Our objective was to evaluate the performance of host gene expression biosignatures for the diagnosis of all-cause sepsis in adults. DATA SOURCES PubMed/Ovid Medline, Ovid Embase, and Cochrane databases from inception to June 2023. STUDY SELECTION We included studies evaluating the performance of host gene expression biosignatures in adults who were diagnosed with sepsis using existing clinical definitions. Controls where applicable were patients without clinical sepsis. DATA EXTRACTION Data including population demographics, sample size, study design, tissue specimen, type of transcriptome, health status of comparator group, and performance of transcriptomic biomarkers were independently extracted by at least two reviewers. DATA SYNTHESIS Meta-analysis to describe the performance of host gene expression biosignatures for the diagnosis of sepsis in adult patients was performed using the random-effects model. Risk of bias was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 117 studies (n = 17,469), comprising 132 separate patient datasets, were included in our final analysis. Performance of transcriptomics for the diagnosis of sepsis against pooled controls showed area under the receiver operating characteristic curve (AUC, 0.86; 95% CI, 0.84-0.88). Studies using healthy controls showed AUC 0.87 (95% CI, 0.84-0.89), while studies using controls with systemic inflammatory response syndrome (SIRS) had AUC 0.84 (95% CI, 0.78-0.90). Transcripts with excellent discrimination against SIRS controls include UrSepsisModel, a 210 differentially expressed genes biosignature, microRNA-143, and Septicyte laboratory. CONCLUSIONS Transcriptomics is a promising approach for the accurate diagnosis of sepsis in adults and demonstrates good discriminatory ability against both healthy and SIRS control subjects.
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Affiliation(s)
- Mervin V. Loi
- Department of Paediatric Subspecialties, Children’s Intensive Care Unit, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Rehena Sultana
- Center for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore
| | - Tuong Minh Nguyen
- Department of Industrial Systems Engineering and Management, College of Design and Engineering, National University of Singapore, Singapore, Singapore
| | - Shi Ting Tia
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Jan Hau Lee
- Department of Paediatric Subspecialties, Children’s Intensive Care Unit, KK Women’s and Children’s Hospital, Singapore, Singapore
- SingHealth-Duke NUS Paediatrics Academic Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Daniel O’Connor
- Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom
- NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom
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Srinivasan R, Ramadoss R, Kandasamy V, Ranganadin P, Green SR, Kasirajan A, Pillai AB. Exploring the regulatory role of small RNAs in modulating host-pathogen interactions: implications for bacterial and viral infections. Mol Biol Rep 2025; 52:115. [PMID: 39799541 DOI: 10.1007/s11033-024-10214-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/30/2024] [Indexed: 01/15/2025]
Abstract
MicroRNAs (miRNAs) and transfer RNA-derived stress-induced RNAs (tiRNAs) have emerged as crucial players in the post-transcriptional regulation of gene expression in various cellular processes, including immunity and host defense against infections. In recent years, increasing evidence has highlighted their complex role in influencing the host response during viral and bacterial infections. miRNAs have been shown to play multiple roles in host-pathogen interaction like TLR activation and altered disease virulence during bacterial infections. In the context of viral infections, miRNAs are involved in regulating viral replication, pathogenesis, and immune evasion. Similarly, tiRNAs have recently emerged as novel players in bacterial and viral infections such as modulating bacterial growth, adaptation to stress conditions, host antiviral responses, and impacting viral replication and pathogenesis. This review provides a comprehensive analysis of the potential of miRNA expression profiles as diagnostic biomarkers to differentiate between bacterial and viral infections. Further discusses the key pathways through which small RNAs regulate bacterial and viral infection-related diseases.
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Affiliation(s)
- Rajesh Srinivasan
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607402, India
| | - Ramya Ramadoss
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607402, India
| | - Vanathy Kandasamy
- Department of Microbiology, Mahatma Gandhi Medical College and Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607402, India
| | - Pajanivel Ranganadin
- Department of Pulmonary Medicine, Mahatma Gandhi Medical College and Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607402, India
| | - Siva Ranganathan Green
- Department of General Medicine, Mahatma Gandhi Medical College and Research Institute (MGMCRI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607402, India
| | - Anand Kasirajan
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607402, India
| | - Agieshkumar Balakrishna Pillai
- Mahatma Gandhi Medical Advanced Research Institute (MGMARI), Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, 607402, India.
- Institute of Advanced Virology, Trivandrum, Kerala, 695 317, India.
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Yuan Y, Xiao Y, Zhao J, Zhang L, Li M, Luo L, Jia Y, Wang K, Chen Y, Wang P, Wang Y, Wei J, Shen K, Hu D. Exosomes as novel biomarkers in sepsis and sepsis related organ failure. J Transl Med 2024; 22:1078. [PMID: 39609831 PMCID: PMC11604007 DOI: 10.1186/s12967-024-05817-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 10/29/2024] [Indexed: 11/30/2024] Open
Abstract
Sepsis, a severe and life-threatening condition arising from a dysfunctional host response to infection, presents considerable challenges to the health care system and is characterized by high mortality rates and substantial economic costs. Exosomes have garnered attention as potential diagnostic markers because of their capacity to mirror the pathophysiological milieu of sepsis. This discourse reviews the progression of sepsis classification from Sepsis 1.0 to Sepsis 3.0, highlighting the imperative for sensitive and specific biomarkers to facilitate timely diagnosis and optimize patient outcomes. Existing biomarkers, such as procalcitonin (PCT) and C-reactive protein (CRP), exhibit certain limitations, thereby prompting the quest for more dependable diagnostic indicators. Exosomal cargoes, which encompass proteins and miRNAs, present a trove of biomarker candidates, attributable to their stability, pervasive presence, and indicative nature of the disease status. The potential of exosomal biomarkers in the identification of sepsis-induced organ damage, including cardiomyopathy, acute kidney injury, and acute lung injury, is emphasized, as they provide real-time insights into cardiac and renal impairments. Despite promising prospects, hurdles persist in the standardization of exosome extraction and the need for extensive clinical trials to validate their efficacy. The combination of biomarker development and sophisticated exosome detection techniques represents a pioneering strategy in the realm of sepsis diagnosis and management, underscoring the significance of further research and clinical validation.
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Affiliation(s)
- Yixuan Yuan
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yujie Xiao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Jiazhen Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Lixia Zhang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Mengyang Li
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Liang Luo
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yanhui Jia
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Kejia Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yuxi Chen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Peng Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Yuhang Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Jingtao Wei
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China
| | - Kuo Shen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China.
- Air Force Hospital of Western Theater Command, Gongnongyuan Street #1, Chengdu, 610065, China.
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #127, Xi'an, 710032, China.
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Xiang G, Li Q, Lian D, Su C, Li X, Deng S, Xie L. FOXO1-mediated autophagy regulation by miR-223 in sepsis-induced immunosuppression. Front Pharmacol 2024; 15:1469286. [PMID: 39439897 PMCID: PMC11493625 DOI: 10.3389/fphar.2024.1469286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/25/2024] [Indexed: 10/25/2024] Open
Abstract
Introduction Immunosuppression is the main cause of the high mortality rate in patients with sepsis. The decrease in the number and dysfunction of CD4+ T lymphocytes is crucial to the immunosuppressed state of sepsis, in turn affecting the development and prognosis of sepsis. Autophagy has been shown to play an important role in the immune imbalance exhibited during sepsis. Methods In this study, we modulate the expression of miR-223 in CD4+ T lymphocytes, via the transfection of a mimic or an inhibitor of miR-223 to establish cell models of miR-223 overexpression and knockdown, respectively. Levels of autophagy were monitored using a double-labeled lentivirus (mRFP-GFP-LC3) and electron microscopy, and western blot analysis was used to estimate the levels of autophagy-related proteins and FOXO1 in the two cell models after co-treatment with lipopolysaccharide (LPS) and siRNA against FOXO1. Results We found that when the expression of miR-223 increased, FOXO1 expression decreased and autophagy decreased; whereas, when FOXO1 expression was inhibited, autophagy decreased significantly in different cell models after LPS induction. Conclusion Thus, this study proved that miR-223 participate in the regulation of LPS-induced autophagy via the regulation of FOXO1 expression in CD4+ T lymphocytes which shed a new light for the diagnosis and treatment of sepsis.
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Affiliation(s)
- Guoan Xiang
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
- Chinese PLA Medical School, Beijing, China
| | - Qi Li
- Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Di Lian
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
| | - Chengcheng Su
- Department of Respiratory and Critical Care Medicine, Pingjin Hospital, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, China
| | - Xin Li
- Department of Emergency, Third Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shoulong Deng
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Lixin Xie
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, China
- Chinese PLA Medical School, Beijing, China
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Huang X, Fei Y, Qiu X, Qian T, Shang Q, Cui J, Song Y, Sheng S, Xiao W, Yu Q, Wang T, Wang X. MiR-625-5p is a potential therapeutic target in sepsis by regulating CXCL16/CXCR6 axis and endothelial barrier. Int Immunopharmacol 2024; 137:112508. [PMID: 38889512 DOI: 10.1016/j.intimp.2024.112508] [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: 01/01/2024] [Revised: 06/14/2024] [Accepted: 06/15/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND MicroRNA plays an important role in the progression of sepsis. We found a significant increase of in miR-625-5p expression in the blood of patients with sepsis, and lipopolysaccharide (LPS)-stimulated EA.hy926 cells. To date, little is known about the specific biological function of miR-625-5p in sepsis. METHODS Changes in miR-625-5p expression were verified through quantitative real-time polymerase chain reaction in 45 patients with sepsis or septic shock and 30 healthy subjects. In vitro, EA.hy926 cells were treated with LPS. Transendothelial electrical resistance assay and FITC-dextran were used in evaluating endothelial barrier function. RESULTS Herein, patients with sepsis or septic shock had significantly higher miR-625-5p expression levels, chemokine (C-X-C motif) ligand 16 (CXCL16) levels, and glycocalyx components than the healthy controls, and miR-625-5p level was positively correlated with disease. Kaplan-Meier analysis demonstrated a strong association between miR-625-5p level and 28-day mortality. Furthermore, the miR-625-5p inhibitor significantly alleviated LPS-induced endothelial barrier injury in vitro. Then, miR-625-5p positively regulated CXCL16 and down-regulated miR-625-5p attenuated CXCL16 transcription and expression in EA.hy926 cells. CXCL16 knockout significantly alleviated vascular barrier dysfunction in the LPS-induced EA.hy926 cells. sCXCL16 treatment in EA.hy926 cells significantly increased endothelial hyperpermeability by disrupting endothelial glycocalyx, tight junction proteins, and adherens junction proteins through the modulation of C-X-C chemokine receptor type 6 (CXCR6). CONCLUSIONS Increase in miR-625-5p level may be an effective biomarker for predicting 28-day mortality in patients with sepsis/septic shock. miR-625-5p is a critical pathogenic factor for endothelial barrier dysfunction in LPS-induced EA.hy926 cells because it activates the CXCL16/CXCR6 axis.
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Affiliation(s)
- Xiao Huang
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yuxin Fei
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Xiaoyu Qiu
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China; Department of Pulmonary and Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Tiantian Qian
- Department of Respiratory Medicine, Ji'nan Zhangqiu District People's Hospital, No. 1920 Mingshuihuiquan Road, Ji'nan, 250200, Shandong, China
| | - Quanmei Shang
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Jinfeng Cui
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yutong Song
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Shurui Sheng
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Wenhan Xiao
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Qilin Yu
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Tao Wang
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China.
| | - Xiaozhi Wang
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China.
