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Du B, Mu K, Sun M, Yu Z, Li L, Hou L, Wang Q, Sun J, Chen J, Zhang X, Zhang W. Biliary atresia and cholestasis plasma non-targeted metabolomics unravels perturbed metabolic pathways and unveils a diagnostic model for biliary atresia. Sci Rep 2024; 14:15796. [PMID: 38982277 PMCID: PMC11233669 DOI: 10.1038/s41598-024-66893-2] [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: 03/11/2024] [Accepted: 07/05/2024] [Indexed: 07/11/2024] Open
Abstract
The clinical diagnosis of biliary atresia (BA) poses challenges, particularly in distinguishing it from cholestasis (CS). Moreover, the prognosis for BA is unfavorable and there is a dearth of effective non-invasive diagnostic models for detection. Therefore, the aim of this study is to elucidate the metabolic disparities among children with BA, CS, and normal controls (NC) without any hepatic abnormalities through comprehensive metabolomics analysis. Additionally, our objective is to develop an advanced diagnostic model that enables identification of BA. The plasma samples from 90 children with BA, 48 children with CS, and 47 NC without any liver abnormalities children were subjected to metabolomics analysis, revealing significant differences in metabolite profiles among the 3 groups, particularly between BA and CS. A total of 238 differential metabolites were identified in the positive mode, while 89 differential metabolites were detected in the negative mode. Enrichment analysis revealed 10 distinct metabolic pathways that differed, such as lysine degradation, bile acid biosynthesis. A total of 18 biomarkers were identified through biomarker analysis, and in combination with the exploration of 3 additional biomarkers (LysoPC(18:2(9Z,12Z)), PC (22:5(7Z,10Z,13Z,16Z,19Z)/14:0), and Biliverdin-IX-α), a diagnostic model for BA was constructed using logistic regression analysis. The resulting ROC area under the curve was determined to be 0.968. This study presents an innovative and pioneering approach that utilizes metabolomics analysis to develop a diagnostic model for BA, thereby reducing the need for unnecessary invasive examinations and contributing to advancements in diagnosis and prognosis for patients with BA.
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Affiliation(s)
- Bang Du
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Kai Mu
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Meng Sun
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Zhidan Yu
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Lifeng Li
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Ligong Hou
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Qionglin Wang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Jushan Sun
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
| | - Jinhua Chen
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008, China.
| | - Xianwei Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
- Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.
| | - Wancun Zhang
- Health Commission of Henan Province Key Laboratory for Precision Diagnosis and Treatment of Pediatric Tumor, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
- Henan International Joint Laboratory for Prevention and Treatment of Pediatric Disease, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
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Zhang Y, Liu Y, Huo W, He L, Li B, Wang H, Meng F, Duan C, Zhou B, Wu J, Chen R, Xing J, Wan Y. The Role of miRNA and Long Noncoding RNA in Cholestatic Liver Diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:879-893. [PMID: 38417698 DOI: 10.1016/j.ajpath.2024.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 02/05/2024] [Accepted: 02/16/2024] [Indexed: 03/01/2024]
Abstract
Cholestatic liver diseases encompass a range of organic damages, metabolic disorders, and dysfunctions within the hepatobiliary system, arising from various pathogenic causes. These factors contribute to disruptions in bile production, secretion, and excretion. Cholestatic liver diseases can be classified into intrahepatic and extrahepatic cholestasis, according to the location of occurrence. The etiology of cholestatic liver diseases is complex, and includes drugs, poisons, viruses, parasites, bacteria, autoimmune responses, tumors, and genetic metabolism. The pathogenesis of cholelstatic liver disease is not completely clarified, and effective therapy is lacking. Clarifying its mechanism to find more effective therapeutic targets and drugs is an unmet need. Increasing evidence demonstrates that miRNA and long noncoding RNA are involved in the progression of cholestatic liver diseases. This review provides a comprehensive summary of the research progress on the roles of miRNA and long noncoding RNA in cholestatic liver diseases. The aim of the review is to enhance the understanding of their potential diagnostic, therapeutic, and prognostic value for patients with cholestasis.
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Affiliation(s)
- Yudian Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Ying Liu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Wen Huo
- Functional Experiment Center, College of Basic and Legal Medicine, North Sichuan Medical College, Nanchong, China
| | - Longfei He
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Bowen Li
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Hui Wang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Fanyin Meng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
| | - Chenggang Duan
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Bingru Zhou
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Jinbo Wu
- Department of Otolaryngology-Head and Neck Surgery, Luzhou Maternal and Child Health Hospital (Luzhou Second People's Hospital), Luzhou, China
| | - Rong Chen
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Juan Xing
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China.
| | - Ying Wan
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, China.
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Kong F, Dong R, Chen G, Sun S, Yang Y, Jiang J, Meng L, Chen H, Zhu J, Zheng S. Progress in Biomarkers Related to Biliary Atresia. J Clin Transl Hepatol 2024; 12:305-315. [PMID: 38426193 PMCID: PMC10899875 DOI: 10.14218/jcth.2023.00260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/12/2023] [Accepted: 01/02/2024] [Indexed: 03/02/2024] Open
Abstract
Biliary atresia (BA) is a congenital cholestatic disease that can seriously damage children's liver function. It is one of the main reasons for liver transplantation in children. Early diagnosis of BA is crucial to the prognosis of patients, but there is still a lack of reliable non-invasive diagnostic methods. Additionally, as some children are in urgent need of liver transplantation, evaluating the stage of liver fibrosis and postoperative native liver survival in children with BA using a straightforward, efficient, and less traumatic method is a major focus of doctors. In recent years, an increasing number of BA-related biomarkers have been identified and have shown great potential in the following three aspects of clinical practice: diagnosis, evaluation of the stage of liver fibrosis, and prediction of native liver survival. This review focuses on the pathophysiological function and clinical application of three novel BA-related biomarkers, namely MMP-7, FGF-19, and M2BPGi. Furthermore, progress in well-known biomarkers of BA such as gamma-glutamyltransferase, circulating cytokines, and other potential biomarkers is discussed, aiming to provide a reference for clinical practice.
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Affiliation(s)
- Fanyang Kong
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Gong Chen
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Song Sun
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Yifan Yang
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Jingying Jiang
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Lingdu Meng
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Huifen Chen
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Jiajie Zhu
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children’s Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
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Motazedian N, Azarpira N, Falamarzi K, Dehghani SM, Ataollahi M, Esfandiari E, Dara M, Toobafard R, Sayadi M, Shekarforoush SA, Owji SH, Malekhosseini SA. Comparison of Mir122 expression in children with biliary atresia and healthy group. MOLECULAR BIOLOGY RESEARCH COMMUNICATIONS 2024; 13:147-154. [PMID: 38915454 PMCID: PMC11194029 DOI: 10.22099/mbrc.2024.49649.1950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Biliary atresia (BA) is the primary cause of neonatal jaundice with various pathological mechanisms. Many BA patients may experience progressive liver dysfunction and eventually need a liver transplant. Therefore, identifying potential non-invasive biomarkers for BA is crucial. miR-122, the most abundant microRNA in the liver, plays significant roles in different liver diseases. This study aimed to assess miR-122 levels in BA patients. Eighteen patients with biliary atresia were selected at random from the Shiraz Pediatric Liver Cirrhosis Cohort Study (SPLCCS), along with 18 healthy controls. Blood samples were collected, and biochemical parameters (such as liver function tests) were measured. Quantitative reverse-transcription PCR (RT-PCR) was conducted on serum samples from both the case and control groups to analyze miR-122 levels. The study results indicated that serum miR-122 expression in BA patients was elevated compared to the control group, although it did not reach statistical significance. Additionally, no correlation was found between miR-122 expression and serum levels of liver enzymes or other laboratory findings in BA cases. miR-122 could be a potential target for diagnosing BA; however, further research with a larger population is necessary to determine if miR-122 could serve as a useful biomarker for diagnosing BA.
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Affiliation(s)
- Nasrin Motazedian
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kimia Falamarzi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Maryam Ataollahi
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elaheh Esfandiari
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahintaj Dara
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Razieh Toobafard
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrab Sayadi
- Cardiovascular Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Seyed Hossein Owji
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Antala S, Taylor SA. Biliary Atresia in Children: Update on Disease Mechanism, Therapies, and Patient Outcomes. Clin Liver Dis 2022; 26:341-354. [PMID: 35868678 PMCID: PMC9309872 DOI: 10.1016/j.cld.2022.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Biliary atresia is a rare disease but remains the most common indication for pediatric liver transplantation as there are no effective medical therapies to slow progression after diagnosis. Variable contribution of genetic, immune, and environmental factors contributes to disease heterogeneity among patients with biliary atresia. Developing a deeper understanding of the disease mechanism will help to develop targeted medical therapies and improve patient outcomes.
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Affiliation(s)
- Swati Antala
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
| | - Sarah A. Taylor
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
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Quelhas P, Cerski C, Dos Santos JL. Update on Etiology and Pathogenesis of Biliary Atresia. Curr Pediatr Rev 2022; 19:48-67. [PMID: 35538816 DOI: 10.2174/1573396318666220510130259] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/16/2022] [Accepted: 02/15/2022] [Indexed: 01/31/2023]
Abstract
Biliary atresia is a rare inflammatory sclerosing obstructive cholangiopathy that initiates in infancy as complete choledochal blockage and progresses to the involvement of intrahepatic biliary epithelium. Growing evidence shows that biliary atresia is not a single entity with a single etiology but a phenotype resulting from multifactorial events whose common path is obliterative cholangiopathy. The etiology of biliary atresia has been explained as resulting from genetic variants, toxins, viral infection, chronic inflammation or bile duct lesions mediated by autoimmunity, abnormalities in the development of the bile ducts, and defects in embryogenesis, abnormal fetal or prenatal circulation and susceptibility factors. It is increasingly evident that the genetic and epigenetic predisposition combined with the environmental factors to which the mother is exposed are potential triggers for biliary atresia. There is also an indication that a progressive thickening of the arterial middle layer occurs in this disease, suggestive of vascular remodeling and disappearance of the interlobular bile ducts. It is suggested that the hypoxia/ischemia process can affect portal structures in biliary atresia and is associated with both the extent of biliary proliferation and the thickening of the medial layer.
