title: The involvement of regulatory non-coding RNAs in sepsis: a systematic review.
abstract: BACKGROUND
  Sepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis.
  
  
  METHODS
  We searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words ("microRNA", "long non-coding RNA", "circular RNA", "sepsis" and/or "septic shock") from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool.
  
  
  RESULTS
  Observational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common.
  
  
  CONCLUSIONS
  Although non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful.
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Ho
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Hung
authors.initials: H
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, Special Administrative Region of China. wonghei@cuhk.edu.hk.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China. wonghei@cuhk.edu.hk.
authors.forename: Sunny H
authors.initials: SH
authors.lastname: Wong
authors.affiliation: The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Maggie H T
authors.initials: MH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, Special Administrative Region of China.|Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China.
authors.forename: Zhangang
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Gordon
authors.initials: G
authors.lastname: Choi
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Czarina C H
authors.initials: CC
authors.lastname: Leung
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Wai T
authors.initials: WT
authors.lastname: Wong
authors.affiliation: Department of Orthopedics Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China.
authors.forename: Tony
authors.initials: T
authors.lastname: Gin
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China. mtvchan@cuhk.edu.hk.
authors.forename: Matthew T V
authors.initials: MT
authors.lastname: Chan
authors.affiliation: Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, Hong Kong, Hong Kong, Special Administrative Region of China. wukakei@cuhk.edu.hk.|State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong, Special Administrative Region of China. wukakei@cuhk.edu.hk.
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000502:physiology*; D006801:Humans; D064887:Observational Studies as Topic; D012313:RNA / Q000235:genetics / Q000378:metabolism; D000079962:RNA, Circular; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism*; D018805:Sepsis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D000079962:RNA, Circular; D022661:RNA, Untranslated; D012313:RNA
keywords: Biomarker; Inflammation; Sepsis; Shock; circRNA; lncRNA; microRNA