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He H, Zhang W, Jiang L, Tong X, Zheng Y, Xia Z. Endothelial Cell Dysfunction Due to Molecules Secreted by Macrophages in Sepsis. Biomolecules 2024; 14:980. [PMID: 39199368 PMCID: PMC11352357 DOI: 10.3390/biom14080980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/25/2024] [Accepted: 08/06/2024] [Indexed: 09/01/2024] Open
Abstract
Sepsis is recognized as a syndrome of systemic inflammatory reaction induced by dysregulation of the body's immunity against infection. The multiple organ dysfunction associated with sepsis is a serious threat to the patient's life. Endothelial cell dysfunction has been extensively studied in sepsis. However, the role of macrophages in sepsis is not well understood and the intrinsic link between the two cells has not been elucidated. Macrophages are first-line cells of the immune response, whereas endothelial cells are a class of cells that are highly altered in function and morphology. In sepsis, various cytokines secreted by macrophages and endothelial cell dysfunction are inextricably linked. Therefore, investigating how macrophages affect endothelial cells could offer a theoretical foundation for the treatment of sepsis. This review links molecules (TNF-α, CCL2, ROS, VEGF, MMP-9, and NO) secreted by macrophages under inflammatory conditions to endothelial cell dysfunction (adhesion, permeability, and coagulability), refining the pathophysiologic mechanisms of sepsis. At the same time, multiple approaches (a variety of miRNA and medicines) regulating macrophage polarization are also summarized, providing new insights into reversing endothelial cell dysfunction and improving the outcome of sepsis treatment.
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Affiliation(s)
- Heng He
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; (H.H.); (W.Z.); (L.J.); (X.T.)
| | - Wei Zhang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; (H.H.); (W.Z.); (L.J.); (X.T.)
| | - Luofeng Jiang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; (H.H.); (W.Z.); (L.J.); (X.T.)
| | - Xirui Tong
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; (H.H.); (W.Z.); (L.J.); (X.T.)
| | - Yongjun Zheng
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; (H.H.); (W.Z.); (L.J.); (X.T.)
| | - Zhaofan Xia
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; (H.H.); (W.Z.); (L.J.); (X.T.)
- Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai 200433, China
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10
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Bindayna K. MicroRNA as Sepsis Biomarkers: A Comprehensive Review. Int J Mol Sci 2024; 25:6476. [PMID: 38928179 PMCID: PMC11204033 DOI: 10.3390/ijms25126476] [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: 03/25/2024] [Revised: 04/21/2024] [Accepted: 04/26/2024] [Indexed: 06/28/2024] Open
Abstract
Sepsis, a life-threatening condition caused by the body's dysregulated response to infection, presents a significant challenge in clinical management. Timely and accurate diagnosis is paramount for initiating appropriate interventions and improving patient outcomes. In recent years, there has been growing interest in identifying biomarkers that can aid in the early detection and prognostication of sepsis. MicroRNAs (miRNAs) have emerged as potential biomarkers for sepsis due to their involvement in the regulation of gene expression and their stability in various biological fluids, including blood. MiRNAs are small non-coding RNA molecules that play crucial roles in post-transcriptional gene regulation by binding to target messenger RNAs (mRNAs), leading to mRNA degradation or translational repression. The diagnostic and prognostic potential of miRNAs in sepsis stems from their ability to serve as sensitive and specific biomarkers reflective of the underlying pathophysiological processes. Compared to traditional biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT), miRNAs offer several advantages, including their early and sustained elevation during sepsis, as well as their stability in stored samples, making them attractive candidates for clinical use. However, despite their promise, the clinical translation of miRNAs as sepsis biomarkers faces several challenges. These include the need for standardized sample collection and processing methods, the identification of optimal miRNA panels or signatures for differentiating sepsis from other inflammatory conditions, and the validation of findings across diverse patient populations and clinical settings. In conclusion, miRNAs hold great promise as diagnostic and prognostic biomarkers for sepsis, offering insights into the underlying molecular mechanisms and potential therapeutic targets. However, further research is needed to overcome existing challenges and realize the full clinical utility of miRNAs in improving sepsis outcomes.
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Affiliation(s)
- Khalid Bindayna
- Department of Microbiology, Immunology and Infectious Diseases, College of Medicine & Medical Sciences, Arabian Gulf University, Manama P.O. Box 26671, Bahrain
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11
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Zhang X, Wang L, Li M, Dong S. Predictive value of miR-7110-5p and miR-223-3p as biomarkers for sepsis secondary to pneumonia. Technol Health Care 2024; 32:2931-2939. [PMID: 38759032 DOI: 10.3233/thc-231137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2024]
Abstract
BACKGROUND Investigating the secondary sepsis of pneumonia is of great significance for rapid diagnosis and early treatment of sepsis. OBJECTIVE This study aimed to investigate the predictive value of micro ribonucleic acids (miRNA) 7110-5p and miR-223-3p in sepsis secondary to pneumonia. A miRNA microarray was used to analyze the differences in miRNA expression between patients with pneumonia and those with sepsis secondary to pneumonia. METHODS The study included a total of 50 patients with pneumonia and 42 patients with sepsis secondary to pneumonia. Quantitative polymerase chain reaction analysis was conducted to measure the circulating miRNA expression levels in patients and assess their correlations with clinical characteristics and prognosis. In this study, nine miRNAs - hsa-miR-4689-5p, hsa-miR-4621-5p, hsa-miR-6740-5p, hsa-miR-7110-5p, hsa-miR-765, hsa-miR-940, hsa-miR-213-5p, hsa-miR-223-3p, and hsa-miR-122 - met the screening criteria of having a fold change ⩾ 2 or < 0.5; p< 0.01 indicated significant differences in the results. RESULTS The expression levels of miR-7110-5p and miR-223-3p differed between the two patient groups, being up-regulated in the plasma of patients with sepsis secondary to pneumonia. miR-7110-5p and miR-223-3p showed higher expression levels in both patients with pneumonia and sepsis compared to healthy controls. Moreover, the receiver operating characteristic curve revealed that the areas under the curve for predicting pneumonia using miR-7110-5p were 0.781 while those for predicting sepsis secondary to pneumonia were 0.862. For miR-223-3p, the corresponding values for predicting pneumonia and sepsis secondary to pneumonia were 0.879 and 0.924, respectively. However, there were no significant differences in the levels of miR-7110-5p and miR-223-3p between the plasma of survived and deceased patients with sepsis. CONCLUSIONS MiR-7110-5p and miR-223-3p have the potential to serve as biological indicators for predicting sepsis secondary to pneumonia.
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Affiliation(s)
- Xinliang Zhang
- Department of Emergency Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lin Wang
- Department of Trauma Emergency, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Mei Li
- Department of Emergency Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shimin Dong
- Department of Emergency Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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12
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential in developing microRNA associated with regeneration as biomarkers to improve prognostication for liver failure syndromes and hepatocellular carcinoma. Expert Rev Mol Diagn 2024; 24:5-22. [PMID: 38059597 DOI: 10.1080/14737159.2023.2292642] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 12/05/2023] [Indexed: 12/08/2023]
Abstract
INTRODUCTION Determining the need for liver transplantation remains critical in the management of hepatocellular carcinoma (HCC) and liver failure syndromes (including acute liver failure and decompensated cirrhosis states). Conventional prognostic models utilize biomarkers of liver and non-liver failure and have limitations in their application. Novel biomarkers which predict regeneration may fulfil this niche. microRNA are implicated in health and disease and are present in abundance in the circulation. Despite this, they have not translated into mainstream clinical biomarkers. AREAS COVERED We will discuss current challenges in the prognostication of patients with liver failure syndromes as well as for patients with HCC. We will discuss biomarkers implicated with liver regeneration. We then provide an overview of the challenges in developing microRNA into clinically tractable biomarkers. Finally, we will provide a scoping review of microRNA which may have potential as prognostic biomarkers in liver failure syndromes and HCC. EXPERT OPINION Novel biomarkers are needed to improve prognostic models in liver failure syndromes and HCC. Biomarkers associated with liver regeneration are currently lacking and may fulfil this niche. microRNA have the potential to be developed into clinically tractable biomarkers but a consensus on standardizing methodology and reporting is required prior to large-scale studies.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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Alikiaii B, Bagherniya M, Askari G, Rajendram R, Sahebkar A. MicroRNA Profiles in Critically Ill Patients. Curr Med Chem 2024; 31:6801-6825. [PMID: 37496239 DOI: 10.2174/0929867331666230726095222] [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: 01/07/2023] [Revised: 05/19/2023] [Accepted: 06/01/2023] [Indexed: 07/28/2023]
Abstract
The use of biomarkers to expedite diagnosis, prognostication, and treatment could significantly improve patient outcomes. The early diagnosis and treatment of critical illnesses can greatly reduce mortality and morbidity. Therefore, there is great interest in the discovery of biomarkers for critical illnesses. Micro-ribonucleic acids (miRNAs) are a highly conserved group of non-coding RNA molecules. They regulate the expression of genes involved in several developmental, physiological, and pathological processes. The characteristics of miRNAs suggest that they could be versatile biomarkers. Assay panels to measure the expression of several miRNAs could facilitate clinical decision-- making for a range of diseases. We have, in this paper, reviewed the current understanding of the role of miRNAs as biomarkers in critically ill patients.
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Affiliation(s)
- Babak Alikiaii
- Anesthesia and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Bagherniya
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gholamreza Askari
- Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rajkumar Rajendram
- Department of Medicine, King Abdulaziz Medical City, King Abdulaziz International Medical Research Center, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University of Health Sciences, Riyadh, Saudi Arabia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Guzeldemir-Akcakanat E, Sunnetci-Akkoyunlu D, Balta-Uysal VM, Özer T, Işik EB, Cine N. Differentially expressed miRNAs associated with generalized aggressive periodontitis. Clin Oral Investig 2023; 28:7. [PMID: 38123758 DOI: 10.1007/s00784-023-05404-5] [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: 07/22/2023] [Accepted: 12/02/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE This study aimed to investigate miRNA expression profiles in individuals with periodontitis which is a chronic inflammatory condition affecting the integrity of the periodontal attachment. miRNAs play a crucial role in gene regulation through various mechanisms, making them potential diagnostic markers and therapeutic targets for various diseases. MATERIALS AND METHODS A total of 25 individuals with aggressive periodontitis and 25 controls were included in the study. Gingival tissues were collected for miRNA isolation and cDNA synthesis. miRNAs associated with periodontitis, including hsa-miR-185-5p, hsa-miR-17, hs-miR-146a, hs-miR-146b, hs-miR-155, hs-miR-203, hs-miR-205, hs-miR-223, and hsa-miR-21-3p, were analyzed using a combination of miRTarBase database analysis and literature mining was performed. Real-time PCR was used to assess the expression patterns of the target miRNAs, and the data were analyzed using the REST program. RESULTS The study revealed upregulated expression levels of hsa-miR-223-3p, hsa-miR-203b-5p, hsa-miR-146a-5p, hsa-miR-146b-5p, and hsa-miR-155-5p in individuals with periodontitis. Conversely, downregulated expression was observed for hsa-miR-185-5p, hsa-miR-21-3p, and hsa-miR-17-3p. CONCLUSION The findings suggest significant differences in the expression of specific miRNAs associated with inflammation in periodontitis. MZB1 acts as a hormone-regulated adipokine/pro-inflammatory cytokine, driving chronic inflammation and influencing cellular expansion. Predominantly expressed in marginal zone and B1 B cells, specialized subsets that respond rapidly to infections, MZB1 impacts immune protein synthesis and immune cell maturation, notably targeting microRNA-185 to potentially impede T cell development. Further research is needed to elucidate the functional significance and potential implications of these miRNAs. CLINICAL RELEVANCE miRNAs regulate the expression of target genes by finely tuning protein expression levels. The current findings provide compelling evidence of notable variations in the expression levels of specific miRNAs associated with inflammation in individuals affected by periodontitis; hence, miRNAs hold promise as potential therapeutic targets for periodontitis.