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Affiliation(s)
- Patrícia Quelhas
- CICS-UBI - Centro de Investigação em Ciências da Saúde, University of Beira Interior, 6200-506 Covilhã, Portugal
| | - Carlos Cerski
- Department of Pathology, University Federal Rio Grande do Sul, 90040-060, Porto Alegre, Brasil
| | - Jorge Luiz Dos Santos
- CICS-UBI - Centro de Investigação em Ciências da Saúde, University of Beira Interior, 6200-506 Covilhã, Portugal
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Elevation of microRNA-214 is associated with progression of liver fibrosis in patients with biliary atresia. Pediatr Surg Int 2022; 38:115-122. [PMID: 34546403 DOI: 10.1007/s00383-021-05009-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) play an important role in regulating fibrogenesis in the liver. The current study examined the ability of microRNA-214 (miR-214) level in liver and serum samples obtained from patients with BA to predict progressive liver fibrosis in patients with biliary atresia (BA). METHODS We examined miR-214 level in relation to conventional markers of liver fibrosis, with liver and serum samples from BA patients. Fifty-two patients with BA who underwent Kasai portoenterostomy and four control patients underwent liver biopsy. In 28 patients with BA, blood samples were collected to analyze circulating serum miR-214. RESULTS MiR-214 levels in liver tissue were significantly upregulated in patients with BA who had severe liver fibrosis (F3-4) compared to those with none to mild fibrosis (F0-2), whereas suppressors-of-fused homolog (Sufu) mRNA levels were significantly suppressed in F3-4. Serum miR-214 levels were significantly higher in patients with F3-4 compared with F0-2. Area under the curve analysis showed that the serum miR-214 cut-off level for predicting F3-4 was 0.805 (p = 0.0046). CONCLUSION Hepatic overexpression of miR-214 is associated with progression of liver fibrosis in patients with BA, and the circulating miR-214 level may serve as a non-invasive predictor of liver fibrosis.
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Seelan RS, Pisano MM, Greene RM. MicroRNAs as Biomarkers for Birth Defects. Microrna 2022; 11:2-11. [PMID: 35168515 DOI: 10.2174/2211536611666220215123423] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/03/2022] [Accepted: 01/10/2022] [Indexed: 11/22/2022]
Abstract
It is estimated that 2-4% of live births will have a birth defect (BD). The availability of biomarkers for the prenatal detection of BDs will facilitate early risk assessment, prompt medical intervention and ameliorating disease severity. miRNA expression levels are often found to be altered in many diseases. There is, thus, a growing interest in determining whether miRNAs, particularly extracellular miRNAs, can predict, diagnose, or monitor BDs. These miRNAs, typically encapsulated in exosomes, are released by cells (including those of the fetus and placenta) into the extracellular milieu, such as blood, urine, saliva and cerebrospinal fluid, thereby enabling interaction with target cells. Exosomal miRNAs are stable, protected from degradation, and retain functionality. The observation that placental and fetal miRNAs can be detected in maternal serum, provides a strong rationale for adopting miRNAs as noninvasive prenatal biomarkers for BDs. In this mini-review, we examine the current state of research involving the use of miRNAs as prognostic and diagnostic biomarkers for BD.
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Affiliation(s)
- Ratnam S Seelan
- Department of Oral Immunology and Infectious Diseases, Division of Craniofacial Development and Anomalies, School of Dentistry, University of Louisville, Louisville, KY 40202, USA
| | - M Michele Pisano
- Department of Oral Immunology and Infectious Diseases, Division of Craniofacial Development and Anomalies, School of Dentistry, University of Louisville, Louisville, KY 40202, USA
| | - Robert M Greene
- Department of Oral Immunology and Infectious Diseases, Division of Craniofacial Development and Anomalies, School of Dentistry, University of Louisville, Louisville, KY 40202, USA
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He L, Ip DKM, Tam G, Lui VCH, Tam PKH, Chung PHY. Biomarkers for the diagnosis and post-Kasai portoenterostomy prognosis of biliary atresia: a systematic review and meta-analysis. Sci Rep 2021; 11:11692. [PMID: 34083585 PMCID: PMC8175424 DOI: 10.1038/s41598-021-91072-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 05/18/2021] [Indexed: 12/11/2022] Open
Abstract
To evaluate the accuracy of biomarkers for the early diagnosis of biliary atresia (BA) and prognostic stratification after Kasai portoenterostomy (KPE). We conducted a systematic review of PubMed, Web of Science, Embase, Scopus and OVID for English literature reporting BA biomarkers published before August 2020. Screening, data extraction, and quality assessment were performed in duplicate. A total of 51 eligible studies were included in the systematic review, and data from 12 (4182 subjects) were extracted for meta-analysis regarding the following 2 domains: (1) serum matrix metallopeptidase-7 (MMP-7), interleukin33 (IL-33) and γ-glutamyl transferase (GGT) to differentiate BA from non-BA; (2) the aspartate aminotransferase to platelet ratio index (APRi) to predict post-KPE liver fibrosis/cirrhosis. The summary sensitivity, specificity and area under the curve (AUC) of MMP-7 for diagnosing BA were 96%, 91% and 0.9847, respectively, and those of GGT were 80%, 79% and 0.9645, respectively. The summary sensitivity and specificity of IL-33 for diagnosing BA were 77% and 85%, respectively. The summary sensitivity and specificity of APRi for predicting post-KPE liver fibrosis were 61% and 80%, respectively, and the summary sensitivity, specificity and AUC of APRi for predicting post-KPE cirrhosis were 78%, 83% and 0.8729, respectively. Moreover, good evidence was shown in investigations of serum IL-18 and IL-33 in distinguishing BA from healthy controls, serum IL-18 for prognosis of post-KPE persistent jaundice, and serum hyaluronic acid and MMP-7 for prognosis of post-KPE significant liver fibrosis. MMP-7, IL-33 and GGT are useful biomarkers to assist in the diagnosis of BA. APRi might be used to predict post-KPE significant liver fibrosis and cirrhosis. These noninvasive biomarkers can be integrated into the management protocol of BA.
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Affiliation(s)
- Lin He
- Department of Radiotherapy, Tangdu Hospital, Air Force Military Medical University, Xi'an, China
| | - Dennis Kai Ming Ip
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, SAR
| | - Greta Tam
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, SAR
| | - Vincent Chi Hang Lui
- Departmet of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, SAR
| | - Paul Kwong Hang Tam
- Departmet of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, SAR
| | - Patrick Ho Yu Chung
- Departmet of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, SAR.
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Santos Silva E, Moreira Silva H, Catarino C, Dias CC, Santos-Silva A, Lopes AI. Neonatal cholestasis: development of a diagnostic decision algorithm from multivariate predictive models. Eur J Pediatr 2021; 180:1477-1486. [PMID: 33410939 DOI: 10.1007/s00431-020-03886-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 11/06/2020] [Accepted: 11/20/2020] [Indexed: 11/28/2022]
Abstract
Despite the recent advances involving molecular studies, the neonatal cholestasis (NC) diagnosis still relays on the expertise of medical teams. Our aim was to develop models of etiological diagnosis and unfavourable prognosis which may support a rationale diagnostic approach. We retrospectively analysed 154 patients born between January 1985 and October 2019. The cohort was divided into two main groups: (A) transient cholestasis and (B) other diagnosis (with subgroups) and also in two groups of outcomes: (I) unfavourable and (II) favourable. Multivariate logistic regression analysis identified the lower gestational age as the only variable independently associated with an increased risk of transient cholestasis and signs and/or symptoms of sepsis with infectious or metabolic diseases. Gamma-glutamyl transferase serum levels > 300 IU/L had a positive predictive value for both diagnosis of biliary atresia and for alpha-1-antitrypsin deficiency (A1ATD) and for unfavourable prognosis. A model of diagnosis for A1ATD (n = 34) showed an area under the ROC curve = 0.843 [confidence interval (CI): 0.773-0.912].Conclusion: This study identified some predictors of diagnosis and prognosis which helped to build a diagnostic decision algorithm. The unusually large subgroup of patients with A1ATD in this cohort emphasizes its predictive diagnostic model. What Is Known • The etiological diagnosis of neonatal cholestasis (NC) requires a step-by-step guided approach, and diagnostic models have been developed only for biliary atresia. • Current algorithms neither address the epidemiology changes nor the application of the new molecular diagnostic tools. What Is New • This study provides diagnostic predictive models for patients with A1ATD, metabolic/infectious diseases, and transient cholestasis, and two models of unfavourable prognosis for NC. • A diagnostic decision algorithm is proposed based on this study, authors expertise and the literature.
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Affiliation(s)
- Ermelinda Santos Silva
- Gastroenterology Unit, Paediatrics Division, Child and Adolescent Department, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Largo da Maternidade, n° 45, 4050-651, Porto, Portugal. .,Integrated Master in Medicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313, Porto, Portugal. .,UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313, Porto, Portugal.
| | - Helena Moreira Silva
- Gastroenterology Unit, Paediatrics Division, Child and Adolescent Department, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Largo da Maternidade, n° 45, 4050-651, Porto, Portugal
| | - Cristina Catarino
- UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313, Porto, Portugal
| | - Cláudia Camila Dias
- MEDCIDS (Departamento de Medicina da Comunidade, Informação e Decisão em Saúde) and CINTESIS (Centro de Investigação em Tecnologias e em Serviços de Saúde), Faculdade de Medicina da Universidade do Porto, Rua Dr Plácido da Costa, s/n, 4200-450, Porto, Portugal
| | - Alice Santos-Silva
- UCIBIO, REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313, Porto, Portugal
| | - Ana-Isabel Lopes
- Paediatric Gastroenterology Unit, Paediatrics Department, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Av. Prof. Egas Moniz, 1600-190, Lisboa, Portugal.,Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal
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11
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Beta-amyloid deposition around hepatic bile ducts is a novel pathobiological and diagnostic feature of biliary atresia. J Hepatol 2020; 73:1391-1403. [PMID: 32553668 DOI: 10.1016/j.jhep.2020.06.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 05/28/2020] [Accepted: 06/04/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. In this study, we aimed to investigate the underlying pathogenesis and molecular signatures associated with BA. METHODS We combined organoid and transcriptomic analysis to gain new insights into BA pathobiology using patient samples and a mouse model of BA. RESULTS Liver organoids derived from patients with BA and a rhesus rotavirus A-infected mouse model of BA, exhibited aberrant morphology and disturbed apical-basal organization. Transcriptomic analysis of BA organoids revealed a shift from cholangiocyte to hepatocyte transcriptional signatures and altered beta-amyloid-related gene expression. Beta-amyloid accumulation was observed around the bile ducts in BA livers and exposure to beta-amyloid induced the aberrant morphology in control organoids. CONCLUSION The novel observation that beta-amyloid accumulates around bile ducts in the livers of patients with BA has important pathobiological implications, as well as diagnostic potential. LAY SUMMARY Biliary atresia is a poorly understood and devastating obstructive bile duct disease of newborns. It is often diagnosed late, is incurable and frequently requires liver transplantation. Using human and mouse 'liver mini-organs in the dish', we unexpectedly identified beta-amyloid deposition - the main pathological feature of Alzheimer's disease and cerebral amyloid angiopathy - around bile ducts in livers from patients with biliary atresia. This finding reveals a novel pathogenic mechanism that could have important diagnostic and therapeutic implications.
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Inflammation Drives MicroRNAs to Limit Hepatocyte Bile Acid Transport in Murine Biliary Atresia. J Surg Res 2020; 256:663-672. [PMID: 32818799 DOI: 10.1016/j.jss.2020.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 05/20/2020] [Accepted: 07/11/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Biliary atresia (BA) is an inflammatory pediatric cholangiopathy with only surgical means for treatment. Many contributors to bile acid synthesis and transport have previously been reported to be downregulated in patients with BA; yet, the driving factors of the abnormal bile acid synthesis and transport in regard to BA have not been previously studied. MATERIALS AND METHODS Wild type or Ig-α-/- mice were injected with salt solution (control) or rotavirus on day of life 0, and analyses were performed on day of life 14. The mRNA levels of bile acid transporters/nuclear receptors and liver microRNAs (miRNAs) were compared between groups. A mouse hepatocyte cell line was used to examine the effects of innate cytokines on miRNA levels and bile acid transporter/nuclear receptor expression and miRNAs on bile acid transporter/nuclear receptor expression. RESULTS BA mice had significantly increased mRNA expression of innate cytokines and miRNAs known to bind bile acid transporters/nuclear receptors (miRNAs -22-5p, -34a-5p, and -222-3p) and decreased mRNA expression of bile acid transporters and nuclear receptors. In vitro, TNF-α and IL-1β decreased BSEP and CYP7A1 while increasing miRNA-34a-5p and miRNA 222-3p. LXR, SHP, CYP7A1, NTCP, and MRP2 were decreased by miRNA-34a-5p, whereas miRNA-222-3p decreased NTCP and MRP4. TNF-α and IL-1β increased expression of miRNAs 34a-5p and 222-3p and these miRNAs then decrease expression of multiple bile acid transporters and nuclear receptors. CONCLUSIONS Loss of bile acid transporters increases hepatotoxicity via bile acid retention. Therapeutic agents that increase bile acid transport or nuclear receptor functioning should be investigated in BA.
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Vij M, Rela M. Biliary atresia: pathology, etiology and pathogenesis. Future Sci OA 2020; 6:FSO466. [PMID: 32518681 PMCID: PMC7273417 DOI: 10.2144/fsoa-2019-0153] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 01/30/2020] [Indexed: 02/06/2023] Open
Abstract
Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice. Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen. Lobular morphological features may include variable multinucleate giant cells, bilirubinostasis and hemopoiesis. The etiopathogenesis of biliary atresia is multifactorial and multiple pathomechanisms have been proposed. Experimental and clinical studies have suggested that viral infection initiates biliary epithelium destruction and release of antigens that trigger a Th1 immune response, which leads to further injury of the bile duct, resulting in inflammation and obstructive scarring of the biliary tree. It has also been postulated that biliary atresia is caused by a defect in the normal remodelling process. Genetic predisposition has also been proposed as a factor for the development of biliary atresia.
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Affiliation(s)
- Mukul Vij
- Senior Consultant Histopathologist, Department of Pathology, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India, 600044
| | - Mohamed Rela
- Institute of Liver Disease & Transplantation, Chairmen, Dr Rela Institute & Medical Centre, Chennai, Tamil Nadu, India, 600044
- Liver Transplant Unit, Kings College Hospital, London SE5 9RS, UK
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Abstract
PURPOSE OF REVIEW Biliary atresia is a poorly understood deadly disease. Genetic predisposition factors are suspected albeit not firmly established. This review summarizes recent evidence of genetic alterations in biliary atresia. RECENT FINDINGS Whole-genome association studies in biliary atresia patients identified four distinct predisposition loci with four different genes potentially involved in the disease occurrence. Variations in these genes were searched for, but none were found in patients with biliary atresia suggesting complex mechanisms. SUMMARY Despite decades since its description and decades of intensive researches, cause of biliary atresia disease remains enigmatic. The inheritance of biliary atresia is not Mendelian. Genetic predisposition factor is one of the explored fields to explain biliary atresia pathogenicity. Biliary atresia has been associated with several inborn syndromes, chromosome anomalies, and gene polymorphisms in specific populations. Four predisposition loci encompassing genes relevant to the disease have been identified, but no pathogenic variations were found in biliary atresia patients. Few reported cases of isolated biliary atresia manifestation in the context of known genetic diseases suggest coincidental findings. Alternatives to classic genetic alterations are proposed to explain genetic predisposition in biliary atresia including noncoding and epigenetic factors. Biliary atresia is most likely related to complex traits making its genetic exploration challenging.
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15
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Church RJ, Watkins PB. Serum biomarkers of drug-induced liver injury: Current status and future directions. J Dig Dis 2019; 20:2-10. [PMID: 30378260 DOI: 10.1111/1751-2980.12684] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 10/26/2018] [Indexed: 12/11/2022]
Abstract
Drug-induced liver injury (DILI), which is caused by drugs and herbal or dietary supplements, remains a serious concern for drug developers, regulators, and clinicians; however, serum biomarkers utilized to detect and monitor DILI have not changed in decades and have limitations. Data-driven mathematical modeling that incorporates the release and clearance kinetics of traditional biomarkers has improved their use in the prediction of liver safety liabilities for new drug candidates. Several newer biomarkers have shown promise in terms of liver specificity, predicting the outcome of DILI events, and providing insight into its underlying mechanisms. For these new biomarkers to be qualified for regulatory acceptance, it will require their assessment in large numbers of patients who are receiving a wide range of compounds and who develop a broad spectrum of liver injuries. The ongoing and evolving international biomarker consortia should play a major role in this effort, which is likely to transform the assessment of liver safety in clinical trials and in the clinic.
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Affiliation(s)
- Rachel J Church
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina, USA.,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
| | - Paul B Watkins
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina, USA.,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
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16
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Lertudomphonwanit C, Mourya R, Fei L, Zhang Y, Gutta S, Yang L, Bove KE, Shivakumar P, Bezerra JA. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Sci Transl Med 2018; 9:9/417/eaan8462. [PMID: 29167395 DOI: 10.1126/scitranslmed.aan8462] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 10/20/2017] [Indexed: 12/24/2022]
Abstract
Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with γ-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and an experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target.
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Affiliation(s)
- Chatmanee Lertudomphonwanit
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA.,Division of Gastroenterology and Hepatology, Department of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Reena Mourya
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA
| | - Lin Fei
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA
| | - Yue Zhang
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA
| | - Sridevi Gutta
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA
| | - Li Yang
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA.,Division of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kevin E Bove
- Division of Pathology, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA
| | - Pranavkumar Shivakumar
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA
| | - Jorge A Bezerra
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH 45229-3031, USA.
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Development and Validation of Novel Diagnostic Models for Biliary Atresia in a Large Cohort of Chinese Patients. EBioMedicine 2018; 34:223-230. [PMID: 30077722 PMCID: PMC6116426 DOI: 10.1016/j.ebiom.2018.07.025] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 07/06/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023] Open
Abstract
Background & aims The overlapping features of biliary atresia (BA) and the other forms of neonatal cholestasis (NC) with different causes (non-BA) has posed challenges for the diagnosis of BA. This study aimed at developing new and better diagnostic models for BA. Methods We retrospectively analyzed data from 1728 newborn infants with neonatal obstructive jaundice (NOJ). New prediction models, including decision tree (DT), random forest (RF), and multivariate logistic regression-based nomogram for BA were created and externally validated in an independent set of 508 infant patients. Results Fiver predictors, including gender, weight, direct bilirubin (DB), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT) were significantly different between the BA and non-BA groups (P < .05), from which DT, RF, and nomogram models were developed. The area under the receiver operating characteristic (ROC) curve (AUC) value for the nomogram was 0.898, which was greater than that of a single biomarker in the prediction of BA. Performance comparison of the three diagnostic models showed that the nomogram displayed better discriminative ability (sensitivity, 85.7%; specificity, 80.3%; PPV, 0.969) at the optimal cut-off value compared with DT and RF, which had relatively similar high sensitivity and PPV (0.941 and 0.947, respectively), but low specificity in the modeling group. In sub-analysis of the discriminative capacity between the nomogram and GGT (<300 or ≥ 300), we found that the nomogram was superior to the GGT alone in the preoperative diagnosis of BA. Conclusions The nomogram has demonstrated better performance for the prediction of BA, holding promise for future clinical application.
A novel nomogram has been established for prediction of biliary atresia (BA). Its discriminatory ability is significantly improved compared with GGT alone. It holds promise for clinical application for better diagnosis of BA.