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Affiliation(s)
- Esra Guzeldemir-Akcakanat
- Department of Periodontology, Faculty of Dentistry, Kocaeli University, 41190 Basiskele, Kocaeli, Turkey.
| | | | - V Merve Balta-Uysal
- Department of Periodontology, Faculty of Dentistry, Kocaeli University, 41190 Basiskele, Kocaeli, Turkey
| | - Tolgahan Özer
- Department of Medical Genetics, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Elif Büşra Işik
- Department of Medical Genetics, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Naci Cine
- Department of Medical Genetics, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
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15
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Fu X, Liu Z, Wang Y. Advances in the Study of Immunosuppressive Mechanisms in Sepsis. J Inflamm Res 2023; 16:3967-3981. [PMID: 37706064 PMCID: PMC10497210 DOI: 10.2147/jir.s426007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/29/2023] [Indexed: 09/15/2023] Open
Abstract
Sepsis is a life-threatening disease caused by a systemic infection that triggers a dysregulated immune response. Sepsis is an important cause of death in intensive care units (ICUs), poses a major threat to human health, and is a common cause of death in ICUs worldwide. The pathogenesis of sepsis is intricate and involves a complex interplay of pro- and anti-inflammatory mechanisms that can lead to excessive inflammation, immunosuppression, and potentially long-term immune disorders. Recent evidence highlights the importance of immunosuppression in sepsis. Immunosuppression is recognized as a predisposing factor for increased susceptibility to secondary infections and mortality in patients. Immunosuppression due to sepsis increases a patient's chance of re-infection and increases organ load. In addition, antibiotics, fluid resuscitation, and organ support therapy have limited impact on the prognosis of septic patients. Therapeutic approaches by suppressing excessive inflammation have not achieved the desired results in clinical trials. Research into immunosuppression has brought new hope for the treatment of sepsis, and a number of therapeutic approaches have demonstrated the potential of immunostimulatory therapies. In this article, we will focus on the mechanisms of immunosuppression and markers of immune monitoring in sepsis and describe various targets for immunostimulatory therapy in sepsis.
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Affiliation(s)
- Xuzhe Fu
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Zhi Liu
- Department of Ophthalmology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Yu Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
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16
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Shin B, Lee JY, Im Y, Yoo H, Park J, Lee JS, Lee KY, Jeon K. Prognostic implication of downregulated exosomal miRNAs in patients with sepsis: a cross-sectional study with bioinformatics analysis. J Intensive Care 2023; 11:35. [PMID: 37537685 PMCID: PMC10399058 DOI: 10.1186/s40560-023-00683-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/30/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND Despite the understanding of sepsis-induced extracellular vesicles (EVs), such as exosomes, and their role in intercellular communication during sepsis, little is known about EV contents such as microRNA (miRNA), which modulate important cellular processes contributing to sepsis in body fluids. This study aimed to analyze the differential expression of exosomal miRNAs in plasma samples collected from sepsis patients and healthy controls, and to identify potential miRNA regulatory pathways contributing to sepsis pathogenesis. METHODS Quantitative real-time PCR-based microarrays were used to profile plasma exosomal miRNA expression levels in 135 patients with sepsis and 11 healthy controls from an ongoing prospective registry of critically ill adult patients admitted to the intensive care unit. The identified exosomal miRNAs were tested in an external validation cohort (35 sepsis patients and 10 healthy controls). And then, functional enrichment analyses of gene ontology, KEGG pathway analysis, and protein-protein interaction network and cluster analyses were performed based on the potential target genes of the grouped miRNAs. Finally, to evaluate the performance of the identified exosomal miRNAs in predicting in-hospital and 90-day mortalities of sepsis patients, receiver operating characteristic curve (ROC) and Kaplan-Meier analyses were performed. RESULTS Compared with healthy controls, plasma exosomes from sepsis patients showed significant changes in 25 miRNAs; eight miRNAs were upregulated and 17 downregulated. Additionally, the levels of hsa-let-7f-5p, miR-331-3p miR-301a-3p, and miR-335-5p were significantly lower in sepsis patients than in healthy controls (p < 0.0001). These four miRNAs were confirmed in an external validation cohort. In addition, the most common pathway for these four miRNAs were PI3K-Akt and mitogen-activated protein kinase (MAPK) signaling pathways based on the KEGG analysis. The area under the ROC of hsa-let-7f-5p, miR-331-3p, miR-301a-3p, and miR-335-5p level for in-hospital mortality was 0.913, 0.931, 0.929, and 0.957, respectively (p < 0.001), as confirmed in an external validation cohort. Also, the Kaplan-Meier analysis showed a significant difference in 90-day mortality between sepsis patients with high and low miR-335-5p, miR-301a-3p, hsa-let-7f-5p, and miR-331-3p levels (p < 0.001, log-rank test). CONCLUSION Among the differentially-expressed miRNAs detected in microarrays, the top four downregulated exosomal miRNAs (hsa-let-7f-5p, miR-331-3p miR-301a-3p, and miR-335-5p) were identified as independent prognostic factors for in-hospital and 90-day mortalities among sepsis patients. Bioinformatics analysis demonstrated that these four microRNAs might provide a significant contribution to sepsis pathogenesis through PI3K-Akt and MAPK signaling pathway.
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Affiliation(s)
- Beomsu Shin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea
| | - Jin Young Lee
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Yunjoo Im
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Hongseok Yoo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea
| | - Junseon Park
- Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Joo Sang Lee
- Department of Artificial Intelligence and Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Ki-Young Lee
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Kyeongman Jeon
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, Republic of Korea.
- Department of Health Sciences and Technology, SAIHST, Sungkyunkawan University, Seoul, Republic of Korea.
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Shin J, Miyaki S, Asahara H, Akimoto T. MicroRNA-140 is not involved in sepsis-induced muscle atrophy. Am J Physiol Cell Physiol 2023; 325:C509-C518. [PMID: 37486067 DOI: 10.1152/ajpcell.00157.2023] [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: 04/24/2023] [Revised: 06/28/2023] [Accepted: 07/10/2023] [Indexed: 07/25/2023]
Abstract
Sepsis is a life-threatening inflammatory response to infection, often accompanied by skeletal muscle atrophy. A previous study demonstrated that the administration of microRNA-140 (miR-140) attenuated lipopolysaccharide (LPS)-induced muscle atrophy, whereas miR-140 knockdown with siRNA promoted atrophy. Therefore, we investigated whether miR-140 is involved in LPS-induced muscle atrophy using a genetic model, miR-140-/- mice. We found that a single injection of LPS induced atrophy both in slow-twitch and fast-twitch muscles. The muscle weights and fiber cross-sectional areas were significantly reduced in both the wild-type (WT) and miR-140-/- mice, with no difference between genotypes. The expression of several proteolysis markers, muscle-specific RING-finger 1 (MuRF1) and MAFbx/atrogin-1, increased in both groups after LPS injection. The ubiquitinated proteins in the miR-140-/- mice were similar to those in the WT mice. Therefore, the deletion of miR-140 did not affect LPS-induced muscle atrophy.NEW & NOTEWORTHY We used miR-140-/- mice to determine the function of miR-140 in LPS-induced skeletal muscle atrophy. To our knowledge, this study is the first to examine slow-twitch muscles in LPS-induced muscle wasting after miR-140 manipulation.
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Affiliation(s)
- Jaehoon Shin
- Laboratory of Muscle Biology, Faculty of Sport Sciences, Waseda University, Saitama, Japan
| | - Shigeru Miyaki
- Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Hiroshi Asahara
- Department of Systems BioMedicine, Advanced Therapeutic Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Japan
| | - Takayuki Akimoto
- Laboratory of Muscle Biology, Faculty of Sport Sciences, Waseda University, Saitama, Japan
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18
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Jiao Y, Wai Tong CS, Rainer TH. An appraisal of studies using mouse models to assist the biomarker discovery for sepsis prognosis. Heliyon 2023; 9:e17770. [PMID: 37456011 PMCID: PMC10344760 DOI: 10.1016/j.heliyon.2023.e17770] [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: 08/24/2022] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Clinicians need reliable outcome predictors to improve the prognosis of septic patients. Mouse models are widely used in sepsis research. We aimed to review how mouse models were used to search for novel prognostic biomarkers of sepsis in order to optimize their use for future biomarker discovery. Methods We searched PubMed from 2012 to July 2022 using "((sepsis) AND (mice)) AND ((prognosis) OR (prognostic biomarker))". Results A total of 412 publications were retrieved. We selected those studies in which mouse sepsis was used to demonstrate prognostic potential of biomarker candidates and/or assist the subsequent evaluation in human sepsis for further appraisal. The most frequent models were lipopolysaccharide (LPS) injection and caecal ligation and puncture (CLP) using young male mice. Discovery technologies applied on mice include setting survival and nonsurvivable groups, detecting changes of biomarker levels and measuring physiological parameters during sepsis. None of the biomarkers achieved sufficient clinical performance for clinical use. Conclusions The number of studies and strategies using mouse models to discover prognostic biomarkers of sepsis are limited. Current mouse models need to be further optimized to better conform to human sepsis. Current biomarker platforms do not achieve predictive performance for clinical use.
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Zhang J, Tian W, Wang F, Liu J, Huang J, Duangmano S, Liu H, Liu M, Zhang Z, Jiang X. Advancements in understanding the role of microRnas in regulating macrophage polarization during acute lung injury. Cell Cycle 2023; 22:1694-1712. [PMID: 37415386 PMCID: PMC10446815 DOI: 10.1080/15384101.2023.2230018] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/11/2023] [Accepted: 06/04/2023] [Indexed: 07/08/2023] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical and life-threatening illness that causes severe dyspnea, and respiratory distress and is often caused by a variety of direct or indirect factors that damage the alveolar epithelium and capillary endothelial cells, leading to inflammation factors and macrophage infiltration. Macrophages play a crucial role in the progression of ALI/ARDS, exhibiting different polarized forms at different stages of the disease that control the disease outcome. MicroRNAs (miRNA) are conserved, endogenous, short non-coding RNAs composed of 18-25 nucleotides that serve as potential markers for many diseases and are involved in various biological processes, including cell proliferation, apoptosis, and differentiation. In this review, we provide a brief overview of miRNA expression in ALI/ARDS and summarize recent research on the mechanism and pathways by which miRNAs respond to macrophage polarization, inflammation, and apoptosis. The characteristics of each pathway are also summarized to provide a comprehensive understanding of the role of miRNAs in regulating macrophage polarization during ALI/ARDS.