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18
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Olaizola P, Lee-Law PY, Arbelaiz A, Lapitz A, Perugorria MJ, Bujanda L, Banales JM. MicroRNAs and extracellular vesicles in cholangiopathies. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1293-1307. [PMID: 28711597 DOI: 10.1016/j.bbadis.2017.06.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 06/27/2017] [Accepted: 06/28/2017] [Indexed: 12/22/2022]
Abstract
UNLABELLED Cholangiopathies encompass a heterogeneous group of disorders affecting biliary epithelial cells (i.e. cholangiocytes). Early diagnosis, prognosis and treatment still remain clinically challenging for most of these diseases and are critical for adequate patient care. In the past decade, extensive research has emphasized microRNAs (miRs) as potential non-invasive biomarkers and tools to accurately identify, predict and treat cholangiopathies. MiRs can be released extracellularly conjugated with lipoproteins or encapsulated in extracellular vesicles (EVs). Research on EVs is also gaining attention since they are present in multiple biological fluids and may represent a relevant source of novel non-invasive biomarkers and be vehicles for new therapeutic approaches. This review highlights the most promising candidate miRs and EV-related biomarkers in cholangiopathies, as well as their relevant roles in biliary pathophysiology. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. RESEARCH STRATEGY PubMed search (April 2017) was done with the following terms: "microRNA", "miRNA", "miR", "extracellular vesicles", "EV", "exosomes", "primary biliary cholangitis", "primary biliary cholangitis", "PBC", "primary sclerosing cholangitis", "PSC", "cholangiocarcinoma", "CCA", "biliary atresia", "BA", "polycystic liver diseases", "PLD", "cholangiopathies", "cholestatic liver disease". Most significant articles in full-text English were selected. The reference lists of selected papers were also considered.
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Affiliation(s)
- P Olaizola
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - P Y Lee-Law
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - A Arbelaiz
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - A Lapitz
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - M J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - L Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - J M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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Shores DR, Everett AD. Children as Biomarker Orphans: Progress in the Field of Pediatric Biomarkers. J Pediatr 2018; 193:14-20.e31. [PMID: 29031860 PMCID: PMC5794519 DOI: 10.1016/j.jpeds.2017.08.077] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 08/04/2017] [Accepted: 08/30/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Darla R Shores
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD.
| | - Allen D Everett
- Division of Cardiology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD
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20
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Baldassarre A, Felli C, Prantera G, Masotti A. Circulating microRNAs and Bioinformatics Tools to Discover Novel Diagnostic Biomarkers of Pediatric Diseases. Genes (Basel) 2017; 8:genes8090234. [PMID: 28925938 PMCID: PMC5615367 DOI: 10.3390/genes8090234] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 09/08/2017] [Accepted: 09/12/2017] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level. Current studies have shown that miRNAs are also present in extracellular spaces, packaged into various membrane-bound vesicles, or associated with RNA-binding proteins. Circulating miRNAs are highly stable and can act as intercellular messengers to affect many physiological processes. MicroRNAs circulating in body fluids have generated strong interest in their potential use as clinical biomarkers. In fact, their remarkable stability and the relative ease of detection make circulating miRNAs ideal tools for rapid and non-invasive diagnosis. This review summarizes recent insights about the origin, functions and diagnostic potential of extracellular miRNAs by especially focusing on pediatric diseases in order to explore the feasibility of alternative sampling sources for the development of non-invasive pediatric diagnostics. We will also discuss specific bioinformatics tools and databases for circulating miRNAs focused on the identification and discovery of novel diagnostic biomarkers of pediatric diseases.
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Affiliation(s)
| | - Cristina Felli
- Bambino Gesù Children's Hospital-IRCCS, Research Laboratories, 00146 Rome, Italy.
| | - Giorgio Prantera
- Department of Ecology and Biology, Università della Tuscia, 01100 Viterbo, Italy.
| | - Andrea Masotti
- Bambino Gesù Children's Hospital-IRCCS, Research Laboratories, 00146 Rome, Italy.
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21
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Leung DH. Hepatic fibrosis scores and serum biomarkers in pediatric hepatology. Clin Liver Dis (Hoboken) 2017; 9:125-130. [PMID: 30992975 PMCID: PMC6467157 DOI: 10.1002/cld.634] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 02/22/2017] [Accepted: 03/13/2017] [Indexed: 02/04/2023] Open
Affiliation(s)
- Daniel H. Leung
- Department of PediatricsBaylor College of MedicineHoustonTX,Division of Pediatric Gastroenterology, Hepatology, and NutritionTexas Children's HospitalHoustonTX
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22
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Govindarajan KK. Biliary atresia: Where do we stand now? World J Hepatol 2016; 8:1593-1601. [PMID: 28083081 PMCID: PMC5192550 DOI: 10.4254/wjh.v8.i36.1593] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 09/09/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023] Open
Abstract
The pathway from clinical suspicion to establishing the diagnosis of biliary atresia in a child with jaundice is a daunting task. However, investigations available help to point towards the correct diagnosis in reasonable time frame. Imaging by Sonography has identified several parameters which can be of utility in the diagnostic work up. Comparison of Sonography with imaging by Nuclear medicine can bring out the significant differences and also help in appropriate imaging. The battery of Biochemical tests, available currently, enable better understanding of the line-up of investigations in a given child with neonatal cholestasis. Management protocols enable standardized care with optimal outcome. The place of surgical management in biliary atresia is undisputed, although Kasai procedure and primary liver transplantation have been pitted against each other. This article functions as a platform to bring forth the various dimensions of biliary atresia.
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Affiliation(s)
- Krishna Kumar Govindarajan
- Krishna Kumar Govindarajan, Department of Pediatric Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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23
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Abstract
OBJECTIVES Biliary atresia (BA) is an idiopathic neonatal liver disease, characterized by inflammatory and fibrotic obliteration of extrahepatic bile ducts. Therefore, reliable methods for noninvasive diagnosis are needed. The present study aimed to analyze circulating microRNAs (miRNAs) in patients with BA using next-generation sequencing for identifying novel diagnostic biomarkers. METHODS An initial screening of miRNAs in plasma from patients with BA and healthy controls (HCs) was performed on an Illumina next-generation sequencing platform. Differential miRNAs were validated by quantitative real-time polymerase chain reaction (qPCR). Target genes and related signal transduction pathways of differential miRNAs were predicted by online software. RESULTS In total, 146 differential miRNAs were identified by deep sequencing. Fifteen miRNAs with read counts >1000, that included 7 upregulated and 8 downregulated miRNAs, were predicted to be associated with liver fibrosis, biliary differentiation, and bile duct development. Of these, 6 miRNAs with read counts >5000 were analyzed by qPCR on an independent sample set comprising 44 patients with BA, 20 cholestatic disease controls, and 20 HCs. Two upregulated miRNAs (miR-122-5p, miR-100-5p) and 2 downregulated miRNAs (miR-140-3p, miR-126-3p) were confirmed by individual qPCR. Only miR-140-3p was significantly different from controls (P < 0.05), yielding an area under receiver operating characteristic curve of 0.75 with sensitivity of 66.7% and specificity of 79.1% at optimal threshold. CONCLUSIONS Our findings indicate that patients with BA exhibit a distinct profile of circulating miRNAs and that plasma miR-140-3p may be a promising diagnostic biomarker for this disease.
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Calvopina DA, Coleman MA, Lewindon PJ, Ramm GA. Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease. Int J Mol Sci 2016; 17:ijms17111795. [PMID: 27801781 PMCID: PMC5133796 DOI: 10.3390/ijms17111795] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/18/2016] [Accepted: 10/20/2016] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs involved in biological and pathological processes of every cell type, including liver cells. Transcribed from specific genes, miRNA precursors are processed in the cytoplasm into mature miRNAs and as part of the RNA-induced silencing complex (RISC) complex binds to messenger RNA (mRNA) by imperfect complementarity. This leads to the regulation of gene expression at a post-transcriptional level. The function of a number of different miRNAs in fibrogenesis associated with the progression of chronic liver disease has recently been elucidated. Furthermore, miRNAs have been shown to be both disease-and tissue-specific and are stable in the circulation, which has led to increasing investigation on their utility as biomarkers for the diagnosis of chronic liver diseases, including those in children. Here, we review the current knowledge on the biogenesis of microRNA, the mechanisms of translational repression and the use of miRNA as circulatory biomarkers in chronic paediatric liver diseases including cystic fibrosis associated liver disease, biliary atresia and viral hepatitis B.
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Affiliation(s)
- Diego A Calvopina
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
| | - Miranda A Coleman
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
| | - Peter J Lewindon
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
- Department of Gastroenterology and Hepatology, Lady Cilento Children's Hospital, 501 Stanley St, South Brisbane, QLD 4101, Australia.
- Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, QLD 4006, Australia.
| | - Grant A Ramm
- Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD 4006, Australia.
- Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, QLD 4006, Australia.
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Chen Y, Zhan J. Physical development and cognitive performance in a monozygotic twins for biliary atresia: Report of a case and literature reviewing. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2016. [DOI: 10.1016/j.epsc.2016.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Biliary atresia: Clinical advances and perspectives. Clin Res Hepatol Gastroenterol 2016; 40:281-287. [PMID: 26775892 DOI: 10.1016/j.clinre.2015.11.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 11/03/2015] [Accepted: 11/16/2015] [Indexed: 02/04/2023]
Abstract
Biliary atresia (BA) is a rare and severe inflammatory and obliterative cholangiopathy that affects both extra- and intrahepatic bile ducts. BA symptoms occur shortly after birth with jaundice, pale stools and dark urines. The prognosis of BA has dramatically changed in the last decades: before the Kasai operation most BA patients died, while nowadays with the sequential treatment with Kasai operation±liver transplantation BA patient survival is close to 90%. Early diagnosis is very important since the chances of success of the Kasai procedure decrease with time. The causes of BA remain actually unknown but several mechanisms including genetic and immune dysregulation may probably lead to the obliterative cholangiopathy. Current research focuses on the identification of blood or liver factors linked to the pathogenesis of BA that could become therapeutic targets and avoid the need for liver transplantation. No similar disease leading to total obstruction of the biliary tree exists in older children or adults. But understanding the physiopathology of BA may highlight the mechanisms of other destructive cholangiopathies, such as sclerosing cholangitis.
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Letelier P, Riquelme I, Hernández AH, Guzmán N, Farías JG, Roa JC. Circulating MicroRNAs as Biomarkers in Biliary Tract Cancers. Int J Mol Sci 2016; 17:ijms17050791. [PMID: 27223281 PMCID: PMC4881607 DOI: 10.3390/ijms17050791] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 04/29/2016] [Accepted: 05/10/2016] [Indexed: 01/17/2023] Open
Abstract
Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9), not having enough sensitivity nor specificity to be used in a differential diagnosis and early stage detection. Thus, better non-invasive methods that can distinguish between normal and pathological tissue are needed. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules of ~20–22 nucleotides that regulate relevant physiological mechanisms and can also be involved in carcinogenesis. Recent studies have demonstrated that miRNAs are detectable in multiple body fluids, showing great stability, either free or trapped in circulating microvesicles, such as exosomes. miRNAs are ideal biomarkers that may be used in screening and prognosis in biliary tract cancers, aiding also in the clinical decisions at different stages of cancer treatment. This review highlights the progress in the analysis of circulating miRNAs in serum, plasma and bile as potential diagnostic and prognostic markers of BTCs.
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Affiliation(s)
- Pablo Letelier
- School of Health Sciences, Universidad Católica de Temuco, Manuel Montt 56, 4813302 Temuco, Chile.
| | - Ismael Riquelme
- Molecular Pathology Laboratory, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Avenida Alemania 0458, 3rd Floor, 4810296 Temuco, Chile.
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Avenida Francisco Salazar 01145, Casilla, 54-D Temuco, Chile.
| | - Alfonso H Hernández
- School of Health Sciences, Universidad Católica de Temuco, Manuel Montt 56, 4813302 Temuco, Chile.
| | - Neftalí Guzmán
- School of Health Sciences, Universidad Católica de Temuco, Manuel Montt 56, 4813302 Temuco, Chile.
| | - Jorge G Farías
- Department of Chemical Engineering, Faculty of Engineering and Sciences, Universidad de La Frontera, 54-D Temuco, Chile.
| | - Juan Carlos Roa
- Department of Pathology, Centre for Investigational Oncology (CITO), Advanced Centre for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Marcoleta 377, 7rd Floor, 8330024 Santiago, Chile.
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Circulating miR-21 and miR-29a as Markers of Disease Severity and Etiology in Cholestatic Pediatric Liver Disease. J Clin Med 2016; 5:jcm5030028. [PMID: 26927196 PMCID: PMC4810099 DOI: 10.3390/jcm5030028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 01/19/2016] [Accepted: 01/27/2016] [Indexed: 02/06/2023] Open
Abstract
Circulating microRNAs have been investigated as markers of disease severity in a variety of conditions. We examined whether circulating miR-21 and miR-29a could serve as markers of hepatic fibrosis and disease etiology in children with various liver diseases. Circulating miR-21 and miR-29a were determined in 58 children (21 female, age 0.1–17.8 (median 9.8) years)) with chronic liver disease and compared to histological grading of hepatic fibrosis. 22 healthy children served as controls for circulating miRNAs. Levels of circulating miR-21 appeared to be age-dependent in healthy children. Children with biliary atresia had significantly higher levels of miR-21 compared both to healthy controls and to age-matched children with other cholestatic liver disease. Circulating miR-29a levels in biliary atresia children did not differ from healthy controls, but tended to be higher than in age-matched children with other cholestatic liver disease. Neither miR-21 nor miR-29a correlated well with hepatic fibrosis. Circulating miR-21 and miR-29a levels can potentially serve as non-invasive diagnostic markers to differentiate biliary atresia from other cholestatic disease in infancy. They do not appear suitable as non-invasive markers for the degree of hepatic fibrosis in an unselected cohort of children with various liver diseases. The discriminating effect regarding neonatal cholestasis should be followed up in a prospective longitudinal study.
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Dong R, Shen Z, Zheng C, Chen G, Zheng S. Serum microRNA microarray analysis identifies miR-4429 and miR-4689 are potential diagnostic biomarkers for biliary atresia. Sci Rep 2016; 6:21084. [PMID: 26879603 PMCID: PMC4754688 DOI: 10.1038/srep21084] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/12/2016] [Indexed: 01/08/2023] Open
Abstract
This study aimed to investigate pathogenesis and novel diagnostic biomarkers of biliary atresia (BA). Serum samples from infants with BA and non-BA neonatal cholestasis (NC) were collected for miRNA microarray analysis, and then differentially expressed miRNAs were screened. Differentially expressed miRNAs were validated by qRT-PCR using an independent serum samples from infants with BA and NC. Diagnostic utility of validated miRNAs was further analyzed using serum samples by receiver-operating characteristic curve analysis. Totally, 13 differentially expressed miRNAs were identified including 11 down-regulated and 2 up-regulated ones. Target genes of hsa-miR-4429 and hsa-miR-4689 were significantly involved in FoxO signaling pathway. Eight differentially expressed miRNAs were chosen for validation by qRT-PCR analysis, and four miRNAs (hsa-miR-150-3p, hsa-miR-4429, hsa-miR-4689 and hsa-miR-92a-3p) were differentially expressed. The area under the curve of hsa-miR-4429 and hsa-miR-4689 was 0.789 (sensitivity = 83.33%, specificity = 80.00%) and 0.722 (sensitivity = 66.67%, specificity = 80.00%), respectively. Differentially expressed miRNAs including hsa-miR-4429 and hsa-miR-4689 might play critical roles in BA by regulating their target genes, and these two miRNAs may have the potential to become diagnostic biomarkers.
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Affiliation(s)
- Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Zhen Shen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Chao Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Gong Chen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai 201102, China
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30
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Esparza-Baquer A, Labiano I, Bujanda L, Perugorria MJ, Banales JM. MicroRNAs in cholangiopathies: Potential diagnostic and therapeutic tools. Clin Res Hepatol Gastroenterol 2016; 40:15-27. [PMID: 26774196 DOI: 10.1016/j.clinre.2015.10.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 09/23/2015] [Accepted: 10/02/2015] [Indexed: 02/07/2023]
Abstract
Cholangiopathies are the group of diseases targeting the bile duct epithelial cells (i.e. cholangiocytes). These disorders arise from different etiologies and represent a current diagnostic, prognostic and therapeutic challenge. Different molecular mechanisms participate in the development and progression of each type of biliary disease. However, microRNA deregulation is a common central event occurring in all of them that plays a key role in their pathogenesis. MicroRNAs are highly stable small non-coding RNAs present in cells, extracellular microvesicles and biofluids, representing valuable diagnostic tools and potential targets for therapy. In the following sections, the most novel and significant discoveries in this field are summarized and their potential clinical value is highlighted.
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Affiliation(s)
- Aitor Esparza-Baquer
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain
| | - Ibone Labiano
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
| | - María J Perugorria
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Jesús M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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31
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Yang B, Liu B, Bi P, Wu T, Wang Q, Zhang J. An integrated analysis of differential miRNA and mRNA expressions in human gallstones. MOLECULAR BIOSYSTEMS 2015; 11:1004-11. [PMID: 25639987 DOI: 10.1039/c4mb00741g] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Gallstone disease, including cholesterol precipitation in bile, increased bile salt hydrophobicity and gallbladder inflammation. Here, we investigated miRNA and mRNA involved in the formation of gallstones, and explored the molecular mechanisms in the development of gallstones. Differentially expressed 17 miRNAs and 525 mRNA were identified based on Illumina sequencing from gallbladder mucosa of patients with or without gallstones, and were validated by randomly selected 6 miRNAs and 8 genes using quantitative RT-PCR. 114 miRNA target genes were identified, whose functions and regulating pathways were related to gallstones. The differentially expressed genes were enriched upon lipoprotein binding and some metabolic pathways, and differentially expressed miRNAs enriched upon ABC transportation and cancer related pathways. A molecular regulatory network consisting of 17 differentially expressed miRNAs, inclusive of their target genes, was constructed. miR-210 and its potential target gene ATP11A were found to be differentially expressed in both miRNA and mRNA profiles. ATP11A was a direct target of miR-210, which was predicted to regulate the ABC-transporters pathway. The expression levels of ATP11A in the gallstone showed inverse correlation with miR-210 expression, and up-regulation of miR-210 could reduce ATP11A expression in HGBEC. This is the first report that indicates the existence of differences in miRNA and mRNA expression in patients with or without gallstones. Our data shed light on further investigating the mechanisms of gallstone formation.
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Affiliation(s)
- Bin Yang
- Department of Hepatobiliary Surgery, the 1st Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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32
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Church RJ, Otieno M, McDuffie JE, Singh B, Sonee M, Hall L, Watkins PB, Ellinger-Ziegelbauer H, Harrill AH. Beyond miR-122: Identification of MicroRNA Alterations in Blood During a Time Course of Hepatobiliary Injury and Biliary Hyperplasia in Rats. Toxicol Sci 2015; 150:3-14. [PMID: 26614776 DOI: 10.1093/toxsci/kfv260] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Identification of circulating microRNAs for the diagnosis of liver injury and as an indicator of underlying pathology has been the subject of recent investigations. While several studies have been conducted, with particular emphasis on miR-122, the timing of miRNA release into the circulation and anchoring to tissue pathology has not been systematically evaluated. In this study, miRNA profiling was conducted over a time course of hepatobiliary injury and repair using alpha-naphthylisothiocyanate (ANIT) and a proprietary compound, FP004BA. ANIT administration (50 mg/kg) to rats caused significant biliary epithelial cell and hepatocellular necrosis between 24 and 72 h, followed by resolution and progression to biliary hyperplasia by 120 h which was associated with miRNA release into the blood. FP004BA (100 mg/kg) was used to confirm associations of miRNA along a time course with similar hepatic pathology to ANIT. Treatment with ANIT or FP004BA resulted in significant alterations of overlapping miRNAs during the early and peak injury phases. In addition to well-characterized liver injury markers miR-122-5p and miR-192-5p, multiple members of the 200 family and the 101 family along with miR-802-5p and miR-30d-5p were consistently elevated during hepatobiliary injury caused by both toxicants, suggesting that these species may be potential biomarker candidates for hepatobiliary injury. After 14 days of dosing with 4BA, miR-182-5p remained elevated-while miR-122-5p and miR-192-5p had returned to baseline-suggesting that miR-182-5p may have added utility to monitor for hepatobiliary injury in the repair phases when there remains histological evidence of ongoing cellular injury.