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Affiliation(s)
- Jianhua Zhang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wanyi Tian
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Fang Wang
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiao Liu
- Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jiang Huang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Suwit Duangmano
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Hao Liu
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Minghua Liu
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Zhuo Zhang
- School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xian Jiang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Anesthesiology, Luzhou People’s Hospital, Luzhou, China
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Kopcho S, McDew-White M, Naushad W, Mohan M, Okeoma CM. SIV Infection Regulates Compartmentalization of Circulating Blood Plasma miRNAs within Extracellular Vesicles (EVs) and Extracellular Condensates (ECs) and Decreases EV-Associated miRNA-128. Viruses 2023; 15:622. [PMID: 36992331 PMCID: PMC10059597 DOI: 10.3390/v15030622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/03/2023] Open
Abstract
Background: This is Manuscript 1 of a two-part Manuscript of the same series. Here, we present findings from our first set of studies on the abundance and compartmentalization of blood plasma extracellular microRNAs (exmiRNAs) into extracellular particles, including blood plasma extracellular vesicles (EVs) and extracellular condensates (ECs) in the setting of untreated HIV/SIV infection. The goals of the study presented in this Manuscript 1 are to (i) assess the abundance and compartmentalization of exmiRNAs in EVs versus ECs in the healthy uninfected state, and (ii) evaluate how SIV infection may affect exmiRNA abundance and compartmentalization in these particles. Considerable effort has been devoted to studying the epigenetic control of viral infection, particularly in understanding the role of exmiRNAs as key regulators of viral pathogenesis. MicroRNA (miRNAs) are small (~20-22 nts) non-coding RNAs that regulate cellular processes through targeted mRNA degradation and/or repression of protein translation. Originally associated with the cellular microenvironment, circulating miRNAs are now known to be present in various extracellular environments, including blood serum and plasma. While in circulation, miRNAs are protected from degradation by ribonucleases through their association with lipid and protein carriers, such as lipoproteins and other extracellular particles-EVs and ECs. Functionally, miRNAs play important roles in diverse biological processes and diseases (cell proliferation, differentiation, apoptosis, stress responses, inflammation, cardiovascular diseases, cancer, aging, neurological diseases, and HIV/SIV pathogenesis). While lipoproteins and EV-associated exmiRNAs have been characterized and linked to various disease processes, the association of exmiRNAs with ECs is yet to be made. Likewise, the effect of SIV infection on the abundance and compartmentalization of exmiRNAs within extracellular particles is unclear. Literature in the EV field has suggested that most circulating miRNAs may not be associated with EVs. However, a systematic analysis of the carriers of exmiRNAs has not been conducted due to the inefficient separation of EVs from other extracellular particles, including ECs. Methods: Paired EVs and ECs were separated from EDTA blood plasma of SIV-uninfected male Indian rhesus macaques (RMs, n = 15). Additionally, paired EVs and ECs were isolated from EDTA blood plasma of combination anti-retroviral therapy (cART) naïve SIV-infected (SIV+, n = 3) RMs at two time points (1- and 5-months post infection, 1 MPI and 5 MPI). Separation of EVs and ECs was achieved with PPLC, a state-of-the-art, innovative technology equipped with gradient agarose bead sizes and a fast fraction collector that allows high-resolution separation and retrieval of preparative quantities of sub-populations of extracellular particles. Global miRNA profiles of the paired EVs and ECs were determined with RealSeq Biosciences (Santa Cruz, CA) custom sequencing platform by conducting small RNA (sRNA)-seq. The sRNA-seq data were analyzed using various bioinformatic tools. Validation of key exmiRNAs was performed using specific TaqMan microRNA stem-loop RT-qPCR assays. Results: We showed that exmiRNAs in blood plasma are not restricted to any type of extracellular particles but are associated with lipid-based carriers-EVs and non-lipid-based carriers-ECs, with a significant (~30%) proportion of the exmiRNAs being associated with ECs. In the blood plasma of uninfected RMs, a total of 315 miRNAs were associated with EVs, while 410 miRNAs were associated with ECs. A comparison of detectable miRNAs within paired EVs and ECs revealed 19 and 114 common miRNAs, respectively, detected in all 15 RMs. Let-7a-5p, Let-7c-5p, miR-26a-5p, miR-191-5p, and let-7f-5p were among the top 5 detectable miRNAs associated with EVs in that order. In ECs, miR-16-5p, miR-451, miR-191-5p, miR-27a-3p, and miR-27b-3p, in that order, were the top detectable miRNAs in ECs. miRNA-target enrichment analysis of the top 10 detected common EV and EC miRNAs identified MYC and TNPO1 as top target genes, respectively. Functional enrichment analysis of top EV- and EC-associated miRNAs identified common and distinct gene-network signatures associated with various biological and disease processes. Top EV-associated miRNAs were implicated in cytokine-cytokine receptor interactions, Th17 cell differentiation, IL-17 signaling, inflammatory bowel disease, and glioma. On the other hand, top EC-associated miRNAs were implicated in lipid and atherosclerosis, Th1 and Th2 cell differentiation, Th17 cell differentiation, and glioma. Interestingly, infection of RMs with SIV revealed that the brain-enriched miR-128-3p was longitudinally and significantly downregulated in EVs, but not ECs. This SIV-mediated decrease in miR-128-3p counts was validated by specific TaqMan microRNA stem-loop RT-qPCR assay. Remarkably, the observed SIV-mediated decrease in miR-128-3p levels in EVs from RMs agrees with publicly available EV miRNAome data by Kaddour et al., 2021, which showed that miR-128-3p levels were significantly lower in semen-derived EVs from HIV-infected men who used or did not use cocaine compared to HIV-uninfected individuals. These findings confirmed our previously reported finding and suggested that miR-128 may be a target of HIV/SIV. Conclusions: In the present study, we used sRNA sequencing to provide a holistic understanding of the repertoire of circulating exmiRNAs and their association with extracellular particles, such as EVs and ECs. Our data also showed that SIV infection altered the profile of the miRNAome of EVs and revealed that miR-128-3p may be a potential target of HIV/SIV. The significant decrease in miR-128-3p in HIV-infected humans and in SIV-infected RMs may indicate disease progression. Our study has important implications for the development of biomarker approaches for various types of cancer, cardiovascular diseases, organ injury, and HIV based on the capture and analysis of circulating exmiRNAs.
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Affiliation(s)
- Steven Kopcho
- Department of Pharmacology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794-8651, USA
| | - Marina McDew-White
- Host Pathogen Interaction Program, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227-5302, USA
| | - Wasifa Naushad
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595-1524, USA
| | - Mahesh Mohan
- Host Pathogen Interaction Program, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227-5302, USA
| | - Chioma M. Okeoma
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595-1524, USA
- Lovelace Biomedical Institute, Albuquerque, NM 87108-5127, USA
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Notch Signaling in Acute Inflammation and Sepsis. Int J Mol Sci 2023; 24:ijms24043458. [PMID: 36834869 PMCID: PMC9967996 DOI: 10.3390/ijms24043458] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/27/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Notch signaling, a highly conserved pathway in mammals, is crucial for differentiation and homeostasis of immune cells. Besides, this pathway is also directly involved in the transmission of immune signals. Notch signaling per se does not have a clear pro- or anti-inflammatory effect, but rather its impact is highly dependent on the immune cell type and the cellular environment, modulating several inflammatory conditions including sepsis, and therefore significantly impacts the course of disease. In this review, we will discuss the contribution of Notch signaling on the clinical picture of systemic inflammatory diseases, especially sepsis. Specifically, we will review its role during immune cell development and its contribution to the modulation of organ-specific immune responses. Finally, we will evaluate to what extent manipulation of the Notch signaling pathway could be a future therapeutic strategy.
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Hobai IA. CARDIOMYOCYTE REPROGRAMMING IN ANIMAL MODELS OF SEPTIC SHOCK. Shock 2023; 59:200-213. [PMID: 36730767 DOI: 10.1097/shk.0000000000002024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
ABSTRACT Cardiomyocyte reprogramming plays a pivotal role in sepsis-induced cardiomyopathy through the induction or overexpression of several factors and enzymes, ultimately leading to the characteristic decrease in cardiac contractility. The initial trigger is the binding of LPS to TLR-2, -3, -4, and -9 and of proinflammatory cytokines, such as TNF, IL-1, and IL-6, to their respective receptors. This induces the nuclear translocation of nuclear factors, such as NF-κB, via activation of MyD88, TRIF, IRAK, and MAPKs. Among the latter, ROS- and estrogen-dependent p38 and ERK 1/2 are proinflammatory, whereas JNK may play antagonistic, anti-inflammatory roles. Nuclear factors induce the synthesis of cytokines, which can amplify the inflammatory signal in a paracrine fashion, and of several effector enzymes, such as NOS-2, NOX-1, and others, which are ultimately responsible for the degradation of cardiomyocyte contractility. In parallel, the downregulation of enzymes involved in oxidative phosphorylation causes metabolic reprogramming, followed by a decrease in ATP production and the release of fragmented mitochondrial DNA, which may augment the process in a positive feedback loop. Other mediators, such as NO, ROS, the enzymes PI3K and Akt, and adrenergic stimulation may play regulatory roles, but not all signaling pathways that mediate cardiac dysfunction of sepsis do that by regulating reprogramming. Transcription may be globally modulated by miRs, which exert protective or amplifying effects. For all these mechanisms, differentiating between modulation of cardiomyocyte reprogramming versus systemic inflammation has been an ongoing but worthwhile experimental challenge.
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Affiliation(s)
- Ion A Hobai
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, GRB 444, Boston, MA
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Ballambattu VB, Gurugubelli KR. Neonatal sepsis: Recent advances in pathophysiology and management. VIRAL, PARASITIC, BACTERIAL, AND FUNGAL INFECTIONS 2023:503-513. [DOI: 10.1016/b978-0-323-85730-7.00010-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Janec P, Mojžíšek M, Pánek M, Haluzík M, Živný J, Janota J. Early-Onset Neonatal Sepsis: Inflammatory Biomarkers and MicroRNA as Potential Diagnostic Tools in Preterm Newborns. Folia Biol (Praha) 2023; 69:173-180. [PMID: 38583178 DOI: 10.14712/fb2023069050173] [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] [Indexed: 04/09/2024]
Abstract
Mortality and morbidity of newborns with sepsis can be improved by early and accurate diagnosis and targeted therapy. To evaluate the early molecular events associated with inflammation and infection, we evaluated markers of endothelial activation and injury and circulating plasma miRNAs in preterm newborns with sepsis. The study group consisted of newborns with gestational age ≤ 32 weeks, with culture-positive early-onset neonatal sepsis (sepsis group, N = 8), and as a control group, we enrolled newborns without sepsis (control group, N = 12). Soluble markers of inflammation were measured using Luminex-based multiplex assay. Platelet-free plasma RNA was used to construct the library for miRNA sequencing analysis. Normalized counts were calculated and used to measure differential expression of individual detected miRNAs. We found a significant increase of interleukin 18 (IL-18) in the cord blood of the sepsis group (mean ± SEM, 104.7 ± 30.4 pg/ml vs 52.7 ± 5.6 pg/ml, P = 0.02). In peripheral blood of sepsis group patients, we found a significant increase of VEGF-A compared to controls (196.0 ± 70.5 pg/ml vs 59.6 ± 8.5 pg/ml, P = 0.02). In the cord blood plasma, eight miRNAs had significantly differential expression (P < 0.05), four miRNAs were up-regulated and four miRNAs down-regulated. In peripheral blood plasma, all nine miRNAs with significant differential expression were up-regulated. In conclusion, in early-onset neonatal sepsis, IL-18 and VEGF-A might be considered in diagnostic workup. Early-onset sepsis in preterm newborns is associated with significant changes in the circulating miRNA pattern.
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Affiliation(s)
- Petr Janec
- Department of Neonatology, Masaryk Hospital Ústí nad Labem, Krajská zdravotní, Ústí nad Labem, Czech Republic
| | - Marek Mojžíšek
- Neonatal Unit, Department of Obstetrics and Gynaecology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Martin Pánek
- Department of Neonatology, Masaryk Hospital Ústí nad Labem, Krajská zdravotní, Ústí nad Labem, Czech Republic
| | - Martin Haluzík
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Jan Živný
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Jan Janota
- Department of Neonatology, Thomayer University Hospital, Prague, Czech Republic.
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
- Neonatal Unit, Department of Obstetrics and Gynaecology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
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25
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Formosa A, Turgeon P, dos Santos CC. Role of miRNA dysregulation in sepsis. Mol Med 2022; 28:99. [PMID: 35986237 PMCID: PMC9389495 DOI: 10.1186/s10020-022-00527-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/05/2022] [Indexed: 11/18/2022] Open
Abstract
Background Sepsis is defined as a state of multisystem organ dysfunction secondary to a dysregulated host response to infection and causes millions of deaths worldwide annually. Novel ways to counteract this disease are needed and such tools may be heralded by a detailed understanding of its molecular pathogenesis. MiRNAs are small RNA molecules that target mRNAs to inhibit or degrade their translation and have important roles in several disease processes including sepsis. Main body The current review adopted a strategic approach to analyzing the widespread literature on the topic of miRNAs and sepsis. A pubmed search of “miRNA or microRNA or small RNA and sepsis not review” up to and including January 2021 led to 1140 manuscripts which were reviewed. Two hundred and thirty-three relevant papers were scrutinized for their content and important themes on the topic were identified and subsequently discussed, including an in-depth look at deregulated miRNAs in sepsis in peripheral blood, myeloid derived suppressor cells and extracellular vesicles. Conclusion Our analysis yielded important observations. Certain miRNAs, namely miR-150 and miR-146a, have consistent directional changes in peripheral blood of septic patients across numerous studies with strong data supporting a role in sepsis pathogenesis. Furthermore, a large body of literature show miRNA signatures of clinical relevance, and lastly, many miRNAs deregulated in sepsis are associated with the process of endothelial dysfunction. This review offers a widespread, up-to-date and detailed discussion of the role of miRNAs in sepsis and is meant to stimulate further work in the field due to the potential of these small miRNAs in prompt diagnostics, prognostication and therapeutic agency. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00527-z.
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Roychoudhury A, Dear JW, Bachmann TT. Proximity sensitive detection of microRNAs using electrochemical impedance spectroscopy biosensors. Biosens Bioelectron 2022; 212:114404. [DOI: 10.1016/j.bios.2022.114404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 05/03/2022] [Accepted: 05/17/2022] [Indexed: 12/12/2022]
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Chen PW, Tseng SY, Chang HY, Lee CH, Chao TH. Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9 between Obesity and Non-Obesity. Int J Mol Sci 2022; 23:ijms23179768. [PMID: 36077166 PMCID: PMC9456424 DOI: 10.3390/ijms23179768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/17/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis. Cilostazol exerts favorable cellular and metabolic effects; however, the effect of cilostazol on the expression of PCSK9 has not been previously reported. Our study aimed to investigate the potential mechanisms of action of cilostazol on the expression of PCSK9 and lipid homeostasis. We evaluated the effects of cilostazol on the expression of PCSK9 in HepG2 cells and evaluated potential molecular mechanisms by measuring signaling molecules in the liver and serum lipid profiles in high-fat diet-induced obese mice and normal chow-fed mice. Cilostazol treatment significantly induced the messenger RNA and protein expression of PCSK9 in HepG2 cells and enhanced PCSK9 promoter activity. Chromatin immunoprecipitation assays confirmed that cilostazol treatment enhanced PCSK9 transcription by binding to peroxisome proliferator-activated receptor-γ (PPARγ) via the PPARγ DNA response element. PPARγ knockdown attenuated the stimulatory effect of cilostazol on PCSK9. In vitro, cilostazol treatment increased PCSK9 expression in vehicle-treated HepG2 cells but decreased PCSK9 expression in palmitic acid-treated HepG2 cells. In vivo, cilostazol treatment increased the serum levels of PCSK9 in normal mice but significantly reduced PCSK9 levels in obese mice. The expressions of PCSK9-relevant microRNAs also showed similar results. Clinical data showed that cilostazol treatment significantly reduced serum PCSK9 levels in patients with obesity. The obesity-dependent effects of cilostazol on PCSK9 expression observed from bench to bedside demonstrates the therapeutic potential of cilostazol in clinical settings.
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Affiliation(s)
- Po-Wei Chen
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Shih-Ya Tseng
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Hsien-Yuan Chang
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Cheng-Han Lee
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
| | - Ting-Hsing Chao
- Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
- Health Management Center, National Cheng Kung University Hospital, Tainan 704, Taiwan
- Correspondence: ; Tel.: +886-6-23523535 (ext. 2392); Fax: +886-6-2753834
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Maiese A, Scatena A, Costantino A, Chiti E, Occhipinti C, La Russa R, Di Paolo M, Turillazzi E, Frati P, Fineschi V. Expression of MicroRNAs in Sepsis-Related Organ Dysfunction: A Systematic Review. Int J Mol Sci 2022; 23:9354. [PMID: 36012630 PMCID: PMC9409129 DOI: 10.3390/ijms23169354] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/10/2022] [Accepted: 08/17/2022] [Indexed: 02/06/2023] Open
Abstract
Sepsis is a critical condition characterized by increased levels of pro-inflammatory cytokines and proliferating cells such as neutrophils and macrophages in response to microbial pathogens. Such processes lead to an abnormal inflammatory response and multi-organ failure. MicroRNAs (miRNA) are single-stranded non-coding RNAs with the function of gene regulation. This means that miRNAs are involved in multiple intracellular pathways and thus contribute to or inhibit inflammation. As a result, their variable expression in different tissues and organs may play a key role in regulating the pathophysiological events of sepsis. Thanks to this property, miRNAs may serve as potential diagnostic and prognostic biomarkers in such life-threatening events. In this narrative review, we collect the results of recent studies on the expression of miRNAs in heart, blood, lung, liver, brain, and kidney during sepsis and the molecular processes in which they are involved. In reviewing the literature, we find at least 122 miRNAs and signaling pathways involved in sepsis-related organ dysfunction. This may help clinicians to detect, prevent, and treat sepsis-related organ failures early, although further studies are needed to deepen the knowledge of their potential contribution.
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Affiliation(s)
- Aniello Maiese
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy
| | - Andrea Scatena
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy
| | - Andrea Costantino
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy
| | - Enrica Chiti
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy
| | - Carla Occhipinti
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy
| | - Raffaele La Russa
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Marco Di Paolo
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy
| | - Emanuela Turillazzi
- Department of Surgical Pathology, Medical, Molecular and Critical Area, Institute of Legal Medicine, University of Pisa, 56126 Pisa, Italy
| | - Paola Frati
- Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy
| | - Vittorio Fineschi
- Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy
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Antonakos N, Gilbert C, Théroude C, Schrijver IT, Roger T. Modes of action and diagnostic value of miRNAs in sepsis. Front Immunol 2022; 13:951798. [PMID: 35990654 PMCID: PMC9389448 DOI: 10.3389/fimmu.2022.951798] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Sepsis is a clinical syndrome defined as a dysregulated host response to infection resulting in life-threatening organ dysfunction. Sepsis is a major public health concern associated with one in five deaths worldwide. Sepsis is characterized by unbalanced inflammation and profound and sustained immunosuppression, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based therapies for sepsis. Yet, the picture is not so straightforward because of the versatile and dynamic features of miRNAs. Clearly, more research is needed to clarify the expression and role of miRNAs in sepsis, and to promote the use of miRNAs for sepsis management.
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Affiliation(s)
| | | | | | | | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland
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Non-Coding RNA Networks as Potential Novel Biomarker and Therapeutic Target for Sepsis and Sepsis-Related Multi-Organ Failure. Diagnostics (Basel) 2022; 12:diagnostics12061355. [PMID: 35741168 PMCID: PMC9222180 DOI: 10.3390/diagnostics12061355] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 02/04/2023] Open
Abstract
According to “Sepsis-3” consensus, sepsis is a life-threatening clinical syndrome caused by a dysregulated inflammatory host response to infection. A rapid identification of sepsis is mandatory, as the extent of the organ damage triggered by both the pathogen itself and the host’s immune response could abruptly evolve to multiple organ failure and ultimately lead to the death of the patient. The most commonly used therapeutic strategy is to provide hemodynamic and global support to the patient and to rapidly initiate broad-spectrum empiric antibiotic therapy. To date, there is no gold standard diagnostic test that can ascertain the diagnosis of sepsis. Therefore, once sepsis is suspected, the presence of organ dysfunction can be assessed using the Sepsis-related Organ Failure Assessment (SOFA) score, although the diagnosis continues to depend primarily on clinical judgment. Clinicians can now rely on several serum biomarkers for the diagnosis of sepsis (e.g., procalcitonin), and promising new biomarkers have been evaluated, e.g., presepsin and adrenomedullin, although their clinical relevance in the hospital setting is still under discussion. Non-codingRNA, including long non-codingRNAs (lncRNAs), circularRNAs (circRNAs) and microRNAs (miRNAs), take part in a complex chain of events playing a pivotal role in several important regulatory processes in humans. In this narrative review we summarize and then analyze the function of circRNAs-miRNA-mRNA networks as putative novel biomarkers and therapeutic targets for sepsis, focusing only on data collected in clinical settings in humans.
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Ding G, An J, Li L. MicroRNA-103a-3p enhances sepsis-induced acute kidney injury via targeting CXCL12. Bioengineered 2022; 13:10288-10298. [PMID: 35510354 PMCID: PMC9278413 DOI: 10.1080/21655979.2022.2062195] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Acute kidney injury (AKI) is a common and fatal complication in inflammatory sepsis. Several microRNAs (miRNAs or miRs) have been identified to control sepsis. MiR-103a-3p has been reported to take part in the various inflammatory response. However, its role in AKI remains unclear. The present research aimed to explore the role and mechanisms of miR-103a-3p in AKI. Neurogenic sepsis mouse model and lipopolysaccharide-induced HK-2 and 293 cell models were established. The renal functions in each group of mice were measured. After evaluating the biological functions of C-X-C motif chemokine 12 (CXCL12) and miR-103a-3p on HK-2 and HEK-293 T cells, their interaction was determined. Detection of CXCL12 and apoptosis and inflammation-related factors in renal tissue was done. MiR-103a-3p was significantly repressed in the sepsis model, while CXCL12 was elevated. Furthermore, miR-103a-3p inversely controlled CXCL12. Knockdown of miR-103a-3p or overexpression of CXCL12 could significantly inhibit the progression of HK-2 and HEK293 cells, whereas elevated miR-103a-3p or knockdown of CXCL12 showed the opposite effects. Collectively, miR-103a-3p heightens renal cell damage caused by sepsis by targeting CXCL12.
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Affiliation(s)
- Gaihong Ding
- Department of Nephrology, Xuchang University Medical College, Xuchang City, Henan Province, China
| | - Jinhua An
- Department of Nephrology, Xuchang University Medical College, Xuchang City, Henan Province, China
| | - Luyao Li
- Department of Nephrology, Xuchang University Medical College, Xuchang City, Henan Province, China
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Tian Y, Wang TS, Bu H, Shao G, Zhang W, Zhang L. Role of Exosomal miR-223 in Chronic Skeletal Muscle Inflammation. Orthop Surg 2022; 14:644-651. [PMID: 35293669 PMCID: PMC9002075 DOI: 10.1111/os.13232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 12/30/2021] [Accepted: 01/19/2022] [Indexed: 12/14/2022] Open
Abstract
As skeletal muscle is one of the largest organs in the body, its damage can directly reflect a decline in somatic function, thus, further affecting daily life and health. Inflammation is a prerequisite for the repair of injured skeletal muscles. Chronic inflammation induced by inadequate repair in skeletal muscle aggravates tissue injury. Exosomes regulate inflammatory responses to facilitate the repair of skeletal muscle injury. Moreover, exosomal miR‐223 with high specificity is the most abundant miRNA in peripheral blood and regarded as biomarkers for inflammation post skeletal muscle injury, which warrants further investigation. Available studies have demonstrated that exosomal miR‐223 negatively correlates with TNF‐α levels in serum and regulates the canonical inflammatory NF‐κB signaling pathway. miR‐223 is a negative feedback regulator with great potential for adjusting inflammatory imbalance and promoting skeletal muscle repair. The research on the regulation of negative feedback factors in the inflammatory signaling pathway is essential in biology and medicine. Therefore, this review mainly elaborates the formation, heterogeneity and markers of exosomes and points out exosomal miR‐223 as a beneficial role in chronic skeletal muscle inflammation and can be expected to be a potential therapeutic target for skeletal muscle damage.