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Affiliation(s)
- Rachel J Church
- *Hamner-UNC Institute for Drug Safety Sciences, RTP, North Carolina 27709
| | - Monicah Otieno
- Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477
| | - James Eric McDuffie
- Preclinical Development and Safety, Janssen Research & Development, LLC, San Diego, California 92121
| | - Bhanu Singh
- Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477
| | - Manisha Sonee
- Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477
| | - LeRoy Hall
- Preclinical Development and Safety, Janssen Research & Development, LLC, Spring House, Pennsylvania 19477
| | - Paul B Watkins
- *Hamner-UNC Institute for Drug Safety Sciences, RTP, North Carolina 27709
| | | | - Alison H Harrill
- *Hamner-UNC Institute for Drug Safety Sciences, RTP, North Carolina 27709; Department of Environmental and Occupational Health, The University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
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Zhou K, Wang J, Xie G, Zhou Y, Yan W, Pan W, Che Y, Zhang T, Wong L, Kwee S, Xiao Y, Wen J, Cai W, Jia W. Distinct Plasma Bile Acid Profiles of Biliary Atresia and Neonatal Hepatitis Syndrome. J Proteome Res 2015; 14:4844-4850. [PMID: 26449593 DOI: 10.1021/acs.jproteome.5b00676] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Biliary atresia (BA) is a severe chronic cholestasis disorder of infants that leads to death if not treated on time. Neonatal hepatitis syndrome (NHS) is another leading cause of neonatal cholestasis confounding the diagnosis of BA. Recent studies indicate that altered bile acid metabolism is closely associated with liver injury and cholestasis. In this study, we systematically measured the bile acid metabolome in plasma of BA, NHS, and healthy controls. Liver bile acids were also measured using biopsy samples from 48 BA and 16 NHS infants undergoing operative cholangiography as well as 5 normal adjacent nontumor liver tissues taken from hepatoblastoma patients as controls. Both BA and NHS samples had significantly elevated bile acid levels in plasma compared to normal controls. BA patients showed a distinct bile acid profile characterized by the higher taurochenodeoxycholic acid (TCDCA) level and lower chenodeoxycholic acid (CDCA) level than those in NHS patients. The ratio of TCDCA to CDCA in plasma was significantly higher in BA compared to healthy infants (p < 0.001) or NHS (p < 0.001). The area under receiver operating characteristic curve for TCDCA/CDCA to differentiate BA from NHS was 0.923 (95% CI: 0.862-0.984). These findings were supported by significantly altered expression levels of bile acid transporters and nuclear receptors in liver including farnesoid X receptor (FXR), small heterodimer partner (SHP), bile salt export pump (BSEP), and multidrug resistant protein 3 (MDR3) in BA compared to NHS. Taken together, the plasma bile acid profiles are distinct in BA, NHS, and normal infants, as characterized by the ratio of TCDCA/CDCA differentially distributed among the three groups of infants.
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Affiliation(s)
- Kejun Zhou
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU) , Shanghai 200092, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research , Shanghai 200092, China
| | - Jun Wang
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU) , Shanghai 200092, China
| | - Guoxiang Xie
- Center for Translational Medicine, Six People's Hospital, SJTU School of Medicine , Shanghai 200092, China
- University of Hawaii Cancer Center , Honolulu, Hawaii 96813, United States
| | - Ying Zhou
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU) , Shanghai 200092, China
| | - Weihui Yan
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research , Shanghai 200092, China
| | - Weihua Pan
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU) , Shanghai 200092, China
| | - Yanran Che
- Department of Infection and Gastroenterology, Shanghai Children's Hospital, SJTU School of Medicine , Shanghai 200092, China
| | - Ting Zhang
- Department of Infection and Gastroenterology, Shanghai Children's Hospital, SJTU School of Medicine , Shanghai 200092, China
| | - Linda Wong
- University of Hawaii Cancer Center , Honolulu, Hawaii 96813, United States
| | - Sandi Kwee
- University of Hawaii Cancer Center , Honolulu, Hawaii 96813, United States
| | - Yongtao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research , Shanghai 200092, China
| | - Jie Wen
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research , Shanghai 200092, China
| | - Wei Cai
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU) , Shanghai 200092, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research , Shanghai 200092, China
| | - Wei Jia
- Center for Translational Medicine, Six People's Hospital, SJTU School of Medicine , Shanghai 200092, China
- University of Hawaii Cancer Center , Honolulu, Hawaii 96813, United States
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34
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MicroRNAs in the Cholangiopathies: Pathogenesis, Diagnosis, and Treatment. J Clin Med 2015; 4:1688-712. [PMID: 26343736 PMCID: PMC4600153 DOI: 10.3390/jcm4091688] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 08/07/2015] [Accepted: 08/11/2015] [Indexed: 12/23/2022] Open
Abstract
The cholangiopathies are a group of liver diseases resulting from different etiologies but with the cholangiocyte as the primary target. As a group, the cholangiopathies result in significant morbidity and mortality and represent one of the main indications for liver transplant in both children and adults. Contributing to this situation is the absence of a thorough understanding of their pathogenesis and a lack of adequate diagnostic and prognostic biomarkers. MicroRNAs are small non-coding RNAs that modify gene expression post-transcriptionally. They have been implicated in the pathogenesis of many diseases, including the cholangiopathies. Thus, in this review we provide an overview of the literature on miRNAs in the cholangiopathies and discuss future research directions.
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35
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Affiliation(s)
- Dong Zhao
- Shanghai Jiao Tong University, Shanghai, China
| | - Xi-Dai Long
- Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Shanghai Jiao Tong University, Shanghai, China
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36
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Zhou K, Xie G, Wang J, Zhao A, Liu J, Su M, Ni Y, Zhou Y, Pan W, Che Y, Zhang T, Xiao Y, Wang Y, Wen J, Jia W, Cai W. Metabonomics reveals metabolite changes in biliary atresia infants. J Proteome Res 2015; 14:2569-2574. [PMID: 25899098 PMCID: PMC6088235 DOI: 10.1021/acs.jproteome.5b00125] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biliary atresia (BA) is a rare neonatal cholestatic disorder caused by obstruction of extra- and intra-hepatic bile ducts. If untreated, progressive liver cirrhosis will lead to death within 2 years. Early diagnosis and operation improve the outcome significantly. Infants with neonatal hepatitis syndrome (NHS) present similar symptoms, confounding the early diagnosis of BA. The lack of noninvasive diagnostic methods to differentiate BA from NHS greatly delays the surgery of BA infants, thus deteriorating the outcome. Here we performed a metabolomics study in plasma of BA, NHS, and healthy infants using gas chromatography-time-of-flight mass spectrometry. Scores plots of orthogonal partial least-squares discriminant analysis clearly separated BA from NHS and healthy infants. Eighteen metabolites were found to be differentially expressed between BA and NHS, among which seven (l-glutamic acid, l-ornithine, l-isoleucine, l-lysine, l-valine, l-tryptophan, and l-serine) were amino acids. The altered amino acids were quantitatively verified using ultraperformance liquid chromatography-tandem mass spectrometry. Ingenuity pathway analysis revealed the network of "Cellular Function and Maintenance, Hepatic System Development and Function, Neurological Disease" was altered most significantly. This study suggests that plasma metabolic profiling has great potential in differentiating BA from NHS, and amino acid metabolism is significantly different between the two diseases.
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Affiliation(s)
- Kejun Zhou
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU), Shanghai 200092, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Guoxiang Xie
- Center for Translational Medicine, Six People’s Hospital, SJTU School of Medicine, Shanghai 200230, China
- University of Hawaii Cancer Center, Honolulu, HI 96813, United States of America
| | - Jun Wang
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU), Shanghai 200092, China
| | - Aihua Zhao
- Center for Translational Medicine, Six People’s Hospital, SJTU School of Medicine, Shanghai 200230, China
| | - Jiajian Liu
- Center for Translational Medicine, Six People’s Hospital, SJTU School of Medicine, Shanghai 200230, China
| | - Mingming Su
- University of Hawaii Cancer Center, Honolulu, HI 96813, United States of America
| | - Yan Ni
- University of Hawaii Cancer Center, Honolulu, HI 96813, United States of America
| | - Ying Zhou
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU), Shanghai 200092, China
| | - Weihua Pan
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU), Shanghai 200092, China
| | - Yanran Che
- Department of Infection and Gastroenterology, Shanghai Children’s Hospital, SJTU School of Medicine, Shanghai 200040, China
| | - Ting Zhang
- Department of Infection and Gastroenterology, Shanghai Children’s Hospital, SJTU School of Medicine, Shanghai 200040, China
| | - Yongtao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Yang Wang
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Jie Wen
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China
| | - Wei Jia
- Center for Translational Medicine, Six People’s Hospital, SJTU School of Medicine, Shanghai 200230, China
- University of Hawaii Cancer Center, Honolulu, HI 96813, United States of America
| | - Wei Cai
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU), Shanghai 200092, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China
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37
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Gradilone SA, O’Hara SP, Masyuk TV, Pisarello MJL, LaRusso NF. MicroRNAs and benign biliary tract diseases. Semin Liver Dis 2015; 35:26-35. [PMID: 25632932 PMCID: PMC4413449 DOI: 10.1055/s-0034-1397346] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Cholangiocytes, the epithelial cells lining the biliary tree, represent only a small portion of the total liver cell population (3-5%), but they are responsible for the secretion of up to 40% of total daily bile volume. In addition, cholangiocytes are the target of a diverse group of liver diseases affecting the biliary tract, the cholangiopathies; for most of these conditions, the pathological mechanisms are unclear. MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate gene expression. Thus, it is not surprising that altered miRNA profiles underlie the dysregulation of several proteins involved in the pathobiology of the cholangiopathies, as well as showing promise as diagnostic and prognostic tools. Here the authors review recent work relevant to the role of miRNAs in the etiopathogenesis of several of the cholangiopathies (i.e., fibroinflammatory cholangiopathies and polycystic liver diseases), discuss their value as prognostic and diagnostic tools, and provide suggestions for further research.