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Affiliation(s)
- Yuan Tian
- Department of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China.,Department of Acupuncture-Moxibustion and Tuina, The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Tie-Shan Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - He Bu
- Department of Acupuncture-Moxibustion and Tuina, The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Guo Shao
- Center for Translational Medicine and Department of Laboratory Medicine, the Third People's Hospital of Longgang District, Shenzhen, China
| | - Wei Zhang
- Department of Pathology, the First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia, China
| | - Li Zhang
- Department of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
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Sankar S, Maruthai K, Bobby Z, Adhisivam B. MicroRNA Expression in Neonates with Late-onset Sepsis - A Cross-sectional Comparative Study. Immunol Invest 2022; 51:1647-1659. [PMID: 35026963 DOI: 10.1080/08820139.2021.2020282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Neonatal sepsis is a major health concern among neonates with higher morbidity and mortality rate. Studies have recently speculated the importance of differential expression of circulating mature micro-RNAs (miRNAs) which could serve as diagnostic as well as prognostic markers for risk of mortality in neonatal sepsis. This study aimed to analyze the expression pattern and to assess the diagnostic/prognostic value of miRNAs miR-21, miR-29a miR-31, miR-146a, and miR-155 in late-onset neonatal sepsis. METHODS A cross-sectional comparative study was conducted including 42 healthy controls and 42 neonates with late-onset neonatal sepsis. SYBR green-based miScript RT-PCR assay was used for the expression analysis and the comparative Ct method 2-delta (Ct) method was used for relative quantification of the candidate miRNAs in plasma. Significantly higher expression of miR-21 and miR-155 and lower expression of miR-29a and miR-146a was observed in cases compared to control except miR-31. In subgroups analysis, miR-21(p = .03) showed a significant difference between pre-term and term neonates and miR-31 (p = .01) and miR-155 (p = .03) showed a significant difference between low-birth-weight and normal-birth-weight neonates. miR-146a showed significantly lower expression in the non-survivor group compared to the survivor group (p = .005). A receiver operating characteristic curve (ROC) analysis of miR-21 and miR-29a (0.829 and 0.787 AUC of ROC curves) showed good discrimination for the identification of sepsis from non-sepsis neonates. CONCLUSION The current study shows evidence of differential expression of miRNAs in neonatal sepsis and this altered expression of candidate miRNAs could be involved in immune dysregulation, thus leading to sepsis-related severity in newborns.
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Affiliation(s)
- Saranya Sankar
- Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education and Research (Jipmer), Puducherry, India
| | - Kathirvel Maruthai
- Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (Jipmer), Puducherry, India.,Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Zachariah Bobby
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (Jipmer), Puducherry, India
| | - Bethou Adhisivam
- Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education and Research (Jipmer), Puducherry, India
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Miranda M, Nadel S. Impact of Inherited Genetic Variants on Critically Ill Septic Children. Pathogens 2022; 11:pathogens11010096. [PMID: 35056044 PMCID: PMC8781648 DOI: 10.3390/pathogens11010096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/05/2022] [Accepted: 01/10/2022] [Indexed: 11/16/2022] Open
Abstract
Sepsis remains an important source of morbidity and mortality in children, despite the development of standardized care. In the last decades, there has been an increased interest in genetic and genomic approaches to early recognition and development of treatments to manipulate the host inflammatory response. This review will present a summary of the normal host response to infection and progression to sepsis, followed by highlighting studies with a focus on gene association studies, epigenetics, and genome-wide expression profiling. The susceptibility (or outcome) of sepsis in children has been associated with several polymorphisms of genes broadly involved in inflammation, immunity, and coagulation. More recently, gene expression profiling has been focused on identifying novel biomarkers, pathways and therapeutic targets, and gene expression-based subclassification. Knowledge of a patient’s individual genotype may, in the not-too-remote future, be used to guide tailored treatment for sepsis. However, at present, the impact of genomics remains far from the bedside of critically ill children.
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Affiliation(s)
- Mariana Miranda
- Paediatric Unit, Imperial College Healthcare NHS Trust, London W2 1NY, UK
- Correspondence:
| | - Simon Nadel
- St. Mary’s Hospital, Imperial College Healthcare NHS Trust, and Imperial College, London W2 1NY, UK;
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Ghafouri-Fard S, Khoshbakht T, Hussen BM, Taheri M, Arefian N. Regulatory Role of Non-Coding RNAs on Immune Responses During Sepsis. Front Immunol 2021; 12:798713. [PMID: 34956235 PMCID: PMC8695688 DOI: 10.3389/fimmu.2021.798713] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/19/2021] [Indexed: 12/22/2022] Open
Abstract
Sepsis is resulted from a systemic inflammatory response to bacterial, viral, or fungal agents. The induced inflammatory response by these microorganisms can lead to multiple organ system failure with devastating consequences. Recent studies have shown altered expressions of several non-coding RNAs such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) during sepsis. These transcripts have also been found to participate in the pathogenesis of multiple organ system failure through different mechanisms. NEAT1, MALAT1, THRIL, XIST, MIAT and TUG1 are among lncRNAs that participate in the pathoetiology of sepsis-related complications. miR-21, miR-155, miR-15a-5p, miR-494-3p, miR-218, miR-122, miR-208a-5p, miR-328 and miR-218 are examples of miRNAs participating in these complications. Finally, tens of circRNAs such as circC3P1, hsa_circRNA_104484, hsa_circRNA_104670 and circVMA21 and circ-PRKCI have been found to affect pathogenesis of sepsis. In the current review, we describe the role of these three classes of noncoding RNAs in the pathoetiology of sepsis-related complications.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tayyebeh Khoshbakht
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Normohammad Arefian
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Yuan S, Wu Q, Wang Z, Che Y, Zheng S, Chen Y, Zhong X, Shi F. miR-223: An Immune Regulator in Infectious Disorders. Front Immunol 2021; 12:781815. [PMID: 34956210 PMCID: PMC8702553 DOI: 10.3389/fimmu.2021.781815] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are diminutive noncoding RNAs that can influence disease development and progression by post-transcriptionally regulating gene expression. The anti-inflammatory miRNA, miR-223, was first identified as a regulator of myelopoietic differentiation in 2003. This miR-223 exhibits multiple regulatory functions in the immune response, and abnormal expression of miR-223 is shown to be associated with multiple infectious diseases, including viral hepatitis, human immunodeficiency virus type 1 (HIV-1), and tuberculosis (TB) by influencing neutrophil infiltration, macrophage function, dendritic cell (DC) maturation and inflammasome activation. This review summarizes the current understanding of miR-223 physiopathology and highlights the molecular mechanism by which miR-223 regulates immune responses to infectious diseases and how it may be targeted for diagnosis and treatment.
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Affiliation(s)
- Shun Yuan
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qi Wu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiwei Wang
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yanjia Che
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Sihao Zheng
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuanyang Chen
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaohan Zhong
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Feng Shi
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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Trung NT, Lien TT, Sang VV, Hoan NX, Manh ND, Thau NS, Quyen DT, Hien TTT, Hoan PQ, Bang MH, Velavan TP, Song LH. Circulating miR-147b as a diagnostic marker for patients with bacterial sepsis and septic shock. PLoS One 2021; 16:e0261228. [PMID: 34914790 PMCID: PMC8675720 DOI: 10.1371/journal.pone.0261228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 11/24/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Early diagnosis, precise antimicrobial treatment and subsequent patient stratification can improve sepsis outcomes. Circulating biomarkers such as plasma microRNAs (miRNAs) have proven to be surrogates for diagnosis, severity and case management of infections. The expression of four selected miRNAs (miR-146-3p, miR-147b, miR-155 and miR-223) was validated for their prognostic and diagnostic potential in a clinically defined cohort of patients with sepsis and septic shock. METHODS The expression of plasma miRNAs was quantified by quantitative PCR (qPCR) in patients with bacterial sepsis (n = 78), in patients with septic shock (n = 52) and in patients with dengue haemorrhagic fever (DHF; n = 69) and in healthy controls (n = 82). RESULTS The expression of studied miRNA was significantly increased in patients with bacterial sepsis and septic shock. The plasma miR-147b was able to differentiate bacterial sepsis from non-sepsis and septic shock (AUC = 0.77 and 0.8, respectively, p≤ 0.05), while the combination of plasma miR-147b and procalcitonin (PCT) predicted septic shock (AUC = 0.86, p≤ 0.05). CONCLUSIONS The plasma miR-147b may be an useful biomarker independently or in combination with PCT to support clinical diagnosis of sepsis and equally prognosis of patients with septic shock.
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Affiliation(s)
- Ngo Tat Trung
- Centre for Genetics Consultation and Cancer Screening, Hanoi, Vietnam
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Molecular Biology, Hanoi, Vietnam
- * E-mail: (LHS); (NTT)
| | - Tran Thi Lien
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
| | - Vu Viet Sang
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
| | - Nghiem Xuan Hoan
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Molecular Biology, Hanoi, Vietnam
| | - Nguyen Dang Manh
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
| | - Nguyen Sy Thau
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
| | - Dao Thanh Quyen
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Molecular Biology, Hanoi, Vietnam
| | | | | | - Mai Hong Bang
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Department of Gastroenterology, Hanoi, Vietnam
| | - Thirumalaisamy P. Velavan
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
| | - Le Huu Song
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
- Institute of Clinical Infectious Diseases, Hanoi, Vietnam
- * E-mail: (LHS); (NTT)
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Jadli AS, Parasor A, Gomes KP, Shandilya R, Patel VB. Exosomes in Cardiovascular Diseases: Pathological Potential of Nano-Messenger. Front Cardiovasc Med 2021; 8:767488. [PMID: 34869682 PMCID: PMC8632805 DOI: 10.3389/fcvm.2021.767488] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases (CVDs) represent a major global health problem, due to their continued high incidences and mortality. The last few decades have witnessed new advances in clinical research which led to increased survival and recovery in CVD patients. Nevertheless, elusive and multifactorial pathophysiological mechanisms of CVD development perplexed researchers in identifying efficacious therapeutic interventions. Search for novel and effective strategies for diagnosis, prevention, and intervention for CVD has shifted research focus on extracellular vesicles (EVs) in recent years. By transporting molecular cargo from donor to recipient cells, EVs modulate gene expression and influence the phenotype of recipient cells, thus EVs prove to be an imperative component of intercellular signaling. Elucidation of the role of EVs in intercellular communications under physiological conditions implied the enormous potential of EVs in monitoring and treatment of CVD. The EVs secreted from the myriad of cells in the cardiovascular system such as cardiomyocytes, cardiac fibroblasts, cardiac progenitor cells, endothelial cells, inflammatory cells may facilitate the communication in physiological and pathological conditions. Understanding EVs-mediated cellular communication may delineate the mechanism of origin and progression of cardiovascular diseases. The current review summarizes exosome-mediated paracrine signaling leading to cardiovascular disease. The mechanistic role of exosomes in cardiovascular disease will provide novel avenues in designing diagnosis and therapeutic interventions.
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Affiliation(s)
- Anshul S Jadli
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Ananya Parasor
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Karina P Gomes
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Ruchita Shandilya
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
| | - Vaibhav B Patel
- Department of Physiology and Pharmacology, Cumming School of Medicine, Calgary, AB, Canada.,Libin Cardiovascular Institute, University of Calgary, Calgary, AB, Canada
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Fatmi A, Chabni N, Cernada M, Vento M, González-López M, Aribi M, Pallardó FV, García-Giménez JL. Clinical and immunological aspects of microRNAs in neonatal sepsis. Biomed Pharmacother 2021; 145:112444. [PMID: 34808550 DOI: 10.1016/j.biopha.2021.112444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/08/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Neonatal sepsis constitutes a highly relevant public health challenge and is the most common cause of infant morbidity and mortality worldwide. Recent studies have demonstrated that during infection epigenetic changes may occur leading to reprogramming of gene expression. Post-transcriptional regulation by short non-coding RNAs (e.g., microRNAs) have recently acquired special relevance because of their role in the regulation of the pathophysiology of sepsis and their potential clinical use as biomarkers. ~22-nucleotide of microRNAs are not only involved in regulating multiple relevant cellular and molecular functions, such as immune cell function and inflammatory response, but have also been proposed as good candidates as biomarkers in sepsis. Nevertheless, establishing clinical practice guidelines based on microRNA patterns as biomarkers for diagnosis and prognosis in neonatal sepsis has yet to be achieved. Given their differential expression across tissues in neonates, the release of specific microRNAs to blood and their expression pattern can differ compared to sepsis in adult patients. Further in-depth research is necessary to fully understand the biological relevance of microRNAs and assess their potential use in clinical settings. This review provides a general overview of microRNAs, their structure, function and biogenesis before exploring their potential clinical interest as diagnostic and prognostic biomarkers of neonatal sepsis. An important part of the review is focused on immune and inflammatory aspects of selected microRNAs that may become biomarkers for clinical use and therapeutic intervention.