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Affiliation(s)
- Sergio A. Gradilone
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota,The Hormel Institute, University of Minnesota, Austin, Minnesota
| | - Steven P. O’Hara
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | - Tetyana V. Masyuk
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | - Maria Jose Lorenzo Pisarello
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota
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38
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Götze T, Blessing H, Grillhösl C, Gerner P, Hoerning A. Neonatal Cholestasis - Differential Diagnoses, Current Diagnostic Procedures, and Treatment. Front Pediatr 2015; 3:43. [PMID: 26137452 PMCID: PMC4470262 DOI: 10.3389/fped.2015.00043] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Accepted: 04/29/2015] [Indexed: 12/18/2022] Open
Abstract
Cholestatic jaundice in early infancy is a complex diagnostic problem. Misdiagnosis of cholestasis as physiologic jaundice delays the identification of severe liver diseases. In the majority of infants, prolonged physiologic jaundice represent benign cases of breast milk jaundice, but few among them are masked and caused by neonatal cholestasis (NC) that requires a prompt diagnosis and treatment. Therefore, a prolonged neonatal jaundice, longer than 2 weeks after birth, must always be investigated because an early diagnosis is essential for appropriate management. To rapidly identify the cases with cholestatic jaundice, the conjugated bilirubin needs to be determined in any infant presenting with prolonged jaundice at 14 days of age with or without depigmented stool. Once NC is confirmed, a systematic approach is the key to reliably achieve the diagnosis in order to promptly initiate the specific, and in many cases, life-saving therapy. This strategy is most important to promptly identify and treat infants with biliary atresia, the most common cause of NC, as this requires a hepatoportoenterostomy as soon as possible. Here, we provide a detailed work-up approach including initial treatment recommendations and a clinically oriented overview of possible differential diagnoses in order to facilitate the early recognition and a timely diagnosis of cholestasis. This approach warrants a broad spectrum of diagnostic procedures and investigations including new methods that are described in this review.
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Affiliation(s)
- Thomas Götze
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
| | - Holger Blessing
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
| | - Christian Grillhösl
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
| | - Patrick Gerner
- Department for Pediatric and Adolescent Medicine, Albert-Ludwigs-University Freiburg , Freiburg , Germany
| | - André Hoerning
- Department for Pediatric and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nuremberg , Erlangen , Germany
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miR-222 overexpression may contribute to liver fibrosis in biliary atresia by targeting PPP2R2A. J Pediatr Gastroenterol Nutr 2015; 60:84-90. [PMID: 25238119 DOI: 10.1097/mpg.0000000000000573] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Biliary atresia (BA) is a devastating liver disease in infants. Progressive hepatic fibrosis is often observed in postoperative patients with BA even after a successful Kasai portoenterostomy procedure. MicroRNA-222 (miRNA) has been linked to the activation of stellate cells and the progression of liver fibrosis. METHODS In this study, the miR-222 expression profile in BA and infants with anicteric choledochal cyst (CC) was determined. The functional effect of miR-222 inhibition on the growth of the human hepatic stellate cell line LX-2 was also evaluated. The downstream signaling pathways and target of miR-222 were determined by coupling gene expression profiling and pathway analysis and by in silico prediction, respectively. In addition, we demonstrated miR-222 overexpression in patients with BA compared with choledochal cyst controls. RESULTS Inhibition of miR-222 in the LX-2 cell line significantly decreased cell proliferation. We also identified protein phosphatase 2A subunit B as a target of miR-222. The downstream signaling pathway, Akt, was also influenced by miR-222. A consistent reduction of Akt phosphorylation and Ki67 in the LX-2 line was shown following miR-222 suppression. CONCLUSIONS Our results show that miR-222 overexpression is common in BA and contributes to LX-2 cell proliferation by targeting protein phosphatase 2A subunit B and Akt signaling.
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O’Hara SP, Gradilone SA, Masyuk TV, Tabibian JH, LaRusso NF. MicroRNAs in Cholangiopathies. CURRENT PATHOBIOLOGY REPORTS 2014; 2:133-142. [PMID: 25097819 PMCID: PMC4119442 DOI: 10.1007/s40139-014-0048-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cholangiocytes, the cells lining bile ducts, comprise a small fraction of the total cellular component of the liver, yet perform the essential role of bile modification and transport of biliary and blood constituents. Cholangiopathies are a diverse group of biliary disorders with the cholangiocyte as the target cell; the etiopathogenesis of most cholangiopathies remains obscure. MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. These small RNAs may not only be involved in the etiopathogenesis of disease, but are showing promise as diagnostic and prognostic tools. In this brief review, we summarize recent work regarding the role of microRNAs in the etiopathogenesis of several cholangiopathies, and discuss their utility as prognostic and diagnostic tools.
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Affiliation(s)
- Steven P. O’Hara
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Sergio A. Gradilone
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Tetyana V. Masyuk
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - James H. Tabibian
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA
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Abstract
Despite significant strides in understanding molecular pathogenesis of cancer, gastrointestinal malignancy (gastric, colorectal, pancreatic, and liver) still ranks among the leading causes of cancer-related mortality and morbidity worldwide. One of the key clinical challenges in effectively reducing disease burden associated with gastrointestinal neoplasia stems from late diagnosis, underscoring the need for early detection, risk assessment, and intervention. Currently available screening approaches are inadequate, and the development of accurate noninvasive molecular biomarkers is very much needed, microRNAs (miRNAs) are short (20-24 nucleotides in length) noncoding RNAs that have emerged as important translational gene regulators in cancer cells. In contrast to genetic markers, miRNAs have a cancer-specific expression pattern. They are present in a remarkably stable form and can be detected in a wide variety of body fluids including blood and feces. These properties make them attractive cancer biomarker targets. Although development of miRNA biomarkers is still in its early stages, burgeoning evidence supports their potential use for development as markers for early detection, prognosis, and prediction of disease recurrence and therapeutic outcome in gastrointestinal cancers. In the future, it is likely that miRNA biomarkers will revolutionize personalized medicine and mitigate disease burden associated with gastrointestinal cancers.
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Chen L, Charrier A, Zhou Y, Chen R, Yu B, Agarwal K, Tsukamoto H, Lee LJ, Paulaitis ME, Brigstock DR. Epigenetic regulation of connective tissue growth factor by MicroRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology 2014; 59:1118-29. [PMID: 24122827 PMCID: PMC3943742 DOI: 10.1002/hep.26768] [Citation(s) in RCA: 197] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 09/20/2013] [Indexed: 12/14/2022]
Abstract
UNLABELLED Connective tissue growth factor (CCN2) drives fibrogenesis in hepatic stellate cells (HSC). Here we show that CCN2 up-regulation in fibrotic or steatotic livers, or in culture-activated or ethanol-treated primary mouse HSC, is associated with a reciprocal down-regulation of microRNA-214 (miR-214). By using protector or reporter assays to investigate the 3'-untranslated region (UTR) of CCN2 mRNA, we found that induction of CCN2 expression in HSC by fibrosis-inducing stimuli was due to reduced expression of miR-214, which otherwise inhibited CCN2 expression by directly binding to the CCN2 3'-UTR. Additionally, miR-214 was present in HSC exosomes, which were bi-membrane vesicles, 50-150 nm in diameter, negatively charged (-26 mV), and positive for CD9. MiR-214 levels in exosomes but not in cell lysates were reduced by pretreatment of the cells with the exosome inhibitor, GW4869. Coculture of either quiescent HSC or miR-214-transfected activated HSC with CCN2 3'-UTR luciferase reporter-transfected recipient HSC resulted in miR-214- and exosome-dependent regulation of a wild-type CCN2 3'-UTR reporter but not of a mutant CCN2 3'-UTR reporter lacking the miR-214 binding site. Exosomes from HSC were a conduit for uptake of miR-214 by primary mouse hepatocytes. Down-regulation of CCN2 expression by miR-214 also occurred in human LX-2 HSC, consistent with a conserved miR-214 binding site in the human CCN2 3'-UTR. MiR-214 in LX-2 cells was shuttled by way of exosomes to recipient LX-2 cells or human HepG2 hepatocytes, resulting in suppression of CCN2 3'-UTR activity or expression of CCN2 downstream targets, including alpha smooth muscle actin or collagen. Experimental fibrosis in mice was associated with reduced circulating miR-214 levels. CONCLUSION Exosomal transfer of miR-214 is a paradigm for the regulation of CCN2-dependent fibrogenesis and identifies fibrotic pathways as targets of intercellular regulation by exosomal miRs.
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Affiliation(s)
- Li Chen
- The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus OH 43205
| | - Alyssa Charrier
- The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus OH 43205,Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus OH 43212
| | - Yu Zhou
- The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus OH 43205
| | - Ruju Chen
- The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus OH 43205
| | - Bo Yu
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210,Nanoscale Science and Engineering Center, The Ohio State University, Columbus, OH 43210
| | - Kitty Agarwal
- Nanoscale Science and Engineering Center, The Ohio State University, Columbus, OH 43210,Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210
| | - Hidekazu Tsukamoto
- Department of Pathology, Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089,Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073
| | - L. James Lee
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210,Nanoscale Science and Engineering Center, The Ohio State University, Columbus, OH 43210
| | - Michael E Paulaitis
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH 43210,Nanoscale Science and Engineering Center, The Ohio State University, Columbus, OH 43210
| | - David R Brigstock
- The Research Institute at Nationwide Children’s Hospital, 700 Children’s Drive, Columbus OH 43205,Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus OH 43212,Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212,Address Correspondence to: David Brigstock, Ph.D., Room 2011, Research Building 2, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus OH 43205, Tel 614-355-2824,
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Etiology of biliary atresia as a developmental anomaly: recent advances. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 20:459-64. [PMID: 23567964 DOI: 10.1007/s00534-013-0604-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Biliary atresia (BA) is a progressive fibro-obliterative cholangiopathy affecting the extra- and intrahepatic biliary tree to various degrees and resulting in obstructive bile flow, cholestasis and icterus in neonates. It is the most common cause of pediatric liver transplantation. The etiology of BA is still unclear, although there is some evidence pointing to viral, toxic, and multiple genetic factors. For new therapeutic options other than liver transplantation to be developed, a greater understanding of the pathogenesis of BA is indispensable. The fact that the pathology of BA develops during a period of biliary growth and remodeling suggests an involvement of developmental anomalies. Recent studies indicate an association of the etiology of BA with some genetic factors such as laterality genes, epigenetic regulation and/or microRNA function. In this paper, we present an overview of recent advances in the understanding of the disease focusing on bile duct developmental anomaly.
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Abstract
BACKGROUND The recent revolutionary advances made in genome-wide sequencing technology have transformed biology and molecular diagnostics, allowing new sRNA (small RNA) classes to be discovered as potential disease-specific biological indicators. Cell-free microRNAs (miRNAs) have been shown to exist stably in a wide spectrum of body fluids and their expression profiles have been shown to reflect an assortment of physiological conditions, underscoring the utility of this new class of molecules to function as noninvasive biomarkers of disease. CONTENT We summarize information on the known mechanisms of miRNA protection and release into extracellular space and compile the current literature on extracellular miRNAs that have been investigated as biomarkers of 20 different cancers, 11 organ damage conditions and 10 diverse disease states. We also discuss the various strategies involved in the miRNA biomarker discovery workflow and provide a critical opinion on the impediments faced by this advancing field that need to be overcome in the laboratory. SUMMARY The field of miRNA-centered diagnostics is still in its infancy, and basic questions with regard to the exact role of miRNAs in the pathophysiology of diseases, and the mechanisms of their release from affected cells into biological fluids are yet to be completely understood. Nevertheless, these noninvasive micromarkers have immense potential in translational medicine not only for use in monitoring the efficacy and safety of therapeutic regimens but also to guide the diagnosis of diseases, to determine the risk of developing diseases or conditions, and more importantly, to inform treatment options.
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Affiliation(s)
- Janani Saikumar
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Environmental Health, Harvard School of Public Health, Boston, MA
| | - Krithika Ramachandran
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Environmental Health, Harvard School of Public Health, Boston, MA
| | - Vishal S Vaidya
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Environmental Health, Harvard School of Public Health, Boston, MA.
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Xiao Y, Wang J, Chen Y, Zhou K, Wen J, Wang Y, Zhou Y, Pan W, Cai W. Up-regulation of miR-200b in biliary atresia patients accelerates proliferation and migration of hepatic stallate cells by activating PI3K/Akt signaling. Cell Signal 2014; 26:925-32. [PMID: 24412919 DOI: 10.1016/j.cellsig.2014.01.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 12/16/2013] [Accepted: 01/02/2014] [Indexed: 01/18/2023]
Abstract
An increasing body of evidence suggests that miRNAs are involved in fibrotic process of several organs including heart, lung and kidney. It has been observed recently that aberrant expression of miR-200s are associated with hepatic fibrosis. However, the role and underlying mechanism of miR-200s in hepatic fibrogenesis remains unknown. Here, we investigate the role of miR-200b in the activation of immortalized human hepatic stallate cells (HSCs), LX-2 cells. We firstly found that miR-200b significantly enhanced proliferation and migration of LX-2 cells. Secondly, our findings showed that miR-200b enhanced the phosphorylation of Akt, a downstream effector of phosphatidyl-inositol 3-Kinase (PI3K). FOG2, as the targets of fly miR-8 and human miR-200s, directly binds to p85α and inhibits the activation of the PI3K/Akt pathway. Here, we showed that FOG2 protein levels in LX-2 cells were suppressed significantly by miR-200b mimics. FOG2 knockdown by siRNAs activated the PI3K/Akt signaling, which increased cell growth and migration that mimicked the effect of miR-200b. Conversely, LY294002, a highly selective inhibitor of PI3K, could block phosphorylation of Akt and effect of miR-200b. In addition, we showed that miR-200b enhanced the expression of matrix metalloproteinase-2 (MMP-2), which may increase the migration of LX-2 cells. Finally, our results indicated that the expression of miR-200b was unregulated in the biliary atresia (BA) and associated with liver fibrotic progression. These data suggest a potential mechanism for Akt activation through FOG2 down-regulation by miR-200b that can lead to HSC growth and migration. In view of the putative pathogenic role of miR-200b in HSCs, miR-200b may constitute a potential marker for HSC activation and liver fibrosis progression.
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Affiliation(s)
- Yongtao Xiao
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Jun Wang
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Yingwei Chen
- Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Kejun Zhou
- Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Jie Wen
- Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Yang Wang
- Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Ying Zhou
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Weihua Pan
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China
| | - Wei Cai
- Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, China.
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Kameswaran V, Bramswig NC, McKenna LB, Penn M, Schug J, Hand NJ, Chen Y, Choi I, Vourekas A, Won KJ, Liu C, Vivek K, Naji A, Friedman JR, Kaestner KH. Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab 2014; 19:135-45. [PMID: 24374217 PMCID: PMC3932527 DOI: 10.1016/j.cmet.2013.11.016] [Citation(s) in RCA: 266] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 09/25/2013] [Accepted: 11/15/2013] [Indexed: 01/09/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased β cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.
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Affiliation(s)
- Vasumathi Kameswaran
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nuria C Bramswig
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Lindsay B McKenna
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Melinda Penn
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jonathan Schug
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas J Hand
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Ying Chen
- Genomics and Computational Biology Graduate Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Inchan Choi
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anastassios Vourekas
- Department of Pathology and Laboratory Medicine, Division of Neuropathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kyoung-Jae Won
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Chengyang Liu
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kumar Vivek
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ali Naji
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joshua R Friedman
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Klaus H Kaestner
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Human RNAi pathway: crosstalk with organelles and cells. Funct Integr Genomics 2013; 14:31-46. [PMID: 24197738 DOI: 10.1007/s10142-013-0344-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 10/03/2013] [Accepted: 10/07/2013] [Indexed: 12/12/2022]
Abstract
Understanding gene regulation mechanisms has been a serious challenge in biology. As a novel mechanism, small non-coding RNAs are an alternative means of gene regulation in a specific and efficient manner. There are growing reports on regulatory roles of these RNAs including transcriptional gene silencing/activation and post-transcriptional gene silencing events. Also, there are several known small non-coding RNAs which all work through RNA interference pathway. Interestingly, these small RNAs are secreted from cells toward targeted cells presenting new communication approach in cell-cell or cell-organ signal transduction. In fact, understanding cellular and molecular basis of these pathways will strongly improve developing targeted therapies and potent and specific regulatory tools. This study will review some of the most recent findings in this subject and will introduce a super-pathway RNA interference-based small RNA silencing network.
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48
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Abstract
Small, noncoding microRNAs (miRNAs) regulate diverse biological functions in the liver and increasing evidence suggests that they have a role in liver pathology. This Review summarizes advances in the field of miRNAs in liver diseases, inflammation and cirrhosis. MicroRNA-122, the most abundant miRNA in hepatocytes, has well-defined roles in HCV replication, and data indicate that it also serves as a viable therapeutic target. The role of miR-122 is also emerging in other liver diseases. Ample evidence exists for the important regulatory potential of other miRNAs in conditions associated with liver inflammation related to alcohol use, the metabolic syndrome or autoimmune processes. In addition, a broad array of miRNAs have been associated with the development of liver fibrosis both in animal models and human studies. The significance of the function and cellular distribution of miRNAs in the liver and the potential of miRNAs as a means of communication between cells and organs is discussed as well as the emerging utility of circulating miRNAs as biomarkers of different forms of liver damage and as early markers of disease and progression in hepatocellular carcinoma. Importantly, miRNA modulation in the liver represents a new therapeutic approach in the treatment armamentarium of hepatologists in the future.
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Wei L, Gong X, Martinez OM, Krams SM. Differential expression and functions of microRNAs in liver transplantation and potential use as non-invasive biomarkers. Transpl Immunol 2013; 29:123-9. [PMID: 24001411 DOI: 10.1016/j.trim.2013.08.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 08/25/2013] [Accepted: 08/26/2013] [Indexed: 02/06/2023]
Abstract
MicroRNAs (miRNAs) are important regulators in many biologic processes and have been implicated in the control of genes relevant to acute rejection and liver functions. Here we review the miRNAs specifically expressed in allografts during acute rejection and discuss potential roles for these miRNAs in liver dysfunction. We focus on miRNAs dysregulated both in the liver and in peripheral blood mononuclear cells and include a discussion of the potential for these miRNAs as non-invasive biomarkers to reflect liver status posttransplant.
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Affiliation(s)
- Liang Wei
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA
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50
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Barnard JA. Recent advances in pediatric gastroenterology, hepatology and nutrition. F1000PRIME REPORTS 2013; 5:25. [PMID: 23864932 PMCID: PMC3702219 DOI: 10.12703/p5-25] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Pediatric gastroenterology, hepatology and nutrition are rapidly evolving, exciting and diverse disciplines. Because the field is so expansive, this commentary highlights important trends, rather than narrowly focusing on specific advances. Examples of advances in the highest impact and rapidly moving areas of pediatric gastroenterology are reviewed, including the intestinal microbiome, biomedical genomics, the biology of unique gastrointestinal cell types, and microRNAs (miRNAs).
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