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Affiliation(s)
- Ahlam Fatmi
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, W0414100, 13000 Tlemcen, Algeria
| | - Nafissa Chabni
- Faculty of Medicine, Tlemcen Medical Centre University, 13000 Tlemcen, Algeria
| | - María Cernada
- Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain; Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain, University and Polytechnic Hospital La Fe, Valencia, Spain
| | - Máximo Vento
- Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain; Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain, University and Polytechnic Hospital La Fe, Valencia, Spain
| | - María González-López
- Department of Pediatrics. Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Mourad Aribi
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, W0414100, 13000 Tlemcen, Algeria; Biotechnology Center of Constantine (CRBt), 25000 Constantine, Algeria
| | - Federico V Pallardó
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain; INCLIVA Health Research Institute, Mixed Unit for Rare Diseases INCLIVA-CIPF, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
| | - José Luis García-Giménez
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain; INCLIVA Health Research Institute, Mixed Unit for Rare Diseases INCLIVA-CIPF, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.
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Xu L, Cao H, Xu P, Nie M, Zhao C. Circ_0114427 promotes LPS-induced septic acute kidney injury by modulating miR-495-3p/TRAF6 through the NF-κB pathway. Autoimmunity 2021; 55:52-64. [PMID: 34730059 DOI: 10.1080/08916934.2021.1995861] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUNDS Septic acute kidney injury (AKI) is a severe illness in clinics. Enriching researches investigated the regulatory network of AKI during the past decades, evidences showed that circular RNAs (circRNAs) were involved in the molecular mechanism of human AKI. However, the special responses remain largely elusive. Thus, the study aims to investigate the function of circ_0114427 in the progression of AKI. METHODS The levels of circ_0114427, miR-495-3p and Tumour Necrosis Factor Receptor-Associated Factor 6 (TRAF6) were both assessed by quantitative real-time polymerase chain reaction (qRT-PCR). In addition, lipopolysaccharide (LPS) was applied to establish AKI cell model, and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was carried out to determine the viability of LPS-induced HK-2 cells. The expression of TRAF6, B-cell lymphoma-2 (Bcl-2), Bcl2-associated X (Bax), cleave-caspase 3, caspase 3, total IκBα (t-IκBα), phospho-IκBα (p-IκBα), total p65 (t-p65) and phospho-p65 (p-p65) were all detected via western blot. The levels of IL-1β and TNF-α were identified by western blot and ELISA. What's more, cell apoptosis was measured by flow cytometry. Lastly, dual-luciferase reporter, RNA Immunoprecipitation (RIP) and RNA pull-down assays were employed to verify the relationships between miR-495-3p and circ_0114427 or TRAF6 in vitro. RESULTS The level of miR-495-3p was remarkably restrained while circ_0114427 and TRAF6 levels were specially reinforced in AKI patient serum samples and LPS-induced HK-2 cells. Moreover, IL-1β and TNF-α were highly expressed in LPS-induced AKI cells. Functionally, circ_0114427 was a sponge of miR-495-3p, and circ_0114427 silence-mediated effects in LPS-induced HK-2 cells were partly ameliorated by the addition of miR-495-3p inhibitor. Moreover, TRAF6 was a target gene of miR-495-3p, and the inhibiting effect of miR-495-3p on cell apoptosis and inflammatory response was mitigated by TRAF6 overexpression. Mechanistically, the circ_0114427/miR-495-3p/TRAF6 axis modulated cell apoptosis and inflammatory response via NF-κB/p65 signalling pathway in AKI. CONCLUSION Circ_0114427 regulated cell apoptosis and inflammatory response through miR-495-3p/TRAF6 axis via NF-κB/p65 signalling pathway, providing a novel mechanism in clinical treatment of AKI patients.HighlightsCirc_0114427 is upregulated in serum specimens from septic AKI patients and LPS-induced HK-2 cells.LPS treatment suppresses cell viability and promotes apoptosis and inflammation in HK-2 cells.Circ_0114427 knockdown ameliorates the effects of LPS on cell viability, apoptosis and inflammation in HK-2 cells.Circ_0114427 regulates LPS-induced HK-2 cell injury by regulating miR-495-3p/TRAF6/NF-κB/p65 axis.
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Affiliation(s)
- Lei Xu
- Department of Emergency, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Hongxia Cao
- Department of Emergency, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Peng Xu
- Department of Emergency, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Mingxi Nie
- Department of Emergency, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
| | - Chun Zhao
- Department of Geriatrics, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei, China
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Wang B, Wang Y, Xu K, Zeng Z, Xu Z, Yue D, Li T, Luo J, Liu J, Yuan J. Resveratrol alleviates sepsis-induced acute kidney injury by deactivating the lncRNA MALAT1/MiR-205 axis. Cent Eur J Immunol 2021; 46:295-304. [PMID: 34764801 PMCID: PMC8574118 DOI: 10.5114/ceji.2021.109195] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 05/19/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Resveratrol plays a protective role against sepsis development, and the long noncoding RNA (lncRNA) MALAT1 is an inflammation-relevant biomarker. This investigation attempted to reveal whether resveratrol attenuated inflammation of sepsis-induced acute kidney injury (AKI) by regulating MALAT1. MATERIAL AND METHODS In total 120 rats were divided into a control group (n = 20), a Sham group (n = 20), a sepsis group (n = 40) and a resveratrol group (n = 40), and serum levels of inflammatory cytokines and AKI biomarkers were determined. An equal number of rats under identical treatments were, additionally, tracked for their survival, and the serum level of lncRNA MALAT1 was measured by RT-PCR. Moreover, septic cell models were constructed by treating HK-2 cells with lipopolysaccharide (LPS), and tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6 levels released by the cells were determined with ELISA. RESULTS Resveratrol treatment significantly brought down serum levels of inflammatory cytokines (i.e. TNF-α, IL-1β and IL-6), kidney function indicators (i.e. Scr, blood urea nitrogen [BUN] and Scys C), AKI biomarkers (i.e. NGAL and KIM-1) and MALAT1 in cecal ligation and puncture (CLP)-induced septic model rats (all p < 0.05), and the life span of septic rats was elongated by resveratrol treatment (p < 0.05). Viability and cytokine release of LPS-treated HK2 cells were rescued by resveratrol (p < 0.05), which was accompanied by a marked fall of MALAT1 expression (p < 0.05). In addition, si-MALAT1 diminished viability and suppressed cytokine release of HK2 cells, while pcDNA3.1-MALAT1 hindered the impact of resveratrol on the inflammatory response of HK2 cells (p < 0.05). Ultimately, miR-205, a protective molecule in sepsis-relevant AKI, was down-regulated by resveratrol and si-MALAT1 (p < 0.05). CONCLUSIONS Resveratrol relieved sepsis-induced AKI by restraining the lncRNA MALAT1/miR-205 axis.
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Affiliation(s)
- Biao Wang
- The Second Hospital, University of South China, China
| | | | - Ke Xu
- Chenzhou No. 1 People’s Hospital, China
| | - Zhenhua Zeng
- Nanfang Hospital, Southern Medical University, China
| | | | | | - Tao Li
- Chenzhou No. 1 People’s Hospital, China
| | - Jihui Luo
- Chenzhou No. 1 People’s Hospital, China
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Li Y, Lu B, Yu M, Zhai J, Yao Y, Chai Y. Diagnostic value and significance of serum miR-132 combined with miR-223 for sepsis-induced cardiomyopathy. Exp Ther Med 2021; 22:1396. [PMID: 34650644 PMCID: PMC8506955 DOI: 10.3892/etm.2021.10832] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 02/01/2021] [Indexed: 12/15/2022] Open
Abstract
In previous studies, miR-132 and miR-223 were considered to be involved in cellular and pathological processes of diseases. However, the role of early diagnosis and prognosis evaluation in sepsis-induced cardiomyopathy (SIC) remains unknown. The present study aimed to explore the diagnostic value of combined detection of miR-132 and miR-223 for SIC and their correlation with creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor α (TNF-α), and interleukin-6 (IL)-6. SIC patients (n=80) admitted to Tianjin Medical University General Hospital were assigned to the research group (RG), while 60 healthy participants receiving physical examinations at the same period were assigned to the control group (CG). Serum expression profiles of miR-132 and miR-223 were detected by the RT-qPCR. CK-MB and cTnI were assessed using chemiluminescence assay, and TNF-α and IL-6 by enzyme-linked immunosorbent assay (ELISA). Serum miR-132 and miR-223 levels were significantly lower in the RG than in the CG (P<0.001). The sensitivity and specificity for the diagnosis of SIC were 82.50 and 71.67% for miR-132, 95.00 and 61.67% for miR-223, as well as 86.25 and 86.67% for miR-132 combined with miR-223. Serum miR-132 and miR-223 levels were significantly higher in the survivor group than in the deceased group (P<0.001). The sensitivity and specificity for the prognosis of SIC were 85.96 and 65.22% for miR-132 combined with miR-223. Serum miR-132 and miR-223 were negatively correlated with serum CK-MB, cTnI, TNF-α, and IL-6 (P<0.001). miR-132 combined with miR-223 can be used for early diagnosis and prognostic evaluation of SIC, and the two are correlated with CK-MB, cTnI, TNF-α, and IL-6.
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Affiliation(s)
- Yanping Li
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Bin Lu
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Muming Yu
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jianhua Zhai
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Ying Yao
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Yanfen Chai
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Wang Q, Liu K, Jin C. Clinical value of microRNA-378a-3p in sepsis and its role in sepsis-induced inflammation and cardiac dysfunction. Bioengineered 2021; 12:8496-8504. [PMID: 34565302 PMCID: PMC8806767 DOI: 10.1080/21655979.2021.1985339] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This study explored the clinical meaning of miR-378a-3p in sepsis and its influence on sepsis-induced inflammation and cardiac dysfunction. Serum levels of miR-378a-3p were detected by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The Receiver Operating Characteristic (ROC) curve was used to evaluate its diagnostic value. The effects of miR-378a-3p on inflammation and cardiac function were evaluated by monitoring left ventricular systolic pressure (LVSP), left ventricular and end-diastolic pressure (LVEDP), maximum rate of change in left ventricular pressure (± dp/dtmax) and detecting the levels of troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interleukin-1β (IL-1β) via enzyme linked immunosorbent assay (ELISA). Serum miR-378a-3p was increased in sepsis patients and rat model. ROC curve indicated that miR-378a-3p might have diagnostic significance for sepsis miR-378a-3p antagomir improved the cardiac function by upregulating the levels of LVSP and ± dp/dtmax, and decreasing the levels of LVEDP, cTnI and CK-MB in rat model. miR-378a-3p antagomir also significantly alleviated the inflammatory responseby down-regulating the expression of TNF-a, IL-6, and IL-1β. Besides, logistics regression analysis illustrated that miR-378a-3p was an independent influencing factor for the onset of cardiac dysfunction in sepsis. miR-378a-3p has the potential as a diagnostic biomarker for sepsis and decreasing the level of miR-378a-3p had the ability to ameliorate cardiac dysfunction and inflammatory response caused by sepsis.
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Affiliation(s)
- Qing Wang
- Department Of Emergency, Emergency General Hospital, Beijing, China
| | - Kuo Liu
- Department Of Emergency, Emergency General Hospital, Beijing, China
| | - Changming Jin
- Department Of Emergency, Emergency General Hospital, Beijing, China
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Cao J, Shi D, Zhu L, Song L. Circ_RASGEF1B Promotes LPS-Induced Apoptosis and Inflammatory Response by Targeting MicroRNA-146a-5p/Pdk1 Axis in Septic Acute Kidney Injury Cell Model. Nephron Clin Pract 2021; 145:748-759. [PMID: 34438395 DOI: 10.1159/000517475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/21/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND We intended to investigate the function of circular RNA RasGEF domain family member 1B (circ_RASGEF1B) in lipopolysaccharide (LPS)-induced septic acute kidney injury (AKI) cell model and its associated mechanism. METHODS TCMK-1 cells were exposed to 10 μg/mL LPS for 24 h to establish a septic AKI cell model. Mice were intraperitoneally injected with 10 mg/kg LPS to establish a septic AKI mice model. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were used to measure RNA and protein expression, respectively. Cell viability and apoptosis were assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. Cell inflammatory response was analyzed using enzyme-linked immunosorbent assay. Dual-luciferase reporter assay was conducted to confirm the predicted target relationship between microRNA-146a-5p (miR-146a-5p) and circ_RASGEF1B or pyruvate dehydrogenase kinase 1 (Pdk1). RESULTS The circ_RASGEF1B level was upregulated in LPS-induced TCMK-1 cells and septic AKI mice models. LPS exposure reduced cell viability and promoted cell apoptosis and inflammatory response partly by upregulating circ_RASGEF1B. Circ_RASGEF1B bound to miR-146a-5p and miR-146a-5p interference partly overturned circ_RASGEF1B silencing-mediated effects in LPS-induced TCMK-1 cells. Pdk1 was a target of miR-146a-5p, and Pdk1 accumulation partly counteracted miR-146a-5p-induced influences in TCMK-1 cells upon LPS stimulation. CONCLUSION Circ_RASGEF1B promoted LPS-induced apoptosis and inflammatory response in renal tubular epithelial cells partly by upregulating Pdk1 via acting as miR-146a-5p sponge.
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Affiliation(s)
- Jianghong Cao
- Department of Intensive Care Unit, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Dongwu Shi
- Department of Intensive Care Unit, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Lili Zhu
- Department of Intensive Care Unit, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Lu Song
- Department of Intensive Care Unit, Shanxi Provincial People's Hospital, Taiyuan, China
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45
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Tian X, Li L, Fu G, Wang J, He Q, Zhang C, Qin B, Wang J. miR-133a-3p regulates the proliferation and apoptosis of intestinal epithelial cells by modulating the expression of TAGLN2. Exp Ther Med 2021; 22:824. [PMID: 34149870 PMCID: PMC8200801 DOI: 10.3892/etm.2021.10256] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis is one of the most common diseases in patients in intensive care units. Intestinal barrier dysfunction serves a critical role in the pathogenesis and progression of sepsis. Therefore, preservation of the intestinal epithelial barrier function is an area of ongoing research in the treatment of sepsis. The present study investigated the effects of miR-133a-3p on the proliferation and apoptosis of intestinal epithelial cells and the possible mechanism underlying its actions. miR-133a-3p was used to upregulate the intestinal epithelial FHs 74 Int cell line and cell proliferation and apoptosis were investigated. A luciferase reporter assay was used to determine whether the 3'-UTR of TAGLN2 mRNA was a binding target of miR-133a-3p. FHs 74 Int cells were transfected with TAGLN2 shRNA and the effects of TAGLN2 on the proliferation and apoptosis of intestinal epithelial cells were investigated. It was found that miR-133a-3p inhibited the proliferation and promoted the apoptosis of intestinal epithelial cells. A luciferase reporter assay confirmed that miR-133a-3p targeted TAGLN2 directly. In addition, low expression of TAGLN2 inhibited the proliferation and promoted the apoptosis of intestinal epithelial cells. The results of the present study suggested that the miR-133a-3p inhibition of proliferation and promotion of apoptosis occurred via the inhibition of TAGLN2. These results suggested that miR-133a-3p may be a promising therapeutic target for the diagnosis and treatment of gut-origin sepsis.
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Affiliation(s)
- Xiaoxi Tian
- Department of Emergency, Tangdu Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Lihong Li
- Department of Emergency, Tangdu Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Guoqiang Fu
- Department of Emergency, Tangdu Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Jianyu Wang
- Department of Emergency, Tangdu Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Qianfeng He
- Department of Emergency, Tangdu Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Cuicui Zhang
- Department of Emergency, Tangdu Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Bingrui Qin
- Medical College of Air Force Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jiahui Wang
- Medical College of Air Force Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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46
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Khan HN, Jongejan A, van Vught LA, Horn J, Schultz MJ, Zwinderman AH, Cremer OL, Bonten MJ, van der Poll T, Scicluna BP. The circulatory small non-coding RNA landscape in community-acquired pneumonia on intensive care unit admission. J Cell Mol Med 2021; 25:7621-7630. [PMID: 34272809 PMCID: PMC8358855 DOI: 10.1111/jcmm.16406] [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: 12/05/2020] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/11/2022] Open
Abstract
Community‐acquired pneumonia (CAP) is a major cause of sepsis. Despite several clinical trials targeting components of the inflammatory response, no specific treatment other than antimicrobial therapy has been approved. This argued for a deeper understanding of sepsis immunopathology, in particular factors that can modulate the host response. Small non‐coding RNA, for example, micro (mi)RNA, have been established as important modifiers of cellular phenotypes. Notably, miRNAs are not exclusive to the intracellular milieu but have also been detected extracellular in the circulation with functional consequences. Here, we sought to determine shifts in circulatory small RNA levels of critically ill patients with CAP‐associated sepsis and to determine the influence of clinical severity and causal pathogens on small RNA levels. Blood plasma was collected from 13 critically ill patients with sepsis caused by CAP on intensive care unit admission and from 5 non‐infectious control participants. Plasma small RNA‐sequencing identified significantly altered levels of primarily mature miRNAs in CAP relative to controls. Pathways analysis of high or low abundance miRNA identified various over‐represented cellular biological pathways. Analysis of small RNA levels against common clinical severity and inflammatory parameters indices showed direct and indirect correlations. Additionally, variance of plasma small RNA levels in CAP patients may be explained, at least in part, by differences in causal pathogens. Small nuclear RNA levels were specifically altered in CAP due to Influenza infection in contrast to Streptococcus pneumoniae infection. Pathway analysis of plasma miRNA signatures unique to Influenza or Streptococcus pneumoniae infections showed enrichment for specific proteoglycan, cell cycle, and immunometabolic pathways.
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Affiliation(s)
- Hina N Khan
- Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, The Netherlands.,Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Aldo Jongejan
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Lonneke A van Vught
- Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, The Netherlands
| | - Janneke Horn
- Department of Intensive Care & Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Marcus J Schultz
- Department of Intensive Care & Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands.,Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand
| | - Aeilko H Zwinderman
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Olaf L Cremer
- Department of Intensive Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marc J Bonten
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.,Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Tom van der Poll
- Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, The Netherlands.,Division of Infectious Diseases, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Brendon P Scicluna
- Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, The Netherlands.,Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
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Kronstadt SM, Pottash AE, Levy D, Wang S, Chao W, Jay SM. Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment. ADVANCED THERAPEUTICS 2021; 4:2000259. [PMID: 34423113 PMCID: PMC8378673 DOI: 10.1002/adtp.202000259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Indexed: 12/14/2022]
Abstract
Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.
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Affiliation(s)
- Stephanie M Kronstadt
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Alex E Pottash
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Daniel Levy
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Sheng Wang
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Steven M Jay
- Fischell Department of Bioengineering and Program in Molecular and, Cell Biology, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
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48
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Osca-Verdegal R, Beltrán-García J, Pallardó FV, García-Giménez JL. Role of microRNAs As Biomarkers in Sepsis-Associated Encephalopathy. Mol Neurobiol 2021; 58:4682-4693. [PMID: 34160774 PMCID: PMC8220114 DOI: 10.1007/s12035-021-02445-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/06/2021] [Indexed: 12/29/2022]
Abstract
Sepsis-associated encephalopathy (SAE) is a neurological complication of sepsis, characterized by brain dysfunction without any direct central nervous system infection. The diagnosis of SAE is currently a challenge. In fact, problems in making a diagnosis of SAE cause a great variability of incidence that can reach up to 70% of all septic patients. Even more, despite SAE is the most frequent type of encephalopathy occurring in critically ill patients, the molecular mechanisms that guide its progression have not been completely elucidated. On the other hand, miRNAs have proven to be excellent biomarkers for both diagnosis and prognosis, especially in brain pathologies because of their small size they can cross the blood–brain barrier easier than other biomolecules. The identification of new miRNAs as biomarkers may help to improve SAE diagnosis and prognosis and also to design new therapies for this clinical manifestation that produces diffuse cerebral dysfunction. This review is focused on SAE physiopathology and the need to have clear criteria for its diagnosis; thus, this work postulates some miRNA candidates to be used for SAE biomarkers because of their role in both, neurological damage and sepsis.
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Affiliation(s)
- Rebeca Osca-Verdegal
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
| | - Jesús Beltrán-García
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
- Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
| | - Federico V. Pallardó
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
- Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
| | - José Luis García-Giménez
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina Y Odontología, Universitat de València, València, Spain
- Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
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Caserta S, Ghezzi P. Release of redox enzymes and micro-RNAs in extracellular vesicles, during infection and inflammation. Free Radic Biol Med 2021; 169:248-257. [PMID: 33862160 DOI: 10.1016/j.freeradbiomed.2021.04.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/27/2021] [Accepted: 04/08/2021] [Indexed: 12/11/2022]
Abstract
Many studies reported that redox enzymes, particularly thioredoxin and peroxiredoxin, can be released by cells and act as soluble mediators in immunity. Recently, it became clear that peroxiredoxins can be secreted via the exosome-release route, yet it remains unclear how this exactly happens and why. This review will first introduce briefly the possible redox states of protein cysteines and the role of redox enzymes in their regulation. We will then discuss the studies on the extracellular forms of some of these enzymes, their association with exosomes/extracellular vesicles and with exosome micro-RNAs (miRNAs)/mRNAs involved in oxidative processes, relevant in infection and inflammation.
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Affiliation(s)
- Stefano Caserta
- Department of Biomedical Sciences, Hardy Building, The University of Hull, Hull, HU6 7RX, United Kingdom
| | - Pietro Ghezzi
- Department of Clinical Experimental Medicine, Brighton & Sussex Medical School, Brighton, BN19RY, United Kingdom.
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Abstract
OBJECTIVES Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures. DATA SOURCES Online search of published scientific literature via Pubmed using the term "epigenetics" in combination with the terms "sepsis", "infection", "bacterial infection", "viral infection", "critical illness", "acute respiratory distress syndrome", and "acute lung injury". STUDY SELECTION Articles were chosen for inclusion based on their relevance to sepsis, acute inflammation, sepsis-related immune suppression, and sepsis-related organ failure. Reference lists were reviewed to identify additional relevant articles. DATA EXTRACTION Relevant data was extracted and synthesized for narrative review. DATA SYNTHESIS Epigenetic regulation is a key determinant of gene expression in sepsis. At the onset of infection, host-pathogen interactions often result in epigenetic alterations to host cells that favor pathogen survival. In parallel, the host inflammatory response is characterized by epigenetic modifications in key regulatory genes, including tumor necrosis factor and interleukin-1β. In human sepsis patients, multiple epigenetic modifying enzymes show differential expression in early sepsis, suggesting a role for epigenetics in coordinating the response to infection. In the later stages of sepsis, epigenetic modifications accompany endotoxin tolerance and the immune-suppressed state. In animal models, treatment with epigenetic modifiers can mitigate the effects of sepsis and improve survival as well as reverse sepsis-associated organ injury. CONCLUSIONS Epigenetic modifications are associated with key phases of sepsis, from the host-pathogen interaction, to acute inflammation, to immune suppression. Epigenetic markers show promise in the diagnosis and prognosis of sepsis and epigenetic modifying agents show promise as therapeutic tools in animal models of sepsis. Human studies in the area of epigenetics are sorely lacking and should be a priority for sepsis researchers.
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